tbuckley/cabot-search huggingface dataset:
Combination of local ablation and chemotherapy for intrahepatic cholangiocarcinoma: Survival trends from the National Cancer Database.
Authors: Johannes Uhlig, Cortlandt Sellers, Stacey Stein, Jill Lacy, Hyun S. "Kevin" Kim
Journal: Journal of Clinical Oncology (2018)

e16150 Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common intrahepatic malignancy. Local ablation can be implemented for both primary and metastatic intrahepatic tumors. To date, there is no population level evidence on the benefit of local ablation in addition to chemotherapy for ICC. Methods: Patients with primary ICC treated with chemotherapy and local ablation + chemotherapy were retrospectively identified from the 2003-2015 National Cancer Database. Demographic factors were compared between treatment groups. Patients were 1:1 matched based on their propensity to receive combination therapy. Overall survival was compared in the matched cohort. Results: Of 18,343 patients diagnosed with ICC, 7,462 (41%) received chemotherapy, and 108 additional local ablation. A higher likelihood of treatment via local ablation + chemotherapy was observed for patients with less comorbidities, lower tumor stage and those treated at academic centers. The propensity score matched cohort comprised 90 patients in each treatment group with balanced distribution of baseline variables and tumor factors, including tumor stage and grade. In the matched cohort, treatment via local ablation + chemotherapy was associated with an increase in overall survival compared to chemotherapy alone (HR = 0.6659, 95% CI: 0.4835-0.917, p = 0.013). Median overall survival was higher for patients treated via ablation + chemotherapy (20.5 months) versus chemotherapy (12.5 months). Conclusions: A relevant proportion of ICC patients does not undergo resection of the primary tumor. In these patients, combination of local ablation and chemotherapy yields superior survival compared to chemotherapy alone. Our results warrant prospective studies to optimize treatment approaches in surgically ineligible ICC patients.
Accuracy of ultrasound in the diagnosis of cervical lymph node metastasis in esophageal cancer: A meta-analysis.
Authors: Xue-Feng Leng, Yi Zhu, Ge-Ping Wang, Jian Jin, Lei Xian, Yu-Hong Zhang
Journal: Journal of Clinical Oncology (2016)

e15502 Background: Esophageal cancer is considered a serious malignancy with respect to the prognosis and mortality rate. Cervical lymph node (CLN) status is one of the keys to determine prognosis and treatment methods. However, published data on the accuracy of ultrasound in the diagnosis of CLN metastasis has varied. We performed a meta-analysis to assess the accuracy of ultrasound for detecting CLN metastasis in esophageal cancer patients. Methods: PubMed/MEDLINE, EMBASE, Web of science, Cochrane Library databases were searched, and 22 studies comprising 3513 patients met our inclusion criteria. We used a bivariate meta-analysis following a random effects model to summarize the data and plotted summary receiver operating characteristic (SROC) curves as well as hierarchical summary receiver operation characteristic (HSROC) curves. The area under the curve (AUC) serves as an indicator of the diagnostic accuracy. The heterogeneity of studies was explored by meta-regression, subgroup and sensitivity analyses. Publication bias was assessed with Deeks funnel plot. Results: The area under the receiver operating characteristic curve (AUROC) was 0.97 (95% CI: 0.95-0.98), and pooled diagnostic odds ratio (DOR) was 121.00 (95% CI: 47.57-307.79). The diagnostic threshold analysis showed that there was no threshold effect. The meta-regression and subgroup analysis suggested the cut-off value is the main source of heterogeneity. With the cut-off values of 5 mm and > 5mm for CLN size, the sensitivity and specificity (95%CI) for ultrasound detection of the CLN metastasis were 84% (67%-93%) and 93% (90%-95%), and 94%(76%-98%) and 98% (89%-100%), respectively. Deeks’ funnel plot showed there was no existence of publication bias. Conclusions: We evidenced for the first time that the diagnostic efficacy for predicting CLNs positive-metastasis in esophageal cancer with ultrasound. Our analysis showed that ultrasonography may provide an effective and reliable approach to detect CLN metastasis in esophageal cancer. However, to accommodate heterogeneity, high-quality studies are needed to further verify the efficacy of ultrasound detection.
Impact of post-autologous stem cell transplant (ASCT) maintenance therapy on outcomes in patients (Pts) with newly diagnosed multiple myeloma (NDMM) using the large prospective community-based Connect MM registry.
Authors: Sundar Jagannath, Rafat Abonour, Brian G. Durie, Jatin J. Shah, Mohit Narang, Howard R. Terebelo, Cristina Gasparetto, Kathleen Toomey, James W. Hardin, Lynne I. Wagner, Amit Agarwal, Shankar Srinivasan, Amani Kitali, Faiza Zafar, Michael Sturniolo, Robert M. Rifkin
Journal: Journal of Clinical Oncology (2017)

