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1. Clinical and dosimetric outcomes of image-guided, dose-painted radiotherapy in muscle invasive bladder cancer

Author

Inmaculada Navarro-Domenech, Shinthujah Arulanantham, Zhihui Amy Liu, Michael Tjong, Vickie Kong, Victor Malkov, Tony Tadic, Neil Fleshner, Girish Kulkarni, Alexandre R Zlotta, Charles Catton, Alejandro Berlin, Srikala Sridhar, Di (Maria) Jiang, Peter Chung, and Srinivas Raman

Subjects
Bladder cancer, Radiotherapy, Dose-painted, Lipiodol, Tri-modal therapy, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Purpose/Objective Definitive radiotherapy (RT) is an alternative to radical cystectomy for select patients with muscle invasive bladder cancer (MIBC); however, there is limited data on dose-painted RT approaches. We report the clinical and dosimetric outcomes of a cohort of MIBC patients treated with dose-painted RT. Material/Methods This was a single institution retrospective study of cT2-4N0M0 MIBC patients treated with external beam radiotherapy (EBRT) to the bladder, and sequential or concomitant boost to the tumor bed. The target delineation was guided by either intravesical injection of Lipiodol or through fusion of the pre-treatment imaging. The majority were treated with daily image-guidance. Kaplan-Meier was used to characterize overall survival (OS) and progression-free survival (PFS). Cumulative incidence function (CIF) was used to estimate local (intravesical) recurrence (LR), regional recurrence (RR) and distant metastasis (DM). Univariable and multivariable cause-specific hazard model was used to assess factors associated with LR and OS. Results 117 patients were analyzed. The median age was 73 years (range 43, 95). The median EQD2 to the boost volume was 66 Gy (range 52.1, 70). Lipiodol injection was used in 64 patients (55%), all treated with IMRT/VMAT. 95 (81%) received concurrent chemotherapy, of whom, 44 (38%) received neoadjuvant chemotherapy. The median follow-up was 37 months (IQR 16.2, 83.3). At 5-year, OS and PFS were 79% (95% CI 70.5–89.2) and 46% (95% CI 36.5–57.5). Forty-five patients had bladder relapse, of which 30 patients (67%) were at site of the tumor bed. Nine patients underwent salvage-cystectomy. Late high-grade (G3-G4) genitourinary and gastrointestinal toxicity were 3% and 1%. Conclusion Partial boost RT in MIBC is associated with good local disease control and high rates of cystectomy free survival. We observed a pattern of predominantly LR in the tumor bed, supporting the use of a dose-painted approach/de-escalation strategy to the uninvolved bladder. Prospective trials are required to compare oncological and toxicity outcomes between dose-painted and homogeneous bladder RT techniques.

Published
2023
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3. The role of cytoreductive nephrectomy and systemic therapy in the management of tumour thrombus in patients with metastatic renal cell carcinoma

Author

Abhenil Mittal, Esmail Al-Ezzi, Xuan Li, Brian Moloney, Brooke Wilson, Pavlina Spiliopoulou, Srikala Sridhar, Nazanin Fallah-Rad, Peter Chung, Robert James Hamilton, Martin O’malley, and Aaron R. Hansen

Subjects
Cancer Research, Oncology
Abstract

Background Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. Methods Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan–Meier method (log-rank). Results Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8–27.7) vs. 13.9 m (7.9–21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4–48.9) vs. 12.1 m (8.8–27.7), p = 0.01]. Conclusion In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.

Published
2023
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4. Targeting the FGFR Pathway in Urothelial Carcinoma: the Future Is Now

Author

Jenny, Peng, Srikala, Sridhar, Arlene Odelia, Siefker-Radtke, Shamini, Selvarajah, and Di Maria, Jiang

Subjects
Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Oncology, Humans, Pharmacology (medical), Immunotherapy, Protein Kinase Inhibitors
Abstract

As we come to better understand cancer genomics, we are increasingly shifting towards precision medicine. FGFR has been elucidated as one of the oncogenic driver pathways in urothelial carcinoma, leading to exciting targeted drug development. Although many agents are being investigated, erdafitinib is the only FGFR inhibitor currently approved by the FDA for treating platinum-refractory metastatic urothelial carcinoma harboring susceptible FGFR2/3 alterations, with seemingly higher response rates than second-line chemotherapy or immunotherapy. In this review, we summarize the clinical data supporting FGFR inhibition, ways to optimize its use in routine clinical practice including FGFR testing, dosing, and toxicity management. We also highlight ongoing efforts evaluating combination strategies and testing in earlier treatment settings to further expand this targeted therapeutic approach in urothelial carcinoma.

