tbuckley/cabot-search huggingface dataset:
Hyperproliferative keratinocytic cutaneous adverse events and inflammatory palmoplantar erythrodysesthesia in melanoma patients treated with encorafenib compared to other BRAF inhibitors.
Authors: Simone M. Goldinger, Natalie P Graf, Nadja Galliker, Samuel Conrad, Reinhard Dummer
Journal: Journal of Clinical Oncology (2017)

9590 Background: BRAF inhibitor (BRAFi) an MEK inhibitor (MEKi) monotherapies have shown to cause more cutaneous adverse events (cuAEs) in monotherapy compared to combination therapy. Encorafenib in combination with binimetinib showed improved PFS in patients with BRAF mutant melanoma (14.9 months). Furthermore, encorafenib showed superiority over vemurafenib. Objective: The aim of this study was to investigate cuAEs of melanoma patients treated with encorafenib and/or binimetinib and compare them to other BRAFi and MEKi induced cuAEs reported in the literature and observed in our control population. Methods: Patients treated with encorafenib, binimetinib, and other BRAFi/MEKi within approved clinical trials at the University Hospital of Zurich were collected and analyzed. Clinical and histological assessments were performed. Results: In 111 patients treated with BRAFi and/or MEKi, 212 related or possibly related cuAEs were identified. The percentage of patients with at least one cuAE is shown in the table below. The most frequent cuAEs observed in patients treated with encorafenib where palmoplantar hyperkeratosis (PPH, 50%), palmoplantar erythrodysesthesia (PPD, 53.8%) and alopecia (42.3%), whereas acanthopapillomas (83%), maculopapular exanthemas (63.3%), PPH and PPD (each 50%) prevailed in patients treated with vemurafenib. The most frequent observed cuAE in patients with dabrafenib/trametinib combination therapy were maculopapular exanthemas (18.2%) and erythema-annulare-like eruptions (18.2%), with encorafenib/binimetinib combination therapy PPH (10.6%) respectivly. Conclusions: Encorafenib showed less hyperproliferative cuAEs as previous BRAFi. However, PPH and PPD seem to occur more often compared to the literature of other BRAFi. Both is supporting the argument that encorafenib is a second generation BRAFi with a longer dissociation time. [Table: see text]
The role of depth of response and single-nucleotide polymorphisms as a prediction of the efficacy for third line chemotherapy in metastatic colorectal cancer.
Authors: Ka-rham Kim, Hyun-Jeong Shim, Woo Kyun Bae, Jun Eul Hwang, Ik-Joo Chung, Sanghee Cho
Journal: Journal of Clinical Oncology (2016)

e15096 Background: There is limited data on clinical and biological parameters indicating which patient would benefit from additional line of chemotherapy after disease progression in metastatic colorectal cancer (mCRC). We evaluated the role of early tumor shrinkage (ETS) and depth of response (DoR) as clinical decision parameters, and single-nucleotide polymorphisms (SNPs) as biomarkers, and assessed their associations with clinical outcomes and benefit from additional chemotherapy after disease progression. Methods: We retrospectively reviewed tumor response using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), ETS and DoR after first line chemotherapy in patients with mCRC. And factors affecting survival outcomes after more than third line chemotherapy were investigated. We analyzed the relationship between clinical outcomes and SNPs known to be associated with chemotherapy response as well. Results: In total, 170 patients were evaluated. Overall response and ETS were found in 73 (42.9%) and 71 patients (41.8%), respectively, and the median DoR was 38.37±31.33%. Statistically significant differences between ETS, DoR and survival outcomes such as PFS, PPS and OS were found. Better OS was shown in patients with XRCC1(G399A) AG/AA genotype, DoR over 60%, ECOG performance status 0-1 and no bone metastasis. Among these patients, 88 (51.8%) received third line chemotherapy, which mostly included fluoropyrimidine as rechallenging therapy. There was survival benefit from third line chemotherapy in patients with MTHFR(C677T) CC genotype and a DoR over 60%. Conclusions: XRCC1(G399A) AG/AA genotype, DoR over 60%, ECOG performance status 0-1 and bone metastasis have better survival outcome in patients with mCRC. Patients with a DoR over 60% after first line chemotherapy and MTHFR(C677T) CC genotype could get benefit from more than third line chemotherapy using fluoropyrimidine, even which has been previously used.
Updated report of a randomized phase III trial comparing 4 and 8 courses of S-1 adjuvant chemotherapy for p-stage II gastric cancer: JCOG1104 (OPAS-1).
Authors: Masanori Terashima, Takaki Yoshikawa, Junki Mizusawa, Souya Nunobe, Yasunori Nishida, Masahide Kaji, Norimasa Fukushima, Shinji Hato, Yasuhiro Choda, Hiroshi Yabusaki, Kazuhiro Yoshida, Kazunari Misawa, Atsushi Takeno, Masahiro Tsuda, Yasuyuki Kawachi, Hiroshi Katayama, Haruhiko Fukuda, Narikazu Boku, Takeshi Sano, Mitsuru Sasako
Journal: Journal of Clinical Oncology (2018)

