tbuckley/cabot-search huggingface dataset:
Association Between Neurological Disorders and Death by Suicide in Denmark
Authors: Annette Erlangsen, Egon Stenager, Yeates Conwell, Per Kragh Andersen, Keith Hawton, Michael Eriksen Benros, Merete Nordentoft, Elsebeth Stenager
Journal: JAMA (2020)

<h3>Importance</h3> Neurological disorders have been linked to suicide, but the risk across a broad spectrum of neurological disorders remains to be assessed. <h3>Objectives</h3> To examine whether people with neurological disorders die by suicide more often than other people and to assess for temporal associations. <h3>Design, Setting, and Participants</h3> Nationwide, retrospective cohort study on all persons 15 years or older living in Denmark, from 1980 through 2016 (N = 7 300 395). <h3>Exposures</h3> Medical contact for head injury, stroke, epilepsy, polyneuropathy, diseases of myoneural junction, Parkinson disease, multiple sclerosis, central nervous system infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington disease, dementia, intellectual disability, and other brain diseases from 1977 through 2016 (n = 1 248 252). <h3>Main Outcomes and Measures</h3> Death by suicide during 1980-2016. Adjusted incidence rate ratio (IRRs) were estimated using Poisson regressions, adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and self-harm. <h3>Results</h3> Of the more than 7.3 million individuals observed over 161 935 233 person-years (49.1% males), 35 483 died by suicide (median duration of follow-up, 23.6 years; interquartile range, 10.0-37.0 years; mean age, 51.9 years; SD, 17.9 years). Of those, 77.4% were males, and 14.7% (n = 5141) were diagnosed with a neurological disorder, equivalent to a suicide rate of 44.0 per 100 000 person-years compared with 20.1 per 100 000 person-years among individuals not diagnosed with a neurological disorder. People diagnosed with a neurological disorder had an adjusted IRR of 1.8 (95% CI, 1.7-1.8) compared with those not diagnosed. The excess adjusted IRRs were 4.9 (95% CI, 3.5-6.9) for amyotrophic lateral sclerosis, 4.9 (95% CI, 3.1-7.7) for Huntington disease, 2.2 (95% CI, 1.9-2.6) for multiple sclerosis, 1.7 (95% CI, 1.6-1.7) for head injury, 1.3 (95% CI, 1.2-1.3) for stroke, and 1.7 (95% CI, 1.6-1.8) for epilepsy. The association varied according to time since diagnosis with an adjusted IRR for 1 to 3 months of 3.1 (95% CI, 2.7-3.6) and for 10 or more years, 1.5 (95% CI, 1.4 to 1.6,<i>P</i> &lt; .001). Compared with those who were not diagnosed with a neurological disorder, those with dementia had a lower overall adjusted IRR of 0.8 (95% CI, 0.7-0.9), which was elevated during the first month after diagnosis to 3.0 (95% CI, 1.9-4.6;<i>P</i> &lt; .001). The absolute risk of suicide for people with Huntington disease was 1.6% (95% CI, 1.0%-2.5%). <h3>Conclusions and Relevance</h3> In Denmark from 1980 through 2016, there was a significantly higher rate of suicide among those with a diagnosed neurological disorder than persons not diagnosed with a neurological disorder. However, the absolute risk difference was small.
Quantification of immune response after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.
Authors: William M. Kamp, Hong-Jai Park, Ryan J. Slovak, Johannes M. Ludwig, Insoo Kang, Hyun S. Kim
Journal: Journal of Clinical Oncology (2020)