Published
2022
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5. Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study

Author

Evan Y. Yu, Michael P. Kolinsky, William R. Berry, Margitta Retz, Loic Mourey, Josep M. Piulats, Leonard J. Appleman, Emanuela Romano, Gwenaelle Gravis, Howard Gurney, Martin Bögemann, Urban Emmenegger, Anthony M. Joshua, Mark Linch, Srikala Sridhar, Henry J. Conter, Brigitte Laguerre, Christophe Massard, Xin Tong Li, Charles Schloss, Christian H. Poehlein, and Johann S. de Bono

Subjects
Male, Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, Urology, Antineoplastic Combined Chemotherapy Protocols, Abiraterone Acetate, Humans, Prednisone, Androgen Antagonists, Docetaxel, Prostate-Specific Antigen, Antibodies, Monoclonal, Humanized, Disease-Free Survival
Abstract

Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments.To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC.The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening.Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/mThe primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS).Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size.Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted.We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.

Published
2022
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6. PD09-03 INVERSE PROBABILITY TREATMENT WEIGHTING COMPARISON OF RADICAL CYSTECTOMY TO TRIMODALITY THERAPY FOR CT2-CT4 MUSCLE INVASIVE BLADDER CANCER

Author

Alexandre Zlotta, Leslie Ballas, Andrzej Niemierko, Katherine Lajkosz, Cynthia Kuk, Gus Miranda, Michael Drumm, Andrea Mari, Ethan Thio, Neil Fleshner, Girish Kulkarni, Michael Jewett, Rob Bristow, Charles Catton, Padraig Warde, Alejandro Berlin, Srikala Sridhar, Anne Schuckman, Hooman Djaladat, Adam Feldman, Matthew Wszolek, Douglas Dahl, Richard Lee, Philip Saylor, Marc Michaelson, David Miyamoto, Anthony Zietman, William Shipley, Peter Chung, Sia Daneshmand, and Jason Efstathiou

Subjects
Urology
Published
2023
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9. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial

