tbuckley/cabot-search huggingface dataset:
Royal College of Psychiatrists adds voice to concerns over NICE guidance on depression
Authors: Nigel Hawkes
Journal: BMJ (2019)

Patients coming off antidepressants have a wide range of experiences and some have severe symptoms, the Royal College of Psychiatrists has acknowledged in a statement urging the National Institute for Health and Care Excellence (NICE) to update its guidance.

The college is a late recruit to a campaign that has been waged in The BMJ , the press, and on social media over what is seen as complacency in the face of many complaints from patients. At the heart of the argument is NICE, strongly criticised for a draft revision of its 2009 guidance published in July 2017.

Critics have said that the draft relied on inadequate data and largely ignored the views of patients. This week 35 organisations including the British …
Aircraft Cabin Hypoxia and Adverse Medical Events
Authors: Thomas G. Smith, Nick P. Talbot
Journal: JAMA (2019)

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LONG TERM opioid use in RURAL NON-metastatic colon cancer patients.
Authors: Emilio Paul Araujo-Mino, Ajaz Bulbul, Hamza Minhas, Adriana Bautista, Lisa Lentkowski, Masoud Khorsand-Sahbaie
Journal: Journal of Clinical Oncology (2019)

e15174 Background: Cancer related pain and subsequent long-term opioid (LTO) use worsens the opioid epidemic and facilitates abuse. Non-metastatic colon cancer (CC) is a potentially curable malignancy and prescription opioid (PO) may increase risks of adverse events when CC has been eradicated. Methods: A retrospective study evaluated stage I-III CC patients between January 2013 and January 2018 across rural cancer clinics in New Mexico who received PO during their cancer diagnosis and treatment. It excluded patients with stage IV CC, concurrent malignancies and non-cancer pain. Descriptive statistics, Chi-square and logistic regression were performed to identify correlation and predictors of LTO use. Results: Among 197 patients identified, opioids were prescribed in 24% (48/197); 22 patients met inclusion criteria. Mean age was 65.1±9.8 years; 68% male; Stage I (4.5%), II (36.3%), III (59.1%). Adjuvant chemotherapy was given in 91% (20/22). Oxaliplatin regimen was used in 63.6% (14/22). One year after therapy, 27.3% (6/22) still had neuropathy. The rate of opioid use was 72.7% (16/22) at 3 months, 54.5% (12/22) at 6 months and 41% (9/22) at 12 months; 56.2% (9/16) of opioid users at 3 months were also using opioids at 12 months from initial prescription (X 2 5.71 p = 0.046). Also, 75% (9/12) of opioid users at 6 months, continued using opioids at 12 months (X 2 12.7 p = 0.0001). Patients with smoking history, unemployed and PO from a surgeon, were more likely to be LTO users at 12 months; however, it was not statistically significant. Conclusions: Non-metastatic CC patients who continue to use opioids at 3 months are at a significantly higher risk of LTO use at one year. Biological and social factors in rural communities can be important determinants of this use pattern. The challenges surrounding opioid use and the need for safe and effective alternative analgesics require urgent attention and regulatory discourse.
Preliminary study of S-1 maintenance therapy in extensive stage small-cell lung cancer.
Authors: Keke Nie, Chunling Zhang, Ketao Lan, Youxin Ji
Journal: Journal of Clinical Oncology (2019)

