tbuckley/cabot-search huggingface dataset:
Proton pump inhibitors (PPIs) and survival outcomes in patients with metastatic renal cell carcinoma (mRCC).
Authors: Aly-Khan A. Lalani, Rana R. McKay, Xun Lin, Ronit Simantov, Marina D. Kaymakcalan, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

493 Background: PPIs are potent inhibitors of gastric acid secretion and can affect the bioavailability of orally administered cancer targeting therapies, such as vascular endothelial growth factor tyrosine-kinase inhibitors (VEGF-TKIs). Smaller preclinical and clinical studies have attempted to assess the interaction between VEGF-TKIs and PPIs in patients with advanced cancers; however, these studies are limited and larger analyses from rigorous datasets have been lacking. We investigate the impact of PPI use on survival in patients with mRCC treated with oral VEGF-TKIs. Methods: A pooled analysis of mRCC patients treated on phase II and III clinical trials was conducted. The primary outcome was to assess overall survival (OS) between PPI users, defined as patients receiving a PPI at baseline, compared to non-PPI users. Secondary outcomes included progression-free survival (PFS), objective response rates (ORR), and adverse events. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. Results: Our cohort consisted of 2,188 patients treated with sunitinib (n = 952), axitinib (n = 626), or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users demonstrated similar OS compared to non-PPI users (median 24.1 vs. 21.3 months, adjusted hazard ratio [aHR] 1.051, 95% confidence interval (CI) 0.769-1.438, p = 0.754). Similarly, PFS (5.5 vs. 8.0 months, aHR 1.016, 95% CI 0.793-1.301, p = 0.902) and ORR (23.3% versus 27.4%, p = 0.344) were not different between PPI users and non-users. These findings were consistent across International mRCC Database Consortium risk groups and by line of therapy. Adverse events were also similar between both groups. Conclusions: In this analysis, we demonstrate that PPI use does not appear to negatively impact the efficacy of VEGF-TKIs in mRCC patients treated in the targeted therapy era. Given the current landscape expanding to include more self-administered treatments, documentation of concomitant medications, and patient education on potential drug interactions are critical for optimizing the utilization of oral cancer targeting therapy.
Phase I trial of intraperitoneal (IP) administration of a measles virus (MV) derivative expressing the human carcinoembryonic antigen (CEA) in ovarian cancer patients
Authors: E. Galanis, L. C. Hartmann, W. Cliby, P. J. Zollman, P. P. Peethambaram, H. J. Long, J. S. Kaur, J. A. Sloan, K. W. Peng, S. J. Russell
Journal: Journal of Clinical Oncology (2006)

5028 Background: Edmonston vaccine strains of MV have significant antitumor activity against ovarian cancer xenografts (Peng et al, Cancer Res, 2002). Oncolytic selectivity is due to overexpression of the MV CD46 receptor in ovarian cancer cells. Furthermore, engineering the virus to express the marker peptide CEA (MV-CEA) allows real time monitoring of viral gene expression/propagation in vivo. Methods: We are conducting a Phase I trial of MV-CEA in patients (pts) with recurrent, taxol and platinum refractory, ovarian or primary peritoneal carcinoma. Eligible pts should have protective anti-MV antibody (ab) titers and normal CEA levels. A standard phase I cohorts of three statistical design is employed. MV-CEA is administered IP via a port-a-cath, q 4 wks for up to 6 cycles. Results: To date, 12 pts have received viral doses from 10 3 to 10 6 TCID50. No dose-limiting toxicity has been observed. Most common toxicities included grade 1–2 nausea (4 pts); grade 1–2 fatigue (4 pts); grade 1 fever (3 pts); grade 1 abdominal pain (2 pts). One pt had grade 2–3 arthralgias in cycles 4–6. There was no treatment induced immunosuppression as assessed by DTH, CD4, CD8, immunoglobulin and complement levels, no significant increase in the titers of anti-MV abs in serum or ascites in response to treatment, and no development of anti-CEA abs. Viral genomes were detected in the peripheral blood mononuclear cells of 2 asymptomatic pts by QRT-PCR. No CEA elevation in the serum was observed in the dose range tested, and there was no viral shedding in urine or mouth gargle specimens. Testing of pt tumor samples for CD46 by IHC demonstrated overexpression of the target receptor in 7/8 pts. Best objective response was stable disease (2 - 9 mo duration) in 5 pts, while 3 pts had significant decrease in CA125 levels, of 44%, 72%, and 78%, respectively. Conclusions: In this first human application of an engineered oncolytic MV strain, we have observed excellent tolerance after repeat IP administration of the virus. Despite the low doses employed so far, there is early evidence of biologic activity. Dose escalation continues to the target dose of 10 9 TCID50. No significant financial relationships to disclose.
Incidence of brain metastases and overall survival in patients with primary cardiac sarcoma: A retrospective case series.
Authors: Maryann Shango, Lili Zhao, Monika Leja, Jonathan B. McHugh, Scott Schuetze, Rashmi Chugh
Journal: Journal of Clinical Oncology (2013)

