tbuckley/cabot-search huggingface dataset:
Severe covid-19 pneumonia: pathogenesis and clinical management
Authors: Amy H Attaway, Rachel G Scheraga, Adarsh Bhimraj, Michelle Biehl, Umur Hatipoğlu
Journal: BMJ (2021)

Severe covid-19 pneumonia has posed critical challenges for the research and medical communities. Older age, male sex, and comorbidities increase the risk for severe disease. For people hospitalized with covid-19, 15-30% will go on to develop covid-19 associated acute respiratory distress syndrome (CARDS). Autopsy studies of patients who died of severe SARS CoV-2 infection reveal presence of diffuse alveolar damage consistent with ARDS but with a higher thrombus burden in pulmonary capillaries. When used appropriately, high flow nasal cannula (HFNC) may allow CARDS patients to avoid intubation, and does not increase risk for disease transmission. During invasive mechanical ventilation, low tidal volume ventilation and positive end expiratory pressure (PEEP) titration to optimize oxygenation are recommended. Dexamethasone treatment improves mortality for the treatment of severe and critical covid-19, while remdesivir may have modest benefit in time to recovery in patients with severe disease but shows no statistically significant benefit in mortality or other clinical outcomes. Covid-19 survivors, especially patients with ARDS, are at high risk for long term physical and mental impairments, and an interdisciplinary approach is essential for critical illness recovery.
Health-related quality-of-life outcomes from a phase II open-label trial of two different starting doses of lenvatinib in combination with everolimus for treatment of renal cell carcinoma following one prior VEGF-targeted treatment.
Authors: Cristiane Decat Bergerot, Sun Young Rha, Sumanta K. Pal, Piotr Koralewski, Daniil Stroyakovskiy, Boris Alekseev, Francis Parnis, Daniel Castellano, Jae-Lyun Lee, Kaisa Sunela, Tudor Ciuleanu, Daniel Yick Chin Heng, Hilary Glen, Jinyi Wang, Lee Bennett, Janice Pan, Karen O'Hara, Javier Puente
Journal: Journal of Clinical Oncology (2021)

314 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer, constituting 80% to 85% of primary renal neoplasms. Preserving health-related quality of life (HRQOL) is an important goal during RCC treatment, but HRQOL analyses in prospective clinical trials in RCC are limited. We report changes in HRQOL, a secondary endpoint of this phase II trial. Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of two different starting doses of lenvatinib (18 mg vs. 14 mg daily [QD]) in combination with everolimus (5 mg QD), following one prior vascular endothelial growth factor–targeted treatment (NCT03173560). HRQOL was measured using three different instruments, including the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L. Change from baseline HRQOL was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale (i.e., 10 points for EORTC, 3 points for FKSI-DRS, 0.08 points for EQ-5D index, and 10 points for EQ-VAS). The distribution of TTD and median TTD for each treatment arm were estimated using the Kaplan-Meier method. Results: Baseline characteristics, including baseline scores of the 343 participants randomly assigned to 14 mg QD lenvatinib (n = 172) and 18 mg QD lenvatinib (n = 171), were well balanced. The average scores for the 18 mg QD group were generally higher, with lower symptom severity than the 14 mg QD group. The least squares mean estimates for change from baseline were favorable for the 18 mg QD group over the 14 mg QD group for the FKSI-DRS and most EORTC QLQ-C30 scales; however, the differences between treatments did not exceed the minimally important difference for clinical significance. Both study arms showed an increase diarrhea severity. Median TTD was longer among participants in the 18 mg QD group than those in the 14 mg QD group for most scales. Conclusions: In most scales, participants who received an 18 mg QD lenvatinib starting dose had better HRQOL and longer time to deterioration than those who received a 14 mg QD starting dose. These findings suggest that the approved treatment regimen of an 18 mg starting dose of lenvatinib in combination with everolimus remains favorable for RCC treatment, following one prior vascular endothelial growth factor–targeted treatment. Clinical trial information: NCT03173560 .
Covid-19: Budget has failed to provide recovery funding for NHS, health leaders warn
Authors: Adrian O’Dowd
Journal: BMJ (2021)

Health leaders have criticised the “striking absence” of any plan for long term recovery of health and social care services in the government’s latest budget.1

In his annual budget statement on 3 March, the UK chancellor Rishi Sunak pledged an extra £1.65bn (€1.9bn; $2.3bn) to support the continued rollout of the covid-19 vaccination programme, on top of the £55bn of covid support for public services in 2021-22 that was announced in the last spending review in 2020.