e20080 Background: 4-6 cycles platinum and etoposide (EP) or platinum and irinotecan (IP) chemotherapy is the mainstay treatment for the extensive-stage small-cell lung cancer (SCLC); but the role of maintenance treatment is not fully understood. This study compared the efficacy and toxicities of 4-6 cycles EP or IP chemotherapy treatment followed by S-1 maintenance treatment or placebo control. Methods: In this phase 2, open-label, three-center preliminary study, patients who reached complete response (CR), partial response (PR) or stable disease (SD) after 4-6 cycles of EP or IP therapy were randomly assigned (1:1) with a minimization procedure. One group received oral S-1 25mg/mg 2 twice a day as maintenance treatment until disease progression or unacceptable toxic effects. The other group was received placebo and routine follow-up. The primary end point of this study was progression-free survival (PFS) and the secondary end points were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT03769935. Results: A total of 89 patients were enrolled, of whom 45 received S-1 maintenance therapy and 44 received placebo. The median PFS was 6.35 months in the S-1 group, as compared with 5.98 months in the placebo group (hazard ratio for progression in the S-1 group, 1.057; 95% confidence interval [CI], 0.656-1.707; P = 0.820). The median OS was 10.82 months in the S-1 group, as compared with 10.09 months in the placebo group (hazard ratio for death in the S-1 group, 0.860; 95% CI, 0.374-1.617; P = 0.905). Tumor regression rate influenced patients’ survival. The PFS was 7.2 months and 5.3 months (p = 0.015), and OS was 12.9 months and 10.9 months (p = 0.042) in patients with CR or PR compared to in patients with SD after induction chemotherapy respectively. The adverse events were mild to moderate skin rash and acne, diarrhea, alopecia, dry skin and fatigue; which were mainly induced by induction chemotherapy and S-1 administration. Conclusions: S-1 maintenance treatment for extensive-stage SCLC had acceptable toxicities; however, there was no significant difference in PFS or OS statistically. Further research with novel agents in the maintenance setting is warranted. Clinical trial information: NCT03769935.
Determining clinical relevance of genomic heterogeneity in an ethnically diverse cohort of newly diagnosed patients with breast cancer.
Authors: Padma Sheila Rajagopal, Nike Beaubier, Masaya Hattori, Lise Sveen, Galina Khramtsova, Taylor Abboushi, Mathew Barber, Fang Liu, Toshio Yoshimatsu, Yonglan Zheng, Kevin White, Dezheng Huo, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2019)

3084 Background: The trajectory from early breast cancer to distant metastasis has not been precisely characterized. We are building an ethnically diverse, longitudinal cohort of prospectively ascertained breast cancer patients with integrated genomic, transcriptomic, epidemiological and clinical data, with the goal of identifying biomarkers that can improve on clinical predictors. Methods: Our goal is 500 histologically confirmed invasive cases with a minimum follow-up of 5 years. To date, Tempus Labs, Inc. has completed xT assays (595-gene panel DNA-seq and full-transcriptome RNA-seq) on 127 cases with matched tumor-normal samples. Clinical information was obtained from electronic health records and our cancer registry. Results: Median age of diagnosis was 51, with 47% African-Americans. 73% had stage 2 or 3 disease (2 patients were stage 4). 24.4% had TNBC; 30% had HER2+ and 62.2% HR+ status. Somatic alterations were identified in 560 genes with most common mutations in TP53 (56%), MCL1 (35%), PIK3CA (30%) and ERBB2 (17%). Somatic mutations in BRCA1 (10%) and BRCA2 (5%) were associated with increased tumor mutation burden (TMB). 2 patients were MSI high; 6 were equivocal. After a median follow-up of 6.5 years, 46 patients died and 38 had recurrent disease. With adjustment for clinical factors, TMB showed a slight nonsignificant negative association with recurrence-free survival (HR: 0.97, 95% CI: 0.91-1.00, p = 0.31). TP53 was associated with recurrence-free survival (HR: 1.76, 95% CI 0.94-3.29; p = 0.08) as was MSI (HR: 0.24, 95% CI: 0.06-1.06, p = 0.06). Conclusions: These data support the importance of integrating tumor sequencing in a diverse cohort with full clinical annotation to assess the diversity of actionable genomic alterations at the time of primary diagnosis to develop interventions for prevention of metastases.
The comprehensive geriatric assessment in malignancies and prognostic factors: Description of a prospective cohort of 889 Brazilian elderly cancer patients.
Authors: Jurema Telles O Lima, Raissa Viana, Mirella Rebello, Maria Julia Gonçalves Mello, Letícia telles Sales, Anke Bergmann, Zilda Cavalcanti, Luiz Claudio Santos Thuler
Journal: Journal of Clinical Oncology (2019)

