Publications by authors named "Sumati Gupta"

30 Publications

  • Page 1 of 1

Optimal Pathologic Response After Neoadjuvant Chemotherapy For Muscle-Invasive Bladder Cancer: Results From A Global, Multi-Center Collaboration.

BJU Int 2021 Apr 28. Epub 2021 Apr 28.

Dana-Farber Cancer Institute, Boston, MA, USA.

Objectives: To evaluate outcomes of patients achieving
Patients & Methods: Patients from 10 international centers who underwent NAC for cT2-4aN0-1 MIBC and achieved
Results: 625 patients were included. Median age was 66 years and 80% were male. Gemcitabine and cisplatin (GC, 56%) and methotrexate, vinblastine, doxorubicin and cisplatin (MVAC)/dose-dense (dd) MVAC (32%) were the most common NAC regimens. ypT0, pure ypTis, ypTa+/-ypTis and ypT1+/-ypTis were attained in 58.1%, 20.0%, 7.6% and 14.2% of patients respectively. The cumulative incidence of recurrence at 5 years was 9%, 16%, 29% and 30% respectively. Pathologic stage was prognostic for recurrence, with ypTa+/-Tis (HR=3.20 [1.40-7.30]) and ypT1+/-Tis disease (HR=4.03 [2.13-7.63]) associated with a significantly higher recurrence risk. Pure ypTis (HR=1.66 [0.82-3.38]) and the type of NAC regimen (ddMVAC: HR=1.59 [0.55-4.56]; MVAC: HR=1.18 [0.25-5.54]; ref: GC) were not associated with recurrence.

Conclusion: We propose that optimal pathologic response after NAC be defined as attainment of ypT0N0/ypTisN0 at RC. Patients with ypTaN0 or ypT1N0 disease (with or without Tis) at RC displayed a significantly higher risk of recurrence and may be candidates for trials investigating adjuvant therapy.
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http://dx.doi.org/10.1111/bju.15434DOI Listing
April 2021

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

J Immunother Cancer 2020 12;8(2)

Stanford University Medical Center, Stanford, California, USA

Since the publication of the Society for Immunotherapy of Cancer's (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients.
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http://dx.doi.org/10.1136/jitc-2020-000705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713206PMC
December 2020

Hyperphosphatemia Secondary to the Selective Fibroblast Growth Factor Receptor 1-3 Inhibitor Infigratinib (BGJ398) Is Associated with Antitumor Efficacy in Fibroblast Growth Factor Receptor 3-altered Advanced/Metastatic Urothelial Carcinoma.

Eur Urol 2020 12 23;78(6):916-924. Epub 2020 Aug 23.

City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address:

Background: Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition.

Objective: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC.

Intervention: Oral infigratinib 125 mg/d for 21 d every 28 d.

Design, Setting, And Participants: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed.

Outcome Measurements And Statistical Analysis: Clinical outcomes were compared in groups with/without hyperphosphatemia.

Results And Limitations: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size.

Conclusions: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial.

Patient Summary: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.
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http://dx.doi.org/10.1016/j.eururo.2020.08.002DOI Listing
December 2020

Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer.

J Clin Oncol 2020 06 9;38(16):1797-1806. Epub 2020 Apr 9.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA.

Purpose: Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons.

Patients And Methods: Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS).

Results: Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank = .04; maximum efficiency robust test = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.

Conclusion: Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.
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http://dx.doi.org/10.1200/JCO.19.03091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255983PMC
June 2020

Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell-free DNA results.

Cancer 2020 06 24;126(11):2597-2606. Epub 2020 Mar 24.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings.

Methods: Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin-fixed, paraffin-embedded tissues. Blood was collected for cell-free DNA analysis using a 600-gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response [PR] plus complete response [CR]) and disease control rate (DCR; CR plus PR plus stable disease [SD]) were characterized.

Results: A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%).

Conclusions: Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3-restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.
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http://dx.doi.org/10.1002/cncr.32806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515773PMC
June 2020

Harnessing Population Pedigree Data and Machine Learning Methods to Identify Patterns of Familial Bladder Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 05 25;29(5):918-926. Epub 2020 Feb 25.

