tbuckley/cabot-search huggingface dataset:
A phase 1 study of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing docetaxel (DOC), in patients with refractory solid tumors.
Authors: Ben Markman, Paul L. De Souza, Elizabeth Claire Dees, Tara C. Gangadhar, Adam Cooper, Aflah Roohullah, Vishal Boolell, William Zamboni, Curran Murphy, Adrian Mario Senderowicz, HongWei Wang
Journal: Journal of Clinical Oncology (2016)

2526 Background: CRLX301 is an investigational NDC with DOC covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer designed to enhance delivery to tumor tissue. Preclinical studies of CRLX301 showed enhanced drug accumulation in tumor and greater tumor growth suppression in murine models compared to DOC. Methods: Patients (pt) with advanced solid tumors were treated with escalating doses of CRLX301 IV once every 21 days (Q3W). The first two cohorts were single pt cohorts and then adjusted to 3+3 design. Primary objective: MTD and/or RP2D. Secondary objectives: safety, anti-tumor activity and PK. Results: 20 pts were enrolled. All were evaluable for DLT. Prior lines of chemotherapy: median 3 (range 0 to 6); 8 pts had prior taxane therapy. Tumor types: cholangiocarcinoma (5), head and neck (3), lung (2) and others (10). All drug-related AEs were toxicities typically associated with DOC. The most common drug-related AEs (all grades) were fatigue (70%), infusion reaction (40%), nausea (35%), diarrhea (30%), neutropenia (30%), and peripheral neuropathy (20%). Most AEs were ≤ grade 2. Two DLTs, reversible grade 3 transaminases with grade 2 bilirubin ( < 3 d) and grade 4 febrile neutropenia ( < 3 d), were observed at 90 mg/m2. One gr3 and one gr4 infusion reactions were observed at 90 mg/m2; both resolved within 24 hours. Certain common AEs related to DOC, such as fluid retention, were not observed. MTD with Q3W dosing is 75 mg/m2. A pt with B-RAF mutant unknown primary and resistant to a prior B-Raf inhibitor had tumor shrinkage per CT and partial metabolic response per FDG-PET. Stable disease lasting ≥ 3 cycles was observed in 5 pts (max 15 cycles). Plasma PK compared to commercial DOC at equivalent dose of 75 mg/m2: increased Cmax (5 – 8 fold) and increased AUC (60 fold) of total DOC and 25 fold less peak concentrations but more prolonged exposures of released DOC. Conclusions: The data suggest CRLX301 has a predictable and acceptable safety profile with preliminary signs of anti-tumor activity and distinct PK compared to DOC. MTD/RP2D were established as 75 mg/m2 for Q3W dosing. Weekly dosing and expansion cohorts in selected tumor types are planned. Clinical trial information: NCT02380677.
TCT-417 Long-term mortality of patients undergoing transcatheter aortic valve replacement for bicuspid versus tricuspid aortic stenosis
Authors: Raymundo Quintana, Adrian DaSilva-DeAbreu, Uday Sandhu, Giovanni Davogustto, Ali Denktas, None Hani Jneid, David Paniagua
Journal: Journal of the American College of Cardiology (2018)
DNA repair mutations and treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) as hallmarks of distinct subgroups of metastatic castration resistant prostate cancer (mCRPC): Data from the West Coast Prostate Cancer Dream Team.
Authors: Rahul Raj Aggarwal, Paul Lloyd, Jiaoti Huang, Tomasz M. Beer, Li Zhang, George V. Thomas, Lawrence D. True, Joshi J. Alumkal, Verena Friedl, Alana Weinstein, Robert Evan Reiter, Matthew Rettig, Primo Lara, Martin Gleave, Adam Foye, Denise Playdle, Felix Y Feng, Kim N. Chi, Josh Stuart, Eric Jay Small
Journal: Journal of Clinical Oncology (2018)

