tbuckley/cabot-search huggingface dataset:
Association Between Chronologic Age and Geriatric Assessment–Identified Impairments: Findings From the CARE Registry
Authors: Smith Giri, Mustafa Al-Obaidi, Alice Weaver, Kelly M. Kenzik, Andrew McDonald, Deanna Clark, Crystal Young-Smith, Ravi Paluri, Lakshmin Nandagopal, Olumide Gbolahan, Mackenzi Pergolotti, Smita Bhatia, Grant R. Williams
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: The NCCN Guidelines for Older Adult Oncology recommend that, when possible, older adults with cancer undergo a geriatric assessment (GA) to provide a comprehensive health appraisal to guide interventions and appropriate treatment selection. However, the association of age with GA-identified impairments (GA impairments) remains understudied and the appropriate age cutoff for using the GA remains unknown. Patients and Methods: We designed a cross-sectional study using the Cancer and Aging Resilience Evaluation (CARE) registry of older adults with cancer. We included adults aged ≥60 years diagnosed with gastrointestinal malignancy who underwent a patient-reported GA prior to their initial consultation at the gastrointestinal oncology clinic. We noted the presence of GA impairments and frailty using Rockwood’s deficit accumulation approach. We studied the relation between chronologic age and GA impairments/frailty using Spearman rank correlation and chi-square tests of trend. Results: We identified 455 eligible older adults aged ≥60 years with gastrointestinal malignancies; the median age was 68 years (range, 64–74 years) and colorectal (33%) and pancreatic (24%) cancers were the most common cancer type. The correlation between chronologic age and number of geriatric impairments was weak and did not reach statistical significance (Spearman ρ, 0.07; P =.16). Furthermore, the prevalence of domain-specific impairments or frailty was comparable across the 3 age groups (60–64 years, 65–74 years, ≥75 years) with the exception of comorbidity burden. Notably, 61% of patients aged 60 to 64 years had ≥2 GA impairments and 35% had evidence of frailty, which was comparable to patients aged 65 to 74 years (66% and 36%, respectively) and ≥75 years (70% and 40%, respectively). Conclusions: Using chronologic age alone to identify which patients may benefit from GA is problematic. Future studies should identify screening tools that may identify patients at high risk of frailty and GA impairments.
Role of Platelets in Chronic Kidney Disease
Authors: Nishank Jain, Adam L. Corken, Amudha Kumar, Clayton L. Davis, Jerry Ware, John M. Arthur
Journal: Journal of the American Society of Nephrology (2021)

Platelet-dependent mechanisms for excessive clotting and bleeding in CKD remain undefined. Moreover, platelets' contribution to inflammation, and specifically to CKD, are equally elusive. To date, descriptions of changes in the functional properties of circulating platelets during CKD have provided confusing interpretations. Experimental approaches that can advance our understanding of platelet dysfunction in CKD are needed, and studies that provide mechanistic insights into the dynamic relationships between thrombosis, bleeding, and inflammation associated with CKD will be essential to improve clinical management and outcomes for this vulnerable population. This article summarizes existing literature characterizing platelets in CKD and identifies areas that need further investigation.
Childcare Attendance and Academic Achievement at Age 16 Years
Authors: Marie-Pier Larose, Catherine Haeck, Isabelle Ouellet-Morin, Edward D. Barker, Sylvana M. Côté
Journal: JAMA Pediatrics (2021)

