tbuckley/cabot-search huggingface dataset:
Impact of variant allele frequency of mutant <i>PTPN11</i> in AML: Single institution experience of 122 patients.
Authors: Mansour Alfayez, Keyur Patel, Jorge E. Cortes, Tapan M. Kadia, Farhad Ravandi, Courtney Denton Dinardo, Naval Guastad Daver, Naveen Pemmaraju, Hagop M. Kantarjian, Gautam Borthakur
Journal: Journal of Clinical Oncology (2018)

7046 Background: Mutations in PTPN11, encoding tyrosine phosphatase SHP2, are present in 4-6% of AML. Largest report includes 27 patients (pts). Methods: Analysis included AML patients (pts) treated at MD Anderson Cancer Center between 2012 and 2017, positive for PTPN11 mutations by next generation sequencing. We evaluated baseline parameters, co-ocurring mutations,allelic burden and clinical outcome. Results: We identified 122 pts [62 (51%) male; median age 64.5 yrs (19-86)], among whom 64 (52.5%) treatment naïve and 58 (47.5%) salvage. In treatment naïve group, 26.6% had favorable risk (per ELN2017) [median overall survival (mOS) = 617 days (range 8-1151)], 23.4% intermediate [mOS = 336 days (Range 1-1403)] and 50% poor risk [mOS = 226 days (Range 3-540)] (P = 0.0086). Chr 3 abnormalities were present in 9 pts (14.1%), 14 pts (18.8%) had complex karyotype and 33 pts (39%) were diploid. Most common co-mutations were TET2 (51.9%), DNMT3A (33.3%), NPM1 (31.3%), and FLT3-ITD (26.6%), [Table]. Variant allelic frequency (VAF) for mutant PTPN11 with a cutoff of 0.4 further stratified poor risk AML into very poor (VAF ≥0.4; mOS = 194 days (Range 18-305)) and poor (VAF < 0.4; mOS = 314 days (Range 3-645)), [P = 0.01; HR 6.16, CI 95% 1.5-24.6). Similarly among patients with non-diploid karyotype, the same VAF cut off stratified patient survival (p = 0.007, HR 3.27, CI 95% 1.2-8.7). In the salvage group also, VAF stratified pts for survival; [≥0.4 vs < 0.4 (P = 0.01, HR 5.14, CI 95% 1.48-17.8)]. Conclusions: We report the largest survey of PTPN11 mutations among adult leukemia patients. Reminiscent of experience with FLT3-ITD mutation, VAF appears to have impact on patient outcomes. Targeted therapies have the potential of improving outcomes. Molecular and cytogenetics characteristics. Characteristics Treatment Naive (N = 64) (%) Salvage (N = 57) (%) TET2 28/54 (51.8) 27/46 (58.6) RAS 14/63 (22.2) 20/56 (35.7) KIT 8/63 (12.6) 12/55 (21.8) FLT3-ITD 17/57 (26.5) 8/57 (14.0) TP53 7/63 (11.1) 10/55 (18.2) NPM1 20/64 (31.3) 7/55 (12.7) Cytogenetics 33 (51.6) 11 (19) Diploid Complex 12 (18.8) 22 (38) Chr 3 abnormalities 9 (14.1) 15 (25.8) -5/5q- and/or -7/7q- 13 (20.3) 21(36)
Phase I dose finding study for melatonin in paediatric oncology patients with relapsed solid tumors.
Authors: Donna Johnston, Susan Zupanec, Darcy Nicksy, Daniel A. Morgenstern, Aru Narendran, Rebecca Deyell, Yvan Samson, Sylvain Baruchel
Journal: Journal of Clinical Oncology (2018)

