62 results on '"Arpita Desai"'
Search Results
2. Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer
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Tanya Jindal, Xiaolin Zhu, Rohit Bose, Vipul Kumar, Edward Maldonado, Prianka Deshmukh, Chase Shipp, Stephanie Feng, Michelle S. Johnson, Austin Angelidakis, Daniel Kwon, Hala T. Borno, Ivan de Kouchkovsky, Arpita Desai, Rahul Aggarwal, Lawrence Fong, Eric J. Small, Anthony Wong, Sima Porten, Jonathan Chou, Terence Friedlander, and Vadim S. Koshkin
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urothelial carcinoma ,antibody drug conjugate (ADC) ,enfortumab vedotin ,genetic markers ,next generating sequencing ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundEnfortumab vedotin (EV) is an antibody-drug conjugate approved for patients with treatment-refractory advanced urothelial carcinoma (aUC), however data on biomarkers of response is lacking.MethodsWe retrospectively identified all aUC patients at our institution who received EV monotherapy and had next-generation sequencing (NGS) data available. Patients were considered responders if they had a complete response or partial response on restaging scans during treatment. Observed response rate (ORR) was evaluated by local investigator and compared between responders and non-responders using Chi-squared test. A univariable analysis was conducted using the Cox proportional hazard test to assess for associations between baseline characteristics and most common somatic alterations (in ≥10% of patients) with patient survival outcomes [progression-free survival (PFS) and overall survival (OS)]. Somatic alterations were then individually evaluated in separate multivariate models while accounting for patient and clinical characteristics using Cox regression models.ResultsAmong 29 patients treated with EV monotherapy, 27 had available NGS data. Median age was 70, 24 (83%) were men, 19 (62%) were Caucasian, 15 (52%) had pure urothelial histology and 22 (76%) had primary tumor in the bladder. ORR was 41%, and PFS and OS for the overall cohort were 5.1 months and 10.2 months. Responders were enriched among patients with TP53, KDM6A and MDM2 alterations. Patients with these alterations, as well as those with composite TP53/MDM2 alterations (alterations in either TP53 or MDM2), also had increased ORR with EV treatment compared to patients without these alterations. In the univariable analysis, baseline albumin level ≥ 3.0g/dL and presence of composite TP53/MDM2 alterations were associated with a prolonged OS. Baseline ECOG 0/1, TP53 alterations and TP53/MDM2 alterations were associated with a prolonged PFS. In the multivariable analysis, TP53 and TP53/MDM2 alterations were genomic markers predictive of improved PFS after accounting for the relevant clinical characteristics.ConclusionIn this single-center retrospective analysis of aUC patients treated with EV, presence of TP53 or MDM2 somatic alterations, lower ECOG PS scores (ECOG 0 or 1) and higher albumin levels (≥3 g/dL) were associated with improved outcomes with EV treatment. Prospective and external validation of these findings in larger cohorts is warranted.
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- 2023
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3. APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer
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Divya Natesan, Li Zhang, Henry J. Martell, Tanya Jindal, Patrick Devine, Bradley Stohr, Carlos Espinosa-Mendez, James Grenert, Jessica Van Ziffle, Nancy Joseph, Sarah Umetsu, Courtney Onodera, Michelle Turski, Emily Chan, Arpita Desai, Rahul Aggarwal, Anthony Wong, Sima Porten, Jonathan Chou, Terence Friedlander, Lawrence Fong, Eric J. Small, Alejandro Sweet-Cordero, and Vadim S. Koshkin
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bladder cancer ,APOBEC mutational signature ,tumor mutational burden ,next-generation sequencing ,urothelial cancer ,hypermutated ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionTumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study.MethodsWe retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest.ResultsAmong 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months vs 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months vs 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.ConclusionsIn a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment.
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- 2022
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4. TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor
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Li Zhang, Divya Natesan, Lawrence Fong, Emily Chan, David Y Oh, Son Ho, Ivan de Kouchkovsky, Errol J Philip, Francis Wright, Daniel M Kim, Daniel Kwon, Hansen Ho, Sima P Porten, Anthony C Wong, Arpita Desai, Franklin W Huang, Jonathan Chou, Raj S Pruthi, Eric J Small, Terence W Friedlander, and Vadim S Koshkin
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.Methods We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.Results We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).Conclusions The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.
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- 2021
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5. Outcomes With First-Line PD-1/PD-L1 Inhibitor Monotherapy for Metastatic Renal Cell Carcinoma (mRCC): A Multi-Institutional Cohort
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Pedro Barata, Whitley Hatton, Arpita Desai, Vadim Koshkin, Ellen Jaeger, Charlotte Manogue, Patrick Cotogno, Malcolm Light, Brian Lewis, Jodi Layton, Oliver Sartor, Arnab Basu, Deepak Kilari, Hamid Emamekhoo, and Mehmet A. Bilen
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metastatic renal cell carcinoma ,immunotherapy ,PD-1/PD-L1 inhibitor ,monotherapy ,first-line treatment ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: The treatment landscape of metastatic renal cell carcinoma has advanced significantly with the approval of combination regimens containing an immune checkpoint inhibitor (ICI) for patients with treatment-naïve disease. Little information is available regarding the activity of single-agent ICIs for patients with previously untreated mRCC not enrolled in clinical trials.Methods: This retrospective, multicenter cohort included consecutive treatment-naïve mRCC patients from six institutions in the United States who received ≥1 dose of an ICI outside a clinical trial, between June 2017 and October 2019. Descriptive statistics were used to analyze outcomes including objective best response rate (ORR), progression-free survival (PFS), and tolerability.Results: The final analysis included 27 patients, 70% men, median age 64 years (range 42–92), 67% Caucasian, and 33% with ECOG 2 or 3 at baseline. Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC. All patients had evidence of metastatic disease involving the lungs (59%), lymph node (41%), CNS (19%), liver (11%), adrenal gland (11%), and bone (11%). The median time on ICI was 3.1 (0.1–26.8) months, and the median PFS was 6.3 (95% CI, 0–18.6) months. Among the 21 patients with an evaluable response, the best ORR was 33%, including two complete responses and five partial responses. The ORR was 29% (n = 1 complete response, n = 5 partial response) in clear cell and 5% (n = 1 complete response) in non-clear cell RCC. Adverse events (AEs) of any cause were reported in 37% and included fatigue (11%), dermatitis (11%), diarrhea (7%), and shortness of breath (7%). Significant AEs (30%) included shortness of breath (7%), acute kidney injury (4%), dermatitis (4%), Clostridium difficile infection (4%), cerebrovascular accident (4%), and fatigue (7%). Three patients discontinued therapy due to grade 4 AEs.Conclusions: In this multi-institutional case series, single-agent ICI demonstrated objective responses and was well tolerated in a heterogeneous treatment-naïve mRCC cohort. ICI monotherapy is not the standard of care for patients with mRCC, and further investigation is necessary to explore predictive biomarkers for optimal treatment selection in this setting.
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- 2020
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6. Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options
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Arpita Desai, Smitha P. Menon, and Grace K. Dy
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RAS ,RAF ,MEK ,receptor tyrosine kinases (RTK) ,fibroblast growth factor receptor (FGFR) ,non-small cell lung cance (NSCLC) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
During the last decade, we have seen tremendous progress in the therapy of lung cancer. Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects. In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway.
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- 2016
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7. Impact of squamous differentiation on clinical outcomes and molecular profiling in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint inhibitors (ICIs) or enfortumab vedotin (EV)
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Tanya Jindal, Li Zhang, Prianka Deshmukh, Kevin Reyes, Emily Chan, Vipul Kumar, Xiaolin Zhu, Edward Maldonado, Stephanie Feng, Michelle Johnson, Austin Angelidakis, Daniel Kwon, Arpita Desai, Hala T Borno, Rohit Bose, Anthony Wong, Julian Hong, Peter Carroll, Maxwell Meng, Sima Porten, Rahul Aggarwal, Eric J Small, Lawrence Fong, Jonathan Chou, Terence Friedlander, Ivan de Kouchkovsky, and Vadim S Koshkin
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Oncology ,Urology - Published
- 2023
8. Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology
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Robert J. Motzer, Eric Jonasch, Neeraj Agarwal, Ajjai Alva, Michael Baine, Kathryn Beckermann, Maria I. Carlo, Toni K. Choueiri, Brian A. Costello, Ithaar H. Derweesh, Arpita Desai, Yasser Ged, Saby George, John L. Gore, Naomi Haas, Steven L. Hancock, Payal Kapur, Christos Kyriakopoulos, Elaine T. Lam, Primo N. Lara, Clayton Lau, Bryan Lewis, David C. Madoff, Brandon Manley, M. Dror Michaelson, Amir Mortazavi, Lakshminarayanan Nandagopal, Elizabeth R. Plimack, Lee Ponsky, Sundhar Ramalingam, Brian Shuch, Zachary L. Smith, Jeffrey Sosman, Mary A. Dwyer, Lisa A. Gurski, and Angela Motter
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Oncology ,Humans ,Medical Oncology ,Carcinoma, Renal Cell ,Kidney Neoplasms ,Article - Abstract
The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as “Preferred,” “Other Recommended Regimens,” or “Useful in Certain Circumstances.” This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.
