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56 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. 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

4. 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

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

Author: Jiao, W, Atwal, G, Polak, P, Karlic, R, Cuppen, E, Al-Shahrour, F, Bailey, P, Biankin, A, Boutros, P, Campbell, P, Chang, D, Cooke, S, Deshpande, V, Faltas, B, Faquin, W, Garraway, L, Getz, G, Grimmond, S, Haider, S, Hoadley, K, Kaiser, V, Kato, M, Kubler, K, Lazar, A, C. 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, E, Bartlett, J, Bartolome, J, Bassi, C, Bathe, O, Baumhoer, D, Bavi, P, Baylin, S, Bazant, W, Beardsmore, D, Beck, T, Behjati, S, Behren, A, Niu, B, Bell, C, Beltran, S, Benz, C, Berchuck, A, Bergmann, A, Bergstrom, E, Berman, B, Berney, D, Bernhart, S, Beroukhim, R, Berrios, M, Bersani, S, Bertl, J, Betancourt, M, Bhandari, V, Bhosle, S, Bieg, M, Bigner, D, Binder, H, Birney, E, Birrer, M, Biswas, N, Bjerkehagen, B, Bodenheimer, T, Boice, L, Bonizzato, G, De Bono, J, Boot, A, Bootwalla, M, Borg, A, Borkhardt, A, Boroevich, K, Borozan, I, Borst, C, Bosenberg, M, Bosio, M, Boultwood, J, Bourque, G, Bova, G, Bowen, D, Bowlby, R, Bowtell, D, Boyault, S, Boyce, R, Boyd, J, Brazma, A, Brennan, P, Brewer, D, Brinkman, A, Bristow, R, Broaddus, R, Brock, J, Brock, M, Broeks, A, Brooks, A, Brooks, D, Brors, B, Brunak, S, Bruxner, T, Bruzos, A, Buchanan, A, Buchhalter, I, Buchholz, C, Bullman, S, Burke, H, Burkhardt, B, Burns, K, Busanovich, J, Bustamante, C, Butler, A, Butte, A, Byrne, N, 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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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Experimental approaches for studying semaphorin signals in tumor growth and metastasis in mouse models

Author: Jonathan R. Terman, Moiso, Enrico, Accardo, Massimo, Tamagnone, Luca, Tamagnone, Luca (ORCID:0000-0002-2884-7946), Jonathan R. Terman, Moiso, Enrico, Accardo, Massimo, Tamagnone, Luca, and Tamagnone, Luca (ORCID:0000-0002-2884-7946)
Abstract: Tumor growth and metastatic dissemination are complex multistep processes. They clearly depend on the intrinsic behavior of cancer cells, but are remarkably influenced by a variety of stromal cells present in the tumor microenvironment, which include those implicated in tumor angiogenesis, as well as bone marrow-derived cells recruited from the circulation. Moreover, multiple molecular signals exchanged between cancer cells and non-neoplastic stromal cells control tumor growth and metastasis; notably, members of the semaphorin family are emerging players in this scenario. In vivo tumor models represent the best setting for studying metastatic tumor progression, as they allow recapitulating the contribution of multiple cell types and signaling molecules in a complex tissue context, subject to pathophysiological local and systemic responses, such as metabolic changes, hypoxia, necrosis, fibrosis, inflammation, and cytokine release. Here, we describe some experimental approaches based on murine models to study the role of semaphorin signaling in tumor growth and metastatic progression in vivo.
Published: 2017

15. Clinical Target Volume in Biliary Carcinoma: A Systematic Review of Pathological Studies

Author: Marinelli, Ilaria, Guido, Alessandra, Fuccio, Lorenzo, Farioli, Andrea, Panni, Valeria, Giaccherini, Lucia, Arcelli, Alessandra, Ercolani, Giorgio, Brandi, Giovanni, Cammelli, Silvia, Galuppi, Andrea, Macchia, Gabriella, Frakulli, Rezarta, Mattiucci, Gian Carlo, Cellini, Francesco, Buwenge, Milly, Renzulli, Matteo, Deodato, Francesco, Cilla, Savino, Valentini, Vincenzo, Tombolini, Vincenzo, Golfieri, Rita, Morganti, Alessio Giuseppe, Mattiucci, Gian C (ORCID:0000-0001-6500-0413), Cellini, Francesco (ORCID:0000-0002-2145-2300), Deodato, Francesco (ORCID:0000-0003-1276-5070), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), Morganti, Alessio G, Marinelli, Ilaria, Guido, Alessandra, Fuccio, Lorenzo, Farioli, Andrea, Panni, Valeria, Giaccherini, Lucia, Arcelli, Alessandra, Ercolani, Giorgio, Brandi, Giovanni, Cammelli, Silvia, Galuppi, Andrea, Macchia, Gabriella, Frakulli, Rezarta, Mattiucci, Gian Carlo, Cellini, Francesco, Buwenge, Milly, Renzulli, Matteo, Deodato, Francesco, Cilla, Savino, Valentini, Vincenzo, Tombolini, Vincenzo, Golfieri, Rita, Morganti, Alessio Giuseppe, Mattiucci, Gian C (ORCID:0000-0001-6500-0413), Cellini, Francesco (ORCID:0000-0002-2145-2300), Deodato, Francesco (ORCID:0000-0003-1276-5070), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), and Morganti, Alessio G
Abstract: Background/Aim: Radiotherapy is a treatment option for both adjuvant and neo-adjuvant settings for biliary tract cancer. Guidelines on the delineation of the target volume of lymph nodes are lacking; only generic indications are available, without specific recommendations for different primary tumour locations (e.g. intrahepatic, extrahepatic biliary tract or gallbladder cancer). The aim of this study was to systematically review available literature to provide recommendations on lymph node target volume delineation in patients with unresectable biliary tumour. Materials and Methods: A systematic search of electronic databases was performed up to July 2016. The primary outcome measure was the rate of lymph node involvement according to the location of primary biliary tumour. Sites with = 5% of nodal metastases were considered in the clinical target volume for radiotherapy planning. Results: Twelve studies (1075 patients) were included. The most frequent site of lymph node metastasis in intrahepatic biliary tree carcinoma was retroportal (61.1%, 95% confidence interval (CI)= 50.7-706%). Other frequently involved lymph nodes were along the hepatoduodenal ligament [ frequency=38.7%, 95% CI=31.0-47.0%], those along the common hepatic artery (17.0%, 95% CI=8.2-31.9%) and the hilar nodes (16.9%, 95% CI=13.2-21.4%). In extrahepatic biliary tree cancer, the most frequently involved lymph nodes were the pericholedochal (42.7%, 95% CI=33.8-52.1%) and those along the hepatoduodenal ligament (40.3%, 95% CI=32.4-48.8%). Other commonly involved nodal regions included retroportal lymph nodes (30.9%, 95% CI=23.0-40.1%), pancreaticoduodenal anterior and posterior nodes (30.1%, 95% CI=12.2-57.1%), those along the common hepatic artery (19.7%, 95% CI=11.8-31.0%) and para_aortic nodes (15.2%, 95% CI=8.0-27.0%). The most common site of metastases in gallbladder cancer were the pericholedochal nodes (25.2%, 95% CI=18.6-33.2%), those along the cystic duct (23%, 95% CI=16.6-30.8%), and ret
Published: 2017

