tbuckley/cabot-search huggingface dataset:
Maternal and child gluten intake and association with type 1 diabetes: The Norwegian Mother and Child Cohort Study
Authors: Nicolai A. Lund-Blix, German Tapia, Karl Mårild, Anne Lise Brantsaeter, Pål R. Njølstad, Geir Joner, Torild Skrivarhaug, Ketil Størdal, Lars C. Stene
Journal: PLoS Medicine (2020)

Background The relationship between maternal gluten intake in pregnancy, offspring intake in childhood, and offspring risk of type 1 diabetes has not been examined jointly in any studies. Our aim was to study the relationship between maternal and child intake of gluten and risk of type 1 diabetes in children. Methods and findings We included 86,306 children in an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), with recruitment from 1999 to 2008 and with follow-up time to April 15, 2018. We used registration of type 1 diabetes in the Norwegian childhood diabetes registry as the outcome. We used Cox proportional hazard regression to estimate hazard ratios (HRs) for the mother’s intake of gluten up to week 22 of pregnancy and offspring gluten intake when the child was 18 months old. The average time followed was 12.3 years (0.70–16.0). A total of 346 children (0.4%) children were diagnosed with type 1 diabetes, resulting in an incidence rate of 32.6/100,000 person-years. Mean gluten intake per day was 13.6 g for mothers and 8.8 g for children. There was no association between the mother’s intake of gluten in pregnancy and offspring type 1 diabetes, with an adjusted HR (aHR) of 1.02 (95% confidence interval [CI] 0.73–1.43, p = 0.91) for each 10-g-per-day increment. There was an association between offspring intake of gluten and a higher risk of type 1 diabetes, with an aHR of 1.46 (95% CI 1.06–2.01, p = 0.02) for each 10-g-per-day increment. Among the limitations are the likely imprecision in estimation of gluten intake and that we only had information regarding gluten intake at 2 time points in early life. Conclusions Our results show that, while the mother’s intake of gluten in pregnancy was not associated with type 1 diabetes, a higher intake of gluten by the child at an early age may give a higher risk of type 1 diabetes.
Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma
Authors: Jia-qiao Fan, Meng-Fei Wang, Hai-Long Chen, Dong Shang, Jugal K. Das, Jianxun Song
Journal: Molecular Cancer (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.
Optimal sequence strategy with nivolumab and targeted therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Juliette Logeart, Audrey Simonaggio, Reza Thierry Elaidi, Sophie Hans, Constance Thibault, Stephane Oudard, Yann-Alexandre Vano
Journal: Journal of Clinical Oncology (2020)

700 Background: Nivolumab is an approved standard tretatment for pts with mRCC after one VEGFR-TKI failure. Some reports suggest that Nibolumab provides similar response rate across treatment line. Nevetheless, no comparative data has been reported on the sequence of 2nd line Nivolumab followed by TKI vs TKI followed by Nivolumab in 3rd or later line. Objective: To determine the optimal sequence of Nivolumab monotherapy and anti-VEGFR-TKI in mRCC beginning from the 2nd line. Methods: We included in a French expert center all patients with mRCC who received real-life experienced of anti-PD1 nivolumab monotherapy in 2nd line setting or later were included in a French expert center. Clinical characteristics were prospectively recorded including IDMC prognostic factors. Patients who did not receive TKI on the 1st line were excluded. Survival outcomes and subgroups analysis were performed using log rank test and univariate cox regression analysis. Results: 91 patients with mRCC received Nivolumab between January 2006 and May 2018, 58 pts received nivolumab in 2nde line (63%) and 33 in 3rd line and more. Median follow-up was 18.9 [0.1;143] months starting from the beginning of the 2nd line. All received first line anti-VEGFR TKI, 83%/11% sunitinib/pazopanib. At the beginning of 2 nd line, IMDC prognostic groups were Fav 19%/Int 56%/ Poor 24%, with similar repartition (p=0,8) between pts treated with Nivolumab vs others. PFS at 6 months for 2nd line was in favor of patients treated by targeted treatments with respectively 63% (IC95% [46%;80%]) and 34% (IC95% [23%;49%]), p=0,06. OS at 24 months for 2nd line was significatively higher for patients treated by targeted treatments with 72% (IC95% [56;87%]) and 46% (IC95% [31%;61%]), p=0,007. Conclusions: We report for the first time the optimal timing to sequence Nivolumab – targeted therapy in patients with mRCC. We found better PFS and OS when Nivolumab is given after the 2nde line of treatment. Subgroups analysis including IMDC prognostic groups and duration of fist line TKI will be presented at the meeting.
Fasting before or after wound injury accelerates wound healing through the activation of pro-angiogenic SMOC1 and SCG2
Authors: Ming-Jie Luo, Shan-Shan Rao, Yi-Juan Tan, Hao Yin, Xiong-Ke Hu, Yan Zhang, Yi-Wei Liu, Tao Yue, Ling-Jiao Chen, Li Li, Ya-Rong Huang, Yu-Xuan Qian, Zheng-Zhao Liu, Jia Cao, Zhen-Xing Wang, Zhong-Wei Luo, Yi-Yi Wang, Kun Xia, Si-Yuan Tang, Chun-Yuan Chen, Hui Xie
Journal: Theranostics (2020)

