tbuckley/cabot-search huggingface dataset:
Impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the obesity paradox.
Authors: Shintaro Narita, Ryuichi Ito, Mingguo Huang, Kazuyuki Numakura, Hiroshi Tsuruta, Atsushi Maeno, Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya, Shigeru Satoh, Tomonori Habuchi
Journal: Journal of Clinical Oncology (2017)

449 Background: Obesity increases the risk of renal cell carcinoma (RCC); however, obese patients experience longer survival than non-obese patients. The mechanism of this “obesity paradox” is unknown. We examined the impact of obesity, total adiponectin (AD) level, and intratumoral AD receptors expression on RCC aggressiveness and survival, and also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells with exogenous adiponectin stimulation. Methods: A total of 129 RCC patients treated with surgery were included in the analyses. Preoperative BMI, serum total adiponectin (AD) level, total AD secretion from perinephric adipose tissue, and intratumoral AD receptors mRNA and protein expression were analyzed. Caki-2 and 786- cells were used for in vitro functional analyses. Results: Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003, and p = 0.027, respectively). Cancer-specific survival in overweight and obese patients was significantly better than in normal patients in all patients (p = 0.035). A weak inverse correlation existed between serum AD level and BMI in RCC patients (r = −0.344). Tumor size was slightly correlated with serum AD level, and high serum AD was significantly associated with poor overall survival in patients without metastasis (p = 0.035). The AD level of perinephric adipose tissue and intratumoral AdipoR1/R2 expression in tumors did not correlate with RCC aggressiveness and survival. Exogenous AD significantly enhanced proliferation, but not invasion or migration in 786-O and Caki-2 cells. Exogenous AD significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL in these cells. Conclusions: Low BMI and high AD level are associated with cancer aggressive and poor survival in RCC patients treated surgically. AD modulates proliferation and apoptosis, which may underlie the “obesity paradox” of RCC.
Sorafenib but not sunitinib affects the induction of immune responses
Authors: M. M. Hipp, N. Hilf, S. Walter, D. Werth, L. Kanz, T. Weinschenk, H. Singh, P. Brossart
Journal: Journal of Clinical Oncology (2007)

3504 Background: The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are approved for the treatment of patients with metastatic renal cell cancer. To analyze the possible use of these compounds in combination with immunotherapeutic approaches we investigated the effects of both TKIs on function of human dendritic cells (DCs) and induction of primary immune responses in vitro and in vivo. Methods: Human monocytes-derived DCs were treated with DMSO, sorafenib or sunitinib. Functional and phenotypic analyses as well as the possible impact on signal transduction pathways were performed. Furthermore, induction of immune responses in vivo was analyzed in animals treated with both compounds. Results: Sorafenib but not sunitinib inhibits function of DCs. Exposure of DCs to sorafenib reduces expression of CD1a, MHC and costimulatory molecules in response to stimuli via TLR ligands. Sorafenib reduces cytokine production by DCs as well as their ability to migrate and stimulate T cell (TC) responses. We found that these inhibitory effects of sorafenib are mediated via inhibition of PI3K, MAP kinases and NFκB signaling. The TKIs have no influence on phenotype and proliferation of TCs. To analyze the effects of TKIs on the generation of immune responses in vivo, induction of TC responses was assessed by peptide vaccination with the model antigen OVA-001 in C57BL/6 mice. When mice were pretreated with both TKIs which were also given during vaccination, it was observed that sorafenib, but not sunitinib significantly reduces the generation of vaccine-specific CD8+ TCs. Numbers of CD4+ CD25+ regulatory TCs are reduced in sunitinib-treated mice, but not in sorafenib-treated animals. All effects of the TKIs are reversible, and the immune responses go back to normal levels if mice are immunized after discontinuation of treatment. Conclusions: In summary, sunitinib represents an interesting compound to be used in combination with immunotherapeutic approaches to treat cancer patients. No significant financial relationships to disclose.
Common and rare <i>EGFR</i> mutations (<i>EGFR</i>m) in the RADIANT trial: Final follow-up with 5 year data.
Authors: Frances A. Shepherd, Wilfried Ernst Erich Eberhardt, Nasser K. Altorki, Mary E.R. O'Brien, Joe Wang, Jun Wu, Stan Gill, Kenneth Iwata, Frank C Richardson, Julie D. Horan, Margaret A. Foley, Karen Kelly
Journal: Journal of Clinical Oncology (2015)

