tbuckley/cabot-search huggingface dataset:
Screening patients for fluoropyrimidine-related toxicity risk.
Authors: Olivier Capitain, Valérie Seegers, Jean-Philippe Metges, Roger Faroux, Claire Stampfli, Marc Ferec, Tamara Matysiak-Budnik, Helene Senellart, Valerie Rossi, Nadege Blouin, Michele Boisdron-Celle, Jonathan Dauve, Mario Campone
Journal: Journal of Clinical Oncology (2019)

3529 Background: Severe, sometimes fatal, toxicity can occur during the 1 st or 2 nd course of chemotherapy using fluoropyrimidines (FPs), and poses a serious public health problem. FPs carry a 3-5% risk of grade ≥ 3 early toxicities and 0.2% risk of death linked to Dihydropyrimidine Dehydrogenase (DPD) deficiency. Methods: Of 29,000 patients screened since July 2000, 472 were referred to us due to severe toxicity during 1 st round 5-FU, or because pre-screening was done too late. Toxicity evaluation was performed according to the NCI scale of adverse reactions to cancer drugs (0=none, 5=death). Patients were previously 5-FU naïve, had different cancers, and received various protocols, eg. 5FU or Capecitabine; bolus±continuous or per os. The reliability of the following 4 pre-treatment screening tests to predict grade≥ 4 toxicity was assessed: 1) DPYD genotype mutation (*2A,*2B,*7, 13, HapB3) 2) Plasma uracil (U) level, 3) Plasma dihydrouracil/uracil ratio (UH 2 /U) 4) a multiparametric approach with genotyping, UH 2 /U ratio and key patient factors (age, sex, etc.). McNemar’s test with Bonferroni correction was used for statistical analysis. Results: Of the 472 referred patients, 169 had grade 4 or 5 toxicity, of which 41 died from toxicity. 98 had one or plus DPYD mutation: 42(42.9%)*2A; 43(43.9%)*2B; 3(3%)*7; 4(4%)*13; 8(8.16%) HapB3; 1 was homozygous *2A. Data below compare the 4 screening methods for predicting grade 4-5 toxicity. Conclusions: The multiparametric approach is statistically (p&lt;0.0001) the most efficient in terms of preventing grade 4 and 5 toxicity (death) due to 5-FU treatment. Around 290,000 patients are treated with 5-FU per year in the USA. Assuming a 0.2% mortality rate due to toxicity, around 580 lives could be saved per year using the multiparametric pre-treatment test. [Table: see text]
Real-world clinical burden of aggressive disease (AD) in advanced/metastatic non small cell lung cancer (aNSCLC).
Authors: Marta Batus, Victoria Jennifer Stefaniak, Cliff Molife, Jeffrey Melson Clarke, Katherine B. Winfree, Lucy Mitchell, Zhanglin Lin Cui, Philip D. Bonomi
Journal: Journal of Clinical Oncology (2019)

e20723 Background: Clinical trials have shown that aNSCLC patients (pts) with AD, including those with rapid disease progression (RDP) on initial therapy (time to progression ≤ 12 weeks), have poor prognosis. This retrospective study evaluates the real world clinical burden associated with AD, defined as the difference in clinical effectiveness outcomes during subsequent treatment following RDP v non-RDP on platinum-based (Pt) therapy. Methods: Adult aNSCLC pts receiving standard post-Pt progression therapy (immune checkpoint inhibitors, single agent chemo, ramucirumab) between 03/01/2015 and 06/30/2018, after Pt therapy, with ≥ 3 months of potential follow up, were identified in the Flatiron EHR-derived deidentified database and assigned to RDP (n = 158) and non-RDP (n = 518) cohorts. Real-world tumor response (rwTR) was collected using technology-enabled abstraction. Overall survival (OS) from start of 1L, and real-world (rw) progression free survival (PFS) &amp; rw tumor response outcomes (rw objective response rate [rwORR], rw disease control rate [rwDCR], rw time to first response [rwTTFR], rw duration of response [rwDOR] &amp; rw best response [rwBR]) during post-Pt progression therapy were estimated. Results: Of 676 eligible pts, 23% had RDP. Clinical outcomes in the RDP and non-RDP cohorts are shown in table. Conclusions: Findings from this real world cohort underscore the clinical burden &amp; unmet medical need for more effective treatment strategies in pts with aggressive aNSCLC pts who rapidly progress on initial therapy. As the treatment landscape evolves, characterization of these pts is warranted to identify potential risk factors. [Table: see text]
How Long Does Antidepressant Withdrawal Typically Last?
Authors: Michael P. Hengartner, James Davies, John Read
Journal: American Journal of Psychiatry (2019)