For biosciences, the government said that it was investing £5m on top of £9m funding to help create a “library” of mRNA vaccines for covid-19 variants for possible rapid response deployment and £28m to boost the UK’s vaccine testing capacity. In addition, it was providing £22m for new and expanded vaccine studies.

But although health leaders welcomed …
Considerations for active surveillance in select Gleason grade group 2 patients: A preliminary study.
Authors: Jillian Egan, Cheyenne Williams, Nabila Khondakar, Luke P. O'Connor, Michael Daneshvar, Nitin Yerram, Maria Merino, Peter L. Choyke, Bradford Wood, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2021)

206 Background: While active surveillance (AS) has become the preferred management strategy for patients with NCCN very-low and low risk prostate cancer, its use in the setting of intermediate risk disease continues to be controversial. Current guidelines state that AS can be considered in favorable intermediate risk disease, but data on outcomes in this cohort of patients is lacking. We aim to report on our experience with AS of Gleason grade group (GG) 2 at the National Cancer Institute (NCI)/National Institutes of Health (NIH). Methods: Our IRB-approved, institutional database was reviewed for men who enrolled on our AS protocol at NIH with GG2 disease from 2007-2020. All patients received MRI-targeted and systematic biopsy at the time of enrollment, diagnosing or confirming GG2 disease. MRI and PSA were performed annually, and majority of patients underwent annual combined MRI targeted and systematic prostate biopsy. If PSA and MRI were stable, annual biopsy was postponed in several patients based on their preference. Differences in PSA and PSAD at enrollment on AS and at progression were compared using Wilcoxon signed rank test. P value &lt; 0.05 was considered significant. Results: 98 patients with GG2 disease enrolled in AS at NIH. Average age at enrollment was 64 years old and the majority of patients were Caucasian. 36/98(37%) of these patients progressed to GG3 or higher while on AS. Median PSA at time of progression was significantly higher than at the time of enrollment on AS (5.2 [IQR 4.0-8.9] vs 8.5 [IQR 5.8-10.9], z = -3.12, p &lt; 0.01). PSAD was also significantly higher at time of progression (0.12[IQR 0.1-0.16] vs 0.13[IQR 0.10-0.22], z = -2.65, p &lt; 0.01). Highest PIRADS score on MRI was largely unchanged. Median time to progression was 71 months. The majority of patients progressed to GG3, and progression was the trigger for definitive treatment. All patients were alive at the end of the follow up period. Conclusions: AS is a reasonable option for compliant patients diagnosed with GG2 prostate cancer. While a significant percentage of these men will progress on AS, they do so at a median of 71 months, avoiding treatment-related harms of definitive therapy for over 5 years. Further research with larger sample sizes are needed to better evaluate the oncologic outcomes of AS for GG2 disease, as well as predictors of more aggressive disease that may be better served with upfront definitive treatment. [Table: see text]
Reduced calf muscle pump function is a risk factor for venous thromboembolism: a population-based cohort study
Authors: Damon E. Houghton, Aneel Ashrani, David Liedl, Ramila A. Mehta, David O. Hodge, Thom Rooke, Paul Wennberg, Waldemar Wysokinski, Robert McBane
Journal: Blood (2021)
Responsive Degradable Theranostic Agents Enable Controlled Selenium Delivery to Enhance Photothermal Radiotherapy and Reduce Side Effects
Authors: Nannan Zheng, Qi Wang, Chunlin Li, Xiang Wang, Xijian Liu, Xingyan Wang, Guoying Deng, Jinxia Wang, Linjing Zhao, Jie Lu
Journal: Advanced Healthcare Materials (2021)