16. Perinatal outcome in pregnant women with cancer: are there any effects of chemotherapy?

Author: Garofalo, Serafina, Degennaro, Valentina Anna, Salvi, Silvia, De Carolis, Maria Pia, Capelli, Giovanni, Ferrazzani, Sergio, De Carolis, Sara, Lanzone, Antonio, Garofalo, S., Degennaro, V. A., Salvi, S. (ORCID:0000-0001-7793-9612), De Carolis, M. P. (ORCID:0000-0003-2054-8228), Capelli, G., Ferrazzani, S. (ORCID:0000-0001-7382-2951), De Carolis, S. (ORCID:0000-0002-5160-7609), Lanzone, A. (ORCID:0000-0003-4119-414X), Garofalo, Serafina, Degennaro, Valentina Anna, Salvi, Silvia, De Carolis, Maria Pia, Capelli, Giovanni, Ferrazzani, Sergio, De Carolis, Sara, Lanzone, Antonio, Garofalo, S., Degennaro, V. A., Salvi, S. (ORCID:0000-0001-7793-9612), De Carolis, M. P. (ORCID:0000-0003-2054-8228), Capelli, G., Ferrazzani, S. (ORCID:0000-0001-7382-2951), De Carolis, S. (ORCID:0000-0002-5160-7609), and Lanzone, A. (ORCID:0000-0003-4119-414X)
Abstract: Cancer is the leading cause of death in women of reproductive age. During the last decades and especially in developed countries, the incidence of cancer is increasing dramatically, with an incidence of 1 in 1,000 pregnancies. This is mostly related to delay of pregnancy into the late reproductive years. The aim of this study was to investigate the outcome of pregnancy in women with diagnosis of cancer; in particular, neonatal morbidity and mortality, after in utero exposure to chemotherapy, were evaluated. A total of 59 singletons and one twin pregnancy complicated by cancer were followed at our tertiary centre over the last 15 years. A different treatment, based on surgery and/or chemotherapy in pregnancy or delayed to the postpartum period, was employed. There were 59 live births (97%), one foetal loss and one stillbirth at 28 weeks. The congenital malformation rate was 5% (n = 3). The rate of preterm birth was 83%. The mean birthweight and mean birthweight percentile were 2,098 g (740–3930) and 46 (7–93), respectively; 32% of neonates were small for gestational age (SGA). Dividing the population into treated or untreated with chemotherapy, the rate of SGA was not statistically significant different between the two groups. Our results showed that chemotherapy administered during the second trimester or later did not influence intrauterine foetal growth, but the high prevalence of SGA neonates in the two groups, exposed or not exposed to chemotherapy, suggests an influence of maternal cancer per se on foetal growth.
Published: 2017

17. European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma

Author: Gaujoux, S., Mihai, R., Carnaille, B., Dousset, B., Fiori, C., Porpiglia, F., Hellman, P., Iacobone, M., Kraimps, J. L., Donatini, G., Langenhuijsen, J., Lorenz, K., Mathonnet, M., Mirallié, E., Blanchard, C., van Dijkum, E. Nieveen, Raffaelli, Marco, Rayes, N., Sébag, F., Triponez, F., Valeri, A., Waldmann, J., Zinzindohoue, F., Raffaelli, Marco (ORCID:0000-0002-1259-2491), Gaujoux, S., Mihai, R., Carnaille, B., Dousset, B., Fiori, C., Porpiglia, F., Hellman, P., Iacobone, M., Kraimps, J. L., Donatini, G., Langenhuijsen, J., Lorenz, K., Mathonnet, M., Mirallié, E., Blanchard, C., van Dijkum, E. Nieveen, Raffaelli, Marco, Rayes, N., Sébag, F., Triponez, F., Valeri, A., Waldmann, J., Zinzindohoue, F., and Raffaelli, Marco (ORCID:0000-0002-1259-2491)
Abstract: Background: Radical surgery provides the best chance of cure for adrenocortical carcinoma (ACC), but perioperative surgical care for these patients is yet to be standardized. Methods: A working group appointed jointly by ENSAT and ESES used Delphi methodology to produce evidence-based recommendations for the perioperative surgical care of patients with ACC. Papers were retrieved from electronic databases. Evidence and recommendations were classified according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, and were discussed until consensus was reached within the group. Results: Twenty-five recommendations for the perioperative surgical care of patients with ACC were formulated. The quality of evidence is low owing to the rarity of the disease and the lack of prospective surgical trials. Multi-institutional prospective cohort studies and prospective RCTs are urgently needed and should be strongly encouraged. Conclusion: The present evidence-based recommendations provide comprehensive advice on the optimal perioperative care for patients undergoing surgery for ACC.
Published: 2017

18. Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells

Author: Talarico, G, Orecchioni, S, Dallaglio, K, Reggiani, F, Mancuso, P, Calleri, A, Gregato, G, Labanca, V, Rossi, T, Noonan, D, Albini, A, Bertolini, F, Noonan, DM, Talarico, G, Orecchioni, S, Dallaglio, K, Reggiani, F, Mancuso, P, Calleri, A, Gregato, G, Labanca, V, Rossi, T, Noonan, D, Albini, A, Bertolini, F, and Noonan, DM
Abstract: Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.
Published: 2016

19. Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells

Author: Talarico, G, Orecchioni, S, Dallaglio, K, Reggiani, F, Mancuso, P, Calleri, A, Gregato, G, Labanca, V, Rossi, T, Noonan, D, Albini, A, Bertolini, F, Noonan, DM, Talarico, G, Orecchioni, S, Dallaglio, K, Reggiani, F, Mancuso, P, Calleri, A, Gregato, G, Labanca, V, Rossi, T, Noonan, D, Albini, A, Bertolini, F, and Noonan, DM
Abstract: Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.
Published: 2016

20. Microwave ablation of hepatic tumors with a third generation system: Loco-regional efficacy in a prospective cohort study with intermediate term follow-up

Author: Meloni, M, Galimberti, S, Dietrich, C, Lazzaroni, S, Goldberg, S, Abate, A, Sironi, S, Andreano, A, GALIMBERTI, STEFANIA, SIRONI, SANDRO, ANDREANO, ANITA, Meloni, M, Galimberti, S, Dietrich, C, Lazzaroni, S, Goldberg, S, Abate, A, Sironi, S, Andreano, A, GALIMBERTI, STEFANIA, SIRONI, SANDRO, and ANDREANO, ANITA
Abstract: Purpose: To evaluate the safety and intermediate-term efficacy of percutaneous microwave ablation (MWA) in primary and secondary liver tumors using a third generation MWA device, under ultrasound guidance. Patients and methods: Sixty-two patients (median age 74 years, 73 % males) with 69 liver tumors were enrolled in this prospective observational study. Forty-seven patients (76 %) had hepatocellular carcinoma (HCC) and 15 (24 %) metastases. Median follow-up was 3.6 years. Results: Median tumor diameter at contrast enhanced computed tomography was 23 mm (I-III quartiles, 18 - 31 mm). All procedures were performed percutaneously using a 2.45 GHz generator. Median ablation time was 10 minutes (I-III quartiles, 10 - 14 minutes). A single percutaneous antenna insertion was performed for 56/69 (81 %) of the tumors. Technical success was obtained in all tumors. Primary efficacy at 24 hours was achieved in 68/69 (99 %) tumors. The overall one-year cumulative local tumor progression rate was 15.1 % (95 % CI, 7.7 - 24.8 %) with no significant difference between HCC and metastases (p = 0.26). There was one procedure-related mortality (1.6 %) and one major bleeding (1.6 %). Conclusion: Microwave ablation is a valid option for thermal ablation of HCC and liver metastases with comparable complication rate to other local ablative procedures.
Published: 2016

