tbuckley/cabot-search huggingface dataset:
Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) HER2-negative breast cancer (BC): Results from TEXT and SOFT.
Authors: Meredith M. Regan, Prudence A. Francis, Olivia Pagani, Gini F. Fleming, Barbara Walley, Giuseppe Viale, Marco Colleoni, Istvan Lang, Henry Leonidas Gomez, Carlo Alberto Tondini, Graziella Pinotti, Angelo Di Leo, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber
Journal: Journal of Clinical Oncology (2018)

503 Background: The TEXT and SOFT trials randomly assigned premenopausal women with HR+ BC to exemestane plus ovarian function suppression (E+OFS), tamoxifen+OFS (T+OFS) and T alone. We previously examined absolute treatment effects on any BC recurrence across a continuum of recurrence risk to individualize endocrine therapy decision making. After 8.5 yrs median follow-up we now consider effects on freedom from distant recurrence. Methods: The TEXT and SOFT HR+/HER2- analysis population included 4891 pts and was stratified by chemotherapy use. The endpoint was distant recurrence-free interval (DRFI; time from randomization to first appearance of DR). For each pt, a previously defined continuous, composite recurrence risk index (CRI) was calculated from a Cox model incorporating age, nodal status, tumor size and grade, and ER, PgR and Ki-67 expression levels. Subpopulation Treatment Effect Pattern Plot (STEPP) methodology estimated 8yr absolute treatment effects for subpopulations defined by CRI values. Results: Overall 8yr DRFI was 91% (433 DRs) and ranged from ~100% to 63% across lowest CRI of 0.2 to highest CRI of 3.4. TEXT pts (n = 2267) had median [IQR] CRI of 1.7 [1.2-2.3]. Overall 8yr DRFI was 92% (194 DRs) and absolute benefit of E+OFS vs T+OFS was 3%; benefit ranged from 0% at lowest CRI (both therapies having 100% 8yr DRFI) to 15% at highest CRI. SOFT pts who remained premenopausal after chemo (n = 1271) had median CRI of 2.1 [1.5-2.7]. Overall 8yr DRFI was 82% (216 DRs) and absolute benefit of E+OFS vs T was 5%; benefit ranged from 2% to 10% across CRI. For T+OFS vs T the absolute benefit ranged 0% to 5%. The SOFT no-chemo cohort (n = 1353) had median CRI of 1.1 [0.3-1.4]. Overall 8yr DRFI was 99% (23 DRs), and across CRI exceeded 97% with all three endocrine therapies. Conclusions: Premenopausal pts with HR+/HER2- BC and high recurrence risk, as defined by clinicopathological characteristics, may experience 10-15% absolute improvement in 8yr DRFI with E+OFS vs T+OFS or T alone. Potential benefit of escalating endocrine therapy vs T alone is minimal for those at low risk, and may be 4-5% for pts at intermediate risk. Clinical trial information: NCT00066690, NCT00066703.
Are the loading dose treatment groups superior to the 150 mg without loading dose group in the secukinumab FUTURE 5 study?
Authors: Bernardo Matos da Cunha
Journal: Annals of the Rheumatic Diseases (2018)

I read with great interest the article by Mease  et al 1 because equivalence in efficacy with lesser secukinumab total doses could be less expensive to payers and more safe and comfortable to patients. However, I am somewhat disappointed with the reported results.

The …
Trends in hospitalization for acute bronchiolitis in Portugal: 2000–2015
Authors: A. Mendes-da-Silva, M. Gonçalves-Pinho, A. Freitas, I. Azevedo
Journal: Pulmonology (2018)

