tbuckley/cabot-search huggingface dataset:
Open access publishing under Plan S to start in 2021
Authors: Nigel Hawkes
Journal: BMJ (2019)

From 2021, all research funded by public or private grants should be published in open access journals, according to a group of funding agencies called coALition S.1

The plan is the final version of a draft that was put to public consultation last year and attracted 344 responses from institutions, almost half of them from the UK.2 The responses have been considered and some changes made to the new system called Plan S, a briefing at the Science Media Centre in London was told on 29 May.

The main change has been to delay implementation for a year, to 1 January 2021, to allow more time for those involved—researchers, funders, institutions, publishers, and repositories—to make the necessary changes, said John-Arne Rottingen, chief executive of the Research Council of Norway.

“All research contracts signed after that date should include the obligation to publish in an open access journal,” he said. That …
Effects of different exercise modalities on novel hepatic steatosis indices in overweight women with type 2 diabetes
Authors: Ebrahim Banitalebi, Mohammad Faramarzi, Samira Nasiri, Majid Mardaniyan, Vahid Rabiee
Journal: Clinical and Molecular Hepatology (2019)

Background/Aims Fatty liver is a clinical and pathologic condition in individuals with type 2 diabetes (T2D). The purpose of this study is to examine the effects of different exercise modalities on non-alcoholic fatty liver indices (fatty liver index [FLI], lipid accumulation product [LAP], hepatic steatosis index [HSI], and Framingham Steatosis Index [FSI]) in women with T2D. Methods Fifty-two women with T2D and a mean age of 55.07±5.92 yrs, body mass index (BMI) 28.94±4.09 kg/m2 , and hemoglobin A1c (HbA1c) 9.41±0.82% were randomized to a sprint interval training (SIT) (n=17), combined aerobic and resistance (A+R) training (n=17), or control group (n=18) for 10 weeks. Two-way repeated analysis of variance (ANOVA) was used to find differences between groups and the effects of time and Time×Group interactions after 10 weeks on non-alcoholic fatty liver indices. After this, ANOVA models were constructed to determine the effects of group allocation and change in non-alcoholic fatty liver indices. Results There were significant time interactions for FLI (P<0.001), HSI (P<0.001), and LAP (P<0.001). Also, there were significant Time×Group interactions for fasting blood glucose (P=0.034), and HbA1c (P=0.006). Conclusions Results highlight that exercise training, independent of mode of training, is an effective strategy to improve some indices related to hepatic steatosis and blood glucose profiles in women with T2D. Keywords: High-intensity interval training; Non-alcoholic fatty liver disease; Diabetes mellitus, Type 2
Response to PD-1 inhibition in early- and late-relapsing cutaneous melanoma.
Authors: Kelly Fitzgerald, Adil Daud
Journal: Journal of Clinical Oncology (2019)

e21038 Background: Up to 45% of stage I-II melanomas will relapse within 5 years, and some relapses occur more than 10 years after surgical resection. Little is known about the differences in tumor characteristics, including immunogenicity, of early- vs. late-relapsing melanoma, or the implication of these differences in response to PD-1 inhibition. Methods: A retrospective cohort study was conducted to compare time from definitive treatment of localized melanoma to relapse with response to pembrolizumab. Patients with prior stage I-II melanoma who relapsed, and then treated with pembrolizumab, were included in the study. Time to relapse was compared with overall response rate. Results: Among the study population, 66 patients initially presented with early stage disease that relapsed within the study period. The median time to relapse was 5 years (range 0.5-33 years, interquartile range 7.25, Q 1 = 2, Q 2 = 9.25). 9 patients (14%) relapsed within 2 years of surgery; these patients had a higher overall response rate to pembrolizumab than late-relapsing patients with marginal significance (88% vs 50%, p = 0.056). The difference became less significant when patients who relapsed before or after 5 years (70% vs 47%, respectively, p = 0.20), and before or after 10 years (64% vs 45%, p = .31). Conclusions: Patients with early-relapsing melanoma had higher ORR to pembrolizumab than patients with late-relapsing disease, with early relapse defined as earlier than 2 years from definitive surgical intervention. Late relapsing tumors may harbor mechanisms of resistance to immune checkpoint inhibition.
Cervical cancer outcomes after chemoradiation and brachytherapy in New York City comparing public versus private hospitals.
Authors: Amnon Asher Berger, Omar Ishaq, John Patrick Curtin, Bhavana Pothuri, Siobhan Marie Kehoe, Peter B. Schiff, Leslie R. Boyd, Stella C. Lymberis
Journal: Journal of Clinical Oncology (2019)