Low school preparedness is linked to high school dropout, poor employment, and negative outcomes. Childcare attendance may increase school readiness and foster academic achievement.To explore whether childcare attendance was associated with academic achievement at the end of compulsory schooling (age 16 years in the UK), whether maternal education level was a moderator, and the benefit-cost ratio of childcare regarding productivity returns of academic achievement.In this cohort study, data were included from the Avon Longitudinal Study of Parents and Children (ALSPAC) born from April 1991 to December 1992 and the UK National Pupil Database for examination results. Data on academic achievement at age 16 years were available for 11 843 participants. Data were collected from June 2006 to June 2008, and data were analyzed from September 2019 to May 2020.On average, 3.7%, 5.9%, and 90.4% attended childcare full time, part time, and less than 10 hours per week, respectively. Maternal education was assessed by questionnaire during pregnancy. Analyses included weights for population representativeness and propensity score weights to account for parental selection into childcare.Academic achievement was defined as no certificate, Level 1 General Certificate of Secondary Education (GCSE; limited training), or Level 2 GCSE (qualification for academic post-16 education; high school diploma equivalent). Lifetime productivity return estimates were withdrawn from previous economic analysis based on pupil's qualifications.Of 14 541 children in the ALSPAC study, 8936 children had complete data on childcare attendance, academic achievement, and maternal education levels. Of these, 4499 (50.3%) were male. Attending childcare was associated with higher probabilities of obtaining a Level 1 or 2 GCSE qualification (Level 1: relative risk, 1.41; 95% CI, 1.16-1.73; Level 2: relative risk, 1.62; 95% CI, 1.30-2.01); however, this association was moderated by the child's maternal education level. When children of mothers with low education attended childcare, their probability of no GCSE qualification went from 28.9% (95% CI, 26.8-31.0) to 20.3% (95% CI, 18.0-22.8), whereas children of mothers with higher education had a probability of no qualification of less than 10% regardless of childcare attendance. The benefit-cost ratio for each £1 (US $1.40) invested in full-time childcare attendance for children of mothers with low education was £1.71 (95% CI, 1.03-2.45; US $2.39; 95% CI, 1.44-3.43) for those who reached a Level 2 GCSE qualification.Promoting universal childcare with facilitated access for children of lower socioeconomic backgrounds deserves to be considered as a way to reduce the intergenerational transmission of low academic achievement.
Clinico-pathological and genomic features of <i>NRAS</i>- or <i>HRAS</i>-mutated non-small cell lung cancer (NSCLC) identified in large-scale genomic screening project (LC-SCRUM-Asia).
Authors: Yutaro Tamiya, Shingo Matsumoto, Takaya Ikeda, Kiyotaka Yoh, Terufumi Kato, Kazumi Nishino, Masahiro Kodani, Atsushi Nakamura, Naoki Furuya, Shoichi Kuyama, Shingo Miyamoto, Ryo Toyozawa, Masato Shingyoji, Tomoyuki Naito, Satoshi Oizumi, Hiroshi Tanaka, Hibiki Udagawa, Kaname Nosaki, Yoshitaka Zenke, Koichi Goto
Journal: Journal of Clinical Oncology (2021)