21. Intraoperative ultrasound: A review on its role in liver surgery for primitive and metastatic tumors

Author: Garancini, M, Gianotti, L, Delitala, A, Romano, F, Degrate, L, Giardini, V, GARANCINI, MATTIA, GIANOTTI, LUCA VITTORIO, DELITALA, ALBERTO, ROMANO, FABRIZIO, DEGRATE, LUCA, GIARDINI, VITTORIO, Garancini, M, Gianotti, L, Delitala, A, Romano, F, Degrate, L, Giardini, V, GARANCINI, MATTIA, GIANOTTI, LUCA VITTORIO, DELITALA, ALBERTO, ROMANO, FABRIZIO, DEGRATE, LUCA, and GIARDINI, VITTORIO
Abstract: Intra-operative ultrasound is an invaluable tool in hepatic surgery, either for restaging either as a guidance during resection of liver neoplasms. Nowadays, intraoperative ultrasound is still considered the most accurate diagnostic technique for detecting focal liver lesions in both hepatocellular carcinoma and colorectal liver metastases, which represent the most frequent indication for liver resection. Moreover, the use of ultrasound guidance is mandatory for planning the surgical strategy, deciding the exact resection plane and during the parenchymal transection, in order to respect the surrounding vessels and biliary structures. Every surgical procedure performed on the liver is strictly dependent from the knowledge of the liver anatomy and from the ultrasounds; definitely in liver surgery the ultrasounds represent the link between the surgical anatomy and the surgical intervention. To maximize the benefit, intraoperative ultrasound should be carried out by the surgeon himself in the perspective of surgical guidance. Here is presented an updated and extensive review of the role of ultrasounds in liver surgery, describing and analyzing the possible applications of this invaluable tool from the surgeon's point of view. Technical aspects, principles of intraoperative re-staging and ultrasound-guided liver resection, application and possible advantages of laparoscopic ultrasound and new perspective in intraoperative study of the liver are discussed.
Published: 2016

22. Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer

Author: Loupakis, Fotio, Moretto, Roberto, Aprile, Giuseppe, Muntoni, Marta, Cremolini, Chiara, Iacono, Donatella, Casagrande, Mariaelena, Ferrari, Laura, Salvatore, Lisa, Schirripa, Marta, Rossini, Daniele, De Maglio, Giovanna, Fasola, Gianpiero, Calvetti, Lorenzo, Pilotto, Sara, Carbognin, Luisa, Fontanini, Gabriella, Tortora, Giampaolo, Falcone, Alfredo, Sperduti, Isabella, Bria, Emilio, Bria, Emilio (ORCID:0000-0002-2333-704X), Loupakis, Fotio, Moretto, Roberto, Aprile, Giuseppe, Muntoni, Marta, Cremolini, Chiara, Iacono, Donatella, Casagrande, Mariaelena, Ferrari, Laura, Salvatore, Lisa, Schirripa, Marta, Rossini, Daniele, De Maglio, Giovanna, Fasola, Gianpiero, Calvetti, Lorenzo, Pilotto, Sara, Carbognin, Luisa, Fontanini, Gabriella, Tortora, Giampaolo, Falcone, Alfredo, Sperduti, Isabella, Bria, Emilio, and Bria, Emilio (ORCID:0000-0002-2333-704X)
Abstract: Background:In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features.Methods:Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated.Results:In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05-19.92), female gender (OR: 2.90, 95% CI 1.14-7.37) and mucinous histology (OR: 4.95, 95% CI 1.90-12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2%; specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy.Conclusions:Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.
Published: 2016

23. Low-dose radiotherapy and concurrent FOLFIRI-bevacizumab: A Phase II study

Author: Morganti, Alessio Giuseppe, Cellini, Francesco, Mignogna, Samantha, Padula, Gilbert Da, Caravatta, Luciana, Deodato, Francesco, Picardi, Vincenzo, Macchia, Gabriella, Cilla, Savino, Buwenge, Milly, Lullo, Liberato DI, Gambacorta, Maria Antonietta, Balducci, Mario, Mattiucci, Gian Carlo, Autorino, Rosa, Valentini, Vincenzo, Cellini, Francesco (ORCID:0000-0002-2145-2300), Deodato, Francesco (ORCID:0000-0003-1276-5070), Gambacorta, Maria Antonietta (ORCID:0000-0001-5455-8737), Balducci, Mario (ORCID:0000-0003-0398-9726), Mattiucci, Gian Carlo (ORCID:0000-0001-6500-0413), Valentini, Vincenzo (ORCID:0000-0003-4637-6487), Morganti, Alessio Giuseppe, Cellini, Francesco, Mignogna, Samantha, Padula, Gilbert Da, Caravatta, Luciana, Deodato, Francesco, Picardi, Vincenzo, Macchia, Gabriella, Cilla, Savino, Buwenge, Milly, Lullo, Liberato DI, Gambacorta, Maria Antonietta, Balducci, Mario, Mattiucci, Gian Carlo, Autorino, Rosa, Valentini, Vincenzo, Cellini, Francesco (ORCID:0000-0002-2145-2300), Deodato, Francesco (ORCID:0000-0003-1276-5070), Gambacorta, Maria Antonietta (ORCID:0000-0001-5455-8737), Balducci, Mario (ORCID:0000-0003-0398-9726), Mattiucci, Gian Carlo (ORCID:0000-0001-6500-0413), and Valentini, Vincenzo (ORCID:0000-0003-4637-6487)
Abstract: Aims: Low-dose radiation therapy (LDRT) can increase biological efficacy of chemotherapy. This Phase II trial evaluates LDRT plus FOLFIRI-bevacizumab (FOLFIRI-B) in metastatic colorectal cancer. Materials & methods: Primary objective: raising the clinical complete response rate from 5 to 25%. Secondary objectives: toxicity, progression-free survival. Patients underwent 12 FOLFIRI-B cycles plus two daily LDRT fractions (20 cGy/6 h interval) on each cycle. Statistical analysis was planned on 18 patients. Results: Results on 18 patients are reported. Specifically considering irradiated sites: 15/18 patients had a partial (11/18) or complete (4/18) response. Among 11 partial responders, three became a pathological CR after surgery. Grade 3-4 toxicity was recorded in two patients (11.1%). At median follow-up of 30 months (range: 8-50), 7/18 patients progressed in irradiated sites. Conclusion: Seven out of 18 patients (38.9%) had clinical or pathological CR in lesions treated with LDRT. Further studies on this newer treatment modality seem justified.
Published: 2016

24. Cancer stem cells and the tumor microenvironment: Interplay in tumor heterogeneity

Author: Albini, A, Bruno, A, Gallo, C, Pajardi, G, Noonan, D, Dallaglio, K, Albini, Adriana, Bruno, Antonino, Gallo, Cristina, Pajardi, Giorgio, Noonan, Douglas M., Dallaglio, Katiuscia, Albini, A, Bruno, A, Gallo, C, Pajardi, G, Noonan, D, Dallaglio, K, Albini, Adriana, Bruno, Antonino, Gallo, Cristina, Pajardi, Giorgio, Noonan, Douglas M., and Dallaglio, Katiuscia
Abstract: Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.
Published: 2015

25. Cancer stem cells and the tumor microenvironment: Interplay in tumor heterogeneity

Author: Albini, A, Bruno, A, Gallo, C, Pajardi, G, Noonan, D, Dallaglio, K, Albini, Adriana, Bruno, Antonino, Gallo, Cristina, Pajardi, Giorgio, Noonan, Douglas M., Dallaglio, Katiuscia, Albini, A, Bruno, A, Gallo, C, Pajardi, G, Noonan, D, Dallaglio, K, Albini, Adriana, Bruno, Antonino, Gallo, Cristina, Pajardi, Giorgio, Noonan, Douglas M., and Dallaglio, Katiuscia
Abstract: Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a "proliferating" cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.
Published: 2015

26. Portal vein-circulating tumor cells predict liver metastases in patients with resectable pancreatic cancer

Author: Bissolati, M, Sandri, M, Burtulo, G, Zorzino, L, Balzano, G, Braga, M, Bissolati, Massimiliano, Sandri, Maria Teresa, Burtulo, Giovanni, Zorzino, Laura, Balzano, Gianpaolo, Bissolati, M, Sandri, M, Burtulo, G, Zorzino, L, Balzano, G, Braga, M, Bissolati, Massimiliano, Sandri, Maria Teresa, Burtulo, Giovanni, Zorzino, Laura, and Balzano, Gianpaolo
Abstract: Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch® system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45 %) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC-negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC-negative patients (53 vs. 8 %, p = 0.038). CTCs were found in 45 % of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery.
Published: 2015

27. Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF-mutated human melanoma cells

Author: Tabolacci, Claudio, Cordella, Martina, Turcano, Lorenzo, Rossi, Stefania, Lentini, Alessandro, Mariotti, Sabrina, Nisini, Roberto, Sette, Giovanni, Eramo, Adriana, Piredda, Lucia, De Maria Marchiano, Ruggero, Facchiano, Francesco, Beninati, Simone, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Tabolacci, Claudio, Cordella, Martina, Turcano, Lorenzo, Rossi, Stefania, Lentini, Alessandro, Mariotti, Sabrina, Nisini, Roberto, Sette, Giovanni, Eramo, Adriana, Piredda, Lucia, De Maria Marchiano, Ruggero, Facchiano, Francesco, Beninati, Simone, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
Abstract: Aim of this study was to extend the knowledge on the antineoplastic effect of aloe-emodin (AE), a natural hydroxyanthraquinone compound, both in metastatic human melanoma cell lines and in primary stem-like cells (melanospheres). Treatment with AE caused reduction of cell proliferation and induction of SK-MEL-28 and A375 cells differentiation, characterized by a marked increase of transamidating activity of transglutaminase whose expression remained unmodified. In vitro antimetastatic property of AE was evaluated by adhesion and Boyden chamber invasion assays. The effect of AE on melanoma cytokines/chemokines production was determined by a multiplex assay: interestingly AE showed an immunomodulatory activity through GM-CSF and IFN-Î3 production. We report also that AE significantly reduced the proliferation, stemness and invasive potential of melanospheres. Moreover, AE treatment significantly enhanced dabrafenib (a BRAF inhibitor) antiproliferative activity in BRAF mutant cell lines. Our results confirm that AE possesses remarkable antineoplastic properties against melanoma cells, indicating this anthraquinone as a promising agent for differentiation therapy of cancer, or as adjuvant in chemotherapy and targeted therapy. Further, its mechanisms of action support a potential efficacy of AE treatment to counteract resistance of BRAF-mutated melanoma cells to target therapy.
Published: 2015

28. Role of gonadotropin-releasing hormone analogues in metastatic male breast cancer: Results from a pooled analysis

Author: Di Lauro, Luigi, Pizzuti, Laura, Barba, Maddalena, Sergi, Domenico, Sperduti, Isabella, Mottolese, Marcella, Amoreo, Carla Azzurra, Belli, Franca, Vici, Patrizia, Speirs, Valerie, Santini, Daniele, De Maria Marchiano, Ruggero, Maugeri-Saccà, Marcello, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Di Lauro, Luigi, Pizzuti, Laura, Barba, Maddalena, Sergi, Domenico, Sperduti, Isabella, Mottolese, Marcella, Amoreo, Carla Azzurra, Belli, Franca, Vici, Patrizia, Speirs, Valerie, Santini, Daniele, De Maria Marchiano, Ruggero, Maugeri-Saccà, Marcello, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
Abstract: Background: Male breast cancer is a rare malignancy. Despite the lack of prospectively generated data from trials in either the adjuvant or metastatic setting, patients are commonly treated with hormone therapies. Much controversy exists over the use of gonadotropin-releasing hormone analogues in metastatic male breast cancer patients. We conducted this study to provide more concrete ground on the use of gonadotropin-releasing hormone analogues in this setting. Methods: We herein present results from a pooled analysis including 60 metastatic male breast cancer patients treated with either an aromatase inhibitor or cyproterone acetate as a monotherapy (23 patients) or combined with a gonadotropin-releasing hormone analogue (37 patients). Results: Overall response rate was 43.5 % in patients treated with monotherapy and 51.3 % with combination therapy (p = 0.6). Survival outcomes favored combination therapy in terms of median progression-free survival (11.6 months versus 6 months; p = 0.05), 1-year progression-free survival rate (43.2 % versus 21.7 %; p = 0.05), median overall survival (29.7 months versus 22 months; p = 0.05), and 2-year survival rate (64.9 % versus 43.5 %; p = 0.05). Conclusions: In metastatic male breast cancer patients, the combined use of gonadotropin-releasing hormone analogues and aromatase inhibitors or antiandrogens seems to be associated with greater efficacy, particularly in terms of survival outcomes, compared with monotherapy. Collectively, these results encourage considering these agents in the metastatic setting.
Published: 2015

29. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells

Author: Bartucci, M., Dattilo, R., Moriconi, C., Pagliuca, Alfredo, Mottolese, M., Federici, G., Di Benedetto, A., Todaro, M., Stassi, G., Sperati, F., Amabile, M. I., Pilozzi, E., Patrizii, M., Biffoni, M., Maugeri-Saccà, M., Piccolo, S., De Maria Marchiano, Ruggero, Pagliuca, A., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Bartucci, M., Dattilo, R., Moriconi, C., Pagliuca, Alfredo, Mottolese, M., Federici, G., Di Benedetto, A., Todaro, M., Stassi, G., Sperati, F., Amabile, M. I., Pilozzi, E., Patrizii, M., Biffoni, M., Maugeri-Saccà, M., Piccolo, S., De Maria Marchiano, Ruggero, Pagliuca, A., and De Maria Marchiano, R. (ORCID:0000-0003-2255-0583)
Abstract: Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
Published: 2015

30. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells

Author: Bartucci, M, Dattilo, R, Moriconi, C, Pagliuca, A, Mottolese, M, Federici, G, Benedetto, A. Di, Todaro, M, Stassi, G, Sperati, F, Amabile, M. I, Pilozzi, E, Patrizii, M, Biffoni, M, Maugeri Saccà, M, Piccolo, Salvatore, De Maria Marchiano, Ruggero, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Bartucci, M, Dattilo, R, Moriconi, C, Pagliuca, A, Mottolese, M, Federici, G, Benedetto, A. Di, Todaro, M, Stassi, G, Sperati, F, Amabile, M. I, Pilozzi, E, Patrizii, M, Biffoni, M, Maugeri Saccà, M, Piccolo, Salvatore, De Maria Marchiano, Ruggero, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
Abstract: Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
Published: 2015

31. KRAS early testing: Consensus initiative and cost-effectiveness evaluation for metastatic colorectal patients in an italian setting

Author: Barone, C, Pinto, C, Normanno, N, Capussotti, L, Cognetti, F, Falcone, A, Mantovani, L, Barone, C, Pinto, C, Normanno, N, Capussotti, L, Cognetti, F, Falcone, A, and Mantovani, L
Abstract: KRAS testing is relevant for the choice of the most appropriate first-line therapy of metastatic colorectal cancer (CRC). Strategies for preventing unequal access to the test should be implemented, but their relevance in the practice is related to economic sustainability. The study adopted the Delphi technique to reach a consensus on several topics. Issues related to execution of KRAS testing were identified by an expert's board and proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The emerging proposal was evaluated by decision analyses models employed by technology assessment agencies in order to assess cost-effectiveness. Alternative therapeutic strategies included most commonly used chemotherapy regimens alone or in combination with cetuximab or bevacizumab. The survey indicated that time interval for obtaining KRAS test should not exceed 15 days, 10 days being an optimal interval. To assure the access to proper treatment, a useful strategy should be to anticipate the test after radical resection in patients at high risk of relapse. Early KRAS testing in high risk CRC patients generates incremental cost-effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained. In extensive sensitivity analyses ICER's were always below 15,000 Euro per QALY gained, far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy. In metastatic CRC a time interval higher than 15 days for result of KRAS testing limits access to therapeutic choices. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability and cost-effectiveness profile of cetuximab in first-line mCRC. Early KRAS testing may prevent this inequality in high-risk patients, whether they develop metastases, and is a cost-effective strategy. Based on these results, present joined recommendations of Italian societies of Oncology and Pathology sho
Published: 2014

