tbuckley/cabot-search huggingface dataset:
Effect of coadministered beta blocker and COX-2 inhibitor to patients with pancreatic cancer prior to receiving albumin-bound (Nab) paclitaxel.
Authors: Gouri Shankar Bhattacharyya, K Govind Babu, Shailesh Arjun Bondarde, Ghanashyam Biswas, Anantbhushan Ranade, Purvish M. Parikh, Newell F. Bascomb, Hemant Malhotra
Journal: Journal of Clinical Oncology (2015)

302 Background: Paclitaxel protein-bound particles nab-paclitaxel plus gemcitabine is rapidly becoming the standard of care for patients with metastatic adenocarcinoma of the pancreas (mPCa). Preclinical and clinical studies of beta-blockers and NSAIDs show a benefit of these drugs in pancreatic cancer. The aim of this study was to evaluate the impact of the co-administration of the beta blocker propranolol (P) and the selective COX-2 inhibitor etodolac (E) on survival of patients with mPCa receiving GemNab as standard of care. PE is presumed to target the adrenergic and prostaglandin stress systems activated in cancer that induce changes in tumor microenvironment, immune system, and HPA axis leading to tumor promotion and immune tolerance. Data on the use of nab-paclitaxel plus gemcitabine (GemNab) with a beta blocker and NSAID in the clinical setting is lacking. Methods: Patients with mPCa were eligible for this randomized investigator initiated trial. Patients received PE daily for one week prior to starting GemNab. PE was administered in a chronodosed regimen to maximize the therapeutic benefit and minimize side effects. The primary endpoint was survival. Twenty-three patients were randomized to either GemNab or GemNab after one week of propranolol and etodolac (PEGemNab). The median age was 62.8 years; 68.2% male. Pain at time of diagnosis as reported in 80% of the patients in the GemNab arm and in 76.9% of the PEGemNab arm and jaundice was observed in 40% and 23% of the GemNab and PEGemNab arms, respectively. Results: Progression free survival was 7.2 and 11.8 months in the GemNab and PEGemNab arms, respectively. Overall survival was 10.5 months for the GemNab arm and 15.9 months for the PEGemNab arm. The treatment was well-tolerated with no unexpected adverse events. Conclusions: Administration of PE one week prior to Paclitaxel protein-bound particles with gemcitabine significantly increased progression free and overall survival. No unexpected adverse reactions were seen. Additional data on cytokine and cancer markers will be presented.
Influence of single agent paclitaxel (TAX) schedule on the pattern of response and toxicity in patients with advanced breast and lung cancer: A systematic review
Authors: E. Barrajon, A. Lopez, E. Adrover, G. Esquerdo, C. Llorca
Journal: Journal of Clinical Oncology (2005)

2124 Background: Dose density of chemotherapy has been advocated as a way to improve results in patients with cancer. While increasing dose, and the area under the curve of concentration-time (AUC), may increase response, it also increases toxicity, reducing the clinical benefit. For phase-specific agents such as TAX, different schedules with the same dose and AUC may produce different patterns of efficacy and toxicity. Partial comparisons between schedules in clinical trials may answer which of two or three schedules is better, but not which schedule is optimal. A systematic analysis of all different schedules of TAX, integrating clinical, pharmacodynamic and pharmacokinetic data in a mathematical model may provide an optimum, as was previously provided for fluorouracil (Proc ASCO 2004; 23:a2139). Methods: Clinical trials of single agent TAX in advanced breast and lung cancer have been searched in PubMed, references of published clinical trials, and presentations in cancer meetings. Prognostic factors (age, sex, sex, performance status, previous chemotherapy, proportion of patients with metastasis), schedule details (dose, time and frequency of infusions), response rate and percent of toxicity (hematological, mucosal, diarrhea and neurotoxicity) were analyzed in a multivariate model. In vitro data (concentration and time of exposure of TAX in human cell lines) and pharmacologic data (pharmacokinetic and pharmacodynamic) were included in the model, estimating the area under the curve of concentration-time above a concentration threshold (AUCt) obtained for every clinical schedule. AUCt and clinical prognostic factors were included in a multivariate regression model to estimate the influence on response and toxicity. Results: Over 5500 patients were included in 58 advanced breast cancer and 28 advanced lung cancer trials. Median dose of TAX was 175 mg/m2 (range 60–250 mg/m2); median time of infusion was 3 hours (range 0.5–96 hours). An adjusted model showing the influence of dose, time and interval of infusion, will be presented.Conclusions: Besides dose density, there is room for improvement of paclitaxel schedule in clinical practice. No significant financial relationships to disclose.
Efficacy and safety of everolimus in patients with advanced low- or intermediate-grade pancreatic neuroendocrine tumors previously treated with chemotherapy: RADIANT-3 subgroup analysis.
Authors: Catherine Lombard-Bohas, James C. Yao, Timothy J. Hobday, Eric Van Cutsem, Edward M. Wolin, Ashok Panneerselvam, Ramon Castellana, Sotirios G. Stergiopoulos, Gaurav D. Shah, Manisha H. Shah, Rodney F. Pommier
Journal: Journal of Clinical Oncology (2013)

