tbuckley/cabot-search huggingface dataset:
Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study
Authors: John C. Byrd, Richard R. Furman, Steven E. Coutre, Ian W. Flinn, Jan A. Burger, Kristie Blum, Jeff P. Sharman, William Wierda, Weiqiang Zhao, Nyla A. Heerema, Ying Luan, Emily A. Liu, James P. Dean, Susan O'Brien
Journal: Clinical Cancer Research (2020)

Abstract Purpose: The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date. Patients and Methods: Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL. Results: Overall response rate was 89%, with similar rates in first-line (87%; complete response, 35%) and relapsed/refractory settings (89%; 10%). Estimated 7-year progression-free survival (PFS) rates were 83% in first-line and 34% in relapsed/refractory settings. Forty-one patients had CLL progression (n = 11 with Richter's transformation). Median PFS was not reached with first-line ibrutinib. In relapsed/refractory CLL/SLL, median PFS was 52 months overall, 26 months in patients with chromosome 17p deletion, 51 months with 11q deletion, not reached with trisomy 12 or 13q deletion, and 88 months in patients without these cytogenetic abnormalities. Estimated 7-year overall survival rates were 84% in first-line and 55% in relapsed/refractory settings. Grade ≥3 adverse events (AE) in &amp;gt;15% of patients were hypertension (28%), pneumonia (24%), and neutropenia (18%). These grade ≥3 AEs generally declined over time, except hypertension. AEs leading to discontinuation in ≥2 patients were observed only in the relapsed/refractory setting (sepsis, diarrhea, subdural hematoma, and Richter's transformation). Conclusions: With up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.
Abstract P5-03-09: Multigene panel analysis in breast and ovarian cancer
Authors: Elisabeth Katharina Trapp, Michael Speicher, Jochen B Geigl, Vassiliki Kolovetsiou-Kreiner, Julia Reisinger, Josef Haas, Edgar Petru, Karl Tamussino, Gunda Pristauz
Journal: Cancer Research (2020)

Abstract Background: Genetic testing is of prognostic and predictive importance in patients with ovarian cancer and breast cancer. The best explored mutations are those of the BRCA 1 and BRCA2 genes, and the result of BRCA testing impacts treatment and prophylactic options. Data on other breast-cancer-associated genes are accumulating. Methods: All patients who underwent genetic counseling and testing for BRCA 1 and BRCA 2 between 2007 and 2019 at the Medical University of Graz were reviewed. If BRCA testing was negative patients were offered panel testing for other breast and ovarian cancer associated genes including ATM, PETEN, RAD50, RAD51D, RAD51C, TP53, STK11, ATM, NBN, CDH, MSH6, MSH2, MLH1, CHEK2, PALB2, BRIP1, SMO, PETEN, SMO. Results: In total 1905 patients were counseled for genetic testing between 2007 to 2019. In 292 patients (mean age 53yrs) panel gene testing was performed. 114 (39%) of these 292 BRCA-negative patients (55 with breast cancer, 24 with ovarian cancer) had a pathogenic variant (n=32) or a mutation of unknown significance (n=82). The most common pathogenic variant occurred in the CHEK2 gene (n=15). Interpretation: In this series approximately one third of high-risk patients who tested negative for a BRCA mutation had a mutation of unknown significance and/or pathogenic mutation in gene panel testing. This indicates that genetic panel testing should be considered more frequently. Citation Format: Elisabeth Katharina Trapp, Michael Speicher, Jochen B Geigl, Vassiliki Kolovetsiou-Kreiner, Julia Reisinger, Josef Haas, Edgar Petru, Karl Tamussino, Gunda Pristauz. Multigene panel analysis in breast and ovarian cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-09.
“Can’t Stop the Feeling”: Symptoms as the Key to Trial Success in Bronchiectasis?
Authors: Pierre-Régis Burgel, Sanjay H. Chotirmall
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Can't Stop the Feeling": Symptoms as the Key to Trial Success in Bronchiectasis?Bronchiectasis, which is characterized by chronic, inflammatory, and irreversible airway dilatation, has a considerable disease burden, complex clinical heterogeneity, and broad etiology, and often has no identifiable cause (1, 2).Recognizable endophenotypes are emerging that may explain difficulties encountered in clinical trials (3,4).Exacerbation frequency and associated symptoms are central to a clinician's approach to caring for patients with bronchiectasis; however, assessing symptom burden, frequency, and variation among patients and even within an individual patient remains challenging.In a study presented in this issue of the Journal, Gao and colleagues (pp.1499-1507) addressed this issue by examining data from 333 patients with bronchiectasis from a single center in the United Kingdom (5).The authors assessed bronchiectasis symptoms according to St. George's Respiratory Questionnaire (SGRQ) symptom scores and the Leicester Cough Questionnaire (LCQ), using the former to classify patients as having a high, moderate, or low symptom burden.At baseline, patients with a high symptom burden exhibited more exacerbations in the preceding year, higher rates of bacterial isolation (especially Pseudomonas aeruginosa), higher body mass index, lower FEV 1 , and worse cough-related quality of life (lower LCQ score), suggestive of a relationship between symptom burden and more severe disease.Importantly, patients with a high symptom burden at baseline also experienced approximately twice the number of exacerbations per patient per year, a sixfold increase in hospitalizations, and shorter times to first exacerbation than patients with a low symptom burden, even after adjustment for cofounding variables such as age, sex, radiology, bacterial infection, and bronchiectasis etiology.The authors extended these findings by reporting a comparable association between symptoms and the risk of future exacerbations.Interestingly, Gao and colleagues reanalyzed results from a previously published, unsuccessful randomized clinical trial of inhaled mannitol, which failed to reduce bronchiectasis exacerbations compared with placebo (6).Although the original trial recruited patients with a history of multiple exacerbations, intriguingly, by classifying the patients' symptom burden at study entry (using the SGRQ symptom score), the authors were able to show that highly symptomatic patients (i.e., those with high baseline symptom burdens) in the
DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients
Authors: Samar M. Said, Nelson Leung, Mariam Priya Alexander, Lynn D. Cornell, Mary E. Fidler, Joseph P. Grande, Loren Hernandez Herrera, Sanjeev Sethi, Pingchuan Zhang, Samih H. Nasr
Journal: Kidney International (2020)
Covid-19: Trump extends physical distancing to 30 April, as cases climb in New York
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