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- 2022
9. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
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Thomas Powles, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Stefan N Symeonides, Jaroslav Hajek, Howard Gurney, Yen-Hwa Chang, Jae Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Mauricio Mahave, Naomi B Haas, Piotr Sawrycki, Joseph E Burgents, Lei Xu, Kentaro Imai, David I Quinn, Toni K Choueiri, Toni Choueiri, Thomas R. Ferguson, Tzu-Ping Lin, Stefan N. Symeonides, Naomi B. Haas, Howard P. Gurney, Christine Chevreau, John M. Burke, Gurjyot Doshi, Bohuslav Melichar, Delphine Topart, Stephane Oudard, Evgeniy Kopyltsov, Hans-Joerg Hammers, David I. Quinn, Ajjai Alva, Juliana de Janoski Menezes, Adriano Goncalves e Silva, Eric W. Winquist, Alketa Hamzaj, Giuseppe Procopio, Boguslawa Karaszewska, Ewa M. Nowakowska-Zajdel, Boris Y. Alekseev, Rustem A. Gafanov, Adel Izmailov, Andrey Semenov, Sergey G. Afanasyev, Oleg N. Lipatov, Thomas B. Powles, Sandy Srinivas, David McDermott, Samith T. Kochuparambil, Ian D. Davis, Katriina Peltola, Roberto Sabbatini, Jinsoo Chung, Michail I. Shkolnik, Vsevolod B. Matveev, Pablo Gajate Borau, Steven McCune, Thomas E. Hutson, Alejandro Dri, Silvio Correia Sales, Carrie Yeung, Carmen Marcela Alcala Castro, Peter Bostrom, Brigitte Laguerre, Consuelo Buttigliero, Ugo de Giorgi, Eugeniy A. Fomin, Yousef Zakharia, Clara Hwang, Eric A. Singer, Jeffrey T. Yorio, David Waterhouse, Ruben Dario Kowalyszyn, Margarita Sonia Alfie, Eduardo Yanez Ruiz, Tomas Buchler, Krista Kankaanranta, Gianluigi Ferretti, Go Kimura, Kazuo Nishimura, Naoya Masumori, Satoshi Tamada, Haruaki Kato, Hiroshi Kitamura, Iwona Danielewicz, Joanna Wojcik-Tomaszewska, Nuria Sala Gonzalez, Kun-Yuan Chiu, Michael B. Atkins, Elisabeth Heath, Gustavo Adolfo Rojas-Uribe, Manuel Enrique Gonzalez Fernandez, Susan Feyerabend, Sandro Pignata, Kazuyuki Numakura, Bozena Cybulska Stopa, Ruslan Zukov, Miguel Angel Climent Duran, Pablo Jose Maroto Rey, Alvaro Montesa Pino, Chao-Hsiang Chang, Salil Vengalil, Tom S. Waddell, Patrick W. Cobb, Ralph Hauke, Daniel M. Anderson, John Sarantopoulos, Theodore Gourdin, Tian Zhang, Gautam Jayram, Luis Enrique Fein, Carole Harris, Patricia Medeiros Milhomem Beato, Francisco Flores, Angela Estay, Juan Andres Rubiano, Jens Bedke, Stefan Hauser, Andreas Neisius, Jonas Busch, Satoshi Anai, Hiroyuki Tsunemori, Dariusz Sawka, Bozena Sikora-Kupis, Jose Angel Arranz, Ignacio Delgado, Chung-Hsin Chen, Elizabeth Gunderson, Scott Tykodi, Alan Koletsky, Kevin Chen, Manish Agrawal, Diego Lucas Kaen, Juan Pablo Sade, Marcelo Daniel Tatangelo, Francis Parnis, Fernando Maciel Barbosa, Genevieve Faucher, Nayyer Iqbal, Daniele Marceau, Jean-Benoit Paradis, Nawar Hanna, Alejandro Acevedo, Carolina Ibanez, Luis Villanueva, Pedro Pablo Galaz, Isabel Cristina Durango, Ray Manneh, Zdenek - Kral, Petra Holeckova, Heikki Hakkarainen, Hanna Ronkainen, Sophie Abadie-Lacourtoisie, Sophie Tartas, Peter J. Goebell, Marc-Oliver Grimm, Thomas Hoefner, Manfred Wirth, Andrej Panic, Wolfgang Schultze-Seemann, Akira Yokomizo, Ryuichi Mizuno, Hirotsugu Uemura, Masatoshi Eto, Masao Tsujihata, Yoshihisa Matsukawa, Yoji Murakami, Miso Kim, Paul Hamberg, Malgorzata Marczewska-Skrodzka, Cezary Szczylik, Alison C. Humphreys, Peter Jiang, Birendra Kumar, Gary Lu, Arpita Desai, Jose Antonio Karam, George Keogh, Mark Fleming, Juan Jose Zarba, Viviana E. Leiva, Guillermo Ariel Mendez, Samuel J. Harris, Stephen J. Brown, Joao Neif Antonio Junior, Rita de Cassia Costamilan, Roberto Odebrecht Rocha, David Muniz, Leandro Brust, Aly-Khan Lalani, Jeffrey Graham, Michael Levesque, Francisco Orlandi, Rostislav Kotasek, Jean L. Deville, Delphine Borchiellini, Axel Merseburger, Michael Rink, Frederik Roos, Ray McDermott, Masafumi Oyama, Yoshiaki Yamamoto, Yoshihiko Tomita, Yuji Miura, Naomasa Ioritani, Hans Westgeest, Tomasz Kubiatowski, Wieslaw Bal, Regina Girones Sarrio, Julie Rowe, Debra M. Prow, Francis Senecal, Neda Hashemi-Sadraei, Scott W. Cole, Stephan D. Kendall, Donald A. Richards, Ian D. Schnadig, and Mukul Gupta
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Adult ,Oncology ,Double-Blind Method ,Antineoplastic Combined Chemotherapy Protocols ,Hypertension ,Humans ,Antibodies, Monoclonal, Humanized ,Carcinoma, Renal Cell ,Nephrectomy ,Kidney Neoplasms ,Follow-Up Studies - Abstract
Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (
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- 2022
10. Differential treatment outcomes in BRCA1/2 ‐, CDK12 ‐, and ATM ‐mutated metastatic castration‐resistant prostate cancer
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Melissa A. Reimers, Vadim S. Koshkin, Felix Y. Feng, Hala T. Borno, Alexander W. Wyatt, Steven Yip, Francis Wright, Rahul Aggarwal, Li Zhang, Daniel Kwon, Kim N. Chi, Ajjai Alva, Arpita Desai, Eric J. Small, Mallika Sachdev Dhawan, and Jonathan Chou
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Ataxia Telangiectasia Mutated Proteins ,Docetaxel ,Carboplatin ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Nitriles ,medicine ,Humans ,Enzalutamide ,030212 general & internal medicine ,education ,Retrospective Studies ,Chemotherapy ,education.field_of_study ,BRCA1 Protein ,Proportional hazards model ,business.industry ,medicine.disease ,Cyclin-Dependent Kinases ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,chemistry ,Cabazitaxel ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Background DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. Methods A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. Results The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. Conclusions Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.
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- 2021
11. Serial stereotactic body radiation therapy for oligometastatic prostate cancer detected by novel PET-based radiotracers
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Daniel H. Kwon, Nonna Shakhnazaryan, David Shui, Julian C. Hong, Osama Mohamad, Ivan de Kouchkovsky, Hala T. Borno, Rohit Bose, Jonathan Chou, Arpita Desai, Lawrence Fong, Terence W. Friedlander, Vadim S. Koshkin, Rahul R. Aggarwal, Felix Y. Feng, Thomas A. Hope, and Eric J. Small
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Oncology ,Urology - Abstract
Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11 and F-18-Fluciclovine, are increasingly used to inform therapies for prostate cancer (CaP). Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic CaP has been shown to improve progression free survival (PFS) and delay androgen deprivation therapy (ADT) compared to observation. For men who subsequently develop oligorecurrent CaP, outcomes following second SBRT are unknown.A retrospective cohort study was conducted. Eligibility criteria included patients with oligometastatic (1-5 lesions) CaP detected on PSMA or Fluciclovine PET who underwent 2 consecutive SBRT courses to tracer-avid sites. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline ≥50% (PSA50), PFS after SBRT2, and ADT initiation or intensification-free survival after SBRT2. Factors potentially associated with PSA50 after SBRT2 was evaluated with multivariable logistic regression. Factors potentially associated with PFS and ADT initiation/intensification-free survival after SBRT2 were evaluated with separate multivariable Cox proportional-hazards models.Twenty-five patients were identified. At SBRT2, oligorecurrence was detected on PSMA and Fluciclovine PET in 17 (68%) and 8 (32%) patients, respectively. Fifteen (60%) patients had castration-sensitive disease and 10 (40%) had castration-resistant disease. After SBRT2, 16 (64%) achieved a PSA50 response, median PFS was 11.0mo, and median ADT initiation/intensification-free survival was 23.2mo. On multivariable analysis, maximum percent change in PSA after SBRT1 (OR 0.94, 95%CI 0.88-0.99, P = 0.046) and concurrent change in systemic therapy (OR 21.61, 95%CI 1.12-417.9, P = 0.042) were associated with PSA50 responses after SBRT2. PSA50 response after SBRT1 was associated with improved PFS (HR 0.36, 95%CI 0.00-0.42, P = 0.008) and ADT initiation/intensification-free survival (HR 0.07, 95%CI 0.01-0.68, P = 0.021) after SBRT2. From SBRT1 to last follow-up (median 48 months), 7 (28%) patients remained ADT-free.Serial SBRT for oligometastatic CaP detected on PSMA or Fluciclovine PET is feasible and can achieve PSA declines, with or without systemic therapy. Degree of biochemical response to first SBRT warrants further study as a potential predictor of PSA response, PFS, and ADT initiation/intensification-free survival following a subsequent SBRT course. This preliminary evidence provides rationale for larger, prospective studies of this strategy.
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- 2023
12. Association of biomarkers and response to immune checkpoint inhibitors (ICIs) in patients with metastatic urothelial carcinoma (mUC) with high and low tumor mutation burden (TMB)
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Tanya Jindal, Xiaolin Zhu, Li Zhang, Kevin R Reyes, Prianka Deshmukh, Ivan de Kouchkovsky, Vipul Kumar, Edward Maldonado, Chase Shipp, Daniel H Kwon, Hala Borno, Rohit Bose, Arpita Desai, Rahul Raj Aggarwal, Sima P. Porten, Eric Jay Small, Lawrence Fong, Jonathan Chou, Terence W. Friedlander, and Vadim S Koshkin
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Cancer Research ,Oncology - Abstract
534 Background: ICIs are frequently used as therapy in mUC, but only a minority of patients (pts) respond to treatment. High TMB is associated with improved outcomes to ICIs. However, much is unknown about biomarkers associated with ICI outcomes in pts with high and low TMB respectively. Methods: We retrospectively identified mUC pts with known TMB status and available next generation sequencing (NGS) results treated with ICI monotherapy at our institution. TMB high was defined as ≥ 10 mutations/Mb, with the rest being TMB low. Somatic alterations present in ≥10% pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), and presence of DNA damage response (DDR) alterations were assessed as biomarkers of interest. Within the TMB-high and TMB-low pt groups we separately assessed patients based on the presence or absence of these somatic alterations, APOBEC mutational signature and high PD-L1 expression. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. P-value ≤0.05 was considered significant. Results: Among 107 mUC pts treated with ICI monotherapy between 12/2014 and 3/2022 who had NGS data (UCSF500, FoundationOne, Strata), 85 pts had TMB data, including 47 TMB high pts and 38 TMB low pts. Among 85 pts with known TMB status, median age was 76 yrs, the majority were male (55, 65%), Caucasian (57, 67%), had pure urothelial histology (46, 55%) and were treated with ICIs in frontline setting (47, 55%). Median OS was 17.2 mos and median PFS was 3.42 mos. In TMB high pts, presence of DDR , MLL2, KDM6A, PIK3CA and TERTp alterations were each associated with improved outcomes, while presence of CDKN2B alterations was associated with inferior outcomes (Table). Among TMB low pts, those with RB1 alterations had shorter mOS (11.3 months vs 17.2 months; p=0.04) compared to wild-type pts. Conclusions: In this single-center retrospective analysis of mUC pts, we identified somatic alterations that were predictive of outcomes with ICI treatment in TMB high and TMB low pts respectively. Further exploration of biomarkers in patients stratified by TMB status is warranted in larger cohorts. [Table: see text]
- Published
- 2023
13. Molecular Container and Metal Ion Sensor Chiral Cavitands
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Arpita Desai, Thennati Rajamannar, and Shailesh R. Shah
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Metal ,Materials science ,Molecular recognition ,visual_art ,visual_art.visual_art_medium ,General Chemistry ,Selectivity ,Container (type theory) ,Combinatorial chemistry ,Molecular tweezers - Published
- 2020
14. NCCN Guidelines Insights: Kidney Cancer, Version 1.2021
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Brittany McCreery, Bryan Lewis, Naomi B. Haas, Lakshminarayanan Nandagopal, Mary A. Dwyer, Angela D. Motter, Christos Kyriakopoulos, Ajjai Alva, Maria I. Carlo, Phillip M. Pierorazio, M. Dror Michaelson, Sundhar Ramalingam, Brandon Manley, Clayton Lau, Lee Ponsky, Eric Jonasch, Neeraj Agarwal, David C. Madoff, Elizabeth R. Plimack, Bradley G. Somer, Jeffrey A. Sosman, Robert J. Motzer, Amir Mortazavi, Steven L. Hancock, Shawna L. Boyle, Elaine T. Lam, Ithaar Derweesh, Brian Shuch, Katy Beckermann, Arpita Desai, Saby George, Brian A. Costello, Zachary L. Smith, John L. Gore, and Toni K. Choueiri
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,MEDLINE ,Treatment options ,urologic and male genital diseases ,medicine.disease ,Systemic therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Renal cell carcinoma ,030220 oncology & carcinogenesis ,Carcinoma ,Medicine ,030212 general & internal medicine ,business ,Intensive care medicine ,Stage iv ,Kidney cancer ,Genetic testing - Abstract
The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.
- Published
- 2020
15. Synthesis of Calix-Salen Silver Corates for Evaluation of Their Antimicrobial and Anticancer Activities
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Arpita Desai, Hetal Roy, and Mihamee Deolalkar
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Engineering ,Thesaurus (information retrieval) ,business.industry ,medicine.drug_class ,General Chemical Engineering ,Antibiotics ,General Chemistry ,Antimicrobial ,Article ,World Wide Web ,Chemistry ,medicine ,business ,QD1-999 - Abstract
Silver-based products are becoming popular as antimicrobial agents because of the failure of antibiotics available for tackling the drug-resistant microbial strains. As silver is well tolerated by normal human cells, silver complexes have emerged as important antineoplastic agents. Further, if silver ions are encapsulated within an organic molecule—an azacorand—it may serve as a better substitute for cisplatin or other metal complexes. The calix-salen-type corates were synthesized using silver ions as the template. 5,5′-methylene-bis-salicylaldehyde was reacted with ethylene diamine in methanol at room temperature in the presence of silver nitrate. The resultant corand trapped the silver template in their cavity. The electron-withdrawing and electron-releasing groups like −NO2, −Br, −C(CH3)3, and −OCH3 were substituted on the bis-aldehyde to study their effects on the antimicrobial and anticancer activities of silver corates. The silver corates were found to have better antimicrobial activity than some of the standard drugs. Bromo-substituted corate-3, nitro-substituted corate-4, and tert-butyl-substituted corate-5 were found to be potent antibacterial agents among all. The bromo-substituted corate-3 was found to be the most potent fungicidal agent among all silver corates. The result of antineoplastic activity suggests that unsubstituted corate-1 and bromo-substituted corate-3 are potential candidates to be used as therapeutic molecules for cancer treatment, which requires further validation.