Author

Thomas Powles, Michiel S van der Heijden, Daniel Castellano, Matthew D Galsky, Yohann Loriot, Daniel P Petrylak, Osamu Ogawa, Se Hoon Park, Jae-Lyun Lee, Ugo De Giorgi, Martin Bögemann, Aristotelis Bamias, Bernhard J Eigl, Howard Gurney, Som D Mukherjee, Yves Fradet, Iwona Skoneczna, Marinos Tsiatas, Andrey Novikov, Cristina Suárez, André P Fay, Ignacio Duran, Andrea Necchi, Sophie Wildsmith, Philip He, Natasha Angra, Ashok K Gupta, Wendy Levin, Joaquim Bellmunt, Michiel S. van der Heijden, Jae Lyun Lee, Bernhard J. Eigl, Som D. Mukherjee, Cristina Suarez, Hans Westgeest, Aude Flechon, Yen-Chuan Ou, Inkeun Park, Vsevolod Matveev, Begoña Pérez-Valderrama, Susanna Cheng, Stephen Frank, Urbano Anido, Alketa Hamzaj, Margitta Retz, Srikala Sridhar, Giorgio Vittorio Scagliotti, Jens Voortman, Boris Alekseev, Anna Alyasova, Boris Komyakov, Herlinde Dumez, Michel Pavic, Go Kimura, Atsushi Mizokami, Susanne Osanto, Jose Angel Arranz, Djura Piersma, Sang Joon Shin, Oleg Karyakin, Ignacio Delgado, Jose Luis Gonzalez, See-Tong Pang, Anna Tran, Oleg Lipatov, Wen-Pin Su, Thomas Flaig, Ajjai Alva, Hwa Park Kyong, Evgeny Kopyltsov, Elena Almagro, Monserrat Domenech, Yen-Hwa Chang, Brieuc Sautois, Andre Ravaux, Gerasimos Aravantinos, Vasileios Georgoulias, Sasja Mulder, Yu Jung Kim, Fabio Kater, Christine Chevreau, Scott Tagawa, Pawel Zalewski, Florence Joly, Gencay Hatiboglu, Luca Gianni, Franco Morelli, Rosa Tambaro, Yasuhiro Hashimoto, Alexander Nosov, Albert Font, Alejo M. Rodriguez-Vida, Robert Jones, Naveen Vasudev, Sandhya Srinivas, Jingsong Zhang, Thierry Gil, Daygen Finch, Marc-Oliver Grimm, Yu-Li Su, Simon Chowdhury, Christopher Hocking, Eugen Plas, Scott North, Niels Viggo Jensen, Christine Theodore, Florian Imkamp, Avivit Peer, Takashi Kobayashi, Hideki Sakai, Naoto Sassa, Kazuhiro Yoshimura, Maureen Aarts, Ana Ferreira Castro, Marlen Topuzov, Juan Francisco Rodriguez, Federico Jose Vazquez, Yu-Chieh Tsai, Simon Crabb, Syed Hussain, Johanna Bendell, Marine Gross-Goupil, Gravis Gwenaelle, Raanan Berger, Galina Statsenko, Linda Evans, Alexandra Drakaki, Bradley Somer, Ian Davis, James Lynam, Giuliano Borges, Aldo Dettino, André P. Fay, Graziella Martins, Luis Eduardo Zucca, Mads Agerbaek, Haralambos Kalofonos, Eli Rosenbaum, Hideki Enokida, Hiroaki Kikukawa, Kazuo Nishimura, Satoshi Tamada, Motohide Uemura, Yamil Lopez, Jourik Gietema, Marcin Slojewski, Isabel Fernandes, Alexey Smolin, Danish Mazhar, Arash Rezazadeh Kalebasty, Bradley Carthon, Wolfgang Loidl, Fabio Franke, Gustavo Girotto, Nimira Alimohamed, Robyn Macfarlane, Helle Pappot, Guenter Niegisch, Dimitrios Mavroudis, Avishay Sella, Camillo Porta, Shin Ebara, Motonobu Nakamura, Wataru Obara, Norihiko Okuno, Nobuo Shinohara, Mikio Sugimoto, Akitaka Suzuki, Noriaki Tokuda, Hiroji Uemura, Akito Yamaguchi, Francisco Ramirez, Pawel Rozanowski, Pawel Wiechno, Bhumsuk Keam, Nikolay Kislov, Denis Plaksin, Irfan Cicin, Satish Kumar, Matthew D. Galsky, Daniel P. Petrylak, Joseph Rosales, Ulka Vaishampayan, Stephane Culine, Christos Papandreou, Taketoshi Nara, Mustafa Erman, Laurence Kreiger, Juliana Janoski, Diogo Rosa, Mariana Siqueira, Christina Canil, Lisa Sengelov, Jean-Marc Tourani, Gaku Arai, Katsuyoshi Hashine, Mutsushi Kawakita, Noboru Nakaigawa, Hayahito Nomi, Hiroaki Shiina, Hiroyoshi Suzuki, Junji Yonese, Roberto Kuri, Eleazar Macedo, Samuel Rivera, Alberto Villalobos Prieto, Anna Polakiewicz-Gilowska, Renata Zaucha, Fabio Lopes, Roman Ponomarev, Mark Pomerantz, Shahrokh Shariat, Cynthia Luk, Krzysztof Lesniewski-Kmak, Graduate School, CCA - Cancer Treatment and quality of life, Internal medicine, Medical oncology, Powles, T., van der Heijden, M. S., Castellano, D., Galsky, M. D., Loriot, Y., Petrylak, D. P., Ogawa, O., Park, S. H., Lee, J. -L., De Giorgi, U., Bogemann, M., Bamias, A., Eigl, B. J., Gurney, H., Mukherjee, S. D., Fradet, Y., Skoneczna, I., Tsiatas, M., Novikov, A., Suarez, C., Fay, A. P., Duran, I., Necchi, A., Wildsmith, S., He, P., Angra, N., Gupta, A. K., Levin, W., Bellmunt, J., Lee, J. L., Westgeest, H., Flechon, A., Ou, Y. -C., Park, I., Matveev, V., Perez-Valderrama, B., Cheng, S., Frank, S., Anido, U., Hamzaj, A., Retz, M., Sridhar, S., Scagliotti, G. V., Voortman, J., Alekseev, B., Alyasova, A., Komyakov, B., Dumez, H., Pavic, M., Kimura, G., Mizokami, A., Osanto, S., Arranz, J. A., Piersma, D., Shin, S. J., Karyakin, O., Delgado, I., Gonzalez, J. L., Pang, S. -T., Tran, A., Lipatov, O., Su, W. -P., Flaig, T., Alva, A., Park Kyong, H., Kopyltsov, E., Almagro, E., Domenech, M., Chang, Y. -H., Sautois, B., Ravaux, A., Aravantinos, G., Georgoulias, V., Mulder, S., Kim, Y. J., Kater, F., Chevreau, C., Tagawa, S., Zalewski, P., Joly, F., Hatiboglu, G., Gianni, L., Morelli, F., Tambaro, R., Hashimoto, Y., Nosov, A., Font, A., Rodriguez-Vida, A. M., Jones, R., Vasudev, N., Srinivas, S., Zhang, J., Gil, T., Finch, D., Grimm, M. -O., Su, Y. -L., Chowdhury, S., Hocking, C., Plas, E., North, S., Jensen, N. V., Theodore, C., Imkamp, F., Peer, A., Kobayashi, T., Sakai, H., Sassa, N., Yoshimura, K., Aarts, M., Ferreira Castro, A., Topuzov, M., Rodriguez, J. F., Vazquez, F. J., Tsai, Y. -C., Crabb, S., Hussain, S., Bendell, J., Gross-Goupil, M., Gwenaelle, G., Berger, R., Statsenko, G., Evans, L., Drakaki, A., Somer, B., Davis, I., Lynam, J., Borges, G., Dettino, A., Martins, G., Zucca, L. E., Agerbaek, M., Kalofonos, H., Rosenbaum, E., Enokida, H., Kikukawa, H., Nishimura, K., Tamada, S., Uemura, M., Lopez, Y., Gietema, J., Slojewski, M., Fernandes, I., Smolin, A., Mazhar, D., Kalebasty, A. R., Carthon, B., Loidl, W., Franke, F., Girotto, G., Alimohamed, N., Macfarlane, R., Pappot, H., Niegisch, G., Mavroudis, D., Sella, A., Porta, C., Ebara, S., Nakamura, M., Obara, W., Okuno, N., Shinohara, N., Sugimoto, M., Suzuki, A., Tokuda, N., Uemura, H., Yamaguchi, A., Ramirez, F., Rozanowski, P., Wiechno, P., Keam, B., Kislov, N., Plaksin, D., Cicin, I., Kumar, S., Rosales, J., Vaishampayan, U., Culine, S., Papandreou, C., Nara, T., Erman, M., Kreiger, L., Janoski, J., Rosa, D., Siqueira, M., Canil, C., Sengelov, L., Tourani, J. -M., Arai, G., Hashine, K., Kawakita, M., Nakaigawa, N., Nomi, H., Shiina, H., Suzuki, H., Yonese, J., Kuri, R., Macedo, E., Rivera, S., Villalobos Prieto, A., Polakiewicz-Gilowska, A., Zaucha, R., Lopes, F., Ponomarev, R., Pomerantz, M., Shariat, S., Luk, C., Lesniewski-Kmak, K., Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Urologic Neoplasms, Durvalumab, Time Factors, medicine.medical_treatment, Population, Neutropenia, Antibodies, Monoclonal, Humanized, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, education, Immune Checkpoint Inhibitors, Aged, Chemotherapy, education.field_of_study, business.industry, Hazard ratio, Carcinoma, Antibodies, Monoclonal, Middle Aged, medicine.disease, Gemcitabine, Carboplatin, 030104 developmental biology, Treatment Outcome, Oncology, chemistry, 030220 oncology & carcinogenesis, Female, Urothelium, business, Tremelimumab, medicine.drug
Abstract

