tbuckley/cabot-search huggingface dataset:
Precision medicine approach in kidney cancer: A pan renal cell carcinoma (RCC) study across three cancer genome atlas (TCGA) datasets for clinically relevant target identification.
Authors: Bradley Murray, Laurence Albiges, Eliezer Mendel Van Allen, Andrew Cherniack, Andre Poisl Fay, Matthew Meyerson, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2015)

4564 Background: Comprehensive molecular evaluation of clear cell (ccRCC),papillary (pRCC) and chromophobe (ChRCC) tumors through TCGA has provided significant insights into the biology of RCC. Yet, the translation of these efforts in terms of clinical impact remains under developed. We aim to report clinically relevant molecular alterations events that can be identified by precision medicine screening approach across 3 RCC datasets. Methods: TCGA datasets for ccRCC, pRCC and ChRCC were analysed for focal mutations using a previously reported 121-gene panel relevant for genomics-driven therapy (TARGET) that may have therapeutic, prognostic and diagnostic implications for patients with cancer (Van Allen, Nature Medicine 2014), and for relevant copy number alterations (CNA) defined as focal amplification (Amp) or homozygote deletion. Results: Overall, 760 RCC including 420 ccRCC, 275 pRCC and 65 ChRCC were analysed. A total of 1,089 clinically relevant somatic mutations and 110 clinically relevant somatic CNA were identified. Tumor specific incidence of mutation and CNA are reported (Table). Conclusions: Overall, at least 78.7% of RCC tumors (598/760) present a genomic alteration considered potentially clinically relevant. Both ccRCC and pRCC exhibit a large number of small incidence events. This report provides a strong rational for including RCC in ongoing clinical trials of target identification and to assess the clinical relevance of these events. ccRCC pRCC ChRCC Number of cases 420 275 65 Mutation % of cases with at least one TARGET gene with somatic mutation 89% 64% 75% High (>10% ) VHL PBRM1 SETD2 BAP1 53% 32% 11% 10% MET 19% 12% somatic, 7% germline P53 PTEN 48% 14% Intermediate (2-10%) MTOR PTEN ATM NOTCH2 SMARCA4 PI3K 7% 4.7% 3.5% 3% 2.8% 2.4% SETD2 BAP1, SMARCA4 PBRM1 NF2 NOTCH2 TET2, TSC2 FGFR3, mTOR, PI3K, PTEN, SMARCB1 BRAF, ERBB2, ERBB3, KRAS,PIK3R1, NF1 6.5% 4.7% 4% 3.6% 3% 2.5% 2.2% 2% RB1 ATM, NOTCH1, TSC2, GNAQ ERG, ATR, EPHA3, ERBB3, FBXW7, MTOR, SETD2, NTRK3 6% 4.5% 3.1% CNA Amp – High Level MYC 2.4% MET 2.5% Homozygous Deletion CDKN2A PTEN 7.2 % 4.8% CDKN2A NF2 4.9% 2.7% PTEN 3.1%
Interim safety and efficacy analysis of a phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer.