160 Background: Checkpoint inhibitors have demonstrated significant clinical impact in colorectal cancer with deficient mismatch repair (MMR) and high microsatellite instability. However, most patients have disease with stable microsatellites and typically respond poorly to most immunotherapies. The purpose of this study was to quantify the immune responses induced by mono versus dual immune checkpoint blockade (DICB) in a MMR proficient model of colorectal cancer. Methods: A MMR proficient model of colorectal cancer was established in 30 BALB/c mice via bilateral subcutaneous flank injections of 0.5x10 6 CT26.WT murine colorectal cancer cells (CRL- 2638; ATCC, Manassas, VA). Mice were assigned to receive either sham antibodies (InVivoMAb IgG controls), monotherapy with anti-PD-1 antibodies (Clone J43; BioXcell, West Lebanon, NH, USA), or DICB with anti-PD-1 and anti-CTLA-1 antibodies (Clone 9D9; BioXcell). Tumor growth was monitored over time and mice were sacrificed at either 7 or 14 days post-treatment. Single cell suspensions of harvested tumors and spleens were analyzed using FACS. The number of CD8 + and CD4 + T cells as well as the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3 was quantified in each sample. Results: DICB was associated with a reduction in tumor volume as compared to either mono PD-1 inhibition or control (p &lt; 0.05). Neither monotherapy nor DICB significantly affected tumor infiltration by lymphocytes. Tumor infiltrating CD8 + T cells in the DICB treatment group demonstrated less expression of PD-1 and LAG3 compared to the control and monotherapy groups (PD-1: 1723±90.5 [Mean fluorescence intensity ± SEM] vs 2489±119.9 &amp; 2404±117.9; p &lt; 0.05) (LAG3: 453.8±21.58 vs 664.1±53.21 &amp; 719.7±14.25; p &lt; 0.05). The DICB group also showed increased expression of TIM3 (11,779±1271 vs 2832±380.9 &amp; 4081±426.6; p &lt; 0.05). Conclusions: These results suggest dual therapy with anti-CTLA and anti-PD-1 antibodies inhibits the growth of stable microsatellite colorectal cancer by suppressing key immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism that could be a target for future combination immunotherapies.
Proteomic Profiling of the ECM of Xenograft Breast Cancer Metastases in Different Organs Reveals Distinct Metastatic Niches
Authors: Jess D. Hebert, Samuel A. Myers, Alexandra Naba, Genevieve Abbruzzese, John M. Lamar, Steven A. Carr, Richard O. Hynes
Journal: Cancer Research (2020)

Abstract Metastasis causes most cancer-related deaths, and one poorly understood aspect of metastatic cancer is the adaptability of cells from a primary tumor to create new niches and survive in multiple, different secondary sites. We used quantitative mass spectrometry to analyze the extracellular matrix (ECM), a critical component of metastatic niches, in metastases to the brain, lungs, liver, and bone marrow, all derived from parental MDA-MB-231 triple-negative breast cancer cells. Tumor and stromal cells cooperated in forming niches; stromal cells produced predominantly core, structural ECM proteins and tumor cells produced a diverse array of ECM-associated proteins, including secreted factors and modulators of the matrix. In addition, tumor and stromal cells together created distinct niches in each tissue. Downregulation of SERPINB1, a protein elevated in brain metastases, led to a reduction in brain metastasis, suggesting that some niche-specific ECM proteins may be involved in metastatic tropism. Significance: Tumor and stromal cells together create distinct ECM niches in breast cancer metastases to various tissues, providing new insight into how tumor cells adapt to survive in different tissue environments.
Phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2).
Authors: Benjamin Adam Weinberg, Hongkun Wang, Katrina Pedersen, Amikar Sehdev, Max W. Sung, Jimmy J. Hwang
Journal: Journal of Clinical Oncology (2020)