7539 Background: Data on EGFRm in early stage NSCLC are limited. RADIANT was a prospectively randomized Phase 3 trial of adjuvant erlotinib (E) v placebo (P) in 973 patients (pts) with completely resected Stage IB–IIIA NSCLC that was EGFR +ve by IHC or FISH (ASCO14 #7501; ESMO14 #1178PD). Methods: EGFRm in exons 18–21 was determined by WAVE HS and confirmed by Sanger sequencing. Two EGFRm groups were defined: Common refers to exon del19 or L858R irrespective of the presence of another EGFRm; Rare Only refers to EGFRm without del19 or L858R. Exploratory analysis of disease-free survival (DFS) was performed by subgroup (June 11, 2014 data cutoff). Results: 921 pts had EGFRm status determined; 198 pts (21.5%) had EGFRm (161 Common, 37 Rare Only). There was no sex difference between the groups, but pts with Rare Only EGFRm were less likely to be Asian (32.4% v 47.2%) or non-smokers (48.6% v 62.7%). With a median follow-up of 5 years, updated DFS by mutation type is shown below. The DFS HR was lower in the Common group (HR [E/P] 0.75, CI 0.48, 1.16) than in the Rare Only group (HR 1.19, CI 0.44, 3.22). Conclusions: The effect of E on DFS in EGFRm subgroups remains inconclusive. Clinical trial information: NCT00373425. EGFRm (n) Subgroup Arm n DFS Events Median (m) HR (E/P), 95% CI Common* (161): Del 19/L858R EP 10259 4934 47.828.5 0.75 (0.48–1.16) Del 19 E P 56 33 29 19 46.4 26.4 0.82 (0.46–1.46) L858R E 46 20 54.1 0.68 (0.35–1.34) P 26 15 29.3 Rare Only (37): All EP 1918 79 NR46.5 1.19 (0.44–3.22) Exon 20 (21) E P 11 10 4 6 NR 40.7 0.96 (0.27–3.43) Rare Only (n)** Detail Arm n DFS Min, Max Exon 18 G719X (8) G719A, G719A+E709A, G719A+E709K E 5 0.0+, 58.0+ G719A P 3 39.7+, 47.6+ Other Exon 18 (4) L692, G719A+E709A, G719A+E709K E 3 0.0+, 28.2 V689L P 1 59.7+ Exon 19 (2) R748T E 1 54.4+ L747S P 1 57.5+ Exon 20 Ins_dup (17) A767_S768Ins, H773_V774ins, V774_C775ins, A767_V769dup, N771_H773dup, P772_H773dup E 10 0.0+, 54.5+ N771_H773dup, P772_H773ins, A767_V769dup, A763_Y764ins, H773dup P 7 16.2, 59.7+ Exon 20 other (4) S768I E 1 58.0+ R776H, S768I+V774M, R776H P 3 39.7+, 64.0+ Exon 21 (8) L861Q, E868K E 2 1.9, 42.1+ D830N, L861Q, L844P, V845E P 6 1.8, 58.3+ NR = Not Reached. *Includes 12 pts with another EGFRm in addition to del19 or L858R. + Indicates censoring; **Pts may have > 1 rare EGFRm.
What is the extent of the AYA gap for young adults with cancer?
Authors: Julie Anna Wolfson, Can-Lan Sun, Tongjun Kang, Arti Hurria, Smita Bhatia
Journal: Journal of Clinical Oncology (2014)