224 Background: In the phase 3 RADIANT-3 trial, everolimus (EVE) demonstrated significantly improved median progression-free survival (PFS) versus placebo (PBO) (11.0 vs 4.6 months; HR=0.35, p &lt; 0.0001) in patients (pts) with pancreatic neuroendocrine tumors (pNET) (Yao et al, NEJM, 2011). Here we present a planned exploratory analysis by prior chemotherapy (chemo) use. Methods: Pts with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemo use and randomized (1:1) to EVE 10 mg/d (n = 207) or PBO (n = 203) plus best supportive care. Results: Of the 410 pts, 206 (50%) had received prior chemo and 204 (50%) were chemo naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for pts with/without prior chemo. More chemo-naive pts were newly diagnosed (time since initial diagnosis ≤ 6 mo: 50 [25%] vs. 7 [3%] pts with prior chemo). A lower proportion of chemo-naive pts received prior somatostatin therapy (45% vs. 54% prior chemo). EVE significantly prolonged median PFS regardless of prior chemo use (with prior chemo: 11.0 vs. 3.2 months; HR = 0.35, 95% CI 0.25-0.49, p &lt; 0.001; chemo naive: 11.4 vs. 5.4 months; HR = 0.42, 95% CI 0.29-0.60; p &lt; 0.001). Stable disease was the best overall response in 73% of EVE-treated pts irrespective of prior chemo use. The benefit from EVE irrespective of prior chemo was further demonstrated by disease stabilization or minor tumor shrinkage and in the lower incidence of progressive disease in waterfall plots. Safety of EVE was consistent regardless of prior chemo use. The most common drug-related adverse events (chemo vs chemo naive) included rash (53% vs. 52%), stomatitis (52% vs. 56%), diarrhea (41% vs. 52%), and fatigue (37% vs. 51%). Conclusions: This planned subgroup analysis demonstrated the beneficial effects of EVE in pts with pNET regardless of prior chemo use. These findings support the possible first-line use of EVE for pts with pNET.
Genetics and genomics of dilated cardiomyopathy and systolic heart failure
Authors: Upasana Tayal, Sanjay Prasad, Stuart A. Cook
Journal: Genome Medicine (2017)

Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.
Identification of <i>ALK</i> gene alterations in urothelial carcinoma (UC).
Authors: J. Bellmunt, S. Selvarajah, S. Rodig, M. Salido, I. Costa, B. Bellosillo, L. Werner, C. Namgyal, F. A. B. Schutz, F. Pons, R. O'Brien, J. Barretina, S. Signoretti, M. Loda, J. Albanell, T. K. Choueiri, D. M. Berman, P. W. Kantoff, J. E. Rosenberg
Journal: Journal of Clinical Oncology (2011)