8040 Background: Maintenance therapy (MT) improved progression-free survival (PFS) and overall survival (OS) in MM clinical trials. The observational Connect MM registry, which is largely community based, was used to assess impact of MT on outcomes in ASCT-eligible NDMM pts. Methods: Adult NDMM pts ≤60 days from diagnosis were eligible for enrollment. Pts receiving induction and ASCT were included and analyzed by 4 MT regimens: No MT, lenalidomide-based (LEN), bortezomib-based (BORT), and LEN+BORT MT. Duration was from 100 days post-ASCT (no MT group) or start of MT until progressive disease, death, discontinuation, or data cutoff. End points were PFS, 2 nd PFS, OS, and safety. An exploratory analysis of the impact of baseline characteristics was performed. Results: Of 1493 enrolled pts (Cohort 1; Sep 2009 – Dec 2011), 1450 were treated; 81% (n=1173) were in a community setting. A total of 432 (29%) met analysis criteria. Data cutoff was Jan 7, 2016 (median follow-up of 39.3 mo). Median age was 60 y (range, 24-78 y); 60%, men; and 86%, white. 165 pts did not receive MT. Of 267 pts receiving MT, 213 (80%) received LEN; 30 (11%), BORT; and 16 (6%), LEN+BORT. Only LEN MT is presented, as interpretation of other MT data was limited by small sample sizes. Median treatment duration for LEN MT vs No MT was 35.2 vs 26.1 mo, respectively. PFS and OS significantly increased with LEN MT vs No MT (Table); 2 nd PFS was similar for both. Exploratory analyses showed generally similar PFS and OS improvements across subgroups (age, ECOG status, ISS stage, risk group, and induction regimen). No new safety signals were observed. Conclusions: In ASCT-eligible NDMM pts, PFS and OS improved with LEN MT vs No MT and appeared to be independent of induction regimen. Preliminary analysis of 2 nd PFS suggests no impact on the efficacy of 2 nd line therapy. These data from a largely community-based setting confirm results from randomized phase III trials. Clinical trial information: NCT01081028. [Table: see text]
Simultaneous molecular alterations in solid tumors with <i>IDH1</i> or <i>IDH2</i> mutations.
Authors: Filip Janku, John Frederick De Groot, Milind M. Javle, Marta Penas-Prado, Rachna T. Shroff, Rajyalakshmi Luthra, Kimberly Banks, Richard B. Lanman, Anthony Paul Conley, Russell Broaddus, Michael A. Davies, Scott Kopetz, W. K. Alfred Yung, John Heymach, Siqing Fu, Kenna Rael Shaw, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2017)

11609 Background: Somatic mutations in IDH1 or IDH2 genes are prevalent in diverse solid tumors and implicated in tumorigenesis. Therapeutic responses to IDH inhibitors are infrequent plausibly due to presence of simultaneous alterations activating compensatory molecular pathways. Methods: We retrospectively reviewed results from clinical genomic profiling with targeted next-generation sequencing in two independent data sets of archival formalin-fixed paraffin-embedded (FFPE) tumor samples (Ion Torrent &lt; 50 genes, 300; FoundationOne &lt; 343 genes, 30; Oncomine 128 genes, 4) and plasma liquid biopsies (Guardant360 &lt; 73 genes panel, 337 samples) from patients with solid tumors of all stages. Results: In 334 FFPE samples the most represented cancers were gliomas (50%), melanomas (14%), cholangiocarcinomas (11%), and non-small cell lung cancer (NSCLC, 6%). In 296 IDH1-mutated FFPE samples the most frequent simultaneous alterations were in TP53 (45%), BRAF (11%), KRAS (9%), and PIK3CA (26, 9%). In the most represented IDH1-mutated tumor types commonly altered genes were TP53 (66%) in gliomas, BRAF (53% [V600K/R 30%, V600E 19%]) in melanomas, PIK3CA (13%), CDKN2A (13%) in cholangiocarcinomas and KRAS (65%) in NSCLC. In 38 IDH2-mutated FFPE samples the most frequent simultaneous alterations were in TP53 (32%), and KRAS (16%). In 337 plasma samples the most represented cancers were NSCLC (39%), cholangiocarcinoma (13%), and breast cancer (8%). In 172 IDH1-mutated plasma samples the most frequent simultaneous alterations were in TP53 (40%), KRAS (23%), EGFR (16%) and BRAF (16%). In the most represented IDH1-mutated tumors commonly altered genes were TP53 (48%), KRAS (37%) in NSCLC and TP53 (37%), KRAS (24%), BRAF (18%) in cholangiocarcinoma. In 161 IDH2-mutated plasma samples the most frequent simultaneous alterations were in TP53 (43%), EGFR (20%), and KRAS (19%). In the most represented IDH2-mutated tumors commonly altered genes were TP53 (43%), EGFR (32%), KRAS (18%) in NSCLC and TP53 (18%), ESR1 (18%), KRAS (18%) in breast cancer. There were 4 tumors with IDH1 and IDH2mutations. Conclusions: IDH1 and IDH2 mutations often coexist with simultaneous oncogenic alterations including these in potentially druggable molecular targets.
Impact of adjuvant chemotherapy in non-metastatic node positive bronchial neuroendocrine tumors (BNET).
Authors: Gustavo Figueiredo Marcondes Westin, Samer Alsidawi, Konstantinos Leventakos, Thorvardur Ragnar Halfdanarson, Julian R. Molina
Journal: Journal of Clinical Oncology (2017)