5039 Background: Genomic alterations in DNA repair genes are present in approximately 20-30% of patients with mCRPC. t-SCNC may be increasing in prevalence and is associated with adverse clinical outcomes. Potential overlap between these two subsets of mCRPC was assessed. Methods: Eligible patients (pts) underwent a metastatic tumor core needle biopsy at one of 5 centers. Tumor tissue was sent for consensus pathology call (JH, GT, LT) and targeted next-generation DNA sequencing. Chi-square test was used to compare the frequency of genomic alterations in select DNA repair genes (BRCA1, BRCA2, ATM, CDK12, RAD51, PALB2, FANCA, CHEK2, MLH1, MSH2, MLH3, and MSH6) between tumors with versus those without small cell histology. Frozen tissue from the same metastatic tumor underwent RNA sequencing (RNA-seq). Pts were prospectively followed for overall survival (OS). Results: 119 consecutive biopsies with sufficient tumor to permit histologic assessment and targeted NGS were included, including 14 biopsies (13%) with t-SCNC. In the overall cohort, DNA repair mutations were present in 41 biopsies (34%). By histologic subtype, mutations were present in 40/105 (38%) of adenocarcinoma tumors vs. only 1 of 14 (7%) biopsies with t-SCNC histology (p = 0.047). In contrast, TP53 and/or RB1 loss were enriched in the t-SCNC cohort (83% vs. 34%, p = 0.0015). Unsupervised hierarchical analysis of the transcriptome identified small cell-enriched cluster of biopsies (N = 12) that were mutually exclusive of DNA repair mutations and enriched for E2F transcriptional targets on RNA-seq. The presence of t-SCNC histologic differentiation was associated with worse OS from date of mCRPC (median OS 44.5 vs. 36.6 months; log-rank p = 0.027); the presence of DNA repair mutations was not (p = 0.734). Conclusions: Tumors harboring DNA repair pathway mutations or t-SCNC differentiation may represent distinct disease subsets of mCRPC with differing clinical outcomes. Added together, the two subsets account for approximately 40% of mCRPC pts. Independent prospective validation of these findings is warranted. Clinical trial information: NCT02432001.
Evolution of induction chemotherapy in the pre- and post-taxane era for locally advanced laryngeal cancer: A National Cancer Data Base analysis.
Authors: Sagar Anil Patel, Muhammad M. Qureshi, Michael A. Dyer, Daniel N. Cagney, Minh Tam Truong
Journal: Journal of Clinical Oncology (2018)

e18080 Background: TAX-323/324 showed improved response rate and overall survival (OS) with the addition of docetaxel (T) to induction cisplatin/5-FU (PF) prior to radiotherapy (ICRT) for stage III/IV laryngeal cancer. However, concomitant chemoradiation (CCRT) is the predominant larynx-preserving (LP) technique based on trials comparing it to PF-only ICRT. This study evaluates ICRT vs. CCRT utilization and outcomes in the United States before and after publication of TAX-323/324. Methods: We identified 8,992 patients in the NCDB with stage III/IV laryngeal squamous cell carcinoma treated between 2003-2013 with either CCRT or ICRT. Treatment date was stratified by pre-taxane (2003-2007) and post-taxane (2008-2013) eras based on the publication date of TAX-323/324. Kaplan-Meier method was used to estimate overall survival (OS), and subgroups were compared using Cox regression modeling, adjusting for treatment facility type, age, gender, race, insurance status, tumor stage, and Charlson-Deyo comorbidity score. Results: Three-year OS for CCRT was 60% and 61.4% between 2004-2007 and 2008-2013, respectively (log-rank p= .16), while 3-year OS for ICRT was 63.9% and 63.6% between 2004-2007 and 2008-2013, respectively (p= .44). In both the pre- and post-taxane era, ICRT was associated with improved OS compared to CCRT (2004-2007: aHR 0.83, 95% CI 0.71-0.97, p= .02; 2008-2013: aHR 0.87, 95% CI 0.77-0.99, p= .04). However, while ICRT use increased in this cohort from 2004 (9%) to 2009 (13%), there has been a steady decline in its use since 2009 with only 7% of this cohort treated with ICRT in 2013. Moreover, ICRT use was not associated with stage in pre-taxane era but was significantly more likely to be used in T4 and N2-3 tumors in post-taxane era. Conclusions: In this population-based cohort, ICRT resulted in superior OS compared to CCRT for locally advanced laryngeal cancer, even in the pre-taxane era. However, there was no OS difference in patients treated with ICRT in 2004-2007 vs. 2008-2013, possibly due to more advanced tumors treated with ICRT in post-taxane era. Regardless, ICRT is a viable LP regimen that needs to be prospectively compared against CCRT using TPF induction regimen.
RNA sequencing for the detection of MET exon 14 skipping in specimens with splice-site mutations.
Authors: Parth Sitlani, Durga Prasad Cherukuri, Maya P Panjikaran, Dana Weiner, Francesca Fike, Yu Xia, Lauryn Keeler, Richard Tseng, Paris Petersen, Chris Scott, Gregory Sims, Jeffrey Falk, Armin Graber
Journal: Journal of Clinical Oncology (2018)