Authors: Dung T. Le, Andrea Wang-Gillam, Vincent J. Picozzi, Tim F. Greten, Todd S. Crocenzi, Gregory M. Springett, Michael Morse, Herbert Zeh, Deirdre Jill Cohen, Robert Lance Fine, Beth Onners, Jennifer N. Uram, Aimee Murphy, Justin Skoble, Ed Lemmens, John J. Grous, Thomas Dubensky, Dirk G. Brockstedt, Elizabeth M. Jaffee
Journal: Journal of Clinical Oncology (2013)

4040^ Background: GVAX is composed of GM-CSF-secreting allogeneic pancreas cancer cell lines and administered with low-dose cyclophosphamide (CY) to inhibit regulatory T cells. In prior studies, GVAX induced mesothelin-specific T cell responses that correlated with survival. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express human mesothelin. CRS-207 stimulates potent innate and adaptive immunity and has shown synergy with GVAX in mouse tumor models. Anecdotal survival benefit was observed in the CRS-207 phase I study in patients who received prior GVAX. Methods: Patients were enrolled with metastatic pancreatic ductal adenocarcinoma (PDA) who received or refused ≥ 1 prior chemotherapy, had ECOG ≤ 1 and adequate organ function. Patients were randomized 2:1 to receive 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B) every 3 weeks. Clinically stable patients were offered additional 20-week courses. The primary endpoint was comparison of OS between treatment arms. Secondary endpoints were to evaluate safety, clinical and immune responses. Results: 90 patients were treated (Arm A: 61, Arm B: 29). As of Jan 2013, 27 patients completed 1 course (A: 24, B: 3) and 17 patients (A: 15, B: 2) initiated a 2 nd course. Median age was 63. Median number of prior regimens was 3. No treatment-related serious adverse events (SAEs) or unexpected toxicities were observed. The most frequent Grade (G) 3/4 related toxicities were fever, lymphopenia, hypophosphatemia, elevated liver enzymes, and fatigue following CRS-207 in &lt;5% of subjects. Of 51 patients evaluated post-treatment, 34% had stable disease in Arm A vs. 19% in Arm B. OS for all patients treated was 6 months in Arm A vs. 3.4 months in Arm B (two-sided, p=0.0114). Conclusions: Combined CY/GVAX pancreas and CRS-207 was generally well-tolerated with no treatment-related SAEs or unexpected G3/4 toxicities. The significant difference in OS between treatment arms met the criteria for early stopping. This indicates that the combination immunotherapy may extend OS for metastatic PDA patients with minimal toxicity and should continue to be developed as an effective therapy. Clinical trial information: NCT01417000.
Development and validation of a model and web application to predict 5-year distant relapse-free survival in women receiving neoadjuvant chemotherapy.
Authors: Jahan Mohiuddin, Allison Mary Deal, Amy Drobish, Maggie Chon U. Cheang, Katherine Elizabeth Reeder-Hayes, Lisa A. Carey
Journal: Journal of Clinical Oncology (2013)

1077 Background: Response to neoadjuvant chemotherapy (NAC) is an increasingly recognized intermediate marker for prognosis, but we still lack validated prognostic tools that incorporate tumor factors and response. This study aimed to create a prognostic model and nomogram for 5-year distant relapse-free survival (DRFS) and to develop a web application for providers and patients to predict the probability of distant relapse within 5 years. Methods: The prognostic model was developed using data from patients treated with NAC in the UNC Neoadjuvant Database and the Cox proportional hazards method. Patients who received NA trastuzumab were included in model data, but patients who received NA endocrine therapy were not included. The model was internally validated with bootstrap resampling, and externally validated with an independent, public data set (n=411) (Cancer Res 2011;71(24 Suppl):Abs S5-2). A web tool was developed to calculate probability of 5-year DRFS. Results: Four-hundred and seven stage I-III patients, including 106 relapse events, were used for model development. The following factors were ultimately included in the model: RCB class, age, overall grade, HER2 status, hormone receptor (HR) status, and an interaction term between age and HR status. Validation showed agreement between predicted and observed outcomes in all patients and more specifically HR+/HER2- and HR-/HER2- patients (Table). There were an insufficient number of HER2+ patient in the validation data to reliably analyze that subgroup. Conclusions: An externally validated predictive modelincorporating patient, tumor, and response variables is accurate in predicting 5-year distant relapse risk for patients undergoing NAC. The model can be conveniently accessed as an online application at www.NeoadjuvantRelapse.info for precise risk prediction. [Table: see text]
A phase II trial of pralatrexate (P) plus oxaliplatin (O) in advanced esophago-gastric cancer (aEGC): survival analysis and pharmacogenetic correlates.