4024 Background: Postoperative S-1 for 1 year (corresponding to 8 courses) is one of standard adjuvant chemotherapies for p-stage II gastric cancer. We reported 4-courses of S-1 was inferior to 8-courses of S-1 in terms of relapse-free survival (RFS) for p-stage II gastric cancer at the first planned interim analysis (ESMO2017). Here, we report the updated results of this trial. Methods: Patients with p-stage II except T1Nany and T3N0 (7th edition of TNM), performance status 0-1, R0 resection were randomized either 8-courses or 4-courses. Primary endpoint was RFS. The total sample size was determined to be 1,000 with a non-inferiority margin of hazard ratio (HR) of 1.37, with one-sided alpha of 5% and power of 80%. Results: Between Feb 2012 and Mar 2017, 590 (295 in each arm) patients were enrolled and analyzed. Proportion of patients in treatment of S-1 at 6 months was 76.9% for the 8-courses and was 80.1% for the 4-courses, and that at 12 months was 59.3% in 8-courses. The RFS at 3 years was 89.8% for 4-courses and 93.1% for 8-courses (HR 1.84, 95% CI 0.93-3.63). The overall survival at 3 years was 92.6% for 4-courses and 96.1% for the 8-courses (HR 3.34, 95% CI 1.22-9.12). The cumulative incidence of recurrence at 3 years was 7.7% for the 8-coursesand 5.5% for the 4-courses (HR 1.59, 95% CI 0.75-3.39). For safety analysis, 8 patients who did not receive the protocol treatment were excluded. Adverse events were mild in both arms, but slightly less frequent in the 4-courses arm than in the 8-courses arm. Conclusions: The updated primary results confirmed that non-inferiority of 4-courses S-1 were not demonstrated in RFS. S-1 adjuvant chemotherapy for p-stage II gastric cancer should be continued for one year considering the efficacy, acceptable toxicities, and high compliance. Clinical trial information: UMIN000007306.
Toxicity related to first line, platinum-based chemotherapy in BRCA1-associated epithelial ovarian cancer: Is DNA repairing impairment associated with more adverse events?
Authors: Agnieszka Badora-Rybicka, Magdalena Budryk, Danuta Starzyczny-Słota, Elzbieta Nowara
Journal: Journal of Clinical Oncology (2016)