President Donald Trump has extended physical distancing guidelines for the US to 30 April, reversing his earlier call for them to end on 30 March and for the nation to “get back to business” by Easter (12 April). He said that that had been “an aspirational goal.”

Trump said that on 31 March he would present a plan for the future approach to the epidemic in the US.

Trump predicted that the peak of US deaths would occur in about two weeks and that by 1 June the nation would be well on the way to recovery. He has apparently abandoned his plan to rank the nation’s 3007 counties as being at low, medium, or high risk and to permit some to reopen soon for business.

The US had 143 055 cases …
Gastric perforation during ligation-assisted endoscopic mucosal resection of a neuroendocrine tumor: banding without resection may be a safer option
Authors: Francesc Bas-Cutrina, Raquel Ballester-Clau, Ferran González-Huix, Joan B. Gornals
Journal: Endoscopy (2020)

The management of small gastrointestinal subepithelial tumors (SETs) considers periodic endoscopic surveillance vs. endoscopic removal for entities with malignant potential such as neuroendocrine tumor (NET), gastrointestinal stromal tumor or others [1]. Excision by ligation-assisted endoscopic mucosal resection (EMR) is an option for small SETs [2].
An ocular glymphatic clearance system removes β-amyloid from the rodent eye
Authors: Xiaowei Wang, Nanhong Lou, Allison Eberhardt, Yujia Yang, Peter Kusk, Qiwu Xu, Benjamin Förstera, Sisi Peng, Meng Shi, Antonio Ladrón-de-Guevara, Christine Delle, Björn Sigurdsson, Anna L. R. Xavier, Ali Ertürk, Richard T. Libby, Lu Chen, Alexander S. Thrane, Maiken Nedergaard
Journal: Science Translational Medicine (2020)

