tbuckley/cabot-search huggingface dataset:
Institutional scientific review of cancer clinical research protocols: Impact of requirement on activation timelines.
Authors: Martin Frederik Dietrich, Ning Ning, Jingsheng Yan, Xian-Jin Xie, David E. Gerber
Journal: Journal of Clinical Oncology (2017)

e18224 Background: The National Cancer Institute (NCI) requirement that clinical trials at NCI-designated cancer centers undergo institutional scientific review in addition to Institutional Review Board review is unique among medical specialties. We evaluated the impact of this process on protocol activation timelines. Methods: We analyzed oncology clinical trials that underwent full board review by the Harold C. Simmons Comprehensive Cancer Center Protocol Review and Monitoring Committee (PRMC) from January 1, 2009, through June 30, 2013. We analyzed associations between trial characteristics, PRMC decisions, protocol modifications, and process timelines using Chi-square test, Fisher’s exact test, Wilcoxon rank-sum test, Kruskal-Wallis test, and logistic regression. Results: A total of 226 trials were analyzed. Of these, 77% were industry-sponsored and 23% were investigator-initiated. While only 40% of trials were approved initially, 97% of trials were eventually approved after a mean of 0.6 protocol changes were requested and a mean of 0.5 protocol changes were implemented. Protocol changes were more likely to be requested ( P&lt; 0.001) and implemented ( P= 0.008) for investigator-initiated trials. Median time from submission to PRMC approval was 55 days. The longest component interval was from submission initiation to completion of required documents by the study team (median 29 days). Total process duration depended on approval timing: median 35 days for first review, 68 days (2 nd review), and 116 days (3 rd review) ( P&lt; 0.001). Similarly, process duration was also associated with the number of changes/clarifications requested: median 39 days for none, 64 days for 1-3, and 73 days for ≥4) ( P&lt; 0.001). Requested changes/clarifications had greater impact on timelines for industry-sponsored trials than for investigator-initiated trials. Conclusions: NCI-mandated institutional scientific review of cancer clinical trials contributes substantially to protocol activation timelines. Further evaluation of this process and the value added to research quality is warranted.
Multimodal therapy for cancer related fatigue in patients with prostate cancer receiving radiotherapy and androgen deprivation therapy.
Authors: Sriram Yennu, Karen Basen-Engquist, Valerie Klairisa Reed, Cindy L. Carmack, Andrew Lee, Usama Mahmood, Seungtaek Choi, Kenneth R. Hess, Jimin Wu, Janet L. Williams, Zhanni Lu, David Cella, Deborah A. Kuban, Eduardo Bruera
Journal: Journal of Clinical Oncology (2017)

10114 Background: There are limited studies to evaluate treatments that target causative mechanisms of Cancer-related-fatigue (CRF) using validated tools in a defined population. The objective is to determine the feasibility, and the preliminary estimates of the effects of various combinations of standardized exercise, cognitive behavioral therapy (CBT), and methylphenidate (multimodal therapy, or MMT) on CRF as measured by AUC of Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) subscale scores in Pts with prostate cancer receiving radiotherapy with androgen deprivation therapy. Methods: Prostate cancer Pts with CRF scheduled to receive radiotherapy with androgen deprivation therapy were eligible. Using a double blind (patient, investigators) randomized factorial study design, eligible Pts were randomized into 1 of the 8 arms, which included all possible combinations of the interventions (exercise, CBT, and methylphenidate) and/or their corresponding placebo treatments for a duration of 8 weeks. Results: 62/69 (89%) randomized Pts were evaluable. There were no differences in the demographics and baseline fatigue between groups. The adherence rates for pills, exercise and CBT were 96.5%, 67%, and 90% respectively. The study was feasible and there was no significant difference in adverse events by groups. Table 1 shows the comparison of AUC by treatment. For Pts receiving drug compared to placebo, the median FACIT-F AUC was 2328 vs 2095. The drug effect (estimate, 95% CI) in Pts who received Exercise was 596 (68.3, 1125); CBT was 354 (-121, 830); combined Exercise and CBT was -187 (-802,427); and control Exercise, control CBT was 294 (-192,781). Conclusions: Methylphenidate containing combinations were superior to no drug combinations. Methylphenidate + Exercise provided the best signal and should proceed to large randomized control trials. Clinical trial information: NCT01410942. [Table: see text]
TCT-640 Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement Outcomes in Patients on Dialysis: Systematic Review and Meta-analysis
Authors: Mohinder Vindhyal, Sinan Khayyat, Sachin Srinivasan, Sachin Srinivasan, Tabitha Muutu, Sumaya Hammami, Paul Ndunda, Zaher Fanari
Journal: Journal of the American College of Cardiology (2018)
Granulocyte colony stimulating factor (G-CSF) from guidelines to efficiency: A single institution study.
Authors: Hossam Ragab Mohammad Abdulkhalek, Ehab Ahmed Ibrahim, Medhat Mahmoud Faris, Fahd Saad Ibnshamsah, Hani Hassan Alhashmi
Journal: Journal of Clinical Oncology (2018)