Healing of the chronic diabetic ulceration and large burns remains a clinical challenge.Therapeutic fasting has been shown to improve health.Our study tested whether fasting facilitates diabetic and burn wound healing and explored the underlying mechanism.Methods: The effects of fasting on diabetic and burn wound healing were evaluated by analyzing the rates of wound closure, re-epithelialization, scar formation, collagen deposition, skin cell proliferation and neovascularization using histological analyses and immunostaining.In vitro functional assays were conducted to assess fasting and refeeding on the angiogenic activities of endothelial cells.Transcriptome sequencing was employed to identify the differentially expressed genes in endothelial cells after fasting treatment and the role of the candidate genes in the fasting-induced promotion of angiogenesis was demonstrated.Results: Two times of 24-h fasting in a week after but especially before wound injury efficiently induced faster wound closure, better epidermal and dermal regeneration, less scar formation and higher level of angiogenesis in mice with diabetic or burn wounds.In vitro, fasting alone by serum deprivation did not increase, but rather reduced the abilities of endothelial cell to proliferate, migrate and form vessel-like tubes.However, subsequent refeeding did not merely rescue, but further augmented the angiogenic activities of endothelial cells.Transcriptome sequencing revealed that fasting itself, but not the following refeeding, induced a prominent upregulation of a variety of pro-angiogenic genes, including SMOC1 (SPARC related modular calcium binding 1) and SCG2 (secretogranin II).Immunofluorescent staining confirmed the increase of SMOC1 and SCG2 expression in both diabetic and burn wounds after fasting treatment.When the expression of SMOC1 or SCG2 was down-regulated, the fasting/refeeding-induced pro-angiogenic effects were markedly attenuated. Conclusion:This study suggests that fasting combined with refeeding, but not fasting solely, enhance endothelial angiogenesis through the activation of SMOC1 and SCG2, thus facilitating neovascularization and rapid wound healing.
Immune checkpoint inhibitors plus tyrosine kinase inhibitors combination in the first-line setting of metastatic clear cell renal cell carcinoma: A meta-analysis of randomized clinical trials.
Authors: Maria Cruz Martin Soberón, Alberto Carretero-González, Guillermo de Velasco, Lucia Carril, Daniel Castellano
Journal: Journal of Clinical Oncology (2020)

