tbuckley/cabot-search huggingface dataset:
Loss of BAP1 and PBRM1 expression in non-clear cell renal cell carcinomas compared to clear cell renal cell carcinomas.
Authors: Thai Huu Ho, Payal Kapur, Richard Wayne Joseph, Daniel Serie, Jeanette Eckel-Passow, Mansi Parasramka, John C. Cheville, James Brugarolas, Alexander S. Parker
Journal: Journal of Clinical Oncology (2014)

4529 Background: Loss of function mutations in PBRM1 (41-50%) and BAP1(5-15%) are associated with poor outcomes for patients with clear cell renal cell carcinoma (ccRCC) tumors. However, there are no data regarding the prevalence of these mutations in other RCC subtypes (non-ccRCC). We evaluated loss of PBRM1 and BAP1 expression in ccRCC and non-ccRCC tumors using an IHC assay for which negative staining correlates with loss of function mutations. Methods: From our Registry database, we identified 311 and 105 patients treated surgically for ccRCC and non-ccRCC. We performed IHC assays to evaluate PBRM1 and BAP1 protein expression. We classified tumors as BAP1 or PBRM1 negative when tumor cells showed diffuse absence of nuclear staining. We compared loss of expression of these two proteins between ccRCC and non-ccRCC using Fisher’s exact tests. Results: Of the total cohort of 416 patients, we successfully stained BAP1 in 406 (97.5%) and PBRM1 in 372 (89.4%). Of those with successful staining, we further excluded samples with focal negative or weak positive expression of BAP1 (n=59) or PBRM1 (n=55). Thus, we were left with 186 ccRCC and 79 non-ccRCC patient samples that had both BAP1 and PBRM1 available for analysis. We observed BAP1 loss of expression in 9% (17/186) of the ccRCC tumors but only 1% (1/79) of the non-ccRCC tumors (p=0.016). Similarly, we noted loss of expression of PBRM1 in 43% (80/186) of the ccRCC tumors but only 4% (3/79) of the non-ccRCC tumors (p=0.0001). Of note, within the non-ccRCC group, we observed 0% (0/61) papillary tumors and 5% (1/18) chromophobe tumors with loss of BAP1. By comparison, 3% (2/61) of papillary tumors and 1/18 (5%) of chromophobe tumors showed loss of PBRM1 expression. Conclusions: Our data are the first to suggest that loss of function mutations in PBRM1 and BAP1 are less common in non-ccRCC tumors compared to ccRCC. If these findings are independently confirmed, they suggest that while loss of PBRM1 and BAP1 are key events in ccRCC, disruption of other pathways may support tumorigenesis in non-ccRCC subtypes. BAP1/PBRM1 Papillary Chromophobe ccRCC -/- 0 (0%) 0 (0%) 3 (2%) -/+ 0 (0%) 1 (5%) 14 (8%) +/- 2 (3%) 1 (5%) 77 (41%) +/+ 59 (97%) 16 (90%) 92 (49%) 61 18 186
Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): Randomized, double-blind, multicenter phase 2 trial.