e18837 Background: Chemotherapy-induced febrile neutropenia is a serious side effect of cancer treatment. Recombinant human granulocyte colony stimulating factor (G-CSF) is the only agent currently approved that can treat or prevent neutropenia and therefore reduce its associated complications. There is a need to better define those patients who are most likely to benefit from G-CSF support. G-CSF guidelines are developed in order to have a degree of consistency across the department of adult medical oncology. Methods: The implementation of these guidelines started July 2014. The outcome indicators of compliance are percentage of G-CSF over-use (patients are receiving G-CSF while it is not indicated) and percentage of G-CSF under-use (patients are not receiving G-CSF while it is indicated). The clinical audit is conducted quarterly and reported annually. 1200 medical records are reviewed and auditted over a period of 36 months of outpatient clinic visits. The compliance audit items include: complete differential blood count, sickling test, documentation of chemotherapy regimen, assessment of G-CSF indication as per guidelines and documetation of patient education. The data is collected, analysed and blotted in bar chart in comparison to baseline data collected before implemntation of the guidelines. Results: Baseline data collection is done in first quarter of 2014, the percentage of G-CSF administered while not indicated was 52 % and the percentage of administered G-CSF while indicated was 48% of the total administered G-CSF. The latest report in fourth quarter 2017 showed overall percentage of G-CSF over-use of 2% in comparison to 52% baseline percentage before implementation of guidelines. The percetage of G-CSF under-use is 10% in comparison to 29% baseline percetage. Calculation of cost reduction per year showed that the improved compliance to the guidelines saved 67,524 SAR. Conclusions: Implementation of G-CSF clinical practice guidelines is cost-effective process and promote allignment with best practice. Further prospective studies are needed across the country.
Genomic landscape of defective DNA damage response and repair mechanisms (DDR) across cancer types.
Authors: MinYuen Teo, Emily Craig Zabor, Gopa Iyer, Richard Bambury, Mariel Elena Boyd, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2016)

e23219 Background: Genomic instability related to DDR defects leads to accumulation of somatic alterations that promote tumorigenesis, may confer sensitivity to platinum-based chemotherapy and may promote neoantigens that that might enhance immunotherapy sensitivity. We examined the prevalence of deleterious DDR gene alterations across cancer types as well as their correlation with total mutation number (mut) and copy number alterations (CNA). Methods: The Cancer Genome Atlas (TCGA) datasets were accessed via cBioportal to extract clinical data and mutation status of 146 DDR genes. Cases were selected for having availability of total mut number, and only disease subtypes with ≥ 20 patients were included. Missense muts were evaluated with both Polyphen-2 and Mutation Assessor. Results: In 4359 tumors representing 37 different diseases, 33.3% of tumors harbor at least one deleterious DDR alteration. but only 15 genes (10.3%) were mutated in > 1% of cases. The most frequently mutated genes were ATM (4.2%), BRCA2 (2.7%), BRCA1 (2.0%), POLE (1.9%) and ATR (1.8%). Mut in POLE were associated with high background mut rate (median 468/tumor vs. 62/tumor, p < .01) and therefore excluded from subsequent analysis. DNA damage sensing (9.6%) and Fanconi Anemia (FA) (8.0%) were the most frequently affected pathways. A single DDR gene alteration in any of the pathways was significantly associated with the total mut load (adjusted p < .01) but only DDR alteration in homologous recombination (HR) and FA pathways led to increased CNA burden (adjusted p = .01). We observed higher rate of DDR mutations in smokers (46.7% vs. 38.4%, p = .02), in older patients ( > 70: 40.0% vs. < 50: 31.8%, p < .01) and in stage IV disease (37.8% vs. 32.7% for stages I-III, p = .03). Conclusions: Deletrious DDR gene alterations occur in one third of cancer cases. Further work should explore their role as a potential marker for prognosis, immunosensitivity, and chemosensitivity.
Management of gastrointestinal (GI) toxicity associated with nivolumab (NIVO) plus ipilimumab (IPI) or IPI alone in phase II and III trials in advanced melanoma (MEL).
Authors: Jeffrey S. Weber, James M. G. Larkin, Dirk Schadendorf, Jedd D. Wolchok, John Wagstaff, Reinhard Dummer, David Hogg, Massimo Guidoboni, Jeffrey Alan Sosman, Bartosz Chmielowski, Winald Gerritsen, Rafia Bhore, Dana Walker, Rene Gonzalez
Journal: Journal of Clinical Oncology (2017)