e17092 Background: The presence of BRCA germline mutations in patients with ovarian cancer has been shown to have predictive and prognostic significance, including increased platinum-sensitivity. It is explained by the fact that DNA damaging agents cause impaired DNA repair among BRCA mutated patients. The aim of the study was to evaluate if patients with BRCA1-associated ovarian cancer have more treatment related adverse events and, if so, does it have impact on chemotherapy outcomes. Methods: We conducted a retrospective analysis of medical records of 172 patients with newly diagnosed epithelial ovarian cancer, treated in Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch between 2007 and 2013. 96 of these patients have known BRCA mutation status – 21 patients were BRCA1(+) and 75 BRCA1(-). All analyzed patients received first line chemotherapy based on platinum salts and paclitaxel. Treatment related adverse events (AE’s) were: haematological toxicity, nausea/vomiting, neuropathy and mucositis. Haematological toxicity and mucositis were considered as DNA damage dependent. Results: Median PFS was 28.6 (8.4 -69.2) months among BRCA1(+) patients and 22.2 (6.3-79.7) months in BRCA1(-) (p = 0.45). Median OS was 39.6 (16.3-79.8) months for BRCA1(+) patients and 38.2 (7.2-93.9) months for BRCA1(-) (p = 0.62). Grade 3-4 haematological AE’s were significantly more common among BRCA1(+) patients (OR = 3.86; 95% CI 1.14-13.23; p = 0.02). However, there was no association between BRCA1 mutation status and neuropathy (p = 0.73) or nausea/vomiting (p = 0.91). Occurrence of above mentioned AE’s has no significant association with PFS (p = 0.75, 0.64, 0.97 respectively) and OS (p = 0.64, 0.69, 0.73 respectively). The number of patients with mucositis was also too small to conduct credible analysis. Conclusions: Among patients with BRCA1-associated ovarian cancer we observed significantly more grade 3-4 haematological adverse events, which are considered as DNA damage dependent.
Offline: The new politics of health in India
Authors: Richard Horton
Journal: The Lancet (2018)

"There is a full-blown crisis in India." So said Rahul Gandhi, President of the Indian National Congress Party, during a visit to the London School of Economics last month. He was talking about a "jobs crisis". But there is also a health crisis, as five papers published across three Lancet specialty journals—Lancet Oncology, Global Health, and Public Health—set out this week. Now is the right moment to be debating the future health of the world's largest democracy. In April, 2019, Indian voters will go to the polls in the most important general election since India achieved independence in 1947.
Abstract 10949: Left Bundle Branch Block in Suspected Acute Myocardial Infarction
Authors: Nuria Farre, Merce Camprubi, Isabel Serrano, Xavier Oliva, Jordi Guarinos, Francisco Fernandez, Mohsen Mohandes, Alfredo Bardaji
Journal: Circulation (2013)

INTRODUCTION: According to guidelines, patients presenting with chest pain and ST elevation (STE) or (presumed) new LBBB should undergo a primary angioplasty. Our objective was to evaluate the clin...
New global prognosis score (GPSc) in resectable oral squamous cell carcinoma (OSCC): Joining up tumor and patient-related data.
Authors: Ursula Jariod-Ferrer, Sara Blanco-Sanfrutos, Marina Gavin-Clavero, Manuel Ignacio Molina-Barraguer, Tomas Uson-Bouthelier, Bartolome Nadal-Cristobal, Ignacio Moral-Saez, Esther Saura-Fillat, Isabel Pajares Bernad, Ana Isabel Cisneros-Gimeno, Javier Martinez-Trufero
Journal: Journal of Clinical Oncology (2018)