Authors: Harry H. Yoon, Johanna C. Bendell, Fadi S. Braiteh, Irfan Firdaus, Philip Agop Philip, Allen Lee Cohn, Nancy Lewis, Daniel M. Anderson, Edward Arrowsmith, Jonathan D. Schwartz, Yihuan Xu, Minori Koshiji, Steven R. Alberts, Zev A. Wainberg
Journal: Journal of Clinical Oncology (2014)

4004 Background: RAM, an anti-VEGFR2 monoclonal antibody, improved overall survival (OS) in 2 phase 3 trials in patients (pts) with previously treated gastric/gastroesophageal junction (GEJ) AC. We report the first assessment of RAM as 1st-line Rx for GE-AC. Methods: Pts with untreated metastatic or locally advanced unresectable GE-AC (PS ≤1) were randomized 1:1 to mFOLFOX6 plus RAM (8 mg/kg IV) v placebo (PL), q14d. Primary endpoint was progression-free survival (PFS), with 80% power to detect HR 0.71 (α =.3). Secondary endpoints included OS, response rate (RR), disease control rate (DCR), and safety. Results: 168 pts (RAM 84 v PL 84) enrolled at 47 US sites, 04/11 – 08/12. Pt characteristics: age (65 v 60); male (75% v 73%); gastric (23% v 24%), GEJ (31% v 27%), esophageal (46% v 49%); metastatic (95% v 94%). Median PFS 6.4 v 6.7 m (HR 0.98 [95% CI 0.69 – 1.37]; p =.89) and OS 11.7 v 11.5 m (HR 1.08 [0.73-1.58]). Subgroup analyses by primary tumor location: for esophageal, median PFS was 5.6 v 6.1 m (HR 1.30); for gastric/GEJ, PFS was 8.7 v 7.1 m (HR 0.77 [0.48 – 1.24]; p =.28) and OS 14.6 v 12.5 m. PFS rate at 3 m was higher in RAM v PL (89% v 75%, p =.020), but not at 6, 9, or 12 m. RR (CR, PR) 45% v 46%. DCR (SD, CR, PR) 85% v 67% (p =.008). Most common grade ≥3 adverse events (AEs): neutropenia (27% v 36%), fatigue (18% v 15%), neuropathy (9% v 11%). Grade ≥3 AEs of special interest were uncommon, except hypertension. Median cycles of OX were similar among arms (8.5 v 9.5), but cycles of 5FU or RAM/PL (both 9 v 11) were lower in RAM arm. Rx discontinuation for non-progressive disease (PD) was more common in RAM: pt/physician decision (27% v 10%), AEs (21% v 6%). In exploratory analyses that censored PFS at Rx discontinuation for non-PD, HR for PFS favored RAM arm (HR 0.76; p =.194), mainly in gastric/GEJ pts (PFS 9.3 v 7.6 m; HR 0.53 [0.29 – 0.97]; p =.036). Conclusions: Addition of RAM to FOLFOX did not improve median PFS but showed PFS difference at 3 m and improved DCR. Longer PFS in RAM v PL was observed in gastric/GEJ cancer pts. A higher non-PD discontinuation rate and lower drug exposure in RAM arm may have impacted PFS assessment. These data are critical for clinical development of RAM in gastric cancer. Clinical trial information: NCT01246960.
Life after cervical cancer: Sexual function and quality of life in long-term survivors of carcinoma uterine cervix among Indian women.
Authors: Abhishek Shankar, Jaineet Patil, Kavita Mandrelle, Anil Luther
Journal: Journal of Clinical Oncology (2014)

e16503 Background: Carcinoma cervix is the second most common type of cancer in the world. With the increasing proportion of women surviving carcinoma of the cervix, quality of life has been an important clinical issue. Since there are very few studies from India, this study is to assess sexual dysfunction and quality of life in patients of carcinoma cervix treated with multimodality therapy using the LENT SOMA scores. Methods: The study was prospective and patients treated between 1995 - 2007 on follow up were included in this study after ethical clearance. A total of 85 patients were accrued comprising 6 stage IB, 6 stage II A,25 stage II B, 2 stage IIIA, 45 stage III B and 1 stage IV A disease. Sixty six patients were treated with radiotherapy in which 46 patients received chemoradiotherapy and 19 had surgery prior to post-operative radiotherapy. The mean age was 47.81 years with a range of 25-68 years. Completion of LENT SOMA scale and Statistical analysis was done. Results: Initial data were obtained for 85 women. Mean sexual function and satisfaction score was higher in 20-29 years age group(p – 0.002). Average objective score was more in higher age group patients (p-0.001). Average subjective score was significantly more in stage IIIA and IIIB in comparison to IB(p - 0.004 and 0.024 respectively). Average overall LENT SOMA scale was higher in stage IIIB patients in comparison to stage IB and IIB(p – 0.023 and 0.004 respectively). Average overall LENT SOMA scale was higher in pelvic field when compared to extended field(p – 0.044). Average subjective, objective and overall LENT SOMA score was more in surgery followed by chemoradiotherapy group and in patients treated by 2 fields. Probability of DFS at 15 years was found to be 0.972. Recurrences was reported in 3.51% patients and mean time was 31.66 months. Conclusions: The LENT SOMA system was acceptable and feasible to use and gave us an insight into the morbidity in our patients. Since it is one of few studies in India on late morbidity in treated patients of carcinoma cervix, It will also help us to develop effective management plans to reduce the post treatment symptoms and improve quality of life.