32. Effectiveness of trastuzumab in first-line her2+ metastatic breast cancer after failure in adjuvant setting: A controlled cohort study

Author: Negri, E, Zambelli, A, Franchi, M, Rossi, M, Bonifazi, M, Corrao, G, Moja, L, Zocchetti, C, La Vecchia, C, La Vecchia, C., FRANCHI, MATTEO, CORRAO, GIOVANNI, Negri, E, Zambelli, A, Franchi, M, Rossi, M, Bonifazi, M, Corrao, G, Moja, L, Zocchetti, C, La Vecchia, C, La Vecchia, C., FRANCHI, MATTEO, and CORRAO, GIOVANNI
Abstract: Background. The evidence supporting the use of trastuzumab (T) in a metastatic setting comes from studies that included (almost) only patients who never received prior T. We investigated the effectiveness of T as first-line therapy for metastatic breast cancer (mBC) in women previously treated with T in the adjuvant setting.Materials and Methods. By using record linkage of five administrative health care databases of Lombardy, Italy, we identified 2,046women treated with T for early breast cancer (eBC) in 2006-l2009, 96 of whom developed a metastasis and were retreated with T in first-line treatment for mBC (treatment group).We compared the overall survival (OS) of these women with that of 197 women treated with T in firstline treatment for mBC, who were treated with therapies other than T for early disease (control group).We computed Kaplan-Meier 2-year OS and used a proportional hazard model to estimate the multivariate hazard ratio (HR) of death in the intervention group compared with the control group, adjusted by age, use of endocrine therapy, and site of metastasis.Results. Two-year OS was 60.0% in the treatment group and 59.5% in the control group. The adjusted HR of death in the treatment group compared with the control group was 0.79 (95% confidence interval, 0.50–1.26).Conclusion. Our data provide convincing evidence that the outcome of women receiving first-line T treatment for mBC after T failure in the adjuvant setting is comparable to that of women not receiving T for eBC. These data are of specific interest, given the unavailability of data from randomized clinical trials.
Published: 2014

33. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases

Author: Aurilio, G, Disalvatore, D, Pruneri, G, Bagnardi, V, Viale, G, Curigliano, G, Adamoli, L, Munzone, E, Sciandivasci, A, De Vita, F, Goldhirsch, A, Nolè, F, Nolè, F., BAGNARDI, VINCENZO, Aurilio, G, Disalvatore, D, Pruneri, G, Bagnardi, V, Viale, G, Curigliano, G, Adamoli, L, Munzone, E, Sciandivasci, A, De Vita, F, Goldhirsch, A, Nolè, F, Nolè, F., and BAGNARDI, VINCENZO
Abstract: Background The discordance in oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status between primary and recurrent breast cancer is being intensively investigated and a large amount of data have been produced. However, results from different studies are heterogeneous and often conflicting. To highlight this issue, a meta-analysis of published data was performed. Methods A literature search was performed using Medline, and all the studies published from 1983 to 2011 comparing changes in ER, PgR and/or HER2 status in patients with matched breast primary and recurrent tumours were included. We used random-effects models to estimate pooled discordance proportions. Results We selected 48 articles, mostly reporting retrospective studies. Thirty-three, 24 and 31 articles were focused on ER, PgR and HER2 changes, respectively. A total of 4200, 2739 and 2987 tumours were evaluated for ER, PgR and HER2 discordance, respectively. The heterogeneity between study-specific discordance proportions was high for ER (I2 = 91%, p < 0.0001), PgR (I2 = 79%, p < 0.0001) and HER2 (I2 = 77%, p < 0.0001). Pooled discordance proportions were 20% (95% confidence interval (CI): 16-35%) for ER, 33% (95% CI: 29-38%) for PgR and 8% (95% CI: 6-10%) for HER2. Pooled proportions of tumours shifting from positive to negative and from negative to positive were 24% and 14% for ER (p = 0.0183), respectively. The same figures were 46% and 15% for PgR (p < 0.0001), and 13% and 5% for HER2 (p = 0.0004). Conclusion Our findings strengthen the concept that changes in receptor expression may occur during the natural history of breast cancer, suggesting clinical implications and a possible impact on treatment choice. © 2013 Elsevier Ltd. All rights reserved.
Published: 2014

34. Secondary analyses from a randomized clinical trial: age as the key prognostic factor in endometrial carcinoma

Author: Benedetti Panici, P, Basile, S, Salerno, M, Di Donato, V, Marchetti, C, Perniola, G, Palagiano, A, Perutelli, A, Maneschi, F, Lissoni, A, Signorelli, M, Scambia, G, Tateo, S, Mangili, G, Katsaros, D, Campagnutta, E, Donadello, N, Greggi, S, Melpignano, M, Raspagliesi, F, Cormio, G, Grassi, R, Franchi, M, Giannarelli, D, Fossati, R, Torri, V, Crocè, C, Mangioni, C, Mangioni, C., LISSONI, ANDREA ALBERTO, Benedetti Panici, P, Basile, S, Salerno, M, Di Donato, V, Marchetti, C, Perniola, G, Palagiano, A, Perutelli, A, Maneschi, F, Lissoni, A, Signorelli, M, Scambia, G, Tateo, S, Mangili, G, Katsaros, D, Campagnutta, E, Donadello, N, Greggi, S, Melpignano, M, Raspagliesi, F, Cormio, G, Grassi, R, Franchi, M, Giannarelli, D, Fossati, R, Torri, V, Crocè, C, Mangioni, C, Mangioni, C., and LISSONI, ANDREA ALBERTO
Abstract: Objective The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. Study Design Survival outcomes of trial patients were analyzed in relation to age (>65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. Results Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in >65 years and >65 years patients, respectively, P <.0001; 5-y CSS 93.8% and 83.5% in >65 years and >65 years patients, respectively, P =.003). Among women >65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients (P =.009 and P =.002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients (P =.55 and P =.58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. Conclusion Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis
Published: 2014

35. Metabolic impact of partial volume correction of [18F]FDG PET-CT oncological studies on the assessment of tumor response to treatment

Author: Stefano, A, Gallivanone, F, Messa, M, Gilardi, M, Castiglioni, I, Castiglioni, I., MESSA, MARIA CRISTINA, GILARDI, MARIA CARLA, Stefano, A, Gallivanone, F, Messa, M, Gilardi, M, Castiglioni, I, Castiglioni, I., MESSA, MARIA CRISTINA, and GILARDI, MARIA CARLA
Abstract: AIM: The aim of this work is to evaluate the metabolic impact of Partial Volume Correction (PVC) on the measurement of the Standard Uptake Value (SUV) from [18F]FDG PET-CT oncological studies for treatment monitoring purpose. METHODS: Twenty-nine breast cancer patients with bone lesions (42 lesions in total) underwent [18F]FDG PET-CT studies after surgical resection of breast cancer primitives, and before (PET-I) and after (PET-II) chemotherapy and hormone treatment. PVC of bone lesion uptake was performed on the two [18F]FDG PET-CT studies, using a method based on Recovery Coefficients (RC) and on an automatic measurement of lesion metabolic volume. Body-weight average SUV was calculated for each lesion, with and without PVC. The accuracy, reproducibility, clinical feasibility and the metabolic impact on treatment response of the considered PVC method was evaluated. RESULTS: The PVC method was found clinically feasible in bone lesions, with an accuracy of 93% for lesion sphere-equivalent diameter >1 cm. Applying PVC, average SUV values increased, from 7% up to 154% considering both PET-I and PET-II studies, proving the need of the correction. As main finding, PVC modified the therapy response classification in 6 cases according to EORTC 1999 classification and in 5 cases according to PERCIST 1.0 classification. CONCLUSION: PVC has an important metabolic impact on the assessment of tumor response to treatment by [18F]FDG PET-CT oncological studies.
Published: 2014

36. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis

Author: Todaro, Matilde, Gaggianesi, Miriam, Catalano, Veronica, Benfante, Antonina, Iovino, Flora, Biffoni, Mauro, Apuzzo, Tiziana, Sperduti, Isabella, Volpe, Silvia, Cocorullo, Gianfranco, Gulotta, Gaspare, Dieli, Francesco, De Maria Marchiano, Ruggero, Stassi, Giorgio, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Todaro, Matilde, Gaggianesi, Miriam, Catalano, Veronica, Benfante, Antonina, Iovino, Flora, Biffoni, Mauro, Apuzzo, Tiziana, Sperduti, Isabella, Volpe, Silvia, Cocorullo, Gianfranco, Gulotta, Gaspare, Dieli, Francesco, De Maria Marchiano, Ruggero, Stassi, Giorgio, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
Abstract: Cancer stem cells drive tumor formation and metastasis, but how they acquire metastatic traits is not well understood. Here, we show that all colorectal cancer stem cells (CR-CSCs) express CD44v6, which is required for their migration and generation of metastatic tumors. CD44v6 expression is low in primary tumors but demarcated clonogenic CR-CSC populations. Cytokines hepatocyte growth factor (HGF), osteopontin (OPN), and stromal-derived factor 1Î± (SDF-1), secreted from tumor associated cells, increase CD44v6 expression in CR-CSCs by activating the Wnt/Î2-catenin pathway, which promotes migration and metastasis. CD44v6- progenitor cells do not give rise to metastatic lesions but, when treated with cytokines, acquire CD44v6 expression and metastatic capacity. Importantly, phosphatidylinositol 3-kinase (PI3K) inhibition selectively killed CD44v6 CR-CSCs and reduced metastatic growth. In patient cohorts, low levels of CD44v6 predict increased probability of survival. Thus, the metastatic process in colorectal cancer is initiated by CSCs through the expression of CD44v6, which is both a functional biomarker and therapeutic target. Â© 2014 Elsevier Inc.
Published: 2014

37. Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma

Author: Castelli, C, Tazzari, M, Negri, T, Vergani, B, Rivoltini, L, Stacchiotti, S, Pilotti, S, Castelli, C, Tazzari, M, Negri, T, Vergani, B, Rivoltini, L, Stacchiotti, S, and Pilotti, S
Abstract: Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma and the clinical management of patients with unresectable, metastatic disease is still challenging. ASPS expresses an array of potentially therapeutically targetable, angiogenesis-related molecules and, importantly, it has a distinctive angiogenic phenotype marked by a peculiar tumor-associated vasculature. Several studies, conducted in transgenic mouse models and in a large variety of human tumors of different histotype, clearly proved the substantial contribution of tumor-infiltrating myeloid cells, such as myeloid derived suppressor cells, monocytes and macrophages, in the formation and maintenance of abnormal blood vessels in tumors. By immunohistochemistry we thus explored the presence and the distribution of cells expressing myeloid markers in the inflammatory infiltrate of surgical treated metastatic ASPS. Indeed, we found that myeloid cells expressing CD14 and CD163 markers constitute the prominent cells in the inflammatory infiltrate of ASPS. These macrophage-like cells form a network surrounding the endothelial cells, or, interspersed in the tumor nest, they keep deep contact with tumor cells. In this commentary, we discussed our findings in relation to the recently published paper by Kummar and colleagues reporting the clinical and molecular results of a phase II clinical trial in patients with unresectable, metastatic ASPS treated with the anti-angiogenic drug cediranib, targeting the VEGFR-1,-2,-3 tyrosine kinases. Â© 2013 Castelli et al.; licensee BioMed Central Ltd.
Published: 2013

38. Obesity increases the incidence of distant metastases in oestrogen receptor-negative human epidermal growth factor receptor 2-positive breast cancer patients

Author: Mazzarella, L, Disalvatore, D, Bagnardi, V, Rotmensz, N, Galbiati, D, Caputo, S, Curigliano, G, Pelicci, P, Pelicci, P., BAGNARDI, VINCENZO, Mazzarella, L, Disalvatore, D, Bagnardi, V, Rotmensz, N, Galbiati, D, Caputo, S, Curigliano, G, Pelicci, P, Pelicci, P., and BAGNARDI, VINCENZO
Abstract: Background: Obesity is a major negative determinant of breast cancer outcome. However, there are contrasting data on the differential impact of obesity on specific breast cancer subtypes. In particular, very little is known on human epidermal growth factor receptor 2-positive (HER2+) tumours. Patients and methods: We assessed the prognostic role of increased body mass index (BMI) on a consecutive series of non-metastatic HER2+ patients treated at our institution before the introduction of adjuvant Trastuzumab. We separately analysed oestrogen receptor-positive (ER+) and -negative (ER-) HER2+ cases. Results: In ER-/HER2+ tumours we observed a significantly worse overall survival (Hazard ratio (HR) 1.79, p-value 0.041) and cumulative incidence of distant metastases (HR 2.03, p-value 0.019) in obese (BMI > 30) versus normal/underweight (BMI < 25) patients. Local relapses appeared to be non-significantly reduced in obese patients, masking the overall effect on disease-free survival. Outcome in ER+ tumours, instead, was not significantly different between BMI groups. Conclusions: Obesity significantly correlates with worse overall survival and cumulative incidence of distant metastases in ER-/HER2 positive breast cancer. Differences in the biology of breast tumours may determine individual susceptibility to obesity. The biology of the underlying tumour should be taken into account in the design of dietary intervention trials in breast cancer. © 2013 Elsevier Ltd. All rights reserved.
Published: 2013

39. Lung cancer in pregnancy: report of nine cases from an international collaborative study

Author: Boussios, S, Han, S, Fruscio, R, Halaska, M, Ottevanger, P, Peccatori, F, Koubková, L, Pavlidis, N, Amant, F, Amant, F., FRUSCIO, ROBERT, Boussios, S, Han, S, Fruscio, R, Halaska, M, Ottevanger, P, Peccatori, F, Koubková, L, Pavlidis, N, Amant, F, Amant, F., and FRUSCIO, ROBERT
Abstract: Lung cancer is an uncommon diagnosis during pregnancy. The combination of smoking in young women, increased maternal age during pregnancy, and increasing incidence of lung cancer worldwide may cause an increase of pregnancy associated lung cancer. The aim of this study was to describe all cases of lung cancer during pregnancy, registered in the international Cancer in Pregnancy registration study (CIP study; www.cancerinpregnancy.org).
Published: 2013

40. Role of 18F-FDG PET in the management of gestational trophoblastic neoplasia

Author: Mapelli, P, Mangili, G, Picchio, M, Gentile, C, Rabaiotti, E, Giorgione, V, Spinapolice, E, Gianolli, L, Messa, M, Candiani, M, MESSA, MARIA CRISTINA, Candiani, M., Mapelli, P, Mangili, G, Picchio, M, Gentile, C, Rabaiotti, E, Giorgione, V, Spinapolice, E, Gianolli, L, Messa, M, Candiani, M, MESSA, MARIA CRISTINA, and Candiani, M.
Abstract: Gestational trophoblastic neoplasia (GTN) is a rare and aggressive tumour that is usually sensitive to chemotherapy. The usefulness of conventional imaging modalities in evaluating treatment response is limited, mainly due to the difficulty in differentiating between residual tumour tissue and necrosis. The aim of the present study was to evaluate the role of FDG PET or PET/CT in primary staging and in monitoring treatment efficacy. The effect of FDG PET and combined PET/CT on the management of patients with GTN was also evaluated comparing the differences between standard treatments based on conventional imaging and alternative treatments based on PET.
Published: 2013

41. Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations

Author: Silvestri, Alessandra, Calvert, Valerie, Belluco, Claudio, Lipsky, Michael, De Maria Marchiano, Ruggero, Deng, Jianghong, Colombatti, Alfonso, De Marchi, Francesco, Nitti, Donato, Mammano, Enzo, Liotta, Lance, Petricoin, Emanuel, Pierobon, Mariaelena, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Silvestri, Alessandra, Calvert, Valerie, Belluco, Claudio, Lipsky, Michael, De Maria Marchiano, Ruggero, Deng, Jianghong, Colombatti, Alfonso, De Marchi, Francesco, Nitti, Donato, Mammano, Enzo, Liotta, Lance, Petricoin, Emanuel, Pierobon, Mariaelena, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)
Abstract: The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC. Â© 2012 Springer Science+Business Media Dordrecht.
Published: 2013

42. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform

Author: Casazza, Andrea, Kigel, Boaz, Maione, Federica, Capparuccia, Lorena, Kessler, Ofra, Giraudo, Enrico, Mazzone, Massimiliano, Neufeld, Gera, Tamagnone, Luca, Tamagnone, Luca (ORCID:0000-0002-2884-7946), Casazza, Andrea, Kigel, Boaz, Maione, Federica, Capparuccia, Lorena, Kessler, Ofra, Giraudo, Enrico, Mazzone, Massimiliano, Neufeld, Gera, Tamagnone, Luca, and Tamagnone, Luca (ORCID:0000-0002-2884-7946)
Abstract: Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading. © 2012 EMBO Molecular Medicine.
Published: 2012

43. MicroRNAs and prostate cancer: From preclinical research to translational oncology

Author: Maugeri-Saccà, Marcello, Coppola, Valeria, Bonci, Désirée, De Maria Marchiano, Ruggero, De Maria, Ruggero (ORCID:0000-0003-2255-0583), Maugeri-Saccà, Marcello, Coppola, Valeria, Bonci, Désirée, De Maria Marchiano, Ruggero, and De Maria, Ruggero (ORCID:0000-0003-2255-0583)
Abstract: The management of prostate cancer patients is rapidly changing. The extended survival seen in randomized phase III trials with new molecules has significantly enriched the therapeutic armamentarium, and ongoing clinical trials are assessing whether the integration of these active drugs within established therapeutic regimens results in a further benefit for patients. This complex scenario is raising the need for the identification and validation of biomarkers able to drive the decision-making process during the course of the disease. Compelling evidence has documented the role of microRNAs in cancer biology, and their multifaceted biological activity makes them an attractive candidate as diagnostic, prognostic, and predictive biomarkers. This review summarizes the current knowledge about microRNA deregulation in prostate cancer, how these molecules have been investigated in the clinical setting, and strategies investigators should consider for sharpening their potential. Copyright Â© 2012 by Lippincott Williams & Wilkins.
Published: 2012

44. Bone metastases, general and clinical issues

Author: Greco, C, Forte, L, Erba, P, Mariani, G, Greco, C, Forte, L, Erba, P, and Mariani, G
Abstract: The skeleton is the most common organ for metastasis from solid tumours. Bone metastases pose significant diagnostic and clinical challenges and represent an important cause of cancer-related morbidity. Without appropriate bone-directed therapy, many patients will be at high risk for potentially debilitating skeletal-related events (SREs), such as pain, bone fractures, neurologic deficits and hypercalcemia, severely impacting on the patient's quality of life. Because of their high incidence, bone metastases impose significant demands on health care resources. The optimal management of skeletal metastases depends on the underlying biology of the disease, the extent of bone involvement, the presence and severity of symptoms, the availability of effective systemic therapies and life expectancy of the patient. This article discusses clinical issues concerning diagnosis and available treatment approaches based on the presentation of skeletal involvement. Emphasis is placed on the role of external beam-radiotherapy as a local mode of treatment for palliation of bone pain, decompression of epidural compression and as potential ablative approach through high-dose image-guided irradiation (IGRT) in patients presenting with oligometastatic disease.
Published: 2011

45. Relationship between psychoncology and psychoneuroendocrinoimmunology (PNEI): Enhanced T-regulatory lymphocyte activity in cancer patients with self-punishement, evaluated by Rorschach test

Author: Messina, G, Lissoni, P, Bartolacelli, E, Magotti, L, Clerici, M, Marchiori, P, Colombo, E, CLERICI, MASSIMO, Colombo, E., Messina, G, Lissoni, P, Bartolacelli, E, Magotti, L, Clerici, M, Marchiori, P, Colombo, E, CLERICI, MASSIMO, and Colombo, E.
Abstract: Background: Psychological studies have documented the presence of a self-punishment profile in cancer patients. Recent immuno-oncological studies have shown that within the group of CD4+ cells, which play a fundamental role in the generation of anticancer immunity, there is a subtype of cells that in contrast mediates the suppression of the anticancer immunity, the so-called T-regulatory cells (T-reg), which may be identified as CD4 +CD25+ cells. Patients and Methods: On this basis, we performed a psychoncological study to evaluate CD4+CD25+ cell numbers in relation to the response to Rorschach's test in a group of 30 cancer patients suffering from the most frequent tumor histotypes. Results: Normal values obtained in our laboratory (95% confidence limits) of T-reg lymphocytes and CD4+/CD4+CD25+ were <240/mm3 and >4mm3, respectively. The psychological profile of self-punishment was found in 18/30 patients (60%). The percentage of patients with abnormally high CD4+CD25+ values observed in the group with self-punishment was significantly higher than that found in patients without self punishment (11/18 vs. 3/12 (25%), p<0.05). In the same way, the percentage of patients with abnormally low CD4+/CD4 +CD25+ ratios was significantly higher in the group with self-punishment (16/18 vs. 4/12, p<0.01). The mean numbers of T-reg lymphocytes observed in the group with self-punishment was significantly higher than that found in patients who had no self-punishment (314±39 vs. 173±27, p<0.05). In addition, the mean CD4+/ CD4 +CD25+ ratio was significantly lower in patients with self-punishment than in the other group (2.6±02 vs. 5.2±0.8, p<0.025). On the contrary, no significant difference was seen in the mean number of CD4+ lymphocytes. Conclusion: The study suggests that self-punishment may inhibit the generation of an effective anticancer immune response by stimulating the activation and proliferation of T-reg lymphocytes, which in turn stimulate tumor dissem
Published: 2010

46. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Author: Casazza, Andrea, Finisguerra, Veronica, Capparuccia, Lorena, Camperi, Andrea, Swiercz, Jakub M., Rizzolio, Sabrina, Rolny, Charlotte, Christensen, Clau, Bertotti, Andrea, Sarotto, Ivana, Risio, Mauro, Trusolino, Livio, Weitz, Jurgen, Schneider, Martin, Mazzone, Massimilano, Comoglio, Paolo M., Tamagnone, Luca, Tamagnone, Luca (ORCID:0000-0002-2884-7946), Casazza, Andrea, Finisguerra, Veronica, Capparuccia, Lorena, Camperi, Andrea, Swiercz, Jakub M., Rizzolio, Sabrina, Rolny, Charlotte, Christensen, Clau, Bertotti, Andrea, Sarotto, Ivana, Risio, Mauro, Trusolino, Livio, Weitz, Jurgen, Schneider, Martin, Mazzone, Massimilano, Comoglio, Paolo M., Tamagnone, Luca, and Tamagnone, Luca (ORCID:0000-0002-2884-7946)
Abstract: Semaphorin 3E (Sema3E) is a secreted molecule implicated in axonal path finding and inhibition of developmental and postischemic angiogenesis. Sema3E is also highly expressed in metastatic cancer cells, but its mechanistic role in tumor progression was not understood. Here we show that expression of Sema3E and its receptor Plexin D1 correlates with the metastatic progression of human tumors. Consistent with the clinical data, knocking down endogenous expression of either Sema3E or Plexin D1 in human metastatic carcinoma cells hampered their metastatic potential when injected into mice, while tumor growth was not markedly affected. Conversely, overexpression of exogenous Sema3E in cancer cells increased their invasiveness, transendothelial migration, and metastatic spreading, although it inhibited tumor vessel formation, resulting in reduced tumor growth in mice. The proinvasive and metastatic activity of Sema3E in tumor cells was dependent on transactivation of the Plexin D1-associated ErbB2/Neu oncogenic kinase. In sum, Sema3E-Plexin D1 signaling in cancer cells is crucially implicated in their metastatic behavior and may therefore be a promising target for strategies aimed at blocking tumor metastasis.
Published: 2010

