tbuckley/cabot-search huggingface dataset:
The genetic profiles of esophageal squamous cell carcinoma (ESCC) in Hebei, a northern province of China.
Authors: Jing Zuo, Yimeng Jia, Yudong Wang, Zhisong Fan, Long Wang, Yu Su, Fengling Liu, Da Jiang
Journal: Journal of Clinical Oncology (2019)

e15558 Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Methods: DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections from 29 ESCC samples. A panel of 520 genes was sequenced with NGS to identify genomic alterations at an average sequencing depth of 1000×. Results: In total, 421 genomic alterations were identified. We identified 230 single nucleotide variants (SNVs) and 35 insertions and deletions (indels) , 147 CNAs, 9 deletions and 0 translocations. The most frequently mutated genes were TP53 (97%), NOTCH1 (31%), CDKN2A (21%), NFKBIA (21%). Most frequent CN gains were observed in FGF3/4/19/CCND1(41%) which were co-occurrence in cBioPortal.By performing targeted NGS in 29 ESCC samples, we found a median TMB of 5.6/Mb (range: 0.8 to 42.9/Mb).TMB-high was located according to TMB &gt; = 10, where 17.2% of the samples were TMB-H.C·G &gt; T·A transversions were the most common mutations, followed by G·C &gt; A·T transitions,The patients with NFKBIA mutation were all significantly older (p = 0.05), and the patients with FGF3/4/19/CCND1 amplification were mostly moderately differentiated, and the patients without high differentiation, suggesting a higher degree of malignancy (p = 0.03). CDKN2A, FGF3/4/19/CCND1 amplification, and NFKBIA mutated were associated with a smaller invasion depth, respectively (p = 0,p = 0.03,p = 0.05). Patients with wild type KMT2D had earlier stage, and all N0 stages were wild type for KMT2D (p = 0.03).Notably, high activity of DNA damage,Cell cycle and Notch signaling pathway might be particularly promising strategies for ESCC.In potential therapeutic target analysis, CDKN2A(20.7%) and PIK3CA (13.8%) were the validated and candidate therapeutic targeted genes. Conclusions: Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.
A randomized, double-blind, placebo-controlled phase Ib/II study of ralimetinib, a p38 MAPK inhibitor, plus gemcitabine (G) and carboplatin (C) versus GC for women with recurrent platinum-sensitive ovarian cancer.
Authors: Ignace Vergote, Florian Heitz, Paul Buderath, Matthew A. Powell, Jalid Sehouli, Christine M. Lee, Anne L. Hamilton, James Fiorica, Kathleen N. Moore, Michael Teneriello, Lisa Golden, Wei Zhang, Celine Pitou, Daphne L. Farrington, Katherine M Bell-McGuinn, Robert Michael Wenham
Journal: Journal of Clinical Oncology (2019)

