tbuckley/cabot-search huggingface dataset:
Predictive value of <i>KRAS</i> mutation status in metastatic colorectal cancer (mCRC) patients treated with capecitabine and bevacizumab (CAP-B) maintenance treatment vs observation in the phase III CAIRO3 study.
Authors: Kaitlyn K.H. Goey, Sjoerd G. Elias, Harm van Tinteren, Miangela M. Lacle, Stefan M. Willems, Wendy W.J. de Leng, Eric Strengman, Celien Vreuls, Geert-Jan Creemers, Ankie Van Der Velden, Cornelis J. A. Punt, Miriam Koopman
Journal: Journal of Clinical Oncology (2016)

3525 Background: The impact of KRAS mutation status in mCRC treated with anti-VEGF therapy is controversial. The randomized phase 3 CAIRO3 study showed benefit of first-line CAP-B maintenance treatment compared to observation in mCRC patients (pts) with stable disease or better after 6 cycles CAPOX-B. We investigated the predictive value of KRAS mutation status within the CAIRO3 study. Methods: We extracted tumor DNA from paraffin blocks and used Next Generation Sequencing (NGS) to detect mutations in KRAS exon 2-4. We supplemented this with KRAS data collected from local laboratories. We used stratified Cox regression models adjusted for baseline covariables to estimate hazard ratios (HR) and to analyze whether treatment effect was modified by KRAS mutation status. Time to first progression (PFS1), time to second progression after CAPOX-B reintroduction (PFS2, primary endpoint), time to second progression on any treatment (TT2PD) and overall survival (OS) were analyzed. Results: KRAS mutation status was available from 448/557 pts (80%), determined by NGS (n = 317) or already available data (n = 131). Tumors were KRAS wild-type (wt) in 240 (54%) and mutant (mt) in 208 (46%) pts. Pts with KRAS wt tumors had significantly more benefit from CAP-B maintenance treatment compared to observation than pts with KRAS mt tumors for all endpoints, except for PFS1. Pts with KRASmt tumors showed significant benefit from maintenance treatment only in PFS1 and PFS2 (Table). Conclusions: Our data suggest that in the first-line treatment of mCRC, pts with KRAS wt tumors benefit most from CAP-B maintenance treatment compared to observation after 6 cycles CAPOX-B. We are currently analyzing the predictive value of RAS, BRAF and mismatch repair status. Clinical trial information: NCT00442637. HR (95% CI) for maintenance vs observation Pinteraction KRASwt KRASmt PFS1 0.27 (0.20 - 0.37) 0.40 (0.29 - 0.55) .07 PFS2 0.45 (0.34 - 0.61) 0.72 (0.53 - 0.98) .03 TT2PD 0.42 (0.31 - 0.57) 0.75 (0.55 - 1.03) .008 OS 0.64 (0.47 - 0.87) 1.07 (0.77 - 1.48) .02
Hepatitis C virus genotype and prognosis of compensated cirrhosis type C
Authors: G. Fattovich, M.L. Ribero, M. Pantalena, G. Diodati, P. Almasio, F. Nevens, F. Tremolada, F. Degos, G.R. Jhinkoe Rai, A. Solinas, D. Mura, A. Tocco, I. Zagni, G. Realdi, S.W. Schalm
Journal: Gut (1999)
Genomic features of normal tissues from prophylactic surgery in BRCA1/2 mutation carriers.
Authors: Vassiliki Kotoula, Efterpi Demiri, Florentia Fostira, Eleni Vrettou, Elpida Charalambous, Ioannis Tikas, Konstantinos Papazisis, Thomas Zaramboukas, Anthoula Asimaki-Vlachopoulou, Spyros Miliaras, Elena Fountzilas, Ananias Ananiadis, Sofia Chrisafi, Christos Poulios, Ioannis Natsiopoulos, Aris Tsiftsoglou, George Fountzilas
Journal: Journal of Clinical Oncology (2017)