4568 Background: 3% to 5% of non-small cell lung cancers demonstrate translocation of the anaplastic lymphoma kinase (ALK) gene. This genetic event is associated with tumor sensitivity to ALK inhibitors. ALK gene translocations, copy number gains or amplification, mutations, and expression, have been not characterized in UC. Our aim was to determine the prevalence of these events in a cohort of clinically annotated and uniformly treated UC patients. Methods: Copy-number (CN) evaluation in all tumor samples were obtained on a single array platform, (Agilent 180K array). ALK status was evaluated by fluorescence in situ hybridization (FISH) with a break-apart probe and a centromeric probe of chromosome 2 (Abbott Molecular Inc) in selected samples with and without CN alteration (CNA) at the ALK locus (2p23). ALK expression was assessed by immunohistochemistry (IHC) (Cell Signaling antibody) and high throughput mutation analysis with the Oncomap 3 platform. Fusion transcripts were evaluated using HTG platform. Results: Tumors from ninety-four UC patients were evaluated. CNA near the ALK locus were found in 3 patients. Polysomy of chromosome 2 (3-6 copies) was observed in 2 patients, and both polysomy and amplification were observed in 1 patient. In patients without CNA, only 1 out of 4 patients presented polysomy (3 copies). ALK expression was undetectable in all 94 samples. mRNA transcript analysis showed 1 case with an atypical (non-EML4) translocation of ALK, and 1 patient with an unconfirmed mutation. Conclusions: ALK alterations are rare events in UC. This is the first description of ALK alterations in UC. The relevance and clinical implications of ALK amplification and translocation in UC merits further evaluation. Sequencing data of the observed mutation and translocation will be presented.
Development and validation of a digital Gleason score biomarker signature for risk stratification of patients with prostate cancer.
Authors: Nicholas Erho, Ismael A. Vergara, Christine Buerki, Mercedeh Ghadessi, Anamaria Crisan, Thomas Sierocinski, Zaid Haddad, Benedikt Zimmermann, Sebastian Harko, Worlanyo Sosu-Sedzorme, Timothy J. Triche, Robert B. Jenkins, Elai Davicioni
Journal: Journal of Clinical Oncology (2012)

40 Background: Gleason score (GS) is the most widely used grading system of cell differentiation in prostate cancer and one of the best pathological predictors of disease progression. Patients with high GS (&gt; 7) are the most likely to experience metastasis, whereas patients with low GS (&lt; 7) are expected to have favorable long-term outcomes. In addition to the subjective nature of GS assessment, patients with GS 7 represent a heterogeneous group in terms of patient outcomes. In this study a biomarker signature is developed and validated which could improve the prediction of high risk disease among GS 7 radical prostatectomy (RP) patients. Methods: Patient specimens from the Mayo Clinic RP Registry (n = 764) were used for feature selection and training of a 392-feature K-nearest neighbor (KNN, k = 11) classifier. These 392 genomic features were identified by assessing differential expression between patients with GS &lt; 7 and those with GS &gt; 7, using a Bonferroni adjusted T-Test with a p-value threshold of 0.05. The classifier was subsequently validated in two independent patient cohorts (Memorial Sloan Kettering [MSKCC] and German Cancer Research Center [DKFZ]) and compared to a state of the art biomarker signature (Penney et al. 2011). Results: In the MSKCC dataset (GSE21034) our model segregated GS &lt; 7 from GS &gt; 7 patients (n = 56) with an area under the receiver operating characteristic curve (AUC) of 0.97, comparable to the AUC of 0.94 obtained by Penney et al. in their independent validation set (n = 45). Strong performance was observed by our model when discriminating between primary Gleason grade (pGG) 3 and pGG 4 &amp; 5 patients in the MSKCC (n = 130) and DKFZ prostate cancer (GSE29079, n = 47) datasets, achieving AUCs of 0.75 and 0.87, respectively. In the challenging GS 7 subset, our model segregated GS 3 + 4 and 4 + 3 patients in the DKFZ dataset (n = 64) with an AUC of 0.81 outperforming the Penney et al. signature (AUC = 0.60). Conclusions: A biomarker signature was developed which discriminates between low and high GS patients, outperforming a previously reported signature. Further validation of this biomarker signature in additional post RP patients, as well as, pretreatment biopsy specimens is warranted.
Association of pancreatic metastasectomy for melanoma with long-term overall survival: A single-institution experience.
Authors: Matthew Doepker, TzuHua Juan, Dung-Tsa Chen, Phuong Nguyen, Amod Sarnaik, Jose Mario Pimiento, Pamela Joy Hodul, Mokenge Peter Malafa
Journal: Journal of Clinical Oncology (2015)