Population Sciences, Huntsman Cancer Institute at the University of Utah, Salt Lake City, Utah.

Background: Relatives of patients with bladder cancer have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking-related behaviors that may concentrate in some families. We demonstrate a novel approach to simultaneously assess risks for multiple cancers to identify distinct multicancer configurations (multiple different cancer types that cluster in relatives) surrounding patients with familial bladder cancer.

Methods: This study takes advantage of a unique population-level data resource, the Utah Population Database (UPDB), containing vast genealogy and statewide cancer data. Familial risk is measured using standardized incidence risk (SIR) ratios that account for sex, age, birth cohort, and person-years of the pedigree members.

Results: We identify 1,023 families with a significantly higher bladder cancer rate than population controls (familial bladder cancer). Familial SIRs are then calculated across 25 cancer types, and a weighted Gower distance with K-medoids clustering is used to identify familial multicancer configurations (FMC). We found five FMCs, each exhibiting a different pattern of cancer aggregation. Of the 25 cancer types studied, kidney and prostate cancers were most commonly enriched in the familial bladder cancer clusters. Laryngeal, lung, stomach, acute lymphocytic leukemia, Hodgkin disease, soft-tissue carcinoma, esophageal, breast, lung, uterine, thyroid, and melanoma cancers were the other cancer types with increased incidence in familial bladder cancer families.

Conclusions: This study identified five familial bladder cancer FMCs showing unique risk patterns for cancers of other organs, suggesting phenotypic heterogeneity familial bladder cancer.

Impact: FMC configurations could permit better definitions of cancer phenotypes (subtypes or multicancer) for gene discovery and environmental risk factor studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196496PMC
May 2020

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.

BJU Int 2020 05 23;125(5):739-746. Epub 2020 Feb 23.

Foundation Medicine, Cambridge, MA, USA.

Objective: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations.

Materials And Methods: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase.

Results: In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFR ) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2 occurred in 3.6% (20/552) of cases. EGFR and ERBB2 occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E-14 and 20% vs 68%, P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations.

Conclusion: EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFR and ERBB2 were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.
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http://dx.doi.org/10.1111/bju.15006DOI Listing
May 2020

Prospective Evaluation of Bone Metabolic Markers as Surrogate Markers of Response to Radium-223 Therapy in Metastatic Castration-resistant Prostate Cancer.

Clin Cancer Res 2020 05 14;26(9):2104-2110. Epub 2020 Jan 14.

Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Purpose: Radium-223 is approved for metastatic castration-resistant prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMMs) as surrogate markers of response to radium-223 in mCRPC.

Patients And Methods: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination.

Results: Thirty-nine men were randomized to RE ( = 27) or enzalutamide ( = 12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% confidence interval, 0.51-0.81; = 0.00048) favored RE versus enzalutamide. Overall, BMMs decreased with the RE therapy compared with enzalutamide. Improved PSA response rate in RE versus enzalutamide ( = 0.024), correlated with decline in BMMs.

Conclusions: BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radium-223 in real-time.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2591DOI Listing
May 2020

Real-world practice patterns in veterans with metastatic castration-resistant prostate cancer.

Urol Oncol 2020 01 5;38(1):1.e1-1.e10. Epub 2019 Nov 5.

George E. Wahlen Veterans Health Administration, Salt Lake City, UT; University of Utah, Salt Lake City, UT.

Background: Metastatic castration-resistant prostate cancer (mCRPC) is incurable, with most patients surviving less than 3 years. However, many treatments that extend survival have been approved in the past decade.

Objective: To describe the patient demographics, disease characteristics, treatment patterns, and outcomes in a cohort of Veterans diagnosed with mCRPC in the Veterans Health Administration.

Design: We identified 3,637 Veterans diagnosed with prostate cancer between January 2006 and August 2015 with evidence of mCRPC through December 2016. We described the most commonly used systemic mCRPC treatments according to mCRPC diagnosis era: Epoch 1 (2006-2010) or Epoch 2 (2011-2016). Patient demographics, disease characteristics, and treatment patterns were examined using descriptive statistics. An unadjusted Kaplan-Meier method was used to estimate the median time to biochemical progression and overall survival (OS) with 95% confidence intervals.