e13055 Background: Genomic alterations in normal tissues from pathogenic germline BRCA1/2 mutation (mut) carriers are as yet poorly described. We investigated the genomic status of normal breast (NB) and hystero-salpingo-oophorectomy (GYN) tissues removed upon prophylactic surgery in a real-life cohort of BRCA1/2 carriers. Methods: By using targeted NGS we examined the mut status of 220 samples (39 peripheral blood and 181 paraffin tissue) from 53 BRCA1/2 carriers who underwent prophylactic surgery, 42 with and 11 without prior cancer manifestation (PCM). We compared germline BRCA1/2 mut status with tumor, NB and GYN mut status. Results: Eight patients carried germline BRCA2 and 45 BRCA1 mut. Somatic mut were most frequent in BRCA2 (28%), BRCA1 (17%), TP53 (7%) among 136 NB and GYN samples; and, in TP53 (49%; p &lt; 0.001) and BRCA1 (38%; p = 0.039) among 45 tumor samples. Among all tissue types, the 85 NB had the lowest mut load (p = 0.001). In NB and GYN, mut load was higher in BRCA1 vs. BRCA2 carriers (p = 0.027) and in those with BRCA1 substitutions/indels vs. exon deleting and skipping mut (p &lt; 0.001). In tumors, only germline BRCA1 substitutions/indels were associated with higher mut load (p = 0.014). Preservation of germline mut in tissues was assessable in 84 samples from 26 patients. The germline mut was lost in 8 tumor and NB samples from 6 patients (23%) with PCM. Somatic deleterious mut in the BRCA1 BRCT-domain emerged in two such cases; the rest had combinations of TP53, MRE11A and NF1 mut. GYN samples from these patients retained the germline mut and presented the highest mut load among all examined samples (p &lt; 0.001). Conclusions: Somatic mut in normal tissues from BRCA1/2 carriers are affected by the inherited mutated gene and by the type of the germline mut concerning BRCA1. Germline BRCA1 mut may be substituted by somatic mut in tumor and normal tissues, in an organ specific manner. Mutagenesis in tumors and normal tissues appear to be driven by different pathways. Our findings shed new light on the biological impact of BRCA1/2 mut in tissues.
Administration of vitamin C in combination with chemotherapeutic agents enhances chemosensitization in oesophageal cancer cells in vitro
Authors: MMM Abdel-Latif, D Kelleher, JV Reynolds
Journal: Endoscopy (2005)

Aims: Chemoresistance to 5-fluorouracil and cisplatin is considered an obstacle for successful chemotherapy. Little is known about possible interactions between vitamin C and anticancer agents in oesophageal cancer. This study investigated the effects of vitamin C in combination with 5-Fu and cisplatin on NF-κB and AP-1 expression in oesophageal cancer.
An online exercise program plus automated coping skills training improved pain and function in chronic knee pain
Authors: Owen D. Williamson
Journal: Annals of Internal Medicine (2017)

Source Citation Bennell KL, Nelligan R, Dobson F, et al. Effectiveness of an internet-delivered exercise and pain-coping skills training intervention for persons with chronic knee pain: a randomized trial. Ann Intern Med. 2017;166:453-62. 28241215
Safety and Efficacy of Direct-Acting Antiviral Drugs in Patients with Haemoglobinophaties and Chronic Hepatitis C Infection
Authors: Antonio Piga, Paolo Rigano, Raffaella Origa, M. Domenica Cappellini, Valeria Pinto, Immacolata Tartaglione, Aldo Filosa, Domenico D'Ascola, Vito Di Marco, Gian Luca Forni
Journal: Blood (2016)
Ideal Cardiovascular Health, Mortality, and Vascular Events in Elderly Subjects
Authors: Bamba Gaye, Marianne Canonico, Marie-Cécile Perier, Cecilia Samieri, Claudine Berr, Jean-François Dartigues, Christophe Tzourio, Alexis Elbaz, Jean-Philippe Empana
Journal: Journal of the American College of Cardiology (2017)