Abstract Radiotherapy (RT) is a popular clinical therapy method for extending cancer patient survival, but is hampered by severe side effects and the weak therapy effect. Herein, responsive degradable selenium (Se) theranostic agents (Se@SiO 2 @Bi nanocomposites (NCs)) are fabricated, which combine computed tomography (CT) imaging and simultaneously enhance the therapeutic effects of photothermal therapy (PTT) and RT, while reducing the side effects of radiation. The Se@SiO 2 @Bi theranostic agents can accumulate at the tumor site, and responsively decompose to releease Se, avoiding systemic toxicity by the element. Se enhances the effect of PTT/RT, simultaneously reducing the side effects of RT. The Se@SiO 2 @Bi NCs as CT agents also exhibit significantly enhanced contrast imaging performance due to the high atomic number of Bi. More importantly, the Se@SiO 2 @Bi NCs can be rapidly excreted without long‐term toxicity, owing to responsive degradation into ultrasmall particles (&lt;5 nm) at the tumor site. In vitro and in vivo results show that the Se@SiO 2 @Bi NCs can remarkably inhibit tumor cells, without causing appreciable toxicity during the treatment. This study opens a new perspective in rationally designing responsive degradable theranostic agents for future tumor therapy with enhanced therapeutic efficacy and lesser side effects.
Human Engineered Heart Tissue Patches Remuscularize the Injured Heart in a Dose-Dependent Manner
Authors: Eva Querdel, Marina Reinsch, Liesa Castro, Deniz Köse, Andrea Bähr, Svenja Reich, Birgit Geertz, Bärbel Ulmer, Mirja Schulze, Marc D. Lemoine, Tobias Krause, Marta Lemme, Jascha Sani, Aya Shibamiya, Tim Stüdemann, Maria Köhne, Constantin von Bibra, Nadja Hornaschewitz, Simon Pecha, Yusuf Nejahsie, Ingra Mannhardt, Torsten Christ, Hermann Reichenspurner, Arne Hansen, Nikolai Klymiuk, M. Krane, C. Kupatt, Thomas Eschenhagen, Florian Weinberger
Journal: Circulation (2021)

Human engineered heart tissue (EHT) transplantation represents a potential regenerative strategy for patients with heart failure and has been successful in preclinical models. Clinical application requires upscaling, adaptation to good manufacturing practices, and determination of the effective dose.Cardiomyocytes were differentiated from 3 different human induced pluripotent stem cell lines including one reprogrammed under good manufacturing practice conditions. Protocols for human induced pluripotent stem cell expansion, cardiomyocyte differentiation, and EHT generation were adapted to substances available in good manufacturing practice quality. EHT geometry was modified to generate patches suitable for transplantation in a small-animal model and perspectively humans. Repair efficacy was evaluated at 3 doses in a cryo-injury guinea pig model. Human-scale patches were epicardially transplanted onto healthy hearts in pigs to assess technical feasibility.We created mesh-structured tissue patches for transplantation in guinea pigs (1.5×2.5 cm, 9-15×106 cardiomyocytes) and pigs (5×7 cm, 450×106 cardiomyocytes). EHT patches coherently beat in culture and developed high force (mean 4.6 mN). Cardiomyocytes matured, aligned along the force lines, and demonstrated advanced sarcomeric structure and action potential characteristics closely resembling human ventricular tissue. EHT patches containing ≈4.5, 8.5, 12×106, or no cells were transplanted 7 days after cryo-injury (n=18-19 per group). EHT transplantation resulted in a dose-dependent remuscularization (graft size: 0%-12% of the scar). Only high-dose patches improved left ventricular function (+8% absolute, +24% relative increase). The grafts showed time-dependent cardiomyocyte proliferation. Although standard EHT patches did not withstand transplantation in pigs, the human-scale patch enabled successful patch transplantation.EHT patch transplantation resulted in a partial remuscularization of the injured heart and improved left ventricular function in a dose-dependent manner in a guinea pig injury model. Human-scale patches were successfully transplanted in pigs in a proof-of-principle study.
Immunohistochemical evaluation of glutaminase expression in prostate adenocarcinoma and correlation with clinicopathologic parameters.
Authors: Zin Myint, Patrick J. Hensley, Andrew Callaway James, Peng Wang, Stephen Strup, Donglin Yan, William H. St Clair, Robert S. DiPaola, Derek B. Allison
Journal: Journal of Clinical Oncology (2021)