Results: The median age at initial prostate cancer diagnosis was 68 years. Approximately 67% of patients were non-Hispanic white, 29% were black, and 4% were other/unknown. A high-risk Gleason score (8-10) was reported in 748 (67%) of patients in Epoch 1 and 1578 (63%) of patients in Epoch 2, and the median prostate-specific antigen level at initial prostate cancer diagnosis was higher in Epoch 1 patients than in Epoch 2 patients (68 vs. 35 ng/ml). Following mCRPC diagnosis, the most common first-line therapies in Epoch 1 patients were docetaxel (83%) and abiraterone (9%), whereas Epoch 2 patients mainly received abiraterone (47%), docetaxel (36%), and enzalutamide (15%). In Epoch 1 and Epoch 2 patients, the median time to biochemical progression (unadjusted) was 9 and 13 months, respectively, and the median OS (unadjusted) was 15 and 23 months, respectively.

Conclusions: The introduction of new therapies has resulted in increased use of the noncytotoxic agents abiraterone and enzalutamide as first-line treatment in lieu of docetaxel. Our results suggest that more recently diagnosed patients (Epoch 2) have a delayed time to biochemical progression and longer OS (unadjusted) compared with patients diagnosed earlier (Epoch 1).
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http://dx.doi.org/10.1016/j.urolonc.2019.09.027DOI Listing
January 2020

Circulating Tumor DNA Alterations in Advanced Urothelial Carcinoma and Association with Clinical Outcomes: A Pilot Study.

Eur Urol Oncol 2020 10 9;3(5):695-699. Epub 2019 Mar 9.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address:

Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.
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http://dx.doi.org/10.1016/j.euo.2019.02.004DOI Listing
October 2020

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes.

Cancer 2019 02 20;125(4):533-540. Epub 2018 Dec 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

Background: The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single-arm, open-label phase 2 study.

Methods: Eligible patients with platinum-treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28-day cycles in a 3-stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.

Results: Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent-to-treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose-normalized maximum serum concentration [C ] after TIW dosing of 0.2 ng/mL/mg).

Conclusions: To the authors' knowledge, the current study represents the first clinical trial using genomic-based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.
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http://dx.doi.org/10.1002/cncr.31817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590473PMC
February 2019

Histone Deacetylase Inhibition Has Targeted Clinical Benefit in -Mutated Advanced Urothelial Carcinoma.

Mol Cancer Ther 2019 01 9;18(1):185-195. Epub 2018 Oct 9.

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had mutations. mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant -mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350908PMC
January 2019

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with Alterations.

Cancer Discov 2018 07 30;8(7):812-821. Epub 2018 May 30.

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of alterations. Patients ( = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. BJG398 is active in patients with alterations in , resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716598PMC
July 2018

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial.

Lancet Oncol 2018 04 9;19(4):451-460. Epub 2018 Mar 9.

Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Lerner College of Medicine, Cleveland, OH, USA.

Background: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma.

Methods: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751.

Findings: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily.

Interpretation: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy.

Funding: Pfizer and Merck.
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http://dx.doi.org/10.1016/S1470-2045(18)30107-4DOI Listing
April 2018

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA.

Cancer 2018 05 8;124(10):2115-2124. Epub 2018 Mar 8.

Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Methods: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes.

Results: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC.

Conclusions: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857169PMC
May 2018

Reversible LSD1 inhibition with HCI-2509 induces the p53 gene expression signature and disrupts the MYCN signature in high-risk neuroblastoma cells.

Oncotarget 2018 Feb 6;9(11):9907-9924. Epub 2018 Jan 6.

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets. HCI-2509 results in increased histone methyl marks and p53 levels along with cell cycle arrest in the G2/M phase and inhibition of colony formation of NGP cells. Our findings indicate that LSD1 inhibition with HCI-2509 has a multi-target effect in neuroblastoma cell lines, mediated in part via p53. MYCN-amplified neuroblastoma cells have a targeted benefit as HCI-2509 downregulates the MYCN upregulated gene set.
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http://dx.doi.org/10.18632/oncotarget.24035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839410PMC
February 2018

Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case-Control Study.

