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4. RIZ1 is potential CML tumor suppressor that is down-regulated during disease progression

Author

Torlakovic Emina, Pastural Elodie, Takahashi Naoto, Lakshmikuttyamma Ashakumary, Amin Hesham M, Garcia-Manero Guillermo, Voralia Michael, Czader Magdalena, DeCoteau John F, and Geyer C Ronald

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background RIZ1 expression and activity are reduced in many cancers. In AML cell lines and patient material, RIZ1 expression is reduced relative to normal bone marrow. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located. RIZ1 is a PR domain methyltransferase that methylates histone H3 lysine 9, a modification important for transcriptional repression. In CML blast crisis cell lines RIZ1 represses insulin-like growth factor-1 expression and autocrine signaling. Together these observations suggest that RIZ1 may have a role in the chronic phase to blast crisis transition in CML. Results In CML patient material, we observed that RIZ1 expression was decreased during progression from chronic phase to blast crisis. RIZ1 was expressed in mature myeloid and CD34+ cells demonstrating that decreased RIZ1 expression in blast crisis is not due to an increased immature cell population. Expression of RIZ1 CML blast crisis cell lines decreased proliferation, increased apoptosis, and enhanced differentiation. Conclusion RIZ1 is a candidate tumor suppressor gene whose expression is decreased in blast crisis. Loss of RIZ1 activity results in decreased apoptosis and differentiation and enhanced proliferation. Together these results suggest that loss of RIZ1 expression will lead to an increase in myeloid blast cell population resulting in CML progression.

Published
2009
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6. Genomic characterisation of hormone receptor-positive breast cancer arising in very young women

Author

Luen, S.J., Viale, G., Nik-Zainal, S., Savas, P., Kammler, R., Dell’Orto, P., Biasi, O., Degasperi, A., Brown, L.C., Láng, I., MacGrogan, G., Tondini, C., Bellet, M., Villa, F., Bernardo, A., Ciruelos, E., Karlsson, P., Neven, P., Climent, M., Müller, B., Jochum, W., Bonnefoi, H., Martino, S., Davidson, N.E., Geyer, C., Chia, S.K., Ingle, J.N., Coleman, R., Solbach, C., Thürlimann, B., Colleoni, M., Coates, A.S., Goldhirsch, A., Fleming, G.F., Francis, P.A., Speed, T.P., Regan, M.M., and Loi, S.

Published
2023
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7. A Novel Single-Tube Next Generation Sequencing Assay for B-Cell Receptor Clonality Testing

Author

Pastushok, Landon, primary, Sarda, Shrutii, additional, Mochoruk, Karen, additional, Hill, Wayne, additional, Pickle, Loni T., additional, Toro, Michelle, additional, Gonzalez, Carolina, additional, Ostresh, Stephanie, additional, Looney, Timothy J., additional, Yang, Chenchen, additional, Stakiw, Julie, additional, Bosch, Mark J., additional, Goubran, Hadi, additional, Geyer, C. Ronald, additional, Lowman, Geoffrey M., additional, and DeCoteau, John F., additional

Published
2024
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14. EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours

Author

Toosi, Behzad M., El Zawily, Amr, Truitt, Luke, Shannon, Matthew, Allonby, Odette, Babu, Mohan, DeCoteau, John, Mousseau, Darrell, Ali, Mohsin, Freywald, Tanya, Gall, Amanda, Vizeacoumar, Frederick S., Kirzinger, Morgan W., Geyer, C. Ronald, Anderson, Deborah H., Kim, TaeHyung, Welm, Alana L., Siegel, Peter, Vizeacoumar, Franco J., Kusalik, Anthony, and Freywald, Andrew

Published
2018
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17. Genomic characterisation of hormone receptor-positive breast cancer arising in very young women

Author

Luen, SJ, Viale, G, Nik-Zainal, S, Savas, P, Kammler, R, Dell'Orto, P, Biasi, O, Degasperi, A, Brown, LC, Lang, I, MacGrogan, G, Tondini, C, Bellet, M, Villa, F, Bernardo, A, Ciruelos, E, Karlsson, P, Neven, P, Climent, M, Mueller, B, Jochum, W, Bonnefoi, H, Martino, S, Davidson, NE, Geyer, C, Chia, SK, Ingle, JN, Coleman, R, Solbach, C, Thurlimann, B, Colleoni, M, Coates, AS, Goldhirsch, A, Fleming, GF, Francis, PA, Speed, TP, Regan, MM, Loi, S, Luen, SJ, Viale, G, Nik-Zainal, S, Savas, P, Kammler, R, Dell'Orto, P, Biasi, O, Degasperi, A, Brown, LC, Lang, I, MacGrogan, G, Tondini, C, Bellet, M, Villa, F, Bernardo, A, Ciruelos, E, Karlsson, P, Neven, P, Climent, M, Mueller, B, Jochum, W, Bonnefoi, H, Martino, S, Davidson, NE, Geyer, C, Chia, SK, Ingle, JN, Coleman, R, Solbach, C, Thurlimann, B, Colleoni, M, Coates, AS, Goldhirsch, A, Fleming, GF, Francis, PA, Speed, TP, Regan, MM, and Loi, S