e23035 Background: According to the World Health Organization (WHO), the definition of "elderly" varies according to the degree of development of the country. In Low and Medium Development Countries (LMDC), a person aged 60 or older is considered elder, opposed to developed countries (65 or older). It is in LMDC that is occurring the largest relative increase in the incidence of cancer, specially those related to aging. The Comprehensive Geriatric Assessment (CGA) is still underutilized in oncological clinical practice, especially in LMDC. Objectives: To determine predictive factors for the occurrence of early death (in the first six months of surveillance) and to perform the development and temporal validation of a practical prognostic score based on the CGA to predict early death (up to 180 days) in elderly cancer patients. Methods: A prospective cohort enrolled elderly patients ≥ 60 years with a recent cancer diagnosis admitted between 2015-2017. The CGA performed at the time of admission included the following instruments: CCI; KPS; MMSE; TUG test; IPAQ; ADL; MNA; MNA-SF; GDS15; PPS and Polypharmacy. The studied outcome was early death, defined as the one that occurred within the first six months after the diagnosis. Survival analysis (Kaplan-Meier) and Cox proportional hazard regression was performed. Results: 889 patients were included in the study, performed at a referral center in cancer of a teaching hospital in Northeastern Brazil. The independent risk factors for death identified by CGA were: Mini exam of mental state (MMSE) as a continuous variable (HR 1.04 95% CI 1.00-1.07), Geriatric depression scale (GDS-15) ≥ 10 (HR 1 , 50 IC95% 1.10-2.07), Karnofsky Functional Performance Scale (KPS) &lt; 50 (HR 1.57 IC95% 1.02-2.42), Katz Index ≤4 (HR 2.58 IC95% 1.68-3.97) and the Mininutrition assessment (MAN-SF) &lt; 12 (HR 2.96 IC95% 2.00-4.39), with higher risk for early death amongst patients with abnormalities detected by the scales performed at admission (log rank &lt; 0.001). Conclusions: Comprehensive geriatric assessment is an important tool to identify fragility in elderly cancer patients. Some of its scales should be incorporated into clinical practice, as they are simple and significant prognostic markers and identify patients with a higher risk of death in the first twelve months.
The internet bias toward nontraditional first line prostate cancer treatments.
Authors: Danny Landau, Alec Landau
Journal: Journal of Clinical Oncology (2019)

e16594 Background: Despite relegation to relapsed localized disease per National Comprehensive Cancer Guidelines, we have noticed upticks in cryotherapy and High-intensity focused ultrasound (HIFU) as initial therapy for prostate cancer in Orlando. We believe internet advertisements play a role in this. When directly questioned, patients confirm our belief. We conducted internet searches to analyze the information available to patients. Methods: Utilizing common search engines, Google and Bing, searches were conducted using the terms “cryotherapy prostate cancer” and “HIFU”. The first three pages of general results and sponsored results were broken into categories. The categories include verified information (VI) properly describing the therapies and their indications, advertisement for traditional care (TC) centers, centers that promote nontraditional care (NTC), or information that is unclassifiable/ misleading (other). A final search was done for “alternative prostate cancer treatments”. The results that mentioned HIFU or cryotherapy were counted manually. Results: Cryotherapy Google general search In total, unverified information or advertisements for centers practicing outside of traditional norms were represented in: General search combined: 26/82: 32% Sponsored searches: 54/75: 73% The general search term “alternative prostate cancer” search including HIFU or Cryotherapy General Search: 3/55 (0.05%) Sponsored Search: 8/39 (21%). Conclusions: Using general search terms, it seems that there is a wealth of information that can influence a patient’s decision making on prostate cancer treatment. While there is more information promoting HIFU/ cryotherapy on sponsored searches, general searches have potential for misunderstanding and abuse in nearly a third of cases.[Table: see text][Table: see text][Table: see text][Table: see text][Table: see text][Table: see text][Table: see text][Table: see text]
Extreme Differences in Recombination Rate between the Genomes of a Solitary and a Social Bee
Authors: Julia C Jones, Andreas Wallberg, Matthew J Christmas, Karen M Kapheim, Matthew T Webster
Journal: Molecular Biology and Evolution (2019)