Authors: Usha Malhotra, Araba Adjei, Austin Miller, Peter Walter Bushunow, Peter Loud, Saikrishna S. Yendamuri, Melissa Robins, Renuka V. Iyer, Nikhil I. Khushalani
Journal: Journal of Clinical Oncology (2015)

e15037 Background: Pre-clinical data has shown synergism between P and platinums. We evaluated combination P plus O in aEGC and correlated the treatment outcomes to single nucleotide polymorphisms (SNP) in genes involved in the metabolism of P. These genes include dihydrofolate reductase (DHFR), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), phosphoribosylaminoimidazolecarboxamide formyltransferase (ATIC), phosphoribosylglycinamide formyltransferase (GART), reduced folate carrier (SLC19A1), proton-coupled folate transporter (SLC46A1) and thymidylate synthase (TYMS) which activate, inactivate, transport and are targets for P. Methods: Objective Response (OR) following P+O was assessed in a 2-stage trial. Patients (pts) with metastatic/unresectable, therapy-naïve EGC were eligible and received biweekly O (85mg/m2) + P (Dose level [D] 1, 120mg/m2; dose level -1 [D-1] 100 mg/m2). SNPs in above genes were evaluated in germline DNA and correlated with outcomes. Results: 35 pts, median age 67 yrs (39-83), majority males (32) and adenocarcinoma (29) were accrued. DLTs were observed in 2/4 pts at D1. All remaining pts were treated at D-1. OR was 26% (0.12 - 0.43), progression-free survival (PFS) was 4.35 months (95% CI 2.85-5.91) and overall survival (OS) was 6.89 months (95% CI 5.78-10.8). Toxicity data reported previously (Malhotra, GI ASCO 2015). 4 SNPs, DHFR rs11951910, GART rs2834233 & rs6517177, & TYMS rs699517 were significantly associated with ¯ PFS (p ≤ 0.05) and SLC19A1 rs2838957 was associated with PFS (p= 0.02). The ATIC rs10932606 SNP was associated with ¯ OS (p≤ 0.01) while GGH rs3780130 was associated with OS (p= 0.02). Conclusions: Combination of O and P did not meet the primary end point of improved OR in aEGC. SNP analysis revealed associations of variants in DHFR, GART, TYMS, ATIC, SLC19A1 and GGH with OS and PFS. Pharmacogenomic analysis may be relevant to use of P in combination with platinums in aEGC. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Allos Therapeutics, a subsidiary of Spectrum Pharmaceuticals, Inc Clinical trial information: NCT01178944.
Ratiometric dosing of irinotecan (IRI) and floxuridine (FLOX) in a phase I trial: A new approach for enhancing the activity of combination chemotherapy
Authors: G. Batist, W. Miller, L. Mayer, A. Janoff, C. Swenson, A. Louie, K. Chi, S. Chia, K. Gelmon
Journal: Journal of Clinical Oncology (2007)

2549 Background: Like many pairs of chemotherapy agents, the combination of IRI and FLOX displays ratio-dependent activity in vitro. CPX-1, a liposome formulation of IRI:FLOX, was developed to maintain a synergistic 1:1 molar ratio in vivo, was highly active in preclinical models, and was evaluated in a phase 1 trial (CLTR0104–101). Methods: Doses were escalated from 30U/m 2 (1U= 1 mg IRI + 0.36 mg FLOX) to 270 U/m 2 given on day 1 and 15 of each 28 day cycle. Adult patients (pts) with advanced solid tumors, ECOG PS&lt;2, adequate bone marrow, liver, and renal function were eligible; 4 pts per cohort. After defining the MTD, additional pts with CRC were enrolled (extension phase). IRI completed greater than 12 months prior to this trial was allowed in the absence of resistance to IRI. PK was done on day 1 and 15 of the 1 st cycle. Results: Safety: The dose escalation phase enrolled 24 pts in 6 cohorts and added 2 pts in the 5 th cohort (210U/m 2 ; the MTD) after noting dose limiting diarrhea (3 pts) and neutropenia (1 pt) including one death from