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185 results on '"Neoplasm Metastasi"'

1. Stereotactic radiotherapy for managing ovarian cancer oligoprogression under poly (ADP-ribose) polymerase inhibitors (PARPi)

Author: Durante, S, Cuccia, F, Rigo, M, Caminiti, G, Mastroleo, F, Lazzari, R, Corrao, G, Caruso, G, Vigorito, S, Cattani, F, Ferrera, G, Chiantera, V, Alongi, F, Colombo, N, Jereczek-Fossa, B, Durante S., Cuccia F., Rigo M., Caminiti G., Mastroleo F., Lazzari R., Corrao G., Caruso G., Vigorito S., Cattani F., Ferrera G., Chiantera V., Alongi F., Colombo N., Jereczek-Fossa B. A., Durante, S, Cuccia, F, Rigo, M, Caminiti, G, Mastroleo, F, Lazzari, R, Corrao, G, Caruso, G, Vigorito, S, Cattani, F, Ferrera, G, Chiantera, V, Alongi, F, Colombo, N, Jereczek-Fossa, B, Durante S., Cuccia F., Rigo M., Caminiti G., Mastroleo F., Lazzari R., Corrao G., Caruso G., Vigorito S., Cattani F., Ferrera G., Chiantera V., Alongi F., Colombo N., and Jereczek-Fossa B. A.
Abstract: Objective: Poly (ADP-ribose) polymerase inhibitors (PARPi) have become a new standard of care for the maintenance treatment of advanced epithelial ovarian cancer. This study aims to evaluate the efficacy and safety of combining stereotactic body radiotherapy with PARPi continuation as a strategy to treat ovarian cancer oligoprogression on PARPi. Methods: This is a multicenter retrospective study including ovarian cancer patients treated with stereotactic body radiotherapy and PARPi continuation for oligoprogression under PARPi maintenance therapy between June 2012 and May 2023 in three Italian centers. PARPi treatment was continued until further disease progression or unacceptable toxicity. The primary endpoint was the next-line systemic therapy-free interval. The Kaplan-Meier method was used to assess local control, progression-free survival, and overall survival. Univariate and multivariate Cox regression analyses were performed to evaluate potential clinical outcomes predictors. Results: 46 patients were included, with a total of 89 lesions treated over 63 radiotherapy treatments. Lymph nodes were the most frequently treated lesions (80, 89.9%), followed by visceral lesions (8, 9%) and one case with a bone lesion (1.1%). Median follow-up was 25.9 months (range 2.8-122). The median next-line systemic therapy-free interval was 12.4 months (95% CI 8.3 to 19.5). A number of prior chemotherapy lines greater than five was significantly associated with a reduced next-line systemic therapy-free interval (HR 3.21, 95% CI 1.11 to 9.32, p=0.032). At the time of analysis, 32 (69.6%) patients started a new systemic therapy regimen, while 14 (30.4%) remained on the PARPi regimen. The 2-year progression-free survival, local failure-free survival, and overall survival rates were 10.7%, 78.1%, and 76.5%, respectively. Four patients (8.7%) experienced acute toxicity with G1 gastrointestinal events. Conclusion: Stereotactic body radiotherapy combined with PARPi continuation may be
Published: 2024

2. Genomic–transcriptomic evolution in lung cancer and metastasis

Author: Martinez-Ruiz, C, Black, J, Puttick, C, Hill, M, Demeulemeester, J, Larose Cadieux, E, Thol, K, Jones, T, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Prymas, P, Rowan, A, Ward, S, Cubitt, L, Athanasopoulou, F, Pich, O, Karasaki, T, Moore, D, Salgado, R, Colliver, E, Castignani, C, Dietzen, M, Huebner, A, Al Bakir, M, Tanic, M, Watkins, T, Lim, E, Al-Rashed, A, Lang, D, Clements, J, Cook, D, Rosenthal, R, Wilson, G, Frankell, A, de Carne Trecesson, S, East, P, Kanu, N, Litchfield, K, Birkbak, N, Hackshaw, A, Beck, S, Van Loo, P, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Bakir, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Karamani, A, Chain, B, Campbell, B, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Martinez-Ruiz C., Black J. R. M., Puttick C., Hill M. S., Demeulemeester J., Larose Cadieux E., Thol K., Jones T. P., Veeriah S., Naceur-Lombardelli C., Toncheva A., Prymas P., Rowan A., Ward S., Cubitt L., Athanasopoulou F., Pich O., Karasaki T., Moore D. A., Salgado R., Colliver E., Castignani C., Dietzen M., Huebner A., Al Bakir M., Tanic M., Watkins T. B. K., Lim E. L., Al-Rashed A. M., Lang D., Clements J., Cook D. E., Rosenthal R., Wilson G. A., Frankell A. M., de Carne Trecesson S., East P., Kanu N., Litchfield K., Birkbak N. J., Hackshaw A., Beck S., Van Loo P., Jamal-Hanjani M., McGranahan N., Swanton C., Bakir M. A., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Karamani A., Chain B., Campbell B. B., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Martinez-Ruiz, C, Black, J, Puttick, C, Hill, M, Demeulemeester, J, Larose Cadieux, E, Thol, K, Jones, T, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Prymas, P, Rowan, A, Ward, S, Cubitt, L, Athanasopoulou, F, Pich, O, Karasaki, T, Moore, D, Salgado, R, Colliver, E, Castignani, C, Dietzen, M, Huebner, A, Al Bakir, M, Tanic, M, Watkins, T, Lim, E, Al-Rashed, A, Lang, D, Clements, J, Cook, D, Rosenthal, R, Wilson, G, Frankell, A, de Carne Trecesson, S, East, P, Kanu, N, Litchfield, K, Birkbak, N, Hackshaw, A, Beck, S, Van Loo, P, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Bakir, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Karamani, A, Chain, B, Campbell, B, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Martinez-Ruiz C., Black J. R. M., Puttick C., Hill M. S., Demeulemeester J., Larose Cadieux E., Thol K., Jones T. P., Veeriah S., Naceur-Lombardelli C., Toncheva A., Prymas P., Rowan A., Ward S., Cubitt L., Athanasopoulou F., Pich O., Karasaki T., Moore D. A., Salgado R., Colliver E., Castignani C., Dietzen M., Huebner A., Al Bakir M., Tanic M., Watkins T. B. K., Lim E. L., Al-Rashed A. M., Lang D., Clements J., Cook D. E., Rosenthal R., Wilson G. A., Frankell A. M., de Carne Trecesson S., East P., Kanu N., Litchfield K., Birkbak N. J., Hackshaw A., Beck S., Van Loo P., Jamal-Hanjani M., McGranahan N., Swanton C., Bakir M. A., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Karamani A., Chain B., Campbell B. B., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., and Thomas M.
Abstract: Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
Published: 2023

3. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial

Author: Chiara Cremolini, Carlotta Antoniotti, Daniele Rossini, Sara Lonardi, Fotios Loupakis, Filippo Pietrantonio, Roberto Bordonaro, Tiziana Pia Latiano, Emiliano Tamburini, Daniele Santini, Alessandro Passardi, Federica Marmorino, Roberta Grande, Giuseppe Aprile, Alberto Zaniboni, Sabina Murgioni, Cristina Granetto, Angela Buonadonna, Roberto Moretto, Salvatore Corallo, Stefano Cordio, Lorenzo Antonuzzo, Gianluca Tomasello, Gianluca Masi, Monica Ronzoni, Samantha Di Donato, Chiara Carlomagno, Matteo Clavarezza, Giuliana Ritorto, Andrea Mambrini, Mario Roselli, Samanta Cupini, Serafina Mammoliti, Elisabetta Fenocchio, Enrichetta Corgna, Vittorina Zagonel, Gabriella Fontanini, Clara Ugolini, Luca Boni, Alfredo Falcone, Filippo Guglielmo Maria De Braud, Evaristo Maiello, Giovanni Luca Frassineti, Teresa Gamucci, Francesco Di Costanzo, Luca Gianni, Patrizia Racca, Giacomo Allegrini, Alberto Sobrero, Massimo Aglietta, Enrico Cortesi, Domenico Cristiano Corsi, Alberto Ballestrero, Andrea Bonetti, Francesco Di Clemente, Enzo Ruggeri, Fortunato Ciardiello, Marco Benasso, Stefano Vitello, Saverio Cinieri, Stefania Mosconi, Nicola Silvestris, Antonio Frassoldati, Samantha Cupini, Alessandro Bertolini, Giampaolo Tortora, Carmelo Bengala, Daris Ferrari, Antonia Ardizzoia, Carlo Milandri, Silvana Chiara, Gianpiero Romano, Stefania Miraglia, Laura Scaltriti, Francesca Pucci, Livio Blasi, Silvia Brugnatelli, Luisa Fioretto, Angela Stefania Ribecco, Raffaella Longarini, Michela Frisinghelli, Maria Banzi, Cremolini, C., Antoniotti, C., Rossini, D., Lonardi, S., Loupakis, F., Pietrantonio, F., Bordonaro, R., Latiano, T. P., Tamburini, E., Santini, D., Passardi, A., Marmorino, F., Grande, R., Aprile, G., Zaniboni, A., Murgioni, S., Granetto, C., Buonadonna, A., Moretto, R., Corallo, S., Cordio, S., Antonuzzo, L., Tomasello, G., Masi, G., Ronzoni, M., Di Donato, S., Carlomagno, C., Clavarezza, M., Ritorto, G., Mambrini, A., Roselli, M., Cupini, S., Mammoliti, S., Fenocchio, E., Corgna, E., Zagonel, V., Fontanini, G., Ugolini, C., Boni, L., Falcone, A., De Braud, F. G. M., Maiello, E., Frassineti, G. L., Gamucci, T., Di Costanzo, F., Gianni, L., Racca, P., Allegrini, G., Sobrero, A., Aglietta, M., Cortesi, E., Corsi, D. C., Ballestrero, A., Bonetti, A., Di Clemente, F., Ruggeri, E., Ciardiello, F., Benasso, M., Vitello, S., Cinieri, S., Mosconi, S., Silvestris, N., Frassoldati, A., Bertolini, A., Tortora, G., Bengala, C., Ferrari, D., Ardizzoia, A., Milandri, C., Chiara, S., Romano, G., Miraglia, S., Scaltriti, L., Pucci, F., Blasi, L., Brugnatelli, S., Fioretto, L., Ribecco, A. S., Longarini, R., Frisinghelli, M., and Banzi, M.
Subjects: Male, 0301 basic medicine, GONO, Organoplatinum Compounds, multicentre, Leucovorin, Colorectal Neoplasm, Gastroenterology, Settore MED/06, Antineoplastic Agents, Immunological, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Metastasis, FOLFOXIRI, progression versus mFOLFOX6 plus bevacizumab, mFOLFOX6, metastatic colorectal cancer, Middle Aged, TRIBE2 trial, FOLFIRI plus bevacizumab, Neoplasm Metastasi, Bevacizumab, FOLFOXIRI plus bevacizumab, triplet FOLFOXIRI, Oncology, Fluorouracil, 030220 oncology & carcinogenesis, Disease Progression, FOLFIRI, Female, metastatic colorectal cancer, triplet FOLFOXIRI , FOLFOXIRI plus bevacizumab, FOLFIRI plus bevacizumab, progression versus mFOLFOX6 plus bevacizumab, TRIBE2, Colorectal Neoplasms, Human, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Analogs & derivatives, open-label, NO, Young Adult, 03 medical and health sciences, Folinic acid, Internal medicine, medicine, cancer, Humans, neoplasms, Aged, Antineoplastic Combined Chemotherapy Protocol, Performance status, business.industry, Organoplatinum Compound, randomised controlled, FOLFOXIRI, bevacizumab, mFOLFOX6, FOLFIRI, metastatic colorectal cancer, TRIBE2 trial, multicentre, open-label, phase 3, randomised controlled, GONO, Irinotecan, 030104 developmental biology, phase 3, TRIBE2, Camptothecin, business
Abstract: Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.
Published: 2020
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4. Genetic trajectory and immune microenvironment of lung-specific oligometastatic colorectal cancer

Author: Gerardo Botti, Angela Lombardi, Nicola Martucci, Giosuè Scognamiglio, Michele Caraglia, Giuseppina Liguori, Salvatore Tafuto, Monica Capozzi, Maria Napolitano, Manuela Buonanno, Fabienne Hermitte, Giovanni Savarese, Luigi D'Amore, Luisa Circelli, Alessandro Ottaiano, Anna Maria Trotta, Jérôme Galon, Fabiana Tatangelo, Annabella Di Mauro, Guglielmo Nasti, Francesco Perri, Antonello La Rocca, Stefania Scala, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), University of the Study of Campania Luigi Vanvitelli, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Columbia University Medical Center (CUMC), Columbia University [New York], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Ottaiano, A., Circelli, L., Lombardi, A., Scala, S., Martucci, N., Galon, J., Buonanno, M., Scognamiglio, G., Botti, G., Hermitte, F., Savarese, G., D'Amore, L., Tatangelo, F., Di Mauro, A., Liguori, G., Trotta, A. M., Napolitano, M., Capozzi, M., Tafuto, S., Perri, F., La Rocca, A., Caraglia, M., and Nasti, G.
Subjects: Male, Cancer Research, Lung Neoplasms, Colorectal cancer, [SDV]Life Sciences [q-bio], Immunology, Disease, Colorectal Neoplasm, Predictive markers, medicine.disease_cause, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Immune system, medicine, Tumor Microenvironment, Humans, Neoplasm Metastasis, lcsh:QH573-671, Gene, neoplasms, 030304 developmental biology, 0303 health sciences, Lung, business.industry, lcsh:Cytology, Point mutation, Cell Biology, medicine.disease, Primary tumor, digestive system diseases, 3. Good health, Lung Neoplasm, Neoplasm Metastasi, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Female, KRAS, Colorectal Neoplasms, business, Human
Abstract: Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype–phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events (ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.
Published: 2020
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5. Searching for novel multimodal treatments in oligometastatic pancreatic cancer

Author: Claudio Ricci, Andrea Palloni, M. Di Marco, Riccardo Carloni, Riccardo Casadei, Daria Maria Filippini, Carla Serra, Elisa Grassi, Giovanni Brandi, Giorgio Ercolani, Filippini D.M., Grassi E., Palloni A., Carloni R., Casadei R., Ricci C., Serra C., Ercolani G., Brandi G., and Di Marco M.
Subjects: Male, Cancer Research, medicine.medical_specialty, FOLFIRINOX, Case Report, Adenocarcinoma, lcsh:RC254-282, Disease-Free Survival, Metastasis, Pancreaticoduodenectomy, 03 medical and health sciences, 0302 clinical medicine, Pancreatic cancer, Genetics, medicine, Adjuvant therapy, Hepatectomy, Humans, 030212 general & internal medicine, Neoplasm Metastasis, Radiofrequency Ablation, business.industry, Liver Neoplasms, Pancreatic Neoplasm, Metastasectomy, Multimodal therapy, Chemoradiotherapy, Middle Aged, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Combined Modality Therapy, Multimodal treatment, Gemcitabine, Irinotecan, Neoplasm Metastasi, Pancreatic Neoplasms, Oncology, Liver Neoplasm, 030220 oncology & carcinogenesis, Radiology, Oligometastatic cancer, Neoplasm Recurrence, Local, business, medicine.drug, Human
Abstract: Background Metastatic pancreatic cancer has a median overall survival of less than 12 months, even if treated with chemotherapy. Selected patients with oligometastatic disease could benefit from multimodal treatments connecting chemotherapy and surgical treatment or radiofrequency ablation (RFA) of metastases. Case presentation We present a patient with oligometastatic pancreatic cancer recurrence who was successfully treated with a multimodal therapeutic approach. A 57-year-old male initially presenting with resectable pancreatic cancer underwent pancreatoduodenectomy. The histopathological diagnosis revealed ductal pancreatic adenocarcinoma with positive surgical resection margins and negative lymph nodes. He completed six cycles of adjuvant therapy with gemcitabine (1000 mg/mq 1,8,15q 28), followed by external radiotherapy (54 Gy in 25 fractions) associated with gemcitabine 50 mg/mq twice weekly. Three years later, the patient developed multiple liver metastases, and he started FOLFIRINOX (oxaliplatin 85 mg/mq, irinotecan 180 mg/mq, leucovorin 400 mg/mq and fluorouracil 400 mg/mq given as a bolus followed by 2400 mg/mq as a 46 h continuous infusion,1q 14) as a first-line treatment. The CT scan showed a partial response after 6 cycles. After multidisciplinary discussion, the patient underwent a laparotomic metastasectomy of the three hepatic lesions. After additional postsurgical chemotherapy with 4 cycles of the FOLFIRINOX schedule, the patient remained free of recurrence for 12 months. A CT scan showed a new single liver metastasis, which was treated with radiofrequency ablation (RFA). A second radiofrequency ablation was performed when the patient developed another single liver lesion 12 months after the first RFA; currently, the patient is free from recurrence with an overall survival of 6 years from the diagnosis. Conclusions Our case has benefited from successful multimodal treatment, including surgical and local ablative techniques and systemic chemotherapy. A multimodal approach may be warranted in selected patients with oligometastatic pancreatic cancer and could improve overall survival. Further research is needed to investigate this approach.
Published: 2020
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6. The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial

Author: Pizzuti, L, Barba, M, Mazzotta, M, Krasniqi, E, Maugeri-Sacca, M, Gamucci, T, Berardi, R, Livi, L, Ficorella, C, Natoli, C, Cortesi, E, Generali, D, La Verde, N, Cassano, A, Bria, E, Moscetti, L, Michelotti, A, Adamo, V, Zamagni, C, Tonini, G, Sergi, D, Marinelli, D, Paoletti, G, Tomao, S, Botticelli, A, Marchetti, P, Tinari, N, Grassadonia, A, Valerio, M, Mirabelli, R, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Meattini, I, Pistelli, M, Giotta, F, Lorusso, V, Garufi, C, Russo, A, Cazzaniga, M, Del Medico, P, Roselli, M, Vaccaro, A, Perracchio, L, di Benedetto, A, Daralioti, T, Sperduti, I, De Maria, R, Di Leo, A, Sanguineti, G, Ciliberto, G, Vici, P, Pizzuti L., Barba M., Mazzotta M., Krasniqi E., Maugeri-Sacca M., Gamucci T., Berardi R., Livi L., Ficorella C., Natoli C., Cortesi E., Generali D., La Verde N., Cassano A., Bria E., Moscetti L., Michelotti A., Adamo V., Zamagni C., Tonini G., Sergi D., Marinelli D., Paoletti G., Tomao S., Botticelli A., Marchetti P., Tinari N., Grassadonia A., Valerio M. R., Mirabelli R., Fabbri M. A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Meattini I., Pistelli M., Giotta F., Lorusso V., Garufi C., Russo A., Cazzaniga M., Del Medico P., Roselli M., Vaccaro A., Perracchio L., di Benedetto A., Daralioti T., Sperduti I., De Maria R., Di Leo A., Sanguineti G., Ciliberto G., Vici P., Pizzuti, L, Barba, M, Mazzotta, M, Krasniqi, E, Maugeri-Sacca, M, Gamucci, T, Berardi, R, Livi, L, Ficorella, C, Natoli, C, Cortesi, E, Generali, D, La Verde, N, Cassano, A, Bria, E, Moscetti, L, Michelotti, A, Adamo, V, Zamagni, C, Tonini, G, Sergi, D, Marinelli, D, Paoletti, G, Tomao, S, Botticelli, A, Marchetti, P, Tinari, N, Grassadonia, A, Valerio, M, Mirabelli, R, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Meattini, I, Pistelli, M, Giotta, F, Lorusso, V, Garufi, C, Russo, A, Cazzaniga, M, Del Medico, P, Roselli, M, Vaccaro, A, Perracchio, L, di Benedetto, A, Daralioti, T, Sperduti, I, De Maria, R, Di Leo, A, Sanguineti, G, Ciliberto, G, Vici, P, Pizzuti L., Barba M., Mazzotta M., Krasniqi E., Maugeri-Sacca M., Gamucci T., Berardi R., Livi L., Ficorella C., Natoli C., Cortesi E., Generali D., La Verde N., Cassano A., Bria E., Moscetti L., Michelotti A., Adamo V., Zamagni C., Tonini G., Sergi D., Marinelli D., Paoletti G., Tomao S., Botticelli A., Marchetti P., Tinari N., Grassadonia A., Valerio M. R., Mirabelli R., Fabbri M. A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Meattini I., Pistelli M., Giotta F., Lorusso V., Garufi C., Russo A., Cazzaniga M., Del Medico P., Roselli M., Vaccaro A., Perracchio L., di Benedetto A., Daralioti T., Sperduti I., De Maria R., Di Leo A., Sanguineti G., Ciliberto G., and Vici P.
Abstract: In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2‐positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.
Published: 2021

7. The senescence-associated secretory phenotype (SASP) from mesenchymal stromal cells impairs growth of immortalized prostate cells but has no effect on metastatic prostatic cancer cells

Author: Gianfranco Peluso, Mariarosa Ab Melone, Tiziana Squillaro, Umberto Galderisi, Giovanni Di Bernardo, Domenico Aprile, Mauro Finicelli, Nicola Alessio, Alessio, N., Aprile, D., Squillaro, T., Di Bernardo, G., Finicelli, M., Melone, M. A. B., Peluso, G., Galderisi, U., Alessio, Nicola, Aprile, Domenico, Squillaro, Tiziana, Di Bernardo, Giovanni, Finicelli, Mauro, Melone, Mariarosa Ab, Peluso, Gianfranco, and Galderisi, Umberto
Subjects: Male, Senescence, Aging, senescence, Cell cycle checkpoint, In Vitro Techniques, Biology, Proinflammatory cytokine, Cell Line, Tumor, medicine, Humans, Neoplasm Metastasis, Cellular Senescence, Cell Line, Transformed, Cell Proliferation, Mesenchymal stem cell, mesenchymal stem cells, In Vitro Technique, fungi, Prostate, Prostatic Neoplasms, Cancer, Cell Biology, medicine.disease, Neoplasm Metastasi, secretome, Apoptosis, Cancer cell, Cancer research, Immortalised cell line, Research Paper, Human
Abstract: Senescent cells secrete inflammatory cytokines, proteases, and other factors, which are indicated as senescence-associated secretory phenotype (SASP). There are contrasting studies on the role of the SASP in cancer. Studies suggested that cancer cells may misuse the senescent secretome for their growth. Other investigations evidenced that the SASP may induce cancer growth arrest, senescence, or apoptosis. These conflicting data can be reconciled considering that cancer cells can coax senescent cells to secrete factors for their survival, thus abrogating the SASP’s anti-cancer effect. Cancer stage may also have an impact on the capacity of the SASP to block tumor proliferation and promote senescence. Indeed, senescence is associated with a permanent cell cycle arrest, which needs functional cell cycle checkpoints. We evaluated the SASP effect on the in vitro biological properties of PNT2 and PC3 cells, which are immortalized prostate cells and metastatic prostatic cancer cells, respectively. We evidenced that SASPs, coming either from mesenchymal stromal cells treated with H202 or with low X-ray doses, induced senescence of immortalized cells but not of cancer cells. Hence, the SASP released by acute senescent cells should be considered as an effective weapon against pre-tumorigenesis events rather than an anti-cancer mechanism acting on malignant cells.
Published: 2019
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8. Sleeping beauty genetic screen identifies miR-23b::BTBD7 gene interaction as crucial for colorectal cancer metastasis

Author: Milena S. Nicoloso, Andrea Vecchione, Luigi Zandonà, Gustavo Baldassarre, Erik Dassi, Ilenia Rigo, Vincenzo Canzonieri, Alex H. Mirnezami, Eleonora Grisard, Maurizio Mongiat, Eva Andreuzzi, Giulia Brisotto, Riccardo Spizzo, Eva Biscontin, Fabio Del Ben, Laura Cesaratto, Gian Luca Rampioni Vinciguerra, E. Poletto, Michela Coan, Matteo Turetta, Alice Paulitti, Grisard, E., Coan, M., Cesaratto, L., Rigo, I., Zandona, L., Paulitti, A., Andreuzzi, E., Rampioni Vinciguerra, G. L., Poletto, E., Del Ben, F., Brisotto, G., Biscontin, E., Turetta, M., Dassi, E., Mirnezami, A., Canzonieri, V., Vecchione, A., Baldassarre, G., Mongiat, M., Spizzo, R., and Nicoloso, M. S.
Subjects: 0301 basic medicine, Research paper, Colorectal cancer, Colorectal Neoplasm, Cell Communication, Metastasis, DNA transposons, 0302 clinical medicine, Neoplasm Metastasis, Tumor, Adaptor Proteins, MicroRNA, General Medicine, Extracellular Matrix, 3. Good health, Neoplasm Metastasi, Gene Expression Regulation, Neoplastic, microRNA target, 030220 oncology & carcinogenesis, RNA Interference, Colorectal Neoplasms, Human, Transposable element, Epithelial-Mesenchymal Transition, Colorectal cancer metastasi, Colorectal cancer metastasis, Settore BIO/11 - Biologia Molecolare, Context (language use), Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Gene interaction, Cell Line, Tumor, microRNA, medicine, Humans, Genetic Testing, Adaptor Proteins, Signal Transducing, Cell Proliferation, Neoplasm Staging, Neoplastic, spleeping beauty, Signal Transducing, DNA transposon, medicine.disease, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, Cancer research, Human genome, Genetic screen
Abstract: Background: Metastatic colorectal cancer (CRC) remains a deadly disease. Identifying locally advanced CRC patients with high risk of developing metastasis and improving outcome of metastatic CRC patients require discovering master regulators of metastasis. In this context, the non-coding part of the human genome is still largely unexplored. Methods: To interrogate the non-coding part of the human genome and disclose regulators of CRC metastasis, we combined a transposon-based forward genetic screen with a novel in vitro assay, which forces cells to grow deprived of cell-substrate and cell-cell contacts (i.e. forced single cell suspension assay - fSCS). Findings: We proved that fSCS selects CRC cells with mesenchymal and pro-metastatic traits. Moreover, we found that the transposon insertions conferred CRC cells resistance to fSCS and thus metastatic advantage. Among the retrieved transposon insertions, we demonstrated that the one located in the 3′UTR of BTBD7 disrupts miR-23b::BTBD7 interaction and contributes to pro-metastatic traits. In addition, miR-23b and BTBD7 correlate with CRC metastasis both in preclinical experiments and in clinical samples. Interpretation: fSCS is a simple and scalable in vitro assay to investigate pro-metastatic traits and transposon-based genetic screens can interrogate the non-coding part of the human genome (e.g. miRNA::target interactions). Finally, both Btbd7 and miR-23b represent promising prognostic biomarkers and therapeutic targets in CRC. Fund: This work was supported by Marie Curie Actions (CIG n. 303877) and Friuli Venezia Giulia region (Grant Agreement n°245574), Italian Association for Cancer Research (AIRC, MFAG n°13589), Italian Ministry of Health (GR-2010-2319387 and PE-2016-02361040) and 5x1000 to CRO Aviano.
Published: 2019
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9. Bone vascular niche E-selectin induces mesenchymal–epithelial transition and Wnt activation in cancer cells to promote bone metastasis

Author: John L. Magnani, Ileana M. Cristea, Nandini Mondal, Corey Cheung, Sue Hwa Lin, Todd M. Greco, Hanqiu Zheng, Yibin Kang, Song Chang Lin, Yong Wei, Chiara Spadazzi, Robert Sackstein, Mark Esposito, Esposito M., Mondal N., Greco T.M., Wei Y., Spadazzi C., Lin S.-C., Zheng H., Cheung C., Magnani J.L., Lin S.-H., Cristea I.M., Sackstein R., and Kang Y.
Subjects: Transcriptional Activation, Epithelial-Mesenchymal Transition, Stromal cell, Bone Neoplasm, Biology, Metastasis, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Fucosyltransferase, Cancer stem cell, Cell Line, Tumor, medicine, Mesenchymal–epithelial transition, Epithelial–mesenchymal transition, Stem Cell Niche, Sialoglycoprotein, Wnt Signaling Pathway, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Animal, Wnt signaling pathway, Bone metastasis, Cell Biology, medicine.disease, Receptors, Fibroblast Growth Factor, Xenograft Model Antitumor Assays, Cell biology, Neoplasm Metastasi, 030220 oncology & carcinogenesis, Cancer cell, Neoplasm, Neoplastic Stem Cell, E-Selectin, Human, Signal Transduction
Abstract: How disseminated tumour cells engage specific stromal components in distant organs for survival and outgrowth is a critical but poorly understood step of the metastatic cascade. Previous studies have demonstrated the importance of the epithelial–mesenchymal transition in promoting the cancer stem cell properties needed for metastasis initiation, whereas the reverse process of mesenchymal–epithelial transition is required for metastatic outgrowth. Here we report that this paradoxical requirement for the simultaneous induction of both mesenchymal–epithelial transition and cancer stem cell traits in disseminated tumour cells is provided by bone vascular niche E-selectin, whose direct binding to cancer cells promotes bone metastasis by inducing mesenchymal–epithelial transition and activating Wnt signalling. E-selectin binding activity mediated by the α1-3 fucosyltransferases Fut3/Fut6 and Glg1 are instrumental to the formation of bone metastasis. These findings provide unique insights into the functional role of E-selectin as a component of the vascular niche critical for metastatic colonization in bone.
Published: 2019
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10. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study

Author: Kenji Tamura, Hirofumi Mukai, Vassiliki Karantza, Hope S. Rugo, Peter Schmid, Rita Nanda, Sylvia Adams, Anne C Armstrong, Sherene Loi, Deborah Toppmeyer, David W. Cescon, H. Iwata, Minetta C. Liu, Larisa Ryvo, Antoinette R. Tan, Y. Ding, Pauline Wimberger, M. De Laurentiis, L. Jia, EP Winer, Adams, S., Loi, S., Toppmeyer, D., Cescon, D. W., De Laurentiis, M., Nanda, R., Winer, E. P., Mukai, H., Tamura, K., Armstrong, A., Liu, M. C., Iwata, H., Ryvo, L., Wimberger, P., Rugo, H. S., Tan, A. R., Jia, L., Ding, Y., Karantza, V., and Schmid, P.
Subjects: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Triple Negative Breast Neoplasms, triple-negative breast neoplasm, Pembrolizumab, Antibodies, Monoclonal, Humanized, B7-H1 Antigen, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Adjuvant therapy, Clinical endpoint, Humans, Medicine, Progression-free survival, Neoplasm Metastasis, Adverse effect, Aged, Aged, 80 and over, business.industry, Hematology, Middle Aged, medicine.disease, Progression-Free Survival, Neoplasm Metastasi, Gene Expression Regulation, Neoplastic, Clinical trial, 030104 developmental biology, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, anti-PD-1, Female, immunotherapy, pembrolizumab, Cohort Studie, business, Human
Abstract: Background Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. Results All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9–31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9–34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0–2.2), and median overall survival was 18.0 months (95% CI 12.9–23.0). Conclusions Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. Clinical trial registration ClinicalTrials.gov, NCT02447003.
Published: 2019
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11. Equivalent Efficacy but Different Safety Profiles of Gemcitabine Plus Nab-Paclitaxel and FOLFIRINOX in Metastatic Pancreatic Cancer

Author: Caterina Vivaldi, Giulia Bartolini, Giovanni Luca Frassineti, Andrea Casadei-Gardini, Alessandro Cucchetti, Valentina Massa, Ilario Giovanni Rapposelli, Alessandro Passardi, Laura Bernardini, Rapposelli I.G., Casadei-Gardini A., Vivaldi C., Bartolini G., Bernardini L., Passardi A., Frassineti G.L., Massa V., and Cucchetti A.
Subjects: Oncology, Male, FOLFIRINOX, medicine.medical_treatment, Leucovorin, Biochemistry, Deoxycytidine, 0302 clinical medicine, metastatic pancreatic cancer, Antineoplastic Combined Chemotherapy Protocols, Medicine, Neoplasm Metastasis, Hazard ratio, Middle Aged, QR1-502, Neoplasm Metastasi, Oxaliplatin, Survival Rate, 030220 oncology & carcinogenesis, Vomiting, 030211 gastroenterology & hepatology, Female, Fluorouracil, medicine.symptom, medicine.drug, Human, Adult, medicine.medical_specialty, Paclitaxel, Anemia, matching-adjusted indirect comparison, Irinotecan, Microbiology, Article, Disease-Free Survival, 03 medical and health sciences, Internal medicine, first-line therapy, Humans, Molecular Biology, Aged, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Retrospective cohort study, medicine.disease, First-line therapy, Matching-adjusted indirect comparison, Metastatic pancreatic cancer, Pancreatic Neoplasms, Gemcitabine, Confidence interval, business
Abstract: FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GN) are the most common chemotherapy regimens in first-line treatment of metastatic pancreatic cancer (PC). They have not been compared each other in a prospective trial, but only in retrospective studies, which can thus be affected by several biases. In order to overcome these biases, we took advantage of matching-adjusted indirect comparison (MAIC), that allows an indirect comparison by reducing cross-trial differences, and compared data from 268 patients treated with GN in a real-world setting with data from the 171 patients included in the FFX arm of the PRODIGE trial. Survival outcomes did not differ between the two populations. Overall survival was 11.1 months for both treatments (hazard ratio (HR) of FFX 1.10, 95% confidence interval (CI) 0.81–1.49, p = 0.527). Progression-free survival was 6.0 months with GN and 6.4 months with FFX (HR of FFX 1.11, 95% CI 0.82–1.50, p = 0.520). On the other hand, we observed a difference in the toxicity profiles: grade 3/4 anemia was more frequent with GN, whereas a higher occurrence of grade 3/4 vomiting and diarrhea was reported with FFX. FFX and GN show an equivalent efficacy but different safety profiles in the first-line therapy of metastatic pancreatic cancer. Searching for reliable predictive biomarkers is advised in order to improve therapeutic strategy in metastatic PC.
Published: 2021

12. Accurate quantification of copy-number aberrations and whole-genome duplications in multi-sample tumor sequencing data

Author: Zaccaria, S, Raphael, B, Zaccaria S., Raphael B. J., Zaccaria, S, Raphael, B, Zaccaria S., and Raphael B. J.
Abstract: Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.
Published: 2020

13. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns

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H., L, Louis, D, Margolin, A, Martin, S, Nahal-Bose, H, Nielsen, G, Nik-Zainal, S, Omberg, L, P'Ng, C, Perry, M, Rheinbay, E, Rubin, M, Semple, C, Sgroi, D, Shibata, T, Siebert, R, Smith, J, Stein, L, Stobbe, M, Sun, R, Thai, K, Wright, D, C. -L., W, Yuan, K, Zhang, J, Danyi, A, de Ridder, J, van Herpen, C, Lolkema, M, Steeghs, N, Morris, Q, Aaltonen, L, Abascal, F, Abeshouse, A, Aburatani, H, Adams, D, Agrawal, N, Ahn, K, Ahn, S, Aikata, H, Akbani, R, Akdemir, K, Al-Ahmadie, H, Al-Sedairy, S, Alawi, M, Albert, M, Aldape, K, Alexandrov, L, Ally, A, Alsop, K, Alvarez, E, Amary, F, Amin, S, Aminou, B, Ammerpohl, O, Anderson, M, Ang, Y, Antonello, D, Anur, P, Aparicio, S, Appelbaum, E, Arai, Y, Aretz, A, Arihiro, K, Ariizumi, S, Armenia, J, Arnould, L, Asa, S, Assenov, Y, Aukema, S, Auman, J, Aure, M, Awadalla, P, Aymerich, M, Bader, G, Baez-Ortega, A, Bailey, M, Balasundaram, M, Balu, S, Bandopadhayay, P, Banks, R, Barbi, S, Barbour, A, Barenboim, J, Barnholtz-Sloan, J, Barr, H, Barrera, 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J., Smid M., Smith-McCune K., Socci N. D., Sofia H. J., Soloway M. G., Song L., Sood A. K., Sothi S., Sotiriou C., Soulette C. M., Span P. N., Spellman P. T., Sperandio N., Spillane A. J., Spiro O., Spring J., Staaf J., Stadler P. F., Staib P., Stark S. G., Stebbings L., Stefansson O. A., Stegle O., Stenhouse A., Stewart C., Stilgenbauer S., Stratton M. R., Stretch J. R., Struck A. J., Stuart J. M., Stunnenberg H. G., Su H., Su X., Sungalee S., Susak H., Suzuki A., Sweep F., Szczepanowski M., Sultmann H., Yugawa T., Tam A., Tamborero D., Tan B. K. T., Tan D., Tan P., Tanaka H., Taniguchi H., Tanskanen T. J., Tarabichi M., Tarnuzzer R., Tarpey P., Taschuk M. L., Tatsuno K., Tavare S., Taylor D. F., Taylor-Weiner A., Teague J. W., Teh B. T., Tembe V., Temes J., Thayer S. P., Thiessen N., Thomas G., Thomas S., Thompson A., Thompson A. M., Thompson J. F. F., Thompson R. H., Thorne H., Thorne L. B., Thorogood A., Tiao G., Tijanic N., Timms L. E., Tirabosco R., Tojo M., Tommasi S., Toon C. W., Toprak U. H., Torrents D., Tortora G., Tost J., Totoki Y., Townend D., Traficante N., Treilleux I., Trotta J. -R., Trumper L. H. P., Tsao M., Tsunoda T., Tubio J. M. C., Tucker O., Turkington R., Turner D. J., Tutt A., Ueno M., Ueno N. T., Umbricht C., Umer H. M., Underwood T. J., Urban L., Urushidate T., Ushiku T., Uuskula-Reimand L., Valencia A., Van Den Berg D. J., Van Laere S., Van Loo P., Van Meir E. G., Van den Eynden G. G., Van der Kwast T., Vasudev N., Vazquez M., Vedururu R., Veluvolu U., Vembu S., Verbeke L. P. C., Vermeulen P., Verrill C., Viari A., Vicente D., Vicentini C., VijayRaghavan K., Viksna J., Vilain R. E., Villasante I., Vincent-Salomon A., Visakorpi T., Voet D., Vyas P., Vazquez-Garcia I., Waddell N. M., Waddell N., Wadelius C., Wadi L., Wagener R., Wala J. A., Wang J., Wang L., Wang Q., Wang W., Wang Y., Wang Z., Waring P. M., Warnatz H. -J., Warrell J., Warren A. Y., Waszak S. M., Wedge D. C., Weichenhan D., Weinberger P., Weinstein J. N., Weischenfeldt J., Weisenberger D. J., Welch I., Wendl M. C., Werner J., Whalley J. P., Wheeler D. A., Whitaker H. C., Wigle D., Wilkerson M. D., Williams A., Wilmott J. S., Wilson G. W., Wilson J. M., Wilson R. K., Winterhoff B., Wintersinger J. A., Wiznerowicz M., Wolf S., Wong B. H., Wong T., Wong W., Woo Y., Wood S., Wouters B. G., Wright A. J., Wright M. H., Wu D. -Y., Wu G., Wu J., Wu K., Wu Y., Wu Z., Xi L., Xia T., Xiang Q., Xiao X., Xing R., Xiong H., Xu Q., Xu Y., Xue H., Yachida S., Yakneen S., Yamaguchi R., Yamaguchi T. N., Yamamoto M., Yamamoto S., Yamaue H., Yang F., Yang H., Yang J. Y., Yang L., Yang S., Yang T. -P., Yang Y., Yao X., Yaspo M. -L., Yates L., Yau C., Ye C., Ye K., Yellapantula V. D., Yoon C. J., Yoon S. -S., Yousif F., Yu J., Yu K., Yu W., Yu Y., Yuan Y., Yuen D., Yung C. K., Zaikova O., Zamora J., Zapatka M., Zenklusen J. C., Zenz T., Zeps N., Zhang C. -Z., Zhang F., Zhang H., Zhang X., Zhang Y., Zhang Z., Zhao Z., Zheng L., Zheng X., Zhou W., Zhou Y., Zhu B., Zhu H., Zhu J., Zhu S., Zou L., Zou X., deFazio A., van As N., van Deurzen C. H. M., van de Vijver M. J., van't Veer L., and von Mering C.
Abstract: In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here,as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
Published: 2020

14. Cancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition

Author: Mara Panero, Antonio D'Ambrosio, Marco Ferrio, Andrea Ballabio, Alberto Pisacane, Elena Geuna, Laura Casorzo, Carla Boccaccio, Gennaro Gambardella, Ermes Candiello, Eliano Cascardi, Filippo Montemurro, Paolo M. Comoglio, Federica Verginelli, Rebecca Senetta, Anna Sapino, Silvia Benvenuti, Verginelli, F., Pisacane, A., Gambardella, G., D'Ambrosio, A., Candiello, E., Ferrio, M., Panero, M., Casorzo, L., Benvenuti, S., Cascardi, E., Senetta, R., Geuna, E., Ballabio, A., Montemurro, F., Sapino, A., Comoglio, P. M., and Boccaccio, C.
Subjects: 0301 basic medicine, Male, Cellular pathology, genetic structures, Carcinogenesis, General Physics and Astronomy, Mice, SCID, Metastasis, Transcriptome, Mice, 0302 clinical medicine, Mice, Inbred NOD, Tumor Cells, Cultured, Neoplasm Metastasis, Carcinogenesi, Multidisciplinary, Cancer stem cells, Phenotype, Primary tumor, Gene Expression Regulation, Neoplastic, Neoplasm Metastasi, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Heterografts, Heterograft, Human, Science, Biology, Malignancy, General Biochemistry, Genetics and Molecular Biology, Article, Cancer of unknown primary, 03 medical and health sciences, Targeted therapies, Cancer stem cell, In vivo, Spheroids, Cellular, medicine, Animals, Humans, Cancer models, Animal, General Chemistry, medicine.disease, Disease Models, Animal, 030104 developmental biology, Cancer research, Neoplasms, Unknown Primary, sense organs, Neoplastic Stem Cell, Neoplasm Transplantation
Abstract: Cancers of unknown primary (CUPs), featuring metastatic dissemination in the absence of a primary tumor, are a biological enigma and a fatal disease. We propose that CUPs are a distinct, yet unrecognized, pathological entity originating from stem-like cells endowed with peculiar and shared properties. These cells can be isolated in vitro (agnospheres) and propagated in vivo by serial transplantation, displaying high tumorigenicity. After subcutaneous engraftment, agnospheres recapitulate the CUP phenotype, by spontaneously and quickly disseminating, and forming widespread established metastases. Regardless of different genetic backgrounds, agnospheres invariably display cell-autonomous proliferation and self-renewal, mostly relying on unrestrained activation of the MAP kinase/MYC axis, which confers sensitivity to MEK inhibitors in vitro and in vivo. Such sensitivity is associated with a transcriptomic signature predicting that more than 70% of CUP patients could be eligible to MEK inhibition. These data shed light on CUP biology and unveil an opportunity for therapeutic intervention., Cancer of unknown primary (CUP) is a mysterious malignancy featuring metastatic dissemination in the absence of a recognizable primary tumor. By characterizing CUP cancer stem cells we show that self-sustained long-term propagation and sensitivity to MEK inhibition are CUP common features.
Published: 2021

15. Effect of Bevacizumab in Combination with Standard Oxaliplatin-Based Regimens in Patients with Metastatic Colorectal Cancer: A Randomized Clinical Trial

Author: Paolo Delrio, Domenico Bilancia, G. Rosati, Lucrezia Silvestro, Chiara Carlomagno, F. Perrone, Luigi Aloj, Gerardo Botti, Antonino Cassata, Anna Nappi, Guglielmo Nasti, Secondo Lastoria, Antonella Petrillo, Fabiana Tatangelo, A. Avallone, Alessandra Leone, Carmela Romano, Elena Di Gennaro, Laura Arenare, Vincenza Granata, Maria Carmela Piccirillo, Alfredo Budillon, Alfonso De Stefano, Valeria Vicario, Francesco Izzo, Ciro Gallo, Avallone, A., Piccirillo, M. C., Nasti, G., Rosati, G., Carlomagno, C., Di Gennaro, E., Romano, C., Tatangelo, F., Granata, V., Cassata, A., Silvestro, L., De Stefano, A., Aloj, L., Vicario, V., Nappi, A., Leone, A., Bilancia, D., Arenare, L., Petrillo, A., Lastoria, S., Gallo, C., Botti, G., Delrio, P., Izzo, F., Perrone, F., and Budillon, A.
Subjects: Adult, Diarrhea, Male, medicine.medical_specialty, Adolescent, Bevacizumab, Colorectal Neoplasm, law.invention, Young Adult, Randomized controlled trial, Interquartile range, law, Internal medicine, medicine, Clinical endpoint, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, Hazard ratio, Nausea, General Medicine, Middle Aged, Chemotherapy regimen, Progression-Free Survival, Oxaliplatin, Neoplasm Metastasi, Treatment Outcome, Response Evaluation Criteria in Solid Tumors, Quality of Life, Female, Drug-Related Side Effects and Adverse Reaction, business, Angiogenesis Inhibitor, Human, medicine.drug
Abstract: Importance Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. Objective To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. Design, Setting, and Participants This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line–treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. Interventions Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo–folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). Main Outcomes and Measures The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). Results Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm;P = .89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm;P = .15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99;P = .04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%];P = .006) and nausea (2 [1.8%] vs 8 [7.0%];P = .05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs −7.41 [2.95] at 24 weeks;P= .02), and constipation scores (mean [SD] change from baseline, −17.2 [3.73] vs −0.62 [4.44];P= .003). Conclusions and Relevance In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. Trial Registration EudraCT Identifier:2011-004997-27; ClinicalTrials.gov Identifier:NCT01718873
Published: 2021

16. Cardio-Metabolic Indices and Metabolic Syndrome as Predictors of Clinical Severity of Gastroenteropancreatic Neuroendocrine Tumors

Author: Luigi Barrea, Giovanna Muscogiuri, Roberta Modica, Barbara Altieri, Gabriella Pugliese, Roberto Minotta, Antongiulio Faggiano, Annamaria Colao, Silvia Savastano, Barrea, L., Muscogiuri, G., Modica, R., Altieri, B., Pugliese, G., Minotta, R., Faggiano, A., Colao, A., and Savastano, S.
Subjects: Oncology, Male, gastroenteropancreatic neuroendocrine tumor, cardio-metabolic indices, Endocrinology, Diabetes and Metabolism, fatty liver index, gastroenteropancreatic neuroendocrine tumors, Blood Pressure, Disease, Type 2 diabetes, Neuroendocrine tumors, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Cardiovascular System, Body Mass Index, Endocrinology, Risk Factors, Non-alcoholic Fatty Liver Disease, Neoplasm Metastasis, Original Research, Adiposity, Anthropometry, Fatty liver, Smoking, Pancreatic Neoplasm, Middle Aged, Neoplasm Metastasi, Neuroendocrine Tumors, Adipose Tissue, Female, Case-Control Studie, Neuroendocrine Tumor, Human, Adult, medicine.medical_specialty, Intestinal Neoplasm, Intra-Abdominal Fat, metabolic syndrome, Stomach Neoplasms, Internal medicine, Intestinal Neoplasms, medicine, Humans, Aged, Cross-Sectional Studie, lcsh:RC648-665, business.industry, cardio-metabolic indice, Risk Factor, Cancer, medicine.disease, Obesity, visceral adiposity index, Pancreatic Neoplasms, Fatty Liver, Cross-Sectional Studies, Case-Control Studies, Metabolic syndrome, business, Progressive disease
Abstract: BackgroundObesity, mainly visceral obesity, and metabolic syndrome (MetS) are major risk factors for the development of type 2 diabetes, cardiovascular diseases, and cancer. Data analyzing the association of obesity and MetS with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are lacking. Fatty liver index (FLI) is a non-invasive tool for identifying individuals with non-alcoholic fatty liver disease (NAFLD). Visceral adiposity index (VAI) has been suggested as a gender-specific indicator of adipose dysfunction. Both indexes have been proposed as early predictors of MetS. This study aimed to investigate the association of FLI VAI as early predictors of MetS with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).MethodsA cross-sectional, case–control, observational study was carried out at the ENETS Centers of Excellence Multidisciplinary Group for Neuroendocrine Tumors, University “Federico II”. VAI and FLI were calculated.ResultsWe enrolled 109 patients with histologically confirmed G1/G2 GEP-NET (53 M; 57.06 ± 15.96 years), as well as 109 healthy subjects, age, sex- and body mass index-matched. Forty-four GEP-NET patients were G2, of which 21 were with progressive disease, and 27 patients had metastases. GEP-NET patients had a higher value of VAI (p < 0.001) and FLI (p= 0.049) and higher MetS presence (p< 0.001) compared with controls. VAI and FLI values and MetS presence were higher in G2 than in G1 patients (p< 0.001), in patients with progressive disease, and in metastaticvsnon-metastatic patients (p< 0.001). In addition, higher values of VAI and FLI and higher MetS presence were significantly correlated with the worst clinical severity of NENs. The cut-off values for the FLI and MetS to predict high grading of GEP-NETs and the presence of metastasis were also provided.ConclusionsThis is the first study investigating an association between VAI and FLI as early predictors of MetS and GEP-NET. Our findings report that the worsening of clinicopathological characteristics in GEP-NET is associated with higher presence of MetS, NAFLD, evaluated by FLI, and visceral adiposity dysfunction, evaluated by VAI. Addressing the clinical evaluation of MetS presence, NAFLD, and visceral adiposity dysfunction might be of crucial relevance to establish targeted preventive and treatment interventions of NEN-related metabolic comorbidities.
Published: 2021

17. Lumican inhibits in vivo melanoma metastasis by altering matrix-effectors and invadopodia markers

Author: Karamanou, Konstantina, Franchi, Marco, Proult, Isabelle, Rivet, Romain, Vynios, Demitrios, Brézillon, Stéphane, Karamanou K., Franchi M., Proult I., Rivet R., Vynios D., Brezillon S., Laboratoire de Biochimie Médicale et Biologie Moléculaire, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), University of Patras [Patras], and Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)
Subjects: Lumican, Lung Neoplasms, Skin Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Invadopodia, Article, Cell Movement, Cell Line, Tumor, Epithelial-to-mesenchymal transi-tion, Biomarkers, Tumor, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cyclin D1, Skin Neoplasm, Neoplasm Metastasis, Hyaluronic Acid, Phosphorylation, lcsh:QH301-705.5, Melanoma, Cell Shape, Cell Proliferation, Focal Adhesions, Animal, lung metastasis, Cell Cycle, Snail Family Transcription Factor, Lung metastasi, Vinculin, Extracellular Matrix, Lung Neoplasm, Mice, Inbred C57BL, Neoplasm Metastasi, lcsh:Biology (General), Snail, Podosomes, Snail Family Transcription Factors, epithelial-to-mesenchymal transition, Focal Adhesion, Cortactin, Podosome, Human, Signal Transduction
Abstract: It was reported that lumican inhibits the activity of metalloproteinase MMP-14 and melanoma cell migration in vitro and in vivo. Moreover, Snail triggers epithelial-to-mesenchymal transition and the metastatic potential of cancer cells. Therefore, the aim of this study was to examine the effect of lumican on Mock and Snail overexpressing melanoma B16F1 cells in vivo. Lung metastasis was analyzed after intravenous injections of Mock-B16F1 and Snail-B16F1 cells in Lum+/+ and Lum−/− mice. At day 14, mice were sacrificed, and lungs were collected. The number of lung metastatic nodules was significantly higher in mice injected with Snail-B16F1 cells as compared to mice injected with Mock-B16F1 cells confirming the pro-metastatic effect of Snail. This effect was stronger in Lum−/− mice as compared to Lum+/+, suggesting that endogenous lumican of wild-type mice significantly inhibits metastasis to lungs. Scanning electron and confocal microscopy investigations demonstrated that lumican inhibits the development of elongated cancer cell phenotypes which are known to develop invadopodia releasing MMPs. Moreover, lumican was shown to affect the expression of cyclin D1, cortactin, vinculin, hyaluronan synthase 2, heparanase, MMP-14 and the phosphorylation of FAK, AKT, p130 Cas and GSK3α/β. Altogether, these data demonstrated that lumican significantly inhibits lung metastasis in vivo, as well as cell invasion in vitro, suggesting that a lumican-based strategy targeting Snail-induced metastasis could be useful for melanoma treatment.
Published: 2021
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18. The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial

Author: Pietro Del Medico, Rossana Berardi, Enzo Veltri, Maria Rosaria Valerio, Alessandra Cassano, Daniele Marinelli, Vito Lorusso, Patrizia Vici, Nicola D’Ostilio, Silverio Tomao, Enrico Cortesi, Nicola Tinari, Emilio Bria, Domenico Sergi, Luca Moscetti, Giuseppe Sanguineti, Teresa Gamucci, Claudio Zamagni, Maddalena Barba, Clara Natoli, Theodora Daralioti, Giancarlo Paoletti, Antonino Grassadonia, Marina Elena Cazzaniga, Icro Meattini, Ornella Garrone, Andrea Michelotti, Giuseppina Sarobba, Nicla La Verde, Laura Pizzuti, Letizia Perracchio, Vincenzo Adamo, Giuseppe Tonini, A. Vaccaro, Francesco Giotta, Corrado Ficorella, Maria Agnese Fabbri, Antonio Russo, Paolo Marchetti, Gennaro Ciliberto, Mirco Pistelli, Rosanna Mirabelli, Marco Mazzotta, Daniele Generali, Marcello Maugeri-Saccà, Mario Roselli, Angelo Di Leo, Anna Di Benedetto, Isabella Sperduti, Ida Paris, Eriseld Krasniqi, Carlo Garufi, Lorenzo Livi, Ruggero De Maria, Andrea Botticelli, Domenico Corsi, Pizzuti, L, Barba, M, Mazzotta, M, Krasniqi, E, Maugeri-Sacca, M, Gamucci, T, Berardi, R, Livi, L, Ficorella, C, Natoli, C, Cortesi, E, Generali, D, La Verde, N, Cassano, A, Bria, E, Moscetti, L, Michelotti, A, Adamo, V, Zamagni, C, Tonini, G, Sergi, D, Marinelli, D, Paoletti, G, Tomao, S, Botticelli, A, Marchetti, P, Tinari, N, Grassadonia, A, Valerio, M, Mirabelli, R, Fabbri, M, D'Ostilio, N, Veltri, E, Corsi, D, Garrone, O, Paris, I, Sarobba, G, Meattini, I, Pistelli, M, Giotta, F, Lorusso, V, Garufi, C, Russo, A, Cazzaniga, M, Del Medico, P, Roselli, M, Vaccaro, A, Perracchio, L, di Benedetto, A, Daralioti, T, Sperduti, I, De Maria, R, Di Leo, A, Sanguineti, G, Ciliberto, G, Vici, P, Pizzuti, Laura, Barba, Maddalena, Mazzotta, Marco, Krasniqi, Eriseld, Maugeri-Saccà, Marcello, Gamucci, Teresa, Berardi, Rossana, Livi, Lorenzo, Ficorella, Corrado, Natoli, Clara, Cortesi, Enrico, Generali, Daniele, La Verde, Nicla, Cassano, Alessandra, Bria, Emilio, Moscetti, Luca, Michelotti, Andrea, Adamo, Vincenzo, Zamagni, Claudio, Tonini, Giuseppe, Sergi, Domenico, Marinelli, Daniele, Paoletti, Giancarlo, Tomao, Silverio, Botticelli, Andrea, Marchetti, Paolo, Tinari, Nicola, Grassadonia, Antonino, Valerio, Maria Rosaria, Mirabelli, Rosanna, Fabbri, Maria Agnese, D’Ostilio, Nicola, Veltri, Enzo, Corsi, Domenico, Garrone, Ornella, Paris, Ida, Sarobba, Giuseppina, Meattini, Icro, Pistelli, Mirco, Giotta, Francesco, Lorusso, Vito, Garufi, Carlo, Russo, Antonio, Cazzaniga, Marina, Del Medico, Pietro, Roselli, Mario, Vaccaro, Angela, Perracchio, Letizia, di Benedetto, Anna, Daralioti, Theodora, Sperduti, Isabella, De Maria, Ruggero, Di Leo, Angelo, Sanguineti, Giuseppe, Ciliberto, Gennaro, Vici, Patrizia, Pizzuti L., Barba M., Mazzotta M., Krasniqi E., Maugeri-Sacca M., Gamucci T., Berardi R., Livi L., Ficorella C., Natoli C., Cortesi E., Generali D., La Verde N., Cassano A., Bria E., Moscetti L., Michelotti A., Adamo V., Zamagni C., Tonini G., Sergi D., Marinelli D., Paoletti G., Tomao S., Botticelli A., Marchetti P., Tinari N., Grassadonia A., Valerio M.R., Mirabelli R., Fabbri M.A., D'Ostilio N., Veltri E., Corsi D., Garrone O., Paris I., Sarobba G., Meattini I., Pistelli M., Giotta F., Lorusso V., Garufi C., Russo A., Cazzaniga M., Del Medico P., Roselli M., Vaccaro A., Perracchio L., di Benedetto A., Daralioti T., Sperduti I., De Maria R., Di Leo A., Sanguineti G., Ciliberto G., and Vici P.
Subjects: 0301 basic medicine, Oncology, Cancer therapy, Receptor, ErbB-2, medicine.medical_treatment, Ado-Trastuzumab Emtansine, progesterone receptor, Settore MED/06, 0302 clinical medicine, human epidermal growth factor receptor 2 (HER2), Antineoplastic Combined Chemotherapy Protocols, estrogen, Neoplasm Metastasis, skin and connective tissue diseases, Multidisciplinary, Brain Neoplasms, Middle Aged, Prognosis, Metastatic breast cancer, Neoplasm Metastasi, 030220 oncology & carcinogenesis, Medicine, Female, Pertuzumab, metastatic breast cancer, Receptors, Progesterone, Breast Neoplasm, HER2 positivity, medicine.drug, Human, Adult, medicine.medical_specialty, medicine.drug_class, Science, trastuzumab-emtansine, Breast Neoplasms, cancer, Article, Disease-Free Survival, Brain Neoplasm, 03 medical and health sciences, Breast cancer, breast cancer, Settore MED/04 - PATOLOGIA GENERALE, pertuzumab, Internal medicine, Progesterone receptor, medicine, Humans, neoplasms, Aged, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Cancer, medicine.disease, HER2-positive, oncology, radiotherapy, chemotherapy, HER2, Radiation therapy, 030104 developmental biology, Estrogen, business, prognostic relevance
Abstract: Breast cancer (BC) heterogeneity is composite in nature, with a wide variety of factors concurring to define several pathological entities, which differ by clinical presentation, pathologic features, therapy administered, and inherent outcomes1. Additional sources of breast cancer heterogeneity may raise during the disease course. In BC patients whose disease was initially diagnosed in the early stage and subsequently progressed with metastatic involvement of one single or multiple site/s, the molecular characteristics of metastatic lesions do not necessary mimic those of the disease initially diagnosed. A well-depicted molecular landscape is crucial for subtype definition, prognostic evaluation and appropriate therapeutic decisions. Accordingly, current guidelines suggest repeating the immunohistochemical (IHC) assessment in patients with metastatic spread and at least one secondary lesion amenable to biopsy2. Discordance in human epidermal growth factor receptor 2 (HER2) status between the tumor and metastatic lesions is widely acknowledged, and not yet completely unraveled in their biologic meaning and prognostic relevance3–11. The overexpression of HER2 or amplification of the related gene is extensively recognized as a feature associated with more aggressive biological behavior12,13. However, the extent to which changes in HER2 status may affect patients’ prognosis is still a matter of debate14. We herein propose an observational study of HER2-positive metastatic breast cancer (mBC) patients treated with the anti-HER2 targeted agents pertuzumab and/or trastuzumab emtansine (T-DM1). Our research question is whether relevant differences exist in long-term outcomes of patients with concordant HER2 status between the primary tumor and its secondary lesion/s compared to patients whose disease revealed HER2-positivity gain at the IHC assessment of metastatic lesions. In our historical cohorts, we also sought to identify factors associated with HER2-positivity gain at the IHC reassessment, for which an impact on prognosis may be foreseen.
Published: 2021

19. Malignancy course of pituitary adenoma in MEN1 syndrome: Clinical-Neuroradiological signs

Author: Giuseppe Salvaggio, Cesare Gagliardo, Paola Feraco, Valeria Putortì, Giovanni Lasio, Caterina Sarno, Giuseppe La Tona, Francesca Incandela, Laura Geraci, Incandela F., Feraco P., Putorti V., Geraci L., Salvaggio G., Sarno C., La Tona G., Lasio G., Gagliardo C., Incandela, Francesca, Feraco, Paola, Putortì, Valeria, Geraci, Laura, Salvaggio, Giuseppe, Sarno, Caterina, La Tona, Giuseppe, Lasio, Giovanni, and Gagliardo, Cesare
Subjects: lcsh:Medical physics. Medical radiology. Nuclear medicine, Pathology, medicine.medical_specialty, medicine.medical_treatment, lcsh:R895-920, Neoplasm metastasis, Tentorium cerebelli, Pituitary neoplasm, Pituitary neoplasms, Malignancy, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Pituitary adenoma, medicine, Endocrine system, Radiology, Nuclear Medicine and imaging, MEN1, Ki-67 antigen, Neoplasm metastasi, Pituitary carcinoma, business.industry, Magnetic resonance imaging, MRI, Settore MED/37 - Neuroradiologia, medicine.disease, Radiation therapy, 030220 oncology & carcinogenesis, Pituitary neoplasms Pituitary carcinoma Pituitary adenoma Neoplasm metastasis Ki-67 antigen Magnetic resonance imaging, MRI, Settore MED/36 - Diagnostica Per Immagini E Radioterapia, business
Abstract: Pituitary carcinomas (PCa) are extremely rare, indistinguishable from pituitary adenomas on histopathological grounds and have a poor prognosis. Most PCa start as PRL or ACTH secreting tumors in males, with relapsing invasive behaviour, refractoriness to medical and radiotherapy and increasing hormonal levels. The presence of distant metastases is still required for the diagnosis of PCa. The association with genetic endocrine diseases must be taken into account, since it adds further risk of evolution towards malignancy. Intradural spinal metastases have also been reported, so a complete craniospinal MR evaluation is recommended, when clinically indicated. We report a case of PCa, associated with MEN1 syndrome, with evidence of meningeal spread to the tentorium cerebelli, clival dura and spinal drop metastases mimicking spinal nerves schwannomas.
Published: 2020

20. Advances in paclitaxel combinations for treating cervical cancer

Author: Pierluigi Giampaolino, Luigi Della Corte, Giulio Evangelisti, Fabio Barra, Giuseppe Bifulco, Virginia Foreste, Simone Ferrero, Della Corte, L., Barra, F., Foreste, V., Giampaolino, P., Evangelisti, G., Ferrero, S., and Bifulco, G.
Subjects: Oncology, medicine.medical_specialty, Uterine Cervical Neoplasm, Paclitaxel, cytotoxic regimen, medicine.medical_treatment, Locally advanced, Uterine Cervical Neoplasms, Disease, Cervical Cancer, chemotherapy, Disease-Free Survival, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Quality of life, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Pharmacology (medical), Stage (cooking), Neoplasm Metastasis, Pharmacology, Cervical cancer, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Cancer, General Medicine, Chemoradiotherapy, medicine.disease, Progression-Free Survival, Bevacizumab, Neoplasm Metastasi, chemistry, investigational drug, quality of life, 030220 oncology & carcinogenesis, Female, Cisplatin, Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery, Human
Abstract: Introduction: Cervical cancer is the fourth common cancer in women worldwide. While, in the past, locally advanced stage disease was treated by pelvic radiotherapy, nowadays the National Cancer Institute strongly recommends chemoradiation protocols. Weekly cisplatin was previously the standard of care in this setting; however, the low response rate and the short median progression-free survival (PFS) of patients have led researchers to investigate combinatory regimens. Area covered: This article is based on literature searches up until April 2019, with current trial registers also analyzed. All data available on this topic has been summarized in this narrative review. Expert opinion: In recent years, it has been demonstrated that cisplatin-based doublets, and in particular, cisplatin plus paclitaxel, are superior to cisplatin as a monotherapy in terms of response rate and progression-free survival of patients with advanced cervical cancer. This double regime combined with bevacizumab is also considered the first-line option for metastatic or recurrent disease. Dose-dense paclitaxel in neo-adjuvant chemotherapy combinations is a promising option in patients with locally advanced cervical cancer. Exploration of novel biological therapies and in vitro combinations based on the use of paclitaxel is warranted.
Published: 2020

21. Does the Unexpected Presence of Non-organ-confined Disease at Final Pathology Undermine Cancer Control in Patients with Clinical T1N0M0 Renal Cell Carcinoma Who Underwent Partial Nephrectomy?

Author: Idir Ouzaid, Paolo Dell'Oglio, Andrea Minervini, James Lingard, Maciej Salagierski, Grant D. Stewart, Sabine Brookman-May, Maria Carmen Mir, Marco Carini, Oscar Rodriguez Faba, Bulent Akdogan, Francesco Montorsi, Marco Roscigno, Luigi F. Da Pozzo, Tobias Klatte, Emanuele Zaffuto, Christian G. Stief, Martin Marszalek, Umberto Capitanio, Capitanio, Umberto, Stewart, Grant D., Klatte, Tobia, Akdogan, Bulent, Roscigno, Marco, Marszalek, Martin, Dell'Oglio, Paolo, Zaffuto, Emanuele, Rodriguez Faba, Oscar, Salagierski, Maciej, Lingard, Jame, Carini, Marco, Ouzaid, Idir, Mir, Maria Carmen, Montorsi, Francesco, Da Pozzo, Luigi Filippo, Stief, Christian, Minervini, Andrea, Brookman-May, Sabine D., Stewart, Grant [0000-0003-3188-9140], Apollo - University of Cambridge Repository, Capitanio, U, Stewart, G, Klatte, T, Akdogan, B, Roscigno, M, Marszalek, M, Dell'Oglio, P, Zaffuto, E, Rodriguez Faba, O, Salagierski, M, Lingard, J, Carini, M, Ouzaid, I, Mir, M, Montorsi, F, Da Pozzo, L, Stief, C, Minervini, A, and Brookman-May, S
Subjects: Male, Pathology, medicine.medical_treatment, 030232 urology & nephrology, Kaplan-Meier Estimate, Disease, Nephrectomy, 0302 clinical medicine, Retrospective Studie, cancer control, Renal cell carcinoma, Partial nephrectomy, Medicine, Neoplasm Metastasis, Multivariate Analysi, Upstaging, Kidney, Cancer control, Kidney cancer, Radical nephrectomy, Renal cancer, Kidney Neoplasm, kidney cancer, Middle Aged, Kidney Neoplasms, Neoplasm Metastasi, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Disease Progression, Female, Human, radical nephrectomy, medicine.medical_specialty, partial nephrectomy, Urology, renal cancer, 03 medical and health sciences, Humans, Propensity Score, Carcinoma, Renal Cell, Proportional Hazards Models, Retrospective Studies, Aged, Neoplasm Staging, business.industry, Proportional hazards model, Retrospective cohort study, medicine.disease, upstaging, Multivariate Analysis, Propensity score matching, Proportional Hazards Model, business
Abstract: Background: A non-negligible proportion of individuals diagnosed with cT1 renal cell carcinoma (RCC) are upstaged to pT3a at final pathology. Few data on oncological outcomes for these patients are available to determine whether partial nephrectomy (PN) might jeopardise cancer control. Objective: To assess, within an international multi-institutional collaboration, whether PN might undermine cancer control relative to radical nephrectomy (RN) in RCC patients with unexpected pT3a disease. Design, setting, and participants: International multi-institutional collaboration including patients with cT1abN0M0-pT3a RCC. Intervention: PN or RN. Outcome measurements and statistical analysis: We used Kaplan-Meier analyses, before and after propensity-score matching, to evaluate differences in metastatic progression (MP) and cancer-specific mortality (CSM) rates during follow-up. Univariable and multivariable Cox regression analyses were used to assess predictors of MP and CSM. Results and limitations: Overall, 309 patients with cT1abN0M0 RCC (cT1aN0M0, n = 107, 34.6%; cT1bN0M0, n = 202, 65.4%) had pT3a disease according to final pathology. Patients were treated with either PN (n = 71, 23%) or RN (n = 238, 77%). MP at 1, 2, and 5 yr was detected in 9.1%, 13.3%, and 24.1% of patients, respectively. CSM was 3.5%, 10.7%, and 18.4% at 1, 2, and 5 yr, respectively. After matching, no difference in terms of MP or CSM was observed between the PN and RN cohorts (both p>0.3). On multivariable analysis, type of surgery (PN vs RN) was not an independent predictor of either MP (p = 0.3) or CSM (p = 0.4). Limitations include the retrospective design. Conclusions: In patients with unexpected pT3a RCC at final pathology, PN does not appear to jeopardise cancer control with regard to MP and CSM. Patient summary: Cancer control is similar between patients treated with removal of the entire kidney and those with only partial removal, even if the final histology examination demonstrates a tumour that is unexpectedly not confined within the kidney. Partial nephrectomy does not undermine cancer control when unexpected pT3a renal cancer is identified at final pathology.
Published: 2018
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22. Genomic profiles of primary and metastatic esophageal adenocarcinoma identified via digital sorting of pure cell populations: results from a case report

Author: Isidori, Federica, Malvi, Deborah, Fittipaldi, Silvia, Forcato, Claudio, Bozzarelli, Isotta, Sala, Claudia, Raulli, Giovanni, D'Errico, Antonia, Fiorentino, Michelangelo, Seri, Marco, Krishnadath, Kausilia K., Bonora, Elena, Mattioli, Sandro, Lugaresi, Maria Luisa, D'Errico, Antonietta, Castellani, Gastone, Fiocca, Roberto, Mastracci, Luca, Räsänen, Jari, Söderström, Henna, CCA - Imaging and biomarkers, Gastroenterology and Hepatology, AGEM - Re-generation and cancer of the digestive system, Isidori, Federica, Malvi, Deborah, Fittipaldi, Silvia, Forcato, Claudio, Bozzarelli, Isotta, Sala, Claudia, Raulli, Giovanni, D'Errico, Antonia, Fiorentino, Michelangelo, Seri, Marco, Krishnadath, Kausilia K., Bonora, Elena, Mattioli, Sandro, Lugaresi, Maria Luisa, Castellani, Gastone, Fiocca, Roberto, Mastracci, Luca, Räsänen, Jari, and Söderström, Henna
Subjects: 0301 basic medicine, Cancer Research, Esophageal Neoplasms, Receptor, ErbB-2, Biopsy, medicine.medical_treatment, Case Report, Somatic evolution in cancer, Targeted therapy, ErbB-2, 0302 clinical medicine, Surgical oncology, Neoplasm Metastasis, Stage (cooking), Esophageal Neoplasm, Tumor, medicine.diagnostic_test, Single Nucleotide, Genomics, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, Neoplasm Metastasi, Oncology, 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Esophageal adenocarcinoma, Human, Receptor, Stromal cell, Polymorphism, Single Nucleotide, lcsh:RC254-282, Clonal Evolution, 03 medical and health sciences, Genetic, Next generation sequencing, Biomarkers, Tumor, Genetics, medicine, Humans, Polymorphism, Neoplasm Staging, Digital cell sorting, Esophageal adenocarcinoma, Next generation sequencing, Adenocarcinoma, Biomarkers, Tumor, Biopsy, Clonal Evolution, Esophageal Neoplasms, Female, Humans, Immunohistochemistry, Mutation, Neoplasm Metastasis, Neoplasm Staging, Polymorphism, Single Nucleotide, Receptor, ErbB-2, Genomics, Whole Genome Sequencing, Whole Genome Sequencing, business.industry, Cancer, medicine.disease, Digital cell sorting, 030104 developmental biology, Mutation, Genomic, Cancer research, business, Biomarkers
Abstract: Background We report on a female patient who underwent primary radical resection for a stage 2B Her-2-positive Barrett’s-type esophageal adenocarcinoma (EAC). Despite Her-2 targeted therapy, her disease recurred and required repeated metastectomies. Case presentation Digital cell sorting and targeted sequencing of cancer sub-clones from EAC and metastases revealed a completely mutated TP53, whereas the sorted stromal cells were wild-type. Her-2 amplification was significantly lower in the metastases when the patient became therapy-resistant. Conclusions The mechanism of therapy resistance illustrated by this case could only be detected through accurate analysis of tumor sub-populations. Investigating tumor sub-populations of recurrent disease is important for adjusting therapy in recurrent EAC. Electronic supplementary material The online version of this article (10.1186/s12885-018-4789-4) contains supplementary material, which is available to authorized users.
Published: 2018
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23. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer

Author: Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J. -O., Hochhauser, D., Arnold, D., Oh, D. -Y., Reinacher-Schick, A., Tortora, Giampaolo, Algul, H., O'Reilly, E. M., Mcguinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L., Tortora G. (ORCID:0000-0002-1378-4962), Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J. -O., Hochhauser, D., Arnold, D., Oh, D. -Y., Reinacher-Schick, A., Tortora, Giampaolo, Algul, H., O'Reilly, E. M., Mcguinness, D., Cui, K. Y., Schlienger, K., Locker, G. Y., Kindler, H. L., and Tortora G. (ORCID:0000-0002-1378-4962)
Abstract: BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group differe
Published: 2019

24. Frozen section accurately allows pathological characterization of endometrial cancer in patients with a preoperative ambiguous or inconclusive diagnoses: our experience

Author: Santoro, Angela, Piermattei, Angelo, Inzani, Frediano, Angelico, G., Valente, Marianna, Arciuolo, D., Spadola, S., Martini, Maurizio, Fanfani, Francesco, Fagotti, Anna, Gallotta, Valerio, Scambia, Giovanni, Zannoni, Gian Franco, Santoro A. (ORCID:0000-0002-6964-5152), Piermattei A. (ORCID:0000-0002-6835-1179), Inzani F., Valente M., Martini M. (ORCID:0000-0002-6260-6310), Fanfani F. (ORCID:0000-0003-1991-7284), Fagotti A. (ORCID:0000-0001-5579-335X), Gallotta V., Scambia G. (ORCID:0000-0003-2758-1063), Zannoni G. F. (ORCID:0000-0003-1809-129X), Santoro, Angela, Piermattei, Angelo, Inzani, Frediano, Angelico, G., Valente, Marianna, Arciuolo, D., Spadola, S., Martini, Maurizio, Fanfani, Francesco, Fagotti, Anna, Gallotta, Valerio, Scambia, Giovanni, Zannoni, Gian Franco, Santoro A. (ORCID:0000-0002-6964-5152), Piermattei A. (ORCID:0000-0002-6835-1179), Inzani F., Valente M., Martini M. (ORCID:0000-0002-6260-6310), Fanfani F. (ORCID:0000-0003-1991-7284), Fagotti A. (ORCID:0000-0001-5579-335X), Gallotta V., Scambia G. (ORCID:0000-0003-2758-1063), and Zannoni G. F. (ORCID:0000-0003-1809-129X)
Abstract: BACKGROUND: The aim of this study was to assess the agreement rate between intraoperative evaluation (IOE) and final diagnosis (FD) in a series of surgically resected endometrial carcinoma (EC), with a preoperative ambiguous or inconclusive diagnosis by endometrial biopsies and imaging. METHODS: A retrospective study was performed selecting patients who underwent surgery with IOE for suspected EC at our institution from 2012 to 2018. A K coefficient was determined with respect to the histotype, tumor grade, myometrial infiltration and cervical involvement. RESULTS: Data analysis has been performed on 202 women. The IOE evaluation was distributed as Endometrioid (n = 180) and Non-Endometrioid (n = 22). The comparison between the frozen section (FS) and the definitive histological subtype showed an overall agreement rate of 93,07% (k = 0.612) and an agreement of 97.2% for Endometrioid vs 59% for Non-Endometrioid tumors. The FIGO system grading was the same in 91,1% of patients, none was upgraded and in 8,9% downgraded. Observed agreements were 89,11% and 95,54% for myometrial and cervical involvement, respectively. CONCLUSIONS: The good agreement between intraoperative grading, myometrial invasion and their histological definition on permanent sections highlights that FS is a good predictor for surgical outcome, in particular in presence of a preoperative ambiguous or inconclusive diagnostic evaluation.
Published: 2019

25. Dose escalation in extracranial stereotactic ablative radiotherapy (DESTROY-1): A multiarm Phase I trial

Author: Deodato, Francesco, Macchia, Gabriella, Cilla, Savino, Ianiro, Anna, Sallustio, Giuseppina, Cammelli, Silvia, Buwenge, Milly, Mattiucci, Gian Carlo, Valentini, Vincenzo, Morganti, Alessio Giuseppe, Deodato, Francesco (ORCID:0000-0003-1276-5070), Sallustio, Giuseppina (ORCID:0000-0002-6641-4914), Mattiucci, Gian Carlo (ORCID:0000-0001-6500-0413), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), Morganti, Alessio G, Deodato, Francesco, Macchia, Gabriella, Cilla, Savino, Ianiro, Anna, Sallustio, Giuseppina, Cammelli, Silvia, Buwenge, Milly, Mattiucci, Gian Carlo, Valentini, Vincenzo, Morganti, Alessio Giuseppe, Deodato, Francesco (ORCID:0000-0003-1276-5070), Sallustio, Giuseppina (ORCID:0000-0002-6641-4914), Mattiucci, Gian Carlo (ORCID:0000-0001-6500-0413), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), and Morganti, Alessio G
Abstract: n/a
Published: 2019

26. Role of CA125/CEA ratio and ultrasound parameters in identifying metastases to the ovaries in patients with multilocular and multilocular-solid ovarian masses

Author: Moro, Francesca, Pasciuto, Tina, Djokovic, D., Di Legge, A., Granato, V., Moruzzi, M. C., Mancari, R., Zannoni, Gian Franco, Fischerova, D., Franchi, D., Scambia, Giovanni, Testa, Antonia Carla, Moro, F., Pasciuto, T. (ORCID:0000-0003-2959-8571), Zannoni, G. F. (ORCID:0000-0003-1809-129X), Scambia, G. (ORCID:0000-0003-2758-1063), Testa, A. C. (ORCID:0000-0003-2217-8726), Moro, Francesca, Pasciuto, Tina, Djokovic, D., Di Legge, A., Granato, V., Moruzzi, M. C., Mancari, R., Zannoni, Gian Franco, Fischerova, D., Franchi, D., Scambia, Giovanni, Testa, Antonia Carla, Moro, F., Pasciuto, T. (ORCID:0000-0003-2959-8571), Zannoni, G. F. (ORCID:0000-0003-1809-129X), Scambia, G. (ORCID:0000-0003-2758-1063), and Testa, A. C. (ORCID:0000-0003-2217-8726)
Abstract: Objectives: To investigate ultrasound features and the best cut-off value of the cancer antigen 125/carcinoembryonic antigen (CA125/CEA) ratio to discriminate ovarian metastases from benign and primary malignant ovarian neoplasms in two selected groups of morphological ovarian masses, namely multilocular masses with five or more locules and multilocular-solid masses. Methods: Patients with multilocular (five or more locules) or multilocular-solid ovarian masses, operated on within 3 months of ultrasound examination, and with tumor markers (CEA and CA125) available at diagnosis, were identified retrospectively from three ultrasound centers. The masses were described using the International Ovarian Tumor Analysis (IOTA) terminology. Ultrasound and clinical characteristics were compared between those with an ovarian neoplasm (including benign and primary malignant neoplasms) and those with an ovarian metastasis. Receiver–operating characteristics curve (ROC) analysis was used to evaluate the ability of CA125, CEA and CA125/CEA to differentiate between ovarian neoplasms and ovarian metastases, and their predictive performance was assessed. Results: In total, 350 (88.4%) patients with an ovarian neoplasm (including 99 benign, 43 borderline and 197 primary epithelial ovarian carcinomas, seven malignant rare tumors and four other types of invasive ovarian tumor) and 46 (11.6%) patients with an ovarian metastasis were analyzed. On ultrasound examination, ovarian neoplasms were smaller than ovarian metastases (median largest diameter, 97 (range, 20–387) mm vs 146 (range, 43–259) mm, respectively; P < 0.0001) and presented with a lower number of cysts with > 10 locules (18.9% vs 54.3%; P < 0.0001). ROC curve analysis showed that the best cut-off value of CEA for distinguishing between ovarian neoplasms and ovarian metastases was 2.33 ng/mL. The predictive performance of this CEA cut-off value was: area under the curve (AUC), 0.791 (95% CI, 0.711–0.870); accuracy, 73.
Published: 2019

27. Sirolimus inhibits the growth and metastatic progression of hepatocellular carcinoma.

Author: Zheng Wang, Jian Zhou, Jia Fan, Chang-Jun Tan, Shuang-Jian Qiu, Yao Yu, Xiao-Wu Huang, and Zhao-You Tang
Subjects: *RAPAMYCIN, *IMMUNOSUPPRESSIVE agents, *TRANSPLANTATION of organs, tissues, etc., *LIVER cancer, *CANCER invasiveness, *CANCER patients, *TUMOR growth
Abstract: Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC. MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression. In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia. The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC. [ABSTRACT FROM AUTHOR]
Published: 2009
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28. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Carlos L. Arteaga, Mark Clemons, Soulef Hachemi, Barbara Pistilli, Javier Cortes, José Baselga, Zefei Jiang, Norikazu Masuda, Agnieszka Jagiełło-Gruszfeld, Bharani Dharan, Seock–Ah –A Im, Masato Takahashi, Patrick Urban, Peter Vuylsteke, Ling Ming Tseng, Hiroji Iwata, Mario Campone, Walter Jonat, Yoshinori Ito, Sara A. Hurvitz, Ahmad Awada, Michele De Laurentiis, Cristian Massacesi, Stephen Chia, Emmanuelle di Tomaso, Baselga, José, Im, Seock-ah, Iwata, Hiroji, Cortés, Javier, De Laurentiis, Michele, Jiang, Zefei, Arteaga, Carlos L, Jonat, Walter, Clemons, Mark, Ito, Yoshinori, Awada, Ahmad, Chia, Stephen, Jagiełło-gruszfeld, Agnieszka, Pistilli, Barbara, Tseng, Ling-ming, Hurvitz, Sara, Masuda, Norikazu, Takahashi, Masato, Vuylsteke, Peter, Hachemi, Soulef, Dharan, Bharani, Di Tomaso, Emmanuelle, Urban, Patrick, Massacesi, Cristian, and Campone, Mario
Subjects: 0301 basic medicine, Morpholine, Aging, Receptor, ErbB-2, DNA Mutational Analysis, Buparlisib, Aminopyridines, Phases of clinical research, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, ErbB-2, 0302 clinical medicine, Receptors, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Metastasis, Fulvestrant, Progesterone, Class I Phosphatidylinositol 3-Kinase, Cancer, education.field_of_study, Tumor, Estradiol, Alanine Transaminase, DNA, Neoplasm, Middle Aged, Neoplasm Metastasi, Postmenopause, Survival Rate, Receptors, Estrogen, Oncology, Response Evaluation Criteria in Solid Tumors, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Retreatment, Female, Drug Eruptions, Receptors, Progesterone, Breast Neoplasm, Human, Receptor, Signal Transduction, medicine.drug, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Morpholines, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Population, Response Evaluation Criteria in Solid Tumor, Breast Neoplasms, Placebo, Article, Disease-Free Survival, DNA Mutational Analysi, 03 medical and health sciences, Breast cancer, Double-Blind Method, Clinical Research, Internal medicine, Breast Cancer, Biomarkers, Tumor, medicine, Humans, Oncology & Carcinogenesis, Aspartate Aminotransferases, education, Survival rate, Aged, Gynecology, Antineoplastic Combined Chemotherapy Protocol, business.industry, Evaluation of treatments and therapeutic interventions, Aspartate Aminotransferase, DNA, Exanthema, medicine.disease, Estrogen, Aminopyridine, 030104 developmental biology, chemistry, Drug Eruption, Hyperglycemia, Neoplasm, Phosphatidylinositol 3-Kinase, business, Biomarkers
Abstract: BackgroundPhosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.MethodsThe BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.FindingsBetween Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [
Published: 2017
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29. Lac-l-TTA, a novel lactose-based amino acid–sugar conjugate for anti-metastatic applications

Author: Hayarpi M. Simonyan, Roberta Iannitti, Valentina Roviello, Caterina Vicidomini, Giovanni N. Roviello, Rosanna Palumbo, Roviello, G. N., Iannitti, R., Palumbo, R., Simonyan, H., Vicidomini, C., and Roviello, V.
Subjects: Male, 0301 basic medicine, Clinical Biochemistry, Disaccharide, Antineoplastic Agents, Lactose, Anti-metastatic, 01 natural sciences, Biochemistry, Antineoplastic Agent, Colony-Forming Units Assay, 03 medical and health sciences, chemistry.chemical_compound, Tumor Cells, Cultured, Humans, Organic chemistry, Monosaccharide, Sugar, Amino Acids, Neoplasm Metastasis, Glycated amino acid, Cell Proliferation, Fructosyl-amino acid, Alanine, chemistry.chemical_classification, 010405 organic chemistry, Organic Chemistry, Prostatic Neoplasms, Fructose, Combinatorial chemistry, 0104 chemical sciences, Amino acid, Neoplasm Metastasi, Amino Acid, 030104 developmental biology, chemistry, Prostatic Neoplasm, Sugars, Derivative (chemistry), Human, Conjugate
Abstract: Here we describe the synthesis, chromatographic purification, MS and NMR characterization of a new lactosyl-derivative, i.e. a lactosyl thiophenyl-substituted triazolyl-thione l-alanine (Lac-L-TTA). This amino acid–sugar conjugate was prepared by solution synthesis in analogy to the natural fructosyl-amino acids. Furthermore, we investigated the inhibition of PC-3 prostate cancer cell colony formation by this lactose derivative in comparison with the less polar fructose-based derivative, Fru-L-TTA. This let us to compare the properties of the artificial derivative, object of the present work, with the monosaccharide-based counterpart and to obtain a preliminary information on the influence of polarity on such biological activity. A significantly higher anticancer effect of Lac-L-TTA with respect to the fructose analogue emerged from our study suggesting that the anti-metastatic potential of fructosyl-amino acids can be enhanced by increasing the polarity of the compounds, for example by introducing disaccharide moieties in place of fructose.
Published: 2017
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30. Detection of liver metastases in cancer patients with geographic fatty infiltration of the liver: the added value of contrast-enhanced sonography

Author: Roberto Lagalla, Tommaso Vincenzo Bartolotta, Adele Taibbi, Andrea Anastasi, Massimo Midiri, Dario Picone, Bartolotta, T., Taibbi, A., Picone, D., Anastasi, A., Midiri, M., and Lagalla, R.
Subjects: medicine.medical_specialty, lcsh:Medical technology, Neoplasm metastasis, Contrast media, Fatty liver, Liver diseases, Liver neoplasms, Ultrasonography, Liver neoplasm, 030218 nuclear medicine & medical imaging, Lesion, Hemangioma, 03 medical and health sciences, 0302 clinical medicine, Text mining, Positive predicative value, medicine, Radiology, Nuclear Medicine and imaging, Neoplasm metastasi, medicine.diagnostic_test, business.industry, Cancer, Magnetic resonance imaging, medicine.disease, Confidence interval, lcsh:R855-855.5, 030220 oncology & carcinogenesis, Original Article, Radiology, medicine.symptom, Settore MED/36 - Diagnostica Per Immagini E Radioterapia, business, Liver disease
Abstract: Purpose The aim of this study is to assess the role of contrast-enhanced ultrasonography (CEUS) in the detection of liver metastases in cancer patients with geographic liver fatty deposition on greyscale ultrasonography (US). Methods Thirty-seven consecutive cancer patients (24 women and 13 men; age, 33 to 80 years; mean, 58.1 years) with geographic liver fatty deposition, but without any detectable focal liver lesion on greyscale US, underwent sulphur hexafluoride-enhanced US. Two readers reported by consensus the presence, size, and location of any detected lesion. All patients underwent magnetic resonance imaging (MRI) as a confirmatory study. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and accuracy were calculated. Results Seven focal liver lesions (size, 4 to 10 mm; mean, 6.1 mm) were detected in 4/37 patients (10.8%): four metastases (size, 5 to 10 mm; mean, 6.7 mm) were detected both by CEUS and MRI, with one hemangioma and two cysts (size range, 4 to 6 mm; mean, 5.3 mm) detected by MRI only. In 1/37 patients (2.7%), CEUS misdiagnosed geographic fatty change as three metastases. In 32/37 patients (86.5%), no lesions were detected. Sensitivity, specificity, PPV, NPV, and accuracy of CEUS were 100% (95% confidence Interval [CI], 1.000 to 1.000), 97.1% (95% CI, 0.914 to 1.027), 75%, 100%, and 97.3%, respectively. No statistically significant differences were found between CEUS and MRI in the detection of focal liver lesions (P=0.480), whereas both of them performed better than baseline US (P
Published: 2017

31. The Clinical Efficacy of Enzalutamide in Metastatic Prostate Cancer: Prospective Single-center Study

Author: Francesco Dieli, Patrizia Dorangricchia, Giuseppe Cicero, Rossella De Luca, Cicero, G., DE LUCA, R., Dorangricchia, P., and Dieli, F.
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_treatment, Docetaxel, Kaplan-Meier Estimate, urologic and male genital diseases, Drug resistant, Antineoplastic Agent, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, Prednisone, Clinical endpoint, Prospective Studies, Neoplasm Metastasis, Prospective cohort study, Aged, 80 and over, General Medicine, Middle Aged, Neoplasm Metastasi, Prostatic Neoplasms, Castration-Resistant, Prostate-specific antigen, Treatment Outcome, 030220 oncology & carcinogenesis, Benzamides, Regression Analysis, Taxoids, Human, medicine.drug, medicine.medical_specialty, Antineoplastic Agents, Adenocarcinoma, Regression Analysi, 03 medical and health sciences, Taxoid, Internal medicine, Nitriles, Phenylthiohydantoin, Enzalutamide, medicine, Chemotherapy, Humans, Aged, business.industry, Prostatic Neoplasms, Prostate-Specific Antigen, medicine.disease, Prospective Studie, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Prostatic Neoplasm, business
Abstract: Background/Aim: To evaluate the effectiveness of enzalutamide in Italian patients with hormone-refractory metastatic castration-resistant prostate cancer, progressing after chemotherapy with docetaxel plus prednisone. Patients and Methods: A total of 60 patients were enrolled. Reduction in serum prostate-specific antigen (PSA) was assessed as the primary endpoint, while reduction in pain, safety, progression-free survival and overall survival represented secondary endpoints. Results: Enzalutamide was well tolerated, with a manageable toxicity profile and a modest objective response rate. A considerable difference in serum levels of PSA before and after treatment was observed. A significant correlation between PSA response and overall survival was also noted. The regression analysis revealed PSA level to be predictive of overall survival. Conclusion: Enzalutamide was shown to be an effective and welltolerated therapeutic option in patients with metastatic castration-resistant prostate cancer progressing after docetaxel plus prednisone treatment.
Published: 2017
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32. Extraskeletal osteosarcoma