Use of Late-Life Expectancy for Assessing the Long-Term Benefit of Immune Checkpoint Inhibitors
Authors: Alexandre Vivot, Perrine Créquit, Raphaël Porcher
Journal: JNCI Journal of the National Cancer Institute (2018)

To grade the long-term benefit of anticancer agents, the American Society of Clinical Oncology Value Framework (ASCO-VF) awards tail-of-the-curve bonus points by using milestone survival at twice the median control survival. Here, we propose an alternative, late-life expectancy that we defined as the area under the Kaplan–Meier curve from median control survival to the end of follow-up. We analyzed all indications of immune checkpoint inhibitors with survival data and found that 9 indications out of 13 (69.2%) qualified for ASCO-VF tail-of-the-curve bonus points either in progression-free or overall survival. Our proposed score recognized a long-term benefit not captured by the ASCO-VF, for example, for CHECKMATE-66 where twice the median overall survival was not reached. We found that nivolumab was associated with an increase of 65.3% (95% CI = 38.9 to 89.5) in overall survival late-life expectancy, which highlights its important long-term benefit. In conclusion, the ASCO-VF could be improved with the use of late-life expectancy.
Safety and Efficacy of Adct-402 (Loncastuximab Tesirine), a Novel Antibody Drug Conjugate, in Relapsed/Refractory Follicular Lymphoma and Mantle Cell Lymphoma: Interim Results from the Phase 1 First-in-Human Study
Authors: Paolo Caimi, Brad S. Kahl, Mehdi Hamadani, Carmelo Carlo-Stella, Shui He, David Ungar, Jay Feingold, Kirit M. Ardeshna, John Radford, Melhem Solh, Leonard Heffner, Owen A. O'Connor
Journal: Blood (2018)
Molecular profiling of testicular cancer.
Authors: Carsten Bokemeyer, Christoph Oing, Kenneth Russell, Sherri Z. Millis, Ryan Bender, Zoran Gatalica, Andreas Voss
Journal: Journal of Clinical Oncology (2014)

4515 Background: The incidence of testicular cancer (TC) has been increasing in many western countries for several decades. For 2013, about 7900 new TC cases with 370 deaths are estimated in the United States. While the overall prognosis in metastatic TC is excellent, treatment options for patients (pts) relapsing with cisplatin-refractory disease are limited. A personalized approach to therapy based upon molecular diagnostic tools to predict response to specific therapeutic agents may help pts in whom standard chemotherapy has failed. Methods: Eighty-five TC cases referred to Caris Life Sciences between 2009 and January 2014 were evaluated; diagnoses were collected from referring physicians and classified at intake based on pathology and clinical history. Specific testing was performed per physician request and included a combination of sequencing (Sanger, NGS or pyrosequencing), protein expression (immunohistochemistry), gene amplification (CISH or FISH), and/or RNA fragment analysis. Results: In this cohort of pts with advanced / refractory TC, the most commonly observed changes in protein expression were upregulation of TOPO2A (66%), TLE3 (45%), SPARC (44%), and TS (42%) and downregulation of PTEN observed in 40% of patients. PIK3CA gene amplification was observed in a single case tested, amplification of EGFR, cMET, and HER2 was observed in 14%, 7%, and 7% of cases, respectively. In 16 cases analyzed by NGS, KRAS was the most common mutation (13%) followed by TP53 (7%) and cKIT mutations (7%). No NRAS or HRAS mutations were found. Further 5 KRAS mutations were detected by PCR or sanger sequencing. Two of seven pts with KRAS mutations also had HER2 amplification, one had a cKIT mutation. All pts with TP53 mutations also had a loss of PTEN protein expression but no other mutations. Pathway profiling revealed that with the exception of loss of PTEN, 93% of patients were predominantly ERK and mTOR pathway wildtype, and activation of the ERK pathway only occurred through the presence of mutations in the KRAS gene. Conclusions: A low prevalence of mutations was observed in advanced / refractory TC. Predictive biomarkers may be used to guide treatment decisions. Targeting the cKIT, HER2 or cMET pathways may warrant treatment options in single pts.