Recent studies show contradictory data on the incidence of hospitalizations for acute bronchiolitis (AB) and an escalating increase in public health burden. We aimed to analyze the population-based admission rate for AB in children under 2 years of age, in Portuguese public hospitals, from 2000 to 2015, to assess trends and regional variations in admission rate; outcomes; associated direct health-care costs; and changes in management after the implementation of national guidelines. Retrospective observational study, conducted using a Portuguese administrative database, which contains all registered public hospitalizations in mainland Portugal, and demographic data from the National Statistics Institute. Over the study period, we recorded 80,491 admissions for AB. The mean admission rate was 26.28 and was higher in the northernmost regions of the country. Along the time, the admission rate rose by an average of 1.6% per year (3.8% in children younger than 3 months) and the average length of stay (LOS) was 6.1 days and decreased, to a minimum of 5.5 days in 2014. The in-hospital mortality rate (0.1%) and the use of invasive ventilation remained stable, but non-invasive ventilation use increased from 0.4% in 2000 to 4% in 2015. The direct estimated total costs were of 72,420,732€. In recent years, there was a decrease in the reported tests and procedures. AB remains a major burden in the healthcare system. The admission rate increased but does not seem to be due to an increase in severity, as LOS decreased, and the use of invasive ventilation and mortality remained unchanged.
A novel technique using high energy synchronous double-wave laser in endoscopic submucosal dissection of patients with superficial esophageal neoplasm
Authors: Jun Yao, Jun Li, Peng Wang, Feng Liu, Zhaoshen Li
Journal: Endoscopy (2018)

BACKGROUND : Endoscopic submucosal dissection (ESD) has been widely used to treat superficial esophageal neoplasms (SENs). Intraoperative bleeding is one of the main concerns that makes ESD in the esophagus more difficult and time consuming with higher complication rates. We introduced a novel laser endoknife system that enabled better intraoperative hemostasis, and preliminarily investigated its feasibility in ESD for patients with SENs.17 consecutive patients with SENs were prospectively enrolled. The laser endoknife system was used in marking and submucosal dissection. Data on therapeutic outcomes were collected and analyzed.The median diameter of the lesions was 2.5 cm and of the resected specimens was 3.0 cm. The median procedure time was 48 minutes. Histologic evaluation revealed 15 high grade intraepithelial neoplasias and two squamous cell carcinomas. No intraoperative bleeding occurred during laser cutting and no significant complications occurred postoperatively. Curative R0 resection was achieved in all patients.Our new laser endoknife system was feasible in the submucosal dissection of SENs and showed great prospects for future application.
Phospho-PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP
Authors: X Xie, C Bartholomeusz, A Kazansky, A A Ahmed, L Diao, K A Baggerly, G N Hortobagyi, N T Ueno
Journal: Cancer Research (2012)
Activity of tesetaxel, an oral taxane, given as a single-agent in patients (Pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (MBC) in a phase 2 study.
Authors: Andrew David Seidman, Lee Steven Schwartzberg, Vinay K. Gudena, Peter Rubin, Stew Kroll, Joseph P. O'Connell, Kevin Tang, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2018)

1042 Background: Chemotherapy treatments that offer improved quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing; no history of hypersensitivity reactions (HSRs); and improved activity against chemotherapy-resistant tumors (Shionoya 2003; Chan 2006). 555 pts have been treated with T in clinical studies. In MBC, T was shown to have robust single-agent activity in 2 multicenter, Phase 2 studies. In TOB203, 46 pts with HER2- MBC received single-agent T Q3W, including 38 pts with HR+ MBC, the population being enrolled in CONTESSA, an ongoing Phase 3 study. Methods: Pts eligible for TOB203 had HER2- MBC, ECOG PS 0-1, measurable disease and adequate organ function. Adjuvant chemotherapy (including taxanes) was allowed. T was administered orally as first-line chemotherapy at 27 mg/m2 on Day 1 of a 21-day cycle, with escalation to 35 mg/m2 in subsequent cycles depending on tolerability, without anti-allergy premedication. ORR was the primary endpoint. Final results are provided for all 38 HR+ pts who received T Q3W. Results: Median age: 58 (36-80 yrs); 74% received prior endocrine therapy; 68% received prior chemotherapy in the adjuvant setting (53% taxane-containing regimen; 50% anthracycline-containing regimen); median organ systems involved: 2 (1-4); 82% had visceral disease. The confirmed ORR per RECIST 1.1 in all 38 pts was 45% (95% CI: 29% - 62%); median duration of response was 8.7 mo (95% CI: 4.3 – 13.6 mo); median PFS was 5.7 mo (95% CI: 4.1 – 9.8 mo). In the 24 HR+ pts receiving 27 mg/m2 without escalation, Grade ≥ 3 neutropenia, the most common Grade ≥ 3 AE, occurred in 29% of pts (febrile neutropenia 4%), there were no cases of Grade ≥ 3 peripheral neuropathy, and the incidence of Grade 1/2 alopecia was 29%/21%. There were no HSRs or study drug-related deaths. Conclusions: T, as a single agent, was well tolerated with significant activity in pts with HER2-, HR+ MBC. T is currently being investigated in CONTESSA, a multinational, multicenter, randomized, Phase 3 study in pts with HER2-, HR+ MBC (NCT03326674). Clinical trial information: NCT01221870.
Adolescents’ Perspectives on Atopic Dermatitis Treatment—Experiences, Preferences, and Beliefs
Authors: Richelle C. Kosse, Marcel L. Bouvy, Maud Daanen, Tjalling W. de Vries, Ellen S. Koster
Journal: JAMA Dermatology (2018)