e22514 Background: Melatonin is a natural health product currently used for the treatment of sleep disturbances and fatigue. In preliminary studies of adults with advanced cancer, melatonin at a dose of 20 mg daily is associated with reduction in anorexia and weight loss. Pediatric oncology patients with relapsed solid tumors often have problems with decreased appetite, and weight loss. However, high doses of melatonin have not been studied in the pediatric population. The purpose of this study was to determine the safety of melatonin at doses up to 20 mg daily in pediatric oncology patients with relapsed solid tumors. Methods: This study was a multicentre single arm phase I dose escalation study utilizing a 3+3 study design. The primary objective was to determine the safety and tolerability of escalating doses of melatonin in pediatric oncology patients with relapsed solid tumors. The secondary objectives were to determine the cumulative effect of an 8-week course of high dose melatonin in pediatric oncology patients with relapsed solid tumors; to establish the pharmacokinetics of melatonin; to establish the cytokines associated with melatonin; and, to determine if melatonin improved weight gain. Melatonin was given for 8 weeks at 3 dose levels, 0.075 mg/kg (maximum 5 mg), 0.15 mg/kg (maximum 10 mg) and 0.3 mg/kg (maximum 20 mg). Results: Melatonin was well tolerated at all 3 dose levels with no significant adverse events experienced. The only grade 3 or 4 toxicities were bone marrow suppression which was attributed to the concomitant chemotherapy and occurred at all dose levels. Grade 2 toxicities included reflux, menorrhagia, diarrhea, yeast infection, and constipation, at dose level 1; skin rash and bladder infection at dose level 2; and nausea, anorexia, dizziness, fatigue and dyspepsia at dose level 3. Weight gain occurred in 7 of 9 patients, with a mean increase of 0.79 kg (range -3.3 to 4.5) or 1.5% (range -10.2 to 8.7), with 2 patients losing weight (one in dose level 1 and the other in level 3). Conclusions: Melatonin is well tolerated at a dose of 0.3 mg/kg, with a maximum of 20 mg, in the pediatric population. This study provides the background for further study of high dose melatonin in pediatric oncology patients. Clinical trial information: NCT01858155.
Genetic variants within the glucocorticoids related genes to predict outcome in patients with metastatic colorectal cancer (mCRC).
Authors: Alberto Puccini, Fotios Loupakis, Shu Cao, Ryuma Tokunaga, Madiha Naseem, Francesca Battaglin, Martin D. Berger, Michelle McSkane, Shivani Soni, Wu Zhang, Joshua Millstein, Christoph Mancao, Chiara Cremolini, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

12098 Background: Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. CRC cells produce immunoregulatory GC, a process regulated by nuclear receptor liver receptor homolog-1 (LRH-1). Additionally, LRH-1 plays a critical role in the control of cell cycle and tumorigenesis. Therefore, CRC cells have a strong steroidogenic potential and tumor-derived GC may contribute to tumor immune evasion. Thus, we aim to evaluate whether variations in LRH1 and GC receptor (NR3C1) genes may predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Methods: Genomic DNA from whole blood samples was obtained from 378 mCRC patients who were treated with FOLFIRI/bev in the TRIBE (discovery cohort; N = 215, female/male 83/132; median age 60; median follow-up 48.9 months) and MAVERICC (validation cohort; N = 163, female/male 60/103; median age 62; median follow-up 23.3 months) trials, and subsequently genotyped through the OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of six selected SNPs in LRH1 and NR3C1 genes were analyzed. Results: In the discovery cohort, patients carrying NR3C1 rs10041520 any C showed a longer OS compared to T/T variant in the univariate analysis (28.9 months vs 20.5 months, HR = 0.69, 95%CI = 0.50-0.97, P = 0.029). LRH1 rs2737656 any T variant showed longer PFS compared to C/C genotype in multivariate analysis (10.3 months vs 9.4 months, HR = 0.62, 95%CI = 0.41-0.93, P = 0.020). Patients carrying any G in LRH1 rs2690034 showed shorter OS compared to those carrying C/C variant in multivariate analysis (25.0 months vs 29.8 months, HR = 1.46, 95%CI = 1.02-2.10, P = 0.040). The NR3C1 rs10041520 findings were validated in the MAVERICC FOLFIRI/bev arm. Here, patients carrying any C variants had a longer OS compared to T/T genotype in multivariate analysis (27.9 months vs 26.5 months, HR = 0.42, 95%CI = 0.19-0.92, P = 0.030). Conclusions: Our results provide the first evidence that the genetic variants within NR3C1 and LRH-1 genes might serve as a prognostic/predictive markers in patients with mCRC treated with first-line FOLFIRI and bevacizumab.
Clinical and pharmacological parameters associated with nivolumab toxicity.
Authors: Laure Hirsch, Audrey Bellesoeur, Marie Allard, Pascaline Boudou-Rouquette, Anne Jouinot, Jennifer ARRONDEAU, Michel Vidal, Audrey Thomas, Jeanne Chapron, Frédérique Giraud, Olivier Huillard, Marco Alifano, Jerome Alexandre, Benoit Blanchet, Francois Goldwasser
Journal: Journal of Clinical Oncology (2018)