- Published
- 2019
16. Mobile Audio Recording Technology to Promote Informed Decision Making in Advanced Prostate Cancer
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Daniel H. Kwon, Sneha Karthikeyan, Alison Chang, Hala T. Borno, Vadim S. Koshkin, Arpita Desai, Rohit Bose, Terence Friedlander, Tammy Rodvelt, Patricia Li, Eric J. Small, Rahul R. Aggarwal, and Jeffrey Belkora
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Male ,Prostatic Neoplasms, Castration-Resistant ,Technology ,Oncology ,Oncology (nursing) ,Health Policy ,Decision Making ,Humans ,Pilot Projects ,Referral and Consultation - Abstract
PURPOSE: Men with metastatic castration-resistant prostate cancer increasingly encounter complex treatment decisions. Consultation audio recordings and summaries promote patient informed decision making but are underutilized. Mobile recording software applications may increase access. Little is known regarding the feasibility of implementation in clinical encounters. METHODS: We conducted a mixed-methods pilot study in men with progressive metastatic castration-resistant prostate cancer. We instructed patients to use a mobile software application to record an oncology visit. Patients could share the recording with our patient scribing program to receive a written summary. We assessed feasibility and acceptability with postvisit surveys. We measured patient-reported helpfulness of the intervention in decision making and change in Decisional Conflict Scale–informed subscale. We conducted semistructured interviews to explore implementation and analyzed transcripts using thematic analysis. RESULTS: Across 20 patients, 18 (90%) recorded their visits. Thirteen of 18 (72%) listened to the recording, and 14 of 18 (78%) received a summary. Eighteen of 20 (90%) visits were telehealth. Fourteen patients (70% of all 20; 78% of 18 question respondents) found the application easy to use. Nine patients (50% of 18 recording patients; 90% of 10 question respondents) reported that the recording helped treatment decision making. Decisional conflict decreased from baseline to 1-week postvisit (47.4-28.5, P < .001). Interviews revealed benefits, facilitators, contextual factors, and technology and patient-related barriers to recordings and summaries. CONCLUSION: In this single-institution academic setting, a mobile application for patients to record consultations was a feasible, acceptable, and potentially valued intervention that improved decision making in the telehealth setting. Studies in larger, diverse populations are needed.
- Published
- 2021
17. Reliability of real-world data for diagnosis of metastatic prostate cancer
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Christina Phuong, Amy M. Lin, Izzy Friesner, Lisa Ni, Rahul Raj Aggarwal, Hala Borno, Vadim S Koshkin, Arpita Desai, Terence W. Friedlander, Lawrence Fong, Rohit Bose, Jonathan Chou, Tammy J. Rodvelt, Osama Mohamad, Anthony C. Wong, Felix Y Feng, Eric Jay Small, and Julian C. Hong
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Cancer Research ,Oncology - Abstract
397 Background: Real-world data (RWD) is playing an increasingly important role in cancer research. Surrogate endpoints such as metastasis-free survival play an important role in prostate cancer research, leading to interest in its computational extraction, typically with use of International Classification of Disease (ICD) metastatic codes. While prior studies have suggested that ICD codes are valid for identification of patients (pts) with metastatic prostate cancer (MPC), delays in coding may impact their accuracy. The objective of this informatics-based study is to quantify the time delay between diagnosis of MPC and entry of ICD MPC-related code and its interaction with changing institutional healthcare processes. Methods: A single institutional EHR data warehouse was queried to identify a random sample of 100 pts with MPC diagnosis based on ICD codes (ICD10 C79 or ICD9 198.5) from 2013-2021 who were also seen in the genitourinary medical oncology program (GUMOP). Of note, in 6/2018, the GUMOP adopted EHR-specific MPC visit diagnosis identifiers (Dx ID) to improve MPC coding during clinic independent of ICD codes typically used by RWD researchers. Thus, the study cohort was designed to include pts whose first follow up after being diagnosed with MPC was before (n = 50) or after (n = 50) Dx ID implementation. Date of first MPC ICD code entry at any point in the EHR was compared against true date of MPC, based on physician review of definitive imaging or pathology. Data analysis was performed with Wilcox Signed rank test, bivariate analyses, and multivariable linear regression. Covariates included modality of diagnosis confirmation and timing with Dx ID implementation. Results: One hundred pts with MPC ICD coded in the EHR were included, with 29 pts diagnosed by PSMA PET and 71 by conventional imaging. Median time from true MPC diagnosis to first subsequent clinic follow up was < 1 month (IQR 0-2), while median time from true MPC diagnosis to entry of ICD MPC-related code was longer at 4mo (IQR 0-15). 5 pts had C79 applied for N1 disease and 10 pts for work-up of biochemical recurrence. On multivariable analysis of potential factors affecting time interval to MPC ICD entry, Dx ID implementation (b = -6.5 mo [95% CI -1.8 to -11.2], p = 0.007) and non-PSMA based diagnosis (b = -5.7 mo [95% CI -0.5 to -10.8], p = 0.03) were independently associated with shorter time to ICD coding. In subset analysis of the cohort after Dx ID implementation, use of both ICD and Dx ID to identify pts with MPC reduced the median time from true MPC diagnosis to EHR coding (1mo, IQR 0-6.3) compared to ICD alone (2mo, IQR 0-8) (p = 0.003). Conclusions: Timing of MPC ICD entry is highly variable and may carry biases derived from healthcare processes, including data entry and diagnostic testing. This may be improved with EHR workflow interventions. It is essential to have domain knowledge of clinical coding practices to improve information retrieval and recognize potential limitations and biases.
- Published
- 2022
18. Micellization and clouding behaviour of an ionic surfactant in a deep eutectic solvent: A case of the reline-water mixture
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Darshna Hirpara, Brijesh Patel, Vishwajit Chavda, Arpita Desai, and Sanjeev Kumar
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Materials Chemistry ,Physical and Theoretical Chemistry ,Condensed Matter Physics ,Spectroscopy ,Atomic and Molecular Physics, and Optics ,Electronic, Optical and Magnetic Materials - Published
- 2022
19. Multi-institutional Analysis of the Clinical and Genomic Characteristics of Black Patients with Metastatic Hormone-Sensitive Prostate Cancer
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Meredith N Freeman, Albert Jang, Jason Zhu, Farhad Sanati, Lakshminarayanan Nandagopal, Deepak Ravindranathan, Arpita Desai, Audrey Phone, Roberto Nussenzveig, Ellen Jaeger, Sydney A Caputo, Vadim S Koshkin, Umang Swami, Arnab Basu, Mehmet A Bilen, Neeraj Agarwal, Oliver Sartor, Earle F Burgess, and Pedro C Barata
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Male ,Cancer Research ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Oncology ,Humans ,Prostatic Neoplasms ,Androgen Antagonists ,Middle Aged ,Hormones ,Retrospective Studies - Abstract
Background The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. Methods A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. Results A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). Conclusion In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.
- Published
- 2021
20. TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor
- Author
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Vadim S. Koshkin, Sima P. Porten, Anthony C. Wong, David Y. Oh, Lawrence Fong, Arpita Desai, Ivan de Kouchkovsky, Eric J. Small, Francis Wright, Hansen Ho, Daniel Kwon, Errol J. Philip, Raj S. Pruthi, Divya Natesan, Terence W. Friedlander, Son Ho, Li Zhang, Jonathan Chou, Emily Chan, Franklin W. Huang, and Daniel M Kim
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,Time Factors ,medicine.medical_treatment ,DNA Mutational Analysis ,Logistic regression ,0302 clinical medicine ,Risk Factors ,Immunology and Allergy ,Telomerase ,Immune Checkpoint Inhibitors ,RC254-282 ,Cancer ,screening and diagnosis ,Tumor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,High-Throughput Nucleotide Sequencing ,Progression-Free Survival ,Detection ,030220 oncology & carcinogenesis ,Cohort ,Molecular Medicine ,Female ,immunotherapy ,urinary bladder neoplasms ,4.2 Evaluation of markers and technologies ,medicine.medical_specialty ,Urologic Neoplasms ,Metastatic Urothelial Carcinoma ,Immunology ,Risk Assessment ,Promoter Regions ,03 medical and health sciences ,Genetic ,Predictive Value of Tests ,Clinical Research ,Internal medicine ,medicine ,Genetics ,Humans ,Retrospective Studies ,Aged ,Pharmacology ,Chemotherapy ,Performance status ,Proportional hazards model ,business.industry ,Carcinoma ,Human Genome ,Immunotherapy ,030104 developmental biology ,Good Health and Well Being ,Genetic marker ,tumor biomarkers ,Mutation ,genetic markers ,Urothelium ,business ,Biomarkers - Abstract
BackgroundImmune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.MethodsWe undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.ResultsWe identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).ConclusionsThe presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.
- Published
- 2021
21. Treatment of advanced renal cell carcinoma patients with cabozantinib, an oral multityrosine kinase inhibitor of MET, AXL and VEGF receptors
- Author
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Arpita Desai and Eric J. Small
- Subjects
0301 basic medicine ,Cancer Research ,Cabozantinib ,Tumor suppressor gene ,Pyridines ,Administration, Oral ,urologic and male genital diseases ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Renal cell carcinoma ,Proto-Oncogene Proteins ,Humans ,Medicine ,Anilides ,Receptor ,Carcinoma, Renal Cell ,Protein Kinase Inhibitors ,neoplasms ,Neoplasm Staging ,Clinical Trials as Topic ,business.industry ,Kinase ,Receptor Protein-Tyrosine Kinases ,General Medicine ,Proto-Oncogene Proteins c-met ,medicine.disease ,Axl Receptor Tyrosine Kinase ,Kidney Neoplasms ,female genital diseases and pregnancy complications ,Receptors, Vascular Endothelial Growth Factor ,Treatment Outcome ,030104 developmental biology ,Oncology ,chemistry ,Von Hippel-Lindau Tumor Suppressor Protein ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Signal transduction ,business ,Carcinogenesis ,Tyrosine kinase ,Signal Transduction - Abstract
Von Hippel–Lindau ( VHL), a tumor suppressor gene, is frequently inactivated in renal cell carcinoma (RCC). It drives tumorigenesis by activating downstream hypoxia responsive genes and proangiogenic factors like VEGFR, and is responsible for the activity of tyrosine kinase inhibitors in RCC. Resistance to VEGFR therapy eventually occurs, in part due to activation of alternative signaling pathways like AXL and MET. Cabozantinib is a potent inhibitor of VEGF, AXL and MET receptors providing rationale for its use in RCC. Cabozantinib has been approved for use in the first- and second-line setting in patients with advanced RCC. This manuscript reviews the preclinical data, pharmacology, clinical efficacy and safety of the use of cabozantinib in RCC.
- Published
- 2019
22. Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy
- Author
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Betsy Morrow, Ming K. Lee, Jun Wei, Anish Thomas, Liqiang Xi, Raffit Hassan, Idrees Mian, Mary Claire King, Tom Walsh, Jingli Zhang, Snehal Patel, Vasiliki Panou, David S. Schrump, Jane E. Churpek, Arpita Desai, Mark Raffeld, Emerson Padiernos, Javed Khan, Meghana Gadiraju, Shaojian Gao, Kathleen A. Calzone, Mary Hesdorffer, Suleyman Gulsuner, Christine Alewine, Seth M. Steinberg, and Hedy L. Kindler
- Subjects
Adult ,Male ,Mesothelioma ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,DNA Repair ,DNA repair ,Pleural Neoplasms ,medicine.disease_cause ,Young Adult ,Survival ,Prostate ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Genotype ,medicine ,Humans ,BAP1 ,Genetic Predisposition to Disease ,Gene ,Germ-Line Mutation ,Aged ,Platinum ,Aged, 80 and over ,Mutation ,Multidisciplinary ,DNA repair genes ,business.industry ,Tumor Suppressor Proteins ,Nherited genetics ,Mesothelioma, Malignant ,Biological Sciences ,Middle Aged ,medicine.disease ,Survival Analysis ,respiratory tract diseases ,medicine.anatomical_structure ,Peritoneal mesothelioma ,Female ,business ,Ubiquitin Thiolesterase - Abstract
Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.