dehydration and renal failure due to prolonged diarrhea (gr3) &amp; vomiting (gr2) at 270U/m 2 . An additional 7 pts with CRC received 210U/m 2 in the extension phase. Grade 3/4 adverse events included diarrhea, nausea, vomiting, neutropenia and thrombocytopenia with most occurring at 270U/m 2 . No new toxicities were observed for this combination. Response: 30/33 pts were evaluable with 2 confirmed PRs (NSCLC and CRC), 21 SD and 7 PD. Median PFS was 5.4 mos. (0.3–11.8 mos.) in 15 pts w/CRC. PK: All pts maintained synergistic plasma IRI:FLOX ratios for 24h. IRI and FLOX AUCs (0-inf) were greater for CPX-1 than expected for conventional drugs. AUCs for SN-38 and 5FU at 210U/m 2 were 0.8 ± 0.1 and 10 ± 8.7 μg-hr/mL, respectively, indicating bioavailability for both drugs. Conclusion: CPX-1 was well tolerated in the outpatient setting and evidence of anti-tumor activity was obtained. This is the first clinical evaluation of ratiometric dosing in which a synergistic drug ratio, pre-selected in vitro based on optimal anti-tumor activity, was maintained systemically to enhance therapeutic benefit. [Table: see text]
Is bisphosphonate-induced osteonecrosis of the jaw (BONJ) an ischemic manifestation of pseudo-osteopetrosis?: Biochemical, densitometric, and imaging evidence
Authors: F. C. Kelleher, M. McKenna, C. Collins, G. M. Brady, J. P. Crown
Journal: Journal of Clinical Oncology (2006)

18621 Background: BONJ is an increasingly recognised but poorly understood complication of long-term B therapy. We hypothesise that the pathophysiology is ischaemic, and is due to an osteopetrosis (OP)-like lesion which causes progressive constriction of maxillo- mandibular perforating arterial foramina. Support for this comes from the observation that the osteoclast ruffled border is functionally impaired in osteopetrosis and structurally lost with B therapy. Cases of maxillomandibular osteomyelitis and avascular necrosis complicating OP exist. Additionally the blood supply of the jaw relies partly on small periosteal perforators. Methods: Bone mineral density (BMD) of 2 female patients (pt) with BONJ was investigated with dual energy x-ray absorbptiometry. Serum creatinine BB-isoenzyme (CK-BB) was determined. Serum acid phosphatase was assessed for patient 1. Bone biochemistry; (serum calcium, phosphate, parathyroid hormone, bone alkaline phosphatase, 25(OH) vitamin D, osteocalcin (intact), N. Ter.procoll1, CTX-1) was assessed. Multislice CT with orthoradial reconstruction was performed on pt 1. Results: CK-BB isoenzyme was increased at 21% and 20% in patients 1 and 2 (upper limit normal 2%). DEXA scan patient 1 results: BMD, lumbar spine; T score 4.9 (152%), Z score 5.4 (160%), femur; T score 2.2 (128%) Z score 2.5 (134%). DEXA scan patient 2 results: BMD lumbar spine; T score 0.2, Z score 1.2, femur; T score 1.2, Z score 1.8. Serum acid phosphatase in pt 1 was normal. Orthoradial reconstruction of the mandible in pt 1 showed absence of lateral lingual canals in affected hemi mandible.Mental foramen and inferior alveolar canal were not constricted. Conclusion: The increased BMD and CK BB isoenzyme seen in our pts are characteristic features of osteopetrosis. The normal acid phosphatase is explained by bisphosphonate-induced osteoclast apoptosis a phenomenon that does not occur in osteopetrosis. Orthoradial reconstruction of the mandible provided radiological correlation. The data was found to be consistent with the hypothesized disease process. No significant financial relationships to disclose.
Development of the SP120 rabbit monoclonal antibody for determining hENT1 status and predicting response to gemcitabine in pancreatic ductal adenocarcinoma.
