tbuckley/cabot-search huggingface dataset:
Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Authors: Heikki Joensuu, Judith Fraser, Hans Wildiers, Riikka Huovinen, Päivi Auvinen, Meri Utriainen, Paul Nyandoto, Kenneth K. Villman, Päivi Halonen, Helena Granstam-Björneklett, Lotta Lundgren, Liisa Sailas, Taina Turpeenniemi-Hujanen, Minna Tanner, Jeffrey Yachnin, Diana Ritchie, Oskar Johansson, Teppo Huttunen, Patrick Neven, Peter Canney, Vernon J. Harvey, Pirkko–Liisa Kellokumpu-Lehtinen, Henrik Lindman
Journal: JAMA Oncology (2018)

Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear.To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab.Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries.Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year.The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety.In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group.Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.ClinicalTrials.gov Identifier: NCT00593697.
Revisiting the association of blood pressure with mortality in oldest old people in China: community based, longitudinal prospective study
Authors: Yue-Bin Lv, Xiang Gao, Zhao-Xue Yin, Hua-Shuai Chen, Jie-Si Luo, Melanie Sereny Brasher, Virginia Byers Kraus, Tian-Tian Li, Yi Zeng, Xiao-Ming Shi
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To examine the associations of blood pressure with all cause mortality and cause specific mortality at three years among oldest old people in China. <h3>Design</h3> Community based, longitudinal prospective study. <h3>Setting</h3> 2011 and 2014 waves of the Chinese Longitudinal Healthy Longevity Survey, conducted in 22 Chinese provinces. <h3>Participants</h3> 4658 oldest old individuals (mean age 92.1 years). <h3>Main outcome measures</h3> All cause mortality and cause specific mortality assessed at three year follow-up. <h3>Results</h3> 1997 deaths were recorded at three year follow-up. U shaped associations of mortality with systolic blood pressure, mean arterial pressure, and pulse pressure were identified; values of 143.5 mm Hg, 101 mm Hg, and 66 mm Hg conferred the minimum mortality risk, respectively. After adjustment for covariates, the U shaped association remained only for systolic blood pressure (minimum mortality risk at 129 mm Hg). Compared with a systolic blood pressure value of 129 mm Hg, risk of all cause mortality decreased for values lower than 107 mm Hg (from 1.47 (95% confidence interval 1.01 to 2.17) to 1.08 (1.01 to 1.17)), and increased for values greater than 154 mm Hg (from 1.08 (1.01 to 1.17) to 1.27 (1.02 to 1.58)). In the cause specific analysis, compared with a middle range of systolic blood pressure (107-154 mm Hg), higher values (&gt;154 mm Hg) were associated with a higher risk of cardiovascular mortality (adjusted hazard ratio 1.51 (95% confidence interval 1.12 to 2.02)); lower values (&lt;107 mm Hg) were associated with a higher risk of non-cardiovascular mortality (1.58 (1.26 to 1.98)). The U shaped associations remained in sensitivity and subgroup analyses. <h3>Conclusions</h3> This study indicates a U shaped association between systolic blood pressure and all cause mortality at three years among oldest old people in China. This association could be explained by the finding that higher systolic blood pressure predicted a higher risk of death from cardiovascular disease, and that lower systolic blood pressure predicted a higher risk of death from non-cardiovascular causes. These results emphasise the importance of revisiting blood pressure management or establishing specific guidelines for management among oldest old individuals.
Primary and subspecialty care trends for adults with a history of childhood cancer.
Authors: Becky N. Lowry, Kyla Alsman, Wendy Hein, Caylin Shankweiler, Hope Krebill, Cheryl Gibson, Rebecca Mount, Gary C. Doolittle
Journal: Journal of Clinical Oncology (2018)