10584 Background: Primary cardiac sarcoma (PCS) is the most common primary cardiac malignancy, but is a rare primary site of sarcoma. We present 21 cases from a tertiary care center to better understand this uncommon malignancy. Methods: A cancer center-based registry and pathology database were searched to identify pts diagnosed with PCS from 1992-2013 at University of Michigan. Kaplan-meier method was used to estimate survival. Cox proportional hazard model was used to associate variables to occurrence of metastases (mets) or death. Results: Atotal of 21 pts (F12, 9M) with PCS were identified, median age 36 (range 11-74). The most common presenting symptoms included dyspnea (16) and chest pain (6; 5 with associated pericardial effusion). Histologies included: angiosarcoma (9), leiomyosarcoma (4), undifferentiated pleomorphic (3), spindle cell (2), fibrosarcoma (1), rhabdomyosarcoma (1) and synovial (1). Sites of origin were R atrium (7), R ventricle (2), L atrium (10) and pericardium (2). Ten pts presented with mets; most common sites were lung (8), liver (2), brain (2), pancreas (2) and bone (2). Surgery was attempted in 12 pts, achieving 1 R0 resection. Pts received a median of 1 (0-7) systemic therapies. Median overall (OS) was 12.6 mos (range 3-79) from diagnosis. Pts without prior surgery were more likely to have mets or death (p=0.038). Brain mets were common, occurring in 7 of 21 pts after a median of 7 mos (range 1-75) from diagnosis. Median OS after diagnosis of brain mets was 8 mos. Of the 7 pts who developed brain metastasis, 5 had PCS originating in the left heart. Of the 2 pts with PCS in the right heart, one was evaluated for and had a right to left shunt. The likelihood of developing brain mets did not correlate with age, chemotherapy, or surgery. Conclusions: PCS portends an extremely poor prognosis, marked by inability to achieve complete resection and a high incidence of disseminated disease at diagnosis. Metastatic disease to the brain was much more common in PCS (33%) as compared to STS of any origin (approximately 1-8%), particularly in pts with PCS originating in the left heart. Clinicians should have a low threshold for brain imaging evaluation of PCS pts.
Next-Generation Sequencing in Myelodysplastic Syndromes: Prognostic Interaction Between Adverse Mutations and IPSS-R
Authors: Naseema Gangat, Terra L. Lasho, Lyla Saeed, Mythri Mudireddy, Mrinal M Patnaik, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Ayalew Tefferi
Journal: Blood (2016)
Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS).
Authors: Angela Q. Qu, Susanna J. Jacobus, Sabina Signoretti, Edward C. Stack, Katherine Maragaret Krajewski, Jonathan E. Rosenberg, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2013)

4530 Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least &gt;50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p&lt;T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score &lt;0.1 (negative) vs. &gt;0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p=0.146). Those achieving RaR had a significantly longer DFS (p=0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(+) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(+) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(+) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.
A 6-gene signature for outcome prediction of grade II/III glioma.
Authors: Tim Lautenschlaeger, Alexander Huebner, Oliver Oehlke, Tareq A. Juratli, Bin Li, Wei Meng, Ahmed Ibrahim, Daniel Erny, Dietmar Krex, Gabriele Schackert, Marco Prinz, Anca Grosu, Arnab Chakravarti
Journal: Journal of Clinical Oncology (2014)