264 Background: Isolated metastatic melanoma to the pancreas is extremely rare. A recent pooled analysis evaluated 11 patients(pts) with metastatic melanoma to the pancreas and reported a median disease free interval(DFI) between the diagnosis of the primary cancer to the diagnosis of the isolated pancreatic metastasis of 48 months and a 5-year overall survival(OS) of 27%. The purpose of this study was to review our experience with resection of metastatic melanoma to the pancreas and compare it to the more common metastatic renal cell carcinoma(RCC) to the pancreas. Methods: Pts with pancreatic metastasis followed by metastasectomy were identified at a single institution from 1998 to 2013. The Kaplan-Meier method was used to report 5-year OS and disease-specific survival (DSS). Results: We identified24 pts with isolated metastasis to the pancreas that underwent curative resections. Eighteen (75%) were males and the overall median age was 64. Eleven RCC (45.8%), 4 melanomas (16.7%), and 9 other histologies (37.5%) were noted. The median DFI between the diagnosis of the primary cancer to the diagnosis of the isolated pancreatic metastasis for RCC, melanoma, and other histologies was 91.3 months (range, 2.0-361.6), 77.8 months (range, 65.3-97.4), and 55.4 months (range, 7.6-154.8) respectively. Nineteen distal pancreatectomies (79.2%) and 5 pancreaticoduodenectomies (20.8%) were performed. Five-year OS and DSS were 51% and 65%. Pts with metastatic melanoma to the pancreas had a 5-year OS of 67% (95% CI=0.05, 0.95) compared to 65% and 30% for RCC and other histologies respectively. The 5-year DSS for pts with melanoma was 67% (95% CI=0.05, 0.95) vs 100% for RCC and 34% for other histologies. After a median follow up of 39.9 months, all melanoma pts recurred after resection, with a median time to recurrence of 17.7 months. Of the 24, 10 died of disease. Conclusions: We report the largest series on pancreatic metastasectomy for melanoma. Our data show comparable DFI and survival to RCC, along with higher OS compared to previously reported data. Pancreatic metastasectomy for melanoma should be considered as evidenced by prolonged DFI and higher OS.
Enhancing the status of quality-of-life diagnostics in caring for breast cancer patients: Results from a multilevel implementation study in a regional tumor centre
Authors: M. Klinkhammer-Schalke, W. Lorenz, B. Steinger, C. Jakob, B. Ernst, F. Hofstädter, M. Koller
Journal: Journal of Clinical Oncology (2005)

659 Background: A three-component-outcome-model comprising quality of life (QL), classic endpoints and an integrated value judgement on clinical relevance (J. Roy. Soc. Med. 95, 481, 2002) was implemented as a curing and caring system for breast cancer patients in a regional tumor center. Methods: The multilevel implementation procedure included the combination of outreach visits, opinion leaders and continuous medical education within a quality circle (Med. Care 39, Suppl. 2, 85, 2000). In the format of a prospective study without a control group, a total of 359 persons participated from June 2003 to September 2004: 218 female breast cancer patients, age 34–86 years, 5 clinical centers, a QL diagnostic unit including 5 experts in oncology and psychology, 38 practitioners coordinating QL therapeutic options, 12 opinion leaders and 72 health care providers for 5 therapeutic options: pain-, psycho-and physiotherapy, nutrition and sports, social rehabilitation. This group worked along a defined clinical pathway with a DRQL profile of each patient derived from EORTC-QLQ-C30 questionnaire and an expert’s report integrating this profile and recommending the therapeutic options. The coordinating practitioners receiving the reports were controlled one month later for taking therapeutic actions. Data were analyzed by descriptive statistics. Results: According to the QL diagnostics 50% of the 218 patients showed no clinically relevant QL deficit (< 50 points on a 0 [bad] to 100 [optimum]). 17% of the patients needed physiotherapy, 23% psychotherapy, 18% pain therapy, 6% nutrition/sports and 18% social rehabilitation. Coordinating practitioners reported major problems to provide help in the areas of psychotherapy (19%) and particularly social rehabilitation (48%). Conclusion: This is the first example of integrating QL diagnostics in a guideline-based system for breast cancer care. The effectiveness of this approach is currently evaluated in the course of a randomized clinical trial. No significant financial relationships to disclose.
Next-generation sequencing (NGS) in metastatic breast cancer (mBC) patients: Translation from sequence data into clinical practice.
Authors: Raphael Brandao Moreira, Renata Peixoto, Tercia Tarciane Soares de Sousa, Marcelo Cruz, Fernando Maluf, Antonio Buzaid
Journal: Journal of Clinical Oncology (2015)