Abstract Social insect genomes exhibit the highest rates of crossing over observed in plants and animals. The evolutionary causes of these extreme rates are unknown. Insight can be gained by comparing recombination rate variation across the genomes of related social and solitary insects. Here, we compare the genomic recombination landscape of the highly social honey bee, Apis mellifera, with the solitary alfalfa leafcutter bee, Megachile rotundata, by analyzing patterns of linkage disequilibrium in population-scale genome sequencing data. We infer that average recombination rates are extremely elevated in A. mellifera compared with M. rotundata. However, our results indicate that similar factors control the distribution of crossovers in the genomes of both species. Recombination rate is significantly reduced in coding regions in both species, with genes inferred to be germline methylated having particularly low rates. Genes with worker-biased patterns of expression in A. mellifera and their orthologs in M. rotundata have higher than average recombination rates in both species, suggesting that selection for higher diversity in genes involved in worker caste functions in social taxa is not the explanation for these elevated rates. Furthermore, we find no evidence that recombination has modulated the efficacy of selection among genes during bee evolution, which does not support the hypothesis that high recombination rates facilitated positive selection for new functions in social insects. Our results indicate that the evolution of sociality in insects likely entailed selection on modifiers that increased recombination rates genome wide, but that the genomic recombination landscape is determined by the same factors.
Incidence and clinical pattern of immune related adverse effects (irAE) due to immune checkpoint inhibitors (ICI).
Authors: Bicky Thapa, Joanna Roopkumar, Ann S Kim, Lorenzo Gervaso, Pradnya Dinkar Patil, Cassandra Calabrese, Alok A. Khorana, Pauline Funchain
Journal: Journal of Clinical Oncology (2019)

e14151 Background: ICIs have revolutionized outcomes in many advanced malignancies, however their use is associated with irAEs. Methods: An IRB-approved, retrospective chart review was done using the Cleveland Clinic pharmacy database. Patients were included who received six FDA approved (nivolumab, ipilimumab, pembrolizumab, atezolizumab, avelumab, or durvalumab) ICIs from July 2015 to December 2017. irAEs were identified from review of electronic medical records. Descriptive analysis was done to evaluate the incidence, pattern, and severity of irAEs. Results: A total of 1091 patients received ICI therapy, 651 (59.7%) were male, 958 (87.4%) white, 95 (8.7%) black. Lung cancer (540, 49.5%) comprised the majority of the cohort, followed by melanoma (152, 13.9%), and renal cell carcinoma (121, 11.1%). About 996 (91.3%) received treatment with only one ICI, 85 (7.8%) with 2 ICIs, and only 10 patients received 3 ICIs. A total of 487 (44.63%) patients encountered irAEs, 128 (11.73%) resulting in treatment cessation. Fatigue (152, 13.9%) was the most common, followed by dermatologic irAEs (131, 12%). Endocrine irAEs occurred in 108 (9.89%), GI toxicities, namely diarrhea and colitis, were seen in 92 (8.4%) and hepatotoxicity in 54 (4.94%). Other irAEs including rheumatologic, pneumonitis, renal, and neurological adverse effects were documented in 6.5%, 5.1%, 2.56%, and 2.01% respectively. Rare irAEs such as ocular toxicity, cardiac toxicity, and vasculitis were seen in 0.8%, 0.73%, and 0.54%, respectively. Compared with a pooled analysis from clinical trials (De Velasco G et al. Comprehensive Meta-analysis of Key irAEs from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients) dermatologic irAEs and fatigue were less frequent; diarrhea/colitis, pneumonitis and rheumatologic irAEs were more frequent. Conclusions: irAEs on ICI therapy are very common. Awareness of the relative frequencies of various irAEs, particularly severe and rare irAEs, in a real-world setting can help improve quality of care for cancer patients receiving ICI. [Table: see text]
Dynamic change of PD-L1 expression on circulating tumor cells in advanced breast cancer undergoing PD-1 blockade therapy.
Authors: Tao Wang, Jinmei Zhou, Shaohua Zhang, Li Bian, Zhiyuan Hu, Zefei Jiang
Journal: Journal of Clinical Oncology (2019)