Authors: Stefan Hubert Boeck, Mitch Raponi, William Richardson, Penny Towne, Jeffrey D. Isaacson, Jim Ranger-Moore, Eric Powell, June Clements, Janine D. Feng, Abigail McElhinny, Steffen Ormanns, Thomas Kirchner, William Regine, Kathryn A. Winter, Daniel Ansari, Lindsey Rolfe, Andrew R. Allen, Roland Andersson, Volker Heinemann, Adam P. Dicker
Journal: Journal of Clinical Oncology (2012)

4041 Background: Human equilibrative nucleoside transporter 1 (hENT1) is the primary membrane channel through which gemcitabine (Gem) enters pancreatic tumor cells. Patients whose tumors have low expression of hENT1 may derive little benefit from Gem therapy. Methods: We have developed and analytically validated a rabbit monoclonal antibody, SP120, immunohistochemistry (IHC) in vitro diagnostic (IVD) assay, used on the VENTANA BenchMark ULTRA automated slide staining platform, for assessing hENT1 expression in pancreatic adenocarcinoma. Results: SP120 was shown to be sensitive and specific for membrane expression of hENT1 with variable expression demonstrated across a panel of primary pancreatic adenocarcinoma samples. Using retrospectively collected primary tumor samples (n = 201) from a randomized controlled clinical adjuvant trial (RTOG 97-04), we developed and verified a hENT1 scoring algorithm and cut-off for identifying patients least likely to benefit from Gem (hENT1-low). We confirmed the predictive value of the hENT1 assay by showing there was no association with clinical outcome in the 5FU-treated control group. The distribution of hENT1 expression was similar between these samples and an independent set of 130 pancreatic adenocarcinoma specimens from the AIO-PK0104 study (77 were confirmed metastatic biopsies). Importantly, 100% concordance in hENT1 status (high vs. low) was demonstrated between 16 primary tumors and paired, contemporaneous metastatic lesions. Overall, using this cut-off, approximately two thirds of pancreatic tumors displayed low-hENT1 expression across the different data sets (n = 363). Conclusions: The hENT1 IHC IVD has been developed and is being used in a pivotal trial of a novel lipid-conjugated Gem (CO-101, which enters tumor cells independently of hENT1), vs. Gem in hENT1-low pancreatic cancer patients (NCT01124786). This study is the first prospective test of the hypothesis that gemcitabine is not active in tumors with low hENT1 expression.
Pain and other symptoms in patients with hepatocellular carcinoma (HCC): A qualitative analysis.
Authors: Zeeshan Butt, Rajiv Mallick, Mary Frances Mulcahy, Al B. Benson, David Cella, Karen Kaiser
Journal: Journal of Clinical Oncology (2013)

e15187 Background: HCC is the second leading cause of cancer related deaths worldwide and incidence is increasing. Most HCC patients are diagnosed late-stage and with pain. Understanding the nature of pain experienced by HCC patients is complicated by co-morbid (including other liver) diseases and treatment related pain. The purpose of this study was to identify pain symptoms that are important and relevant to HCC patients who have received systemic therapy. Methods: We conducted semi-structured thematic interviews with 10 HCC patients who were currently on or previously had received oral systemic therapy (e.g., sorafenib) and had not received local or loco-regional therapy (e.g., surgery, radiation or chemo-embolization) within 4 weeks of the interview. Interviews included open elicitation of key symptoms, side effects and concerns. Patients also completed selected pain items from the FACT-Hep; items had previously been validated for patients with hepatobiliary cancers. Results: Mean age was 58 years (range 33-77); 2 patients had co-morbid cirrhosis, 1 had co-morbid hepatitis, and 4 patients had cirrhosis and hepatitis. When asked to describe the symptoms, side-effects or other issues that most significantly impact their quality of life, patients most often mentioned fatigue (n=5), diarrhea (n=5), skin toxicities (n=5), and loss of appetite (n=4). Nine patients reported experiencing pain over their HCC treatment course. Abdomen (N=7) and lower back (N=3) were the most common sites of pain; 2 patients reported only experiencing temporary pain from prior chemoembolization. The other 7 patients experienced ongoing pain, partly attributed to systemic therapy, ascites, or metastases. Ongoing abdominal and back pain were frequently not attributed to a specific cause. All patients indicated that FACT-Hep items adequately assessed their pain. Conclusions: Although pain was not a major driver of quality of life and for a few HCC patients it was transient and treatment-related, the majority of patients experienced some persistent pain. Abdominal pain and back pain were the most common pain sites for HCC patients. These results support the relevance of pain symptoms that have been previously identified as important in HCC.