For a considerable proportion of pediatric patients, atopic dermatitis symptoms persist into adolescence. Previous studies have focused mainly on (parents of) children, whereas little is known about adolescents with atopic dermatitis.To explore the beliefs, experiences, and preferences of adolescents with atopic dermatitis toward their treatment.We conducted a qualitative study employing focus group interviews of 15 adolescents (aged 12-18 years) who collected at least 1 prescription for topical corticosteroids in class 2 (moderately potent) or 3 (potent) in the preceding year. The study included 9 community pharmacies in 3 different regions in the Netherlands. Data were collected from November to December 2016, until data saturation was reached. Focus groups were recorded, transcribed verbatim, and data were analyzed by 2 researchers.Adolescents' beliefs, experiences, and preferences toward their atopic dermatitis treatment were explored during focus groups. We used a thick analysis approach to analyze the transcripts; both deductive and inductive coding were used to analyze the transcripts.Three focus groups including 15 adolescents (8 male) with a mean age of 15.3 (range, 12-18) years were conducted. Adolescents were in general satisfied with the efficacy of the treatment; however, they prefer a faster and more persistent effect. Most adolescents had little contact with their physicians and did not completely adhere to the prescribed medication regimen; they developed their own routine of using topical corticosteroids in combination with emollients and moisturizers. They also seemed to have incorrect beliefs about the mechanism of action.Adolescents developed their own way of using topical treatment for atopic dermatitis. Some practical suggestions were mentioned to improve medication use. Health care providers should devote special attention to adolescents with atopic dermatitis to make them more aware of the principles of topical treatment and ensure proper use.
Results from a pilot of an innovative 4R Cancer Care Delivery Model in early breast cancer: Impact on timing and sequencing of guideline recommended care.
Authors: Christine B. Weldon, Julia Rachel Trosman, Claudia B. Perez, Swati Kulkarni, Seema Ahsan Khan, Nora Hansen, Valerie Nelson, Jennifer Stein, Melissa A. Simon, Cathy Spagnoli, Jennifer Tepper, Kay Pearson, William John Gradishar
Journal: Journal of Clinical Oncology (2018)