8533 Background: BNET are a rare and frequently indolent group of neoplasms. Lobectomy is frequently done for patients with non-metastatic disease, and the role of adjuvant chemotherapy for patients with node positive disease (N+) is debated. Methods: Utilizing the National Cancer Database from 2004-2012 we identified 1682 patients with N+ non-metastatic BNET. All patients underwent primary resection, had pathologically confirmed diagnosis, complete follow up data, and were alive &gt; 30 days following surgery. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used to compare 2 groups of patients that differed based on receiving or not adjuvant chemotherapy. Subgroup analyses were performed based on histologic subtypes. Cox proportional hazards was performed to control for age, sex, race, grade, surgical margins, type of surgery, year of diagnosis, Charlson/Deyo Score, insurance, facility type, and location. Results: 651 patients with typical carcinoid (CT), 239 atypical carcinoid (ACT), 426 large cell neuroendocrine carcinoma (LCNEC), and 366 neuroendocrine carcinoma (NEC) were analyzed. The cohort median age was 61, and the female:male ratio was 1.8 for CT, ACT and NEC, and 1 for LCNEC 90% of patients were White and there were no significant differences amongst histologic subtypes. 6% of patients with CT received ADJ-CT, compared to 40% ACT, 42% NEC, and 70% LCNEC. In a multivariate analysis, only increasing age was associated with worse prognosis across all histologic subtypes, and non-academic facility for CT, and male sex for NEC. ADJ-CT was not associated with OS benefit for patients with ACT (HR 1.1; 95% CI 0.68-1.78; p:0.6), was associated with inferior OS in CT (HR: 3.8 (95% CI 1.9-7.0; p = 0.004) and NEC (HR: 2.15; 95% CI 1.5-3.0; p &lt; 0.001), and may provide benefit for LCNEC (HR: 0.67; 95% CI 0.5-0.9; p = 0.009). Conclusions: Adjuvant chemotherapy was not associated with survival benefit for patients with node positive and non-metastatic BNET except for LCNEC, and may be harmful for patients with CT and NEC.
PAK4 as a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC).
Authors: Kiruthikah Thillai, Debashis Sarker, Claire Wells
Journal: Journal of Clinical Oncology (2017)