33 Background: With growing numbers of childhood cancer survivors (CCS), having systems for survivorship care coordination is imperative. While studies have compared the comfort and knowledge between primary care and oncology physicians in providing CCS care, few have analyzed primary and subspecialty care rates. Referral trends can be informative for institutions developing systems of care. Correlative measures with referral needs may help institutions prioritize process development for patients. Methods: Retrospective chart reviews were completed on 117 adult CCS from Survivorship Transition Clinic (STC) between 2014-2017. Upon arrival, STC patient self-reports were recorded regarding existing PCP status. Patients with PCPs were enrolled in survivorship consultation care, those without enrolled in survivorship and PCP care. Referrals were tracked by electronic medical record. Two oncology providers performed blinded independent reviews treatment summaries and scored treatments using Children’s Hospital of Philadelphia Intensity of Treatment Rating scale (ITR-3). If scores differed, discussion determined consensus. Final scores were matched with data on subspecialty referral patterns. Results: Of 117 patients, 65 (57%) needed both PCP and survivorship care while 50 (43%) had established PCPs. ITR3 scores were low intensity (1 or2) for 54 patients and high intensity (3 or 4) for 63 patients. The low intensity group had 157 total referrals (3 per patient) compared to 391 total referrals (6 per patient) in the high intensity group. The top 5 subspecialty referrals (by patients referred) were psychological services (46), dermatology (44), fertility (29), hematology / oncology / BMT (22), cardiology (20). Conclusions: Our care coordination trends suggest many CCS do not have established PCPs despite their complex care needs. Not surprisingly, higher intensity treatment correlates with higher subspecialty care needs. Psychological care remains the most prevalent need in our patient population. [Table: see text]
Investigating denosumab as an add-on neoadjuvant treatment for RANK/L-positive or RANK/L-negative primary breast cancer and two different nab-paclitaxel schedules: 2x2 factorial design (GeparX)—An iterim safety analysis.
Authors: Sherko Kummel, Pauline Wimberger, Gunter Von Minckwitz, Valentina Nekljudova, Carsten Denkert, Marianne Just, Claus Hanusch, Oliver J Stoetzer, Jens Bodo Huober, Manfred Hofmann, Christian Jackisch, Jens U. Blohmer, Valentina Vladimirova, Andreas Schneeweiss, Michael Untch, Sibylle Loibl
Journal: Journal of Clinical Oncology (2018)

569 Background: The GeparX study aims to investigate whether denosumab, an antibody targeting RANKL, increases the pCR rate when added to an anthracycline/taxane containing neoadjuvant chemotherapy (NACT) in patients (pts) with primary breast cancer (BC). Methods: GeparX enrolles pts with primary BC cT1c-cT4d, after central assessment of HER2, HR, TILs, Ki67. 778 pts will be randomized to NACT+/-denosumab (120mg s.c. q4w for 6 cycles), stratified by lymphocyte predominant BC (LPBC, ≤50% vs > 50%), subtype (HER2-/HR+ vs triple negative (TNBC) vs HER2+), and epirubicin/cyclophosphamide schedule (EC, q2w vs q3w). Secondarily, pts are randomized to different nab-paclitaxel schedules (nP): nP 125mg/m² weekly or nP 125mg/m² day 1,8 q22 followed by EC. Pts with TNBC receive carboplatin (AUC 2) and with HER2+ BC ABP 980 (trastuzumab biosimilar)+pertuzumab. Co-primary objectives compare the pCR (ypT0 ypN0) rates of NACT+/-denosumab and the pCR rates between nP 125 weekly and nP 125 d1,8 q22. Secondary objectives are toxicity; compliance amongst others. An interim safety analysis is planned after the first 200 pts have completed nP treatment. Results: A total of 202 pts randomized to denosumab and the nP treatment (101 pts with weekly and 101 pts with nP d1,8 q22) were included in the interim analysis. Overall, median age was 50 years [range 23-76]; 38.6% of pts were cN+ and 5% had LPBC, 102 pts (50.5%) had HER2-/HR+ BC; 82 (40.6%) had TNBC and 18 pts (8.9%) HER2+ BC. Overall, 13.5% with and 13.1% w/o denosumab discontinued nP. 21.0 % of pts with nP weekly vs 5.3% with nP d1,8 q22 discontinued nP mainly due to AEs (17.0% vs 3.2%). During nP treatment 24 SAEs with nP weekly vs 25 SAEs with nP d1,8 q22 were reported. 17 (16.7%) SAEs were reported in the HER2-/HR+ cohort, 29 (35.4%) for the TNBC (with carboplatin) and 3 (16.7%) in the HER2+ cohort (dual-blockade, no carboplatin). Conclusions: The addition of denosumab to NACT does not increase toxicity. Weekly nP resulted in a higher rate of treatment discontinuations mainly due to non-serious AEs. The addition of carboplatin resulted in a higher rate of SAEs. Clinical trial information: NCT02682693.
68Ga-DOTA-TOC Uptake in Pleomorphic Adenoma
Authors: S. Tom Laurens, Romana T. Netea-Maier, Erik J.H.G. Aarntzen
Journal: Clinical Nuclear Medicine (2018)