47. Clusterin (CLU) and lung cancer

Author: Panico, F, Rizzi, F, Fabbri, L, Bettuzzi, S, Luppi, F, Fabbri, LM, Panico, F, Rizzi, F, Fabbri, L, Bettuzzi, S, Luppi, F, and Fabbri, LM
Abstract: Lung cancer is the leading cause of cancer-related mortality. It is categorized into two histological groups that have distinct clinical behaviors, the nonsmall cell lung cancers (NSCLC) and the small cell lung cancer (SCLC). When identified at an early stage, NSCLC is treated by surgical resection. However, patients who undergo surgical resection still have a relative low survival rate, primarily for tumor recurrence. Unfortunately, advances in cytotoxic therapy have reached a plateau and new approaches to treatment are needed together with new and better parameters for more accurate prediction of the outcome and more precise indication of the efficacy of the treatment. Several in vitro studies have examined the role of Clusterin (CLU) in carcinogenesis, lung cancer progression, and response to chemo- and radiotherapy. Studies performed in lung cancer cell lines and animal models showed that CLU is upregulated after exposure to chemo- and radiotherapy. A potential role proposed for the protein is cytoprotective. In vitro, CLU silencing by antisense oligonucleotides (ASO) and small-interfering RNAs (siRNA) directed against CLU mRNA in CLU-rich lung cancer cell lines sensitized cells to chemotherapy and radiotherapy and decreased their metastatic potential. In vivo, a recent work analyzed the prognostic role of CLU in NSCLC, showing that CLU-positive patients with lung cancer had a better overall survival and disease-free survival than those with CLU-negative tumors. These data are contradictory to the promising in vitro results. From the results of these studies we may hypothesize that in early-stage lung cancers CLU represents a positive biomarker correlating with better overall survival. In advanced patients, already treated with chemo- and radiotherapy, the induction of CLU may confer resistance to the treatments. However, many studies are needed to better understand the role of CLU in early-stage and advanced lung cancers with the aim to discriminate patients an
Published: 2009

48. Altered expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in high-risk soft tissue sarcomas

Author: Benassi, M, Ponticelli, F, Azzoni, E, Gamberi, G, Pazzaglia, L, Chiechi, A, Conti, A, Spessotto, P, Scapolan, M, Pignotti, E, Bacchini, P, Picci, P, Benassi, M S, Benassi, M, Ponticelli, F, Azzoni, E, Gamberi, G, Pazzaglia, L, Chiechi, A, Conti, A, Spessotto, P, Scapolan, M, Pignotti, E, Bacchini, P, Picci, P, and Benassi, M S
Abstract: In recent years, classification of soft-tissue sarcomas (STS) has improved with cytogenetic analyses, but their clinical behavior is still not easily predictable. The aim of this study was to detect alterations in the urokinase-type plasminogen system, involved in tumor growth and invasion, by comparing mRNA levels of its components with those of paired normal tissues, and relating them with patient clinical course. Real-time PCR was performed on human STS cell lines and tissues from highly malignant STS, including leiomyosarcomas and malignant fibrous histiocytomas, to evaluate the expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of gene products was also performed. Median mRNA values of all genes studied were higher in tumors than in paired normal tissues. In agreement with data on STS cell lines, significant up-regulation for uPA and PAI-1 genes compared to reference values was seen. Moreover, different levels of expression were related to histotype and metastatic phenotype. There was accordance between uPA mRNA and protein expression, while immunodetection of PAI-1 product was weak and scattered. Clearly, the controversial role of PAI-1 protein requires further biological analyses, but evident involvement of uPA/PAI-1 gene overexpression in STS malignancy may highlight a molecular defect useful in discriminating STS high-risk patients
Published: 2007

49. Altered expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in high-risk soft tissue sarcomas

Author: Benassi, M, Ponticelli, F, Azzoni, E, Gamberi, G, Pazzaglia, L, Chiechi, A, Conti, A, Spessotto, P, Scapolan, M, Pignotti, E, Bacchini, P, Picci, P, Benassi, M S, Benassi, M, Ponticelli, F, Azzoni, E, Gamberi, G, Pazzaglia, L, Chiechi, A, Conti, A, Spessotto, P, Scapolan, M, Pignotti, E, Bacchini, P, Picci, P, and Benassi, M S
Abstract: In recent years, classification of soft-tissue sarcomas (STS) has improved with cytogenetic analyses, but their clinical behavior is still not easily predictable. The aim of this study was to detect alterations in the urokinase-type plasminogen system, involved in tumor growth and invasion, by comparing mRNA levels of its components with those of paired normal tissues, and relating them with patient clinical course. Real-time PCR was performed on human STS cell lines and tissues from highly malignant STS, including leiomyosarcomas and malignant fibrous histiocytomas, to evaluate the expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of gene products was also performed. Median mRNA values of all genes studied were higher in tumors than in paired normal tissues. In agreement with data on STS cell lines, significant up-regulation for uPA and PAI-1 genes compared to reference values was seen. Moreover, different levels of expression were related to histotype and metastatic phenotype. There was accordance between uPA mRNA and protein expression, while immunodetection of PAI-1 product was weak and scattered. Clearly, the controversial role of PAI-1 protein requires further biological analyses, but evident involvement of uPA/PAI-1 gene overexpression in STS malignancy may highlight a molecular defect useful in discriminating STS high-risk patients
Published: 2007

50. Risk factors for distant metastases in head and neck squamous cell carcinoma

Author: Garavello, W, Ciardo, A, Spreafico, R, Gaini, R, GARAVELLO, WERNER, GAINI, RENATO MARIA, Garavello, W, Ciardo, A, Spreafico, R, Gaini, R, GARAVELLO, WERNER, and GAINI, RENATO MARIA
Abstract: OBJECTIVES: To evaluate the frequency of distant metastases (DM) and to determine the ability of certain clinical and pathologic factors to predict the development of distant metastases. DESIGN: Retrospective analysis. SETTING: University hospital. PATIENTS: A total of 1972 patients with oral, oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinomas who were treated from 1981 to 1998 and who were not diagnosed as having DM at the time of initial treatment. MAIN OUTCOME MEASURES: We evaluated the frequency of DM and the influence of different variables in their appearance. RESULTS: A total of 181 patients (9.2%) (95% confidence interval, 7.9%-10.5%) developed DM. Younger age (<45 years), hypopharyngeal localization, an advanced T stage and/or N stage tumor according to the TNM staging system, high histologic grade, and locoregional control were found to be significantly associated with the risk of DM at both univariate and multivariate analyses. CONCLUSIONS: The incidence of DM in subjects with head and neck squamous cell carcinoma is relatively low. The risk of DM is influenced by age, site of primary cancer, local and/or regional extension, grading, and achievement of locoregional control.
Published: 2006

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