9523 Background: NIVO and IPI are approved as monotherapy and in combination for treatment of MEL. These treatments are associated with select (potentially immune-related) adverse events (AEs) of the GI tract, most commonly diarrhea and colitis. We describe the management of GI toxicity in patients (pts) treated with NIVO+IPI or IPI from phase II (CheckMate 069) and III (CheckMate 067) trials. Methods: Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until progression or unacceptable toxicity, or IPI 3 mg/kg Q3W x 4, followed by placebo. Minimum follow-up was 2 yrs for CheckMate 069 and 18 months for CheckMate 067. Results: Of 407 pts treated with NIVO+IPI, 195 (48%) experienced any grade select GI AEs, and of 357 pts treated with IPI, 132 (37%) experienced any grade select GI AEs. Grade 3/4 select GI AEs were reported in 67 (16%) pts treated with NIVO+IPI and in 41 (11%) pts treated with IPI; median time to onset was 7.1 weeks (range 0.9-48.9) with NIVO+IPI and 7.3 weeks (range 0.6-14.9) with IPI. To manage these AEs, immune-modulating medications (IMM) were used in 61/67 (91%) pts in the NIVO+IPI group and in 41/41 (100%) in the IPI group. Corticosteroids (CS) were used in 61/67 (91%) and 41/41 (100%) pts, and infliximab (IFX) was used in 21/67 (31%) and 14/41 (34%) pts in the NIVO+IPI and IPI groups, respectively. In the NIVO+IPI group, the resolution rate of grade 3/4 select GI AEs was 96%, 97%, and 95% with a median time to resolution of 3.3, 3.0, and 3.9 weeks in all treated pts, CS, and CS+IFX managed pts, respectively; 88%, 92%, and 79% resolved with a median time to resolution of 3.9, 2.4, and 7.8 weeks in the IPI group, respectively. Objective response rates (ORR) were unchanged in the presence of any grade select GI AEs, or by using CS or CS+IFX (Table). Conclusions: NIVO+IPI or IPI alone is associated with a high incidence of GI select AEs, but most are effectively managed by IMMs, which do not appear to inhibit tumor response. Clinical trial information: NCT01844505; NCT01927419. [Table: see text]
PD-L1 and IDO1 expression and clinical outcome in 305 patients with surgically resected esophageal cancer.
Authors: Yoshifumi Baba, Takatsugu Ishimoto, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Journal: Journal of Clinical Oncology (2018)