In the December 2018 issue of the Journal, Jha and colleagues (1) claim that antidepressant withdrawal typically resolves spontaneously over 2-3 weeks.They offer only three references in support.Two of these were case reports that included one and three patients (2, 3).In Pyke (3), the withdrawal reaction resolved in 3 weeks, whereas in the case report by Frost and Lal, withdrawal symptoms lasted between 3 and 23 weeks (2).The third reference, a small cohort study of 20 patients by Fava et al. ( 4), reported that a withdrawal reaction was observed in nine patients (45% of all patients examined), even though the drugs were tapered at the slowest possible pace.The withdrawal syndrome subsided within 4 weeks in six patients (67% of all patients experiencing withdrawal), whereas in three patients (33% of all patients with withdrawal), serious withdrawal symptoms persisted for several months after discontinuation.Not only did Jha and colleagues select only three studies, representing a total of just 24 patients, but the three studies they present to readers as evidence for their 2-3 weeks claim do not actually support their claim at all.In Frost and Lal (2), the three individual withdrawal reactions described lasted between 3 and 23 weeks, and in Fava et al. ( 4), withdrawal effects lasted considerably longer than 4 weeks in one-third of patients.Based on this evidence, the conclusion that withdrawal reactions "typically resolve spontaneously over 2-3 weeks" is fallacious and arbitrary.Moreover, two references were merely case reports, which have very little external validity.In our view, it is problematic to quote (or, rather, misquote) such anecdotal evidence to corroborate a controversial claim that should represent the broader antidepressant user population.Although there undoubtedly is a need for more research on this important issue, systematic reviews of the existing literature conclude that withdrawal is common, is often severe, and frequently lasts much longer than merely 2-3 weeks, with and without tapering (5, 6).
<i>RSPO2</i> abnormal transcripts result from read-through in liver tumours with high ß-catenin activation and <i>CTNNB1</i> mutations
Authors: Quentin Bayard, Jean-Charles Nault, Jessica Zucman-Rossi
Journal: Gut (2019)

Thomas Longerich and collaborators1 recently published an intriguing observation in hepatocellular adenoma (HCA) showing an activation of the Wnt/s-catenin signalling pathway without CTNNB1 or APC mutations. The authors identified a recurrent deletion leading to a fusion between a short interspersed nuclear element (SINE) sequence and RSPO2 gene in three HCAs and three hepatocellular carcinomas (HCCs) all activated for s-catenin, including one tumour with CTNNB1 mutations and five tumours without APC or CTNNB1 mutations. The authors proposed RSPO2 fusion as a recurrent mechanism of s-catenin activation in liver tumourigenesis.

Following this original observation, we analysed the expression and rearrangement of RSPO2 in a series of 10 HCAs and 163 HCCs analysed with RNAseq. We identified a correlation of RSPO2 mRNA expression with several genes known to be positively …
Prediction of olaparib sensitivity for variants of unknown significance in homologous repair genes.
Authors: Sandy Chevrier, Isabelle Desmoulins, Laure Favier, François Ghiringhelli, Leila Bengrine, Laurent Arnould, Romain Boidot
Journal: Journal of Clinical Oncology (2019)