The benefit of ideal cardiovascular health (CVH) on health-related outcomes in middle-aged patients is firmly established. In the growing elderly population, the high prevalence of comorbidities and medications for chronic diseases may offset such benefit. This study analyzed the association of ideal CVH with mortality, incident coronary heart disease, and stroke events in elderly individuals from the community. Between 1999 and 2001, 9,294 men and women, noninstitutionalized and aged 65 years and over were examined, and thereafter followed up for the occurrence of vascular events and mortality within the Three-City Study. Hazard ratios (HRs) were estimated by Cox proportional hazard model and compared subjects with 3 to 4 and subjects with 5 to 7 ideal metrics with those with 0 to 2 ideal metrics, respectively. The mean age was 73.8 ± 5.3 years, and 36.7% were men. Only 5% of the participants had ≥5 metrics at the ideal level. After a median follow-up of 10.9 years and 8.6 years, respectively 1,987 deaths and 680 adjudicated coronary heart disease or stroke events had occurred. In multivariate analysis, the risk of mortality and of vascular events decreased across the categories of ideal metrics. In particular, in subjects with ≥5 metrics at the ideal level (compared with those with ≤2), there was a 29% (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.55 to 0.90) decreased risk of all-cause mortality and 67% (HR: 0.33; 95% CI: 0.19 to 0.57) for coronary heart disease and stroke combined (p for trend <0.001). Even in the elderly, higher CVH status is highly beneficial regarding mortality and vascular event risks.
Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction
Authors: Scott D. Solomon, Adel R. Rizkala, Jianjian Gong, Wenyan Wang, Inder S. Anand, Junbo Ge, Carolyn S.P. Lam, Aldo P. Maggioni, Felipe Martinez, Milton Packer, Marc A. Pfeffer, Burkert Pieske, Margaret M. Redfield, Jean L. Rouleau, Dirk J. Van Veldhuisen, Faiez Zannad, Michael R. Zile, Akshay S. Desai, Victor C. Shi, Martin P. Lefkowitz, John J.V. McMurray
Journal: JACC Heart Failure (2017)
PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/β-catenin signaling pathway
Authors: Ping Zhan, Bin Zhang, Guang-min Xi, Ying Wu, Hong-bing Liu, Ya-fang Liu, Wu-jian Xu, Qing-qing Zhu, Feng Cai, Ze-jun Zhou, Ying-ying Miu, Xiao-xia Wang, Jia-jia Jin, Qian Li, Li-ping Qian, Tang-feng Lv, Yong Song
Journal: Molecular Cancer (2017)

Protein regulator of cytokinesis-1 (PRC1) belongs to the microtubule-associated proteins (MAPs) family, and is involved in cytokinesis. Recent investigations suggest PRC1 involvement in human carcinogenesis, including breast carcinoma, hepatocellular carcinoma and etc. However, whether PRC1 contributes to lung adenocarcinoma tumorigenesis remains unknown. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blotting and Immunohistochemical staining (IHC) were used to evaluate and contrast the PRC1 expression profile in lung adenocarcinoma and adjacent normal lung tissues. We examined the clinical use of PRC1 in lung adenocarcinoma prognosis. Additionally, the tumorigenesis impact of PRC1 in lung adenocarcinoma cells was verified via in vitro and in vivo metastasis and tumorigenesis assays. Notably, Next Generation Sequencing (NGS) was performed to investigate the molecular mechanism underlying the oncogenic role of PRC1 in lung adenocarcinoma. PRC1 mRNA and protein expressions were upregulated in lung adenocarcinoma tissues compared to adjacent normal lung tissues. PRC1 protein overexpression correlated with lymph node metastasis and was an independent poor prognostic factor for lung adenocarcinoma patients. Our data implied that PRC1 depletion limited the proliferation and invasion of lung adenocarcinoma cells in vitro and lowered tumor development and lung metastasis in vivo. Remarkably, limiting PRC1 substantially prompted G2/M phase cell cycle arrest and apoptosis. Mechanistically, by conducting NGS on PRC1-depleted A549 cells and control cells, we discovered that PRC1 expression was significantly correlated with the Wnt signaling pathway. This investigation offers confirmation that PRC1 is a prognostic and promising therapeutic biomarker for people with lung adenocarcinoma and takes on a key part in the activation of the Wnt/β-catenin pathway in lung adenocarcinoma development.
Reply to Lorenzo Marconi, Steven MacLennan, Thomas B.L. Lam, et al's Letter to the Editor re: Maria Carmen Mir, Ithaar Derweesh, Francesco Porpiglia, Homayoun Zargar, Alexandre Mottrie, Riccardo Autorino. Partial Nephrectomy Versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta-analysis of Comparative Studies. Eur Urol 2017;71:606–17
Authors: Ithaar H. Derweesh, Maria C. Mir, Riccardo Autorino
Journal: European Urology (2017)
Improved Outcomes in Patients with Thalassemia Major Transplanted with Peripheral Blood and Marrow Grafts in Comparison with Cord Blood and Bone Marrow Grafts from Sibling Donors
Authors: Qiao chuan Li, Jian ming Luo, Zhong ming Zhang, Lian jin Liu, Ling ling Shi, Ying hua Chen, Yi zhen Zhou, Rong rong Liu, Paul Schwarzenberger, Yong rong Lai
Journal: Blood (2016)
Deconstructing a popular myth: why knee arthroscopy is no better than placebo surgery for degenerative meniscal tears
Authors: Jonas Bloch Thorlund
Journal: British Journal of Sports Medicine (2017)

There are many myths in modern medicine.1 Myths are good stories that are easy to remember, and when they include a mechanical explanation for changes in pain that make intuitive sense, they catch on and live for a long time. One such story is that meniscal tears cause pain, which can be relieved by removal of the damaged meniscal tissue.1 This myth has been ‘busted’ by randomised, double-blinded trials in middle-aged and older patients demonstrating knee arthroscopy to be no better for degenerative meniscal tears than placebo surgery.2 3 But why does knee arthroscopy provide no better pain relief than placebo surgery?