Author: Andreas Leithner, R. Capanna, R. J. Grimer, Silvia Ferrari, M. De Lisa, Gianni Bisogno, Guido Scoccianti, Paul C Jutte, Giovanni Grignani, Andreas H. Krieg, Lia D'Ambrosio, Alessandra Longhi, Madeleine Willegger, Reinhard Windhager, Davide Maria Donati, Craig Gerrand, José Casanova, David Biau, Alessandro Gronchi, Jeremy Whelan, Frank M. Klenke, Stefan S. Bielack, Stefanie Hecker-Nolting, Longhi, A., Bielack, S.S., Grimer, R., Whelan, J., Windhager, R., Leithner, A., Gronchi, A., Biau, D., Jutte, P., Krieg, A.H., Klenke, F.M., Grignani, G., Donati, D.M., Capanna, R., Casanova, J., Gerrand, C., Bisogno, G., Hecker-Nolting, S., De Lisa, M., D'Ambrosio, L., Willegger, M., Scoccianti, G., Ferrari, S., Man, Biomaterials and Microbes (MBM), Public Health Research (PHR), and Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE)
Subjects: 0301 basic medicine, Oncology, EMSOS, Extraskeletal osteosarcoma, Localised osteosarcoma, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Chemoradiotherapy, Child, Disease-Free Survival, Europe, Female, Humans, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Metastasis, Neoplasm Recurrence, Local, Osteosarcoma, Retrospective Studies, Risk Factors, Soft Tissue Neoplasms, Tumor Burden, Young Adult, Cancer Research, medicine.medical_treatment, CLINICOPATHOLOGICAL ANALYSIS, 0302 clinical medicine, Retrospective Studie, 80 and over, 610 Medicine & health, Neoadjuvant therapy, Univariate analysis, Ifosfamide, TUMORS, Neoplasm Metastasi, Local, 030220 oncology & carcinogenesis, Europa, medicine.drug, Human, medicine.medical_specialty, Extraskeletal Osteosarcoma, SOFT-TISSUES, BREAST, Quimiorradioterapia, 03 medical and health sciences, Internal medicine, medicine, Soft Tissue Neoplasm, Neoplasias dos Tecidos Moles, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Risk Factor, Retrospective cohort study, Radiation therapy, Regimen, 030104 developmental biology, Neoplasm Recurrence, business, OSTEOGENIC-SARCOMA
Abstract: Purpose: Prognosis of extraskeletal osteosarcoma (ESOS) is reported to be poorer than that of skeletal osteosarcoma. This multicenter retrospective study aimed to evaluate factors influencing ESOS prognosis.Patients and methods: Members of the European Musculoskeletal Oncology Society (EMSOS) submitted institutional data on patients with ESOS.Results: Data from 274 patients treated from 1981 to 2014 were collected from 16 EMSOS centres; 266 patients were eligible. Fifty (18.7%) had metastases at diagnosis. Of 216 patients with localised disease, 211 (98%) underwent surgery (RO = 70.6%, R1 = 27%). Five-year overall survival (OS) for all 266 patients was 47% (95% CI 40-54%). Five-year OS for metastatic patients was 27% (95% CI 13-41%). In the analysis restricted to the 211 localised patients who achieved complete remission after surgery 5-year OS was 51.4% (95% CI 44-59%) and 5-year disease-free survival (DFS) was 43% (95% CI 35-51%). One hundred twenty-one patients (57.3%) received adjuvant or neoadjuvant chemotherapy and 80 patients (37.9%) received radiotherapy. A favourable trend was seen for osteosarcoma-type chemotherapy versus soft tissue sarcoma-type (doxorubicin +/- ifosfamide) regimens. For the 211 patients in complete remission after surgery, patient age, tumour size, margins and chemotherapy were positive prognostic factors for DFS and OS by univariate analysis.At multivariate analysis, patient age (40 years) (P = 0.05), tumour size (P = 0.0001) and receipt of chemotherapy (P = 0.006) were statistically significant prognostic factors for survival.Conclusion: Patient age and tumour size are factors influencing ESOS prognosis. Higher survival was observed in patients who received perioperative chemotherapy with a trend in favour of multiagent osteosarcoma-type regimen which included doxorubicin, ifosfamide and cisplatin. (C) 2017 Elsevier Ltd. All rights reserved.
Published: 2017

33. Chemotherapy versus endocrine therapy as first-line treatment in patients with luminal-like HER2-negative metastatic breast cancer: A propensity score analysis

Author: Grazia Arpino, Fabio Puglisi, Marta Bonotto, Massimo Di Maio, Gianpiero Fasola, Lorenzo Gerratana, S. Moroso, Mauro Mansutti, Sabino De Placido, Donatella Iacono, Monica Milano, Carmine De Angelis, Marika Cinausero, Brigida Stanzione, Alessandro Marco Minisini, Piera Gargiulo, Bonotto, Marta, Gerratana, Lorenzo, Di Maio, Massimo, DE ANGELIS, Carmine, Cinausero, Marika, Moroso, Stefano, Milano, Monica, Stanzione, Brigida, Gargiulo, Piera, Iacono, Donatella, Minisini, Alessandro Marco, Mansutti, Mauro, Fasola, Gianpiero, DE PLACIDO, Sabino, Arpino, Grazia, and Puglisi, Fabio
Subjects: 0301 basic medicine, Oncology, Multivariate analysis, Receptor, ErbB-2, medicine.medical_treatment, Hormone antagonist, Antineoplastic Agent, Metastatic breast neoplasms, 0302 clinical medicine, Retrospective Studie, Age Factor, Metastatic breast neoplasm, Neoplasm Metastasis, Treatment outcome, Multivariate Analysi, Chemotherapy, Decision making, Drug therapy, education.field_of_study, Age Factors, General Medicine, Middle Aged, Metastatic breast cancer, Neoplasm Metastasi, 030220 oncology & carcinogenesis, Female, Breast Neoplasm, Human, medicine.medical_specialty, Population, Antineoplastic Agents, Breast Neoplasms, Disease-Free Survival, 03 medical and health sciences, Hormone Antagonists, Pharmacotherapy, Internal medicine, medicine, Humans, Propensity Score, education, Aged, Retrospective Studies, business.industry, Retrospective cohort study, medicine.disease, Surgery, Hormone Antagonist, 030104 developmental biology, Multivariate Analysis, Propensity score matching, business
Abstract: Background According to current guidelines, endocrine therapy (ET) is recommended as first-line treatment of luminal-like metastatic breast cancer (MBC), whereas chemotherapy (CT) should be considered in presence of life-threatening disease. In daily practice, CT is often used outside of this clinical circumstance. Factors influencing first-line choice and the relative impact on outcome are unknown. Methods A consecutive series of luminal-like HER2-negative MBC patients treated from 2004 to 2014 was analyzed to test the association of disease- and patient-related factors with the choice of first-line treatment (ET vs. CT). A propensity score method was used to estimate impact of first-line strategy on outcome. Results Of 604 consecutive luminal-like MBC patients identified, 158 cases were excluded due to unknown or positive HER2-status. Among 446 HER2-negative cases, 171 (38%) received first-line CT. On multivariate analysis, the only factors significantly associated with lower CT use were old age (OR 0.25, 95%C.I. 0.13–0.49) or presence of bone metastases only (OR 0.26, 95%C.I. 0.13–0.53). In propensity score matched population, no differences were observed between CT and ET as first-line treatment either in terms of overall survival (37.5 months and 33.4 months respectively, log-rank test, P = 0.62) or progression-free survival (13.3 months and 9.9 months respectively, log-rank test, P = 0.92). Conclusions High percentage of patients with luminal-like MBC received CT as first-line therapy in real-life. The choice was mainly driven by age and site of metastases. With the limitations of a non-randomized comparison, no differences on patients' outcome were observed depending on the first-line strategy.
Published: 2017
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34. Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis

Author: Stefano Leporatti, Jennifer Chapelle, Simone Borgoni, Mariafrancesca Cascione, Sara Bulfamante, Sammy Ferri-Borgogno, Paola Defilippi, Moitza Principe, Paola Nisticò, Paola Cappello, Francesca Di Modugno, Michela Capello, Francesco Novelli, Michelle Samuel Chattaragada, Chiara Riganti, Principe, M., Borgoni, S., Cascione, M., Chattaragada, M. S., Ferri-Borgogno, S., Capello, M., Bulfamante, S., Chapelle, J., Di Modugno, F., Defilippi, P., Nistico, P., Cappello, P., Riganti, C., Leporatti, S., and Novelli, F.
Subjects: 0301 basic medicine, Pathology, Cancer Research, Integrins, Alpha-v beta-3, ENO1, Gene Expression, Apoptosis, Integrin, Cell morphology, chemistry.chemical_compound, Mice, Atomic force microscopy, 0302 clinical medicine, Invasion, Medicine, Neoplasm Metastasis, Cellular Senescence, Integrin alphaVbeta3, biology, Pancreatic Neoplasm, Cell migration, Hematology, lcsh:Diseases of the blood and blood-forming organs, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell biology, Neoplasm Metastasi, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, Vitronectin, Human, medicine.medical_specialty, DNA-Binding Protein, lcsh:RC254-282, Receptors, Urokinase Plasminogen Activator, 03 medical and health sciences, Cell Line, Tumor, Biomarkers, Tumor, Cell Adhesion, Animals, Humans, Neoplasm Invasiveness, Gene Silencing, Cell adhesion, Molecular Biology, Cell Shape, Neoplasm Invasivene, Tumor Suppressor Protein, business.industry, Animal, lcsh:RC633-647.5, Research, Tumor Suppressor Proteins, Apoptosi, Pancreatic cancer, Urokinase receptor, Pancreatic Neoplasms, 030104 developmental biology, chemistry, Phosphopyruvate Hydratase, biology.protein, business
Abstract: Background We have previously shown that in pancreatic ductal adenocarcinoma (PDA) cells, the glycolytic enzyme alpha-enolase (ENO1) also acts as a plasminogen receptor and promotes invasion and metastasis formation. Moreover, ENO1 silencing in PDA cells induces oxidative stress, senescence and profoundly modifies PDA cell metabolism. Although anti-ENO1 antibody inhibits PDA cell migration and invasion, little is known about the role of ENO1 in regulating cell-cell and cell-matrix contacts. We therefore investigated the effect of ENO1 silencing on the modulation of cell morphology, adhesion to matrix substrates, cell invasiveness, and metastatic ability. Methods The membrane and cytoskeleton modifications that occurred in ENO1-silenced (shENO1) PDA cells were investigated by a combination of confocal microscopy and atomic force microscopy (AFM). The effect of ENO1 silencing was then evaluated by phenotypic and functional experiments to identify the role of ENO1 in adhesion, migration, and invasion, as well as in senescence and apoptosis. The experimental results were then validated in a mouse model. Results We observed a significant increase in the roughness of the cell membrane due to ENO1 silencing, a feature associated with an impaired ability to migrate and invade, along with a significant downregulation of proteins involved in cell-cell and cell-matrix adhesion, including alpha v/beta 3 integrin in shENO1 PDA cells. These changes impaired the ability of shENO1 cells to adhere to Collagen I and IV and Fibronectin and caused an increase in RGD-independent adhesion to vitronectin (VN) via urokinase plasminogen activator receptor (uPAR). Binding of uPAR to VN triggers integrin-mediated signals, which result in ERK1-2 and RAC activation, accumulation of ROS, and senescence. In shENO1 cancer cells, the use of an anti-uPAR antibody caused significant reduction of ROS production and senescence. Overall, a decrease of in vitro and in vivo cell migration and invasion of shENO1 PDA cells was observed. Conclusion These data demonstrate that ENO1 promotes PDA survival, migration, and metastasis through cooperation with integrins and uPAR. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0385-8) contains supplementary material, which is available to authorized users.
Published: 2017
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35. Third- and later-line treatment in advanced or metastatic gastric cancer: a systematic review and meta-analysis

Author: Ilaria Maggio, Angela Dalia Ricci, Fabiola Lorena Rojas Limpe, Maria Massucci, Veronica Mollica, Andrea Ardizzoni, Alessandro Rizzo, Francesca Di Fabio, Rizzo A., Mollica V., Ricci A.D., Maggio I., Massucci M., Rojas Limpe F.L., Fabio F.D., and Ardizzoni A.
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Salvage therapy, chemotherapy, Placebo, law.invention, 03 medical and health sciences, molecular oncology, 0302 clinical medicine, Randomized controlled trial, Stomach Neoplasm, law, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Progression-free survival, Neoplasm Metastasis, Adverse effect, Survival rate, Randomized Controlled Trials as Topic, Salvage Therapy, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, gastrointestinal/colorectal, General Medicine, Progression-Free Survival, Neoplasm Metastasi, Survival Rate, 030104 developmental biology, Clinical Trials, Phase III as Topic, biological therapy, 030220 oncology & carcinogenesis, Meta-analysis, solid tumor, business, Human
Abstract: Aim: We performed a systematic review and meta-analysis to investigate the efficacy and safety of third-line (TLT) and salvage treatment (ST) in advanced or metastatic gastric cancer. Materials & methods: Eligible studies included randomized clinical trials assessing TLT and ST versus placebo or best supportive care. Outcomes of interest included: overall survival, objective response rate and disease control rate in TLT; progression-free survival in ST; grade 3–4 adverse events in ST. Results: The use of TLT and ST was superior to placebo or best supportive care in terms of prolonging overall survival and progression-free survival. Hematological toxicities were more frequent in ST. Conclusion: TLT and ST are considerable and tolerable treatment options for patients with advanced or metastatic gastric cancer. Given the substantial heterogeneities affecting the efficacy analyses, these results have to be interpreted cautiously.
Published: 2019

36. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author: Carolina Nor, Martin Komosa, Olga Sirbu, Nabil Ahmed, Joonas Haapasalo, Kristen Fousek, Jonelle G. Pallota, Betty Luu, Cynthia Hawkins, Kenneth Aldape, Uri Tabori, David Przelicki, Srinidhi Varadharajan, Liam D. Hendrikse, Meenakshi Hegde, Claudia M. Kuzan-Fischer, Ana Guerreiro Stucklin, Tajana Douglas, Ahmed Z. Gad, Xiaochong Wu, Randy Van Ommeren, Polina Balin, Alex Manno, Sachin Kumar, Raul Suarez, Avesta Rastan, Craig Daniels, Mads Daugaard, Maria C. Vladoiu, Stephen Yip, Cory Richman, Michelle Ly, Matthew L. Baker, Kaitlin Kharas, Laura K. Donovan, Stephen C. Mack, Claudia C. Faria, Pasqualino De Antonellis, Ning Huang, Poul H. Sorensen, Zied Abdullaev, Lei Qin, Livia Garzia, Alyssa C. M. Joynt, A. Sorana Morrissy, Michael D. Taylor, Sujith K. Joseph, Antony Michealraj, Dilakshan Srikanthan, Florence M.G. Cavalli, Borja L. Holgado, John M. Maris, Alberto Delaidelli, Vijay Ramaswamy, Kevin Bielamowicz, Juliette Hukin, Donovan, L. K., Delaidelli, A., Joseph, S. K., Bielamowicz, K., Fousek, K., Holgado, B. L., Manno, A., Srikanthan, D., Gad, A. Z., Van Ommeren, R., Przelicki, D., Richman, C., Ramaswamy, V., Daniels, C., Pallota, J. G., Douglas, T., Joynt, A. C. M., Haapasalo, J., Nor, C., Vladoiu, M. C., Kuzan-Fischer, C. M., Garzia, L., Mack, S. C., Varadharajan, S., Baker, M. L., Hendrikse, L., Ly, M., Kharas, K., Balin, P., Wu, X., Qin, L., Huang, N., Stucklin, A. G., Morrissy, A. S., Cavalli, F. M. G., Luu, B., Suarez, R., De Antonellis, P., Michealraj, A., Rastan, A., Hegde, M., Komosa, M., Sirbu, O., Kumar, S. A., Abdullaev, Z., Faria, C. C., Yip, S., Hukin, J., Tabori, U., Hawkins, C., Aldape, K., Daugaard, M., Maris, J. M., Sorensen, P. H., Ahmed, N., and Taylor, M. D.
Subjects: 0301 basic medicine, Ependymoma, Male, medicine.medical_treatment, T-Lymphocytes, Immunotherapy, Adoptive, Mice, 0302 clinical medicine, Cerebrospinal fluid, Drug Delivery Systems, HEK293 Cell, Cancer immunotherapy, Tumor Cells, Cultured, Neoplasm Metastasis, Child, Cerebrospinal Fluid, Receptors, Chimeric Antigen, Brain Neoplasms, General Medicine, Neoplasm Metastasi, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, Female, Cancer Vaccine, Human, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, Brain Neoplasm, 03 medical and health sciences, medicine, Animals, Humans, Cerebellar Neoplasms, neoplasms, Injections, Intraventricular, Medulloblastoma, Animal, business.industry, Cerebellar Neoplasm, Infant, Immunotherapy, Recurrent Medulloblastoma, medicine.disease, Interleukin-13 receptor, Xenograft Model Antitumor Assays, Chimeric antigen receptor, 030104 developmental biology, HEK293 Cells, T-Lymphocyte, Cancer research, business, Drug Delivery System
Abstract: Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
Published: 2019

37. 68Ga-PSMA-11 Positron Emission Tomography Detects Residual Prostate Cancer after Prostatectomy in a Multicenter Retrospective Study