561 Background: Under the “NCI ASCO Teams” Project, we proposed a 4R Model of teamwork and patient self-management (Trosman JOP ’16). 4R = Right Info / Care / Patient / Time. It enables patient and care team to manage timing / sequencing of interdependent care with an innovative multimodality personalized 4R Care Project Plan. We piloted 4R at 3 centers (academic, community, safety net) and assessed impact on timing / sequencing of guideline based care. Methods: 4R Plans were administered to breast cancer patients stage 0-III Sept ’17 – Aug ’17. Clinical data for 185 patients who received 4R (4R cohort) were compared with a historical control cohort of comparable patients who received care pre-4R, Jun ’16 – May ’17. We used simple frequencies and Fisher’s exact test in analyses. Results: We improved timing / sequencing of 7 guideline recommended metrics (Table). Significant improvements were shown for care lacking in the control cohort. 4R improved rate of patients receiving genetic test results and fertility in a timely manner. Neoadjuvant therapy rate doubled, but low sample size precluded statistical conclusions. However, timing / sequencing of care needed prior to neoadjuvant therapy (eg fertility, flu shot) were significantly improved. Conclusions: The 4R model significantly improved timing / sequencing of guideline recommended care in early breast cancer. An ongoing 4R pilot at 12 additional cancer centers across the U.S. is continuing to accrue patients and focusing on other guideline-recommended metrics. Metric Guideline % 4R cohort N = 185 % Control cohort N = 162 P value Patient Goal of Care discussion documented in medical record NAM ‘13, NCCN PAL-4 98 2 .0001 Distress Screening w/in 30 days of diagnosis ASCO ‘14, NCCN DIS-A 95 11 .0001 Dental referral before therapy ADA ‘08 74 0 .0001 Complete dental work before therapy ADA ‘08 49 NA - Referral to Primary Care before treatment NCCN OAO-D 72 16 .0001 Referral to genetics NCCN BR/OV-1 36 7 .0001 Genetic results prior to surgery NCCN BR/OV-1 84 64 NS Flu shot before therapy NCCN INF-7 34 0 .0001 Fertility consult & services before treatment, < 50 years old NCCN BINV-C 24 14 NS Neoadjuvant Therapy NCCN BINV-11 15 7 NS NS = not significant
Poly(ADP-Ribose) Polymerase Inhibitors (PARPi) for patients (pts) with locally advanced or metastatic breast cancer (BC): A meta-analysis.
Authors: Martin Tio, Sujata Patil, Tiffany A. Traina, Mark E. Robson, Mustafa Khasraw
Journal: Journal of Clinical Oncology (2018)

1076 Background: We performed a quantitative meta-analysis of randomized clinical trials of PARPi in pts with BC. Methods: 2 registries (ClinicalTrials.gov, WHO ICTRP) and 4 electronic databases (CBCG SR, CENTRAL, Medline, EMBASE) were searched from 2008 to 1/2018 for randomized clinical trials (RCTs) of PARPi therapy vs. control in BC. RCTs that reported overall survival (OS) or progression-free survival (PFS) were included. Pooled hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated using a fixed effects model. Results: We identified 418 citations, of which 2 RCTs with a pooled sample size of n = 733 were included. There was a low/moderate risk of bias in both RCTs (Table). Both RCTs compared a PARPi to physician's choice of chemotherapy in pts with germline BRCA mutated HER2-negative BC in first or later line setting, with PFS as the primary outcome. The pooled analysis of PFS showed a statistically significant improvement with PARPi therapy, with an HR 0.56 (95% CI 0.45-0.68). The pooled analysis of OS did not show a statistically significant improvement, with an HR of 0.82 (95% CI 0.64-1.05). There was an acceptable safety profile with PARP therapy in both RCTs, with a grade ≥ 3 adverse event rate of 25.5% and 36.6% in the 2 RCTs respectively. Conclusions: The use of PARPi in pts with germline BRCA mutated HER2-negative BC offers a PFS benefit compared to physician's choice of chemotherapy in the first or later line setting, with an acceptable adverse events rate. Lack of OS benefit may be explained by availability of further lines of therapy, relative immaturity of the trials and not being powered to assess OS. This systematic review is part of a planned Cochrane Breast Cancer Group protocol. Sequence generation Allocation concealment Blinding pts & staff Blinding outcome assessment Incomplete outcome data Selective reporting Intention to treat Robson et al, 2017 Centralized random number generator Allocation concealed Not blinded Blinded. Primary outcome reported 98% of pts No selective reporting Yes Risk L L H L L L L Litton et al, 2017 Not described Not described Not blinded Blinded Primary outcome reported 96% of pts No selective reporting Yes Risk H H H L L L L H: High; L: Low
Divergent Allele Advantage at Human MHC Genes: Signatures of Past and Ongoing Selection
Authors: Federica Pierini, Tobias L Lenz
Journal: Molecular Biology and Evolution (2018)