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

Published
2020
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10. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Beverly Moy, Hiroji Iwata, Gunter von Minckwitz, Stephen K L Chia, Janine Mansi, Carlos H Barrios, Michael Gnant, Zorica Tomašević, Neelima Denduluri, Robert Šeparović, Erhan Gokmen, Anna Bashford, Manuel Ruiz Borrego, Sung-Bae Kim, Erik Hugger Jakobsen, Audrone Ciceniene, Kenichi Inoue, Friedrich Overkamp, Joan B Heijns, Anne C Armstrong, John S Link, Anil Abraham Joy, Richard Bryce, Alvin Wong, Susan Moran, Bin Yao, Feng Xu, Alan Auerbach, Marc Buyse, Arlene Chan, Vernon Harvey, Rudolf Tomek, Nicholas J. Robert, Ira Gore, John W. Smith, Norikazu Masuda, S. Di Sean Kendall, William Graydon Harker, Katarina Petrakova, Angel Guerrero Zotano, Amparo Ruiz Simon, Zora Neskovic Konstantinovic, Nicholas O. Iannotti, Pierfrancesco Tassone, Gladys I. Rodriguez, Noelia Jáñez Martinez, Carmen Crespo Massieu, Snezana Smickoska, Isil Somali, Ugur Yilmaz, Mirta Garcia Alonso, Adolfo Murias Rosales, Soeren Cold, Ann Soegaard Knoop, Debra Patt, Beth A. Hellerstedt, Serafin Morales Murillo, Ingrid A. Mayer, Julie Ann Means-Powell, Rina Hui, Francis M. Senecal, Richard Hendry De Boer, Zhenzhou Shen, Adam Andrzej Luczak, Joanna W.Y. Chui, Janice Wing-hang Tsang, Istvan Lang, Yoshiaki Rai, Yasuo Hozumi, Albert J. Ten Tije, Manish Bhandari, Cynthia R.C. Osborne, Shoichiro Ohtani, Kenji Higaki, Kenichi Watanabe, Kazunori Taguchi, Masato Takahashi, Sladjana Filipovic, Vincent L. Hansen, Vijayarama Phooshkooru Rao, Manish Gupta, Petar Petrov, Bruno Coudert, Zeljko Vojnovic, Zsofia Polya, Toshiko Miyaki, Naohito Yamamoto, Stephen Brincat, Krzysztof Lesniewski-Kmak, Ewa Chmielowska, Ruemu E. Birhiray, Marc L. Citron, Steven William Papish, William R. Berry, Sven Tyge Langkjer, José Angel Garcia Sáenz, Ana Maria Arance, Noa Efrat, Tomasz Sarosiek, Lukasz Grzeda, Yvonne Manalo, Julie C. Smith, Irfan Vaziri, Tabitha Healey, Yasmin Rahim, Cynthia Luk, Brian Dingle, Sandra Franco, Peter Grundtvig Sorensen, Anjana Anand, Sarah Khan, George Fountzilas, Kenjiro Aogi, Satoru Shimizu, Milada Mikulova, Stanislav Spanik, Robert A. Somer, Patrick J. Flynn, Jermaine Coward, Paul Mainwaring, Guy Jerusalem, Carine Segura-Ojezzar, Christelle Levy, Thierry Delozier, David Khayat, Robert E. Coleman, Martin J. Rolles, Robert Maisano, Mario Nardi, Yoshinori Ito, Perran Fulden Yumuk, Gul Basaran, Nazim Serdar Turhal, Mary J. Wilkinson, Nathan B. Green, Algis P. Sidrys, Sigrun Hallmeyer, Douglas J. Testori, Srikala Sridhar, Jose Chang, Qiang Sun, Carlos Jara-Sanchez, Xabier Rubio, Maria Lomas Garrido, Juan Rafael De La Haba Rodriguez, Antonia Perello Martorell, Antoni Avelia Mestre, Julio Rifa Ferrer, Sonia del Barco Berron, Zsuzsanna Nagy, Maki Tanaka, Young-Hyuck Im, Robert R. Carroll, Laura C. Dickerson, Joseph R. Mace, Ragene Rivera, Leonard M. Klein, Robert Ruxer, Sharon T. Wilks, Dusan Kotasek, Vasil Popov, Violina Taskova, Violetka Marinova-Venkova, Constanta Timcheva, Christine Desbiens, Jean-Pierre Ayoub, Debjani Grenier, Norbert Marschner, Hans Tesch, Hans-Joachim Lueck, Jan Janssen, Ingo Schwaner, Stine Wahlstrom, Eva Harder Brix, Susanne Vallentin, Dan Kristensen, Anna Andreeva, Vesna Glavicic, Isabel Calvo Plaza, Antonio Anton Torres, Corinne Veyret, Jean-Pierre Bergerat, Emmanuelle Bourbouloux, Wendy Ann Ella, Hafiz Algurafi, Anne Robinson, Seung Jin Kim, Tetsuya Taguchi, Elona Juozaityte, Stanley Madretsma, Sandra Radema, Malgorzata Czerniawska-Meier, Wojciech Rogowski, Maria Wagnerova, Donald A. Richards, Elizabeth Tan-Chiu, Asskikis Vasileios, Charles Arthur Henderson, Viran Roger Holden, Xiaojia Wang, Zhongsheng Tong, Junlan Yang, Manuel Enrique Gonzalez, Mahdi Rezai, John Hackmann, Eduardo Martinez de Dueñas, Begoña