Randomized phase II study with dendritic cell (DC) immunotherapy in patients with resected hepatic metastasis of colorectal carcinoma.
Authors: Javier Rodriguez, Ruth Vera, Fernando Pardo, Javier Herrera, Ana Chopitea, Irene Hernandez, Antonio Viudez, Carlos Garzon, Carlos Alfaro, Jose Luis Perez-Gracia, Alberto Benito, Alvaro Gonzalez, Ivan Peñuelas, Maria Rodriguez-Ruiz, Miguel F. Sanmamed, Carmen Oñate, Carmen Ochoa, Juan Pablo Fusco, Ignacio Melero
Journal: Journal of Clinical Oncology (2014)

TPS3129 Background: Cellular immunotherapy with DC is a feasible strategy with proved activity in the treatment of cancer. Preclinical and clinical data indicate that efficacy of DC immunotherapy is improved when used in clinical settings of minimal residual disease, and Sipuleucel-T is the first approved treatment based in this approach. We are exploring the efficacy of an autologous vaccine of DC loaded with self-tumor antigens that we developed in a previous pilot trial (Alfaro, J Immunology 2011) in patients with colorectal cancer with completely resected hepatic metastasis following standard adjuvant treatment. Methods: In this randomized phase II study, patients with colorectal carcinoma with hepatic metastasis treated with complete surgical resection and standard adjuvant chemotherapy are randomized to receive DC vaccine or observation. The two-cycle vaccination protocol includes the following strategies: (1) pretreatment with cyclophosphamide to decrease regulatory T cells; (2) maturation and activation of DC with TNF-alpha, interferon-alpha and poly I:C, a potent inducer of type I interferon; (3) use of autologous tumor from resected liver metastasis as antigenic source to load antigens onto DC, including antigens that are exclusive of tumor cells; and (4) administration of daily intradermal vaccines during four consecutive days in 2 cycles every 4 weeks. The strategy is to replicate the immune response induced during an acute viral infection in terms of activation signals and persistence of antigens in lymph nodes. The main objective is progression-free survival. Thirty-six patients will be included, allowing to detect a HR=1.75 (alpha error=0.2, beta error=0.35). Secondary objectives include assessment of toxicity, overall survival and immunologic response (in vitro lymphocyte responses against tumor antigens; delayed hypersensitivity reactions; induction of tumor antibody responses; DC activation parameters including IL-12 and IL-6 production and expression of CD80, CD83, CD86, B7-H1, B7-H4 and B7-DC; assessment of DC maturation by expression of pro-inflammatory cytokines; and DC migration). Clinical trial information: NCT01348256.
Trends in health-related quality of life (HRQoL) and income over time in older adults with and without cancer: Evidence from the Surveillance, Epidemiology, and End Results–Medicare Health Outcomes Survey (SEER–MHOS) linked database.