e18078 Background: Disease stage is the most powerful prognostic factor in OSCC, but is not accurate enough to identify highest risk patients. Other patient-related conditions as comorbidity and PLR (Platelet to Lymphocyte Ratio) may add relevant prognostic value. We created a Global Prognosis Score (GPSc) including these data to better predict outcome. Methods: Retrospective review of patients with resectable OSCC from 2011 to 2014. Baseline pretreatment comorbidity data were collected according to Adult Comorbidity Evaluation–27. Clinical, pathological, presurgical blood samples and treatment data were collected. Kaplan-Meier and Cox proportional hazards modeling were used to determine associations with OS (Overall Survival), DSS (Disease-Specific Survival) and DFS (Disease-Free Survival). We calculated GPSc out of our multivariable model (MM) according to specific value following Hazard Ratio (HR). We stratified patients in high (≥8), moderate (5 - 7) and low risk (≤ 4). Results: Among 215 patients, median age was 67 years (range 32-96). Median follow-up was 31 months (1– 78). 74% suffered at least one previous comorbid condition. 3-year OS, DSS and DFS were 68%, 77% y 65%, respectively. Selected variables after MM are showed in Table 1. Risk of death is 13 times higher among the high-risk group compared to the low group [OS: HR = 13.29 95%CI = 6.5-27.15 p < 0.001 and DSS: HR = 13.35 95%CI = 5.73-31.09 p < 0.001]. Concerning risk of recurrence, it is 3 times higher [DFS: HR = 3.18 95%CI = 1.8- 5.6 p < 0.001]. Conclusions: We described the first specific GPSc in OSCC, adding clinical and easily accessible information to tumor stage, capable of discriminating prognostic groups to individualize treatment plan. Table 1. GPSc Variable HR 95%CI p Score Low comorbidity 2.61 [0.95-7.21] 0.006 1 Moderate comorbidity 3.17 [1.24-8.11] 0.02 2 Severe comorbidity 6.24 [2.08-18.67] < 0.001 3 Haemoglobin < 13.6 g/dL 1.92 [1.04-3.55] 0.04 1 Stage II 2.57 [0.87-7.58] 0.009 1 Stage III-IV 4.10 [1.15-14.67] 0.03 2 N0. Watchful waiting 2.82 [0.98 – 8.12] 0.05 1 Therapeutic neck disection 2.57 [1- 6.60] 0.05 1 PLR > 66 3.98 [0.88-17.93] 0.07 2 Age > 80 2.88 [1.28-6.46] 0.01 1
NCI9673: A multi-institutional eETCTN phase II study of nivolumab in refractory metastatic squamous cell carcinoma of the anal canal (SCCA).
Authors: Van Karlyle Morris, Kristen Keon Ciombor, Mohamed E. Salem, Halla Sayed Nimeiri, Syma Iqbal, Preet Paul Singh, Blase N. Polite, Dustin A. Deming, Emily Chan, James Lloyd Wade, Tanios S. Bekaii-Saab, Hope Elizabeth Uronis, Manolo G Pasia, Gail Bland, Robert A. Wolff, Aki Ohinata, Chimela Ohaji, Jane Rogers, Padmanee Sharma, Cathy Eng
Journal: Journal of Clinical Oncology (2016)

3503 Background: The incidence of SCCA continues to rise annually in the US. 20% of patients (pts) will develop metastatic (met) disease which lacks a consensus approach to treatment. SCCA is largely driven by immune evasion of HPV-specific CD8 and CD4 T cells which promote oncogenesis for SCCA. Nivolumab (Nivo), a monoclonal antibody targeting PD-1 on T cells, promotes immune-mediated anti-tumor activity of T cells against HPV-positive cells in vitro. This is the first phase II trial of Nivo for pts with refractory met SCCA. Methods: Previously treated but immunotherapy naïve met SCCA pts were eligible. PD-L1 expression was not required. HIV+ (CD4 count > 300/uL) and hepatitis B/C pts were eligible. A Simon two-stage phase II trial (Ho: p < .05, Ha: p ≥ .20) was conducted. All pts were evaluated by RECIST Criteria 1.1. Pts received Nivo (3 mg/kg) IV every 2 weeks. Optional pre-treatment and on-treatment tissue biopsies and plasma samples were collected for immune biomarkers and HPV/p16 status. All correlatives were evaluated at MDACC by the Immunotherapy Platform team and the Core Facility. Results: 39 pts were screened across the ETCTN network (May 2015 - October 2015); 37 pts were eligible. Median age was 56 years (interquartile range [IQR], 51.1-63.6); M:F was 12:25. Median number of prior therapies: 2 (range 1-8). All pts were evaluable for toxicity; 33 pts were evaluable for response. Median number of cycles: 6 (IQR, 3-10). Seven (21%) pts had a partial response and 19 (58%) pts had stable disease; disease control rate of 79%. Ten pts (one HIV+) remain on study [7 pts for > 6 months (M)]. Median progression-free survival was 4.1M. Common adverse events (AE): fatigue, nausea, and rash. Six pts had grade 3 AE's: fatigue (N = 2) and one pt each of pneumonitis, rash, anemia, and hyperglycemia. Conclusions: Currently, there is no consensus approach for met SCCA. NCI9673 is the first prospective phase II trial of nivolumab in refractory metastatic SCCA. Single agent nivolumab demonstrated potentially meaningful activity and was well tolerated. Further evaluation of immune checkpoint therapy in met SCCA is justified. Updated clinical results will be presented. Exploratory correlative work is ongoing. Clinical trial information: NCT02314169.
HuMab-5B1 (MVT-5873), a mAb targeting sLe<sup>a</sup>, in combination with first-line gemcitabine plus nab-paclitaxel (gem/nab-P) for patients with pancreatic cancer (PDAC) and other CA19-9 positive malignancies.
Authors: Eileen Mary O'Reilly, Erkut Hasan Borazanci, Kenneth H. Yu, Anna M. Varghese, Hayley Estrella, David Kamins, Teresa Melink, Kirsten Dorr, Paul Maffuid, John Gutheil, Judy Sing-Zan Wang, Todd Michael Bauer
Journal: Journal of Clinical Oncology (2018)