e17018 Background: In the US, cervical cancer (CC) disproportionately impacts minorities and women with insufficient access to care. In our department, patients (pts) with advanced CC referred from a public hospital (PbH) and a private hospital (PrH) are treated with the same integrated team of physicians. We sought to determine whether referral source affects outcome post definitive chemoradiation (CRT) and brachytherapy (BT) for CC pts. Methods: An IRB approved retrospective review was conducted for pts diagnosed with CC and treated with definitive CRT. All pts were treated with external beam RT and chemotherapy followed by intracavitary BT boost (median 7 Gy x 4 fractions) delivered via two insertions of intracavitary BT two weeks apart with image-guided CT/MR delineation. Disease free survival (DFS) and overall survival (OS) were analyzed with the Kaplan-Meier method. Multivariate Cox hazards analysis was run to identify the effects of covariates, using R v3.5.1. Results: Between 7/2009 and 9/2017, 106 pts were diagnosed with FIGO stage IA(1), IB(22), IIA(10), IIB(46), IIIA(3), IIIB(24) and IVA(2) CC. 81 (76.4%) pts were diagnosed and received chemotherapy and operative insertion at PbH, 25 (23.6%) at PrH. Median age was 54 years (y), range (28-83). At median follow-up of 32.2 months (3.8-110.2), local control was 82%. 5-y DFS and OS was 62.4% and 84.2%. 19.8% pts were diagnosed at age 65 or greater. PbH pts were diagnosed at a younger median age of 52.4y (28.1-77.7) compared to 59.8y (30-83) at PrH (P = 0.03). PbH vs PrH pts were more likely to present at earlier stages I/II (79% vs 56%), than stages III/IV (21% vs 44%), p = 0.04 and have better outcomes; PbH vs PrH DFS was 65.0% vs 54.5% (P = 0.1), while OS was 89.3% vs 54.9% (P = 0.01). In Cox multivariate analysis, only stage at diagnosis was a significant independent predictor of survival (P = 0.006). Conclusions: Our data suggests that patients referred from a public hospital do not have worse outcomes when treated by a centralized multidisciplinary team. PrH pts presented at older age, more advanced stage and had worse OS than PbH pts. Twenty percent of pts diagnosed with advanced CC were above age 65, highlighting the need for continued screening.
Circulating tumor DNA (ctDNA) kinetics to predict survival in patients (pts) with unresectable or metastatic melanoma treated with dabrafenib (D) or D + trametinib (T).
Authors: Mahrukh M Syeda, JENNIFER M WIGGINS, Broderick Corless, Georgina V. Long, Keith Flaherty, Dirk Schadendorf, Paul D. Nathan, Caroline Robert, Antoni Ribas, Michael A. Davies, Jean Jacques Grob, Eduard Gasal, Matthew Squires, Mahtab Marker, Jan C. Brase, David Polsky
Journal: Journal of Clinical Oncology (2019)