TPS593 Background: Biliary tract cancers (BTCs) are rare and aggressive malignancies. The current standard of care for advanced BTC is gemcitabine (GEM) plus cisplatin . Although there is no established second-line treatment, regimens such as FOLFOX, XELOX, FOLFIRI, XELIRI, GEM, and capecitabine have activity. Nal-IRI contains IRI free base encapsulated in liposome nanoparticles which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral levels of SN-38 compared with IRI. FU/LV/nal-IRI has shown overall survival benefit and acceptable toxicity in patients (pts) with metastatic pancreatic adenocarcinoma following GEM-based therapy in the NAPOLI-1 trial. Methods: This is a single arm, open label, multicenter phase II study of pts with advanced BTC previously treated with gemcitabine plus platinum chemotherapy. Pts will receive nal-IRI 70 mg/m 2 IV over 90 minutes, LV 400 mg/m 2 IV over 30 minutes, and FU 2400 mg/m 2 over 46 hours, every 14 days. The primary objective is to determine progression-free survival (PFS) rate at 4 months (4mo) using RECIST v. 1.1 criteria and central radiology review. Response assessments will occur using imaging every 8 weeks. All pts who receive at least 1 dose of the study treatment will be eligible for the primary analysis. We will substitute pts who screen fail or do not begin treatment. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy is 3 months with a PFS 4mo of 30%. FU/LV/nal-IRI would be of interest if it could increase the PFS 4mo to 50% or higher. We will use a 2-stage Simon Minimax design. Using a one-sided α of 0.05 and 80% power, 39 pts will be required to detect a difference in PFS 4mo between 30% and 50%. Assuming a dropout rate of 10%, 44 pts will be enrolled across the 5 study sites. Enrollment began in Q2 2019. Clinical trial information: NCT04005339.
Early nutritional risk assessment by NRS 2002 to predict survival in patients with advanced biliary tract cancer.
Authors: Se Eung Oh, Hei-Cheul Jeung
Journal: Journal of Clinical Oncology (2020)

505 Background: Biliary tract cancer (BTC) has heterogenous disease with dismal prognosis. We investigated the predictors of overall survival (OS) among Korean patients with advanced BTC according to their baseline nutritional risks estimated by Nutritional Risk Screening (NRS) 2002 score. Methods: From September 2006 to July 2017, we retrospectively reviewed the data of 601 patients with BTC. Data on demographic and clinical parameters were collected from electronic medical records, and overall survival (OS) and progression-free survival (PFS) was estimated using the Kaplan–Meier method. Stepwise Cox regression analysis was used to determine the factors associated with survival. Patients with a NRS 2002 score ≤2 were classified as “no-risk; ” those with a score of 3 were classified as “moderate-risk; ” and those with a score of ≥4 were classified as “high-risk.” Results: Following nutritional screening at baseline, 333 patients (55%) were classified as the “no risk” group; 109 patients (18%), as the “moderate risk” group; and 159 patients (27%) as the “high risk” group. Survival analysis showed significant differences in the median OS according to the NRS 2002 groups: “no risk” group: 12.6 months (95% CI: 11.5–13.7); “moderate risk” group: 6.1 months (95% CI: 4.3–8.0); and “high risk” group: 3.9 months (95% CI: 3.2 – 4.6) (p&lt;0.001). On the Cox’s regression analysis, NRS 2002 score came out as the most independent factor for OS (for “moderate-risk” HR 1.610, 95% CI 1.288-2.027, p&lt;0.001; for “high-risk”, HR 2.121, 95% CI 1.728-2.612, p&lt;0.001), compared with other prognostic factors including liver metastasis, peritoneal seeding, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, cholesterol, CEA, and CA19-9. Conclusions: Our study demonstrated OS of advanced BTC was strongly related to their baseline nutritional status assessed by NRS 2002. Constitutional nutritional assessment can help to improve patient prognosis through proactive and individualized nutritional intervention. Baseline nutritional status should be integrated for implementing prognostic scoring system, which can provide more sophisticated risk stratification of patients with metastatic BTC.
Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma.
Authors: Hongjae Chon, Chang Gon Kim, Sangeun Yoon, Chan Kim, Beodeul Kang, Hye Jin Choi, Ho Yeong Lim
Journal: Journal of Clinical Oncology (2020)