2002 Background: Grade II and III gliomas are very heterogeneous in their outcome, leaving some uncertainty as to what the best treatment is for the individual patient. Methods: We used multiple datasets totaling 756 glioma patients to develop a prognostic 6-gene signature for grade II and III gliomas. Three risk groups were defined (low, medium, and high risk). This 6-gene classifier was then validated in multiple independent glioma data sets totaling over 500 patients and translated into a PCR-based assay. Results: The classifier was validated in a 214 grade II/III glioma patient independent validation set (TCGA, HR=4.03; 95% CI, 1.82-8.92; p= 0.001, for low vs high risk group) and a 287 patient grade IV glioblastoma set (updated TCGA, HR, 2.42; 95% CI, 1.69-3.47; p< 0.001, for low vs high risk group). The classifier was then translated into a PCR based assay in an independent 32 grade II/III glioma patient pilot cohort (multi-institutional, HR=6.3; 95% CI, 1.7-23.6; p= 0.006, for low vs high risk group). Multivariate Cox regressions validated the risk classifier independent of other clinical or molecular factors (grade, histology, IDH1 status) in all three data sets. ROC analysis for 3 year overall survival demonstrate that the classifier can predict 3 year survival better than grade, histology or IDH1 mutation status (AUC, 0.82; 95% CI, 0.70-0.93; p< 0.0001) in patients with grade II/III tumors. Of note, ROC analysis for 3 year overall survival demonstrated that the 6-gene classifier was also an excellent predictor of 3 year survival in glioblastoma (AUC, 0.84; 95% CI, 0.76-0.91; p< 0.0001). Conclusions: The 6-gene classifier can reliably predict 3-year outcome for patients older than 40 years and 7-year outcome for patients younger than 40 years old with grade 2 and 3 gliomas independent of histology, grade or IDH1 mutation status.
Expanding participation to non-group members in phase III cooperative group treatment trials
Authors: A. M. Denicoff, J. R. Hopkins, S. E. Riordan, J. M. Adler, D. M. Marinucci, K. Geisen, R. Lambersky, R. B. Catalano, M. M. Mooney, J. S. Abrams
Journal: Journal of Clinical Oncology (2007)

6533 Background: The NCI initiated the Cancer Trials Support Unit (CTSU) Independent Clinical Research Site (CICRS) Program at the ASCO Annual meeting in 2002. Building upon the CTSU's initial aim to expand participation of any NCI-sponsored Cooperative Group (Group) phase 3 trial to all Group and Community Clinical Oncology Program (CCOP) members, the CICRS initiative has enabled unaffiliated sites to enroll patients in a wide variety of Group trials. Methods: Interested oncology practices submitted applications that were reviewed by a committee, including external reviewers, to select the most qualified sites. They had to meet standards similar to those for Group members and were assessed for the quality of investigator credentials and site preparedness. Sites were required to demonstrate functioning IRBs, pharmacy facilities, and data management standard operating procedures to ensure a high level of clinical trials practice. A CTSU research nurse mentor was added to address challenges faced by the sites. Sites were required to enroll at least 5 patients per year to remain active participants. Results: Via the CTSU, a trial menu of over 60 Group phase 3 studies, and selected phase 2 trials, were made available to CICRS participants. Active CICRS sites are distributed over 19 states and 6 of the 7 highest accruers are in population areas with less than 300,000 persons. Participating sites were surveyed in January 2006 to better understand barriers to clinical trials enrollment and 68% percent reported the main barriers were dedicated staff, time, adequate IRB and financial support for research. Conclusions: Obstacles for participation in the CICRS program have been defined and strategies to overcome them are being implemented. Results of these efforts will be updated, including provision of survey results, updated accrual, audit results and a review of successful enrollment strategies. No significant financial relationships to disclose. [Table: see text]
A phase I trial of MK-2206 and hydroxychloroquine(HCQ) in solid tumors, melanoma, renal, and prostate cancer to examine the role of autophagy in tumorigenesis.
Authors: Amanda D. Kaveney, Janice M. Mehnert, Antoinette R. Tan, Joseph Aisner, Rebecca Anne Moss, Darlene Gibbon, Shari Adams, Jane Fischer, Pamela Scott, Christian Gable, Austin Doyle, Robert S. DiPaola, Mark N. Stein
Journal: Journal of Clinical Oncology (2014)