J Natl Cancer Inst 2018 05;110(5):527-533

Division of Urology, Department of Surgery, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT.

Background: Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering.

Methods: Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancer-free controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided.

Results: First- and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001; HR = 1.04, 95% CI = 1.02 to 1.07, P = .001) and urothelial cancer (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001; HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), cervical (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01), and lung cancer (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR = 1.35, 95% CI = 1.2 to 1.5, P < .001) and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02). Spouses showed an increased risk for laryngeal (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) and cervical cancer (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007). These results did not substantively change after correction for suspected smoking behaviors.

Conclusion: Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies.
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http://dx.doi.org/10.1093/jnci/djx237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946951PMC
May 2018

Comprehensive Genomic Sequencing of Urothelial Tumors Identifies Rare SMARCB1 (INI-1)-Deficient Carcinomas of the Urinary System.

Clin Genitourin Cancer 2018 04 7;16(2):e373-e382. Epub 2017 Sep 7.

Foundation Medicine Inc, Cambridge, MA.

Purpose: Tumor genomic profiling helps direct therapy for advanced urothelial carcinoma (UC). In the course of clinical care, we encountered a patient with a complete loss of SMARCB1 (switch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), which encodes INI-1 (integrase interactor 1), as the sole detected driver of their urinary tract tumor. Our objective was the identification and genomic characterization of urinary tract neoplasia with complete SMARCB1 loss.

Patients And Methods: Tissue from 1287 patients with UC was assayed by hybrid capture-based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA), such as, base substitutions, insertions/deletions, amplifications, copy number alterations, fusions/rearrangements, and targeted therapy opportunities. A total of 315 genes frequently altered in cancer were assayed.

Results: CGP identified 10 patients with SMARCB1 alterations. Of the 10 patients, 4 (1 each with renal pelvis, ureter, bladder, and unknown primary cancer) had complete loss of SMARCB1, and 6 had loss of heterozygosity with an unknown effect on function or heterozygous loss. Patients with complete SMARCB1 loss had few or no additional alterations. Compared with conventional UC, the tumor mutational burden was significantly lower (P = .004). All 4 patients with complete SMARCB1-loss tumors were < 56 years old and 3 were female.

Conclusion: The genomic profiles of the tumors from patients with UC revealed a population of tumors driven by complete loss of SMARCB1. This previously uncharacterized subset of INI-1-deficient urinary tract tumors might constitute a new tumor category that could be sensitive to targeted therapy, including EZH2 (enhancer of zeste homolog 2) inhibition. Clinical trial testing could be challenging owing to the rarity of the disease.
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http://dx.doi.org/10.1016/j.clgc.2017.09.001DOI Listing
April 2018

Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications.

Oncotarget 2017 May;8(20):33614-33620

Division of Medical Oncology, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Introduction: Tumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. Our objective was to assess if GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary.

Results: When controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When comparing GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways.

Materials And Methods: Results of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischer's exact test was used to compare the incidence of mutations in selected molecular pathways.

Conclusions: When controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.
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http://dx.doi.org/10.18632/oncotarget.16833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464894PMC
May 2017

Inherited DNA repair gene mutations detected by tumor next generation sequencing in urinary tract cancers.

Fam Cancer 2017 10;16(4):545-550

Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.

Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.
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http://dx.doi.org/10.1007/s10689-017-9980-2DOI Listing
October 2017

Efficacy of Eplerenone in the Management of Mineralocorticoid Excess in Men With Metastatic Castration-resistant Prostate Cancer Treated With Abiraterone Without Prednisone.

Clin Genitourin Cancer 2017 08 5;15(4):e599-e602. Epub 2017 Jan 5.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. Electronic address:

Background: Abiraterone acetate has been approved for metastatic castration-resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long-term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real-world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy.

Patients And Methods: The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression-free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischer's exact test or χ test, as appropriate. PFS was compared using the Kaplan-Meier method.

Results: Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts.