133 Background: A considerable number of patients with mBC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mBC and its clinical utility. Methods: We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 315 genes and selective intronic sequencing from 28 genes for refractory mBC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. Results: Samples from 20 patients were tested. Histologic subtype consisted of triple negative (50%), HER 2 +, hormonal receptor [HR] - 15%, HR + and HER 2 - (35%). A targetable genomic alteration was identified in 14 (70%) patients, most frequently in TP53 (11 [55%]), PIK3CA (8 [40%]), FGFR1 (4 [20%]), CCND1 (3 [15%]), PTEN (3[15%]) and BRCA2 (2[10%]). Therapy could be personalized in 9 (45%) of 14 patients. Of the 9 patients who were received targeted therapy, 7 (77%) had an objective response and had stable disease for more than 3 months. Conclusions: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced breast cancer patients. The assay provided clinical benefit in 35% of the patients.
A pilot study of neoadjuvant chemoradiotherapy for unresectable locally advanced adherent colon cancer: Assessing local tumor response.
Authors: Xin Yu, WeiWei Xiao, Rong Zhang, LuNing Zhang, Bo Qiu, ZhiFan Zeng, Pei-Rong Ding, Zhi-zhong Pan, Li-ren LI, Yuan-Hong Gao
Journal: Journal of Clinical Oncology (2016)

727 Background: To analyze the outcomes of neoadjuvant chemoradiotherapy (neoCRT) in the management of unresectable locally advanced adherent colon cancer (LAACC). Methods: 40 unresectable LAACC patients were identified from Sun Yat-Sen university cancer-center Database from October 2010 to December 2014. Unresectability was determined by multidisciplinary consultation (MDT) according to image examination or confirmed by exploratory laparotomy. NeoCRT followed by surgery and postoperative chemotherapy were given to these patients. There were 27 males and 13 females. Median age was 56 years old. The location of primary tumors were as sigmoid 31, descending colon 3, ascending colon 5, and cecum1, respectively. All the patients were treated with 45-50Gy/25F using 3D-CRT or IMRT, and concomitantly with capecitabine-based chemotherapy every 3 weeks. Surgery was scheduled 6-8 weeks after completion of radiotherapy. Results: A total of 40 patients completed neoCRT and 33 patients (82.5%) received radical resection for the locally diseases, with R0 and R2 resection in 30 and 3 patients, respectively. Seven patients were assessed as unresectable after neoCRT and 3 of them received only colostomy while the other 4 continued chemotherapy. Pathological complete response was documented in 8 patients (20.0%). Multivisceral resection was necessary in 15 patients (36.6%). Among the 33 patients underwent curative surgery, bladder invasion was noticed at diagnosis in 17 patient and bladder function was preserved in all these patients, with full bladder preserving approach in 6 and partial cystectomy in 11 patients. Grade-2 post-operative complications were observed in 4 patients (10.0%) with no 30-day mortality. Median follow-up was 26 months. For all the patients, the 3-year overall survival, local progression-free survival and progression-free survival were 70.8%, 88.2%, 74.5%, respectively. Conclusions: NeoCRT is an effective strategy for the treatment of unresectable LAACC, with high R0 resection rate, satisfactory organ preservation, good local control and acceptable treatment toxicity. NeoCRT in LAACC is worthy of further clinical research.