TPS2640 Background: AKT is a frequently hyperactivated oncogenic kinase in human cancers (Degenhardt 2006). Inhibition of AKT activates autophagy, promoting tumor survival, and hence AKT inhibitors may limit their own efficacy. HCQ inhibits autophagy and may prevent this survival mechanism. Treating renal cell carcinoma lines with temsirolimus, an mTOR inhibitor, promoted autophagy-mediated stress tolerance and the concomitant inhibition of autophagic degradation with chloroquine, enhanced tumor cell death (Bray 2012, Xie 2013). A similar phenomenon was reported with AKT inhibition (Degtyarev 2008, Cheny 2011) We hypothesize that Akt inhibition by the allosteric inhibitor MK-2206 will induce autophagy which may be inhibited by the addition of HCQ, potentially enhancing cell death and improving therapeutic outcomes. The purpose of this study is to define the maximum tolerated dose of MK-2206 and HCQ when used in combination, to determine the pharmacokinetic (PK) profile of the combination and to assess surrogate markers of autophagy modulation in blood and tumor samples from these patients. Methods: We designed an open-label Phase I trial using a 3+3 design to enroll patients with advanced solid tumors who were refractory to or declined standard therapy with the primary objective of determining the MTD of the combination. Treatment cycles were 3 weeks in length. Patients received MK-2206 alone in Cycle (C) 1 with HCQ beginning on C2, Day 1. Dose level (DL1) enrolled patients at a dose of MK-2206 135 mg weekly, with HCQ given at 200 mg twice a day (BID). Dose escalation is planned to a maximum dose of 200mg weekly and a maximum dose of 600mg BID for MK-2206 and HCQ respectively. We will assess changes in PK parameters of MK-2206 and HCQ co-administration. We will examine expression of Beclin1 and LC3, known to accumulate with autophagy inhibition. Surrogate markers will be used to assess the activation of the AKT pathway. Correlations between steady-state plasma concentration of HCQ and the degree of autophagy inhibition will be assessed. To date, twenty-seven patients have been enrolled and enrollment continues with HCQ 600mg BID and MK-2206 135mg/day. Clinical trial information: NCT01480154.
HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5FU on the ESPAC trials.
Authors: John P. Neoptolemos, William Greenhalf, Paula Ghaneh, Daniel H. Palmer, Trevor F. Cox, Elizabeth Garner, Fiona Campbell, John Robert Mackey, Malcolm J. Moore, Juan W. Valle, Alec Mcdonald, Niall C. Tebbutt, Christos Dervenis, Bengt Glimelius, Richard M. Charnley, Francois Lacaine, Julia Mayerle, Charlotte Louise Rawcliffe, Claudio Bassi, Markus W. Buchler
Journal: Journal of Clinical Oncology (2013)