Bermejo de las Heras, Louis Marie Dourthe, Dorothee Chocteau-Bouju, Philippe Bougnoux, Stylianos Kakolyris, Haralabos Kalofonos, Dimitrios Pectasidis, Ting Ying Ng, Gabor Pajkos, Eva Ezer Somogyine, Giuseppe Tonini, Dario Giuffrida, Shintaro Takao, Makoto Ishitobi, Hideo Inaji, Yutaka Tokuda, Katarzyna Wozniak, Dan Lungulescu, Yen-Shen Lu, King-Jen Chang, Julian Hill, Christopher Charles Croot, Albert Dekker, Neil D. Belman, Miguel Conde, Richard A. Michaelson, Kathleen Kemmer, Stephen Chui, Shiuh-Wen Luoh, Kenneth Nahum, Andrew R. Greenspan, Joni C. Nichols, Carlos A. Encarnacion, Thomas M.J. Niederman, Theresa Lee, Roland Alexander, Robert Gordon, Antoanet Tomova, Daniel Rauch, Razvan Andrei Popescu, Gustavo Adolfo Rojas, Jaroslav Vanasek, Tanja Neunhoeffer, Jana Barinoff, Gerd Graffunder, Abenhardt Wolfgang, Peter Bojko, Bernhard Heinrich, Albert von der Assen, Bogovic Jurij Antonovic, Lene Adrian, Manuel Ramos Vazquez, Santiago Gonzalez Santiago, Veronique Dieras, Jill Mercia Bishop, Timothy John Perren, Ioannis Varthalitis, Dimitris Mavroudis, Vassilis Georgoulias, Louis W.C. Chow, Chung Cheung Thomas Yau, Raymond Hin-Suen Liang, Béla Pikó, Agnes Wéber, Bella Kaufman, Karen Drumea, Francesco Nuzzo, Andrea De Matteis, Giacomo Carteni, Eriko Tokunaga, Mayumi Ishida, Shinji Ohno, Nobuaki Sato, Katsumasa Kuroi, Reiki Nishimura, Junichiro Watanabe, Yoon Ji Choi, Kyong Hwa Park, Marek Wojtukiewicz, Jacek Jassem, Niklas Loman, Sercan Askoy, Mustafa Kadri Altundag, Pinar Saip, Muhammad Amjad Ali, James Lloyd Wade, Amy Jo Chien, Debra Brandt, Yelena Novik, Chirag Jani, Robert L. Rice, Yousuf A. R Gaffar, Mark R. Keaton, Rajesh Bajaj, Gretchen Kimmick, David Campbell, Theodore Turnquest, Sideras Lucas, Pierre Dube, Binghe Xu, Joerg Schilling, Klaus Apel, Peter Michael Vestlev, Brita Bjerregaard Jensen, Vera Haahr, Alvaro Rodriguez Lescure, Begona Grana Suarez, Cristina Saura Manich, Jean-Philippe Jacquin, Ahmed Samreen, Ion Boiangiu, Magdolna Dank, Cristina Falci, Antonio Jirillo, Saverio Cinieri, Takayuki Ueno, Fumiaki Sato, Hiroyasu Yamashiro, Tomoharu Sugie, Keun Seok Lee, Jung Sil Ro, In Hae Park, Anita Zarina Bustam, Malgorzata Suszko-Kazarnowicz, Artur Piktel, Krzysztof Krzemieniecki, Polizenia Georgeta Iorga, Yoon Sim Yap, Marian Kakalejcik, Alper Sevinc, Mustafa Ozguroglu, Shin-Cheh Chen, Richard H. Greenberg, Allan Daniel Eisemann, Robert Droder, M. Rashid Abbasi, Marina Vaysburd, Humberto Jose Caldera, Barbara Bacsik Haley, Erwin Robin, Roger C. Inhorn, David Hufnagel, Peter D. Kenyon, Ellen Spremulli, Paula Silverman, Sharad Jain, Robert Weigand, Jeroen Mebis, Tatyana Koynova, Bernard Lesperance, Jana Prausova, Claus-Henning Kohne, Andreas Schneeweiss, Christian Jackisch, Stefan Fuxius, Ricardo Cubedo Cervera, Ander Urruticoechea Ribate, Sonia Pernas Simon, Jose Valero Gallego, Angels Arcusa Lanza, Maria del Pilar Alvarez, Jesus Florian Gerico, Laurent Cany, Justin Stebbing, Dejan Labudovic, Damir Gugic, Damir Vrbanec, Fausto Roila, Sandro Barni, Paolo Bidoli, Hirofumi Mukai, Vanessa Bermudez, Alexandru Eniu, Barry C. Mirtsching, Emad Ibrahim, Joan Trey, Paul Francis Hergenroeder, Aftab Mahmood, Anneliese Gonzalez, Edward H. Kaplan, Stacy Ban, Dhimant Patel, Billy Clowney, Karen Hoelzer, Garry H. Schwartz, Mohamed Salkeni, Jame Abraham, Sunil Narula, Khaled Jabboury, Robert Scott Mocharnuk, Richard H. McDonough, David H. Sikes, Ronald H. Kawanchi, Larry Schlabach, Samuel Spence McCachren, Thomas M. Cosgriff, Luke Dreisbach, Angela DeMichele, Lawrence Pawl, Jennifer Lucas, Lowell C. Shinn, Nabiel Alkhouri, Manish Monga, Deborah L. Lindquist, Thomas C. Anderson, Humera Khurshid, Sabrina Witherby, Nicholette Erickson, Ann Traynor, Ron Bose, Timothy J. Pluard, Michael C. Jones, Sucharu Prakash, Fabio Volterra, Gerardo Capo, Lawrence E. Flaherty, Elaina