Conclusion: In a real-world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation.
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http://dx.doi.org/10.1016/j.clgc.2016.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501307PMC
August 2017

A phase I study to determine the pharmacokinetics and urinary excretion of belinostat and metabolites in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2016 Nov 15;78(5):1059-1071. Epub 2016 Oct 15.

Huntsman Cancer Institute, The University of Utah, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT, 84112, USA.

Purpose: Belinostat is an inhibitor of histone deacetylase enzymes, resulting in DNA repair inhibition and apoptosis. Present data are lacking to provide dosing recommendations in renal insufficiency. The purpose of this trial was to assess the pharmacokinetics (PK) of belinostat and belinostat metabolites in plasma and urine.

Methods: This was a phase I, single-center, open-label, two-part study. In Part I, patients received single-agent belinostat 1000 mg/m. Blood and urine samples were collected at pre-specified time points to determine PK of belinostat and metabolites and their elimination in urine. In Part II, patients were permitted to continue belinostat in 21-day cycles on Days 1 through 5 until disease progression, unacceptable toxicity, or according to patient preference.

Results: A total of nine patients with advanced solid tumors were treated. Median t for belinostat was observed 10 min after the start of infusion. Concentrations of belinostat rapidly declined with a t of 2.9 h. The mean fraction of belinostat excreted unchanged in urine was 0.926 %. The metabolites belinostat glucuronide and 3-ASBA represented the largest fractions of belinostat dose excreted in urine (30.5 and 4.61 %, respectively), while renal excretion appeared to be a minor route of elimination for the parent belinostat (<1 %). The most common adverse events were nausea, fatigue, and diarrhea. One Grade 3 adverse event (constipation) was thought to be treatment related.

Conclusions: Urinary elimination of parent belinostat was minimal, although a combined 36.7 % of belinostat metabolites were excreted in urine. Since these metabolites are primarily inactive, belinostat may not require dosage adjustment in renal dysfunction.
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http://dx.doi.org/10.1007/s00280-016-3167-7DOI Listing
November 2016

Conditional survival of metastatic renal cell carcinoma patients treated with high-dose interleukin-2.

Ecancermedicalscience 2016 29;10:676. Epub 2016 Sep 29.

University of Utah Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.

Conditional survival (CS) is a clinically useful prediction measure which adjusts a patient's prognosis based on their duration of survival since initiation of therapy. CS has been described in numerous malignancies, and recently described in patients with metastatic renal cell carcinoma (mRCC) who received vascular endothelial growth factor tyrosine kinase inhibitor (VEGFTKI) therapy. However, CS has been not reported in the context of mRCC treated with high-dose interleukin-2 therapy (HDIL-2). A total of 176 patients with histologically confirmed metastatic clear cell RCC (mccRCC) treated with HDIL-2 at the University of Utah Huntsman Cancer Institute from 1988-2012 were evaluated. Using the Heng/IMDC model, they were stratified by performance status and prognostic risk groups. Two-year CS was defined as the probability of surviving an additional two years from initiation of HDIL-2 to 18 months after the start of HDIL-2 at three-month intervals. The median overall survival (OS) was 19.9 months. Stratifying patients into favourable (n = 35; 20%), intermediate (n = 110; 63%), and poor (n = 31; 18%) prognostic groups resulted in median OS of 47.5 (HR 0.57, 95% CI 0.35-0.88, p = 0.0106 versus intermediate), 19.6 (HR 0.33, 95% CI 0.10-0.33, p < 0.0001 versus poor), and 8.8 (HR 5.34, 95% CI 3.00-9.62, p < 0.0001 versus favourable) months respectively. Two-year overall CS increased from 43% at therapy initiation to 100% at 18 months. These results have significant ramifications in prognostication. Furthermore, it is important when counseling patients with mccRCC who have completed treatment with HDIL-2 and are in active follow-up.
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http://dx.doi.org/10.3332/ecancer.2016.676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045298PMC
September 2016

Phase II study of amrubicin (SM-5887), a synthetic 9-aminoanthracycline, as first line treatment in patients with metastatic or unresectable soft tissue sarcoma: durable response in myxoid liposarcoma with TLS-CHOP translocation.