A 56-year-old man who was recently diagnosed with a carcinoid tumor of the os petrosum was referred for a Ga-DOTA-TOC PET/CT scan. Besides the moderately increased Ga-DOTA-TOC accumulation in the carcinoid tumor, the scan showed strongly increased and focal Ga-DOTA-TOC uptake in an additional lesion in the right parotid gland. The markedly different Ga-DOTA-TOC avidity suggested a different etiology, and histological examination demonstrated a pleomorphic adenoma.
An Integrative Approach for Deciphering the Causal Associations of Physical Activity and Cancer Risk: The Role of Adiposity
Authors: Edward Giovannucci
Journal: JNCI Journal of the National Cancer Institute (2018)

Higher physical activity levels have been associated with about 10% to 25% reductions in up to 13 cancers. In isolation, these results are suggestive but not compelling enough to conclude causal associations, except for colon and breast cancer. However, knowledge on the relationships between obesity and cancer, between physical activity and overall and visceral adiposity, and between physical activity and obesity-related mediators of cancer risk can inform the epidemiology of physical activity and cancer. Excluding primarily smoking-related malignancies, for which residual confounding by smoking may occur, all 13 cancers associated with lower physical activity are also obesity-related. Moreover, the magnitude of the inverse association between physical activity and cancer type correlates highly with the association with body mass index (BMI) and cancer type (Spearman r = .79, two-sided P = .004). Physical activity lowers essentially all the obesity-related mediators of cancer, probably mediated largely through reductions in visceral adiposity. These findings strongly suggest that physical activity and adiposity are largely operating through similar carcinogenic mechanisms. That BMI has more robust associations than physical activity with cancer largely reflects that most populations studied have had great variation in BMI and little in physical activity. In populations with higher levels of physical activity and a lower range of BMI, physical activity may appear relatively more important. It may be useful to emphasize to clinicians and the public that physical activity, by acting on the same mechanisms, is likely to reduce risk of obesity-related cancers, even if the impact on lowering BMI is minimal.
Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial
Authors: Hong-Hu Zhu, De-Pei Wu, Xin Du, Xi Zhang, Lin Liu, Jun Ma, Zong-Hong Shao, Han-Yun Ren, Jian-Da Hu, Kai-Lin Xu, Jing-Wen Wang, Yong-Ping Song, Mei-Yun Fang, Juan Li, Xiao-Yan Yan, Xiao-Jun Huang
Journal: The Lancet Oncology (2018)
hiPSC hepatocyte model demonstrates the role of unfolded protein response and inflammatory networks in α1-antitrypsin deficiency
Authors: Charis-Patricia Segeritz, Sheikh Tamir Rashid, Miguel Cardoso de Brito, Maria Paola Serra, Adriana Ordonez, Carola Maria Morell, Joseph E. Kaserman, Pedro Madrigal, Nicholas R.F. Hannan, Laurent Gatto, Lu Tan, Andrew A. Wilson, Kathryn Lilley, Stefan J. Marciniak, Bibek Gooptu, David A. Lomas, Ludovic Vallier
Journal: Journal of Hepatology (2018)