550 Background: Immune checkpoint blockade with PD-1 inhibitors has shown promising clinical efficacy in patients with hepatocellular carcinoma (HCC). However, emerging evidences show that PD-1 blockade can sometimes lead to a flare-up of tumor growth with rapid clinical deterioration (hyperprogressive disease, HPD). This study aimed to evaluate the incidence and pattern of HPD in a multicenter, real-world cohort of East Asian patients with advanced HCC treated with PD-1 blockade. Methods: We enrolled 148 advanced HCC patients treated with nivolumab between March 2016 and December 2018 in Korea. Clinicopathologic variables, tumor growth dynamic, and treatment outcomes were comprehensively analyzed. Progressive disease was assessed using tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF), and patient with HPD were defined as those who met the criteria of progressive disease by both TGK and TGR. Results: In this large cohort of HCC patients, the median age was 60 years and the majority were male (85%) and HBV-infected (72%). The objective response rate was 17.6% including two complete responders (1.4%). Ongoing responses were seen in 46% of responders at data cut-off. The incidence of HPD after PD-1 blockade was 23%. HCC patients with HPD had dismal prognosis with worse progression-free survival (PFS) and overall survival (OS) (HR, 1.947; 95% CI, 1.226-3.093 and HR, 1.839; 95% CI, 1.108-3.055, respectively) than progressive disease without HPD. Among various baseline clinicopatholgic parameters, elevated neutrophil-to-lymphocyte ratio (NLR) was only significantly associated with HPD. The optimal cut-off value of NLR for HPD prediction was 3.74 determined by ROC curves, and NLR &gt; 3.74 was associated with worse PFS and OS. Conclusions: The real-world efficacy of PD-1 blockade in HCC patients was consistent with previous studies. However, there was also a corresponding risk of HPD as well as a clinical benefit. Therefore, careful patient selection using immunologic biomarkers, such as NLR, could enhance the therapeutic benefit of PD-1 blockade in clinical trials and real-world practice of HCC
Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040.
Authors: Thomas Yau, Vittorina Zagonel, Armando Santoro, Mirelis Acosta-Rivera, Su Pin Choo, Ana Matilla, Aiwu Ruth He, Antonio Cubillo Gracián, Anthony B. El-Khoueiry, Bruno Sangro, Tarek Eldawy, Jordi Bruix, Giovanni Frassineti, Gina M. Vaccaro, Marina Tschaika, Christian Scheffold, Yun Shen, Jaclyn Neely, Fabio Piscaglia
Journal: Journal of Clinical Oncology (2020)

478 Background: The programmed death-1 inhibitor NIVO had durable responses and a manageable safety profile in pts with aHCC in CheckMate 040 (NCT01658878; El-Khoueiry et al. Lancet 2017) and is approved in the United States, Canada, Australia, and elsewhere for sorafenib (SOR)-treated pts with aHCC. In another CheckMate 040 cohort, NIVO + IPI combination therapy had durable responses in SOR-treated pts with aHCC, with objective response rates (ORRs) &gt; 30% in each dosing arm (Yau et al. J Clin Oncol 2019). CABO is also approved for SOR-treated pts with aHCC; a pivotal phase 3 trial reported median overall survival (OS) of 10.2 mo (Abou-Alfa et al. N Engl J Med 2018). This is the first report of efficacy and safety of NIVO + CABO +/- IPI (doublet and triplet) combinations in pts with aHCC. Methods: SOR-naive or -experienced pts with aHCC were randomized to 2 arms: [1] NIVO 240 mg Q2W + CABO 40 mg daily or [2] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W + CABO 40 mg daily. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included ORR (investigator assessed using RECIST v1.1) and safety/tolerability. Data cutoff was January 2019. Results: 71 pts were randomized to NIVO + CABO (n = 36) or NIVO + IPI + CABO (n = 35). Investigator-assessed ORR was 17% (6 pts with partial response [PR]) in the NIVO + CABO arm and 26% (9 pts with PR) in the NIVO + IPI + CABO arm. Disease control rate was 81% for the NIVO + CABO arm and 83% for the NIVO + IPI + CABO arm; median progression-free survival was 5.5 mo for the NIVO + CABO arm and 6.8 mo for the NIVO + IPI + CABO arm. Median OS was not reached in either arm. Grade 3-4 treatment-related adverse events (TRAEs) were reported in 15 pts (42%) in the NIVO + CABO arm and 25 pts (71%) in the NIVO + IPI + CABO arm and led to discontinuation in 1 (3%) and 7 (20%) pts, respectively. No new safety signals were observed in either arm. Updated data describing the efficacy and safety of the combinations will be shown. Conclusions: In pts with aHCC, NIVO + CABO +/- IPI combination therapy led to clinically meaningful responses. Although the triplet had a higher rate of TRAEs observed than the doublet regimen, the majority of AEs were manageable and reversible. Clinical trial information: NCT01658878.
Abstract 13054: Right Ventricular Strain Rate at Peak Exercise Accurately Diagnoses Athletes With Right Ventricular Arrhythmias
Authors: Mathias Claeys, Guido Claessen, Hein Heidbuchel, Piet Claus, Jens-Uwe Voigt, Rik Willems, Andre La Gerche
Journal: Circulation (2018)

