tbuckley/cabot-search huggingface dataset:
Efficacy of cabozantinib (C) vs everolimus (E) in patients (pts) with advanced renal cell carcinoma (RCC) and bone metastases (mets) from the phase III METEOR study.
Authors: Bernard J. Escudier, Thomas Powles, Robert J. Motzer, Thomas Olencki, Osvaldo Rudy Aren, Stephane Oudard, Sergio Bracarda, Piotr Tomczak, Daniel E. Castellano, Leonard Joseph Appleman, Harry A. Drabkin, Daniel A. Vaena, Steven Milwee, Jillian Youkstetter, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2016)

4558 Background: In pts with metastatic RCC, bone mets are prognostic for poor outcomes and represent an unmet medical need. The Phase 3 METEOR trial (NCT01865747) assessed the efficacy and safety of C vs E in pts with RCC and ≥1 prior VEGFR TKI. The trial met its primary endpoint of improving progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.75; P<0.001) (Choueiri NEJM 2015). As C has shown clinical activity in bone mets in prostate cancer pts (Smith JCO 33 2015 abs 139), we evaluated clinical outcomes in RCC pts with bone mets in METEOR. Methods: 658 pts were randomized (stratified by MSKCC risk group and number of prior VEGFR TKIs) 1:1 to receive C (60 mg qd) or E (10 mg qd). Clinical outcome measures included PFS, ORR, overall survival (OS), and safety. Exploratory endpoints included bone scan response (BSR) in pts with bone scan lesions at baseline (Brown Nucl Med Commun 2012 33:384), incidence of skeletal-related events (SRE), and changes in bone turnover markers. Results: 142 pts had bone mets at baseline; of these, 112 had visceral mets also. MSKCC risk groups in pts with bone mets were consistent with the overall study population.PFS HRs of C vs E were 0.33 (bone; 95% CI 0.21—0.51) and 0.26 (bone+visceral; 95% CI 0.16—0.43). Median PFS with C was 7.4 mo in pts with bone mets and 5.6 mo in pts with bone and visceral mets compared to 2.7 mo and 1.9 mo with E respectively. The ORR with C was 17% and 20%, respectively. BSR by IRC was 18% (C) vs 10% (E). 12% (C) and 14% (E) of randomized pts had at least one SRE, including 4 (C) and 8 (E) cases of spinal cord compression. For pts with an SRE pre-randomization, the incidence of post-randomization SREs was 16% (C) and 34% (E) and included 0 (C) and 5 (E) cases of spinal cord compression. Reductions in bone markers were greater with C vs E (Table). The most common AEs in pts with bone mets were consistent with the safety profile in the overall study population. Conclusions: Treatment with C was associated with improved PFS and ORR in pts with or without bone mets as compared to E. This clinical benefit was supported by the outcomes of bone metastasis-related endpoints. Clinical trial information: NCT01865747. C E Baseline* Week 5* Baseline* Week 5* P1NP 48.5 38.9 49.9 44.1 CTx 0.40 0.19 0.43 0.43 *Median, ug/L.
Onset of Cardiac Iron Loading in a Large and Homogeneous Cohort of Thalassemia Major Paediatric Patients
Authors: Alessia Pepe, Antonella Meloni, Brunella Favilli, Marcello Capra, Domenico Giuseppe D'Ascola, Giovanni Palazzi, Antonella Quarta, Tommaso Casini, Maria Caterina Putti, Paolo Cianciulli, Lucia De Franceschi, Vincenzo Positano, Daniele De Marchi, Massimo Lombardi, Aldo Filosa
Journal: Blood (2011)
More Complete and Stable Reperfusion with Platelet IIb/IIIa Antagonism Plus Thrombolysis for AMI: The PARADIGM Trial
Authors: DJ Moliterno, RA Harrington, MW Krucoff, PW Armstrong, Frans Van de Werf, A Kristinsson, W Hui, A Paraschos, MV Bhapkar, A Rames
Journal: Circulation (1996)
Faecal blood testing cuts unnecessary colonoscopies by a third, shows study
Authors: Susan Mayor
Journal: BMJ (2016)

Undertaking faecal blood testing before referring patients with suspected colorectal disease for further investigations reduces unnecessary colonoscopies by just under a third, a primary care study has shown.1

Most patients referred by GPs for colonoscopy did not have significant colorectal disease and so were unnecessarily exposed to a small but significant risk of complications. A Dutch research group evaluated whether using …
Should general practice be a specialty in its own right?
Authors: Richard J McManus, F D Richard Hobbs
Journal: BMJ (2016)

GPs in the UK are already specialists in all but name

General practice as known today in the UK developed in the 19th and early 20th centuries.1 General practitioners (GPs) became gradually separated from physicians and surgeons centred in hospitals and took on the role of a personal doctor working in the community. This generalist role was differentiated from “specialists,” who consulted patients referred to them by GPs.