Author: Davide Pianori, Jeremie Calais, Veronica Cervati, Ali Afshar-Oromieh, Matthias Eiber, Stefano Fanti, F. Barbato, Manuel Weber, Andrei Gafita, Alberto Briganti, Jochen Walz, Harun Ilhan, Wolfgang P. Fendler, Ken Herrmann, Axel Wetter, Fabian Spohn, Boris Hadaschik, Andrea Farolfi, Uwe Haberkorn, Farolfi, A., Gafita, A., Calais, J., Eiber, M., Afshar-Oromieh, A., Spohn, F., Barbato, F., Weber, M., Ilhan, H., Cervati, V., Wetter, A., Hadaschik, B., Briganti, A., Walz, J., Pianori, D., Fanti, S., Haberkorn, U., Herrmann, K., Fendler, W. P., and Farolfi A, Gafita A, Calais J, Eiber M, Afshar-Oromieh A, Spohn F, Barbato F, Weber M, Ilhan H, Cervati V, Wetter A, Hadaschik B, Briganti A, Walz J, Pianori D, Fanti S, Haberkorn U, Herrmann K, Fendler WP.
Subjects: Oncology, Male, medicine.medical_specialty, Neoplasm, Residual, diagnostic imaging, Urology, medicine.medical_treatment, 030232 urology & nephrology, prostate specific antigen, 68Ga-PSMA-11, 03 medical and health sciences, Prostate cancer, neoplasm metastasis, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, medicine, Medical imaging, Biomarkers, Tumor, Humans, In patient, Edetic Acid, Aged, Retrospective Studies, Prostatectomy, medicine.diagnostic_test, business.industry, Prostatic Neoplasms, Retrospective cohort study, Middle Aged, Prostate-Specific Antigen, medicine.disease, Magnetic Resonance Imaging, prostatic neoplasms, Prostate-specific antigen, Positron emission tomography, Positron-Emission Tomography, neoplasm metastasi, positron-emission tomography, Radiopharmaceuticals, business, Oligopeptides
Abstract: Purpose: Prostate specific antigen persistence after radical prostatectomy is associated with adverse outcomes in patients with prostate cancer. We sought to define regions at risk for residual disease as well as the accuracy of prostate specific membrane antigen ligand positron emission tomography in patients with prostate specific antigen persistence. Materials and methods: At 6 participating centers a total of 191 patients who underwent 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography or positron emission tomography/magnetic resonance imaging for persistently elevated postoperative prostate specific antigen (0.1 ng/ml or greater) were retrospectively included in study. The detection rate and the positive predictive value were determined. In 33 patients with additional prostate specific membrane antigen ligand positron emission tomography before prostatectomy we also determined the rate of positron emission tomography based persistence and recurrence. Results: Prostate specific membrane antigen ligand positron emission tomography localized prostate cancer in 130 of 191 patients (68%) with prostate specific antigen persistence at a median prostate specific antigen of 1.1 ng/ml. The detection rate significantly increased with prostate specific antigen (p
Published: 2019

38. Anti-EGFR-resistant clones decay exponentially after progression: Implications for anti-EGFR re-challenge

Author: A.A. Talasaz, Benny Johnson, Xian De Liu, Jason Henry, Naveen Garg, Bryan K. Kee, Michael J. Overman, Ryan B. Corcoran, David S. Hong, Arvind Dasari, Katherine Clifton, Kanwal Pratap Singh Raghav, Kimberly C. Banks, Stefania Napolitano, R.B. Lanman, John H. Strickler, Scott Kopetz, Christine Megerdichian Parseghian, Van K. Morris, V.M. Raymond, Ji Yuan Wu, Allan Andresson Lima Pereira, Jonathan M. Loree, Eduardo Vilar, Parseghian, C. M., Loree, J. M., Morris, V. K., Liu, X., Clifton, K. K., Napolitano, S., Henry, J. T., Pereira, A. A., Vilar, E., Johnson, B., Kee, B., Raghav, K., Dasari, A., Wu, J., Garg, N., Raymond, V. M., Banks, K. C., Talasaz, A. A., Lanman, R. B., Strickler, J. H., Hong, D. S., Corcoran, R. B., Overman, M. J., and Kopetz, S.
Subjects: 0301 basic medicine, Oncology, Colorectal cancer, Mutant, Colorectal Neoplasm, 0302 clinical medicine, Retrospective Studie, Anti-EGFR therapy, Epidermal growth factor receptor, Neoplasm Metastasis, biology, Hematology, Prognosis, Neoplastic Cells, Circulating, ErbB Receptors, Neoplasm Metastasi, Survival Rate, Ectodomain, 030220 oncology & carcinogenesis, Disease Progression, Colorectal Neoplasms, Human, medicine.medical_specialty, Prognosi, Protein Kinase Inhibitor, Follow-Up Studie, 03 medical and health sciences, Exponential growth, Internal medicine, medicine, Humans, Progression-free survival, ErbB Receptor, Protein Kinase Inhibitors, Retrospective Studies, Circulating tumor DNA, business.industry, Retrospective cohort study, Original Articles, medicine.disease, ras Protein, Discontinuation, 030104 developmental biology, Drug Resistance, Neoplasm, Mutation, biology.protein, ras Proteins, business, Clonal decay, Follow-Up Studies
Abstract: Background Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. Patients and methods We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. Results Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. Conclusion These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.
Published: 2019

39. Trastuzumab emtansine for residual invasive HER2-positive breast cancer

Author: Von Minckwitz G., Huang C. -S., Mano M. S., Loibl S., Mamounas E. P., Untch M., Wolmark N., Rastogi P., Schneeweiss A., Redondo A., Fischer H. H., Jacot W., Conlin A. K., Arce-Salinas C., Wapnir I. L., Jackisch C., DiGiovanna M. P., Fasching P. A., Crown J. P., Wulfing P., Shao Z., Caremoli E. R., Wu H., Lam L. H., Tesarowski D., Smitt M., Douthwaite H., Singel S. M., Geyer C. E, De Laurentiis M., Von Minckwitz, G., Huang, C. -S., Mano, M. S., Loibl, S., Mamounas, E. P., Untch, M., Wolmark, N., Rastogi, P., Schneeweiss, A., Redondo, A., Fischer, H. H., Jacot, W., Conlin, A. K., Arce-Salinas, C., Wapnir, I. L., Jackisch, C., Digiovanna, M. P., Fasching, P. A., Crown, J. P., Wulfing, P., Shao, Z., Caremoli, E. R., Wu, H., Lam, L. H., Tesarowski, D., Smitt, M., Douthwaite, H., Singel, S. M., Geyer, C. E., De Laurentiis, M., Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut du Cancer de Montpellier (ICM)
Subjects: Oncology, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Breast Neoplasms, Chemotherapy, Adjuvant, Disease-Free Survival, Female, Humans, Lymphatic Metastasis, Maytansine, Middle Aged, Neoadjuvant Therapy, Neoplasm Metastasis, Neoplasm Staging, Neoplasm, Residual, Peripheral Nervous System Diseases, Radiotherapy, Receptor, ErbB-2, Trastuzumab, Treatment Outcome, Young Adult, [SDV]Life Sciences [q-bio], medicine.medical_treatment, 030204 cardiovascular system & hematology, Ado-Trastuzumab Emtansine, chemistry.chemical_compound, ErbB-2, 0302 clinical medicine, 80 and over, Medicine, Neoplasm, 030212 general & internal medicine, skin and connective tissue diseases, Adjuvant, Neoadjuvant therapy, integumentary system, General Medicine, 3. Good health, Neoplasm Metastasi, Immunological, Residual, Sacituzumab govitecan, Breast Neoplasm, Receptor, Human, medicine.medical_specialty, Antineoplastic Agents, 03 medical and health sciences, Breast cancer, Internal medicine, Chemotherapy, business.industry, Lymphatic Metastasi, medicine.disease, Clinical trial, Radiation therapy, chemistry, Trastuzumab emtansine, Peripheral Nervous System Disease, business
Abstract: International audience; BACKGROUND:Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.METHODS:We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).RESULTS:At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P
Published: 2019
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40. Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model

Author: John K. Cowell, Muthusamy Thangaraju, Khaled A. Hassan, Mustafa Guzel, Hasan Korkaya, Esteban Celis, Maria Ouzounova, Ali S. Arbab, Raziye Piranlioglu, Eunmi Lee, Daniela Marasco, Ahmed Chadli, Max S. Wicha, Roni J. Bollag, Alicia Vinyard, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Piranlioglu, Raziye, Lee, EunMi, Bollag, Roni J., Vinyard, Alicia H., Arbab, Ali S., Cowell, John K., Thangaraju, Muthushamy, Chadli, Ahmed, Celis, Esteban, Korkaya, Hasan Augusta Univ, Dept Biochem & Mol Biol, Georgia Canc Ctr, 1410 Laney Walker Blvd CN2136, Augusta, GA 30912 USA, Ouzounova, Maria Canc Res Ctr Lyon, 28 Rue Laennec, F-69008 Lyon, France, Marasco, Daniela Univ Naples Federico II, Dept Pharm, I-80134 Naples, Italy, Guzel, Mustafa Medipol Univ, REMER, Kavacik Mah Ekinciler Cad 19, TR-34810 Istanbul, Turkey, Hassan, Khaled A., Wicha, Max S. Univ Michigan, Comprehens Canc Ctr, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA, Ouzounova, Maria -- 0000-0001-8934-3461, Korkaya, Hasan -- 0000-0002-0719-5862, Guzel, Prof. Mustafa -- 0000-0002-1423-0435, Bollag, Roni -- 0000-0003-4963-6619, Piranlioglu, Raziye -- 0000-0003-2450-3887, Piranlioglu, R., Lee, E. M., Ouzounova, M., Bollag, R. J., Vinyard, A. H., Arbab, A. S., Marasco, D., Guzel, M., Cowell, J. K., Thangaraju, M., Chadli, A., Hassan, K. A., Wicha, M. S., Celis, E., and Korkaya, H.
Subjects: 0301 basic medicine, Adoptive cell transfer, Disseminated Tumor Cells (DTC), [SDV]Life Sciences [q-bio], General Physics and Astronomy, Triple Negative Breast Neoplasms, 02 engineering and technology, CD8-Positive T-Lymphocytes, Metastasis, Mice, Neoplasms, Disease Models, Animal, Biological, Neoplasm Metastasis, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Tumor, 021001 nanoscience & nanotechnology, Primary tumor, 3. Good health, Neoplasm Metastasi, Survival Analysi, 0210 nano-technology, Primary, Tail, Science, Cells, Models, Biological, Article, General Biochemistry, Genetics and Molecular Biology, Veins, 03 medical and health sciences, Triple Negative Breast, Immunity, Cell Line, Tumor, medicine, Animals, Humans, Neoplasm Invasiveness, Cell Proliferation, Cell growth, business.industry, General Chemistry, CD8-Positive T-Lymphocyte, medicine.disease, Survival Analysis, Lymphocyte Subsets, Disease Models, Animal, 030104 developmental biology, Tumor progression, Cell culture, Cancer research, lcsh:Q, business, CD8
Abstract: Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2−/− mice, an effect mimicked by CD8+ T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8+ T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression., Dissemination of tumor cells from the primary site is an early event. Here, the authors show that the early disseminated tumor cells are actively cleared by the host cytotoxic T lymphocytes induced by the primary tumor and that infiltration of granulocytic myeloid-derived suppressor cells counteracts such immune protection and allow metastasis development.
Published: 2019
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41. A novel CCK2/gastrin receptor-localizing radiolabeled peptide probe for personalized diagnosis and therapy of patients with progressive or metastatic medullary thyroid carcinoma: A multicenter phase I GRAN-T-MTC study

Author: Erba, P, Maecke, H, Mikolajczak, R, Decristoforo, C, Zaletel, K, Maina-Nock, T, Peitl, P, Garnuszek, P, Froberg, A, Goebel, G, De Jong, M, Jabrocka-Hybel, A, Konijnenberg, M, Virgolini, I, Nock, B, Lenda-Tracz, W, Pawlak, D, Rangger, C, Trofmiuk-Muldner, M, Sowa-Staszczak, A, Tomaszuk, M, Von Guggenberg, E, Scarpa, L, Hubalewska-Dydejczyk, A, Erba P. A., Maecke H., Mikolajczak R., Decristoforo C., Zaletel K., Maina-Nock T., Peitl P. K., Garnuszek P., Froberg A., Goebel G., De Jong M., Jabrocka-Hybel A., Konijnenberg M., Virgolini I., Nock B., Lenda-Tracz W., Pawlak D., Rangger C., Trofmiuk-Muldner M., Sowa-Staszczak A., Tomaszuk M., Von Guggenberg E., Scarpa L., Hubalewska-Dydejczyk A., Erba, P, Maecke, H, Mikolajczak, R, Decristoforo, C, Zaletel, K, Maina-Nock, T, Peitl, P, Garnuszek, P, Froberg, A, Goebel, G, De Jong, M, Jabrocka-Hybel, A, Konijnenberg, M, Virgolini, I, Nock, B, Lenda-Tracz, W, Pawlak, D, Rangger, C, Trofmiuk-Muldner, M, Sowa-Staszczak, A, Tomaszuk, M, Von Guggenberg, E, Scarpa, L, Hubalewska-Dydejczyk, A, Erba P. A., Maecke H., Mikolajczak R., Decristoforo C., Zaletel K., Maina-Nock T., Peitl P. K., Garnuszek P., Froberg A., Goebel G., De Jong M., Jabrocka-Hybel A., Konijnenberg M., Virgolini I., Nock B., Lenda-Tracz W., Pawlak D., Rangger C., Trofmiuk-Muldner M., Sowa-Staszczak A., Tomaszuk M., Von Guggenberg E., Scarpa L., and Hubalewska-Dydejczyk A.
Published: 2018

42. Treatment of advanced breast cancer with a metronomic schedule of oral vinorelbine: what is the opinion of Italian oncologists?

Author: Cazzaniga, M, Munzone, E, Montagna, E, Pappagallo, G, Cazzaniga M. E., Munzone E., Montagna E., Pappagallo G., Cazzaniga, M, Munzone, E, Montagna, E, Pappagallo, G, Cazzaniga M. E., Munzone E., Montagna E., and Pappagallo G.
Abstract: Background: The aim of this study was to record the opinions of Italian oncologists about the use of oral vinorelbine administered metronomically in patients with advanced breast cancer. Methods: A series of meetings were held throughout Italy, and participants were asked how much they agreed with each of the several statements. Results: The majority of oncologists agreed that the concept of the minimum biologically effective dose should be used for drugs administered metronomically. Over 50% agreed that metronomic vinorelbine is an option in first-line chemotherapy for patients with advanced breast cancer, including those with a terminal illness and the elderly, as well as in young and fit patients. Just over one-third of experts agreed that a combination of two chemotherapy agents instead of one is not desirable in metastatic breast cancer because of increased toxicity. Most experts agreed that the main aim of a first-line therapy is to control the disease over time and to preserve quality of life. Conclusion: Metronomically administered oral vinorelbine, either as monotherapy or in combination with other drugs, is effective in the long-term treatment of patients with advanced breast cancer. The clinical profiles of patients should be carefully considered to determine the appropriate treatment strategy.
Published: 2018

43. Does the Unexpected Presence of Non-organ-confined Disease at Final Pathology Undermine Cancer Control in Patients with Clinical T1N0M0 Renal Cell Carcinoma Who Underwent Partial Nephrectomy?

Author: Capitanio, U, Stewart, G, Klatte, T, Akdogan, B, Roscigno, M, Marszalek, M, Dell'Oglio, P, Zaffuto, E, Rodriguez Faba, O, Salagierski, M, Lingard, J, Carini, M, Ouzaid, I, Mir, M, Montorsi, F, Da Pozzo, L, Stief, C, Minervini, A, Brookman-May, S, Capitanio U., Stewart G. D., Klatte T., Akdogan B., Roscigno M., Marszalek M., Dell'Oglio P., Zaffuto E., Rodriguez Faba O., Salagierski M., Lingard J., Carini M., Ouzaid I., Mir M. C., Montorsi F., Da Pozzo L. F., Stief C., Minervini A., Brookman-May S. D., Capitanio, U, Stewart, G, Klatte, T, Akdogan, B, Roscigno, M, Marszalek, M, Dell'Oglio, P, Zaffuto, E, Rodriguez Faba, O, Salagierski, M, Lingard, J, Carini, M, Ouzaid, I, Mir, M, Montorsi, F, Da Pozzo, L, Stief, C, Minervini, A, Brookman-May, S, Capitanio U., Stewart G. D., Klatte T., Akdogan B., Roscigno M., Marszalek M., Dell'Oglio P., Zaffuto E., Rodriguez Faba O., Salagierski M., Lingard J., Carini M., Ouzaid I., Mir M. C., Montorsi F., Da Pozzo L. F., Stief C., Minervini A., and Brookman-May S. D.
Abstract: Background: A non-negligible proportion of individuals diagnosed with cT1 renal cell carcinoma (RCC) are upstaged to pT3a at final pathology. Few data on oncological outcomes for these patients are available to determine whether partial nephrectomy (PN) might jeopardise cancer control. Objective: To assess, within an international multi-institutional collaboration, whether PN might undermine cancer control relative to radical nephrectomy (RN) in RCC patients with unexpected pT3a disease. Design, setting, and participants: International multi-institutional collaboration including patients with cT1abN0M0–pT3a RCC. Intervention: PN or RN. Outcome measurements and statistical analysis: We used Kaplan-Meier analyses, before and after propensity-score matching, to evaluate differences in metastatic progression (MP) and cancer-specific mortality (CSM) rates during follow-up. Univariable and multivariable Cox regression analyses were used to assess predictors of MP and CSM. Results and limitations: Overall, 309 patients with cT1abN0M0 RCC (cT1aN0M0, n = 107, 34.6%; cT1bN0M0, n = 202, 65.4%) had pT3a disease according to final pathology. Patients were treated with either PN (n = 71, 23%) or RN (n = 238, 77%). MP at 1, 2, and 5 yr was detected in 9.1%, 13.3%, and 24.1% of patients, respectively. CSM was 3.5%, 10.7%, and 18.4% at 1, 2, and 5 yr, respectively. After matching, no difference in terms of MP or CSM was observed between the PN and RN cohorts (both p>0.3). On multivariable analysis, type of surgery (PN vs RN) was not an independent predictor of either MP (p = 0.3) or CSM (p = 0.4). Limitations include the retrospective design. Conclusions: In patients with unexpected pT3a RCC at final pathology, PN does not appear to jeopardise cancer control with regard to MP and CSM. Patient summary: Cancer control is similar between patients treated with removal of the entire kidney and those with only partial removal, even if the final histology examination demonstrates a tumo
Published: 2018