3066 Background: The occurrence of severe, acute limiting toxicity in patients receiving anti-PD-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found associated with anti-CTLA4 acute toxicity (Daly LE et al, Br J Cancer 2017). We studied the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. Methods: From June 2015 to December 2016, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship, using logistic regression, between muscle mass, assessed by computed tomography and by Janmahasatian formula, nivolumab trough levels (Cmin) assayed using ELISA method, and the occurrence of grade 3 or 4 toxicity or any toxicity leading to treatment discontinuation (ALT). Univariate and multivariate analysis were made for parameters associated with nivolumab concentration. Results: Out of 92 patients, 81 were analyzable for body composition and 84 for nivolumab pharmacokinetics. The population included 63% males, median age 65 years, a majority had lung cancer (72%). We observed 20 ALT including 4 pneumonitis and 4 colitis in 20 (21.7%) patients and 825 (2.4%) nivolumab infusions. The ALT events were more frequent in sarcopenic patients (OR = 3.29, 95% CI: 0.96-11.28, p = 0.06). Sarcopenic overweight patients were the most susceptible to experience ALT (OR = 5.08, CI: 0.53-48.9; p = 0,16), as already reported by our group in melanoma patients (Heidelberger V et al, Invest N Drugs, 2017). The nivolumab Cmin was 17.0 ± 5.9 μg/mL on day 14. In multivariate analysis, low nivolumab Cmin was independently associated with hypoalbuminemia ( < 35g/L) (OR = 0.03, 95% CI: 0.002-0.34, p = 0.005) and sarcopenia (OR = 0.13, 95% CI: 0.03-0.54, p = 0.005). The recycling of albumin and nivolumab is both mediated by the neonatal Fc receptor (FcRn) and therefore albumin levels may reflect the abundance and efficiency of FcRn. Conclusions: Body composition influences both nivolumab pharmacokinetics and acute toxicity.
TCT-571 Outcomes of percutaneous balloon aortic valvuloplasty for severe aortic stenosis in patients presenting with cardiogenic shock
Authors: Ozan Demir, Giuseppe Lanzillo, Antonio Mangieri, Satoru Mitomo, Mauro Gitto, Matteo Pagnesi, Marco Ancona, Damiano Regazzoli, Francesco Giannini, Antonio Colombo, Azeem Latib
Journal: Journal of the American College of Cardiology (2018)
Efficacy and safety of endoscopic radiofrequency ablation for metastatic pancreatic renal cell carcinoma: A monocentric experience.
Authors: Gwenaelle Gravis, Brice Chanez, Jochen Walz, Jean-Philippe Ratone, Geraldine Pignot, Christian Pesenti, Jeanne Thomassin, Fabrice Caillol, Serge Brunelle, Naji Salem, Erwan Bories, Marc Giovannini
Journal: Journal of Clinical Oncology (2018)

e16549 Background: Glandular metastasis (GM) from metastatic renal cell carcinoma (mRCC) are rare but associated with good prognosis and pancreas metastasis (PM) is the more frequent site. The management of PM only, is surgery or tyrosine kinase inhibitor (TKI). Endoscopic radiofrequency ablation (ERFA) is a very innovative approach to control metastasis and have never been reported to treat PM from mRCC. Methods: We report a monocentric, prospective analysis for local control and toxicity of patients (pts) treated by ERFA for progressive PM from mRCC. ERFA was performed under general anesthesia, with a linear EUS scope and a 19 G RFA needle; time of ablation was short (30sec -1 mn), 1 or 2 shots were needed to ablate a 2 cm lesion. Results: 6 pts from Paoli Calmettes Institute (France) were recruited between May 2017 and January 2018. Median age was 72y (69-73), 4/6 female, ECOG 0 (100%). The median time from diagnosis to PM was 14 years (9.98-22.18), median number of PM was 2 (1-3), 5/6 was documented by histology and all were classified as progressive before ERFA. PM localizations was: head in 40%, body 40%, tail 20% and average size was 19.6 mm. 80% of pts (4/6) had other mRCC spread, 4/6 received systemic treatment and 2 of them were on therapy at ERFA time (1 TKI, 1 Nivolumab). Two pts had ERFA as the only treatment for oligometastatic RCC. Median number of ERFA sessions was 2 (1-3). With a median follow up of 6.6 months (0.5-9.3), 5/6 pts had local control (with 2 CR). One patient treated by TKI during procedure, developed a paraduodenal abscess 2 months after ERFA and was drained endoscopically. Pancreatitis or diabetes were not reported and no toxicity was observed for pt treated with nivolumab. Conclusions: ERFA is feasible and displays an excellent local control for PM without any major side effect. However TKI should be stop before the procedure to avoid complications. ERFA could be a valuable option, less morbid than pancreas resection for progressive PM.
Cancer clinical trials education: Insights from patient experiences and preferences.
Authors: Claire Saxton
Journal: Journal of Clinical Oncology (2017)