5537 Background: p38 mitogen-activated protein kinase (MAPK) regulates cytokine production in the tumor microenvironment and enables therapeutic resistance of cancer cells. Ralimetinib (R) is a selective small-molecule inhibitor of p38α and p38β MAPKs. Methods: Main inclusion criteria: ≥18 y; recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal, cancer after first-line treatment. Phase (Ph)1b was to determine the recommended Ph2 dose (RP2D) of R administered 12-hourly (Q12H) on Days 1-10 (21-day cycle [Q21D]) in combination with gemcitabine (G: 1000 mg/m 2 on Days 3 and 10) and carboplatin (C: AUC 4 on Day 3) for 6 cycles. In Ph2, patients (pts) were randomized double-blind, 1:1 to RP2D R+GC or placebo (P)+GC, for 6 cycles, followed by R 300 mg Q12H or P on Days 1-14, Q28D until disease progression. The stratified log-rank test compared progression-free survival (PFS; primary endpoint) between treatment groups in Ph2, at a 1-sided α level of 0.2. ClinicalTrials.gov, NCT01663857. Results: 118 pts received ≥1 dose of R or P (safety population); 8 in Ph1b and 110 in Ph2 (R+GC N = 58; P+GC N = 52). The RP2D for R in combination with GC was 200 mg Q12H. The study met its primary objective (median PFS: R+GC 10.3 mo vs P+GC 7.9 mo; HR = 0.773, 2-sided p = 0.246). The secondary objectives of median overall survival (R+GC 29.2 mo vs P+GC 25.1 mo; HR = 0.827, p = 0.469) or overall response rate (R+GC 46.6% vs P+GC 46.2%; p = 0.967) were not statistically significant, and 32.4% vs 25.0% of pts had normalized CA125 at the end of cycle 6. Most pts (safety population) experienced ≥1 Grade 3/4 treatment-emergent adverse event (TEAE: R+GC 63/66 [95.5%]; P+GC 48/52 [92.3%]). Decreased neutrophil count (60.6% vs 76.9%), platelet count (43.9% vs 38.5%), and white blood cell count, (30.3% vs 26.9%), anemia (22.7% vs 25.0%), and increased alanine aminotransferase (ALT) (19.7% vs 3.8%) were the Grade 3/4 TEAEs in ≥10% of pts in the R+GC and P+GC arms, respectively. Conclusions: Addition of ralimetinib to GC resulted in modest improvements in PFS. Grade 3/4 elevated ALT was more common in the ralimetinib arm. Clinical trial information: NCT01663857.
Preclinical studies evaluate pivotal TNFα nanomedicine clinical trial design.
Authors: Naris Nilubol, David Oarr, Lawrence Tamarkin
Journal: Journal of Clinical Oncology (2019)

e14646 Background: The clinically-tested CYT-6091 nanomedicine is comprised of TNF alpha (TNF) bound to 27 nm pegylated gold nanoparticles. Preclinical research has shown that CYT-6091 disrupts solid tumor blood vessels, reduces interstitial fluid pressure and increases accumulation of follow-on chemotherapy in the tumor microenvironment. While systemic toxicity has limited treatment of cancer patients with TNF, isolated limb perfusion of patients with in-transit melanoma using 1-4 mg of TNF followed by chemotherapy has demonstrated up to 90% complete response rates with one treatment. In a single-agent, phase I clinical study in advanced-stage cancer patients, we found that multiple CYT-6091 treatments can systemically and safely deliver up to 1.2 mg of TNF per dose. Methods: Our current research was conducted to validate administering CYT-6091 prior to standard-of-care chemotherapy in a phase II clinical trial. As part of the NCI’s Experimental Therapeutics (NExT) evaluation, CYT-6091 was studied in combination with paclitaxel (PTX) in C57BL/6 murine xenografts, using three cancer cell lines: MC-38 colon carcinoma (cancer cells sensitive to TNF, but insensitive to PTX), B16/F10 melanoma (cancer cells insensitive to TNF, but sensitive to PTX), Lewis lung carcinoma (cancer cells insensitive to both TNF and PTX), where sensitivity was based on inhibiting cancer cell growth at the studied dosing amounts and frequency. CYT-6091 was administered 3-hours before PTX, and three PTX doses were administered in each model. Results: In every model, CYT-6091 + any dose of PTX was more effective in reducing or controlling tumor growth than the highest dose of PTX alone (p &lt; 0.01). Interestingly, we also found that CYT-6091 alone demonstrated significant anti-cancer activity (p &lt; 0.01), suggesting that additional studies may be warranted to determine optimal frequency and dose of CYT-6091 as a single agent. Conclusions: These preclinical studies demonstrate for the first time that CYT-6091 + PTX was superior to PTX (p &lt; 0.01) or CYT-6091 alone (P &lt; 0.05) in TNF insensitive cell lines, which represent the majority of cancers. Findings support systemically administering CYT-6091 plus standard-of-care chemotherapy in a pivotal clinical trial.
Cost-effectiveness analysis of chemoradiation compared to radiation alone in the treatment of nonmetastatic oropharyngeal cancer.
Authors: Husam Albarmawi, Ebere Onukwugha, Kevin J. Cullen, Olga G. Goloubeva
Journal: Journal of Clinical Oncology (2019)