- Published
- 2019
23. An interplay between spacer nature and alkyl chain length on aqueous micellar properties of cationic Gemini surfactants: A multi-technique approach
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Kushan Parikh, Sneha Singh, Arpita Desai, and Sanjeev Kumar
- Subjects
chemistry.chemical_classification ,Aqueous solution ,Aggregation number ,Conductometry ,Chemistry ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,Krafft temperature ,Micelle ,Atomic and Molecular Physics, and Optics ,0104 chemical sciences ,Electronic, Optical and Magnetic Materials ,Dynamic light scattering ,Critical micelle concentration ,Materials Chemistry ,Physical chemistry ,Physical and Theoretical Chemistry ,0210 nano-technology ,Spectroscopy ,Alkyl - Abstract
Micellar parameters (critical micelle concentration (cmc), degree of micellar ionization (α), Krafft temperature (Tk), micro-polarity, aggregation number (Nagg) and dielectric constant (ea)) of aqueous cationic geminis (denoted as m-s-m; where, m = 12 or 14 and s = polymethylene, diester, diamido or diester isosorbate) have been studied by multi-technique approach (conductometry, fluorescence and 1H NMR) and compared with alkyltrimethylammonium bromide (CmTAB). Geminis show lower cmc and Tk than CmTAB. Among the geminis, hydrophilic spacer containing geminis show even lower cmc and Tk than the polymethylene spacer geminis. Temperature dependence of cmc shows a decrease, constancy followed by an increase (U-shaped behaviour) as s or m changes. Thermodynamic parameters have been obtained by temperature dependence of cmc. Intra-micellar monomeric arrangement and micellar size information have been acquired by 2D NOESY/COSY 1H NMR and dynamic light scattering (DLS), respectively. Data suggest that the hydrophilic spacer based geminis produce compact micelles with higher polarity compared to polymethylene spacer geminis (or CmTAB). The approach might be employed to tune the micellar interior environment/size, by changing the nature of the spacer or m.
- Published
- 2019
24. Calix-salen cavitand as colorimetric chemosensor for Cu2+ and anticancer activity of copper cavitate
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R.N. Jadeja, Arpita Desai, and Hetal Roy
- Subjects
inorganic chemicals ,Chemistry ,Cavitand ,chemistry.chemical_element ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Alkali metal ,01 natural sciences ,Copper ,Transition metal ions ,0104 chemical sciences ,Ion ,Inorganic Chemistry ,Materials Chemistry ,Physical and Theoretical Chemistry ,Absorption (chemistry) ,0210 nano-technology ,Cytotoxicity ,Stoichiometry ,Nuclear chemistry - Abstract
The calix-salen cavitand is found to bind Cu2+ preferentially among the 1st raw transition metal ions and alkali metal ions. The marked change was observed in the absorption maximum of cavitand on recognition of Cu2+ ion. The binding of copper ion also reflected in the visual colour change from yellow to green. The binding was selective for Cu2+ with little interference from iron. From Job's plot it is found that the cavitand binds copper with 1:1 stoichiometry which is further supported by DFT calculations. We synthesized the copper-cavitate and characterized it by spectroscopic techniques. Cytotoxicity assay using MTT was performed to determine anti-proliferative efficacy of copper-cavitate on IMR 32, MCF-7 and L132 cell lines. The copper cavitate is found to be potent antineoplastic agent. The same has been confirmed by gene expression studies.
- Published
- 2019
25. Mixed micellization/clouding assisted solubilization of polycyclic aromatic hydrocarbon: Potential in environmental remediation
- Author
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Sneha Singh, Sanjeev Kumar, Sanjay Kumar Yadav, Sandhya Dixit, Arpita Desai, and Kushan Parikh
- Subjects
chemistry.chemical_classification ,Anthracene ,Inorganic chemistry ,Polycyclic aromatic hydrocarbon ,02 engineering and technology ,Fluorene ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,Micelle ,Atomic and Molecular Physics, and Optics ,0104 chemical sciences ,Electronic, Optical and Magnetic Materials ,Hydrophobic effect ,chemistry.chemical_compound ,chemistry ,Critical micelle concentration ,Materials Chemistry ,Pyrene ,Physical and Theoretical Chemistry ,Solubility ,0210 nano-technology ,Spectroscopy - Abstract
Micellization and clouding behaviors of an anionic gemini surfactant, phosphoric acid, P, P′‑1,4‑butanedieyl P, P′‑didodecyl ester, disodium salt (12-4-12A), in aqueous solution, have been investigated in the presence of a surface active ionic liquid (SAIL), tetra n‑pentylammonium bromide (TPeAB). Critical micelle concentration and 1H NMR data show synergistic interactions/intercalation of n‑pentyl chain between the 12-4-12A monomers constituting the micelle, respectively. 12-4-12A + TPeAB system showed the cloud point (CP) at distinctly lower [12-4-12A]. Amino acid/cyclodextrin has been used to tune the CP. DLS and TEM data suggest the formation of n‑pentyl chain (of the SAIL) mediated linked aggregates whose size decreases with lowering [TPeAB] while compactness increases by β-CD. POM data showed that larger aggregates are formed near the CP. This may be due to increased hydrophobic interactions (between dodecyl chains of the gemini and pentyl chains of the TPeAB) and decreased electrostatic repulsion (as indicated by lowering zeta-potential value at CP). Mixtures, with or without β-CD, are used for solubilization/co‑solubilization of polyaromatic hydrocarbon (PAHs-anthracene, pyrene or fluorene). Molar solubilization ratio (MSR) has been computed using UV–Visible spectrophotometry. The percentage MSR value increases in order: Anthracene > Pyrene > Fluorene in comparison to pure 12-4-12A. Cloud point extraction of anthracene shows that it concentrates ~93% in surfactant rich phase (SRP). However, anthracene content decreases (~80%) when the system contains β-CD. GZrO2 nanocomposite has shown nearly complete adsorption of anthracene. Strategies, like mixed micellization, tuning of clouding and co-solubilization, can enhance solubility/bioavailability, extraction and subsequent degradation of PAHs from the aquatic/soil environment.
- Published
- 2018
26. Outcomes With First-Line PD-1/PD-L1 Inhibitor Monotherapy for Metastatic Renal Cell Carcinoma (mRCC): A Multi-Institutional Cohort
- Author
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Mehmet Asim Bilen, Jodi Lyn Layton, Whitley Hatton, Hamid Emamekhoo, Vadim S. Koshkin, Patrick Cotogno, Arpita Desai, Ellen Jaeger, Oliver Sartor, Charlotte Manogue, Pedro C. Barata, Brian E. Lewis, Arnab Basu, Deepak Kilari, and Malcolm Light
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cancer Research ,Chromophobe cell ,Gastroenterology ,metastatic renal cell carcinoma ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,medicine ,Adverse effect ,Lymph node ,Original Research ,business.industry ,Acute kidney injury ,PD-1/PD-L1 inhibitor ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Tolerability ,Oncology ,030220 oncology & carcinogenesis ,monotherapy ,Cohort ,immunotherapy ,business ,first-line treatment - Abstract
Introduction: The treatment landscape of metastatic renal cell carcinoma has advanced significantly with the approval of combination regimens containing an immune checkpoint inhibitor (ICI) for patients with treatment-naive disease. Little information is available regarding the activity of single-agent ICIs for patients with previously untreated mRCC not enrolled in clinical trials. Methods: This retrospective, multicenter cohort included consecutive treatment-naive mRCC patients from six institutions in the United States who received ≥1 dose of an ICI outside a clinical trial, between June 2017 and October 2019. Descriptive statistics were used to analyze outcomes including objective best response rate (ORR), progression-free survival (PFS), and tolerability. Results: The final analysis included 27 patients, 70% men, median age 64 years (range 42-92), 67% Caucasian, and 33% with ECOG 2 or 3 at baseline. Most patients had intermediate risk (85%, IMDC) with clear cell (56%), papillary (26%), unclassified (11%), chromophobe (4%), and translocation (4%) RCC. All patients had evidence of metastatic disease involving the lungs (59%), lymph node (41%), CNS (19%), liver (11%), adrenal gland (11%), and bone (11%). The median time on ICI was 3.1 (0.1-26.8) months, and the median PFS was 6.3 (95% CI, 0-18.6) months. Among the 21 patients with an evaluable response, the best ORR was 33%, including two complete responses and five partial responses. The ORR was 29% (n = 1 complete response, n = 5 partial response) in clear cell and 5% (n = 1 complete response) in non-clear cell RCC. Adverse events (AEs) of any cause were reported in 37% and included fatigue (11%), dermatitis (11%), diarrhea (7%), and shortness of breath (7%). Significant AEs (30%) included shortness of breath (7%), acute kidney injury (4%), dermatitis (4%), Clostridium difficile infection (4%), cerebrovascular accident (4%), and fatigue (7%). Three patients discontinued therapy due to grade 4 AEs. Conclusions: In this multi-institutional case series, single-agent ICI demonstrated objective responses and was well tolerated in a heterogeneous treatment-naive mRCC cohort. ICI monotherapy is not the standard of care for patients with mRCC, and further investigation is necessary to explore predictive biomarkers for optimal treatment selection in this setting.
- Published
- 2020
27. Biomarkers predictive of response to enfortumab vedotin (EV) treatment in advanced urothelial cancer (aUC)
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Tanya Jindal, Li Zhang, Jonathan Chou, David Shui, Sima P. Porten, Anthony C. Wong, Emily Chan, Bradley A. Stohr, Ivan de Kouchkovsky, Hala Borno, Rohit Bose, Daniel H Kwon, Arpita Desai, Franklin W. Huang, Rahul Raj Aggarwal, Eric Jay Small, Lawrence Fong, Terence W. Friedlander, and Vadim S Koshkin
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Cancer Research ,Oncology - Abstract
531 Background: EV is an antibody-drug conjugate which recently received full FDA approval for treatment-refractory aUC. Molecular biomarkers and characteristics of patients (pts) most likely to respond to EV therapy have not been well defined. Methods: We retrospectively identified all aUC pts treated with EV at our institution. Clinicopathologic, treatment and response data were abstracted from pt charts. Pts were considered responders to EV if they had a complete response on initial scans after 2-3 months of treatment, or were treated with EV for ≥ 6 months. Responders and non-responders were compared in terms of their molecular and clinical characteristics using Chi-squared test. Most common somatic alterations present in ≥10 pts ( TERTp, TP53, CDKN2A, CDKN2B) were also used to divide pts with available next-generation sequencing (NGS) results into groups with and without these alterations. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. Results: Between 1/2020 and 8/2021 a total of 32 pts received EV and 28 had NGS data available with either FoundationOne (14 pts), UCSF500 (13 pts) or Strata (1). Median age was 69.5 years, 24 (75%) were male, 22 (69%) Caucasian, 22 (69%) had pure urothelial histology and 22 (69%) primary tumor location in the bladder. At EV start, 24 (75%) had visceral metastases (mets), 8 (25%) had liver mets, and 13 (41%) had bone mets. Median follow-up from EV start was 12.5 months (range 0.5-36); 20 (63%) pts received EV monotherapy, and 12 (37%) received EV as part of a combination regimen. Non-responders were more likely to have bone metastases (69% vs 21%, p
- Published
- 2022
28. Serial stereotactic body radiation therapy for oligometastatic prostate cancer (PCa) detected by positron emission tomography (PET) imaging
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David Shui, Hala Borno, Rohit Bose, Jonathan Chou, Arpita Desai, Lawrence Fong, Terence W. Friedlander, Franklin W. Huang, Vadim S Koshkin, Ivan de Kouchkovsky, Julian C. Hong, Osama Mohamad, Felix Y Feng, Rahul Raj Aggarwal, Thomas A Hope, Eric Jay Small, and Daniel H Kwon
- Subjects
Cancer Research ,Oncology ,urologic and male genital diseases - Abstract
109 Background: Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11, F-18-fluciclovine, and choline C-11, are increasingly used to stage and inform therapies for PCa. Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic PCa has been shown to improve progression free survival (PFS) compared to observation. However, for men who subsequently develop oligorecurrent disease, outcomes following second SBRT are unknown. Methods: A retrospective, single-center, cohort study was conducted. Pts were identified through electronic health records. Inclusion criteria included pts with oligometastatic (1-5 lesions) PCa detected on PSMA, fluciclovine, or choline C-11 PET who underwent 2 consecutive courses of SBRT to tracer-avid oligometastatic disease between 7/2013 and 7/2021. Exclusion criteria included presence of visceral metastases and pure small cell neuroendocrine PCa. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline of ≥50% (PSA50), ≥90% (PSA90), and PSA-PFS. SBRT2 outcomes were compared based on change of concurrent systemic therapy with SBRT2 (e.g., addition of abiraterone or anti-androgen withdrawal) and PSA50 to SBRT1 using Fisher’s exact text and Wilcoxon rank sum test, respectively. Results: A total of 12 pts met eligibility criteria. At SBRT1, 10 (83%) pts had hormone-sensitive PCa (HSPC) and 2 (17%) had castration-resistant PCa (CRPC). For PET tracers, 7 (58%) used PSMA, 4 (33%) fluciclovine, and 1 (8%) choline. After SBRT1, 12 pts (100%) had a PSA decline, 8 (67%) had a PSA50 response, and 6 (50%) a PSA90 response. Median PSA PFS after SBRT1 was 30mo (95%CI 9-65mo). Six (50%) SBRT1 pts had a concurrent change in systemic therapy. At SBRT2, 8 (67%) pts had HSPC and 4 (33%) had CRPC; 7 (58%) used PSMA and 5 (42%) fluciclovine. After SBRT2, 12 (100%) pts had a PSA decline, 8 (67%) had a PSA50 response, and 8 (67%) a PSA90 response. After SBRT2, median PSA PFS was 23mo (95%CI 12-35mo). Among 7 pts who had a concurrent change in systemic therapy with SBRT2, all (100%) had a PSA50 response; among 5 who did not (4 of whom did not receive any systemic therapy), 1 (20%) had a PSA50 response (P=0.01). Among 8 pts who had a PSA50 response to SBRT1, 7 (88%) had one to SBRT2; among 4 who did not have a PSA50 response to SBRT1, 1 (25%) had one to SBRT2 (P=0.01). No complications related to SBRT were documented. Conclusions: Serial SBRT for oligometastatic PCa detected on fluciclovine, PSMA, or choline PET is feasible and can achieve PSA declines independent of systemic therapy. PSA responses were greater when systemic therapy was changed. This preliminary evidence of benefit, based on PSA responses and PSA PFS, provides rationale for larger, prospective studies of serial SBRT for oligometastatic PCa.