Introduction: Ventricular arrhythmias (VA) in athletes are frequently associated with only mild structural or functional abnormalities and often originate from the right ventricle (RV). Deformation...
Dietary Nonheme, Heme, and Total Iron Intake and the Risk of Diabetes in Adults: Results From the China Health and Nutrition Survey
Authors: Jingjing He, Aiping Fang, Siwang Yu, Xin Shen, Keji Li
Journal: Diabetes Care (2020)

OBJECTIVE Excessive iron intake has been linked to diabetes risk. However, the evidence is inconsistent. This study examined the association between dietary heme and nonheme iron intake and diabetes risk in the Chinese population. RESEARCH DESIGN AND METHODS We included 17,026 adults (8,346 men and 8,680 women) who were part of the China Health and Nutrition Survey (1991–2015) prospective cohort. Dietary intake was measured by three consecutive 24-h dietary recalls combined with a household food inventory. Diabetes cases were identified through a questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS A total of 547 men and 577 women developed diabetes during 202,138 person-years of follow-up. For men, the adjusted HRs (95% CIs) for quintiles of nonheme iron intake were 1.00, 0.77 (0.58–1.02), 0.72 (0.54–0.97), 0.63 (0.46–0.85), and 0.87 (0.64–1.19) (P-nonlinearity = 0.0015). The corresponding HRs (95% CIs) for women were 1.00, 0.63 (0.48–0.84), 0.57 (0.43–0.76), 0.58 (0.43–0.77), and 0.67 (0.49–0.91) (P-nonlinearity &amp;lt; 0.0001). The dose-response curves for the association between nonheme iron and total iron intake and diabetes followed a reverse J shape in men and an L shape in women. No significant associations were observed between heme iron intake and diabetes risk. CONCLUSIONS Total iron and nonheme iron intake was associated with diabetes risk, following a reverse J-shaped curve in men and an L-shaped curve in women. Sufficient intake of nonheme or total iron might be protective against diabetes, while excessive iron intake might increase the risk of diabetes among men.
Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation
Authors: Meirong Huo, Honglan Wang, Ying Zhang, Han Cai, Pan Zhang, Lingchao Li, Jianping Zhou, Tingjie Yin
Journal: Journal of Controlled Release (2020)
A network meta-analysis of immunotherapy-based regimens for first-line treatment of advanced non-squamous non-small cell lung cancer.
Authors: Himani Agg, Kerigo Ndirangu, Catherine Muehlenbein, Katherine B. Winfree, Yajun Emily Zhu, Howard Thom, Vanita Tongbram
Journal: Journal of Clinical Oncology (2020)