The highly polymorphic genes of the major histocompatibility complex (MHC) play a key role in adaptive immunity. Divergent allele advantage, a mechanism of balancing selection, is proposed to contribute to their exceptional polymorphism. It assumes that MHC genotypes with more divergent alleles allow for broader antigen-presentation to immune effector cells, by that increasing immunocompetence. However, the direct correlation between pairwise sequence divergence and the corresponding repertoire of bound peptides has not been studied systematically across different MHC genes. Here, we investigated this relationship for five key classical human MHC genes (human leukocyte antigen; HLA-A, -B, -C, -DRB1, and -DQB1), using allele-specific computational binding prediction to 118,097 peptides derived from a broad range of human pathogens. For all five human MHC genes, the genetic distance between two alleles of a heterozygous genotype was positively correlated with the total number of peptides bound by these two alleles. In accordance with the major antigen-presentation pathway of MHC class I molecules, HLA-B and HLA-C alleles showed particularly strong correlations for peptides derived from intracellular pathogens. Intriguingly, this bias coincides with distinct protein compositions between intra- and extracellular pathogens, possibly suggesting adaptation of MHC I molecules to present specifically intracellular peptides. Eventually, we observed significant positive correlations between an allele's average divergence and its population frequency. Overall, our results support the divergent allele advantage as a meaningful quantitative mechanism through which pathogen-mediated selection leads to the evolution of MHC diversity.
Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma
Authors: Brian A. Walker, Konstantinos Mavrommatis, Christopher P. Wardell, T. Cody Ashby, Michael Bauer, Faith E. Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Philippe Moreau, Brian Durie, A. Keith Stewart, Hartmut Goldschmidt, Marc S. Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H. Jackson, Kenneth C. Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth J. Morgan
Journal: Blood (2018)
Publisher Correction: Targeting hepatic glutaminase activity to ameliorate hyperglycemia
Authors: Russell A. Miller, Yuji Shi, Wenyun Lu, David A. Pirman, Aditi Jatkar, Matthew Blatnik, Hong Wu, César Cárdenas, Min Wan, J. Kevin Foskett, Junyoung O. Park, Yiyi Zhang, William L. Holland, Joshua D. Rabinowitz, Morris J. Birnbaum
Journal: Nature Medicine (2018)
Rampant centrosome amplification and aggressive disease course of triple-negative breast cancers.
Authors: Vaishali Pannu, Karuna Mittal, Guilherme Henrique Cantuaria, Michelle D. Reid, Xiaoxian Li, Shashi Donthamsetty, Michelle McBride, Remus Osan, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2015)

1075 Background: Centrosome amplification (CA), a cell-biological trait characteristic of pre-neoplastic and pre-invasive lesions has empirically been associated with tumor aggressiveness suggesting an early and causal role of excess centrosomes in driving tumor progression. Recent studies provide convincing evidence that CA leads to malignant transformation and promotes invasion in mammary epithelial cells. Given that supernumerary centrosomes occur in ~80% of breast cancers, we hypothesize that CA can serve as a predictor of breast cancer aggressiveness. Triple (ER/PR/Her2) negative (TN) breast cancer, a histologically-aggressive breast cancer subtype, commonly afflicts African-American (AA) women and is characterized by high recurrence, metastases, and mortality rates. TN and non-TN breast tumors follow variable kinetics of metastatic progression, and thus constitute a test bed to explore if the severity and nature of CA can distinguish the two subtypes. Methods: Utilizing formalin-fixed paraffin-embedded and fresh-frozen breast cancer tissues, we quantitatively assessed extent of structural and numerical centrosomal aberrations for each patient sample in a large-cohort of grade-matched TNBC (n = 30) and non-TNBC (n = 98) cases employing multi-color immunofluorescence confocal imaging and immunoblotting. Results: Our data establish previously unrecognized differences in incidence and severity of CA between TNBC and non-TNBC cell lines and clinical specimens. We found strong correlation between CA and markers of aggressiveness associated with breast cancer metastasis in 20 pairs of grade-matched TNBC and non-TNBC clinical specimens (p < 0.02). Time-lapse imaging of MDA-MB-231 cells stably-transfected with GFP-tagged centrin harboring amplified centrosomes demonstrated that CA confers enhanced migratory ability. Conclusions: Our study reveals a causative link between CA and breast cancer aggressiveness. Organellar disparity between breast cancer subtypes harboring different metastatic potential has immense translational value as it may allow early-risk prediction and explain higher tumor aggressiveness in TNBC patients.
More Evidence That Abortion Is Not Associated With Increased Risk of Mental Illness
Authors: Nada L. Stotland, Angela D. Shrestha
Journal: JAMA Psychiatry (2018)

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