e21554 Background: Clinical trials offer cancer patients access to innovative treatments, quality care, and hope for a better future. Yet, participation rates across adult cancers remain low. Education is a target intervention. The following research examines patient experiences, beliefs, and preferences related to cancer clinical trial participation. Methods: In 2015-16, the Cancer Support Community conducted an online survey with the goal of developing an educational program that would increase clinical trial awareness and participation. Survey responses from 506 cancer patients were collected. Most respondents were female (85.5%) and Caucasian (84.8%). The average age was 58.7 years old. Nearly half (47.2%) were diagnosed with breast cancer. Of the respondents, 48.3% were currently receiving treatment. Results: Most (81.4%) had heard of clinical trials prior to diagnosis. While 36.3% had participated in trials, 52.5% never considered it. Results found that 56.7% had discussed clinical trials with their healthcare team during treatment, but only 20.2% felt that their goals and concerns were meaningfully addressed. Additionally, 93.1% reported that more time with their doctors to discuss clinical trials would be “somewhat” or “very” helpful. Websites with clinical trial information were shared with just 34.4% of respondents. Survey results indicated that 91.9% felt that a website including clinical trial information would be “somewhat” or “very” helpful. Specifically, 60.2% of respondents reported that a website with patient narratives would be “very” helpful. While, 60.9% felt that tools to help locate clinical trials would be “very” helpful. Most had not been offered or couldn’t independently locate videos (80.7%) or illustrations/images (73.8%) explaining clinical trials. Of the respondents, 94.0% reported that speaking directly with a clinical trial participant would be helpful. Yet, this was only offered to 10.3% of patients. Conclusions: Findings were used to develop content for educational products and programs delivered by CSC for those potentially eligible for clinical trials. Survey data highlight the importance of providing information relevant to eligible participants across multiple formats.
Assessment and treatment of breakthrough cancer pain in Spain: A self-audit study.
Authors: Rafael Lopez, Juan J Reina, Diana Monge, Fernando Caballero, Vicente Guillem, Enrique Aranda, Alfredo Carrato, Eduardo Diaz Rubio, Jesus Garcia-Foncillas, Margarita Feyjoo, Carlos Camps
Journal: Journal of Clinical Oncology (2018)

e18785 Background: Breakthrough cancer pain (BTcP) is a common condition, but its management may be often suboptimal. We aim to determine if physician’s perception of the management and characteristics of BTcP among their patients is in line with the real-life clinical practice, and if there is clinical inertia in the identification and treatment of the BTcP episodes. Methods: Observational and descriptive study conducted in two phases: a) opinion poll (self-completed online) answered by Spanish oncologists, and b) BTcP episodes screening and assesment (performed by the oncologist surveyed) in patients with a prior or current history of cancer pain (5 patients per oncologist). A recent expert consensus (1) and Davies algorithm were used to evaluate the correct diagnosis and optimal management of BTcP. The project was promoted by the ECO Foundation (Excellence and Quality in Oncology) with the collaboration of Francisco de Vitoria University (Madrid). Results: A total of 108 oncologists participated in the study. The number of patients evaluated was 540. 68.5% of doctors considered the frequency of BTcP among their patients to be
TCT-736 Prevalence and Impact of Bleeding Determinants on Risks for out-of-hospital bleeding and coronary thrombosis in patients undergoing percutaneous coronary intervention: Results from a large single-center PCI Registry
Authors: Sabato Sorrentino, Usman Baber, Bimmer Claessen, Anton Camaj, Birgit Vogel, Samantha Sartori, None Paul Guedeney, Jaya Chandrasekhar, Serdar Farhan, Nitin Barman, None Joseph Sweeny, Gennaro Giustino, George Dangas, Annapoorna Kini, Samin Sharma, Roxana Mehran
Journal: Journal of the American College of Cardiology (2018)
Phase 1 study of ANDES-1537: A novel antisense oligonucleotide against non-coding mitochondrial DNA in advanced solid tumors.
Authors: Mallika Sachdev Dhawan, Rahul Raj Aggarwal, Emily Boyd, Kathleen Comerford, Jenna Zhang, Bernadita Méndez, Pablo Valenzuela, Jennifer Grabowsky, Scott Thomas, Pamela N. Munster
Journal: Journal of Clinical Oncology (2018)