52 Background: Immunotherapy (IO) for initial treatment of patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC) has led to improved progression free survival (PFS) and overall survival (OS) vs chemotherapy. The objective of this network meta-analysis (NMA) was to compare the efficacy of IO-based therapies to chemotherapy in the first-line treatment until progression for advanced nsqNSCLC. Methods: A systematic literature review was conducted to identify randomized controlled trials reporting PFS and/or OS data in adult patients who received first-line treatment for stage IIIB or IV nsqNSCLC until progression. MEDLINE, EMBASE and Cochrane Central Register were searched from the start of databases to June 2018. The NMA used fixed-effects models to estimate hazard ratios (HRs) and credible intervals (Crl) for PFS and OS of IO therapies vs pemetrexed + platinum. A subgroup of patients with PD-L1 tumor proportion score (TPS) ≥50% was also analysed. Results: Evidence networks comprised of 18 studies for the overall population and 3 studies for the PD-L1 TPS ≥50% subgroup. In PFS analysis for the overall population, HRs were lower for atezolizumab + bevacizumab + paclitaxel + platinum (HR 0.62; 95% CrI 0.48, 0.8), ipilimumab + nivolumab (HR 0.55; 95% CrI 0.38, 0.8) and pemetrexed + pembrolizumab + platinum regimens (HR 0.52; 95% CrI 0.43, 0.63) vs pemetrexed + platinum. In the PD-L1 TPS ≥50% subgroup, PFS HRs were lower for pembrolizumab (HR 0.81; 95% CrI 0.67, 0.98) and pemetrexed + pembrolizumab + platinum (HR 0.36; 95% CrI 0.25, 0.52) vs pemetrexed + platinum. In the OS analysis for the overall population, pemetrexed + pembrolizumab + platinum had a lower HR (HR 0.5; 95% CrI 0.4, 0.64) vs pemetrexed + platinum. This difference in OS was magnified in the PD-L1 TPS ≥50% subgroup (HR 0.42; 95% CrI 0.26, 0.68). Conclusions: Among all IO-based therapies in this analysis, pemetrexed + pembrolizumab + platinum had the highest PFS and OS benefit vs pemetrexed + platinum in the first-line treatment until progression for advanced nsqNSCLC for both the overall population and high PD-L1 subgroup. These comparative efficacy data may inform clinicians in treatment selection.
Comparative accuracy of simple clinical fibrosis markers, hepascore and fibroscan in the detection of fibrosis in patients with non-alcoholic fatty liver disease
Authors: Luis Bertot, Gary P. Jeffrey, Bastiaan De Boer, Zhengyi Wang, Yi Huang, George Garas, Gerry C. MacQuillan, Michael C. Wallace, Briohny Smith, Leon A. Adams
Journal: Hepatology (2019)
“Truth is ever to be found in simplicity, and not in the multiplicity and confusion of things” — Sir Isaac Newton
Authors: Jaclyn A. Smith, Mike A. Wortley, Sara Bonvini, Mark Birrell, Maria G. Belvisi
Journal: European Respiratory Journal (2020)

We read with interest the recent publication by Morice et al. [1] "The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study" and the accompanying editorial by Turner and Birring [2] "Chronic cough: ATP, afferent pathways and hypersensitivity". The authors of both publications conclude the results are suggestive of two separate neuronal pathways mediating the cough reflex; however, there are significant issues with this interpretation of the data. Over interpretation of cough challenge data only adds to the confusion in our understanding of the mechanisms underlying chronic cough <http://bit.ly/2X52CQt>
GP gets three life sentences for 90 sex offences against patients
Authors: Clare Dyer
Journal: BMJ (2020)

A GP has been given three life sentences for 90 sex offences against patients and been ordered to serve a minimum of 15 years in prison.

Manesh Shah, 50, was convicted of assaulting 23 women and a 15 year old girl between 2009 and 2013 at his surgery in Romford, east London.1

Shah, who specialised in family planning, exploited fears about cancer to induce young women to undergo intimate examinations for his sexual gratification, the court heard. He selected those who were young and vulnerable or who had a family history of cancer.

Sentencing …