e14558 Background: PD-1/PD-L1 checkpoint blockade immunotherapy is revolution- izing the therapeutic strategy of malignancies. Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest, especially in breast cancer. Methods: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 20patients with advanced breast cancerwere enrolled who took PD-1 inhibitortherapy. The CTC numeration and the PD-L1 expression levels were analyzedat the begining and ending of treatment . Results: 20 patients were enrolled, 85%(17/20) were triple-negative breast cancer. 65% of patients had visceral metastases, 60% of patients had ≥3 lines of treatment. Prior the treatment of PD-1 inhibitor, 95% (19/20) patients had CTCs, ranging from1 to 53(median 5). 90% (18/20) had PD-L1positive CTCs, and 75% (15/20) had at least one PD-L1high CTCs. The clinical benefit rate(CBR) rate in PD-L1high patients (26.7%) is much higher than the others (0%). we examined the proportion of PD-L1high CTCs relative to total CTCs. The median proportion of PD-L1high CTCs was 33.3%. Patients with ≥33% PD-L1high CTCs had a significantly longer PFS (median 2.6 vs. 1.4 months( P = 0.027). 100% patients with CBR had PD-L1 high CTCs decreased and 46.7% of patients without CBR decreased. Further analysis showed that the mean proportion of PD-L1 high CTCs at baseline and after treatment was 56.8±20.7%, 19.0±23.7%, p = 0.005. There was no significant difference in the mean proportion of PD-L1 high CTCs before and after treatment in the non-CBR group (28.0±26.2%, 30.3±31.5%, p = 0.846). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of PD-L1high CTCscould indicate the therapeutic response at early time.
Retrospective analysis of overall survival (OS) by subsequent therapy in patients (pts) with <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) receiving irinotecan ± cetuximab in the EPIC study.
Authors: Alberto F. Sobrero, Heinz-Josef Lenz, Cathy Eng, Werner Scheithauer, Gary William Middleton, Wen-Feng Chen, Regina Esser, Johannes Nippgen, Howard A. Burris
Journal: Journal of Clinical Oncology (2019)

3580 Background: The multicenter, open-label, randomized, phase 3 EPIC study (EMR 062202-025) investigated cetuximab + irinotecan vs irinotecan as a second-line (2L) therapy in pts with EGFR-detectable mCRC. A retrospective analysis in the EPIC RAS wt population showed improved overall response rate (29.4% vs 5.0%) and progression-free survival (5.4 vs 2.6 mo) upon the addition of cetuximab to irinotecan. Median OS (mOS) was similar in both treatment arms, possibly due to differences in subsequent therapies. We present OS by post-study therapy in the RAS wt population. Methods: 1298 RAS-unselected pts were enrolled from May 2003 to February 2006. The primary endpoint was OS. RAS status was determined retrospectively in 2018 from existing DNA samples using BEAMing technology; wt status was defined as having a sum of mutated RAS allele frequencies of ≤5%, with all relevant alleles being analyzable. Results: Among the 452 pts with RAS wt mCRC, 231 received cetuximab + irinotecan and 221 received irinotecan. Baseline characteristics were similar in both arms. OS data by post-study therapy are summarized in the Table. No new or unexpected safety signals were observed. Conclusions: Post-study cetuximab was associated with improved OS in both treatment arms compared with post-study therapy without cetuximab and no subsequent therapy, suggesting that cetuximab-based therapy may be suitable as a standard treatment for pts with RAS wt mCRC in the rechallenge setting. Study limitations include a potential bias due to the differences in proportion of subsequent therapies with and without cetuximab between arms (almost 50% of pts in the irinotecan arm received post-study cetuximab) as well as the likelihood for pts who live longer to receive cetuximab in any subsequent therapy line. [Table: see text]