Abstract

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% v

Published
2023

22. Evaluation of nimotuzumab Fab2 as an optical imaging agent in EGFR positive cancers.

Author

Bernhard, Wendy, Barreto, Kris, Toledo, Darien, El-Sayed, Ayman, Jett, Kimberly A., Casaco, Angel, Fonge, Humphrey, and Geyer, C. Ronald

Subjects
OPTICAL images, EPIDERMAL growth factor receptors, POSITRON emission tomography, PEPSIN, COMPUTER-assisted surgery, FLUORESCENT antibody technique, OPTICAL properties
Abstract

Molecular-targeted imaging probes can be used with a variety of imaging modalities to detect diseased tissues and guide their removal. EGFR is a useful biomarker for a variety of cancers, because it is expressed at high levels relative to normal tissues. Previously, we showed the anti-EGFR antibody nimotuzumab can be used as a positron emission tomography and fluorescent imaging probe for EGFR positive cancers in mice. These imaging probes are currently in clinical trials for PET imaging and image-guided surgery, respectively. One issue with using antibody probes for imaging is their long circulation time and slow tissue penetration, which requires patients to wait a few days after injection before imaging or surgery, multiple visits and longer radiation exposure. Here, we generated a Fab2 fragment of nimotuzumab, by pepsin digestion and labeled it with IRDye800CW to evaluate its optical imaging properties. The Fab2 had faster tumor accumulation and clearance in mice relative to the nimotuzumab IgG. The fluorescent signal peaked at 2 h post injection and remained high until 6 h post injection. The properties of the Fab2 allow a higher signal to background to be obtained in a shorter time frame, reducing the wait time for imaging after probe infusion. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Overall survival in the OlympiA phase Ill trial of adjuvant olaparib in patients with germime pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Author

Geyer, C. E., Jr., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmana, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., Elsafy, F., Fein, L. E., Fielding, A., Ford, J. M., Friedman, S., Gelmon, K. A., Gianni, L., Gnant, M., Hollingsworth, S. J., Im, S-A, Jager, A., Lakhani, S. R., Janni, W., Linderholm, B., Liu, T-W, Loman, N., Korde, L., Loibl, S., Lucas, P. C., Marme, F., de Duenas, E. Martinez, McConnell, R., Phillips, K-A, Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C. F., Spanic, T., Stickeler, E., Toi, M., Traina, T. A., Viale, G., Zoppoli, G., Park, Y. H., Yerushalmi, R., Yang, H., Pang, D., Jung, K. H., Mailliez, A., Fan, Z., Tennevet, I, Zhang, J., Nagy, T., Sonke, G. S., Sun, Q., Parton, M., Colleoni, M. A., Schmidt, M., Brufsky, A. M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., Tutt, A. N. J., Johannsson, O. Th, Geyer, C. E., Jr., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmana, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., Elsafy, F., Fein, L. E., Fielding, A., Ford, J. M., Friedman, S., Gelmon, K. A., Gianni, L., Gnant, M., Hollingsworth, S. J., Im, S-A, Jager, A., Lakhani, S. R., Janni, W., Linderholm, B., Liu, T-W, Loman, N., Korde, L., Loibl, S., Lucas, P. C., Marme, F., de Duenas, E. Martinez, McConnell, R., Phillips, K-A, Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C. F., Spanic, T., Stickeler, E., Toi, M., Traina, T. A., Viale, G., Zoppoli, G., Park, Y. H., Yerushalmi, R., Yang, H., Pang, D., Jung, K. H., Mailliez, A., Fan, Z., Tennevet, I, Zhang, J., Nagy, T., Sonke, G. S., Sun, Q., Parton, M., Colleoni, M. A., Schmidt, M., Brufsky, A. M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., Tutt, A. N. J., and Johannsson, O. Th