4025 Background: Immunotherapy with the PD-1/PD-L1 inhibitors has produced potent long-lasting antitumor activity in patients with esophageal cancer. However, as responses are observed in only a fraction of patients and treatment responses are sometimes transient, additional strategies to reverse elements of immune suppression imposed by cancer are needed. IDO1 is the primary enzyme that generates immunosuppressive metabolite, and IDO1 inhibitors are being intensively developed and tested in clinical trials for various human cancers. Nonetheless, prognostic and immunological features of PD-L1 and IDO1 expressions remain still unknown in esophageal cancer. Methods: Using a non-biased database of 305 curatively resected esophageal cancers, PD-L1 expression, IDO1 expression, CD8 expression, and FOXP3 (a maker of Treg) were evaluated by immunostaining. The term “prognostic marker” is used throughout this article according to the REMARK Guidelines. Results: Compared with PD-L1 negative cases (n = 252), PD-L1 positive cases (n = 53) showed significantly worse overall survival [log-rank P = 0.016; hazard ratio (HR): 1.71; 95% confidence interval (CI): 1.08–2.61; P = 0.024; multivariate HR: 1.69; 95% CI: 1.05–2.67; P = 0.033]. The effect of PD-L1 was not significantly modified by any clinical factors (P > 0.05 for all interactions). Second, IDO1 expression was significantly correlated with poor overall survival (log-rank P = 0.0041), low CD8 expression (P = 0.044) and high counts of FOXP3 positive cells (P = 0.02). Importantly, a stratification based on PD-L1 expression and IDO1 expression was also significantly associated with overall survival (log rank P = 0.0013); both positive cases experienced unfavorable clinical outcome compared with other cases. Conclusions: PD-L1 and IDO1 expressions were associated with clinical outcome in esophageal cancer patients. In addition, the subgroups defined on the basis of PD-L1 and IDO1 status possessed diverse prognostic features. PD-L1 and IDO1 expressions in esophageal cancer may serve as a predictive tissue biomarker and may be used for patient selection in clinical trials of drugs targeting the PD-L1 pathway and IDO1.
LKB1 and its importance for survival in EpCAM negative circulating tumor cells (CTC) in metastatic breast cancer.
Authors: Elisabeth Katharina Trapp, Ulrich Andergassen, Julian Gregor Koch, Leonie Majunke, Beate Zill, Ayse Kurt, Nadia Harbeck, Sven Mahner, Marie Lena Johanna Tzschaschel, Thomas W. P. Friedl, Wolfgang Janni, Brigitte Kathrin Rack, Marianna Alunni-Fabbroni
Journal: Journal of Clinical Oncology (2017)

e23061 Background: To reach distant sites, CTC overcome metabolic stress and acquire a mesenchymal phenotype. So we assessed the pro survival function of liver kinase B1 (LKB1) a cellular metabolic stress controller, in combination with the EMT transcription factor Zinc finger E-box binding homeobox factor 1 (ZEB1) and stem cell markers e.g. CD44 in EpCAM negative CTC. Tumor spheroids and targeted si-RNA knockdown of LKB1 were analyzed in two breast cancer cell lines to support transcriptomic data. Methods: CTC were isolated from whole blood of 27 metastatic breast cancer patients. 17 age matched healthy donors were negative control. All patients were analyzed with CellSearch system to detect EpCAM positive CTC, which were eliminated by immunodepletion (AdnaTest BreastCancerSelect Kit, TATAA Biocenter) together with CD45 positive white blood cells (Miltenyi Biotec). RNA transcripts were quantified by qPCR (TaqMan Gene Expression Assay, ThermoFischer Scientific) and the relative expression was calculated by the 2- D Ct method. EpCAM negative CTC and spheroids were analyzed by immunofluorescence. Data were analyzed by non-parametric statistical tests. Results: According to the CellSearch system, most patients (74%, n = 20) were CTC negative. 20% of this sub-group showed enhanced levels of ZEB1, 15% of LKB1, and 40% of stem cell markers. ZEB1 and LKB1 were never co-expressed, while there was an almost significant association between enhanced ZEB1 and stem cell marker expression (p = 0.053). Immunofluorescence analysis on single CTC confirmed the transcriptomic result. MDA-MB 231 cell lines, normally negative for LKB1 and unable to grow in suspension, showed the ability to generate spheroids only if LKB1 expression was activated. Targeted knockdown of LKB1 confirmed these results. Conclusions: CellSearch system negative patients present a heterogeneous CTC population with enhanced levels of ZEB1, CD44, or LKB1. While ZEB1 and CD44 might be highly expressed in cells that already have entered EMT, LKB1 overexpression could represent the response to metabolic stress induced in the early phase of intravasation Hence, LKB1 might represent a novel therapeutic target to chase CTC and prevent metastasis.
Cost-effectiveness of nivolumab for treatment of platinum-resistant recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Kate Carroll, Kathryn Ries Tringale, Kaveh Zakeri, Assuntina Gesualda Sacco, Linda Barnachea, James Don Murphy
Journal: Journal of Clinical Oncology (2017)