3108 Background: the recent use of PARP inhibitors in clinical practice gives very interesting outcome for ovary tumors with BRCA1 or BRCA2 mutation but also in other tumors with homologous repair deficiency. Nevertheless, no hotspot mutations are present, consequently, more than 85% of observed variants have unknown significance, blocking the use of PARP inhibitor. Methods: Exome analysis was performed on a cohort of 27 patients treated with olaparib. After bioinformatics analyses, variant interpretation was performed by interrogating different databases. For variants of unknown significance (VUS), PROVEAN software and allelic frequency normalized with tumor cellular content were used to classify VUS as potentially benign or potentially deleterious. Results: Among the 27 patients analyzed, 16 harbored already classified variants (3 benign and 13 pathogen variants) and 11 had VUS. The first Progression Free Survival (PFS) analysis showed that benign variants did not respond to olaparib with a median survival of 62 days, whereas pathogenic variants had a median of 109 days. Surprisingly, VUS had a median of 136 days, suggesting that some of them could be classified as potentially deleterious. On the subset of 11 patients with VUS, we applied PROVEAN prediction classifying 5 variants as benign and 6 variants as deleterious, with a median PFS of 54 days and 140 days ( p=0.3235), respectively. With the second prediction, based on variant allelic frequency, we obtained PFS of 73.5 months for benign variants and 210 days for deleterious ones ( p=0.29). By combining both predictions, we classified as benign, VUS predicted benign with both predictions, and as deleterious, VUS predicted as deleterious with at least one prediction. Consequently, we perfectly discriminated benign from deleterious variants with a median PFS of 36 days for predicted benign and 177 days for predicted deleterious ( p=0.0084). From all patients, PFS were significantly different ( p=0.0003) between benign (n=6, 56 days) and deleterious variants (n=21, 140 months). Conclusions: Our work tends to show that VUS of homologous repair genes could be predicted as benign or deleterious, and could increase the number of patients eligible for a treatment by PARP inhibitors. The number of patients needs to be increased in order to validate our prediction algorithm.
Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling.
Authors: Wang Xiao Jia, Zhan-Hong Chen, Tian Sun, Zi Yan Yang, Yabing Zheng, Ruoying Yu, Xue Wu, Junrong Yan, Yang Shao, Xiying Shao, Jian Huang, Cao Wenming
Journal: Journal of Clinical Oncology (2019)

e12502 Background: Circulating tumor DNA (ctDNA) from liquid biopsy provides a valuable assessment of invasive breast cancer (BC). We evaluated the utility of ctDNA to reflect the efficacy of HER2-targeted trastuzumab in treating HER2+ BC patients, as well as chemotherapy in treating HER2- BC patients, to monitor trastuzumab and chemotherapy resistance mechanisms. Methods: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed in 41 plasma biopsy samples from 19 HER2+ and 12 HER2- BC patients in a retrospective study. We compared ctDNA somatic mutations and germline mutations for analyzing acquired and innate resistance, respectively. Results: ERBB2 somatic copy number of HER2+ BC patients who developed progressed diseases to HER2-target therapy was significantly higher than those benefited from HER2-target therapy. HER2+ BC patients who developed acquired resistance to trastuzumab showed frequent genomic alterations on ERBB2, TP53, EGFR, NF1 and SETD2 genes. Specifically, in longitudinal analyses, somatic mutations found in the original breast tumor can be detected in the liver metastasis and plasma ctDNA with increased allele frequencies. Newly emerged deleterious mutations occurred when the patient was benefiting from trastuzumab, predicting the poor prognosis. From these newly emerged somatic mutations, EBBB2 L869R was further investigated in vitro and contributed to trastuzumab resistance. In the HER2- BC patients with chemotherapy resistance, frequently genetic alterations on TP53, PIK3CA and DNA damage repair genes were observed in ctDNA mutation profiling. Conclusions: liquid biopsy ctDNA, particularly longitudinal analyses, provides insights into targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2- BC patients, respectively.
Gaps in metastatic breast cancer patient knowledge and understanding in Mexico.
Authors: Cynthia Villarreal-Garza, Alan Fonseca, Claudia Pineda, Ana Platas, Fernanda Rivera, Fernanda Mesa-Chavez, Marisol García-García, Ariel Jasqui, Sylvia de la Rosa-Pacheco, Alejandra Platas
Journal: Journal of Clinical Oncology (2019)