Abstract

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistical

Published
2022

26. Kinderchirurgie I

Author

Bolkenius, M., Metzker, M., v Andrian, Chr., Thil, E., Gräfe, G., Bennek, J., Woitek, G., Geyer, C., Ophoff, K., Riesener, K.-P., Steinau, G., Schumpelick, V., Tröbs, R.-B., Roth, H., Waldschmidt, J., Lochbühler, H., Schlensak, M., Humberg, H.-J., Strube, H.-D., Müller, W., Brock, D., Bühligen, U., Carbon, R., Gusinde, J., Hümmer, H. P., Hennig, F. F., Rothe, K., Seyfriedt, C., Wessel, L., v Knobloch, M., Brands, W., Schuppert, W., Rieger, H., Holmenschlager, F., Neumann, H.-S., Brug, E., Graffstädt, H., David, S., Reetz, M., Pistor, G., Riebel, T., Deindl, Ch., Hartinger, K., Huberts, U., Kaisers, H., Lambrechts, R., Hani, M., Tekin, R., Ragosch, C., Kotlarski, J., Lambrecht, W., Kluth, D., Aalamian, M., Zachariou, Z., Daum, R., Wit, J., Beyer, W., Mau, H., Schaarschmidt, K., Saxena, A. K., Schleef, J., Stratmann, U., Willital, G. H., Pohle, T., Krause, H., Wagemann, W., Lippert, H., Hartel, W., editor, and Hierholzer, G.

Published
1995
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28. Prospective BMI changes in preschool children are associated with parental characteristics and body weight perceptions: the ToyBox-study

Author

Manios, Y, Lambert, Katrina, Karaglani, E, Mavrogianni, C, Moreno, LA, Iotova, V, Świąder-Leśniak, A, Koletzko, B, Cardon, G, Androutsos, O, Moschonis, George, de Bourdeaudhuij, I, Paw, MCA, Summerbell, C, Lobstein, T, Annemans, L, Buijs, G, Reilly, J, Swinburn, B, Ward, D, Grammatikaki, E, Katsarou, C, Apostolidou, E, Livaniou, A, Lymperopoulou, K, Efstathopoulou, E, Lambrinou, CP, Giannopoulou, A, Siatitsa, E, Argiri, E, Maragkopoulou, K, Douligeris, A, Duvinage, K, Ibrügger, S, Strauß, A, Herbert, B, Birnbaum, J, Payr, A, Geyer, C, de Craemer, M, de Decker, E, de Henauw, S, Maes, L, Vereecken, C, van Assche, J, Pil, L, Velde, S te, Mouratidou, T, Fernandez, J, Mesana, M, de Miguel-Etayo, P, González-Gil, EM, Gracia-Marco, L, Oves, B, Yngve, A, Kugelberg, S, Lynch, C, Mosdøl, A, Nilsen, BB, Moore, H, Douthwaite, W, Nixon, C, Kreichauf, S, Wildgruber, A, Socha, P, Kulaga, Z, Zych, K, Góźdź, M, Gurzkowska, B, Szott, K, Lateva, M, Usheva, N, Galcheva, S, Marinova, V, Radkova, Z, Feschieva, N, Aikenhead, A, Dorgelo, A, Nethe, A, Jansen, J, Gmeiner, O, Retterath, J, Wildeis, J, Günthersberger, A, Gibson, L, and Voegele, C

Subjects
111712 Health Promotion, 111707 Family Care, FOS: Health sciences, 111704 Community Child Health
Abstract

Objective: To examine the effect of the intervention implemented in the ToyBox study on changes observed in age and sex specific BMI percentile and investigate the role of perinatal factors, parental perceptions and characteristics on this change. Design: A multicomponent, kindergarten-based, family-involved intervention with a cluster-randomized design. A standardized protocol was used to measure children’s body weight and height. Information was also collected from parents/caregivers via the use of validated questionnaires. Linear mixed effect models with random intercept for country, socioeconomic status and school were used. Setting: Selected preschools within the provinces of Oost-Flanders and West-Flanders (Belgium), Varna (Bulgaria), Bavaria (Germany), Attica (Greece), Mazowieckie (Poland) and Zaragoza (Spain). Participants: A sample of 6,268 pre-schoolers aged 3.5-5.5 (51.9% boys). Results: There was no intervention effect on the change in children’s BMI percentile. However, parents’ underestimation of their children’s actual weight status, parental overweight and mothers’ pre-pregnancy overweight/obesity were found to be significantly and independently associated with increases in children’s BMI percentile in multivariate modelling. Conclusion: Before or as part of the implementation of any childhood obesity intervention initiative, it is important to assist parents/caregivers to correctly perceive their own and their children’s weight status. Recognition of excessive weight by parents/caregivers can increase their readiness to change and as such facilitate higher adherence to favourable behavioural changes within the family.