9510 Background: There are no validated blood-based biomarkers to monitor efficacy in pts with advanced melanoma. Lactate dehydrogenase (LDH) is an established prognostic factor; however, it is not normally used to inform treatment decisions. ctDNA at baseline (BL) is associated with a poor prognosis in pts treated with BRAF inhibitors, but no studies have examined the association between serial changes in ctDNA and survival after BRAF and/or MEK inhibitor therapy. Methods: We measured BRAF V600E/K ctDNA at BL and wk 4 in plasma samples from a pooled population of pts with unresectable or metastatic melanoma treated with D or D+T in the phase 3 COMBI-d trial (NCT01584648). We used mutation-specific droplet digital PCR assays; ctDNA results were categorized as positive/negative (pos/neg) using an analytically validated detection threshold of 0.25 copies/mL. Progression-free (PFS) and overall survival (OS) were analyzed in all pts and by BL LDH level (&gt; or &lt; upper limit of normal). Results: BL ctDNA was detectable in 320/345 pts (92.7%) and was not associated with survival. Nearly all pts had a considerable drop in ctDNA after 4 wks of therapy; 201 pts had paired samples (BL and wk 4) and detectable ctDNA at BL. In 80/201 pts (40%) whose ctDNA changed from pos at BL to neg at wk 4, PFS and OS were prolonged vs in 121/201 (60%) whose ctDNA remained pos (median PFS, 12.9 [95% CI, 9.2-20.2] mo vs 7.1 [5.5-8.9] mo; HR, 0.55 [0.39-0.76]; P = .0003; median OS, 28.2 [20.5-48.8] mo vs 14.6 [11.8-18.7] mo; HR, 0.56 [0.40-0.79]; P = .0007). Undetectable ctDNA at wk 4 was associated with prolonged PFS and OS, especially in pts with high BL LDH (Table). Conclusions: Particularly in pts with high LDH, on-treatment ctDNA monitoring may be helpful for early identification of pts likely to benefit from D or D+T. All ctDNA Samples at Wk 4. Clinical trial information: NCT01584648. [Table: see text]
GP numbers rise in England, mainly owing to more trainees
Authors: Nigel Hawkes
Journal: BMJ (2019)

The number of GPs working in England has crept up in the past year, a rise almost entirely accounted for by an increase in GP trainees.

In March 2019 England’s GPs totalled 44 847, a rise of 350 (0.8%) on the same month in 2018. The full time equivalent count, which allows for some GPs working only part time, showed a similar increase, rising from 34 424 to 34 736 (0.9%).1

But closer examination of the data released by NHS Digital shows that the headcount of fully qualified GPs fell by 494 year on year, while the number of trainees increased by 760. The great majority of these new recruits to the GP workforce were trained in the UK, lending credence to NHS England’s claim that plans to increase recruitment are working.

“Today’s figures highlight the good work being done locally to support GPs through retention …
Pooled safety analysis from phase 3 studies of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric/gastroesophageal junction cancer (mGC/mGEJC) and metastatic colorectal cancer (mCRC).
Authors: Eric Van Cutsem, Howard S. Hochster, Kohei Shitara, Robert J. Mayer, Atsushi Ohtsu, Alfredo Falcone, Takayuki Yoshino, Toshihiko Doi, David H. Ilson, Hendrik-Tobias Arkenau, Ben George, Sandra McGuigan, Lukas Makris, Josep Tabernero
Journal: Journal of Clinical Oncology (2019)