Despite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified an ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve in rodents. β-amyloid (Aβ) was cleared from the retina and vitreous via a pathway dependent on glial water channel aquaporin-4 (AQP4) and driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal Aβ was cleared via the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced efflux, whereas atropine or raising intracranial pressure blocked efflux. In two distinct murine models of glaucoma, Aβ leaked from the eye via defects in the lamina barrier instead of directional axonal efflux. The results suggest that, in rodents, the removal of fluid and metabolites from the intraocular space occurs through a glymphatic pathway that might be impaired in glaucoma.
2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis
Authors: Antonis Fanouriakis, Myrto Kostopoulou, Kim Cheema, Hans-Joachim Anders, Martin Aringer, Ingeborg Bajema, John Boletis, Eleni Frangou, Frederic A Houssiau, Jane Hollis, Adexandre Karras, Francesca Marchiori, Stephen D Marks, Gabriella Moroni, Marta Mosca, Ioannis Parodis, Manuel Praga, Matthias Schneider, Josef S Smolen, Vladimir Tesar, Maria Trachana, Ronald F van Vollenhoven, Alexandre E Voskuyl, Y K Onno Teng, Bernadette van Leew, George Bertsias, David Jayne, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2020)

Objective To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria &lt;0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (&lt;7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria &gt;1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
Does distal laparoscopic pancreatectomy decrease morbidity and mortality? A multicentre study (ERPANDIS)
Authors: Mario Serradilla, Juan Vicente Del Rio, Gerardo Blanco, Fernando Rotellar, Luis Sabater, Alba Manuel, Alberto Carabias, Pedro Hernández, Sara Esteban, Elena Muñoz, Helga Kälviäinen, Fernando Pardo, Marina Garcés, Texell Longoria-Dubocq, Miguel Cantalejo, María Sánchez-Rubio, Juan José Díaz, Sandra Paterna, Alejandro Serrablo, José Manuel Ramia
Journal: International Journal of Surgery (2020)
Obstacles to detecting isoforms using full-length scRNA-seq data
Authors: Jennifer Westoby, Pavel Artemov, Martin Hemberg, Anne Ferguson-Smith
Journal: Genome biology (2020)

Early single-cell RNA-seq (scRNA-seq) studies suggested that it was unusual to see more than one isoform being produced from a gene in a single cell, even when multiple isoforms were detected in matched bulk RNA-seq samples. However, these studies generally did not consider the impact of dropouts or isoform quantification errors, potentially confounding the results of these analyses.
Abstract OT1-01-04: A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy
Authors: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen B Solomon, Jorge Leal, Micaela Rodine, Christina DiLauro Abaya, Sujita Patil, David Page, Larry Norton
Journal: Cancer Research (2020)

Abstract Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this randomized phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo versus standard care in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &amp;lt;10%, PR &amp;lt;10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 160 pts will be randomized to one of two arms: breast surgery (control arm) or ipi/nivo/cryo followed by breast surgery and adjuvant nivo (intervention arm). Pts in the intervention arm will undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen B Solomon, Jorge Leal, Micaela Rodine, Christina DiLauro Abaya, Sujita Patil, David Page, Larry Norton. A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-01-04.
SAT0224 ANTIPHOSPHOLIPID ANTIBODIES AND VASCULAR RENAL LESIONS AS PROGNOSTIC FACTORS IN LUPUS NEPHRITIS
Authors: A. Paglionico, V. Varriano, L. Petricca, G. Vischini, C. DI Mario, M. R. Gigante, G. Tanti, S. Costanzi, G. Grandaliano, B. Tolusso, G. Ferraccioli, E. Gremese
Journal: Annals of the Rheumatic Diseases (2020)