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- 2022
29. NCCN Guidelines Insights: Kidney Cancer, Version 1.2021
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Robert J, Motzer, Eric, Jonasch, Shawna, Boyle, Maria I, Carlo, Brandon, Manley, Neeraj, Agarwal, Ajjai, Alva, Katy, Beckermann, Toni K, Choueiri, Brian A, Costello, Ithaar H, Derweesh, Arpita, Desai, Saby, George, John L, Gore, Naomi, Haas, Steven L, Hancock, Christos, Kyriakopoulos, Elaine T, Lam, Clayton, Lau, Bryan, Lewis, David C, Madoff, Brittany, McCreery, M Dror, Michaelson, Amir, Mortazavi, Lakshminarayanan, Nandagopal, Phillip M, Pierorazio, Elizabeth R, Plimack, Lee, Ponsky, Sundhar, Ramalingam, Brian, Shuch, Zachary L, Smith, Bradley, Somer, Jeffrey, Sosman, Mary A, Dwyer, and Angela D, Motter
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Humans ,Genetic Testing ,Carcinoma, Renal Cell ,Kidney Neoplasms ,Article - Abstract
The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.
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- 2020
30. Evaluating determinants of receipt of molecular imaging in biochemical recurrent prostate cancer
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Vadim S. Koshkin, Arpita Desai, Anobel Y. Odisho, Alexander Bell, Tracy Kuo Lin, Thomas A. Hope, Sylvia Zhang, Kalin Werner, Matthew D. Bucknor, Nichole Legaspi, and Hala T. Borno
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0301 basic medicine ,Oncology ,Glutamate Carboxypeptidase II ,Male ,Cancer Research ,Aging ,Time Factors ,Logistic regression ,Prostate cancer ,0302 clinical medicine ,Pregnancy ,Bayesian multivariate linear regression ,80 and over ,biochemical recurrence ,Medicine ,Cancer ,Original Research ,disparities ,Receipt ,Aged, 80 and over ,screening and diagnosis ,Prostate Cancer ,Health Care Costs ,Middle Aged ,Prognosis ,prostate cancer ,medical oncology ,Surface ,Detection ,Molecular Diagnostic Techniques ,Health ,030220 oncology & carcinogenesis ,Antigens, Surface ,Pacific islanders ,Biomedical Imaging ,Female ,Kallikreins ,Cohort study ,Biochemical recurrence ,Urologic Diseases ,medicine.medical_specialty ,Oncology and Carcinogenesis ,03 medical and health sciences ,Insurance ,Clinical Research ,Predictive Value of Tests ,Internal medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Antigens ,Healthcare Disparities ,Aged ,Retrospective Studies ,Insurance, Health ,business.industry ,Prostatic Neoplasms ,Clinical Cancer Research ,Prostate-Specific Antigen ,medicine.disease ,molecular imaging ,4.1 Discovery and preclinical testing of markers and technologies ,030104 developmental biology ,Good Health and Well Being ,Positron-Emission Tomography ,Biochemistry and Cell Biology ,Molecular imaging ,business - Abstract
Background Molecular imaging with novel radiotracers is changing the treatment landscape in prostate cancer (PCa). Currently, standard of care includes either conventional and molecular imaging at time of biochemical recurrence (BCR). This study evaluated the determinants of and cost associated with utilization of molecular imaging for BCR PCa. Methods This is a retrospective observational cohort study among men with BCR PCa from June 2018 to May 2019. Multivariate logistic regression models were employed to analyze the primary outcome: receipt of molecular imaging (e.g. Fluciclovine PET and Prostate Specific Membrane Antigen PET) as part of diagnostic work‐up for BCR PCa. Multivariate linear regression models were used to analyze the secondary outcome: overall healthcare cost within a 1‐year time frame. Results The study sample included 234 patients; 79.1% White, 2.1% Black, 8.5% Asian/Pacific Islander, and 10.3% Other. The majority were 55 years or older (97.9%) and publicly insured (74.8%). Analysis indicated a one‐unit reduction in PSA is associated with 1.3 times higher likelihood of receiving molecular imaging (p, This study evaluated the determinants of and cost associated with utilization of molecular imaging for biochemically recurrent prostate cancer. Higher prostate‐specific antigen level was associated with lower likelihood for molecular imaging and higher cost in a 1‐year timeframe.
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- 2020
31. Derivatives of 4, 4’-Oxydianiline Show Distinct In Vitro Cytotoxicity, Apoptosis Induction, and Selectivity against HepG2 Cancer Cells
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Vineeta Pillai, Vinay K. Singh, Lipi Buch, and Arpita Desai
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,In vitro cytotoxicity ,General Chemistry ,010402 general chemistry ,Apoptosis induction ,01 natural sciences ,Molecular biology ,0104 chemical sciences ,4,4'-Oxydianiline ,chemistry.chemical_compound ,Cell staining ,Apoptosis ,Cancer cell ,Selectivity ,Dithiocarbamate - Published
- 2017
32. Updated results of phase II trial using escalating doses of neoadjuvant atezolizumab for cisplatin-ineligible patients with nonmetastatic urothelial cancer (NCT02451423)
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Terence W. Friedlander, Vadim S. Koshkin, Li Zhang, Felix Y. Feng, Peter R. Carroll, Matthew R. Cooperberg, Hala T. Borno, Eric J. Small, Rohit Bose, Raj S. Pruthi, Rahul Aggarwal, Divya Natesan, Lawrence Fong, Arpita Desai, Maxwell V. Meng, Anthony C. Wong, David Y. Oh, Daniel Kwon, Jonathan Chou, and Sima P. Porten
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Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Bladder cancer ,business.industry ,medicine.medical_treatment ,medicine.disease ,Systemic therapy ,Atezolizumab ,Internal medicine ,medicine ,Urothelial cancer ,business ,medicine.drug - Abstract
e16510 Background: Patients (pts) with muscle-invasive bladder cancer (MIBC) ineligible for cisplatin-based chemotherapy have no standard systemic therapy options and are prioritized for radical cystectomy (RC) alone. This prospective clinical trial investigated the safety and efficacy of escalating doses of neoadjuvant atezolizumab (N-ATZ) prior to RC in MIBC pts. Methods: This is a single-institution, phase II trial of escalating doses of N-ATZ (1200 mg IV every 3 weeks) in pts with MIBC. Key inclusion criteria were resectable urothelial carcinoma of the bladder (T2-T4a,N0-1,M0) and inability to receive cisplatin-based treatment (eGFR < 60 mL/min, G≥2 neuropathy/hearing loss, pt decision). Pts with high-risk disease at RC were eligible to receive adjuvant ATZ for up to 16 total doses. Pts were followed for up to 2 years following RC. Primary efficacy endpoint was pathologic complete response (pCR; pT0N0). Secondary endpoints were safety of treatment, rate of pathologic downstaging (≤pT1N0), response based on PD-L1 status, and overall survival (OS) and recurrence-free survival (RFS) at 1 and 2 years from RC. Results: A total of 20 pts were enrolled and sequentially treated with one (n=6), two (n=5), and three (n=9) cycles of N-ATZ prior to RC. Median age was 69 (range 61-81), 75% were male and 85% Caucasian. Pts were cisplatin-ineligible due to low GFR (35%), hearing loss (25%) or neuropathy (10%); the rest refused cisplatin (30%). Most pts had pT2 disease (80%); the remainder, pT3/pT4 (15%/5%), and 10% had cN1. Among 17 pts with available tumor PD-L1 status, 76% had PD-L1 positive (CPS≥10) tumors. pCR was observed in 2 pts (10%) with 1 and 2 ATZ doses, whereas pathologic downstaging was observed in 5 pts (25%) across all 3 doses (Table). All pts completed intended treatment and RC within the trial-defined timeframe. Perioperative TRAEs of any grade occurred in 75%, but only 10% had G3 TRAEs (diarrhea, fecal incontinence). There were no G4/G5 events. Median follow-up from RC was 23.6 months and 75% were still followed at the time of data cutoff in 2/2021. Among evaluable pts, 1-year RFS and OS were 72% and 94% while 2-year RFS and OS were 64% and 69%. PD-L1 positive pts had superior OS (logrank p=0.06) and RFS (p=0.10) relative to PD-L1 negative pts. Conclusions: N-ATZ was well tolerated at all three dose levels and did not delay or prevent surgery. As few as 1 to 2 ATZ doses resulted in pathologic downstaging, including pCR. Although pCR rate in this trial was lower than expected, most pts had a durable recurrence-free period and all evaluable pts with tumor downstaging were alive and recurrence-free at 2 years following RC. Increased tumor PD-L1 expression was suggestive of improved outcomes and further biomarker analyses are ongoing. Clinical trial information: NCT02451423. [Table: see text]
- Published
- 2021
33. Rate of skeletal-related events (SREs) for abiraterone acetate (AA) versus enzalutamide (ENZ) in prostate cancer: A population-based study using the SEER-Medicare database
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Vadim S. Koshkin, Franklin W. Huang, Jonathan Chou, Terence W. Friedlander, Li Zhang, Rahul Aggarwal, Lawrence Fong, Hala T. Borno, Eric J. Small, Rohit Bose, Arpita Desai, Daniel Kwon, and Alan Paciorek
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Abiraterone acetate ,Skeletal related events ,Seer medicare ,medicine.disease ,Androgen ,Population based study ,chemistry.chemical_compound ,Prostate cancer ,chemistry ,Internal medicine ,medicine ,Enzalutamide ,business - Abstract
e17038 Background: Skeletal-related events are common in men with prostate cancer, and are associated with significant morbidity and mortality. AA and ENZ are novel androgen signaling inhibitors used in the treatment of metastatic prostate castration-resistant prostate cancer (mCRPC). As directly comparative efficacy data do not exist between AA and ENZ, the differing toxicity profiles inform treatment selection. It is unknown whether SRE rates differ in a real-world population between AA, which is given with corticosteroids, and ENZ, which is associated with imbalance and falls. Methods: The national SEER-Medicare linked database was used to identify men with prostate cancer who received AA or ENZ between 2011-2015; approval during this period was solely for mCRPC. Inclusion criteria included Medicare Part A+B coverage 1 year before and after first receipt of AA/ENZ, without any HMO enrollment. Baseline demographic and comorbidity data were gathered. Diagnosis and procedure claims codes were used to identify SREs, defined as pathologic fracture, surgery to bone, radiation to bone, or spinal cord compression. The time to SRE was defined as time from first receipt of AA/ENZ to the first SRE of any type. A multivariable competing risk regression analysis including death as a competing risk was performed. Results: 5,856 men with prostate cancer who first received AA (N = 4,207) or ENZ (N = 1,649) were identified. The median age at initiation of AA/ENZ was 70 years (range 65-101); 78% were White, 12% Black, 4% Hispanic, 3% Asian, and 4% Other. The median follow-up was 14 months. The overall SRE rate was 13.1% after AA/ENZ start: 574 (13.6%) AA and 194 (11.8%) ENZ, with a cumulative incidence of 11.9% at 2 years. Median overall survival was 16 months (14.4 months for AA and 18.3 months for ENZ). Age, stage at diagnosis, race/ethnicity, baseline comorbidities, and prior history of SRE were balanced between AA vs ENZ, aside from baseline osteoarthritis or rheumatoid arthritis (48.0% AA vs 53.2% ENZ, P < 0.001) and baseline Alzheimer’s dementia (9.2% AA vs 11.1% ENZ, P = 0.03). After controlling for these potential risk factors, receipt of AA versus ENZ was not associated with time to SRE (relative risk ratio [RR] = 0.90, 95% CI 0.77-1.06, P = 0.22). Osteoporosis (RR 1.22, 95% CI 1.01-1.49, P = 0.04), osteoarthritis or rheumatoid arthritis (RR 1.23, 95% CI 1.06-1.43, P < 0.01), and prior history of SRE (RR 1.31, 95% CI 1.07-1.59, P < 0.01) were statistically significant risk factors for SRE. Conclusions: In this real-world population of men with prostate cancer, there was no difference in time to SRE between AA and ENZ. Clinical decision-making on whether to prescribe AA or ENZ should be informed by other potential toxicities as well as cross-resistance with sequencing of these therapies. Analysis of impact of bone protective agent use is underway.