e23139 Background: PDAC is an aggressive cancer and metastatic spread requires reorganization of the actin cytoskeleton, a process dependent on Rho family GTPases and their interaction with downstream effectors. p21 activated kinases (PAK1-6) are effectors of Rho GTPases Cdc42 and Rac, and play a key role in cell migration and survival. PAK4 can be amplified in PDAC and can reciprocally activate the PI3K pathway. Hepatocyte growth factor (HGF), via c-Met, is an established activator of PAK4 and the PI3K pathway and may promote PDAC invasion. We hypothesized that there is a link between PAK4 and PI3K downstream of HGF and thus PAK4 is a potential therapeutic target in PDAC. Methods: Several invasive PDAC cell lines were used including PaTu 8988T, PaTu 8988S, Capan 1, Panc 1 and PaTu 8902. SiRNA transfection allowed transient loss of PAK4 and cell migration was measured using 2D time lapse microscopy. An organotypic model consisting of PDAC and stromal cells within an extracellular gel of collagen was developed to assess 3D invasion. Immunofluorescence staining of cytokeratin and smooth muscle actin allowed analysis of depth of invasion. Protein expression was measured using western blotting and protein interaction by pulldown assays. Results: Treatment with the c-Met ligand HGF increased migration speed, persistence of direction and importantly PDAC invasion. HGF also stimulated the phosphorylation of several proteins within the PI3K pathway including AKT and PRAS40. Loss of PAK4 expression resulted in a concomitant loss in PI3K signalling. Moreover, PAK4 directly binds to the p85α subunit of PI3K in PDAC cells. Reduced PAK4 expression in PDAC cells suppressed HGF-induced migration, and PAK4 depletion significantly inhibited the invasion response to HGF. Conclusions: We demonstrate a novel link between PAK4, PI3K and AKT, and show the significant effects of PAK4 on PDAC cell polarity, migration and invasion. Our results strongly support further investigation of PAK4 as a therapeutic target in PDAC, particularly given the minimal impact of PI3K-AKT pathway inhibitors in PDAC to date.
Abstract 12882: Monotherapy With Bendavia (MTP-131), a Novel Mitochondria-Targeting Peptide, Normalizes H11 Kinase Protein Levels in Nuclear and Mitochondrial Fractions of Left Ventricular Myocardium of Dogs With Advanced Heart Failure
Authors: Ramesh C Gupta, Kristina Szekely, Mengjun Wang, Kefei Zhang, Vinita Singh-Gupta, Hani N Sabbah
Journal: Circulation (2014)

Introduction: The heat shock protein H11 kinase (H11K) is expressed in the heart and rapidly increases in response to increased cardiac workload. Deletion of H11K accelerates LV dysfunction and rem...
Cardiac death rates after irradiation for esophageal cancer: An epidemiologic study among esophageal cancer survivors.
Authors: Remco Jurriaan Molenaar, Tomas Radivoyevitch, Maarten Hulshof, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2017)

4049 Background: Esophageal cancer is frequently treated with radiation in addition to surgery and/or chemotherapy. Long-term survivors that received radiation may be at risk for radiation-induced cardiotoxicity. Methods: Esophageal cancer survivors (defined as surviving &gt; 5 yrs after diagnosis) from all 18 Surveillance Epidemiology and End Results (SEER) registries from 1973 to 2013 were queried for irradiation status, cause of death and survival using SEERaBomb, a package for the R statistical programming language. Results: 6,514 esophageal cancer survivors were identified, of whom 2,892 (44%) received no radiation therapy and 3,448 (53%) received external beam radiotherapy. Mean age at the time of esophageal cancer diagnosis was 64.0 yrs in the no radiation group and 63.0 yrs in the radiation group. Median person years of follow up after esophageal cancer diagnosis was 8.6 yrs (interquartile range [IQR]: 7-12) in pts receiving no radiation and 7.9 yrs (6-11) in pts receiving radiation. A total of 590 esophageal cancer survivors died of cardiac disease; 254 received no radiation and 336 did receive radiation. Median time to cardiac death after esophageal cancer diagnosis was 32.2 yrs (IQR: 19-38) in pts that received no radiation and 25.3 years (15-30) in pts that received radiation (log-rank P&lt; 0.001). Compared with unirradiated pts, irradiated pts had an increased risk of dying of cardiac disease (hazard ratio [HR] = 1.47; 95% confidence interval [CI]: 1.2-1.7, Cox regression P&lt; 0.001). The association between radiation and cardiac death was the strongest in esophageal cancer pts diagnosed before 1995 (HR = 1.75; 95% CI: 1.4-2.2, P&lt; 0.001) and in squamous cell carcinoma of the esophagus (HR = 1.9; 95% CI: 1.4-2.6, P&lt; 0.001) but not in adenocarcinoma (HR = 1.04; 95% CI: 0.8-1.4, P= 0.8). Conclusions: 5-year esophageal cancer survivors that were treated with radiotherapy have an increased risk of dying of cardiac disease, compared with unirradiated counterparts. This association was strongest in pts treated before 1995 and in squamous cell carcinoma pts. This may be due to late radiation-induced cardiotoxicity, decreasing with the use of heart-sparing radiation techniques after 1995.
TCT-319 Clinical Characteristics and Vascular Complications in Patients Undergoing Transcatheter Aortic Valve Replacement and Percutaneous Coronary Interventions
Authors: Shawn Reginauld, Arnav Kumar, Norihiko Kamioka, Stamatios Lerakis, Altayyeb Yousef, Patrick Gleason, Bradley Leshnower, Chandan Devireddy, Kreton Mavromatis, James Stewart, Peter Block, Robert Guyton, Vasilis Babaliaros
Journal: Journal of the American College of Cardiology (2018)
What do oncologists think patients with incurable cancer should be told about their prognosis? A survey of medical oncologists in Australia and New Zealand.
Authors: Anuradha Vasista, Martin R. Stockler, Andrew James Martin, Nicola Jane Lawrence, Belinda E. Kiely
Journal: Journal of Clinical Oncology (2018)