704 Background: ICIs + TKIs have shown to improve outcomes in treatment-naïve metastatic clear-cell renal cell carcinoma (ccRCC). We aimed to analize the efficacy of all combinations published including the subgroup analysis based on age, sex and IMDC prognostic factors score. Methods: We searched published RCTs in MEDLINE and EMBASE comparing ICIs + TKIs vs TKIs in 1L metastatic ccRCC. Outcomes selected to assess efficacy were progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) in the intent-to-treat population. Hazard ratios (HR) for PFS and OS, and relative risk (RR) for ORR with 95% confidence intervals (CI) were used as efficacy measures. Subgroup-based meta-analysis was afterwards performed according to randomized-effect model. Results: We identified two eligible RCTs of ICIs + TKIs (avelumab [avelu] or pembrolizumab [pembro] + axitinib [axi]) versus TKIs (sunitinib). Combined sample size was 1,747 patients (avelu + axi arm 442 patients; pembro + axi arm 432 patients; sunitinib arm 873 patients). Globally, three outcomes favored the combination. Improved HRs for PFS (0.69), OS (0.64) and ORR (1.81) were found for combination (Table). Regarding subgroup analysis HRs for PFS were favorable for combination in male (0.665) and female (0.66). Benefit in combination arms was confirmed in terms of age &lt; 65 years (0.68) and ≥ 65 years (0.66). Intermediate and poor IMDC subgroups showed statistically significant benefit for combination (HR 0.68 and 0.56), whereas PFS in favorable group (0.68) was not statistically significant. Conclusions: ICIs + TKIs combination therapy has consistently demonstrated to be superior in terms of OS, PFS and ORR in 1L ccRCC to TKIs alone. We hereby confirm statistically significant benefit per subgroups except for favorable IMDC subgroup.[Table: see text]
Trends in cardiogenic shock complicating acute myocardial infarction
Authors: Nadia Aissaoui, Etienne Puymirat, Clément Delmas, Sofia Ortuno, Eric Durand, Vincent Bataille, Elodie Drouet, Laurent Bonello, Eric Bonnefoy‐Cudraz, Gilles Lesmeles, Emmanuel Guerot, Francois Schiele, Tabassome Simon, Nicolas Danchin
Journal: European Journal of Heart Failure (2020)
Relative risk of hematological toxicities in patients with advanced renal cell carcinoma treated with upfront immune checkpoint inhibitors.
Authors: Nusrat Jahan, Somedeb Ball, Miguel Quirch, Shabnam Rehman, Kyaw Zin Thein, Lukman Aderoju Tijani
Journal: Journal of Clinical Oncology (2020)

675 Background: Sunitinib was the standard first-line treatment of advanced renal cell carcinoma (aRCC) for the past decade, but it has been associated with significant hematological toxicities. Immune checkpoint inhibitors (ICI) based regimens have become the new preferred treatment for aRCC in the first-line setting. We conducted a meta-analysis of phase 3 randomized controlled trials (RCTs) to determine the relative risk of hematological toxicities associated with upfront use of ICI-based regimens for aRCC. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until May 2019. Phase 3 RCTs using ICIs in the intervention arm for the first-line treatment of aRCC were included. We used the Mantel-Haenszel (MH) method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I 2 value. Results: Four phase 3 RCTs, CheckMate 214, IMmotion151, JAVELIN Renal 101 and KEYNOTE-426, randomizing 3706 patients were included in the analysis of anemia and thrombocytopenia. CheckMate 214 did not report the number of neutropenia. Hence, other 3 RCTs that included 2624 patients were analyzed for neutropenia. Following regimens were used in the study arms — CheckMate 214: nivolumab+ipilimumab, IMmotion151: atezolizumab+bevacizumab, JAVELIN Renal 101: axitinib+avelumab; and KEYNOTE-426: axitinib+ pembrolizumab. Sunitinib was used in the control arms for all the studies. The pooled RR of any-grade hematological toxicities are as follows — anemia: 0.31 (95% CI:0.24-0.41, P&lt; 0.00001, I 2 =39%); thrombocytopenia: 0.11 (95% CI: 0.06-0.19, P&lt;0.00001, I 2 =63%); neutropenia: 0.08 (95% CI: 0.05-0.13, P&lt;0.00001, I 2 =0%). The pooled RR of grade 3 and higher hematological toxicities are as follows — anemia: 0.14 (95% CI:0.08-0.25, P&lt; 0.00001, I 2 =0); thrombocytopenia: 0.06 (95% CI:0.02-0.16, P&lt;0.00001, I 2 =4%); neutropenia: 0.06 (95% CI: 0.02-0.16, P&lt;0.00001, I 2 =0%). Conclusions: ICI-based regimens have significantly reduced risk of any-grade as well as high-grade hematological toxicities compared to sunitinib in patients with aRCC.
Real-world outcomes in patients with locally advanced or metastatic urothelial carcinoma receiving taxane monotherapy following platinum and anti-PD-1/L1 therapy.
Authors: Zsolt Hepp, Sonali Shah, Katherine Tan, Shreya Balakrishna
Journal: Journal of Clinical Oncology (2020)