4039 Background: FTD/TPI was approved in 2015 for pretreated pts with mCRC based on the phase 3 RECOURSE trial. FTD/TPI recently demonstrating significantly improved overall survival vs placebo in pretreated pts with mGC/mGEJC in the phase 3 TAGS trial. Methods: We evaluated the pooled safety of FTD/TPI in TAGS and RECOURSE in all pts who received ≥1 dose of FTD/TPI (safety population). Pts were required to have ECOG PS 0/1 and to have received ≥2 previous chemotherapy lines. Results: FTD/TPI and placebo were administered to 335 and 168 pts, respectively, in TAGS, and 533 and 265 pts in RECOURSE. Baseline characteristics were balanced across treatment groups and reflected the disease populations. In the pooled population, 66% of pts were men and 75% had received ≥3 prior systemic treatments. The safety profile of FTD/TPI was comparable between studies (table). In TAGS and RECOURSE, the most common any-cause grade (gr) ≥3 AEs in FTD/TPI-treated pts were neutropenia (34%; 35%), anemia (19%; 17%), and leukopenia (9%; 13%). Gr ≥3 febrile neutropenia occurred in 2% and 4% of pts and gr ≥3 GI AEs in 21% and 12%. Gr ≥3 cardiac AEs were reported in 1% of FTD/TPI-treated pts (both studies), in contrast to results obtained with other third-line agents. Similar proportions of FTD/TPI-treated pts in both studies had AEs leading to dosing delay, dose reduction, or treatment discontinuation. Dosing delay was used more often than dose reduction to manage AEs. TRAEs leading to death occurred in one FTD/TPI-treated pt ( &lt; 1%) in each trial. Conclusions: In a pooled analysis, FTD/TPI was well tolerated with a consistent safety profile in pts with mGC/mGEJC or mCRC. The most frequent AEs were hematologic and GI, which were managed with dosing delays/dose reductions. Clinical trial information: NCT02500043; NCT01607957. [Table: see text]
Predictive factors for early mortality after initiation of regorafenib or trifluridine/tipiracil in refractory metastatic colorectal cancer.
Authors: Toshiki Masuishi, Toshikazu Moriwaki, Shota Fukuoka, Atsuo Takashima, Yosuke Kumekawa, Takeshi Kajiwara, Kentaro Yamazaki, Taito Esaki, Akitaka Makiyama, Tadamichi Denda, Hironaga Satake, Takeshi Suto, Naotoshi Sugimoto, Kenji Katsumata, Toshiaki Ishikawa, Tomomi Kashiwada, Eiji Oki, Yoshito Komatsu, Kenichi Yoshimura, Yasuhiro Shimada
Journal: Journal of Clinical Oncology (2019)

3560 Background: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been recognized as standard treatments for patients (pts) with refractory metastatic colorectal cancer (mCRC). Because these drugs have limits on efficacy benefit for some pts, we are necessary to select pts who may be better not to receive REG or FTD/TPI. However, no reports are available on how to predict pts with early mortality after initiation of these drugs. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG or FTD/TPI. Predictive factors for early mortality (≤ 12 weeks from initiation of REG or FTD/TPI) were evaluated by multivariate analysis for survival with all variables with P values of &lt;0.05 from the univariate analysis, using the Cox proportional hazards model. In this analysis, the pts who lived at first 15 weeks were defined as censored case. Results: A total of 523 pts (REG, 212; FTD/TPI, 311) were eligible. Predictive factors for early mortality were without primary tumor resection [adjusted hazard ratio (aHR), 1.56; p = 0.02], the low level of albumin (aHR, 2.31; p &lt; 0.0001), the high level of CRP (aHR, 2.31; p &lt; 0.0001), and short time from diagnosis of mCRC (aHR, 1.77; p = 0.002) by multivariate analysis. The pts harboring all these poor factors were classified into the high (H) risk of early mortality group. Two groups of pts with H and non-H were identified, with 12-week mortality rate of 39 and 14%, with 14-week mortality rate of 70 and 18%, and with median survival time (MST) of 2.9 and 7.8 months, respectively (HR of H/non-H, 4.02; p value &lt; 0.0001). In pts treated with REG, H and non-H groups had 12-week mortality rate of 38 and 16%, 14-week mortality rate of 79 and 18%, and MST of 2.8 and 7.8 months, respectively. In pts treated with FTD/TPI, H and non-H groups had 12-week mortality rate of 41 and 13%, 14-week mortality rate of 63 and 18%, and MST of 3.2 and 7.7 months, respectively. Conclusions: Our predictive model for early mortality after initiation of REG or FTD/TPI might be useful for selecting pts who should not receive either these drugs.
Abstract P316: Reproductive Factors Associated With Subclinical Vascular Measures at Late Midlife: SWAN
Authors: Yamnia I Cortes, Janet Catov, Maria Brooks, Carmen Isasi, Elizabeth A Jackson, Sioban Harlow, Karen Matthews, Rebecca Thurston, Emma Barinas-Mitchell
Journal: Circulation (2017)