6591 Background: Poorer outcome is documented among AYA (15-39y at diagnosis [dx]) with cancer as compared to younger (<15y) or older (40-65y) patients with similar dx, coining the term AYA Gap. While this phenomenon has been examined in cancers spanning the age spectrum, those typical in young adults (YA: 22-39y) remain unstudied. Methods: We constructed a population-based cohort of 67,292 patients dxed between 22y - 65y with adult-onset cancers and reported to LA County’s cancer (ca) registry from 1998 - 2008 (YA 22-39y: n=5,801; adults 40-65y: n=61,491). Multivariate Cox regression stratified by disease and adjusted for clinical characteristics (stage, gender, race/ ethnicity) compared outcome between age groups. Analysis of variance compared change in 3y overall survival (OS) over time between age groups; interaction between age/dx year was examined for statistical significance (p<0.05). Results: Outcome by age group is shown in Table: YA with breast ca had poor outcome compared to adults. YA with lung, hepatobiliary, gastric, colorectal ca had superior outcome. There was no difference in mortality in oral or cervical ca. For patients with lung, hepatobiliary and gastric ca, change in 3y OS over time differed significantly (p=0.05) between YA (saw no improvement) and adults (there was improvement); 3y OS over time did not differ significantly (P>.05) between YA and adults with breast or colorectal ca (both saw survival improvements) as well as oral or cervical ca (neither saw change over time). Conclusions: YA with breast ca demonstrate inferior outcome compared with adults. Furthermore, there appears to be no improvement over time for YA with lung, hepatobiliary and gastric ca, while adult patients with similar dx demonstrate improvement in outcome. Thus YA with breast, lung, hepatobiliary and gastric ca constitute a vulnerable population vis a vis their adult counterparts, and need to be studied. Likelihood of mortality [22-39y vs. 40-65y: Adjusted for stage, gender, race/ethnicity]. Primary diagnosis HR CI P value Breast (n=31,767) 1.2 1.1-1.3 <.0001 Hepatobiliary (n=4,194) .7 .6-.9 .0004 Lung (n=10,848) .8 .7-1.0 .02 Colorectal (n=12,301) .8 .7-1.0 .005 Gastric (n=2,667) .8 .7-.9 .003 Cervix (n=3,691) .9 .8-1.0 .1 Oral (n=1,824) 1.0 .7-1.3 .9
Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab.
Authors: Rifaquat Rahman, Alhafidz Hamdan, Rebecca Zweifler, Han Jiang, Andrew David Norden, David A. Reardon, Srinivasan Mukundan, Patrick Y. Wen, Raymond Yi-kun Huang
Journal: Journal of Clinical Oncology (2014)

2058 Background: While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Methods: Baseline and 3-6 week post-treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Results: Baseline ADCL/ADCM within nonenhancing T2/FLAIR volume (> or ≤ 0.64) can stratify OS (HR=2.24, p=0.002) and PFS (HR=1.90, p=0.005). %ADCH within enhancing T1+C volume (> or ≤ 25%) can also stratify OS (HR=0.59, p=0.034) and PFS (HR=0.56, p=0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR= 0.17, p<0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADCH within T1+C volume alone (1.3) or ADCL/ADCMwithin T2/FLAIR alone (1.86). Conclusions: ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma.
A phase I/II trial of erlotinib S-1 therapy in patients with non-small cell lung carcinoma: Thoracic Oncology Reseach Group (TORG) 0808/0913.
Authors: Naoyuki Nogami, Tetsu Shinkai, Toshiyuki Kozuki, Atsuko Ogino, Yuka Kato, Yukio Hosomi, Naoya Hida, Tsuneo Shimokawa, Nobuhiko Seki, Hiroaki Okamoto, Masahiko Shibuya, Koshiro Watanabe
Journal: Journal of Clinical Oncology (2012)