1090 Background: Among patients with metastatic breast cancer (MBC), there is paucity of data regarding knowledge and understanding about disease stage and goals of treatment. The limited evidence shows that up to 40% of MBC patients ignore their stage and reports inadequate educational resources and support. Aim: To assess MBC patients’ knowledge of their disease and satisfaction with the medical information received. Methods: 185 patients diagnosed with MBC who attended follow-up medical appointments at INCan from June to December 2018 were asked to complete a survey to assess their knowledge on MBC curability, subtype, topics reviewed with the oncologist, need of additional information regarding MBC and satisfaction with the quality of the information they received. Clinical data was obtained from the medical records. Descriptive statistics were applied, and the association between qualitative and quantitative variables was assessed with the Chi square test and the Mann Whitney U test, respectively. This study was supported by the SPARC mBC Challenge. Results: Only 52% of patients knew that their disease is not curable, while 31% were not sure and 17% thought it was curable. 82% ignored their MBC subtype and 81% reported to want more information about their cancer. 64% scored their satisfaction with the provided information ≥9 (out of 10), and 74% stated that their most helpful source of information was the medical staff. A statistically significant association was found between the perception of the impossibility of curing MBC and better patient satisfaction (p = 0.038). Likewise, better patients’ satisfaction was associated with older age (p = 0.002), longer time since initial diagnosis (p = 0.018) and since diagnosis of MBC (p = 0.014). Conclusions: Our results dramatically illustrate the lack of understanding patients have regarding their cancer, even when reporting high satisfaction with the received information, and identify a critical need for improvement of healthcare providers’ communication skills. Directed efforts should be implemented to enhance patients’ comprehension to promote their participation in decision-making processes, adherence and, ultimately, outcomes.
Revisiting the ethics of phase 1 oncology trials in the era of precision medicine: A systematic review.
Authors: Michael Patrick Mackley, Nicholas R Fernandez, Benjamin Fletcher, Christy Woolcott, Conrad Vincent Fernandez
Journal: Journal of Clinical Oncology (2019)

e14060 Background: Phase 1 clinical trials are a crucial step in the evaluation of new cancer therapies. However, critics cite a low rate of response to therapy (5%), together with a not insignificant risk of death from associated toxicities (0.5%), suggesting a risk-benefit ratio that may limit the ethics of inviting patients to participate in Phase 1 trials. With the introduction of novel targeted therapies, a contemporary estimate of the risks and benefits is needed. Methods: A systematic review was conducted. Eligible for inclusion were phase 1 trials in both adult and pediatric populations published between Jan 2015 to July 2018 of targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents for solid and hematological malignancies. We systematically searched PubMed and Embase. Rates of objective response (complete and partial), stable disease, and Grades 3, 4 and 5 treatment-related adverse events were extracted and pooled. The protocol was prospectively registered in PROSPERO (CRD42018100386). Results: 116 trials (109 adult, 6 pediatric, 1 mixed) met inclusion criteria. The studies reported on nearly 4300 patients (52% male, 48% female), ages ranging from 1 to 90. Most trials reported on molecularly targeted therapies (58%), followed by immunomodulators (33%). The combined overall objective response rate was 6% (95% CI 4% to 8%), with a complete response rate of 0.3% (0.1% to 0.7%) and a partial response rate of 5% (3% to 7%). The rate of stable disease was 34% (30% to 38%). Of the three types of therapies, the objective response rate appeared highest in the molecularly targeted therapies, at 8% (5% to 11%). Overall, the rate of treatment-related deaths was 0.02% (0% to 0.2%). Conclusions: Our results suggest that response rates for single agent, targeted phase I anti-cancer therapies are not materially different from estimates derived in the conventional chemotherapy setting. In an era where providers tout the benefits of precision medicine, this is an important consideration when counselling patients considering participation in phase I trials. Treatment-related death rates were very low, weakening criticism that participation puts patients at great risk. Reporting was highly inconsistent across included studies, highlighting a need to improve the quality of reporting in phase I trials.
Influence of changes in cholesterol levels and disease activity on the 10 years cardiovascular risk estimated with different algorithms in rheumatoid arthritis patients
Authors: Marco Fornaro, Fabio Cacciapaglia, Vincenzo Venerito, Giuseppe Lopalco, Florenzo Iannone
Journal: Annals of the Rheumatic Diseases (2019)