α1-Antitrypsin deficiency (A1ATD) is an autosomal recessive disorder caused by mutations in the SERPINA1 gene. Individuals with the Z variant (Gly342Lys) retain polymerised protein in the endoplasmic reticulum (ER) of their hepatocytes, predisposing them to liver disease. The concomitant lack of circulating A1AT also causes lung emphysema. Greater insight into the mechanisms that link protein misfolding to liver injury will facilitate the design of novel therapies.Human-induced pluripotent stem cell (hiPSC)-derived hepatocytes provide a novel approach to interrogate the molecular mechanisms of A1ATD because of their patient-specific genetic architecture and reflection of human physiology. To that end, we utilised patient-specific hiPSC hepatocyte-like cells (ZZ-HLCs) derived from an A1ATD (ZZ) patient, which faithfully recapitulated key aspects of the disease at the molecular and cellular level. Subsequent functional and "omics" comparisons of these cells with their genetically corrected isogenic-line (RR-HLCs) and primary hepatocytes/human tissue enabled identification of new molecular markers and disease signatures.Our studies showed that abnormal A1AT polymer processing (immobilised ER components, reduced luminal protein mobility and disrupted ER cisternae) occurred heterogeneously within hepatocyte populations and was associated with disrupted mitochondrial structure, presence of the oncogenic protein AKR1B10 and two upregulated molecular clusters centred on members of inflammatory (IL-18 and Caspase-4) and unfolded protein response (Calnexin and Calreticulin) pathways. These results were validated in a second patient-specific hiPSC line.Our data identified novel pathways that potentially link the expression of Z A1AT polymers to liver disease. These findings could help pave the way towards identification of new therapeutic targets for the treatment of A1ATD.This study compared the gene expression and protein profiles of healthy liver cells and those affected by the inherited disease α1-antitrypsin deficiency. This approach identified specific factors primarily present in diseased samples which could provide new targets for drug development. This study also demonstrates the interest of using hepatic cells generated from human-induced pluripotent stem cells to model liver disease in vitro for uncovering new mechanisms with clinical relevance.
A phase III, randomized, double-blind study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus dacarbazine in patients (pts) with previously untreated, unresectable, or metastatic melanoma (MEL).
Authors: Caroline Robert, Paolo Antonio Ascierto, Michele Maio, Micaela Hernberg, Henrik Schmidt, Ian Waxman, Claus Garbe, Céleste Lebbé, Axel Hauschild
Journal: Journal of Clinical Oncology (2013)

TPS9106 Background: The 5-year survival rate for late-stage MEL is currently only 15%. Despite recent advances with ipilimumab and vemurafenib, a considerable unmet need remains for pts with previously untreated, unresectable or metastatic BRAF wild-type MEL. Objective response rate (ORR) with first-line dacarbazine, a widely used chemotherapy in MEL, is 13%, with median overall survival (OS) ranging from 5.6 to 11 months. Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation through interaction with its ligand, PD-L1. This ligand is overexpressed by multiple tumor types, including advanced MEL. The PD-1 receptor blocking antibody nivolumab demonstrated clinical activity at 0.1-10 mg/kg in a phase I study in pts with advanced MEL (n = 106), with OR in 33 pts and stable disease ≥24 weeks in 6 pts. We describe a double-blind, randomized phase III study designed to compare the clinical benefit of nivolumab vs dacarbazine in pts with advanced MEL. Methods: Approximately 410 pts with untreated, unresectable stage III or stage IV MEL will be randomized 1:1 to receive either nivolumab 3 mg/kg IV every two weeks or dacarbazine 1000 mg/m 2 IV every three weeks until disease progression or unacceptable toxicity. All pts must be BRAF wild-type as per V600 mutational testing. Pts will be stratified by PD-L1 status (positive vs negative/indeterminate) and metastatic (M) stage (M0/M1a/M1b vs M1c). PD-L1 positivity will be defined as ≥5% total membrane staining in tumor cells. Tumor response (per RECIST 1.1) will be assessed 9 weeks following randomization and every 6 weeks thereafter for the first year. After the first year, response will be assessed every 12 weeks until disease progression or treatment discontinuation. Treatment may continue beyond initial progression at the investigator’s discretion for pts showing clinical benefit and tolerating therapy. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, whether PD-L1 expression is a predictive biomarker for OS, and health-related quality of life. Clinical trial information: NCT01721772.
Designing a survivorship and supportive care center at a comprehensive cancer center.
Authors: Katharine Amato, Kathryn M. Glaser, Lynda M. Beaupin, Denise A. Rokitka, Mary E. Reid
Journal: Journal of Clinical Oncology (2018)