Background: Sex-specific features, including adverse pregnancy outcomes (i.e., gestational hypertension, preeclampsia, gestational diabetes), have been associated with increased risk for CVD. However, there is limited research characterizing these associations with menopause features or with subclinical vascular measures at late midlife, when CVD risk increases. Objective: To evaluate associations between reproductive factors (i.e. gestational hypertension, preeclampsia, and gestational diabetes) with validated and reliable markers of subclinical vascular damage and remodeling; carotid intima-media thickness (cIMT), adventitial diameter (cAD), carotid plaque presence, and brachial-ankle pulse wave velocity (baPWV). Methods: A cross-sectional analysis was conducted with 1454 women (50% white, 31% black, 6% Hispanic, 13% Chinese) from the Study of Women’s Health Across the Nation (SWAN). Women were included if they completed a detailed reproductive history questionnaire and had a carotid ultrasound at visit 12 or 13. baPWV was performed at the same follow-up visit. Associations between reproductive history and subclinical CVD were tested using linear and logistic regression models adjusting for demographics and traditional CVD risk factors (age, site, race/ethnicity, financial strain, BMI, SBP, LDL-c, HDL-c, HOMA-IR). Additional models were adjusted for sex hormone levels and number of births. Results: Women were on average 60 years old and mostly postmenopausal (94%). Two hundred fifty-six women (18%) were nulliparous. Approximately 10% of parous women had a self-reported history of gestational hypertension or preeclampsia, and 4% reported gestational diabetes. Among parous women, gestational hypertension was associated with higher mean cIMT (β±SE=0.053±0.015mm; P=0.0003) and preeclampsia was associated with higher odds of plaque (OR=1.7; 95% CI: 1.1, 2.6; P=0.01) in fully adjusted models. History of gestational diabetes was related to higher baPWV (β±SE=64.6±28.4cm/s; P=0.009). Associations between adverse pregnancy outcomes and subclinical vascular measures remained significant after adjusting for baseline estradiol and number of births. Compared to nulliparous women, parity≥3 was associated with higher cAD (β±SE=0.10±0.05mm; P=0.02) when controlling for demographics, but not after adjustment for CVD risk factors. Age at menarche, age at menopause, hormone ever use, and bilateral oophorectomy were not associated with subclinical vascular measures at late midlife. Conclusions: Adverse pregnancy outcomes (i.e., gestational hypertension, preeclampsia, and gestational diabetes) converge to put women at excess risk for CVD, but may affect the vasculature through distinct pathways. Further studies are necessary to assess the joint effects of early and late midlife reproductive factors on future CVD.
Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma(NPC) patients treated between 2004 and 2016: Patient and treatment characteristics and long term outcome.
Authors: Musa Altun, Gizem Kaval, Kamuran Ibis, Kubra Ozkaya, Rasim Meral, Ahmet Nafiz Karadeniz, Murat Sari, Meltem Ekenel, Mert Basaran, Sevil E. Bavbek
Journal: Journal of Clinical Oncology (2019)