9054 Background: RAS ( KRAS, NRAS and HRAS) is a targetable oncogene family in several cancers, including NSCLC, and the clinical development of various RAS-targeted therapies are ongoing. However, the clinical relevance of uncommon RAS mutations, such as NRAS and HRAS mutations, in NSCLC patients (pts) remains unclear. Methods: In a large-scale genomic screening project (LC-SCRUM-Asia), we have prospectively analyzed lung cancer pts for genomic alterations by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay. We evaluated clinico-pathological and genomic characteristics in NRAS- or HRAS-mutated NSCLC pts comparing with those in KRAS-mutated pts based on the LC-SCRUM-Asia database. Results: Since March 2015 to December 2020, 9131 NSCLC pts were enrolled in the LC-SCRUM-Asia, and 8374 of them (92%) were successfully analyzed by NGS. The RAS mutation frequencies were 1134 KRAS (14%), 50 NRAS (0.6%), and 15 HRAS (0.2%). The most frequent variant of NRAS and HRAS mutations was Q61X (78%) and G13X (80%), respectively, whereas that of KRAS was G12X (84%). Patient characteristics were summarized in Table. Male was significantly frequent in NRAS- than in KRAS-group (p=0.03), and smokers were frequent in all the three groups (overall, 79%). The majority of NRAS (70%) and KRAS mutations (89%) were detected in adenocarcinoma (Ad), whereas 60% of HRAS mutations were in squamous cell carcinoma (Sq). Tumor mutation burden (TMB) was significantly higher in NRAS-mutated tumors than in KRAS-mutated tumors (p=0.03). Concomitant TP53 mutations were significantly frequent in HRAS-mutated pts than in KRAS-mutated pts (53% vs. 30%, p=0.05), and STK11 mutations were also tended to be frequent in HRAS-mutated pts than in KRAS-mutated pts (20 vs. 7%, p=0.10). Therapeutic efficacy of PD-1/PD-L1 inhibitors was not different among the three groups in the current follow-up data, but HRAS-mutated tumors did not respond to PD-1/PD-L1 inhibitors (response rate, 0%; median PFS, 1.6 months). Conclusions: NRAS- or HRAS-mutated NSCLCs were different from KRAS-mutated NSCLCs in clinico-pathological and genomic profiles. In particular, the immunotherapies were not effective for HRAS-mutated NSCLCs.[Table: see text]
Genes copy number as a marker of low-invasive assessment of rectal tumors radiotherapy effectiveness.
Authors: Marina A. Gusareva, Natalia G Kosheleva, Natalya B. Fatkina, Anna A. Solntseva, Lyudmila Ya. Rozenko, Aliya K. Donskaya, Ekaterina O. Vasilieva, Elena A. Karnauhova, Julia N. Krokhmal, Peter N. Gabrichidze, Vladimir A. Dontsov, Umar M. Gaziev, Vladislav M. Legostaev, Olga V. Shlyakhova, Natalia A. Lyman, Gennady V. Balitsky, V. A. Nosov, A. B. Kravchenko, Denis S. Kutilin
Journal: Journal of Clinical Oncology (2021)

3025 Background: Radiotherapy (RT) is a key component of rectal cancer (RC) treatment, however, nonresponsiveness in patients to preoperative RT is very common, usually due to the tumor cells radioresistance, mediated by their molecular characteristics, such as gene expression. The features of mRNA rapid degradation in extracellular environment make this indicator unsuitable for low invasive diagnostics. The solution to this problem is possible by switching to a more stable marker - the copy number variation (CNV), which can be determined in the extracellular DNA (cfDNA) circulating in the blood plasma. Therefore, the aim of the study was to identify the relationship between the level of genes CNV in the cfDNA of blood plasma with the effectiveness of rectal tumors RT. Methods: We used cfDNA preparations from blood plasma obtained before RT from 200 patients with RC, as well as from blood plasma of 50 apparently healthy donors (AHD, without cancer). RT was carried out on a linear accelerator Novalis TX (SFD = 2.4 Gy, TFD = 54.0 Gy). Blood samples were separated into plasma and cell fraction by centrifugation. Isolation of cfDNA from blood plasma was performed using the phenol-chloroform method. Determination CNV of 5 genes (BRCA2, H2AX, CASP9, RBBP8 and BCL2) was performed using Real-Time qPCR method. Differences were assessed using Mann-Whitney test; the Bonferroni correction was used to correct multiple comparisons. Results: RT results for 200 patients allowed them to be divided into 2 groups. After RT, 120 patients showed complete tumor regression (group 1), 50 patients showed insignificant tumor regression and 30 patients did not regress (group 2). In cfDNA of group 1 patients was found CNV decrease (p &lt; 0.05) of H2AX and RBBP8 genes by 2.5 and 2.0 times, respectively, relative to AHD group. In the cfDNA of group 2patients an increase (p &lt; 0.05) of BRCA2, H2AX, RBBP8 and BCL2 genes CNV was found by 2.0, 2.2, 2.0 and 2.0 times, respectively, relative to AHD group. Only 2 genes CNV differed in group 1 from group 2: the CNV of H2AX and RBBP8 was 5.4 and 4.0 times less respectively (p &lt; 0.005). Conclusions: Thus, it has been found that increased CNV of genes BRCA2, H2AX, BCL2, RBBP8 in blood plasma cfDNA is associated with low efficiency of RT. At the same time, the CNV of H2AX and RBBP8 genes in cfDNA of patients with RC has the greatest potential as a marker of the RT effectiveness.
Targeted breast surgery: Non-direct approach.
Authors: Peter Kern, Alina Kessel, Oliver Hoffmann, Ann-Kathrin Bittner, Rainer Kimmig
Journal: Journal of Clinical Oncology (2021)