Gartner, Said Baidas, Ian Okazaki, Bichlien Nguyen, Thomas Rakowski, Ira Oliff, Joseph W. Leach, Daniel Anderson, Kendra Kubiak, Michaela Tsai, Philippe Vroman, Ines Deleu, Willem Lybaert, Marleen Borms, Felix Couture, Jonathan J. Wilson, Gordon Hunt, David R. Holland, Walter Mingrone, Shusen Wang, Donggeng Liu, Zefei Jiang, Vera Benesova, Martin Smakal, Petra Garnolova, Anne-Sophie Vesper, Monika Neumann, Wolfgang Janni, Cornelia Liedtke, Dorothea Fischer, Eva-Maria Grischke, Dietmar Seeger, Volker Moebus, Anita Prechtl, Juan Carlos Camara Toral, Alfonso Sanchez Munoz, Sonia Gonzalez Jimenez, Javier Cassinello Espinosa, Beatriz Cirauqui, Mireia Margeli Vila, Norberto Batista Lopez, Jose Ignacio Chacon Lopez-Muniz, Miguel Angel de la Cruz Mora, Audrey Mailliez, Laurence Vanlemmens, Damien Pouessel, Marc Espie, John Conibear, Rebecca Roylance, Adrian Harnett, David Geffen, Enzo Maria Ruggeri, Teresa Gamucci, Cees J. Van Groeningen, Renata Banas, Necati Alkis, Ming-Feng Hou, Amy K. Krie, Nandagopal S. Vrindavanam, Orion M. Howard, Dennis Citrin, Mark S. Morginstin, Ajit Desai, Ines J. Sanchez, David Allen Nixon, Patrick G. Beatty, Kathryn Edmiston, Marilyn McLaughlin, Jonathan D. Eneman, Cynthia A. Lynch, Edward O'Brien, Justin A. Call, Keith S. Lanier, Alison Conlin, Donald J. Brooks, Kristi McIntyre, Marc A. Saltzman, Michael J. Castine, Gregory L. Ortega, Young M. Choi, Craig H. Reynolds, Frankie Ann Brescia, Rita Kramer, Aimee D. Kohn, John P. Micha, Jessica M. Rhee, Satish Shah, David A. Riseberg, William Kevin Patterson, Jean-Paul Salmon, Chantal Andre, Alain Bols, Randal D'hondt, Sylvie Luce, Claire Nouwynck, Gino Pelgrims, Vincent Richard, Johan Verschuere, Kurt Geldhof, Clemens Caspar, Rongcheng Luo, Otakar Bednarik, Kathrin Schwedler, Marcus Schmidt, Romy Neumeister, Joachim Bischoff, Brigitte Rack, Roland Repp, Stefan Fries, Ralf Adrion, Volker Schulz, Peter Klare, Mahmoud Danei, Dirk Ossenbuhl, Jakob Manfred Kusche, Frank Griesinger, Jose Manuel Baena Canada, Purificacion Martinez del Prado, David Machover, Didier Mayeur, Nathalie Trufflandier, Valerie Delecroix, Mireille Mousseau, Marie-Ange Mouret-Reynier, Jean-Marc Nabholtz, Anula D. Chetiyawardana, Christos Papandreou, Lajos Hornyak, Zsolt Faluhelyi, Erzsebet Simo, Mario Di Palma, Francesco Cognetti, Gabriella Gorzegno, Luigi Dogliotti, Cesare Gridelli, Alfredo Falcone, Hector Soto Parra, Calogero Buscarino, Seock-Ah Im, Benito Sanchez Llamas, Wouter Dercksen, Franciscus Erdkamp, Jan B. Ruit, Hans Braun, Joanneke E.A. Portielje, Aydin Ciltas, Suleyman Buyukberber, Mustafa Benekli, Andrew J. Zahalsky, Rebecca Jaslow, Gary W. Thomas, Archana Maini, Israel Wiznitzer, Ali Khojasteh, Manuel Francisco Gonzalez, Lynn R. Kong, Aruna Padmanabhan, William A. Conkright, Sandra M. Swain, Douglas E. Faig, Kirti Jain, Ronald H. Yanagihara, Yvonne Ottaviano, Andrew Delmas, Heather A. Steele, Gordon K. Rainey, Penelope J. Harris, Jason K. Burris, Erik J. Rupard, Esther Tan, Pat W. Whitworth, Abby R. Bova, Ian C. Anderson, Mihran Shirinian, Caesar Tin-u, Timothy J. O'Rourke, Michael S. Roberts, Michael Francisco, A. Scott Pierson, Peter D. Byeff, Peter A. Kovach, John R. Caton, Mark Urban Rarick, William G. Schimidt, Alison T. Stopeck, Rachel Swart, Maria Regina Carrillo Flores, Carlos A. Alemany, Brennely Lozada, Paul L. Weinstein, Wei Wang, Michael Porubcin, David M. Ellison, George F. Geils, Edgardo Rivera, Mahmoud Charif, Martin, M, Holmes, F, Ejlertsen, B, Delaloge, S, Moy, B, Iwata, H, von Minckwitz, G, Chia, S, Mansi, J, Barrios, C, Gnant, M, Tomasevic, Z, Denduluri, N, Separovic, R, Gokmen, E, Bashford, A, Borrego, M, Kim, S, Jakobsen, E, Ciceniene, A, Inoue, K, Overkamp, F, Heijns, J, Armstrong, A, Link, J, Abraham, A, Bryce, J, Wong, A, Moran, S, Yao, B, Xu, F, Auerbach, A, Buyse, M, Chan, A, and Bidoli, P