Invest New Drugs 2016 Apr 20;34(2):243-52. Epub 2016 Feb 20.

Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.

Purpose: Amrubicin is a third generation synthetic 9-aminoanthracycline that specifically inhibits topoisomerase II. Amrubicin preferentially concentrates in tumor cells leading to tumor cell death without causing cardiac toxicity. This phase II multicenter study was done to evaluate the efficacy and tolerability of amrubicin in advanced soft tissue sarcoma (STS).

Patients And Methods: 24 eligible patients with chemotherapy-naive metastatic or unresectable STS were treated with amrubicin 40 mg/m(2) intravenously daily for three consecutive days in 21 days cycles with growth factor support. Patients continued to receive treatment, as long as it was tolerated, in the absence of significant disease progression. The disease was followed on imaging scans every 6 weeks. The primary endpoint of the study was the best overall response rate.

Results: The best overall response rate was 13% in 23 evaluable patients. Median progression-free survival was 5.8 months, and median overall survival was 26 months. Grade 3 to 4 toxicities of febrile neutropenia and anemia occurred in 21% of treated patients. One patient with metastatic myxoid liposarcoma with TLS-CHOP translocation had a durable response and received 40 cycles of amrubicin. There was no significant cardiac toxicity.

Conclusions: Amrubicin has efficacy comparable to doxorubicin in adult STS, is well tolerated and has no significant cardiac toxicity up to a cumulative dose of 4800 mg /m(2). Topoisomerase II inhibition with amrubicin warrants further study as a potential 'targeted therapy' for TLS-CHOP-translocated myxoid liposarcoma. Results from this trial favor the use of amrubicin for the treatment of STS.
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http://dx.doi.org/10.1007/s10637-016-0333-zDOI Listing
April 2016

A phase I clinical trial of the effect of belinostat on the pharmacokinetics and pharmacodynamics of warfarin.

Cancer Chemother Pharmacol 2016 Feb 30;77(2):299-308. Epub 2015 Dec 30.

Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, 84112, UT, USA.

Purpose: Belinostat is a potent small molecule inhibitor that exerts its antitumor effect through inhibition of histone deacetylase. The purpose of this study was to evaluate the pharmacokinetics and pharmacodynamics of warfarin (as a reference drug metabolized by CYP2C9) in the presence and absence of belinostat.

Methods: We conducted a phase I, single-center, open-label, drug-drug interaction study between belinostat and warfarin. In part I, patients were given warfarin 5 mg orally (day-14 and 3) and belinostat 1000 mg/m(2) (days 1 through 5). Patients receiving benefit continued belinostat on days 1 through 5 every 21 days until disease progression, unacceptable toxicity, or per patient preference.

Results: A total of 18 patients were treated. With belinostat, the least-squared means for maximum concentration (C max), area under the curve0-∞, and area under the curve0-t of R-warfarin were slightly increased. However, for the more potent S-warfarin isomer, the same parameters were primarily contained within the pre-specified equivalence limits of 0.80 and 1.25, indicating there was no statistically significant interaction between S-warfarin and belinostat. The most common adverse events were nausea, vomiting, and fatigue. Three grade 3 adverse events (diarrhea 5.6 %, nausea 5.6 %, and vomiting 5.6 %) were thought to be treatment related. Progression-free survival ranged from 0.2 to 13.8 months in all patients.

Conclusions: Belinostat did not significantly affect the pharmacokinetics and pharmacodynamics of warfarin, indicating no clinically relevant effect on the enzymatic activity of CYP2C9.
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http://dx.doi.org/10.1007/s00280-015-2934-1DOI Listing
February 2016

Superstition predicts favorable weight change in an open-placebo trial: a prospective study.

Eat Weight Disord 2015 Sep 22;20(3):389-95. Epub 2014 Nov 22.