e12602 Background: Breast conserving surgery is the standard in T1-T3 primary breast cancer. The cosmetic result is very much depending upon the surgeon ́s experience, the tumor-size/breast ratio and the technique applied. We have proposed a nomogram earlier (1) which has been cited earlier by the American Society of Breast Surgeons Consensus Conference as a concept for avoidance of re-excisions and achievement of a favorable aesthetic result. Our nomogram proposed 5 simple oncoplastic techniques to handle the vast majority of breast cancer cases, with high rates of free margins. However, these techniques all used direct access to the mammary gland through the skin above the tumor, leaving permanent scars in the visible skin of the breast. To avoid this, we now have chosen a more natural access to the mammary gland along natural transitions and Langerhans´s skin lines in this prospective open-label study. Methods: We conducted a prospective open-arm study including all primary invasive and non-invasive breast cancer cases of tumor stages AJCC 0-III A (Version 8.0). Non-palbable tumors and those undergoing neoadjuvant chemotherapy had to be marked by a wire and clipped before. Intraoperative ultrasound was applied before skin incision and after removal of the tumor including ultrasound of the specimen to confirm clear margins). Resection was performed as a segmentectomy and SLN biopsy and axillary clearance was done according to national guidelines. Access to the tumor was chosen in a non-direct approach according to the proximity of the tumor to one of the following natural transitions: 1. areola 2. axillary line 3. inframammary fold. Results: 84 patients with breast conserving targeted breast surgery with a "non-direct to the tumor approach" have been enrolled so far. 76 patients had primary surgery with stage distribution as follows: Tis (1), T1a (3), T1b (8), T1c (30), T2 (30), T3 (4) and T4b(1). 8 patients had neoadjuvant chemotherapy with stage distribution as follows: ypT0 (3), ypT1a (2), ypT1c (1) and ypT2 (2). Histopathology was predominantly invasive-ductal breast cancer (70), followed by invasive-lobular (6), ductulo-lobular (5), invasive- ductal and pure DCIS (1), invasive-ductal and mucinous (1) and mucinous only (1). After first surgery according to our nomogram 77 patients had a tumor resection with free margins and 7 with involved margins, thus 91,6 % tumors were resected with free margins at first surgery. The remaining 8,4 % of cases were margin-free after second surgery. Conclusions: Scars were not visible on the surface of the breast outside of natural transitions and rate of free margins was high with targeted breast surgery at a rate of 91,6 % without any cosmetic impairment due to the remote natural access to the mammary gland. Patient-reported outcome in detail has been evaluated by validated questionnaires and demonstrated a high satisfaction with scar pattern, volume and symmetry.
A phase 1/2 study of selinexor in combination with standard of care therapy for newly diagnosed or recurrent glioblastoma.
Authors: Yazmin Odia, Samuel Aaron Goldlust, Minesh P. Mehta, Andrew B. Lassman, Howard Colman, Priya Kumthekar, Warren P. Mason, Rebecca A. Harrison, Nicholas A. Butowski, Vyshak Venur, Scott Randall Plotkin, Michael Schulder, John A Boockvar, J Paul Duic, Kai Li, Yang Liu, Sharon Tamir, Gregory Mundy, Sharon Shacham, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2021)

TPS2071 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O 6 -methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378.
Hancock comes under renewed pressure from PM’s former chief aide
Authors: Andy Cowper
Journal: BMJ (2021)

The prime minister’s former chief adviser Dominic Cummings has published more information1 to support his testimony to MPs last month, in which he forcefully attacked England’s health and social care secretary, Matt Hancock, for lying and incompetence.2

The evidence that Cummings released on 16 June to substantiate his account of government failings during the pandemic consists largely of screenshots of WhatsApp messages between himself and the prime minister. The messages show that Boris Johnson considered that Hancock’s work on expanding testing capacity had been “totally fucking hopeless” and that he thought the situation with personal protective equipment was a “disaster.”