e18099 Background: Gefitinib has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported. Erlotinib also reduced TS expression and activity. The present studies were designed as study aimed at evaluating the efficacy and safety of erlotinib/ S-1 combination therapy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC. Methods: Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily after meals from days 1 to 14 of each 21-day cycle. In phase I trial(TORG0808), the primary endpoint was to evaluate the DLT and the MTD for the following phase II study, and the secondary endpoint was to evaluate the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary endpoints were PFS, disease control rate, OS, and safety. Results: 7 patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and phase II trial. In phase I trial, the recommended doses for the phase II study were determined to be 150mg/body and 80mg/m2. The ORR was 67%, and 3/4 responders are EGFR positive patients. In phase II trial, the ORR was very low (only one patient).Myelosuppression was relatively mild, but Grade 3 or worse non-hematological toxicities including diarrhea, mucositis, and dermatitis were observed in 6 patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination, and the clinical trial was terminated due to adverse events. Conclusions: Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR positive patients, but less effective and too toxic in EGFR negative patients in phase II trial.
Cross-species synthetic lethal interaction screening as a strategy for the identification of novel therapeutic targets in cancer.
Authors: John P. Shen, Rohith Srivas, Ana Bojorquez-Gomez, Katherine Licon, Jian Feng Li, Robert W. Sobol, Trey Ideker
Journal: Journal of Clinical Oncology (2013)

11105 Background: Mutation, deletion, or epigenetic silencing of tumor suppressor genes is a near universal feature of malignant cells. However, therapeutic strategies for restoring the function of mutated or deleted genes have proven difficult. Synthetic lethality, an event in which the simultaneous perturbation of two genes results in cellular death, has been proposed as a method to selectively target cancer cells. Identifying and pharmacologically inhibiting proteins encoded by genes that are synthetic lethal with known tumor suppressor mutations should result in selective toxicity to tumor cells. Methods: To identify candidate target proteins we measured all pair-wise genetic interactions between all known orthologs of human tumor suppressor genes (162 genes) and all orthologs of druggable human proteins (~400 genes) in the model organism S. Cerevisiae. Analysis of the data uncovered 2,087 distinct synthetic lethal interactions between a tumor suppressor and druggable gene. A computational algorithm was then developed to identify those interactions which were likely to be conserved in humans based on conservation of the synthetic lethal relationship in the distant fission yeast S. pombe. Results: Our bioinformatic analysis suggested a high probability of conservation of the synthetic lethal interactions between the yeast RAD51 (ortholog of BRCA1) and RAD57 (ortholog of XRCC3) with HDA1 (a histone deacetylase; HDAC). We confirmed this by treating LN428 cells with stable lentiviral knockdown of BRCA1 or XRCC3 with the HDAC inhibitors vorinostat (SAHA) and entinostat (MS-275). Both the BRCA1 and XRCC3 knockdown cell lines were significantly more sensitive to HDAC inhibition relative to wild-type (non-silencing lentiviral control) cell line (Table). Conclusions: These results demonstrate that high-throughput approaches for screening synthetic lethal interactions in model organisms such as S. cerevisiae and S. pombecan serve as a valuable resource in helping to identify novel therapeutic targets in human cancer. [Table: see text]
Sulforaphane treatment in men with recurrent prostate cancer.
Authors: Joshi J. Alumkal, Rachel Slottke, Motomi Mori, Jacob Schwartzman, Julie Nicole Graff, Tomasz M. Beer, Christopher W. Ryan, Dennis R Koop, Ganesh Cherala, Myrna Munar, Jason Frederick Flamiatos, Lina Gao, Erin Tucker
Journal: Journal of Clinical Oncology (2013)