The rationale for cutting away damaged meniscal tissue is based on the premise that the injured or damaged parts of the meniscus are the primary cause of the patient’s pain and discomfort. More likely, the knee pain is explained by the presence of early degenerative changes (including degenerative meniscal tissue) or established osteoarthritis in the knee and not because of a direct link between pain and meniscal damage per se.4 Meniscal tears are common in the symptom-free general middle-aged and older population with and without signs of radiographic knee osteoarthritis.5 6 Similarly, in patients with knee trauma, meniscal tears are frequently seen in the uninjured contralateral leg.7 Such studies debunk the explanation that meniscal tears always cause pain; the simple ‘car mechanic’ analogy—cutting tissue away—does not apply.

Meniscal tears often coexist with other knee joint pathology. Factors other than the meniscal …
Revealing the man behind the iron mask – human hepatic iron metabolism gene expression profiles in disorders of iron homeostasis
Authors: F Gleeson, E Ryan, S Barrett, J Russell, J Crowe
Journal: Endoscopy (2006)

Aims: Knockout murine models and cellular iron regulatory networks represent a surrogate marker for the human model of iron metabolism. In this study, human hepatic hepcidin (HAMP), hemojuvelin (HJV), transferrin receptor 2 (TfR2), HFE, IL6 and ferroportin mRNA expression patterns are analysed in physiological iron overload, hereditary haemochromatosis (HH) and normal controls.
Impact of Donor-Recipient Histocompatibility and CMV-Mismatch on Outcome of Allogeneic Stem Cell Transplantation for AML and MDS: A Retrospective Registry Study of the German Stem Cell Transplant Registry (DRST) of the German Working Group for Blood and Marrow Transplantation (DAG-KBT)
Authors: Francis A. Ayuk, Dietrich W. Beelen, Martin Bornhäuser, Matthias Stelljes, Tajana Zabelina, Jürgen Finke, Guido Kobbe, Daniel Wolff, Eva Maria Wagner, Maximilian Christopeit, Christoph Schmid, Hellmut Ottinger, Christoph Groth, Christoph Faul, Hartmut Bertz, Elena Rachlis, Christine Wolschke, Nicolaus Kröger, Wolfgang Bethge
Journal: Blood (2016)
Hémorragies digestives hautes admises en réanimation pendant les horaires de garde: fibroscopie œsogastroduodénale (FOGD) réalisée en urgence ou différée: impact d'un algorithme décisionnel
Authors: JC Lachérade, V Pasquereau, RL Vitte, B de Jonghe, P Fangio, C Eugène, H Outin
Journal: Endoscopy (2005)

L'appel d'un endoscopiste pour une hémorragie digestive reçue pendant la garde est peu standardisé. Il est possible que certaines endoscopies puissent être différées au lendemain sans préjudice pour le patient.
Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease
Authors: Eduardo De Pablo-Fernandez, Carmen Tur, Tamas Revesz, Andrew J. Lees, Janice L. Holton, Thomas T. Warner
Journal: JAMA Neurology (2017)

Evidence suggests that development of autonomic dysfunction (AutD) may negatively affect disease course and survival in patients with synucleinopathies. However, the few available studies on Parkinson disease (PD) have conflicting results, comprise a small number of patients, have short follow-up periods, and lack pathologic confirmation of the diagnosis.To examine the association of time of onset of AutD with disease progression and survival in PD.This retrospective review of clinical data from 100 consecutive patients with an autopsy-confirmed diagnosis of PD from the archives of the Queen Square Brain Bank in London, United Kingdom, from January 1, 2006, to June 3, 2016, included patients with PD regularly seen by hospital specialists (neurologists or geriatricians) in the United Kingdom throughout their disease until death. Patients with dementia before or within 1 year after onset of motor symptoms, monogenic forms of PD, comorbidities that affect autonomic function, a coexisting neuropathologic diagnosis, or insufficient clinical information were excluded.Survival and time from diagnosis to specific disease milestones were calculated to assess disease progression. Autonomic dysfunction was defined as autonomic failure at autonomic function testing or 2 of the following symptoms: urinary symptoms, constipation, upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, or erectile dysfunction. Multivariable Cox proportional hazards regression models on the risk of a disease milestone and death were used.A total of 100 patients (60 [60.0%] male; mean [SD] age at diagnosis, 63.9 [10.3] years; mean [SD] disease duration, 14.6 [7.7] years) were studied. Autonomic dysfunction developed in 85 patients (mean [SD] time from diagnosis, 6.7 [7.7] years) and was associated with older age at diagnosis, male sex, poor initial levodopa treatment response, and postural instability and gait difficulty motor PD subtype in linear regression analysis, but staging of α-synuclein pathologic changes was unrelated. Earlier AutD increased the risk of reaching the first milestone (hazard ratio, 0.86; 95% CI, 0.83-0.89; P < .001) and shortened survival (hazard ratio, 0.92; 95% CI, 0.88-0.96; P < .001). Older age at diagnosis and poorer levodopa treatment response were the other factors associated with shorter survival in adjusted multivariate analysis.Earlier AutD is associated with a more rapid development of disease milestones and shorter survival in patients with PD.
Incidents in the Life of a Physician.
Authors: J Grant
Journal: JAMA (1892)