persisted at 6 months.RRS showed a decrease of estimated CV risk score only after 6 months.On the contrary the 'Progetto Cuore' and the QRISK3-2018 scores did not change neither at three nor at 6 months of follow-up (table 1).Our study shows that the changes in lipid levels and disease activity have different weight on different CV risk scores.Changes in disease activity influence algorithms encompassing RA-related CV risk factors, such as RRS and ERS-RA, for which the timing can impact on the score result.Instead, since QRISK3-2018 and 'Progetto Cuore' scores seem not suffer of the changes in Tot-Chol levels and disease activity, they may be used at any time and level of disease activity by rheumatologists in daily clinical practice.
Relationship between cholangitis, initial chemotherapy regimen, and overall survival in patients with unresectable pancreatic adenocarcinoma.
Authors: Melissa Lumish, Thomas Wang, Elijah Darnell, Yasmin Hernandez-Barco, Kumar Krishnan
Journal: Journal of Clinical Oncology (2019)

e15788 Background: Chemotherapy remains the primary therapy for patients with unresectable pancreatic adenocarcinoma, though response to therapy is variable. Patients with pancreatic adenocarcinoma frequently develop jaundice and cholangitis and require endoscopic biliary stenting. Here, we investigate the association between cholangitis, initial chemotherapy regimen, and one-year survival in patients with unresectable pancreatic adenocarcinoma. Methods: We conducted a retrospective chart review of all patients who received metal stents for biliary obstruction with pancreatic adenocarcinoma over a five-year period at the Massachusetts General Hospital. Only patients with unresectable cancer were included. We compared the association between survival and cholangitis within four subgroups: no chemotherapy, gemcitabine alone or in combination, FOLFOX combination and FOLFIRINOX. The statistical methods used were the chi-squared test for categorical variables, regular ANOVA for continuous variables, and log-rank (Mantel-Cox) test for survival analysis. Results: In total, we identified 74 patients who did not develop cholangitis and 52 patients who developed at least one episode of cholangitis. Among patients undergoing chemotherapy, cholangitis was associated with decreased survival within each subgroup (p-value = &lt; 0.001). At one year from diagnosis, there was an association between cholangitis and decreased survival among patients receiving chemotherapy, independent of the number of episodes of cholangitis. Among those who were not receiving chemotherapy, cholangitis was not associated with survival outcome (p-value = 0.60). Conclusions: In conclusion, the development of cholangitis in patients receiving chemotherapy for metastatic pancreatic cancer is associated with decreased survival. This association is not affected by the number of episodes of cholangitis or by chemotherapy regimen. These data suggest that the development of cholangitis among patients receiving chemotherapy for pancreatic cancer may be a predictor of poor clinical outcomes. Further studies are needed to understand the impact of the local tumor microbial environment and to determine whether cholangitis is a surrogate for a more aggressive disease phenotype.
A functional measurement of MAPK pathway activation to predict response to MEK inhibitors in RAS-mutated patients.
Authors: Shumei Kato, Robert Porter, Ryosuke Okamura, Ori Zelichov, Gabi Tarcic, Michael Vidne, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2019)

3071 Background: MEK inhibitors can be used to treat patients with mutations that affect the MAPK pathway. Several MEK inhibitors are currently FDA-approved and effectively treat BRAF-mutated tumors, but RAS-mutated cancers are considered more resistant. However, it is unclear how the many distinct RAS variants impact the MAPK pathway and are affected by MEK inhibitors. We hypothesized that the level of MAPK pathway activation induced by different RAS mutations may predict response to MEK inhibition. Methods: Thirteen RAS mutations from 34 patients treated with MEK inhibitors at UCSD were synthesized, expressed in a HeLa-derived cell line and analyzed in vitro using a functional mutational analysis assay based on assessing downstream reporters in order to measure the activity of these mutations on the MAPK pathway. Each mutation received an activity score based on known oncogenic RAS mutation. Results: The most common type of cancer was colorectal cancer (N = 13). All patients received the MEK inhibitor, trametinib, based therapy. Patients were stratified into two groups: above an activity score of 1 (14 pts) or below it (20 pts). Median progression-free survival (PFS) after MEK inhibitor treatment correlated with higher MAPK activity score (9 vs 3 months; P = 0.041). Conclusions: Using a novel functional assay methodology for characterization of MAPK activation, we show that various RAS mutations activate the MAPK pathway to different levels. Higher activity is associated with longer PFS after MEK inhibitor treatment, suggesting that the relationship between signal transduction strength and clinical relevance merits additional exploration.