The messages also reveal discussions about the …
Hypertensive disorders in women with peripartum cardiomyopathy: insights from the <scp>ESC</scp> EORP PPCM Registry
Authors: Alice M. Jackson, Mark C. Petrie, Alexandra Frogoudaki, Cécile Laroche, Finn Gustafsson, Bassem Ibrahim, Alexandre Mebazaa, Mark R. Johnson, Petar M. Seferovic, Vera Regitz‐Zagrosek, Amam Mbakwem, Michael Böhm, Hawani S. Prameswari, Doaa A. Fouad, Sorel Goland, Albertino Damasceno, Kamilu Karaye, Hasan A. Farhan, Righab Hamdan, Aldo P. Maggioni, Karen Sliwa, Johann Bauersachs, Peter van der Meer
Journal: European Journal of Heart Failure (2021)

Abstract Aims Hypertensive disorders occur in women with peripartum cardiomyopathy (PPCM). How often hypertensive disorders co‐exist, and to what extent they impact outcomes, is less clear. We describe differences in phenotype and outcomes in women with PPCM with and without hypertensive disorders during pregnancy. Methods and results The European Society of Cardiology EURObservational Research Programme PPCM Registry enrolled women with PPCM from 2012–2018. Three groups were examined: (i) women without hypertension (PPCM‐noHTN); (ii) women with hypertension but without pre‐eclampsia (PPCM‐HTN); (iii) women with pre‐eclampsia (PPCM‐PE). Maternal (6‐month) and neonatal outcomes were compared. Of 735 women included, 452 (61.5%) had PPCM‐noHTN, 99 (13.5%) had PPCM‐HTN and 184 (25.0%) had PPCM‐PE. Compared to women with PPCM‐noHTN, women with PPCM‐PE had more severe symptoms (New York Heart Association class IV in 44.4% vs. 29.9%, P &lt; 0.001), more frequent signs of heart failure (pulmonary rales in 70.7% vs. 55.4%, P = 0.002), a higher baseline left ventricular ejection fraction (LVEF) (32.7% vs. 30.7%, P = 0.005) and a smaller left ventricular end‐diastolic diameter (57.4 ± 6.7 mm vs. 59.8 ± 8.1 mm, P = 0.001). There were no differences in the frequencies of death from any cause, rehospitalization for any cause, stroke, or thromboembolic events. Compared to women with PPCM‐noHTN, women with PPCM‐PE had a greater likelihood of left ventricular recovery (LVEF ≥ 50%) (adjusted odds ratio 2.08, 95% confidence interval 1.21–3.57) and an adverse neonatal outcome (composite of termination, miscarriage, low birth weight or neonatal death) (adjusted odds ratio 2.84, 95% confidence interval 1.66–4.87). Conclusion Differences exist in phenotype, recovery of cardiac function and neonatal outcomes according to hypertensive status in women with PPCM.
An injectable and self-healing hydrogel with controlled release of curcumin to repair spinal cord injury
Authors: Jinghua Luo, Xueshuang Shi, Liming Li, Zan Tan, Feng Feng, Jun Li, Mao Pang, Xiaoying Wang, Liumin He
Journal: Bioactive Materials (2021)

The harsh local micro-environment following spinal cord injury (SCI) remains a great challenge for neural regeneration. Local reconstitution of a favorable micro-environment by biocompatible scaffolds with desirable functions has thus been an area of concern. Herein, a hybrid hydrogel was developed using Fmoc-grafted chitosan (FC) and Fmoc peptide (FI). Dynamic reversible π-π stacking interactions of the fluorenyl rings enabled the FC/FI hybrid hydrogel to exhibit excellent injectable and self-healing properties, as characterized by visual appearances and rheological tests. Furthermore, the FC/FI hybrid hydrogel showed a slow and persistent release of curcumin (Cur), which was named as FC/FI-Cur hydrogel.