e24178 Background: MET exon 14 skipping is detected in 2%-4% of NSCLC and is known to confer increased sensitivity to MET inhibitors. Over 100 distinct DNA sequence variants have been identified that potentially result in MET exon 14 skipping. This variety of DNA alterations has led to incomplete characterization of individual mutations and their effects on splicing. Here we utilize an RNA-sequencing laboratory developed test (LDT) to determine the effect of distinct MET alterations on exon 14 skipping. Methods: FFPE specimens were selected which contain MET variants in close proximity to exon 14 with an emphasis on splice-site mutations. DNA mutation results were obtained from NexCourse Complete Multi-gene assay, a target capture-based NGS LDT. Library preparation for RNASeq was performed using Archer FusionPlex reagents with a custom set of target primers. After sequencing on a NextSeq 500, analysis was done using Archer Analysis Suite. Detected splice junctions were verified with STAR aligner with custom scripts. The results of RNASeq were confirmed by PCR using primers targeting exon 13 and 15 followed by gel electrophoresis on a TapeStation 2200. Results: Preliminary results showed that one mutation of the 5’ acceptor site of exon 14 did not cause exon 14 skipping. Three distinct mutations at the 3’ donor site of exon 14 did lead to exon 14 skipping. Two of these mutations also produced a transcript containing only partial deletion of exon 14. Furthermore, we identified a previously uncharacterized exon 14 mutation, distant from either splice site, which triggered full skipping of exon 14. Interestingly, we also identified a mutation at the 5’ acceptor site of exon 15, which caused both exon 14 skipping, and in a separate transcript, exon 15 skipping. Conclusions: Not all mutations detected in DNA near MET exon 14 are assured to cause exon 14 skipping. On the other hand, mutations distant from exon 14 splice sites may still lead to the deletion of the juxtamembrane region. Since response to MET inhibitors is linked to exon 14 skipping, an RNASeq assay that can detect an exon 14 skipping event is recommended over assays that only identify splice-site mutations.
Impact of location on survival in prostate cancer.
Authors: Edward Maldonado, Timothy Dean Malouff, Sydney Marsh, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2016)

e16590 Background: Geographic area is an aspect to consider when working to reduce health disparities. Differences in prostate cancer mortality, especially in the urban-rural continuum, have seldom been reported worldwide. This is the largest study thus far specific to prostate cancer that aims to determine if a survival difference exists for prostate cancer patients living in metropolitan, urban, or rural areas. Methods: 907,542 prostate cancer patients with adequate survival and location information from 2004-2013 were analyzed using the National Cancer Data Base. Counties were classified based on the 2013 USDA Economic Research Service. Metro was defined as population 250,000+, or if considered metro with size <250,000. Urban was defined as 2,500-200,000+, and rural was defined as <2,500 people. Kaplan-Meier curves were constructed and pairwise comparisons performed via log-rank test. Charlson/Deyo (CD) score tabulates 0, 1, or 2 comorbidities. Results: 83.5% lived in a metro area, 14.5% in an urban area, and 2.0% in a rural area, with no differences in mean age. Mean CD was 0.17 (metro) and 0.20 (urban, rural). Improved survival was found in metro vs. urban and metro vs. rural areas (p<0.05). Depending on stage, urban survival was decreased by 3 to 7 months compared to metro. Rural survival was decreased by 4 to 10 months compared to metro. No significant differences in survival were noted for stage IV regardless of location. All stages of prostate cancer showed no survival differences between urban vs. rural. Stage II survival was slightly increased relative to stage I, while stage IV had the worst mortality. Conclusions: Differences in prostate cancer mortality were observed amongst men with stage I, II, and III prostate cancer living in urban and rural areas when compared to metro. Documentation of such differences may help identify future research into factors contributing to the observed disparity in cancer mortality. Particularly, research into socioeconomic factors (i.e. access, specialist availability, education, treatment offered, attitudes toward treatment, etc.) may prove useful for those involved with cancer care and policy. Average survival in months based on location. Metro Urban Rural Stage I 112 109 107 Stage II 115 110 109 Stage III 105 98 95 Stage IV 46 43 42
Prognostic value of serum Cytokeratin19-2G2 in primary breast cancer patients.
Authors: Xiaoming Xie, Yana Kong, Shuqin Dai, Wanli Liu, Weidong Wei
Journal: Journal of Clinical Oncology (2012)