Authors: Veena Shankaran, Sara Khor, Scott David Ramsey, Anirban Basu
Journal: Journal of Clinical Oncology (2014)

9603 Background: The impact of cancer diagnosis (dx) on the financial health and HRQoL of older adults is not well understood. The goal of this study was to explore longitudinal changes in HRQoL and self-reported income in a population-based sample of older Medicare enrollees with and without cancer. Methods: SEER-MHOS links data on cancer patients (pts) dx in 1998–2007 with a longitudinal HRQoL survey of Medicare Advantage Organization enrollees. We identified pts age ≥ 65 with primary breast, colorectal, prostate, lung, or head and neck cancers who had completed at least 2 MHOS surveys (1 pre and 1 post dx). 2,514 cancer cases were matched 1:4 with 8,616 non-cancer controls by age, gender, race, and time between surveys (mean age 75.3); controls were assigned a pseudo-dx date when their age was the same as the dx age of the matched cancer case. Mean physical component score (PCS) and mental component score (MCS) were determined at various time intervals before and after dx. The proportions of individuals experiencing a decline in household income were also reported. Results: A similar proportion of cases and controls reported declines in at least 1 income category after dx (24.4% vs. 24.1%). More cancer pts than controls reported a transition from owning a home to rented housing after dx (2.9% vs. 1.9%, p < 0.05). Mean PCS and MCS scores were similar in the 2 years leading up to dx but dropped significantly in the 6 months after dx in cancer pts relative to controls. By 2 years post dx, mean PCS and MCS were again similar between groups (Table). Conclusions: Cancer dx has a significant and time-sensitive impact on HRQoL in older Medicare enrollees. While there is some evidence of instability in household income and home ownership in this population, further investigation into the factors associated with these changes is warranted. Pre–Dx Post–Dx -10–12 mo -4–6 mo 0–3 mo 4–6 mo 10–12 mo 22–24 mo Mean PCS Non-cancer 42.1 41.2 39.5 41.1 39.6 40.1 Cancer 41.8 42.0 37.1 36.1 38.2 39.4 P 0.7 0.3 0.003 <0.001 0.1 0.3 Mean MCS Non-cancer 52.8 52.4 51.5 51.8 51.9 52.2 Cancer 53.9 53.4 48.3 50.2 50.5 51.9 P 0.1 0.2 <0.001 0.036 0.05 0.6
Abstract 15968: Rescue of Bupivacaine-induced Cardiac Arrest by Lipid Emulsion is Prevented by Inhibition of Free Fatty Acid Receptor GPR40
Authors: Soban Umar, Alex Centala, Mariam Barseghyan, Behnoosh B Rahavard, Salil Sharma, Parisa Partownavid, Mansoureh Eghbali
Journal: Circulation (2015)

Introduction: Bupivacaine overdose leads to lethal arrhythmias and cardiac arrest. Lipid emulsion (LE) is cardioprotective and rescues Bupivacaine toxicity. Although both lipid sink and metabolic theories have been proposed, yet the exact molecular mechanism is not known. G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor-1 is activated by medium and long chain fatty acids. Among free fatty acid receptors, GPR40 expression is one of the highest in heart. Hypothesis: As GPR40 is activated by medium and long chain fatty acids, we hypothesized that GPR40 may mediate LE’s rescue of Bupivacaine cardiotoxicity. Methods: Male Sprague-Dawley rats were used. Continuous Echocardiography and ECG were done. In protocol-1 (n=6), rats received Bupivacaine bolus (10mg/kg, IV) to induce asystole. Resuscitation with LE 20% (5ml/kg bolus, and 0.5ml/kg/min maintenance) and chest compressions were initiated. In Protocol-2 (n=6) rats were pre-treated with GPR40-antagonist GW1100 (200uM, IV) 30-min before inducing asystole. Heart rate (HR) and ejection-fraction (EF) were measured before and 30-min after GW1100. In both protocols, HR, EF and fractional shortening (FS) were measured before asystole (baseline) and at 1, 5 and 10-min after LE. Means±SEM are reported. Results: In protocol-1, baseline HR and EF were 321±21 beats/min and 72.3±4.6%. Bupivacaine resulted in asystole. LE improved HR gradually within 10min; HR was 86±13 at 1min (27% recovery), 216±10 at 5min (67% recovery), and 228±14 at 10min (71% recovery). LV function fully recovered within 5 min of LE treatment as EF and FS were similar to baseline (EF=72±5%, FS=42±4%). To test our hypothesis, rats were pretreated with GW1100, 30-min before inducing asystole. There were no significant differences between HR and EF before (HR=316.6±3.3, EF=68.0±2.3%) and 30-min after GW1100 (HR=330±5.7, EF=71.6±1.5%) excluding GW1100 effects on hemodynamics. GW1100 pre-treatment however prevented LE rescue, with no recovery of cardiac function even after 10min of LE. Conclusions: This is the first report of involvement of GPR40 in rescue of Bupivacaine-induced cardiac arrest by LE. Discovery of GPR40 as a potential receptor for effects of LE may help us understand LE-induced cardioprotection.