Subjects
0301 basic medicine, Time Factors, Receptor, ErbB-2, Clinical Trial, Phase III, Receptor, ErbB-2/metabolism, Administration, Oral, Kaplan-Meier Estimate, exteNET, 0302 clinical medicine, Japan, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, pan-HER tyrosine kinase inhibitor, Mastectomy, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Middle Aged, neratinib, trastuzumab, breast cancer, adjuvant, Multicenter Study, Treatment Outcome, Oncology, Antibodies, Monoclonal, Humanized/adverse effects, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Randomized Controlled Trial, Neratinib, Quinolines, Neoplasm Invasiveness/pathology, Female, medicine.drug, Adult, medicine.medical_specialty, Quinolines/administration & dosage, Breast Neoplasms, Placebo, Antibodies, Monoclonal, Humanized, Risk Assessment, Disease-Free Survival, Drug Administration Schedule, Trastuzumab/administration & dosage, 03 medical and health sciences, Breast cancer, Breast Neoplasms/drug therapy, Double-Blind Method, Internal medicine, Journal Article, medicine, Adjuvant therapy, Humans, Comparative Study, Neoplasm Invasiveness, HER2-positive breast cancer, Neoplasm Staging, Proportional Hazards Models, Intention-to-treat analysis, Dose-Response Relationship, Drug, business.industry, medicine.disease, Survival Analysis, Mastectomy/methods, Surgery, Clinical trial, Regimen, 030104 developmental biology, business, Follow-Up Studies
Abstract