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Optimising load to optimise outcomes
Authors: Philip Glasgow
Journal: British Journal of Sports Medicine (2017)

The human body is attuned to respond to various forms of mechanical loading and that this is perhaps the primary tool in the repertoire of sports medicine professionals. If exercise is the intervention of choice for a range of conditions, we must appreciate the mechanisms that underpin adaptation so we can refine our prescription and better benefit patients. The current issue of BJSM highlights a range of strategies that can be used to better monitor, manipulate and apply load in a range of contexts.

Mechanical loading can take many different forms and may involve …
A role for peripheral natural killer (NK) cell activity in the response to neoadjuvant chemotherapy in patients with breast cancer.
Authors: Ryungsa Kim, Ami Kawai, Megumi Wakisaka, Hitomi Garaku, Naomi Yasuda, Shoichiro Ohtani, Mitsuya Ito, Koji Arihiro
Journal: Journal of Clinical Oncology (2016)

e12073 Background: Tumor-infiltrating lymphocytes (TILs) have prognostic and potentially predictive value in patients (pts) under neoadjuvant chemotherapy (NAC), especially in human epidermal growth factor receptor 2 (HER2)-positive and triple negative (TN) breast cancer. NK cells can spontaneously recognize and kill cancer cells, and lower levels of NK cells are associated with an increased risk of death from breast cancer. We assessed peripheral NK cell activity for potential associations with pathologic therapeutic response and cancer subtype. Methods: Twenty eight pts with stage II-IV breast cancer were treated with NAC from July 2012 to Sept. 2015 in our clinic using albumin-bound paclitaxel (nab-PTX)/fluorouracil/epirubicin/cyclophosphamide (FEC), nab-PTX/FEC/trastuzumab (HER), docetaxel (DTX)/FEC, FEC/DTX, FEC/DTX/HER. Peripheral NK cell activity was measured before and after NAC. Results: Increased NK cell activity was observed in 16 pts, but was decreased in 12 pts. TILs were found to be present to a lesser extent in the primary lesion (1-20%) after NAC. Six factors including median age, stage, > G2 response, disappearance of axillar lymph node metastasis (Ax+), nuclear grade, and Ki-67-positivity were considered in univariate analyses. Disappearance of Ax+ was found to be significantly associated with increased NK cell activity (p = 0.02). Based on multivariate analysis including the two factors > G2 and disappearance of Ax+, increased NK cell activity was significantly associated with the latter (OR = 8.00, 95% CI = 1.24-51.50, p = 0.02). HER2 type was significantly associated with increased NK cell activity (OR = 7.85, 95% CI = 1.10-56.12, p = 0.03), and TN tended to be associated (p = 0.08). A high Ax+ disappearance rate was observed in association with HER2 and TN type (p = 0.002). Conclusions: Disappearance of Ax+ following NAC tended to be associated with increased NK cell activity after NAC, mostly likely due to activation of NK cell-mediated tumor immunosurveillance and inhibition of metastases. HER-induced antibody-dependent cellular cytotoxicity was especially likely to be involved in this effect.
Combination of diet, exercise, and behaviour change may help weight loss in child obesity
Authors: Susan Mayor
Journal: BMJ (2017)

Interventions combining diet with physical activity and behavioural change can have a small, short term effect in reducing weight among children and adolescents who are overweight or obese, report two Cochrane reviews that analysed all available studies in these age groups.12

The first review analysed evidence from 70 randomised controlled trials assessing the effects of diet, physical activity, and behavioural interventions in 8461 overweight and obese children aged 6 to 11 (median age 10). The studies included children from Europe, Canada, Japan, Malaysia, New Zealand, and the US, who …