e11091 Background: Cytokeratin19-2G2, one of cytokeratin19 fragments, has been considered as one of the most sensitive tumor markers. However, no previous studies reported of CK19-2G2 in breast cancer. The purpose of our study is to evaluate the prognostic value of CK19-2G2 in primary breast cancer patients. Methods: This study included 249 primary breast cancer patients with stage 0-III, 81 healthy controls and 21 breast benign disease patients. Serum samples were conserved before surgery. CK19-2G2, CEA and CA153 were measured by chemiluminescent assay and ER, PR, CerbB2 were assessed by Immunohistochemistry assay. Results: Serum CK19-2G2 levels in breast cancer patients were significantly higher than that in healthy and benign controls (P &lt; 0.001). High serum CK19-2G2 levels (≥2 ng/mL) were associated with stage III (P &lt; 0.001), tumor size (≥2cm) (P &lt; 0.001), lymph node involvement (P &lt; 0.001), negative estrogen receptor (P = 0.005) and progesterone receptor status (P = 0.001). Multivariate analysis revealed that high serum CK19-2G2 level was an independent factor for relapse (P = 0.029) and death (P = 0.040) in primary breast cancer patients. Conclusions: High serum CK19-2G2 levels maybe considered as an independent indicator for prognosis in primary breast cancer.
Timeliness of adjuvant chemotherapy in patients with resected pancreatic cancer.
Authors: David Deng, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

e18038 Background: Timeliness of adjuvant chemotherapy is an important predictor of survival for patients with breast and colorectal cancer whereby long delays has been shown to detrimentally impact outcomes. The effects of adjuvant treatment timing remain largely unknown for early pancreatic cancer. This study aims to identify independent predictors of treatment timeliness and overall survival in this patient population. Methods: We conducted a retrospective, population-based analysis of 179 patients with resected pancreatic cancer who subsequently started adjuvant chemotherapy between 2008 and 2014 at any 1 of 6 cancer centers across British Columbia, Canada. Logistic regression was used to identify predictive factors for adjuvant chemotherapy timing. Prognostic factors for survival were ascertained using multivariate Cox proportional hazards models. Results: Our study cohort included 91 men (51%) and 88 women (49%). At time of diagnosis, 145 patients (81%) had nodal involvement and 107 patients (60%) had good ECOG performance status (ECOG 0-1). The median age of diagnosis was 67 (range 37-85) years. The median interval between surgery and start of adjuvant chemotherapy was 70 (range 19-46) days. Abnormal bilirubin was the only factor significantly correlated with delayed chemotherapy (OR, 3.89; 95% CI, 1.55-9.73; P = 0.004). Median overall survival was 468 days following resection (95% CI, 425-538). Multivariate survival analysis showed that high CA 19-9 levels (HR, 2.44, 95% CI: 1.36-4.40, P = 0.003) and abnormal bilirubin (HR, 0.40; 95% CI, 0.22-0.73; P = 0.003) were prognostic factors for overall survival. Median survival for patients who waited up to 35, 70 or 105 days for chemotherapy following resection were 588 days (95% CI, 270-776), 490 days (95% CI, 360-688) and 466 days (95% CI, 432-538) respectively. Overall, timeliness was not predictive of survival (HR, 1.12; 95% CI, 0.64-1.97; P= 0.70). Conclusions: Patients with hyperbilirubinema experienced delays in adjuvant chemotherapy, likely due to the need for relief of biliary obstruction and subsequent recovery. However, timeliness of adjuvant chemotherapy did not influence outcomes, suggesting that treatment should still be considered irrespective of timing.
Abstract 15337: The Development of Cryo-Vetrification Method in Human Myoblast Cell Sheet for Propagation of Regeneration Therapy
Authors: Hirotatsu Ohkawara, Shigeru Miyagawa, Satsuki Fukushima, Atsuhiro Saito, Yoshiki Sawa
Journal: Circulation (2016)

Introduction: Although tissue engineered cardiac construct have some impacts on the functional recovery in heart failure, how to preserve tissue engineered cardiac constructs may be crucial for ind...
Cost-effectiveness analysis of aprepitant in Japanese patients who received high-dose cisplatin.
Authors: Ikuto Tsukiyama, Shiori Hasegawa, Yoshiaki Ikeda, Masayuki Takeuchi, Sumiyo Tsukiyama, Masaki Sakuma, Yusuke Kurose, Masayuki Ejiri, Ichiro Arakawa, Tadao Inoue, Hiroko Saito, Etsuro Yamaguchi, Akihito Kubo
Journal: Journal of Clinical Oncology (2018)