Published
2022
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29. Prospective BMI changes in preschool children are not effected by changes in EBRBs but by parental characteristics and body weight perceptions: The ToyBox-study

Author

Manios Y., Lambert K.A., Karaglani E., Mavrogianni C., Moreno L.A., Iotova V., Swiader-Lesniak A., Koletzko B., Cardon G., Androutsos O., Moschonis G., de Bourdeaudhuij I., Paw M.C.A., Summerbell C., Lobstein T., Annemans L., Buijs G., Reilly J., Swinburn B., Ward D., Grammatikaki E., Katsarou C., Apostolidou E., Livaniou A., Lymperopoulou K., Efstathopoulou E., Lambrinou C.-P., Giannopoulou A., Siatitsa E., Argiri E., Maragkopoulou K., Douligeris A., Duvinage K., Ibrügger S., Strauß A., Herbert B., Birnbaum J., Payr A., Geyer C., de Craemer M., de Decker E., de Henauw S., Maes L., Vereecken C., van Assche J., Pil L., te Velde S., Moreno L., Mouratidou T., Fernandez J., Mesana M., de Miguel-Etayo P., González-Gil E.M., Gracia-Marco L., Oves B., Yngve A., Kugelberg S., Lynch C., Mosdøl A., Nilsen B.B., Moore H., Douthwaite W., Nixon C., Kreichauf S., Wildgruber A., Socha P., Kulaga Z., Zych K., Gózdz M., Gurzkowska B., Szott K., Lateva M., Usheva N., Galcheva S., Marinova V., Radkova Z., Feschieva N., Aikenhead A., Dorgelo A., Nethe A., Jansen J., Gmeiner O., Retterath J., Wildeis J., Günthersberger A., Gibson L., Voegele C., and ToyBox Study Group

Abstract

Objective: To examine the effect of the intervention implemented in the ToyBox study on changes observed in age and sex specific BMI percentile and investigate the role of perinatal factors, parental perceptions and characteristics on this change. Design: A multicomponent, kindergarten-based, family-involved intervention with a cluster-randomized design. A standardized protocol was used to measure children’s body weight and height. Information was also collected from parents/caregivers via the use of validated questionnaires. Linear mixed effect models with random intercept for country, socioeconomic status and school were used. Setting: Selected preschools within the provinces of Oost-Flanders and West-Flanders (Belgium), Varna (Bulgaria), Bavaria (Germany), Attica (Greece), Mazowieckie (Poland) and Zaragoza (Spain). Participants: A sample of 6, 268 pre-schoolers aged 3.5-5.5 (51.9% boys). Results: There was no intervention effect on the change in children’s BMI percentile. However, parents’ underestimation of their children’s actual weight status, parental overweight and mothers’ pre-pregnancy overweight/obesity were found to be significantly and independently associated with increases in children’s BMI percentile in multivariate modelling. Conclusion: Before or as part of the implementation of any childhood obesity intervention initiative, it is important to assist parents/caregivers to correctly perceive their own and their children’s weight status. Recognition of excessive weight by parents/caregivers can increase their readiness to change and as such facilitate higher adherence to favourable behavioural changes within the family. © 2021 Lippincott Williams and Wilkins. All rights reserved.

Published
2022

34. 119O Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥4 years of follow-up: BrighTNess, a randomized phase III trial

Author

Loibl, S., primary, Sikov, W., additional, Huober, J., additional, Rugo, H.S., additional, Wolmark, N., additional, O'Shaughnessy, J., additional, Maag, D., additional, Untch, M., additional, Golshan, M., additional, Lorenzo, J. Ponce, additional, Metzger, O., additional, Dunbar, M., additional, Symmans, W.F., additional, and Geyer, C., additional

Published
2021
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43. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer

Author

Tutt A, Garber J, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber R, de Azambuja E, Fielding A, Balmana J, Domchek S, Gelmon K, Hollingsworth S, Korde L, Linderholm B, Bandos H, Senkus E, Suga J, Shao Z, Pippas A, Nowecki Z, Huzarski T, Ganz P, Lucas P, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger G, Costantino J, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani S, Yothers G, Campbell C, Geyer C, OlympiA Clinical Trial Steering, and OlympiA Clinical Trial Steering Committee and Investigators

Abstract

BACKGROUND Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P

Published
2021

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