e16235 Background: MVT-5873, a fully human IgG1 mAb, targets sialyl Lewis A (sLea), an epitope on CA19-9. CA19-9 is expressed in PDAC and other GI and lung cancers, plays a role in tumor adhesion and metastasis, and is a marker of an aggressive tumor phenotype. MVT-5873 is active as a single agent (ASCO, 2017). Methods: MVT-5873 given IV weekly in combination with gem/nab-P. Eligibility criteria included untreated locally-advanced/ metastatic PDAC/other CA19-9+ malignancy and ECOG PS ≤1. The definition of Dose limiting toxicity included Grade 4 hematologic, Grade 3+ microangiopathic hemolytic anemia, Grade 2+ hemolysis, Grade 3+ non-hematologic AEs. Dose escalation utilized a 3+3 design followed by a 10-patient expansion at the MTD. Trial endpoints include safety, MTD, pharmacokinetics (PK) and efficacy. Exploratory endpoints include changes in serum CA19-9 levels and tissue CA 19-9 expression. Results: As of Feb 2018, 9 subjects have been entered in Cohort 1 (N = 3, 1 mg/kg) and Cohort 2 (N = 6, 0.125 mg/kg). Dose limiting toxicities included Grade 3 AST, ALT, and bilirubin at 1 mg/kg resulting in de-escalation for Cohort 2 to 0.125 mg/kg. At 0.125 mg/kg, a single DLT (ALT) was observed in 6 subjects. Of toxicities deemed possibly related to MVT-5873, most were low grade including GI toxicity (abdominal pain/cramps/diarrhea/nausea) and G1-2 infusion reactions (mitigated with standard pre-medications and lengthened infusion time). Initial PK data (terminal half-life, 40hs) was comparable to that reported for other mAbs and to single agent MVT-5873. All Cohort 2 subjects had pre-dose downward reductions in CA19-9 (range of reduction from 74% to 97%) compared to baseline. All subjects in Cohort 2 have had reductions in measurable target lesions (range -22 to -77%) with 4 PRs and 2 SDs. Expansion (N = 10) at 0.125mg/kg MVT-5873 is ongoing. Conclusions: MVT-5873 at 0.125 mg/kg in combination with gem/nab-P appears safe and tolerable. DLTs included reversible increases in transaminases. Initial activity is promising and is being further evaluated in an expansion cohort of 10 subjects. Clinical trial information: NCT02672917.
Evaluation of stored liquid biopsies for molecular profiling in patients with non-small cell lung cancer (NSCLC).
Authors: Penelope Ann Bradbury, Keyue Ding, Peter Michael Ellis, Lesley Seymour, Frank De Kievit, Greg Jones, Clive D. Morris, Emma Green, Glenwood D. Goss, Ming Sound Tsao, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2017)