- Published
- 2021
34. Immunogenic priming with 177Lu-PSMA-617 plus pembrolizumab in metastatic castration resistant prostate cancer (mCRPC): A phase 1b study
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Maya Aslam, Srey Luch Sam, Ivan de Kouchkovsky, Lawrence Fong, Arpita Desai, Rahul Aggarwal, Vadim S. Koshkin, Hala T. Borno, Medini Rastogi, Thomas A. Hope, Jonathan Chou, Daniel Kwon, Felix Y. Feng, Terence W. Friedlander, Eric J. Small, Rohit Bose, and Tammy J. Rodvelt
- Subjects
Cancer Research ,177Lu-PSMA-617 ,business.industry ,Immune checkpoint inhibitors ,Priming (immunology) ,Pembrolizumab ,Castration resistant ,medicine.disease ,Prostate cancer ,Oncology ,Radioligand ,Cancer research ,medicine ,Single agent ,business - Abstract
5053 Background: Immune checkpoint inhibitors have limited single agent activity in microsatellite-stable mCRPC. 177Lu-PSMA-617 (Lu) is a PSMA-targeting radioligand therapy that has demonstrated promising anti-tumor activity. We sought to determine whether a single dose of Lu can induce an immunogenic priming effect to improve outcomes of men with mCRPC subsequently treated with pembrolizumab (P). Methods: We undertook a phase 1b, single arm trial enrolling chemotherapy-naïve mCRPC patients (pts) with progression (PD) on at least one prior androgen signaling inhibitor (NCT03805594). Pts were required to have ≥ 3 PSMA-avid lesions on 68Ga-PSMA-11 PET and measurable disease by RECIST 1.1 criteria. No genomic selection was undertaken. Pts were enrolled sequentially on one of three schedules: A) Single dose of Lu (7.4 GBq) followed by initiation of P (200 mg IV q 3 weeks) 28 days later; B) Lu x 1 dose given concomitantly with first P administration; C) Lu x 1 dose given on C2D1 following initiation of P on C1D1. Pts were treated with P until confirmed radiographic or clinical PD. The primary endpoint was safety; key secondary endpoints included PSA response, objective response rate by RECIST 1.1 criteria (ORR), median duration of response (DOR), and radiographic progression-free survival (rPFS). Results: 18 pts were enrolled, 6 per schedule. The median age was 64 (range 51 – 80) and 44% of pts had visceral metastases. The median baseline number of PSMA-avid metastatic lesions was 20 (range 6 – 50+). Six pts (33%) had progressed on prior abiraterone, 4 (22%) on enzalutamide, and 8 (44%) on both. There were no dose-limiting toxicities and one Grade ≥ 3 treatment-related adverse event (AE) (inflammatory arthritis, schedule B). There were no grade ≥ 3 hematologic AEs. The ORR was 8/18 (44%) and median DOR has not been reached (range 1.9+ – 15.9+ months). Four pts (2 on schedule A, 1 on schedule B, 1 on schedule C) with durable partial responses remain on study treatment for 5.4+, 8.9+, 9.2+, and 17.8+ months, respectively. The median rPFS was 6.5 months (95% CI: 2.5 – 9.8). PSA30, PSA50, and PSA90 response rates were 44%, 28%, and 17%, respectively. Fourteen pts (78%), including all durable responders, had somatic genomic data available. One (7%) harbored a DNA repair mutation ( BRCA1, non-responder), none were MSI-high, and all carried low tumor mutational burden (≤ 5 mutations/MB). Single cell sequencing of the immune microenvironment from paired metastatic tumor biopsies is underway. Conclusions: 177Lu-PSMA-617 as a priming dose followed by pembrolizumab was well tolerated and leads to durable responses in a subset of mCRPC without high mutational burden or microsatellite instability, suggesting a possible immunogenic priming effect of radioligand therapy. Further evaluation of the combination is ongoing in a phase 2 study. Clinical trial information: NCT03805594.
- Published
- 2021
35. Outcomes with novel combinations in non-clear cell renal cell carcinoma(nccRCC): ORACLE study
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Rana R. McKay, Abhishek Tripathi, Rohit Jain, Vadim S. Koshkin, Arpita Desai, Aniko Szabo, Nicole Weise, Pooja Ghatalia, Danubia Hester, Huaying Dong, Ajjai Alva, Arnab Basu, Luna Acharya, Ariel Ann Nelson, Matthew D Tucker, Tracy L. Rose, Benjamin L. Maughan, Nancy B. Davis, Deepak Kilari, and Hamid Emamekhoo
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Cancer Research ,Clear cell renal cell carcinoma ,Oncology ,business.industry ,medicine ,Cancer research ,medicine.disease ,business ,Oracle ,Clear cell - Abstract
4580 Background: Despite advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of new combination therapies (including immunotherapy (IO), anti-vascular endothelial growth factor inhibitors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors) in metastatic nccRCC is not known. Methods: In this multicenter retrospective analysis, we explored the efficacy of combination systemic therapies in patients with nccRCC. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints include progression- free survival (PFS), disease control rate (DCR), median duration of response (DOR), overall survival (OS), and biomarker correlates. Results: Among 66 included patients, median age was 59 yr; 60% were male and 62% white. Histologies included papillary (38%), chromophobe (17%), unclassified (24%), translocation (12%), and other (9 %). Sarcomatoid and/or rhabdoid differentiation was present in 18%, 70% had prior nephrectomy, 86% were IMDC intermediate/poor risk, 29% and 32% had liver and bone metastasis respectively. 67% received combination treatment in the first line. Comparison of outcomes based on treatment regimen is shown in the table. Conclusions: Antitumor activity was observed with novel combinations in nccRCC which warrants further prospective studies. Response rates and survival with combination therapy in this dataset remain inferior to rates seen in clear cell RCC.[Table: see text]
- Published
- 2021
36. Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma
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David Fischer, Arthur Wolin, Dezheng Huo, Viswateja Nelakuditi, Buerkley Rose, Zejuan Li, Aliya N. Husain, Arpita Desai, Lauren L. Ritterhouse, Amy K. Johnson, Maria Helgeson, Kiran K. Turaga, Jeremy P. Segal, Oluf Dimitri Røe, Jyoti D. Patel, Sabah Kadri, Emily Skarda, Hedy L. Kindler, Caroline M. Weipert, Vasiliki Panou, Meghana Gadiraju, Shannon R Zhang, Madison Weatherly, Jane E. Churpek, and Nanna Helen Sulai
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Adult ,Male ,Mesothelioma ,0301 basic medicine ,Cancer Research ,Lung Neoplasms ,DNA damage ,Germline ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,Germ-Line Mutation ,Aged ,Aged, 80 and over ,BAP1 ,business.industry ,Mesothelioma, Malignant ,Tunica vaginalis ,High-Throughput Nucleotide Sequencing ,Odds ratio ,Middle Aged ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business - Abstract
Purpose The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). Methods We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. Results Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). Conclusion A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.