6026 Background: The Checkmate 141 randomized trial found that patients with platinum-refractory, recurrent or metastatic (R/M) squamous-cell carcinoma of the head and neck (SCCHN) treated with nivolumab had significantly longer overall survival than those treated with standard, single-agent therapy. However, nivolumab is more expensive than standard treatment. We conducted a cost-effectiveness analysis of nivolumab for the treatment of R/M SCCHN. Methods: We constructed a Markov model to simulate treatment with nivolumab or other single-agent therapy (docetaxel, cetuximab, or methotrexate) for patients with R/M SCCHN. Transition probabilities including disease progression, survival, and toxicity were derived from clinical trial data, while costs (in 2016 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated with values less than $100,000/QALY considered cost-effective from a healthcare payer perspective. We conducted one-way and probabilistic sensitivity analyses to examine model uncertainty. Results: Our base-case model found that treatment with nivolumab increased overall cost by $59,000 and improved effectiveness by 0.2443 QALYs compared to single-agent therapy, leading to an ICER of $241,100/QALY. In sensitivity analyses, the model was most sensitive to the cost of nivolumab and assumptions about survival. Nivolumab would become cost-effective if the cost per cycle decreased from $13,432 to $5,716. If we assumed that all patients alive at the end of the Checkmate 141 trial were cured of their disease then nivolumab was still not considered cost-effective (ICER $160,000/QALY). Probabilistic sensitivity analysis also demonstrated relative stability of the cost-effectiveness model and found that treatment with nivolumab was cost-effective 0% of the time at a willingness-to-pay threshold of $100,000/QALY. Conclusions: While nivolumab significantly improves overall survival, at the current cost it would not be considered a cost-effective treatment option for patients with R/M SCCHN.
The significance of monitoring KRAS, human epidermal growth factor receptor 2, and vascular endothelial growth factor signals in the blood of colorectal cancer patients during treatment.
Authors: Koichi Suzuki, Nao Kakizawa, Yuji Takayama, Kosuke Ichida, Taro Fukui, Fumiaki Watanabe, Rina Kikugawa, Shingo Tsujinaka, Fumi Hasegawa, Hideki Ishikawa, Yasuyuki Miyakura, Kazushige Futsuhara, Hiroshi Noda, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2018)

e24053 Background: Genomic profiles can be altered during treatment in colorectal cancer (CRC), but monitoring real time changes has not been conducted. Methods: Blood monitoring was performed to track status changes in KRAS, human epidermal growth factor receptor (HER)2 and vascular endothelial growth factor (VEGF A, C, and D) in CRC patients. KRAS mutations in blood were identified by digital PCR and in tumors by Scorpion/ARMS. HER2 and VEGF expression levels were determined by enzyme-linked immunosorbent assay. Results: KRAS monitoring was carried out in 57 metastatic (m)CRC patients. Of 38 patients without tumor KRAS mutations, five harbored KRAS mutations in blood during treatment. These were detectable prior to radiographic detection of disease progression, suggesting KRAS monitoring is a useful biomarker of drug resistance. These mutant clones declined in the blood of one patient during late-line treatment. Anti-EGFR antibody re-introduction led to a partial response in the fifth line. HER2 monitoring of the 38 mCRC patients identified two HER2-positive patients (5%) before treatment, which increased to 12 patients (37%) during treatment. These patients may respond to herceptin and lapatinib combination therapy. VEGF (C and D) monitoring was performed in 48 mCRC patients treated with bevacizumab. Mean VEGF-D levels were 440 pg/ml (range, 0–1250), which was set as the cutoff value. Patients with high VEGF-D expression showed a significantly worse prognosis than those with low expression (8.0 m vs.14.7 m, p = 0.0314). No significant difference in prognosis was seen between patients with high vs low VEGF-D in first-line treatment, but patients with high VEGF-D had a significantly worse prognosis when treated with second-line bevacizumab than those with low VEGF-D (2.0 m vs.10.8 m, p = 0.0049). VEGF-C showed no significant correlation with prognosis. Conclusions: Monitoring blood genomic profiles during CRC treatment could provide clinical benefits for evaluating treatment response, and selecting optimal therapies.