9024 Background: Molecular profiling is often limited by access to sufficient tumour tissue for comprehensive analysis and due to tumour heterogeneity, the complete range of tumor DNA abnormalities may not be represented nor accurately reflect the clinical evolution of disease. Circulating tumour DNA (ctDNA) can be used as a liquid biopsy for molecular abnormalities detection, quantification and monitoring for personalised treatment strategies. Methods: Plasma was collected at baseline (BL) and during study therapy from advanced NSCLC patients (pts) enrolled in a placebo controlled phase III trial of a novel irrerversible EGFR inhibitor; all patients had received standard therapy with chemotherapy and gefitinib or erlotinib. Archival tissue was collected when available but biopsy was not required prior to enrolment. BL Plasma ( &lt; 3ml), stored for ~8 years was used to extract DNA and analysed using InVision (enhanced tagged-amplicon sequencing). Results: BL plasma from 387 pts was tested; 289 pts had available tissue results (from archival tissue collected at diagnosis) for EGFR (174WT/115Mut) and 243 for KRAS (205WT/38Mut). Despite age of plasma samples, ctDNA analysis detected cancer mutations in 310 pts (82%): TP53 (45%), KRAS (15%), and EGFR (43%; 56% were EGFR del19 and 29% L858R); T790M was detected in 80 patients. EGFR mutations were identified in 29 patients and KRAS in 10 patients with unknown tissue status. Also of note, STK11 (32 pts, 12 with KRAS), BRAF (5pts, 3 with V600E), MET(7 pts, 4 with MET amp ), ERBB2 (16pts, 10 with ERBB2 amp ) were identified in ctDNA analysis. Median time and median number of lines of systemic therapy between tissue biopsy and blood was 714 days and 3 lines respectively. Further analyses of ctDNA analyses in context of patient and trial outcomes are in progress. Conclusions: Liquid biopsies provide opportunity to evaluate molecular mutation profile in NSCLC patients. We demonstrate a highly sensitive method for ctDNA analysis which is complementary to tissue molecular analysis.
Second-line (SL) chemotherapy containing oxaliplatin (OXA) in metastatic pancreatic cancer (PC): Whom should we trust?
Authors: Chiara Caparello, Caterina Vivaldi, Francesco Montagnani, Gianna Musettini, Giulia Pasquini, Irene Pecora, Silvia Catanese, Monica Lencioni, Alfredo Falcone, Lorenzo Fornaro, Enrico Vasile
Journal: Journal of Clinical Oncology (2017)

e15719 Background: After the intensification of first-line treatment in metastatic PC the number of patients fit and able to receive a SL treatment is increasing; despite these results, the choice of SL chemotherapy remains a challenging issue. The role of OXA in SL setting has given conflicting results in CONKO-003 and PANCREOX trials; the reasons of this inconsistency are difficult to understand. Methods: In order to detect a possible advantage from the use of oxaliplatin in SL, we pooled together the results of randomized phase II/III studies adding OXA to fluoropyrimidines after a gemcitabine-based first-line. Hazard ratios (HRs) for progression-free (PFS) and overall survival (OS) with 95% confidence intervals (CIs) were extracted, while the number of events was used for RR to determine odds ratio (OR) with corresponding 95%CIs. Fixed-effect and random-effect models were used as appropriate, on the basis of the evidence of a non-significant or significant heterogeneity among trials, respectively. The Review Manager software was used (version 5.3). Results: Three studies were identified; main characteristics and results are summarized in the table. No benefit in overall survival derived from the use of OXA (HR 1.03, 95% CI, 0.64-1.67; p=0.90) but significant heterogeneity was reported (p=0.003); the addition of OXA produced a significant benefit in terms of PFS (HR 0.81, 95% CI 0.68-0.97; p=0.02) with a higher chance of response (OR 1.81, 95% CI 1.01-3.24; P=0.05). Interestingly heterogeneity between trials was less evident in PFS and RR than in OS suggesting that this could be a confounding element in the interpretation of data. Conclusions: The reasons of conflicting results concerning the use of oxaliplatin doublets in SL setting are not clear. Given the recent advances in first-line setting, it would be interesting to identify an optimal sequential strategy, hopefully in a personalized approach. [Table: see text]