Some Remarks about the College and Its Future
Authors: Herbert Weiner, Adolf-Ernst Meyer, W. Senf, H. Kordy, M. von Rad, W. Bräutigam, Peter E. Sifneos, Cairns Aitken, Chase Patterson Kimball, Alec Ramsay, Michael von Rad, Johannes Siegrist, Adolf-Ernst Meyer, Herbert Weiner, Adolf-Ernst Meyer, Hubert Speidel, W. Bräutigam, M. von Rad, Adolf-Ernst Meyer, Antje Haag, Christian Müller, Volker Tschuschke, Walter Volk, Reinhard Költzow, Fritz A. Muthny, Adam J. Krakowski, A. Heerlein, G. de la Parra, S. Aronsohn, F. Lolas, W. Ehlers, D. Czogalik, E. Gaus, M. Klingenburg, K. Köhle, Hertha Appelt, Bernhard Strauss, K.W. Bash, Hans-Werner Künsebeck, Wolfgang Lempa, Hellmuth Freyberger, Eike G. Fischer, Nora E. Falke, Antje Haag, Adam J. Krakowski, M.A. Rea, D.H. Hellhammer
Journal: Psychotherapy and Psychosomatics (1984)
Effect of auranofin on oxidative and endoplasmic reticulum stress as well as anti-CLL activity with proteasome inhibitor.
Authors: Suman Kambhampati, Kami J. Maddocks, Rekha Rao, Lata Chauhan, Soumyasri Das Gupta, Siddhartha Ganguly, Ruben Reyes, Omar Salah Aljitawi, Kevin Schorno, Kendra Ford, Eileen D. Dickman, John C. Byrd, Kapil N. Bhalla
Journal: Journal of Clinical Oncology (2012)

e13568 Background: The gold-containing compound auranofin (AF) (Ridaura), is a treatment of rheumatoid arthritis. Recently, AF was shown to inhibit thioredoxin reductase (TRR), increase reactive oxygen species (ROS) and induce apoptosis in cancer cells. Methods: We determined the ability of AF (250 to 1000 nM) to induce oxidative, proteotoxic and lethal endoplasmic reticulum (ER) stress in CD19+ primary CLL cells, including those with deletion of chromosome 17p. Results: Treatment with AF induced 20 to 40% increase in ROS levels, decreased TRR activity (mean of 45%), but not its protein expression, in CLL cells. AF-mediated oxidative stress induced NRF2 activity with increase in hemeoxygenase-1 (HO-1) and glutamate cysteine ligase modifier (GCLM) levels. AF induced ER stress, associated with increase in GRP78 and the pro-apoptotic transcription factor CHOP protein levels. AF also induced the pro-apoptotic BH3-only domain protein BIM. Exposure to AF increased the intracellular levels of misfolded polyubiquitylated proteins. This disrupted the binding of heat shock protein (hsp) 90 with histone deacetylase 6 (HDAC6), resulting in hyperacetylation and inhibition of the chaperone function of hsp90. This led to proteasomal degradation of CLL-relevant hsp90 client proteins, including ZAP70, c-Raf and AKT. Nuclear STAT3 levels also declined. Exposure to AF induced significantly more apoptosis (range 40 to 60%) in primary CLL cells, as compared to CD19+ normal B cells and CD34+ human cord blood and bone marrow progenitor cells (&lt; 15% apoptosis) (p &lt; 0.01). AF treatment also induced apoptosis in CD19+ cells from patients with poor prognosis CLL with deletion of 17p or with deletion of 13q. Co-treatment with AF and the proteasome inhibitor carfilzomib or the GCLM antagonist buthionine sulfoximine (BSO) synergistically induced apoptosis in primary CLL cells. A FDA IND-supported phase II clinical trial of AF (6 to 9 mg PO/day) with correlative biomarker analysis (as above) is underway and three patients are enrolled. Conclusions: These findings support the full evaluation of clinical activity and predictive biomarkers of response to the re-purposed AF in patients with CLL.