Barnard College, Columbia University, New York, USA,

Given the difficulty of losing weight via adhering to healthy lifestyle choices, this study sought to understand how a placebo may elicit favorable weight change. Specifically, we examined if superstition may be related to increased responsiveness to an open-placebo. In this pilot study of 25 undergraduate participants, it was hypothesized that individuals with higher levels of superstition may be more responsive to a 3-week open-placebo weight change trial. Participants were given once-daily saltine crackers to use as open-placebos for weight change in their preferred direction (gain or loss). The weight of each participant was measured before and after the 3-week open-placebo period. A Pearson's r correlation showed a significant positive relationship between superstition and placebo responsiveness, determined by weight gain or loss in the preferred direction, r (25) = 0.493, p < 0.05. We hope these preliminary results engender future research on open-placebo uses for weight management.
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http://dx.doi.org/10.1007/s40519-014-0167-7DOI Listing
September 2015

Complicated grief and deficits in emotional expressive flexibility.

J Abnorm Psychol 2011 Aug;120(3):635-43

Department of Counseling and Clinical Psychology, Teachers College, Columbia University, 525 West 120th Street, Box 102, New York, NY 10027, USA.

There is growing evidence that deficits in emotion regulation may be at the heart of maladaptive reactions after bereavement. Expressive flexibility, or the ability to flexibly enhance or suppress emotional expression, appears to be especially important for adjustment in the aftermath of highly aversive events (Bonanno, Papa, Lalande, Westphal, & Coifman, 2004). In this study, we compared expressive flexibility in a sample of bereaved adults who lost their spouse 1.5-3 years earlier and a comparable sample of married adults. Approximately half of the bereaved adults had Complicated Grief (CG) and half were asymptomatic. Using a within-subjects design, we asked all participants to either enhance or suppress their expressions of emotion or to behave normally while viewing evocative pictures at a computer screen. Observer ratings of expressiveness made blind to condition showed no group differences in overall emotion. However, bereaved adults suffering from CG exhibited deficits in expressive flexibility. Specifically, the CG group was less able to enhance and less able to suppress emotional expression relative to asymptomatic bereaved and married adults.
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http://dx.doi.org/10.1037/a0023541DOI Listing
August 2011

Emotion regulation skills mediate the effects of shame on eating disorder symptoms in women.

Eat Disord 2008 Oct-Dec;16(5):405-17

Department of Counseling & Clinical Psychology, Teachers College, Columbia University, 525 West 120th Street, Box 102, New York, NY 10027, USA.

We examined the impact of negative affectivity, chronic shame, and emotion regulation skills on eating disorder symptoms in undergraduate women (N = 154). We hypothesized that self-reported emotion regulation skills would mediate the well-documented relationship between chronic shame and eating disorder symptoms. Results revealed that chronic shame predicted eating disorder symptoms over and above general negative affectivity. Further, difficulties with emotion regulation mediated the relationship between chronic shame and ED symptoms. These findings suggest that chronic shame's role in eating disorder symptoms can be ameliorated by skillful emotion regulation.
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http://dx.doi.org/10.1080/10640260802370572DOI Listing
January 2009

Lack of effect of long-term use of angiotensin-converting enzyme inhibitors by hemodialysis patients on thirst and fluid weight gain.

Ren Fail 2002 Jul;24(4):461-6

Department of Medicine, Nassau University Medical Center, East Meadow, NY 11554, USA.

Volume overload is a chronic, troublesome problem in many patients on hemodialysis. These patients suffer from hyperdipsia with inability to excrete water. Angiotensin-converting enzyme inhibitor (ACEI) has been shown to decrease thirst and interdialytic weight gain in 2-4 weeks of usage. We investigated the effect of long-term use of ACEI, as levels of angiotensin II tends to go back to normal level after 6 months of use. We compared hemodialysis patients on ACEI for more than 6 months to patients not on ACEI. Seven patients were taking ACEI compared to 51 controls in the other group. Almost one third of patients in each group had an interdialytic weight gain > 5% of dry weight. No significant difference was found between the two groups with regard to interdialytic weight gain, thirst and mouth dryness scores, and interdialytic mean blood pressure change. There was no demonstrable effect of angiotensin receptor blocking drugs on weight gain or thirst. We conclude that long-term ACEI may not continue to suppress inappropriate thirst and fluid intake after 6 months in hemodialysis patients.
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http://dx.doi.org/10.1081/jdi-120006772DOI Listing
July 2002