4006 Background: Some studies in patients with resected pancreatic cancer have suggested that expression of the human equilibrative nucleoside transporter (hENT1) may be predictive of improved survival from gemcitabine but these have either been based on retrospective non-randomized studies or in one study the principal treatment was chemoradiation. The samples collected from the adjuvant ESPAC1/3 randomized trials have provided a unique opportunity to assess to REMARK standards the therapeutic predictability of hENT1 in patients undergoing resection for pancreatic cancer. Methods: Tissue Microarrays (TMAs) were prepared using paraffin embedded tumor specimens from patients randomized to gemcitabine or 5FU/Folinic acid in the ESPAC-1 and -3 trials. Cores were given an H-Score depending on the level of staining with the 10D7G2 anti-hENT1 antibody. Groups were compared using Kaplan-Meier and Cox proportional hazards. Results: Scores were obtained for 176 gemcitabine treated and 176 5FU treated patients. The overall median H-Score was 48 and patients were classified as having high hENT1 if the mean score for their cores was above this. Median overall survival for gemcitabine treated patients was 23.4 (95% CI: 18.3, 26.0) months versus 23.5 (95% CI: 19.8, 27.3) months for 5FU treated patients (χ 2 1 = 0.24, P = 0.623). In the gemcitabine group A significantly lower survival (χ 2 1 = 9.87, P = 0.002) was noted with low hENT1 (median survival 17.1 (95% CI: 14.3, 23.8) versus 26.2 (95% CI: 21.2, 31.4) months). Median survival was 25.6 (95% CI: 20.1, 27.9) and 21.9 (95% CI: 16.0, 28.3) months respectively for high and low hENT1 in the 5FU group, a non-significant difference (χ 2 1 = 0.83, P = 0.362). Multivariate analysis confirmed hENT1 expression as a predictive marker in gemcitabine (Wald χ 2 = 7.10, P = 0.008) but not 5-fluorouracil (Wald χ 2 =0.34, P = 0.560) groups. Conclusions: The study supports use of gemcitabine in patients with high tumor hENT1 expression and 5-fluorouracil in patients with low hENT1.
The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations
Authors: Pearl G. Lee, Jeffrey B. Halter
Journal: Diabetes Care (2017)

Nearly a quarter of older adults in the U.S. have type 2 diabetes, and this population is continuing to increase with the aging of the population. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. The usual defects contributing to type 2 diabetes are further complicated by the natural physiological changes associated with aging as well as the comorbidities and functional impairments that are often present in older people. This paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.
Serum mass spectrometry analysis in primary ovarian cancer (OC) treated with surgery and adjuvant chemotherapy (CT).
Authors: Heinrich Roder, Sabine Kasimir-Bauer, Rainer Kimmig, Pauline Wimberger, Robert Zeillinger, Dan Cacsire Castillo-Tong, Jalid Sehouli, Ignace Vergote, Sven Mahner, Joanna Roder, Julia Grigorieva, Krista Meyer, Bahriye Aktas
Journal: Journal of Clinical Oncology (2013)

5575 Background: To address the unmet need for non-invasive tests to predict outcomes in OC we investigated the effect of the serum test, VeriStrat (VS), in independent cohorts of OC patients (pts) who were treated with platinum based chemotherapy following surgery. VS assigns “Good” (VSG) and “Poor” (VSP) classifications and has been shown to be prognostic in various tumor types and predictive for certain treatments. Methods: Samples from primary OC pts from the University Hospital, Essen (ESSEN), N= 108, and from OVCAD consortium (Berlin, Leuven, Hamburg, Vienna), N = 138, were obtained within 1 week before surgery that was followed by platinum-based CT. VS testing was done blinded to clinical data. Overall survival (OS) was analyzed by Kaplan-Meier method and compared using log-rank p-values. Cox models were used in multivariate analysis. Associations with categorical variables were analyzed by Fisher’s exact test. Results: The cohorts had similar distribution of VSG/VSP classification: 73% VSG (ESSEN), 71% VSG (OVCAD). The distribution by histology (non-serous/serous), and nodal status were different (p = 0.003 and p = 0.049). The results for OS in all pts (ALL), in pts with tumor (and/or metastases) present post-surgery (TPPS-pos), and in pts with complete resection and no metastases (TPPS-neg) are presented in the Table. VS was not associated with circulating tumor cells (ESSEN, p=0.736). In a Cox model analysis for TPPS-pos groups VS was independently significant (p= 0.016, ESSEN) or trended to significance (p=0.063, OVCAD). Conclusions: VS demonstrated similar results in two independent cohorts; in ALL and TPPS-pos populations it significantly correlated with OS in ESSEN, showed same trends in OVCAD, and was not correlated with OS in TTPS-neg pts. While requiring further investigation, VS may provide useful prognostic information. [Table: see text]