458 Background: There are currently limited options for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) following progression on platinum chemotherapy and anti-programmed death 1/death-ligand 1 (PD-1/L1) therapy. Further, limited data are available from clinical trials or real-world studies on outcomes in this population. This retrospective analysis investigated clinical outcomes in patients treated with taxane monotherapy, a commonly used and NCCN guideline-recommended option in this setting. Methods: Patients aged ≥18 years with histologically-confirmed diagnosis of la/mUC on or after 2011, ≥2 clinical visits, and sufficient relevant unstructured data were included from the de-identified nationwide Flatiron Health electronic health record-derived database. The study cohort included patients treated with taxane monotherapy (docetaxel, paclitaxel, or nab-paclitaxel) following anti-PD-1/L1 therapy and who have received prior platinum containing chemotherapy. Baseline characteristics, overall survival (OS), real-world progression-free survival (rwPFS) based on clinician documentation of disease status, and real-world response (rwR) based on clinician-confirmed radiologic assessments were reported. Patients were followed until death, data cutoff, or loss to follow up. Results: Among 276 patients treated following anti-PD-1/L1 therapy and who met all of the inclusion/exclusion criteria, 72 were treated with taxanes and also had documented prior platinum chemotherapy. Patients were mostly male (75%) and Caucasian (74%), with a mean age of 73 years. 65% had &gt; 2 sites of metastasis at index (start date of taxane). Post index, median OS = 7.6 months (95% CI 5.2, 14.4) and median rwPFS = 2.9 months (95% CI, 2.4, 4.0). Among the 50 patients with ≥1 rwR assessment, confirmed rwR = 18% (95% CI: 9%, 32%). Conclusions: In the real-world setting, limited responses to taxanes and short duration of PFS and OS were observed in patients with la/mUC previously treated with a platinum and anti-PD-1/L1 therapy. There is a need for more effective therapies to improve clinical outcomes for this patient population.
Antenatal imaging and clinical outcome in congenital CMV infection: A field-wide systematic review and meta-analysis
Authors: Aikaterini Kyriakopoulou, Stylianos Serghiou, Dimitra Dimopoulou, Ioli Arista, Theodora Psaltopoulou, Argyrios Dinopoulos, Vassiliki Papaevangelou
Journal: Journal of Infection (2020)
Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease
Authors: Matteo Tebaldi, Simone Biscaglia, Gianluca Campo
Journal: New England Journal of Medicine (2019)

residual varicosities, if required, was more costeffective and resulted in greater improvement in quality of life than the use of foam sclerotherapy alone.The trial also showed that the majority of patients who underwent endothermal ablation did not require additional treatment for residual varicosities.This indicates that combinations of less invasive therapies are not always required to achieve the best result for the individual patient.The trial did not set out to look at the effect of endothermal ablation alone, since this policy may lead to undertreatment of patients and prevent them from obtaining the best result.Thus, we do not consider that Jindeel's proposed post hoc analysis to determine the effect of laser therapy alone would help to direct clinical practice.
A phase I/II feasibility study of cetuximab with 5FU and mitomycin C or cisplatin with concurrent radiotherapy in muscle invasive bladder cancer.
Authors: Nicholas D. James, Sarah Pirrie, Wenyu Liu, Daniel Ford, Anjali Zarkar, Elizabeth Southgate, Amisha Desai, Syed A. Hussain
Journal: Journal of Clinical Oncology (2020)