6075 Background: Using concurrent chemoradiation (CRT) to treat oropharyngeal cancer (OPC) has increased since 2000. However, there is limited information regarding the cost-effectiveness of CRT compared to radiation alone (RT) especially given the approval of cetuximab (cetux) in 2006. We conducted a cost-effectiveness analysis of 1) platinum-based CRT compared to RT and 2) cetuximab plus RT (cetux+RT) compared to RT to determine the value of CRT over time. Methods: In this retrospective cohort study, we identified non-metastatic OPC patients aged 66 years or older diagnosed between 2000-2011 using the linked Surveillance, Epidemiology and End Results -Medicare dataset. We defined two cohorts based on the diagnosis period: 2000-2005 (Cohort I) and 2006-2011 (Cohort II). Cetux+RT was identified in Cohort II only. We matched the platinum-based CRT and cetux+RT groups to the RT groups using propensity score models that included age, race, marital status, income, Charlson Comorbidity Index and stage at diagnosis. The outcomes were incremental cost, incremental life-year gained (LYG) and incremental cost-effectiveness ratio (ICER) during the 3 years after diagnosis. Costs were estimated from the Medicare perspective and using 2017 USD. Results: 2,646 OPC patients were eligible for the study. The estimated parameters with the corresponding 95% confidence intervals (CI) are shown in the table. Conclusions: From 2000-2005, platinum-based CRT was a cost-effective option compared to RT. From 2006-2011 and compared to RT, platinum-based CRT provided a survival benefit at higher costs while cetux+RT patients incurred higher costs with no survival benefit. [Table: see text]
Germline BRCA1and BRCA2 mutations in patients with HER2-negative metastatic breast cancer (mBC) treated with first-line chemotherapy: Data from the German PRAEGNANT registry.
Authors: Peter A. Fasching, Chunling Hu, Steven Hart, Andreas D. Hartkopf, Florin A Taran, Wolfgang Janni, Hans Tesch, Lothar Haeberle, Johannes Ettl, Friedrich Overkamp, Michael P Lux, Diana Lüftner, Markus Wallwiener, Volkmar Mueller, Hans-Christian Kolberg, Tanja N. Fehm, Diethelm Wallwiener, Sara Brucker, Andreas Schneeweiss, Fergus Couch
Journal: Journal of Clinical Oncology (2019)

1048 Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.
Abstract 20100: Parental Presence at Cardiac Intensive Care Unit Bedside Transfer Rounds Reduces Parental Anxiety: Results of a Randomized Controlled Trial
Authors: Vijay Anand, Elina Williams, Mohamed Elgendi, Leanne Meakins, Chentel Cunningham, Heather McCrady, Gerda Tawfiq, Nicola Devlin, Kumar Shine, Bodil Larsen, Ivan Rebeyka, Ian Adatia
Journal: Circulation (2015)