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Published
2017
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11. Urethra

Author

Donna E. Hansel, Victor E. Reuter, Bernard H. Bochner, Jason A. Efstathiou, Badrinath R. Konety, Cheryl T. Lee, Elizabeth R. Plimack, Srikala Sridhar, Walter M. Stadler, Raghunandan Vikram, and James M. McKiernan

Subjects
03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, 030218 nuclear medicine & medical imaging
Published
2016
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12. Urinary Bladder

Author

Bernard H. Bochner, Donna E. Hansel, Jason A. Efstathiou, Badrinath Konety, Cheryl T. Lee, James M. McKiernan, Elizabeth R. Plimack, Victor E. Reuter, Srikala Sridhar, Raghunandan Vikram, and Walter M. Stadler

Subjects
03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, 030232 urology & nephrology
Published
2016
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13. Embigin, a developmentally expressed member of the immunoglobulin super family, is also expressed during regression of prostate and mammary gland

Author

Mark Herley, Paul Wong, Srikala Sridhar, Martin Tenniswood, M. Mooibroek, and R. Sean Guenette

Subjects
medicine.medical_specialty, Cell adhesion molecule, Cell growth, Cell, Cell Biology, In situ hybridization, Biology, Cell biology, Extracellular matrix, medicine.anatomical_structure, Endocrinology, Cell culture, Internal medicine, Genetics, medicine, Immunoglobulin superfamily, Cell adhesion, Developmental Biology
Abstract

Cell adhesion molecules (CAMs) are intimately involved in a variety of cellular processes, including development, cell growth, apoptosis, and differentiation. Interaction of CAMs with components of the extracellular matrix (ECM) growth factors, and other CAMs provides an intricate regulatory mechanism for a diverse range of cellular responses. Embigin is a developmentally expressed protein that is a member of the immunoglobulin superfamily (IgSF) class of CAMs. We have identified embigin as a gene expressed during tissue regression in rat prostate and lactating mammary gland following hormonal ablation. In the absence of the appropriate hormone, the secretory epithelial cells of these two tissues undergo successive waves of apoptotic cell death co-incident with extensive reorganization of the surviving tissue. Using Northern analysis, in situ hybridization analysis, RT-PCR, and Western analysis we have characterized the expression of embigin mRNA and protein in both regressing prostate and mammary gland. During development of the prostate gland, increased expression of embigin is correlated with the appearance of highly organized lumenal and ductal structures. Embigin is also expressed in a variety of adult tissues including heart, liver, lung, and brain Zoo-blot analysis with the rat embigin cDNA indicates that embigin homologs exist in species as diverse as Homo sapiens and Drosophila melanogaster, suggesting that it has been highly conserved during evolution. Embigin protein is expressed at readily detectable levels in a variety of prostate and mammary cancer cell lines, and in some cell lines the expression of embigin appears to be down-regulated in the presence of ECM. Our data have led us to propose a model in which embigin functions as a regulator of cell/ECM interactions during development and in the homeostasis of normal adult tissues.

Published
1997
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14. Apoptosis and Tumor Invasion in Hormone-Dependent Cancers

Author

Zhengqi Wang, Martin Tenniswood, Hailun Tang, Ping Zhan, Sean Guenette, Srikala Sridhar, Jacintha O'Sullivan, Johnathon N. Lakins, and Colm Morrissey

Subjects
Extracellular matrix, Programmed cell death, medicine.anatomical_structure, Cytoplasm, Apoptosis, Chemistry, Growth factor, medicine.medical_treatment, Cell, medicine, Fragmentation (cell biology), Pyknosis, Cell biology
Abstract

Accumulating evidence demonstrates that apoptosis is not a single phenomenon, but a series of morphologically and biochemically related processes (1, 2). Cell death of lymphocytes and other cells of reticulo-endothelial origin is dominated by changes in nuclear morphology (3), whereas apoptosis of secretory epithelial cells involves profound cytoplasmic changes and alterations in the cell-cell and cell-substratum interactions typical of highly organized tissues (1, 3). Analysis of electron micrographs has demonstrated that the loss of the secretory epithelium after hormone withdrawal is achieved through the induction of apoptosis in both the prostate (4) and mammary gland (5). In glandular epithelia, the process of apoptosis can be broken down into several stages (Fig. 17.1). During the precondensation stage, many of the genes that are necessary for cell death are induced de novo, or recruited from other functions in the gland. The length of the precondensation stage appears to vary from cell to cell within the same tissue and probably reflects the micro-heterogeneity in the hormone or growth factor environment. The precondensation phase is followed by cytoplasmic condensation that involves the loss of the interactions between the dying cell and its neighbors as the extracellular matrix (ECM) is degraded and the cytoplasmic volume decreases. During nuclear condensation, activation of one or more endonucleases results in the fragmentation of the DNA and its marginalization to the nuclear periphery, producing the hyperchromatic, pyknotic nucleus characteristic of apoptotic cells.

Published
1997
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