Background: Several studies have showed that antiphospholipid antibodies (aPL) positivity represents a predictor of worse renal outcome in patients with Lupus Nephritis (LN). In addition, an association between aPL positivity and the histological data of vascular lesions on the renal biopsies has been reported. Objectives: To determine the prognostic role of aPL and vascular renal lesions in the assessment of clinical outcome during the follow up period, in terms of time to achieve remission, number of renal flares and development of chronic renal damage in patients affected by LN. Methods: Among 120 patients affected by LN from our Rheumatology Unit, 91 patients (age 43.8 ± 12 years, 74 (81.3%) female, disease duration 7.1 ± 7.9 years) have been evaluated and the follow-up data have been collected at the baseline and at 6, 12, 24 months and at the last follow-up visit. Histopathological data of 41 patients were evaluated according to the 2016 revision of ISN/RPS classification. Results: Among the 91 LN patients, 31 (34.1%) were aPL positive (aPL+), 10 (32.2%) of them were affected by Antiphospholipid Antibodies Syndrome (APS), 53.3% showed a single aPL positivity, 23.1% double aPL positivity and 15.4% triple aPL positivity. At the last follow up visit a significant higher number of aPL+ patients showed a persistent complement consumption than aPL negative (aPL-) patients (p=0.001). Evaluating clinical outcome, we observed that aPL- patients showed a remission achievement time slightly earlier than aPL+ patients (13.6 ± 1.0 months vs 16.5 ± 1.5 months; log-rank test: p=0.06, Breslow test: p=0.08) and as expected, patients with a persistent complement consumption achieve remission later (18.2 ± 1.5 months vs 13.0 ± 1 months; log-rank test: p=0.002, Breslow test: p=0.003). Furthermore at the last follow up, a significant higher percentage of aPL+ patients developed persistent proteinuria (p=0.02) and chronic renal failure (p=0.04). Considering histologic features (activity and chronicity index, glomerulonephritis class, presence of mesangiolysis, glomerular wrinkling, glomerular thrombi, interstitial inflammatory infiltrates, interstitial fibrosis and tubular atrophy,tubulitis and vascular lesions) we didn’t observe significant differences between aPL+ and aPL- patients but we found two typical vascular lesions (mesangiolysis and vascular thrombi) only in aPL + patients. Conclusion: aPL positivity is a predictor of worse renal outcome but in our cohort of LN patients we didn’t find an association between aPL positivity and vascular renal lesions at renal biopsy. The worse renal outcome and the late time to achieve remission in aPL+ group can be related to a cumulative vascular damage over time as observed in other organ and systems. Disclosure of Interests: None declared
CEREBRUM: a fast and fully-volumetric Convolutional Encoder-decodeR for weakly-supervised sEgmentation of BRain strUctures from out-of-the-scanner MRI
Authors: Dennis Bontempi, Sergio Benini, Alberto Signoroni, Michele Svanera, Lars Muckli
Journal: Medical Image Analysis (2020)

Many functional and structural neuroimaging studies call for accurate morphometric segmentation of different brain structures starting from image intensity values of MRI scans. Current automatic (multi-) atlas-based segmentation strategies often lack accuracy on difficult-to-segment brain structures and, since these methods rely on atlas-to-scan alignment, they may take long processing times. Alternatively, recent methods deploying solutions based on Convolutional Neural Networks (CNNs) are enabling the direct analysis of out-of-the-scanner data. However, current CNN-based solutions partition the test volume into 2D or 3D patches, which are processed independently. This process entails a loss of global contextual information, thereby negatively impacting the segmentation accuracy. In this work, we design and test an optimised end-to-end CNN architecture that makes the exploitation of global spatial information computationally tractable, allowing to process a whole MRI volume at once. We adopt a weakly supervised learning strategy by exploiting a large dataset composed of 947 out-of-the-scanner (3 Tesla T1-weighted 1mm isotropic MP-RAGE 3D sequences) MR Images. The resulting model is able to produce accurate multi-structure segmentation results in only a few seconds. Different quantitative measures demonstrate an improved accuracy of our solution when compared to state-of-the-art techniques. Moreover, through a randomised survey involving expert neuroscientists, we show that subjective judgements favour our solution with respect to widely adopted atlas-based software.
Covid-19: four fifths of cases are asymptomatic, China figures indicate
Authors: Michael Day
Journal: BMJ (2020)

New evidence has emerged from China indicating that the large majority of coronavirus infections do not result in symptoms.

Chinese authorities began publishing daily figures on 1 April on the number of new coronavirus cases that are asymptomatic, with the first day’s figures suggesting that around four in five coronavirus infections caused no illness. Many experts believe that unnoticed, asymptomatic cases of coronavirus infection could be an important source of contagion.

A total of 130 of 166 new infections (78%) identified in the 24 hours to the afternoon of Wednesday 1 April were asymptomatic, said China’s National Health Commission. And most of the 36 cases in which patients showed symptoms involved arrivals from overseas, down from 48 the previous day, the commission said.

China is rigorously testing arrivals from overseas for fear of importing a …