Genetic variants of CBP and SOX9 to predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI and bevacizumab (FOLFIRI/BEV).
Authors: Yan Ning, Wu Zhang, Dongyun Yang, Sebastian Stintzing, Yu Sunakawa, Stefan Stremitzer, Ana Sebio, Shinichi Yamauchi, Satoshi Matsusaka, Federica Zoratto, Fotios Loupakis, Rita Elie El-Khoueiry, Afsaneh Barzi, Anthony B. El-Khoueiry, Michael Kahn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2014)

e14528 Background: Wnt signaling pathways play divergent roles during development, normal homeostasis and disease. The Cancer Genome Atlas Network (TCGA) CRC data showed Wnt signaling pathway genes CBP and SOX9 are critical for stem cell/progenitor cell maintenance and proliferation and differentiation of intestinal epithelial cells. We tested whether polymorphisms (SNPs) in CBP (rs9392, rs129963) and SOX9 (rs2229989, rs1042667) predict clinical outcome in a cohort of mCRC pts treated with first line FOLFIRI/BEV. Methods: Genomic DNA were extracted from blood of 424 mCRC pts which prospectively enrolled in a pharmacogenetic translational study. Females(n=172) and males(n=252); Median follow up was 2.8 years, median PFS and OS were 10.4 and 27.3 mons, respectively. Results: In the multivariate analysis, CBP rs9392 A/A variant was significantly associated with shorter OS ( 23.5 mos, HR: 1.54 [0.75-3.14], p = 0.04) compared to G/A ( 30.8 mos) and G/G ( 26.3 mos). CBP rs129953 T/T variants was associated with a trend toward shorter PFS (9.3 mos, HR: 1.17 [0.85-1.61], p = 0.07) compared to C/T (10.8 mos) or T/T (10.4 mos). Our data also showed that CBP and SOX9 snps predict clinical outcome by pts gender and tumor location: 1) In right-side tumor pts, SOX9 rs2229989 C/C genotype was associated with worse PFS (9.5 mos, HR: 0.61 [0.38-0.97], p = 0.036) compared to any T allele (10.2 mos). 2) In women, CBP rs129953 T/T variants had worse PFS (8.4 mos, HR: 2.29 [1.28-4.09], p = 0.01) compared to those with C/T (10.8 mos) and T/T genotype (11.6 mos). Conclusions: This is the first report show that Wnt signaling pathway gene CBP (rs9392, rs129963) and SOX9 rs2229989 snps may predict PFS and OS in mCRC pts with first-line FOLFIRI/BEV. Moreover, the predictive value of CBP and SOX9 snps is further strengthen by gender and tumor location.
Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy
Authors: Cihan Yurdaydin, Zaigham Abbas, Maria Buti, Markus Cornberg, Rafael Esteban, Ohad Etzion, Edward J. Gane, Robert G. Gish, Jeffrey S. Glenn, Saeed Hamid, Theo Heller, Christopher Koh, Pietro Lampertico, Yoav Lurie, Michael Manns, Raymundo Parana, Mario Rizzetto, Stephan Urban, Heiner Wedemeyer, A. Wranke, L.M. Pinheiro Borzacov, C. Lobato, S. Hamid, E. Ceausu, G.N. Dalekos, A. Turcanu, G.A. Niro, F. Lubna, M. Abbas, P. Ingiliz, P. Ferenci, T. Vanwolleghem, T. Hayden, N. Dashdorj, A. Motoc, S. Hardtke
Journal: Journal of Hepatology (2018)