Introduction: The transfer of children from the pediatric cardiac intensive care unit (PCICU) to the ward is a time of great anxiety for the parents of children and medical vulnerability for children who are receiving complex therapies. Hypothesis: We assessed the hypothesis that parental presence at bedside transfer rounds would reduce parental anxiety and improve patient safety following transfer of children from PCICU to the ward. Methods: We undertook a randomized controlled trial of children discharged from the PCICU to the ward. Consenting parents were randomized to be absent (control group) or present (intervention group) at multidisciplinary face to face bedside transfer rounds. The primary outcome measure was parental stress measured by the validated Spielberger’s State -Trait Anxiety Inventory (STAI) pre and post transfer. Secondary outcome measures included unplanned readmission to the PCICU, medication errors and emergency calls to the ward. We excluded patients being transferred between intensive care units. Results: We enrolled 230 subjects (control group n=93, intervention group n=91, failed to complete study n= 46). The 2 groups were matched with respect to gender (male 46% control vs 54% intervention), age (median age control 1.9 yrs (range 0.02 to 16.3) vs intervention 0.9 (0.02 to 17), parental age 32 yrs (18-64) vs 33 (20-60), parental years of schooling 15.5 years ( 7-26) vs 15 (9-24), presence of medical co-morbidities (33% each group). There was significantly greater reduction in trait (p=0.004, state (p=0.01) and total anxiety (p=0.0012) pre and post transfer in the intervention group vs the control group. There were no differences in minor medication errors (36 vs 33), unplanned PCICU re-admissions (11 vs 12) and emergency ward calls(7 vs 8) Conclusions: Parental presence at face to face multidisciplinary transfer rounds from the PCICU is associated with reduced parental anxiety without change in medication errors, readmission rates or emergency calls to the ward. Reduced parental anxiety may improve parental satisfaction with their child’s care.
Mortality results from an oral oncolytic symptom management trial.
Authors: Eric Vachon, Victoria Champion
Journal: Journal of Clinical Oncology (2019)

e23139 Background: Although mortality rates have declined, cancer remains the second leading cause of death in the United States. There has been an increase in prescriptions of oral oncolytic agents (OOA), which are typically prescribed to late stage patients as third or fourth line therapy. Because of this, death rates are higher among these patients and may impact attrition rates in OOA intervention trials. For researchers working with late stage patients, attrition by mortality should be considered when determining sample size. The purpose of this report is to identify the mortality incidence and its related factors in a symptom management randomized controlled trial (RCT). Methods: A total of 272 cancer patients newly prescribed OOAs (136 males, 136 females) were entered into the 12-week, multi-site RCT after signing written consent. Hospice patients were ineligible. Patients were randomized to experimental (n = 137) and control (n = 135) groups, with experimental group receiving an automated phone adherence intervention and a Symptom Management Toolkit (SMT). Data were gathered through recruitment site screening, patient interviews, medical record audits (MRA), and obituary searches at 6 months post-enrollment. A multiple logistic regression model was used to test the effect of concurrent intravenous chemotherapy, age, sex, intervention group, OOA class, comorbidities, and emergency room and hospital visits on death. Hematologic patients (n = 26) were excluded as none died, resulting in multicollinearity. Results: Fifteen patients (6%) died during the 12 week study period, while 34 (14%) died during the 6 months after enrollment. ER visits ( p .02), cardiovascular disease ( p.05), and depression ( p .01) were significantly associated with death 6 months from enrollment. Fifty-seven (23%) patients reported visiting the ER and 68 (28%) patients had a hospital stay during the study period. Conclusions: As would be hypothesized, adverse events and comorbidities were associated with death in this RCT. Mortality was similar by intervention group. Behavioral trials, even those lasting six months, should estimate attrition rates considering death and/or entry into hospice. Adequate planning in sampling will be critical for success in these types of trials. Clinical trial information: NCT02043184.
Association between circulating miRNA-141 and miRNA-375 and treatment outcome in metastatic castration-resistant prostate cancer.
Authors: Ahmed Hussien Zedan, Palle Jörn Sloth Osther, Jannie Assenholt, Jonna Skov Madsen, Torben Hansen
Journal: Journal of Clinical Oncology (2019)