- Published
- 2018
37. Change in neutrophil to lymphocyte ratio (NLR) as a predictor of treatment failure in renal cell carcinoma patients: Analysis of the IROC (Investigating RCC Outcomes) cohort
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Vadim S. Koshkin, Rohan Garje, Mollie R. De Shazo, Arpita Desai, Yash Suri, Yousef Zakharia, Audrey Phone, Patrick Sweeney, Tristan Bice, Lakshminarayanan Nandagopal, Deepak Kilari, Arnab Basu, Luna Acharya, Pedro C. Barata, and Abigail Chan
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,fungi ,medicine.disease ,Treatment failure ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,Medicine ,Neutrophil to lymphocyte ratio ,business ,030215 immunology - Abstract
344 Background: IROC is an expanding multi-institution collaborative database which includes socioeconomic, genomic, pathologic, clinical and laboratory data in metastatic RCC patients (pts), primarily in the modern setting. Elevated baseline NLR is now an established poor prognostic factor in renal cell carcinoma (RCC) but currently has limited practical use. We hypothesized that an increase in NLR of 3 or more (NLR Failure) at 2 months on therapy could be a predictor of eventual treatment failure and shorter overall survival and thus augment the utility of this marker. Methods: Patients with complete data on NLR at time = 0 and +2 months of therapy were analyzed. Information on comorbidities, previous therapy, demographics were collected for adjusted analysis. NLR failure was defined as an increase of 3 or more compared to baseline NLR. Cox proportional hazard models were used to analyze the risk of progression and death with NLR failure at 2 months (+/- 2 weeks). Kaplan Meier graphs were constructed to trace survival functions for PFS and OS by NLR. Results: Among 165 pts; 121 were eligible (Table). NLR failure at 2 months was associated with a highly statistically significant increase in the risk of death in < 1 year (HR 6.82, 95% CI [3.16-14.70], p
- Published
- 2021
38. TERT promoter mutation as a prognostic marker in patients with advanced urothelial carcinoma treated with immune checkpoint inhibitors
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Francis Wright, Terence W. Friedlander, Raj S. Pruthi, Jonathan Chou, Li Zhang, Sima P. Porten, Daniel Myung Kim, Vadim S. Koshkin, Daniel Kwon, Ivan de Kouchkovsky, Son Ho, Hansen Ho, Emily Chan, David Y. Oh, Errol J. Philip, Eric J. Small, Franklin W. Huang, Lawrence Fong, Arpita Desai, and Divya Natesan
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Cancer Research ,Metastatic Urothelial Carcinoma ,Oncology ,business.industry ,Immune checkpoint inhibitors ,Locally advanced ,Cancer research ,Medicine ,In patient ,Tert promoter mutation ,business ,Urothelial carcinoma - Abstract
476 Background: Reliable predictive markers are lacking in patients (pts) with locally advanced or metastatic urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICI). We sought to determine whether specific genomic alterations could be used to predict overall survival (OS) in this patient population. Methods: We undertook a retrospective cohort study of pts with aUC who received ICI and underwent genomic profiling by next-generation sequencing (NGS). All patients underwent NGS using commercially available platforms (e.g. Foundation Medicine, Strata, Invitae), or testing on the CLIA-certified institutional panel UCSF500. Associations between the 20 most frequently altered genes and OS were first examined by Cox regression. Genes with a p
- Published
- 2021
39. Implementation of clinician-facing prostate cancer therapeutic clinical trial decision tool at a comprehensive cancer center
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Eric J. Small, Vadim S. Koshkin, Rohit Bose, Franklin W. Huang, Sylvia Zhang, Dame Idossa, Jonathon Chou, Arpita Desai, Hala T. Borno, Rahul Aggarwal, Terence W. Friedlander, Patricia Li, and Tammy J. Rodvelt
- Subjects
Cancer Research ,medicine.medical_specialty ,Decision tool ,business.industry ,Cancer ,medicine.disease ,Clinical trial ,Prostate cancer ,Oncology ,medicine ,Medical physics ,The Internet ,Center (algebra and category theory) ,business - Abstract
19 Background: The conventional model for clinical trial (CT) recruitment relies on clinicians to identify potential CTs for patients. Internet technology can be leveraged as a decision tool to enhance the CT recruitment process. Methods: An internet-based, clinician-facing decision tool was developed in genitourinary medical oncology clinic at a Comprehensive Cancer Center (CCC). The tool provided access to a real-time, tailored list of treatment CTs actively recruiting patients with PCa at the CCC based on clinical characteristics inputted by user. The clinical data was summarized. All clinicians (n = 9) with access to the decision tool completed a survey to assess effectiveness and satisfaction. Results: During a 9-month pilot period, user engagement increased from a baseline of 36 to 136 cases per month, with a total of 644 cases overall. Among cases, 525 had metastatic disease, 436 of which were metastatic castration resistant PCa (mCRPC). Overall, 145 cases were classified as having oligo-metastatic ( < = 3) PCa, 93 of whom were also mCRPC. Prior treatments received included abiraterone in hormone-sensitive PCa (HSPC 19.3%, CRPC 48.7%); enzalutamide (HSPC 3.7%, CRPC 34.9%) apalutamide (HSPC 1.3%, CRPC 6.9%), taxane (HSPC 17.2%, CRPC 27.8%), radium-223 (6.1%), sipuleucel-T (18.3%), parp inhibitors (4%), or check-point inhibitors (6%). Clinician-inputted genomics of cases included CDK12 (20.9%), MSI-high disease (13.6%), BRCA1/2 (32.7%), ARID1a (7.3%), ATM (21.8%), FANCA (4.5%), or CHEK2 (6.4%) and HDAC2 (0.9%). Among survey respondents, use of tool in clinic was reported sometimes (22%), often/always (78%). Results of decision tool were reported to inform treatment sometimes (22%) or often/always (78%). Respondents confidence in often/always knowing all available CTs increased from a baseline of 0% to 89%, and 89% of users reported very/complete satisfaction with decision tool. Conclusions: An internet-based CT decision tool for provides detailed clinical characteristics of patients for whom CTs are being considered at a CCC. Clinicians using the decision tool report high levels of satisfaction. The tool was effective in increasing confidence in knowledge of current available CTs. Data gathered in the decision tool may inform future CT development. Future research with expanded use of decision tool among referring clinicians will assess its impact in promoting diversity among CT participants.
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- 2021
40. Multi-institutional evaluation of the clinical outcomes and genomic correlates of African Americans with metastatic castration-sensitive prostate cancer (mCSPC)
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Audrey Phone, Roberto Nussenzveig, Jorge A Garcia, Vadim S. Koshkin, Neeraj Agarwal, Meredith Mi Freeman, Lakshminarayanan Nandagopal, Jason Zhu, Arpita Desai, Sydney A. Caputo, Ellen Jaeger, Arnab Basu, A. Oliver Sartor, Adam Kessel, Deepak Ravindranathan, Earle F. Burgess, Jodi Lyn Layton, Umang Swami, Pedro C. Barata, and Mehmet Asim Bilen
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Oncology ,African american ,Cancer Research ,medicine.medical_specialty ,business.industry ,Internal medicine ,Medicine ,business ,Prostate cancer incidence ,Castration-sensitive prostate cancer - Abstract
17 Background: Prostate cancer incidence and mortality is higher in African American (AA) as compared with non-AA men. The outcomes of mCSPC have significantly improved through treatment intensification yet, AA representation in those studies was suboptimal. We aimed to report the clinical, treatment outcomes and genomic data of AA men with mCSPC. Methods: Retrospective analysis of consecutive AA men with mCSPC at six Academic Institutions. The primary objective was to report the baseline characteristics and treatment patterns of mCSPC AA patients. The secondary objectives included the germline and somatic data and the clinical outcomes including PSA response, progression-free survival and subsequent treatments. Results: A total of 71 patients, median age 63 years (range, 41-84) with 58% Gleason 8-10, initial PSA of 69.8 ng/mL (0.02-7650), 59% with de-novo and 55% with high-volume (CHAARTED criteria; 20% visceral) disease, were included in this analysis. Twenty-two patients (31%) were treated with androgen deprivation therapy (ADT; 67% prior to year 2017), while 24%, 45% and 3% received docetaxel (median 6 cycles), abiraterone acetate and enzalutamide, respectively. Two patients received triplet therapy with ADT/docetaxel plus abiraterone or enzalutamide. Undetectable PSA was achieved in 35% after a median of 8.9 months (1.8-22.3). Among patients with mCSPC who received radiation therapy to prostate (n = 8), 89% had low volume disease. At time of cut off, thirty-two patients developed CRPC and the estimated median time to CRPC was 2.9 years (95% CI, 1.6-4.2). Subsequent therapies (n = 29) included abiraterone acetate (41%), enzalutamide (24%), bicalutamide (10%), radium-223 (7%), chemotherapy (7%), sipuleucel-T (3%) and others (7%). Five patients (8%) had pathogenic germline alterations (n = 2 BRCA1; n = 1 HOXB13, PALB2 and PMS2). Additionally, the most common somatic alterations among tested patients (n = 27) included CDK12, SPOP, TMPRSS2-ERG fusion, and TP53, all in 11% frequency. Of note, n = 2 BRCA1 and n = 1 high MSI/TMB. Conclusions: In one of the largest reported cohorts to our knowledge, mCSPC AA presented with a high number of de-novo and high-volume disease and might harbor a different germline and somatic genomic profile. The outcomes were comparable to contemporary phase III trials with treatment intensification, yet 31% were treated with ADT. Despite the known limitations associated with retrospective analysis, these data support prior observations where AA might have better initial PSA responses to ADT-based strategies compared with Caucasians, requiring further validation.
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- 2021
41. FGFR Signaling as a Target for Lung Cancer Therapy
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Arpita Desai and Alex A. Adjei
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Antineoplastic Agents ,Fibroblast growth factor ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Humans ,FGFR inhibitors ,Medicine ,Molecular Targeted Therapy ,Receptor ,Lung cancer ,business.industry ,medicine.disease ,Receptors, Fibroblast Growth Factor ,FGFR pathway ,Cell biology ,Review article ,FGFR abberations ,030104 developmental biology ,Oncology ,Fibroblast growth factor receptor ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction ,business ,Carcinogenesis ,Function (biology) ,Signal Transduction - Abstract
Lung cancer is the leading cause of cancer-related death in developed countries. Recently, molecular targeted therapies have shown promising results in the management of lung cancer. These therapies require a clear understanding of the relevant pathways that drive carcinogenesis and maintenance of the malignant phenotype. The fibroblast growth factor receptor (FGFR) signaling axis is one such pathway that plays a central role in normal cellular function. Alterations in this pathway have been found in many cancers. In this review article, we focus on the role of this pathway in lung cancer. We present the molecular structure of FGFR, the interaction of the receptor with its ligands (the fibroblast growth factors), its downstream signaling, and aberrations in the FGFR pathway. We also discuss clinical trials involving selective and multikinase FGFR inhibitors in lung cancer treatment.
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- 2016
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42. 769P APOBEC signatures and high tumour mutational burden as predictors of clinical outcomes and response to therapy in patients with urothelial carcinoma
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James P. Grenert, Vadim S. Koshkin, Patrick Devine, Henry J Martell, Sarah E. Umetsu, Eric J. Small, Lawrence Fong, Arpita Desai, Divya Natesan, Terence W. Friedlander, Li Zhang, J. Van Ziffle, Boris C. Bastian, Jonathan Chou, Bradley A. Stohr, Sima P. Porten, Nancy M. Joseph, A. Sweet-Cordero, Courtney Onodera, and Emily Chan
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Oncology ,APOBEC ,medicine.medical_specialty ,Response to therapy ,business.industry ,Internal medicine ,Medicine ,In patient ,Hematology ,business ,Urothelial carcinoma - Published
- 2020
43. Correlation of tumor mutational burden (TMB) with molecular profiling and clinical characteristics in patients with bladder cancer
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Nancy M. Joseph, Boris C. Bastian, Lawrence Fong, Eric J. Small, Jonathan Chou, Arpita Desai, Patrick Devine, Henry J Martell, Vadim S. Koshkin, Bradley A. Stohr, James P. Grenert, Emily Chan, Jessica Van Ziffle, Terence W. Friedlander, Eric Alejandro Sweet-Cordero, Sima P. Porten, Courtney Onodera, Anthony C. Wong, Sarah E. Umetsu, and Divya Natesan
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Correlation ,Cancer Research ,Bladder cancer ,Oncology ,business.industry ,Cancer research ,Medicine ,Profiling (information science) ,In patient ,business ,medicine.disease ,DNA sequencing - Abstract
e17025 Background: Bladder cancers (BC) are frequently highly mutated. Next generation sequencing (NGS) can both shed light on mutational burden and the specific alterations that provide insights into the underlying biology of individual tumors. Methods: We retrospectively reviewed BC cases assessed with UCSF500, an institutional NGS assay that uses hybrid capture enrichment of target DNA to interrogate approximately 500 frequently mutated cancer genes. Hypermutated tumors were defined as having TMB > 10 mutations/Mb. Fisher’s exact test was used to compare patients (pts) with hypermutated (HM) and non-hypermutated (NHM) tumors. Results: From 2015 to 2019, 74 pts with BC underwent UCSF500 testing; 48 pts were evaluable for TMB, of which 19 pts (40%) had HM tumors. 17/19 pts were evaluable for mutational signatures; all 17 had APOBEC signatures. Signatures were not assessed in NHM tumors due to low TMB. Clinicopathologic characteristics and most common alterations in the two groups are listed in the table. More HM pts had responses to immunotherapy (IO) treatment (86% vs 40%, p = 0.13). Conclusions: In this single-institution BC cohort, HM tumors were common and APOBEC mutational signature was the common underlying biology in HM tumors. There were relevant differences in common alterations between HM and NHM tumors, including more FGFR3 mutations in NHM tumors. HM status and APOBEC signature were suggested as relevant predictive biomarkers of response to IO, which should be investigated further in larger BC cohorts. [Table: see text]