5017 Background: Diets high in cruciferous vegetables are strongly associated with lower prostate cancer risk. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on pre-clinical evidence in multiple tumor models. Our own work demonstrates that sulforaphane inhibits HDAC function and suppresses AR signaling in prostate cancer cells (Gibbs, et al PNAS 2009). However, the anti-tumor efficacy and safety of sulforaphane in men with prostate cancer was unknown. Methods: In this single arm study, we treated patients with biochemical (PSA)-recurrence of prostate cancer with 200 µmol of sulforaphane extracts for up to 20 weeks. The primary endpoint was PSA response rate (&gt;50% decline in PSA). Other efficacy endpoints included: maximal PSA decline and percent change in PSA from baseline to end of study. We also analyzed PSA doubling time changes using a mixed effects model. Genotyping for GSTM1 that contributes to sulforaphane metabolism, sulforaphane pharmacokinetics (PK), and pharmacodynamic (PD) measurements of HDAC inhibition in mononuclear cells (MCs) were also performed. Results: Twenty patients were enrolled, and 16/20 (80%) completed the pre-planned 20 weeks of treatment. One patient experienced a PSA decline &gt;50%. Thirty-five percent of patients had lesser PSA declines (3% to 20%), and 15% of patients had a final PSA lower than baseline. There was a significant reduction in PSA doubling time (6 months pre-study vs. 9.4 months on-study, p=.013). Of note, testosterone levels remained non-castrate in all subjects. PK analysis demonstrated that GSTM1 null genotype correlated with longer sulforaphane T1/2 (half-life) (2.6 hours for GSTM1 null vs. 2.1 hours for GSTM1 intact, p=0.04). Sulforaphane treatment also increased histone acetylation in PD assays in MCs. Finally, no grade three adverse events were seen, and only one patient discontinued study treatment for toxicity (grade one GI discomfort). Conclusions: Treatment with 200 µmol per day of sulforaphane is feasible, safe, and inhibits HDAC function. This combined with the preliminary observation of PSA modulation, which may indicate biologic activity, provides the basis for dose escalation studies of sulforaphane in men with prostate cancer. Clinical trial information: NCT01228084.
Comprehensive genomic sequencing of urothelial tumors to identify rare driver genomic alterations in SMARCB1 in a subset of patients.
Authors: Sumati Gupta, Daniel Joseph Albertson, David Gaston, Marta Elise Heilbrun, Neeraj Agarwal, Ting Liu, Vincent A. Miller, Jeffrey S. Ross, Sherri Z. Millis, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2017)

385 Background: Multiple genomic alterations leading to overlapping dysregulation of cell cycle, kinase and phosphotidyl \inositol-3-OHkinase signaling and chromatin remodeling are the hallmark of urothelial carcinoma (UC). ARID1A and SMARCA2 loss are frequently altered leading to SWI/SNF nucleosome-remodeling complex dysregulation in urothelial cancers. Mutations affecting components of the SWI/SNF complex lead to aggressive de-differentiated neoplasms. SMARCB1 loss has been implicated in malignant rhabdoid tumors, epithelioid sarcoma and renal medullary carcinoma. Upper tract UC patients with SMARCB1 loss may represent a novel, rare subset. Methods: Tissue from UC patients (n=1099) was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities; 315 genes frequently altered in cancer were assayed. One patient had an advanced poorly differentiated neoplasm and received conventional chemotherapy. Results: CGP identified 10 (1%) patients with SMARCB1 alterations and different patterns overall in GAs. Three patients (1 kidney, 1 ureter, and 1 bladder) had bi-allelic loss of SMARCB1, and 7 others had a loss of function alteration with loss of heterozygosity. These patients with SMARCB1 bi-allelic loss had few or no additional alterations, notably no alterations in TP53, CDKN2A/B, or TERT, which are observed in greater than 50% of urothelial tumors, or RB1 alterations observed in ~22% of UC. The patient treated with cisplatin based chemotherapy achieved a pathologic CR. Conclusions: Genomic profiles of tumors from patients with UC revealed a rare population of patients with alterations impacting chromatin regulation and tumor suppression, specifically through loss of SMARCB1. Tumors with SMARCB1 loss have a very low burden of genetic alterations and SMARCB1 loss or deletion may be the sole driving mutation. Conventional chemotherapy may be effective. Inhibitors of EZH2, HDAC and CDK4 may be potential treatment strategies to target this subset of tumors.