e22139 Background: We aimed to determine the attitudes of oncologists regarding their discussions about prognosis with patients with incurable cancer. Methods: We conducted an online survey of medical oncologists and oncology trainees in Australia and New Zealand. Factors associated with providing a numerical survival estimate were assessed using Cox models. Results: 206 medical oncologists and trainees completed the survey (response rate 30%). Respondent characteristics were: median age 40 years (range 27 to 75); male 51%; trainees 22%; and 71% had completed prognosis communication training. Respondents reported seeing a median of 4 new patients per week (interquartile range (IQR) 3 to 5) and discussing expected survival time with a patient a median of 10 times per month (IQR 4 to 15). 82% were always or usually satisfied with their discussions about prognosis. While 88% reported explaining the cancer is incurable to ‘all’ their patients with incurable cancer and 84% reported ‘always’ or ‘usually’ providing a quantitative estimate of survival time; only 27% provided a numerical estimate. Female gender was associated with providing a numerical estimate (OR = 2.3, CI = 1.2 to 4.5, p < 0.0001). The most preferred methods of explaining survival time were providing: “multiple ranges of time with probabilities, e.g. best-case, typical, worst-case scenarios” (52%) and “a range of units of time without numbers e.g. ‘weeks to months’” (22%). ‘Family members requesting that prognostic information not be discussed’ was identified as a major or moderate barrier to discussions about prognosis by 57% and ‘not knowing the expected survival time’ by 46%. 60% of respondents reported always or usually documenting discussions about expected survival time in the patients’ medical record and 49% in letters to other doctors. Conclusions: Almost all respondents reported telling their patients that their cancer is incurable, however only 27% provided a numerical survival estimate. Barriers to providing a numerical estimate were not knowing the expected survival time and family members requesting that this be withheld from the patient.
Phase Ib pharmacokinetics of non-hormonal SM88 in patients with non-metastatic recurrent prostate cancer.
Authors: Giuseppe Del Priore, John Rothman, Gerald H. Sokol, Karen Hoffman, Avi S. Retter, Steve Hoffman
Journal: Journal of Clinical Oncology (2017)

e14061 Background: SM88 is a combination of tyrosine isomers ( TI) and repurposed drugs (modulators of CYP3A4, mTOR, and oxidative stress). This regimen has previously reported non-toxic activity in cancers including prostate (PC) ( J Clin Oncol 2013 31: e22095). We present summary data from a completed Ib trial of non-metastatic recurrent PC (nmPC), an ideal candidate for a well-tolerated, non-androgen based treatment. Methods: This was an open-label safety and PK trial of SM88 in patients with nmPC. Cohort 1 received 230 and cohort 2 - 460 mg/day of TI, along with the lowest available doses of the other 3 agents. Multiple samples were drawn at pre-dose and up to 48 h post dosing from 4 patients after a single TI dose; after a single dose of all 4 components; and after 2 weeks of steady state daily combined dosing (SS). Only cohort 2 results are presented. Results: See table below. Each of the 3 approved drugs had expected PK results that will be provided. There was no evidence that the combination altered the expected PKs at SS. There were no serious drug related adverse events. Favorable biomarker activity was documented at both TI dose levels. Conclusions: Single dose and SS TI results from this completed phase Ib trial are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (suppl_6): 1605P). TI PK results changed transiently with the additional components but returned to desirable levels at SS including a higher Cmax, AUC, and more rapid Tmax, indicating rapid absorption. The PK results (not shown) are consistent with the published data for the approved agents, despite the use of lower than typical label doses. Based on these results, the higher TI dose was chosen for the ongoing phase II expansion cohort in nmPC patients. SM-88 appears to have predictable PK as an effective metabolomic regimen for the treatment of advanced prostate cancer devoid of significant toxicities. [Table: see text]