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- 2020
44. First-line PD-1/PD-L1 inhibitor monotherapy for advanced renal cell carcinoma (aRCC): A multi-institutional cohort
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Whitley Hatton, Mehmet Asim Bilen, Ellen Jaeger, Vadim S. Koshkin, Arpita Desai, Arnab Basu, Jodi Lyn Layton, Patrick Cotogno, Deepak Kilari, Spencer Krane, Brian E. Lewis, Elisa Ledet, Charlotte Manogue, Oliver Sartor, and Pedro C. Barata
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Cancer Research ,biology ,business.industry ,First line ,medicine.disease ,Programmed cell death ligand 1 ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Renal cell carcinoma ,030220 oncology & carcinogenesis ,Programmed cell death 1 ,Cohort ,Cancer research ,biology.protein ,Medicine ,business ,PD-L1 inhibitor ,030215 immunology - Abstract
e17109 Background: Combination regimens containing a programmed cell death protein 1 (PD-1) or a programmed cell death ligand 1 (PD-L1) inhibitor improve the clinical outcomes of previously untreated aRCC. These regimens are clinically active but are associated with adverse events (AEs). One prospective study (KEYNOTE-427) has shown clinical activity of pembrolizumab monotherapy in aRCC. We aimed to describe the utilization and outcomes of single-agent PD-1/PD-L1 in previously untreated aRCC patients (pts). Methods: Consecutive pts treated with front-line PD-1/PD-L1 monotherapy for aRCC were included. Descriptive statistics were used to analyze outcomes including overall response rate (ORR), progression-free survival (PFS) and safety. Results: A total of 28 pts (median age 60; 32% ECOG 2/3; intermediate/poor risk 86%/14%; 35% non-clear cell aRCC) were identified. Common sites of metastases included lung (57%), lymph nodes (39%), bone (21%) and brain (21%). Pts received pembrolizumab (n = 9), avelumab (n = 1) or nivolumab (n = 18) due to pt/physician’s decision (46%), poor performance status (29%) or clinical trial (21%). In evaluable pts (n = 24), the ORR was 33% in ccRCC and 30% in nccRCC. With a median follow up of 13 months (mo), the median PFS was 6.3 mo (CI 95%, 1.5-11.1) and 16 pts progressed on therapy. Frequent AEs (57%) included fatigue (21%), myalgias/arthralgias (11%) and hypothyroidism (7%). No significant grade AEs (G3+) were noted. After progression on PD-1/PD-L1 (n = 16), 39% received a subsequent anti-VEGF (cabozantinib n = 6; sunitinib n = 4; pazopanib n = 1), 42% went to hospice or died and 21% were lost to follow up. Conclusions: First-line single-agent treatment with PD-1/PD-L1 inhibitors showed a favorable safety profile and clinical activity in patients with clear cell and non-clear cell aRCC who were not considered for a combination regimen. [Table: see text]
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- 2020
45. Treatment outcomes in metastatic prostate cancer patients with DNA damage repair mutations
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Felix Y. Feng, Daniel Kwon, Jonathan Chou, Hala T. Borno, Rahul Aggarwal, Franklin W. Huang, David Y. Oh, YaoYao Pollock, Lawrence Fong, Arpita Desai, Thomas A. Hope, Eric J. Small, Rohit Bose, Terence W. Friedlander, Li Zhang, Vadim S. Koshkin, and Francis Wright
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Cancer Research ,Chemotherapy ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Optimal treatment ,Treatment outcome ,Androgen ,medicine.disease ,DNA Damage Repair ,Prostate cancer ,Oncology ,medicine ,Cancer research ,business ,Sequence (medicine) - Abstract
187 Background: DNA damage repair mutations (DDM) are common in prostate cancer (PCa). Optimal treatment sequence and outcomes of androgen signaling inhibitors (ASIs) and chemotherapy in this population are unclear. Methods: A retrospective, single-institution study of patients (pts) with mPCa and DDM detected on next-generation sequencing between January 2016 and July 2019 was conducted. For pts with metastatic castration-resistant prostate cancer (mCRPC), chi-squared and Wilcoxon sum rank tests were used to compare PSA50 and Time to Next Treatment (TNT) among different treatment groups, respectively. Results: Among 70 pts with mPCa and DDM, the most common mutations were BRCA2 (24, 27%), ATM (20, 22%), CDK12 (19, 21%), and MLH1/MSH2/MSH6/PMS2 (10, 11%). Fifty-seven pts (81%) received systemic treatment for mCRPC and 68% received ≥3 mCRPC treatments. Among 57 pts with ≥1 mCRPC treatment, 19 (33%) received first abiraterone, and 18 (32%) first enzalutamide. There was a trend toward higher PSA50 (74% vs 47%, P=0.196) and longer TNT (55 vs 34 wk, P=0.286) with first abiraterone vs enzalutamide. Upon switching between ASIs, 0 of 10 pts had a PSA50 response. When given chemotherapy at any point during CRPC treatment, 16/27 (59%) pts had a PSA50 response to docetaxel alone and/or cabazitaxel alone, and 14/24 (58%) to carboplatin-based regimens. Conclusions: To our knowledge, this is the largest single-institution cohort providing real-world treatment data for pts with mPCa and DDM. In the frontline mCRPC setting, abiraterone had a trend suggesting increased activity over enzalutamide that was not statistically significant. Switching ASIs at progression produced no additional responses, suggesting cross-resistance. Responses to taxanes were similar to previously reported data in all-comers. Validation in a larger, prospective cohort is needed to confirm these preliminary findings.
- Published
- 2020
46. Disparities in receipt of molecular imaging in biochemical recurrent prostate cancer
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Vadim S. Koshkin, Thomas A. Hope, Arpita Desai, Nichole Legaspi, Anobel Y. Odisho, Hala T. Borno, Alexander Bell, Tracy Kuo Lin, and Kalin Werner
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Oncology ,Receipt ,Cancer Research ,medicine.medical_specialty ,Standard of care ,business.industry ,medicine.disease ,Prostate cancer ,Internal medicine ,medicine ,Recurrent prostate cancer ,Molecular imaging ,business - Abstract
297 Background: Molecular imaging with novel radiotracers is changing treatment landscape in prostate cancer (PCa). Currently, standard of care includes both conventional and molecular imaging, leaving uncertainty in prescription decision. This study evaluated the determinants of and disparities in utilization of molecular imaging for biochemical recurrent (BR) PCa. Methods: This is an observational, single institution, cohort study within the University of California, San Francisco (UCSF). Data were obtained on all men with BR PCa seen at UCSF from June 2018 to May 2019, regardless of histologic subtype. Multivariate logistic regression models were employed to analyze the primary outcome: receipt of molecular imaging (e.g. Fluciclovine PET, Prostate Specific Membrane Antigen PET) as part of diagnostic work-up for BR PCa. Multivariate linear regression models were used to analyze the secondary outcome: overall healthcare cost (hereafter cost) within a one-year time-frame. Results: The study sample included 245 patients; 88% non-Hispanic White (White), 2 % non-Hispanic Black (Black), 9% Asian/Pacific Islander (Asian), and 10% Other. The majority were 55 years or older (66%) and privately insured (73%). Analysis indicated that a one unit reduction in PSA is associated with 1.4 times higher likelihood of receiving molecular imaging (p
- Published
- 2020
47. Efficacy of immune checkpoint inhibitors (ICIs) in rare histological variants of bladder cancer
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Hala T. Borno, Errol J. Philip, Vadim S. Koshkin, Edna Cheung, Terence W. Friedlander, Jonathan Chou, Hansen Ho, Lawrence Fong, Daniel Myung Kim, Sima P. Porten, Francis Wright, Arpita Desai, Rahul Aggarwal, Eric J. Small, Daniel Kwon, Anthony C. Wong, Son Ho, David Y. Oh, and Emily Chan
- Subjects
Cancer Research ,Metastatic Urothelial Carcinoma ,Bladder cancer ,business.industry ,Immune checkpoint inhibitors ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,business ,030215 immunology - Abstract
502 Background: ICIs are effective agents in metastatic urothelial carcinoma in both platinum-refractory and frontline settings. Responses in patients (pts) with non-urothelial histological variants are not well defined. Methods: We undertook a retrospective analysis of pts with metastatic bladder cancer treated with ICI monotherapy. Pts were identified as having a variant histology if any non-urothelial component was present. Fisher’s exact test was used to assess differences in ORR by histology. Results: Between 12/2014 and 10/2019, 102 pts received ICI monotherapy, of whom 93 were evaluable for response and 33 had variant histology. Median age was 70 yrs, 66% were male, 50% received prior platinum-based chemotherapy. Most received pembrolizumab (66%) or atezolizumab (33%). ORR in the overall cohort was 26% (15% PR, 11% CR), with 12% having SD. Histology breakdown and responses are shown in Table. Although twice as many responses were seen in urothelial pts as in pts with variant histologies (ORR 31% vs 15%), this difference was non-significant (p = 0.14). Conclusions: In this large single-institution cohort, ORR in a heterogeneous population of bladder cancer pts was consistent with data previously reported in clinical trials. Pts with variant histologies had numerically lower responses relative to pure urothelial histology, but this difference was not statistically significant. Clinical benefit to ICIs was seen across multiple variant histologies suggesting potential efficacy in this patient population that should be confirmed prospectively.[Table: see text]
- Published
- 2020
48. Metal-free synthesis of calixsalen-type cavitands for the recognition of fluoride ion
- Author
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Arpita Desai and Dharti Rana
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chemistry.chemical_classification ,010405 organic chemistry ,Organic Chemistry ,Substituent ,Salt (chemistry) ,Cavitand ,Ethylenediamine ,010402 general chemistry ,01 natural sciences ,Fluorescence ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Polymer chemistry ,Polar effect ,Nitro ,Fluoride - Abstract
Novel calixsalen-type cavitands have been synthesized using metal-free synthesis from simple and inexpensive materials, such as ethylenediamine and 5,5′-methylene-bis-salicylaldehyde derivatives. The cavitand 1 containing salen functionality recognizes fluoride ion. Fluoride ions switch on fluorescence on binding with the cavitand 1. Substitution on bis-salicylaldehyde part of calixsalen-type cavitand shows change in recognition behavior. On the attachment of electron withdrawing substituent, such as nitro group, the cavitand lost its fluorescence properties but proved to be a better colorimetric probe showing marked color change from pale yellow to red on addition of tetrabutyl ammonium salt of fluoride ion to the solution of cavitand. The nitro substituted cavitand is highly sensitive and selective for fluoride anion and hence is a promising candidate for development of colorimetric chemosensor. The binding of the cavitands with fluoride ion is investigated using 1H NMR-titration experiments.
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- 2018
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49. Final analysis of a phase II study of MRI based functional imaging of bone metastases in men with metastatic castrate-resistant prostate cancer (mCRPC) receiving cabozantinib
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Guimin Gao, Walter M. Stadler, Arpita Desai, Daniel H. Shevrin, Greg S. Karczmar, Theodore Karrison, Aytekin Oto, Russell Z. Szmulewitz, Jamie Renee Brewer, and Milica Medved
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Cancer Research ,biology ,medicine.diagnostic_test ,Cabozantinib ,business.industry ,Castrate-resistant prostate cancer ,Phases of clinical research ,Receptor tyrosine kinase ,Functional imaging ,chemistry.chemical_compound ,Oncology ,Bone scintigraphy ,chemistry ,biology.protein ,medicine ,Cancer research ,medicine.symptom ,Bone pain ,business - Abstract
213 Background: Cabozantinib (C) is a small molecule inhibitor of receptor tyrosine kinases including VEGFR-2, c-MET. C trials have shown significant improvements in bone pain and bone scintigraphy in mCRPC patients (pts). We hypothesized that functional imaging using MRI could elucidate underlying biological processes by demonstrating an early decrease in vascular permeability (decrease in transfer consant - Ktrans) and subsequent decrease in cell density (increase in apparent diffusion coefficient - ADC) within bone metastases. Methods: mCRPC pts received C 60 mg daily. The primary endpoint was change in Ktrans at 2 weeks (wks) of treatment. Secondary endpoints included Ktrans and ADC longitudinal changes, and correlation with bone scan, PSA, RECIST, and changes in reported pain. All pts underwent MRI at baseline, day 0, day 15 and every 12 wks. Results: 17 pts were treated at two sites. Median age: 68 yrs (range:51-83), baseline PSA 94.78 ng/mL (7.4-2971), number of prior CRPC therapies 2 (1-8). Median progression free survival was 5.1 months; 5 pts discontinued therapy for adverse events, and 12 for progressive disease. The most common grades 3/4 toxicities were fatigue (24%) and palmarplantar erythrodysesthesia (12%). 14 pts were evaluable for the primary endpoint. At 2 wks, Ktrans decreased an average 35%, 0.074 to 0.048 min-1 (SD=0.016, p
- Published
- 2019
50. Phase II trial of pembrolizumab (P) in patients (pts) with previously-treated mesothelioma (MM)
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Buerkley Rose, Bianca Hill, Yi-Hung Carol Tan, Tanguy Y. Seiwert, Hedy L. Kindler, Arpita Desai, Erika Pemberton, Theodore Karrison, and Christopher M. Straus
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Population ,Pembrolizumab ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,In patient ,Mesothelioma ,business ,Previously treated ,education - Abstract
8565Background: We conducted a phase II trial (NCT02399371) of P in previously treated MM to characterize activity in a non-selected population and determine a PD-L1 expression threshold Methods: E...
- Published
- 2018
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