e16507 Background: Metastatic castration resistant prostate cancer (mCRPC) is associated with high mortality. Monitoring of disease activity at this stage, with lack of validated prognostic models, is still a major clinical challenge. The role of microRNAs (miRNAs) has been widely investigated in prostate cancer with both diagnostic and prognostic potential. The aim of this study was to investigate the relationship between circulating miRNAs and treatment outcome in mCRPC patients. Methods: The relative expression of four miRNAs was investigated in plasma samples from 84 mCRPC patients; 40 patients were treated with docetaxel and 44 patients with abiraterone. Real-time polymerase chain reaction was used for analysis. Blood was sampled at baseline, before the second treatment cycle, and at radiological progression (RP). Associations to prognoses were analyzed using the Cox Regression analyses. Results: The plasma levels of all four miRNAs decreased significantly after treatment initiation in patients receiving docetaxel, and for miRNA-141 and miRNA-375 the level increased again at the time of RP. High baseline levels of miRNA-141 were significantly associated with a shorter time to RP in patients receiving both abiraterone, hazard ratio (HR) 3.18 (95% confidence interval (CI) 1.31-7.32), p &lt; 0.01, and docetaxel HR 2.56 (95% CI 1.45-4.50), p &lt; 0.01, and a shorter overall survival (OS), HR 3.20 (95% CI 1.25-9.37), p = 0.02, and HR 1.77 (95% CI 1.07-2.83), p = 0.02, respectively. Likewise, high baseline levels of miRNA-375 were also significantly associated with a shorter time to RP in both cohorts and OS in patients receiving docetaxel. Conclusions: Plasma levels of miRNA-141 and miRNA-375 were of prognostic importance in patients with mCRPC receiving both abiraterone and docetaxel and may be used in treatment monitoring irrespective of treatment modality.
Impact of germline DNA-repair gene BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-naïve prostate cancer: A single center analysis.
Authors: Vsevolod Borisovich Matveev, Liudmila Lyubchenko, Andrey Kirichek
Journal: Journal of Clinical Oncology (2019)

5056 Background: Germline mutations in DNA repair genes are common in patients with andvanced and metastatic prostate cancer (mPCa). Although BRCA mutation carriers have worse outcomes than noncarriers when conventionally treated for local or locally advanced PCa, recent studies reported conflicting results regarding their aggressiveness in patients with advanced disease. This study aimed to examine the impact of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with mPCa, receiving hormonal androgen deprivation therapy (ADT). Methods: A total of 76 patients with hormone-naive mPCa treated with first line ADT by luteinizing hormone-releasing hormone analogue (LHRHa) between 2014 and 2017 were recruited. Median follow-up was 34,8 mo. We focused on age, volume of metastatic spread, histologic grade, family history. All patients were genotyped for germline mutations in the BRCA1, BRCA2 and CHEK2 genes by polymerase chain reaction real-time and the Sanger sequencing. We used the standard definition of castration-resistance PCa (CRPC). Median time to CRPC were estimated using the Kaplan-Meier method, generated curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA1/2 and CHEK2 mutations. Results: Pathogenic and likely pathogenic germline mutations in the BRCA2 and CHEK2 gene were identified in 19 (25 %) patients. No cases of BRCA1 mutations were detected. Median time to CRPC was significantly shorter in BRCA2 and CHEK2 mutation carriers (7.9 mo, 95 % confidence interval (CI) 2.6 – 13.3), than in non-carriers (48.7 mo, 95 % CI 31.1 – 68.3, p &lt; 0,001). There was no significant difference in median time to CRPC in BRCA2 (7.9 mo, 95 % CI 0.0 - 16.3) and CHEK2 mutation carriers (6.1 mo, 95 CI 5.0 - 7.2, p = 0,448) meanwhile both were shorter than in non-carriers (p = 0.002 and &lt; 0,001). Multivariate analysis confirmed both BRCA2 (hazard ratio [HR]: 2.63; 95 CI 1.32-5.26, p = 0.006) and CHEK2 (HR 6.66, 95 CI 2.35-18.89, p &lt; 0.001) mutations as an independent prognostic factor for time to CRPC, particularly in mPCa with low-volume metastatis spread (HR 3.09, 95 % CI 1.36–7.05, р = 0.007 and HR 14.1, 95 % CI 3.65-54.4, p &lt; 0.001). Conclusions: BRCA2 and CHEK2 carriers had worse outcomes (shortened time to CRPC) than noncarriers when conventionally treated for metastatic PCa by standard first-line hormone treatment with LHRHa.