e17507 Background: Standard treatment of locoregionally advanced nasopharyngeal carcinoma (LRA-NPC) is CCRT with or without adjuvant chemotherapy (CT). The value of adding IC to CCRT in LRA-NPC is unclear. We aimed to retrospectively evaluate LRA-NPC patients treated with IC followed by CCRT and analyse patient, tumor, treatment characteristics and outcome. Methods: Between 2004 and 2016, 202 patients with nonmetastatic LRA-NPC (stage 3-4), 144 males and 58 females ranging from 17 to 75 (median 49) years old were treated with IC followed by CCRT. Eleven (%5.4) patients had keratinised (WHO I), and 191 (%94.6) had nonkeratinised or undiffrentiated (WHO II-III) carcinoma. Cumulative radiation dose to primary tumor ranged from 60 to 74 (median 70) Gy. Ninety-one (%45) of the patients received 2-dimensional and 111 (%55) received intensity modulated radiotherapy (IMRT). IC consisted of taxane (T)(75 mg/ m 2 ) and platinum (P)(75 mg/m 2 ) combination (199 patients) or P and fluoruracil or epirubicine (3 patients) combination and 188 of the patients received 3 cycles of IC. Concomittant P was used either weekly (40 mg/m 2 , 25 patients) or every 3-weekly (100 mg/m 2 , 177 patients) application. Follow-up ranged from 5 to 167 months (median, 72.5 months). Results: Treatment failure was observed in 52 (%25.7) of the patients (21 local, 13 regional and 27 distant failures). Distant failure rate of all the patients exceeds 13%. Five and 10 years disease free survival (DFS) rates are 75.2% and 70.4% and overall survival (OS) rates are 78.9% and 64% respectively. In univariate analysis patient age favoring those below 49 and stage of disease favoring WHO II-III were all significant predictors of DFS and OS. In addition pathology was a significant predictor of DFS. Conclusions: LRA-NPC patients treated with IC followed by CCRT have a high locoregional control rate. Despite the use of systemic (induction) chemotherapy distant control remains insufficient and continues to be a challenge in NPC treatment. Besides improving locoregional control more effective systemic therapy is needed. [Table: see text]
Beyond TILs: Predictors of pathologic complete response (pCR) in triple-negative breast cancer (TNBC) patients with moderate tumor-infiltrating lymphocytes (TIL) receiving neoadjuvant therapy.
Authors: Nour Abuhadra, Kenneth R. Hess, Jennifer Keating Litton, Gaiane M Rauch, Alastair Mark Thompson, Bora Lim, Beatriz E Adrada, Elizabeth A. Mittendorf, Senthil Damodaran, Rosalind P Candelaria, Banu Arun, Wei Tse Yang, Naoto T. Ueno, Lumarie Santiago, Rashmi Krishna Murthy, Nuhad K. Ibrahim, Aysegul A. Sahin, William Fraser Symmans, Stacy L. Moulder, Lei Huo
Journal: Journal of Clinical Oncology (2019)

572 Background: Increased TIL in TNBC is associated with higher rates of pCR. High TIL is also associated with improved disease free survival and overall survival. The aim of this study is to identify data cut-points of pre-treatment low, moderate and high TIL count based on pCR and to identify clinical and pathological predictors of pCR in patients with moderate TIL. Methods: We evaluated the relationship between pCR and TIL in 180 patients with stage I-III TNBC enrolled in the ARTEMIS trial (NCT02276443). Recursive portioning was used to identify cut-points. Clinical and pathological variables such as age at diagnosis, stage, race, histology as well as Ki-67, vimentin, and androgen receptor (AR) by immunohistochemistry, were evaluated in pts with moderate TIL. A multivariable logistic regression model identified variables independently, significantly associated with pCR. Results: Four TIL groups were identified with pCR rates of 23%, 31%, 48% and 78% respectively (p &lt; 0.0001) (Table A). In the two combined moderate TIL groups, 90 (97%) pts were evaluable for the multivariate model. Stage I-II disease, high Ki-67 and low AR were associated with increased probability of pCR (Table B). The multivariable logistic regression model area under the ROC curve was 0.78 (95% CI=0.68-0.88; p&lt;0.0001). A model of computed risk score [ Stage I-II (score 2)+Ki-67≥ 50% (score 1)+AR&lt;10% (score 1)] predicted a probability of 67% for pCR when all three variables were favorable (Table). Conclusions: Four TIL groups were identified. In pts with moderate TIL levels, early stage disease, high Ki-67 and low AR were associated with increased probability of pCR with neoadjuvant therapy. [Table: see text]