e18924 Background: Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse event in cancer chemotherapy. Aprepitant, in combination with a serotonin receptor antagonist and dexamethasone, is effective in preventing CINV. The objective of this study was to define, from the perspective of the Japanese National Health Insurance system, the cost-effectiveness of aprepitant for patients receiving high-dose cisplatin. Methods: We developed a decision analytic model based on the results of a phase II randomized clinical trial comparing aprepitant containing three-drug regimen versus non-aprepitant two drug regimen on Japanese patients who received cisplatin-containing highly emetogenic chemotherapy. Resource use data were based on the randomized clinical trial and routine clinical practice. Incremental cost effectiveness ratio (ICER) was calculated both in the outpatient care setting (OCS) and in the inpatient care setting (ICS). Deterministic and probabilistic sensitivity analysis addressed uncertainty in model parameters. Results: The use of aprepitant-containing regimen was associated with improved quality-adjusted-life-years (QALYs) compared with non-aprepitant regimen, with an increment in QALY of 0.0016. The incremental total medical costs associated with the use of aprepitant regimen compared with non-aprepitant regimen in OCS and ICS were 58.12 USD (6,323 JPY) and 91.12 USD (9,913 JPY), respectively. ICER was calculated as 36,671 USD (3,906,697 JPY) per QALY gained in OCS and 57,545 USD (6,195,781 JPY) per QALY gained in ICS. Considering the threshold of willingness to pay commonly accepted (50,000 USD in the US and 5 million JPY (45,960 USD) in Japan), the cost-effectiveness of the aprepitant-containing antiemetic therapy was limited in OCS. The cost of aprepitant was offset when aprepitant containing antiemetic therapy effectively prevented CINV and reduced rescue therapies, especially in OCS in which costs for rescue medications, revisiting clinics or re-hospitalization were high. Conclusions: The aprepitant containing prophylactic antiemetic therapy was cost-effective in OCS, not in ICS, in patients who received high-dose cisplatin in the Japanese health care system.
Incidence of abnormal HER2 values in the serum of breast cancer patients: influence of disease stage and HER2 status.
Authors: Annegret Barbara Quade, Susanne Herz, Jutta Anna Kurbacher, Gustav Quade, Carsten Bartling, Gabriele Wessling, Katja Monreal, Annegret Quade, Christian M. Kurbacher
Journal: Journal of Clinical Oncology (2016)

e23053 Background: This translational study sought to elucidate the incidence of abnormal sHER2 values in a real-world population of breast cancer (BC) patients (pts) with primary and recurrent disease. Methods: 4050 sera from 218 BC pts were analyzed (median: 13 per pt) using a commercial chemiluminescence assay (Siemens Healthcare, Eschborn, Germany) with 15.2 ng/mL defined as the upper normal threshold. 83 pts presented with HER2+ disease and 135 pts were HER2-. Among HER2+ pts, 48 (57.8%) were diagnosed with primary BC (PBC) and 35 (42.2%) with local or distant recurrences (LDR). In the HER2- group, the corresponding numbers were: PBC, n = 80 (59.3%); LDR, n = 55 (40.7%). In both groups, the proportions of pts with normal (0% pathological sHER2 values), moderately abnormal (1-50% pathological sHER2 values), and highly abnormal ( > 50% pathological sHER2 values) sHER2 expression were compared by using Chi-square tests as were differences between PBC and RLC pts within both groups. Results: Among HER2+ pts with PBC, 32 (66.7%) showed normal, 14 (29.2%) showed moderately abnormal and 2 (4.2%) showed highly abnormal sHER2 expression. The corresponding results in HER2+ pts with LDR were: normal, 7 (20.0%); moderately abnormal, 18 (51.4%); highly abnormal, 10 (28.6%). Among HER2- pts with PBC, 64 (80.0%) had normal, 12 (15.0%) had moderately, and 4 (5.0%) had highly abnormal sHER2 expression. The corresponding results for sHER2 expression in pts with HER2- LDR were: normal, 16 (29.1%); moderately abnormal, 22 (40.0%); highly abnormal, 17 (30.9%), Differences in sHER2 expression between PBC and LDR were highly significant in both HER2+ and HER2- pts (p < 0.0001). In contrast, differences in sHER2 expression between HER2+ and HER2- patients with either PBC or LDR all lacked statistical significance. Conclusions: Our results show that sHER2 should not be used as a substitute of HER2 determination in tissue. However, the high incidence of abnormal sHER2 in all LDR argues in favor of the presence of HER2+ subpopulations of BC cells in many of these pts, irrespectively of their HER2 status. sHER2 should thus seriously considered as an additional parameter to be used for both diagnosis and treatment decisions in BC pts with LDR.