44. Possible delayed diagnosis and treatment of metastatic differentiated thyroid cancer by adopting the 2015 ATA guidelines

Author: Albano, D, Bertagna, F, Bonacina, M, Durmo, R, Cerudelli, E, Gazzilli, M, Panarotto, M, Formenti, A, Mazziotti, G, Giustina, A, Giubbini, R, Albano, Domenico, Bertagna, Francesco, Bonacina, Mattia, Durmo, Rexhep, Cerudelli, Elisabetta, Gazzilli, Maria, Panarotto, Maria Beatrice, Formenti, Anna Maria, Mazziotti, Gherardo, Giustina, Andrea, Giubbini, Raffaele, Albano, D, Bertagna, F, Bonacina, M, Durmo, R, Cerudelli, E, Gazzilli, M, Panarotto, M, Formenti, A, Mazziotti, G, Giustina, A, Giubbini, R, Albano, Domenico, Bertagna, Francesco, Bonacina, Mattia, Durmo, Rexhep, Cerudelli, Elisabetta, Gazzilli, Maria, Panarotto, Maria Beatrice, Formenti, Anna Maria, Mazziotti, Gherardo, Giustina, Andrea, and Giubbini, Raffaele
Abstract: Objective: According to the 2015 American Thyroid Association (ATA) guidelines, thyroid ablation by iodine-131 (I-131) therapy is absolutely recommended only in patients with high-risk differentiated thyroid cancer (DTC). Often distant metastases are not recognized early and they can stay silent for long time. The aim of our study was to retrospectively analyze the prevalence of metastatic disease before and after I-131 and to evaluate the influence of the new ATA guidelines in the management of DTC. Methods: We retrospectively analyzed 140 patients showing distant metastases. All metastases were detected by whole-body scan after I-131 and confirmed by histology and/or other imaging modalities. Results: In 26/140 patients metastases were detected before I-131, while in 114/140 were discovered after I-131. Comparing patients with metastases detected before and after I-131, no differences were demonstrated considering age, sex, histotype, tumor size, multifocality of cancer and metastatic localization. Metastatic DTC discovered before radioiodine had higher thyroglobulin and received a higher radioiodine total activity and number of treatments. Considering patients with distant metastases, according to the 2015 ATA guidelines, 38 patients would have been categorized as high risk, 22 as low risk and 80 as intermediate risk. Among intermediate-risk patients, only in 25 cases (31%) I-131 treatment would have been appropriate according to 2015 ATA recommendations; in the remaining 56 cases (69%), I-131 would not have been recommended. Conclusions: According to the 2015 ATA guidelines, most of metastatic patients would not have been treated after surgery, with the risk of late diagnosis and delayed treatment
Published: 2018

45. miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene

Author: Piero Picci, Stefania Benini, Emanuela Palmerini, Mattia Vitale, Maria Serena Benassi, Serena Pollino, Marco Gambarotti, Cristina Ferrari, Elisa Bientinesi, Laura Pazzaglia, Pazzaglia, Laura, Pollino, Serena, Vitale, Mattia, Bientinesi, Elisa, Benini, Stefania, Ferrari, Cristina, Palmerini, Emanuela, Gambarotti, Marco, Picci, Piero, and Benassi, Maria Serena
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Receptors, CXCR4, Adolescent, Prognosi, Down-Regulation, Biology, MicroRNA-494.3p, CXCR4, Metastasis, Synovial sarcoma, Fusion gene, 03 medical and health sciences, Chemokine receptor, Sarcoma, Synovial, Young Adult, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, medicine, Humans, Cell migration, Neoplasm Metastasis, Aged, Cell Proliferation, Regulation of gene expression, Oncogene, MicroRNA, Biomarker, Cell cycle, Middle Aged, medicine.disease, Prognosis, Survival Analysis, Neoplasm Metastasi, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, C-X-C chemokine receptor 4, Cancer research, Disease Progression, Female, Survival Analysi, Human
Abstract: Synovial sarcoma (SS) is a rare tumour, with dismal survival when metastasis occurs. SS contains a characteristic translocation (X;18)(p11;q11) and the fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. Novel prognostic and predictive factors are required. The C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor 4 (CXCR4) axis is involved in tumour development and metastatic spread in many types of cancer and previous data have demonstrated a pivotal role of CXCR4 in SS cell migration and invasion. Bioinformatics and biological data indicated CXCR4 is a possible candidate target of miR-494.3p, known to be involved in tumour progression. In this study, we analysed the expression of miR-494.3p and its potential target, CXCR4, in a series of SS specimens. A significantly lower miR-494.3p expression was found in the tumour compared to normal tissue associated with higher levels of CXCR4 both at the gene and protein level. The role of CXCR4 as a potential target of miR-494.3p was assessed in two SS cell lines (SW982 and SYO-I). Transfection with miR-494.3p expression plasmid led to a marked decrease in CXCR4 gene and protein expression, concomitant with a transitory decrease in cell proliferation and migration. The SYO-I cells also responded with an increased apoptotic fraction. The data of this study also demonstrate that the downregulation of miR-494.3p in SS surgical specimens, concomitant with an increased expression of its potential target, CXCR4, was more evident in the metastatic subset. In vitro experiments confirmed that miR-494.3p functioned as a tumour suppressor through the involvement of CXCR4 and ongoing studies are directed to better clarify its role in SS therapeutic strategies.
Published: 2018

46. Colonic metastasis from breast carcinoma detection by CESM and PET/CT: A case report

Author: Simone Mele, Guglielmo Ferrari, Maurizio Zizzo, Giuseppe Falco, Gianluca Gatta, Saverio Coiro, Graziella Di Grezia, Rita Vacondio, Paolo Cecinato, Giulia Besutti, Falco, Giuseppe, Mele, Simone, Zizzo, Maurizio, Di Grezia, Graziella, Cecinato, Paolo, Besutti, Giulia, Coiro, Saverio, Gatta, Gianluca, Vacondio, Rita, and Ferrari, Guglielmo
Subjects: Pathology, positron emission tomography, Breast pathology, Metastasis, Breast cancer, 0302 clinical medicine, Positron Emission Tomography Computed Tomography, Receptors, Medicine, Breast, Neoplasm Metastasis, skin and connective tissue diseases, Colectomy, Colonic Neoplasm, lobular, General Medicine, Colonoscopy, Neoplasm Metastasi, medicine.anatomical_structure, Treatment Outcome, 030220 oncology & carcinogenesis, Invasive lobular carcinoma, Cell Surface, Colonic Neoplasms, population characteristics, 030211 gastroenterology & hepatology, Female, Breast carcinoma, contrast-enhanced spectral mammography, Colon, Contrast-enhanced spectral mammography, Lobular, Positron emission tomography, Aged, Asymptomatic Diseases, Breast Neoplasms, Carcinoma, Lobular, Fluorodeoxyglucose F18, Humans, Mammography, Mucin-1, Neoplasm Invasiveness, Receptors, Cell Surface, Breast Neoplasm, Human, Research Article, medicine.medical_specialty, 03 medical and health sciences, Text mining, breast cancer, Peritoneum, parasitic diseases, Carcinoma, metastasis, Clinical Case Report, Colonic metastasis, Neoplasm Invasivene, Asymptomatic Disease, PET-CT, business.industry, medicine.disease, body regions, business, human activities
Abstract: Introduction: Metastatic spread in invasive lobular carcinoma (ILC) of breast mainly occurs in bones, gynecological organs, peritoneum, retroperitoneum, and gastrointestinal (GI) tract. Metastases to the GI tract may arise many years after initial diagnosis and can affect the tract from the tongue to the anus, stomach being the most commonly involved site. Clinical presentations are predominantly nonspecific, and rarely asymptomatic. CEA, CA 15–3, and CA 19–9 may be informative for symptomatic patients who have had a previous history of breast cancer. Case presentation: We introduce the case of asymptomatic colonic metastasis from breast carcinoma in a 67-year-old woman followed-up for Luminal A ILC. Diagnosis was performed through positron emission tomography/computed tomography (PET/CT) scan and contrast-enhancement spectral mammography (CESM), steering endoscopist to spot the involved intestinal tract and in ruling out further dissemination in the breast parenchyma. Conclusion: In colonic metastases, tumor markers might not be totally reliable. In asymptomatic cases, clinical conditions might be underappreciated, missing local or distant recurrence. CT and PET/CT scan might be useful in diagnosing small volume diseases, and steering endoscopist toward GI metastasis originating from the breast. CESM represents a tolerable and feasible tool that rules out multicentricity and multifocality of breast localization. Moreover, particular patients could tolerate it better than magnetic resonance imaging (MRI).
Published: 2018

47. MiR-205-5p inhibition by locked nucleic acids impairs metastatic potential of breast cancer cells

Author: Alessia Lamolinara, Matilde Todaro, Manuela Iezzi, Antonella De Cola, Paola Lanuti, Cosmo Rossi, Vincenzo De Laurenzi, Marco Marchisio, De Cola A., Lamolinara A., Lanuti P., Rossi C., Iezzi M., Marchisio M., Todaro M., and De Laurenzi V.
Subjects: 0301 basic medicine, Cancer Research, Epithelial-Mesenchymal Transition, medicine.medical_treatment, Antagomir, Settore MED/50 - Scienze Tecniche Mediche Applicate, Immunology, Transplantation, Heterologous, Oligonucleotides, Breast Neoplasms, Biology, Article, Targeted therapy, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, Breast cancer, ErbB, Cell Movement, Mice, Inbred NOD, Oligonucleotide, Cell Line, Tumor, microRNA, medicine, Gene silencing, Animals, Humans, Epithelial–mesenchymal transition, lcsh:QH573-671, Neoplasm Metastasis, Cell Proliferation, Animal, lcsh:Cytology, Cancer, Antagomirs, MicroRNA, Cell Biology, medicine.disease, Neoplasm Metastasi, MicroRNAs, 030104 developmental biology, Cancer research, Female, Stem cell, Breast Neoplasm, Human
Abstract: Mir-205 plays an important role in epithelial biogenesis and in mammary gland development but its role in cancer still remains controversial depending on the specific cellular context and target genes. We have previously reported that miR-205-5p is upregulated in breast cancer stem cells targeting ERBB pathway and leading to targeted therapy resistance. Here we show that miR-205-5p regulates tumorigenic properties of breast cancer cells, as well as epithelial to mesenchymal transition. Silencing this miRNA in breast cancer results in reduced tumor growth and metastatic spreading in mouse models. Moreover, we show that miR-205-5p knock-down can be obtained with the use of specific locked nucleic acids oligonucleotides in vivo suggesting a future potential use of this approach in therapy.
Published: 2018

48. Dabrafenib-trametinib combination in 'field-practice': An Italian experience

Author: Stefano Cascinu, F. De Rosa, Roberta Depenni, Massimo Guidoboni, Giovanni Pellacani, Giovanni Ponti, Stefano Greco, Laura Ridolfi, Depenni, R., De Rosa, F., Greco, S., Ridolfi, L., Pellacani, G., Ponti, G., Cascinu, S., and Guidoboni, M.
Subjects: Oncology, Male, Cancer Research, number of metastasi, Kaplan-Meier Estimate, Pyridone, Oxime, 0302 clinical medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Oximes, 80 and over, dabrafenib/trametinib, LDH baseline level, metastatic melanoma, number of metastasis, prognosis, real-life setting, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Imidazoles, Italy, Melanoma, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasm Staging, Prognosis, Pyridones, Pyrimidinones, Treatment Outcome, Young Adult, 030212 general & internal medicine, Young adult, Trametinib, Pyrimidinone, education.field_of_study, General Medicine, Neoplasm Metastasi, 030220 oncology & carcinogenesis, medicine.drug, Human, medicine.medical_specialty, Metastatic melanoma, Prognosi, Population, Subgroup analysis, Follow-Up Studie, 03 medical and health sciences, Internal medicine, medicine, education, Imidazole, Antineoplastic Combined Chemotherapy Protocol, business.industry, Dabrafenib, medicine.disease, Neoplasm, Observational study, business
Abstract: Aim: This observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma. Patients & methods: Seventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included. Results: Median progression-free survival was 9 months (95% CI: 7–11) and median overall survival was 14 months (11–16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported. Conclusion: Dabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous ‘real life’ population comprising patients with adverse prognostic features.
Published: 2018

49. Possible delayed diagnosis and treatment of metastatic differentiated thyroid cancer by adopting the 2015 ATA guidelines

Author: Raffaele Giubbini, Mattia Bonacina, Elisabetta Cerudelli, Andrea Giustina, Rexhep Durmo, Maria Gazzilli, Anna Maria Formenti, Francesco Bertagna, Maria Beatrice Panarotto, Gherardo Mazziotti, Domenico Albano, Albano, D, Bertagna, F, Bonacina, M, Durmo, R, Cerudelli, E, Gazzilli, M, Panarotto, M, Formenti, A, Mazziotti, G, Giustina, A, Giubbini, R, Albano, D., Bertagna, F., Bonacina, M., Durmo, R., Cerudelli, E., Gazzilli, M., Panarotto, M. B., Formenti, A. M., Mazziotti, G., Giustina, A., and Giubbini, R.
Subjects: Male, Delayed Diagnosis, medicine.medical_treatment, Endocrinology, Diabetes and Metabolism, Disease, Iodine Radioisotopes, Iodine Radioisotope, 0302 clinical medicine, Endocrinology, Retrospective Studie, Whole Body Imaging, Neoplasm Metastasis, Thyroid cancer, Thyroid Neoplasm, Aged, 80 and over, Thyroid, Delayed Diagnosi, General Medicine, Middle Aged, Combined Modality Therapy, Neoplasm Metastasi, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Thyroidectomy, Female, Radiology, Human, Adult, Risk, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, Thyroglobulin, 03 medical and health sciences, Internal medicine, medicine, Humans, Thyroid Neoplasms, Retrospective Studies, Aged, business.industry, Cancer, Retrospective cohort study, medicine.disease, business
Abstract: ObjectiveAccording to the 2015 American Thyroid Association (ATA) guidelines, thyroid ablation by iodine-131 (I-131) therapy is absolutely recommended only in patients with high-risk differentiated thyroid cancer (DTC). Often distant metastases are not recognized early and they can stay silent for long time. The aim of our study was to retrospectively analyze the prevalence of metastatic disease before and after I-131 and to evaluate the influence of the new ATA guidelines in the management of DTC.MethodsWe retrospectively analyzed 140 patients showing distant metastases. All metastases were detected by whole-body scan after I-131 and confirmed by histology and/or other imaging modalities.ResultsIn 26/140 patients metastases were detected before I-131, while in 114/140 were discovered after I-131. Comparing patients with metastases detected before and after I-131, no differences were demonstrated considering age, sex, histotype, tumor size, multifocality of cancer and metastatic localization. Metastatic DTC discovered before radioiodine had higher thyroglobulin and received a higher radioiodine total activity and number of treatments. Considering patients with distant metastases, according to the 2015 ATA guidelines, 38 patients would have been categorized as high risk, 22 as low risk and 80 as intermediate risk. Among intermediate-risk patients, only in 25 cases (31%) I-131 treatment would have been appropriate according to 2015 ATA recommendations; in the remaining 56 cases (69%), I-131 would not have been recommended.ConclusionsAccording to the 2015 ATA guidelines, most of metastatic patients would not have been treated after surgery, with the risk of late diagnosis and delayed treatment.
Published: 2018

50. A single-institution retrospective analysis of metachronous and synchronous metastatic bronchial neuroendocrine tumors

Author: Eleonora Pisa, Antonio Ungaro, Francesca Spada, Giuseppe Badalamenti, Antonio Russo, Filippo de Marinis, Nicole Romentz, Lorenzo Spaggiari, Marta Peri, Chiara Maria Grana, Nicola Fazio, Roberto Gasparri, Edoardo Botteri, Peri, Marta, Botteri, Edoardo, Pisa, Eleonora, Marinis, Filippo De, Ungaro, Antonio, Spada, Francesca, Grana, Chiara Maria, Gasparri, Roberto, Spaggiari, Spaggiari, Romentz, Nicole, Badalamenti, Giuseppe, Russo, Antonio, and Fazio, Nicola
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Multivariate analysis, Settore MED/06 - Oncologia Medica, Population, Disease, 030204 cardiovascular system & hematology, Neuroendocrine tumors, Carcinoid tumor, Neoplasm metastasis, Neuroendocrine tumors (NETs), Recurrence, 03 medical and health sciences, 0302 clinical medicine, medicine, education, Lymph node, Survival analysis, Neoplasm metastasi, education.field_of_study, Lung, business.industry, medicine.disease, Clinical trial, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Original Article, Radiology, business
Abstract: Background: Broncho-pulmonary neuroendocrine tumors (bpNETs) are rare malignancies and there is no consensus on therapeutical management of metastatic disease and follow-up after radical resection. Methods: Clinical records of patients with a cytological or histological diagnosis of bpNETs and distant metastases (metachronous or synchronous), evaluated at the European Institute of Oncology between 1997 and 2014, were retrospectively analyzed. Data on patient demographics, pathology, imaging exams, surgical and non-surgical treatments were collected. P value descriptive data, uni- and multi-variate survival analysis were generated for all variables. Results: With a median follow-up of 53 [9–215] months, 61 patients with metachronous and 47 with synchronous metastases were analysed. The most common tool of first recurrence detection was computed tomography. Liver (67%), lymph node (25%), bone (22%) and lung (16%) were the most common sites of relapse. Median time to recurrence was 5 years. Median overall survival (OS) was 72 months for the whole population, with no significant difference between patients with synchronous and metachronous metastases. Age, bone metastases, liver metastases and Ki-67 as a continuous variable all significantly correlated with prognosis at the multivariate analysis. Conclusions: This is one of the largest, single-centre, series of metastatic bpNETs. Among patients with metachronous metastases the pattern of recurrences was heterogeneous as were the follow-up exams used to detect them. The results of our analysis may represent solid bases for designing prospective clinical trials in homogeneous settings of bpNETs.
Published: 2018

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