2557 Background: New non-coding RNAs, which appear to be involved in cell proliferation in animal cells, have been discovered by L.Burzio and co-workers. Andes-1537 is a short single stranded phosphorothioate-deoxyoligonucleotide which binds by base pairing to one of these newly discovered non-coding RNAs, named Antisense non-coding mitochondrial RNA (ASncmtRNA). The resulting RNA-DNA hybrid is then hydrolyzed by two cellular RNases: RNase H and DICER resulting in microRNAs. In vitro experiments with cells have shown Andes-1537 affects cancer cells by: a) inducing apoptosis by lowering the expression of anti-apoptotic proteins such as survivin b) decreasing proliferative signaling through inhibition of the expression of proteins such as cyclin D1 and cyclin B1, and c) inhibition of tissue invasion/metastatic proteins such as n-cadherin, B-catenin and metastasis inducing factors. Methods: The safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) characteristics and efficacy of Andes -1537 was assessed in a phase 1 study. Patients with all solid tumors were enrolled in 5 cohorts at 100 mg subcutaneous (SC), 200 mg SC, 400 mg SC, 600 mg SC and 800 mg SC twice weekly. Results: 22 patients (14 M: 8F) with heavily pretreated solid tumors were enrolled in 5 cohorts. Two dose-limiting toxicities occurred at the 800 mg dose level both of which were injection site reactions: one precluding full cycle 1 dose delivery, and one involving grade 3 skin necrosis due to vascular occlusion and inflammation. No other grade 3/4 toxicities were seen. Grade 2 toxicities including injection site reactions and erythema. The MTD has been determined to be 600 mg SC twice weekly. Two patients (one with pancreatic cancer and one with cholangiocarcinoma) had stable disease on scans beyond six months. No partial or complete responses were seen with Andes 1537. PK data reveals a linear PK profile. Conclusions: Andes-1537 is a well-tolerated drug with a novel mechanism. It was determined to be tolerable at 600 mg SC twice weekly. An efficacy signal in pancreatic cancer and cholangiocarcinoma was seen at 200 mg dose level and thus dose expansion is under consideration. Clinical trial information: NCT02508441.
Association of DRB1 and DRBQ haplotype 04:01~03:01 with HPV positive head and neck squamous cell carcinoma.
Authors: Arun Khattri, Zhixiang Zuo, Y-H Carol Tan, Nishant Agrawal, Mark W. Lingen, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2017)

6054 Background: The incidence of human papilloma virus (HPV) associated oropharyngeal head and neck cancer (HNC) is increasing rapidly in the US, Europe, and Asia. HPV16 is etiologic in 90-95% of HPV+ HNC. Sexual transmission and inability to clear infection leading to viral genome integration or chronic presence of episomal HPV16 DNA are precursors to HPV+ HNC carcinogenesis. However it remains unclear why a majority of HPV16 exposed individuals are able to clear the initial infection and avoid the risk of cancer. We hypothesized that difference in the ability eradicate infection may be mediated by certain HLA haplotypes. Methods: HPV(+) HNC patients from the TCGA cohort were HLA-typed based on available exome sequencing data. HLA typing was performed using the ATHLATES algorithm. We compared the distribution of alleles and haplotypes of classical HLA genes (A, C, B, DRB1 and DQB1) among HPV(+) HNC patients with those found in HPV(-) patients. Furthermore we evaluated enrichment of candidate alleles compared to publically available data in Caucasian non-cancer individuals. Results: Out of 528 HNC samples in the TCGA cohort, 450 were of Caucasian ancestry. The DRB1~DQB1 haplotype 04:01~03:01 was significantly increased in HPV(+) HNSCC patients compared to normal, non-cancer individuals ( p-value = 0.0045, OR = 2.52, 95% CI = 1.2–5.03). This was not the case for HPV(-) HNC patients. The number of African American samples in TCGA was comparably small (N = 48, with N = 5 being HPV+) however the frequency of DRB1~DQB1 haplotype 04:01~03:01 in the general African American population is significantly lower. Conclusions: DRB1~DQB1 haplotype 04:01~03:01 associates with an elevated risk for HPV+ HNC. Similar findings were reported 17 years ago for cervical cancer (Br J Cancer, 82(7), 1348–1352), and further validate our findings across tumor types. Mechanistic studies to understand potential DRB1~DQB1 haplotype 04:01~03:01 HPV specific immune dysfunction, as well as evaluation in different risk and racial populations are indicated.