251 Background: Glutaminolysis plays a significant role in the metabolic reprogramming of cancer cell growth and proliferation. Glutaminase (GLS1), the rate-limiting enzyme of the glutamine pathway, is frequently dysregulated in cancer. High GLS1 expression is reported in colorectal and breast cancers and has been found to correlate with the tumor stage and disease progression. Furthermore, a new orally bioavailable glutaminase inhibitor (CB-839) is in early phase clinical trials in select tumors. The purpose of this study is to investigate the status of GLS1 expression in prostate cancer (PCa) and to correlate expression levels with clinicopathologic parameters. Methods: Radical prostatectomy samples from 154 patients with prostate adenocarcinoma were retrospectively reviewed and used to evaluate GLS1 expression by immunohistochemistry (IHC). The IHC expression score was calculated by multiplying the intensity of the stain by the proportion of cells staining; cases were then segmented into negative, low, or high expression groups. In addition, 41 samples of benign prostate tissue were used as a control. Associations between GLS1 levels and clinicopathologic parameters were analyzed by Pearson’s chi-squared and Log-rank tests. Results: GLS1 expression in the benign controls were negative, low, and high in 59%, 41%, 0% of cases, respectively, compared to 53%, 21.5%, 25.5%, respectively, in PCa (p &lt; 0.003). Most PCa patients were age &lt; 60 (55.8%), white (78.6%), stage T2 (52.9%), node negative (80.5%), Grade Group 3 (44%), and non-smokers (63.6%). There was no difference between GLS1 expression and age, race, Gleason score, stage, node status, and smoking status by univariate analysis. The median biochemical-progression free survival for negative, low, and high expression was 10, 9, and 10 years, respectively (p = 0.7). Conclusions: In our study, PCa samples were more likely to have GLS1 expression compared to benign controls. Although GLS1 expression did not appear to be a prognostic marker, our cohort was enriched for cases with localized disease and low-to-intermediate grade PCa. As a result, future studies are warranted to evaluate the expression levels in high grade and advanced PCa cases to determine a role for prognostic and or therapeutic implication to justify future preclinical studies with CB-839.
Identifying triggers for hidradenitis suppurativa flare: a patient survey
Authors: A.M. Thompson, J.M. Fernandez, J. Rick, A.J. Hendricks, M. Maarouf, E.M. Mata, E.K. Collier, T.R. Grogan, J.L. Hsiao, V.Y. Shi
Journal: British Journal of Dermatology (2021)
Utilization and reproducibility of World Endoscopy Organization post-colonoscopy colorectal cancer algorithms: retrospective analysis
Authors: David Beaton, Iosif Beintaris, Matthew D. Rutter
Journal: Endoscopy (2021)

Abstract Background Colorectal cancer (CRC) diagnosed following a cancer-negative colonoscopy is termed post-colonoscopy CRC (PCCRC). In addition to calculating PCCRC rates, the World Endoscopy Organization (WEO) recommends review of individual PCCRC cases, including categorization into interval/non-interval PCCRCs, and root cause analysis to determine the most plausible explanation. We aimed to test the usability, reproducibility, and outcomes of the WEO algorithms. Methods All CRC cases diagnosed from January 2015 to December 2016 in a single organization were cross referenced with local endoscopy and pathology databases to identify cases of PCCRC. We assessed: 1) WEO most plausible explanation for PCCRC; and 2) WEO PCCRC interval/non-interval subtype categorization. Interobserver agreement was measured using Cohen’s kappa (κ). Cases with interobserver variation underwent panel discussion to reach consensus. Results Among 527 patients with CRC, 48 PCCRCs were identified. A consistent most plausible explanation was found in 97 % of cases, showing almost perfect agreement (κ = 0.94). Most PCCRCs (66 %) were attributed to “possible missed lesion, prior examination adequate.” Interval/non-interval categorization was consistent in 77 %, showing substantial agreement (κ = 0.67). Following panel discussion, consensus was reached in all cases. Overall, 15 % were categorized as interval and 85 % as non-interval PCCRCs (12 % type A, 31 % type B, and 42 % type C). Conclusions Review of PCCRC cases using WEO recommendations was performed accurately at a local level using readily available clinical information. The high number of non-interval type B PCCRCs suggests a significant proportion of PCCRCs could be avoided by better adherence to recommended surveillance intervals.
Response to Standard Therapies and Comprehensive Genomic Analysis for Patients with Lung Adenocarcinoma with <i>EGFR</i> Exon 20 Insertions
Authors: Noura J. Choudhury, Adam J. Schoenfeld, Jessica Flynn, Christina J. Falcon, Hira Rizvi, Charles M. Rudin, Mark G. Kris, Maria E. Arcila, Glenn Heller, Helena A. Yu, Marc Ladanyi, Gregory J. Riely
Journal: Clinical Cancer Research (2021)

exon 20 insertions (ex20ins) are an uncommon genotype in non-small cell lung cancer (NSCLC) for which targeted therapies are under development. We sought to describe treatment outcomes and genomic and immunophenotypic characteristics of these tumors.
EAU Guidelines on Assessment and Nonsurgical Management of Urinary Incontinence
Authors: Arjun K. Nambiar, Ruud Bosch, Francisco Cruz, Gary E. Lemack, Nikesh Thiruchelvam, Andrea Tubaro, Dina A. Bedretdinova, David Ambühl, Fawzy Farag, Riccardo Lombardo, Marc P. Schneider, Fiona C. Burkhard
Journal: European Urology (2018)
Diagnostic Performance of the European Society of Cardiology 0/1-h Algorithms in Late Presenters
Authors: Jasper Boeddinghaus, Thomas Nestelberger, Pedro Lopez-Ayala, Luca Koechlin, Michael Buechi, Oscar Miro, Dagmar I. Keller, Maria Rubini Gimenez, Raphael Twerenbold, Christian Mueller
Journal: Journal of the American College of Cardiology (2021)
Abstract IA009: Dact1 biomolecular condensates mediate TGFβ-Wnt crosstalk in bone metastasis
Authors: Yibin Kang
Journal: Cancer Research (2021)