159 Background: Unmet physical, psychosocial, and other support needs of cancer survivors may lead to increased distress, anxiety, and decreased quality of life. Survivorship Clinics may be tailored for specific issues identified through a needs assessment. Methods: An invitation to complete a web-based survey was mailed to 35,420 active patients at a comprehensive cancer center in November 2015. The survey domains included demographics, cancer history, comorbidities, lifestyle, cancer prevention, spiritual and emotional support, symptom management, and interest in specific services. Results: 1,054 surveys were completed. The majority of respondents were female (55.2%; n = 582/1054), had Stage I cancer at diagnosis (43.9%; n = 360/820), and had completed treatment (69.0%; n = 727/1054). Genitourinary (23.0%; n = 238/1034) and breast (20.5%; n = 212/1034) were the most common cancer types among the respondents. Participants identified an average of 4.60 side effects experienced during or after treatment (n = 804); the most common were fatigue (64.5%), pain (37.3%), weight change (33.4%), sleep disturbance (30.2%), and gastrointestinal problems (29.4%). One third of participants reported having a physical side effect that caused anxiety and emotional distress (33.3%; n = 331/995), in particular, sexual function (69.7%; n = 136/195) and cognitive dysfunction (43.6%; n = 85/195). A total of 23.9% of participants had financial concerns due to costs of cancer treatment (n = 238/955). Participants were interested in integrative therapies, most notably yoga (75.1%; n = 289/385), acupuncture (72.4%; n = 155/214), aerobics (62.3%; n = 240/385), Swedish massage (60.5%; n = 225/372), aromatherapy (60.2%; n = 224/372), and homeopathy (55.1%; n = 118/214). Most respondents endorsed wanting information on nutrition (81.5%; n = 380/466). Conclusions: Cancer survivors report vast physical and psychosocial needs during and after cancer treatment, and they have a high interest in nutrition education and integrative therapies. Improved care coordination from a dedicated cancer survivorship and supportive care clinic at a comprehensive cancer center may specifically address survivors’ issues.
Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial
Authors: Françoise Huguet, Sylvie Chevret, Thibaut Leguay, Xavier Thomas, Nicolas Boissel, Martine Escoffre-Barbe, Patrice Chevallier, Mathilde Hunault, Norbert Vey, Caroline Bonmati, Stéphane Lepretre, Jean-Pierre Marolleau, Thomas Pabst, Philippe Rousselot, Agnès Buzyn, Jean-Yves Cahn, Véronique Lhéritier, Marie C. Béné, Vahid Asnafi, Eric Delabesse, Elizabeth Macintyre, Yves Chalandon, Norbert Ifrah, Hervé Dombret
Journal: Journal of Clinical Oncology (2018)

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P &lt; .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.
Cortisol Metabolism and Hepatic Expression of 11 beta-Hydroxysteroid Dehydrogenase Type 1 in Patients with Non Alcoholic Fatty Liver Disease.
Authors: A Ahmed, T Brady, C Brown, P Guest, A Wagenmakers, P Newsome, S G Hubscher, E Elias, D H Adams, J W Tomlinson, P M Stewart
Journal: Endocrine Reviews (2010)