491 Background: Chemoradiotherapy (cRT) with 5FU and Mitomycin C (5FU/MMC) is an accepted standard of care for muscle invasive bladder cancer. Cetuximab is an approved radio-sensitiser in head and neck cancer and EGFR is over-expressed in bladder cancer. We report a phase 1/2 trial of the addition of cetuximab to standard cRT. Methods: Phase 1/2 single-arm, multicentre, open-label study conducted in 5 UK centres. Treatment: RT: 64 Gy/32 fractions, 5FU 2.5g/m2 over days 1-5 &amp; 22-26, MMC 12g/m2 day 1, cetuximab 400mg/m2 day -8, 200mg/m2 day 1 and weekly x7. Main inclusion criteria: T2-4aN0M0 urothelial cancer, PS 0-1; prior neoadjuvant therapy permitted. Endpoints: Phase 1; feasibility and safety of cRT with cetuximab + 5FU/MMC in combination. Phase 2; local control (LC) at 3 months. Secondary outcomes: invasive loco-regional progression free survival (LPFS), noninvasive LPFS, metastasis free survival (MFS), overall survival (OS) &amp; patient reported outcomes (PROMs). Sample size; phase 1 between 6 and 18, phase 2 up to 45 including those recruited in phase 1. Results: Between Sept 2012 and Oct 2016, 33 patients were recruited; 7 in phase 1 26 in phase 2. Median age 70.1 (IQR 65.4-80.2) yrs, 60.6% WHO Performance Status 0; 81.8% male, 26/33 neoAd chemotherapy. 3 patients ineligible post registration. 30 evaluable pts started RT, 1 patient didn’t complete RT due to serious adverse event (interstitial pneumonitis), 3 with delays. Phase 1, 6/7 pts completed Cetux therapy, 1 omitted 1 dose for grade 3 rash. LC was 77% (95% CI 58, 90). Overall median dose intensities Cetux 100%, MMC 99% 5FU 99.8%. 8 pts developed recurrence; 2 MIBC. The 6 &amp; 12 month muscle-invasive LPFS was 93 &amp;; non-invasive LPFS 97% &amp; 85%, MFS 90% &amp; 90%, OS 97% &amp; 87%. PROMs showed a transient dip at 1 mo, back to baseline at 3 mo. Conclusions: Phase 1 data demonstrate it’s feasible and safe to add cetuximab to cRT with 5FU/MMC with high delivered dose intensities. Although recruitment failed to reach the pre-specified target for phase 2 exploratory analysis indicate the 3 month bladder control rates and recurrence rates are above those reported in BC2001 with good PROMs provides evidence to consider further evaluation of cetuximab. Clinical trial information: 80733590.
Mild parenchymal lung disease and/or low diffusion capacity impacts survival and treatment response in patients diagnosed with idiopathic pulmonary arterial hypertension
Authors: Robert A. Lewis, A.A. Roger Thompson, Catherine G. Billings, Athanasios Charalampopoulos, Charlie A. Elliot, Neil Hamilton, Catherine Hill, Judith Hurdman, Smitha Rajaram, Ian Sabroe, Andy J. Swift, David G. Kiely, Robin Condliffe
Journal: European Respiratory Journal (2020)

There are limited published data defining survival and treatment response in patients with mild lung disease and/or reduced gas transfer who fulfil diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH). Patients diagnosed with IPAH between 2001 and 2019 were identified in the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre) registry. Using prespecified criteria based on computed tomography (CT) imaging and spirometry, patients with a diagnosis of IPAH and no lung disease were termed IPAH no-LD (n=303), and those with minor/mild emphysema or fibrosis were described as IPAH mild-LD (n=190). Survival was significantly better in IPAH no-LD than in IPAH mild-LD (1- and 5-year survival 95% and 70% versus 78% and 22%, respectively; p&lt;0.0001). In the combined group of IPAH no-LD and IPAH mild-LD , independent predictors of higher mortality were increasing age, lower diffusing capacity of the lung for carbon monoxide ( D LCO ), lower exercise capacity and a diagnosis of IPAH mild-LD (all p&lt;0.05). Exercise capacity and quality of life improved (both p&lt;0.0001) following treatment in patients with IPAH no-LD , but not IPAH mild-LD . A proportion of patients with IPAH no-LD had a D LCO &lt;45%; these patients had poorer survival than patients with D LCO ≥45%, although they demonstrated improved exercise capacity following treatment. The presence of even mild parenchymal lung disease in patients who would be classified as IPAH according to current recommendations has a significant adverse effect on outcomes. This phenotype can be identified using lung function testing and clinical CT reports. Patients with IPAH, no lung disease and severely reduced D LCO may represent a further distinct phenotype. These data suggest that randomised controlled trials of targeted therapies in patients with these phenotypes are required.