Abstract TGF-β signaling is a well established pathway driving different steps of bone metastasis progression. Wnt signaling plays a dichotomous role in bone metastasis, with recent studies showing that inhibition of Wnt signaling by DKK1 is critical for avoidance of immune clearance of dormant bone micrometastasis and activation of osteoclast activity during osteolytic outgrowth. On the other hand, engagement of bone vascular E-selectin by disseminated tumor cells (DTCs) promotes metastatic colonization in bone by activating Wnt signaling to enhance tumor initiating activity of DTCs. These findings imply a complex interplay between TGF-b and Wnt signaling in different stages of bone metastasis development that allows efficient colonization, dormancy and outgrowth of secondary tumors in bone. What mediates the dynamic transition of TGF-β and Wnt signaling states during metastasis is currently unknown. Here we present data describing a novel phase-separated organelle organized by bone metastasis promoting protein Dact1 which mediates the crosstalk of TGF-β and Wnt signaling. We found that Dact1 is induced by TGF-β signaling and forms dynamically regulated biomolecular condensates that suppress Wnt signaling. A high level of Dact1 expression is associated with an elevated risk of bone metastasis in breast cancer patients and Dact1 is necessary for bone metastasis in mouse models of breast and prostate cancers. Citation Format: Yibin Kang. Dact1 biomolecular condensates mediate TGFβ-Wnt crosstalk in bone metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA009.
Endoscopic ultrasound-guided jejunojejunostomy with rendezvous contrast-filling assistance in afferent limb syndrome
Authors: Michihiro Yoshida, Hiroyuki Imafuji, Kazuki Hayashi, Itaru Naitoh, Yasuki Hori, Akihisa Kato, Yoichi Matsuo
Journal: Endoscopy (2021)

A 79-year-old man who previously underwent pancreaticoduodenectomy for distal biliary duct cancer presented with abdominal pain and jaundice. Computed tomography (CT) and magnetic resonance cholangiopancreatography showed dilation of the afferent loop, intrahepatic bile duct, and pancreatic duct, with peripancreatic fat stranding ([Fig. 1]), and revealed a recurrent tumor obstructing the biliojejunal anastomotic site.
Superior molecular pathology of urothelial bladder cancer using urinary cell-free DNA.
Authors: Ruiyun Zhang, Feng Xie, Yue Zhang, Yiqiu Wang, Zhixin Zhao, Pan Du, Shidong Jia, Haige Chen, Guanglei Zhuang, Yiqiu Wang
Journal: Journal of Clinical Oncology (2021)

491 Background: Both urinary and blood cell-free DNA (cfDNA) have been implicated in noninvasive detection and surveillance of urothelial bladder cancer (UBC). However, a direct comparison of their diagnostic performance in the real-world setting is lacking. Methods: 59 eligible cases with pathologically confirmed disease and accompanying tissue/urine pairs were prospectively enrolled and consented to Institutional Review Board-approved protocols. Baseline peripheral blood mononuclear cell (PBMC) and plasma specimens were collected during clinic visit. The 180-gene Predicine liquid biopsy assay was applied for ultra-deep targeted sequencing and somatic alteration identification in tumor tissue-based DNA (tDNA), urinary cfDNA (ucfDNA) and blood cfDNA (bcfDNA). Results: The 59 studied subjects constituted a natural UBC cohort of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), including 48 (81.4%) NMIBC and 42 (71.2%) male patients. Diverse quantitative metrics such as VAF (variant allele frequency) and TMB (tumor mutational burden) were invariably concordant between tDNA and ucfDNA, but not bcfDNA. The mutational landscape captured by tDNA or ucfDNA highly resembled each other and mirrored previously described genomic panorama of UBC, whereas a significant proportion of bcfDNA aberrations stemmed from clonal hematopoiesis. Using tDNA-informed variants as the ground truth, ucfDNA assays achieved a specificity of 99.3%, a sensitivity of 86.7%, a positive predictive value (PPV) of 67.2%, a negative predictive value (NPV) of 99.8%, and a diagnostic accuracy of 99.1%, which were generally lower in the case of bcfDNA analysis. Conclusions: Urine-based molecular pathology provides valid and complete genetic information about neoplastic lesions, and represents a faithful surrogate for genotyping and monitoring UBC.