However, the respective roles of GPs and hospital specialists have become blurred, especially since the 1990s, with GPs taking on much of the traditional hospital care in the diagnosis and management of major diseases (diabetes, hypertension, thyroid disease, mental health); most preventive medicine (cancer screening, immunisation, maternity); and even minor procedures (insertion of intrauterine devices, joint injections, and lesion removal). This has resulted in the disappearance of the general physician role within hospitals and greater specialisation of consultants. What has not transferred has been the specialist label for the doctors now delivering …
Inhibition of the Shear-Induced Platelet Microparticle Formation by a mAb Against GPIb alpha Is Associated with Protein Tyrosine Dephosphorylation and the Blockade of Filamin Cleavage.
Authors: Julio Reséndiz, Luca Pontiggia, Riitta Lassila, Beat Steiner, Hans Deckmyn, Hans Ulrichts, Juerg H. Beer
Journal: Blood (2004)
Endoscopic submucosal dissection of a gastric neoplasm with osseous metaplasia
Authors: Rita Costa, Sofia Carvalho, Ana Silva, Aníbal Ferreira
Journal: Endoscopy (2016)

Heterotopic ossification is a phenomenon that is described in a variety of tissue types, in both neoplastic and non-neoplastic conditions, although it is more often seen in degenerative diseases. In the gastrointestinal (GI) tract, osseous metaplasia is less common but it can occur in carcinomas and some benign neoplasms [1].
Adoption of CT-based simulation and outcomes following radiation for stage III non-small cell lung cancer.
Authors: A. B. Chen, B. A. Neville, D. Schrag
Journal: Journal of Clinical Oncology (2010)

6007 Background: Technical studies suggest CT-based simulation can improve the therapeutic ratio for thoracic radiation (RT), though few studies have evaluated clinical outcomes. We assessed adoption of CT-based simulation and outcomes following CT-based versus conventional simulation. Methods: We analyzed claims of fee-for-service Medicare-enrolled men over age 65 living in SEER surveillance areas with stage III non-small cell lung cancer who had RT as initial treatment for primary cancers diagnosed from 2000 to 2005. Predictors of CT simulation and survival following CT versus conventional simulation were analyzed using logistic and Cox regression. Results: The proportion of RT patients having CT simulation increased from 2.6% in 1994 to 34.0% in 2000 to 77.6% in 2005. We identified 5,540 patients treated with RT from 2000-2005, with 60.0% having CT simulation. On multivariable analysis, rates of CT simulation were lower in the South (53.9%, adj OR 0.66) and West (58.2%, adj OR 0.75) compared to the Northeast (66.6%, referent) and Midwest (65.1%, adj OR 1.03) (overall p < 0.01), and urban residents had higher rates of CT simulation than rural residents (61.9% vs 45.2%, adj OR 1.75, p < 0.01). Patients receiving chemotherapy were also more likely to have CT simulation (65.2% vs 51.2%, adj OR 1.67 p < 0.01), though we did not observe a relationship between use of surgery and likelihood of CT simulation. Asian race, earlier year of diagnosis, and fewer comorbidities were associated with less use of CT simulation. Controlling for demographic, tumor, comorbidity, year of diagnosis, chemotherapy, and surgery characteristics, we found that use of CT simulation was associated with lower risk of death (HR .77, p < 0.01), compared to conventional simulation. Conclusions: CT-based simulation has been widely adopted for the treatment of stage III non-small cell lung cancer since the 1990s and is associated with higher survival rates in patients receiving RT. No significant financial relationships to disclose.
RTOG 9804: A prospective randomized trial for “good risk” ductal carcinoma in situ (DCIS), comparing radiation (RT) to observation (OBS)
Authors: Beryl McCormick
Journal: Journal of Clinical Oncology (2012)

1004 Background: Whole breast RT following conservation surgery (BCS) for low risk DCIS has remained controversial despite several large trials comparing RT to OBS, all showing significant benefit in local control with RT. RTOG 9804 compares RT to OBS for mammographically detected disease, of low or intermediate nuclear grade, &lt;2.5 cm size, and surgical margins ≥ 3 mm. Tamoxifen (TAM) use for 5 years was allowed but not required. Methods: The primary endpoint was ipsilateral breast local failure (LF). LF and contralateral breast failures (CBF) were estimated by the cumulative incidence method and treatment arms compared by log-rank test. Disease-free (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method and treatment arms compared by log-rank test. Patients were stratified by age, margin width, grade, TAM use, and primary size. With 1790 patients, 80% power and using a 2-sided log rank test at 0.05, the study was designed to detect a reduction in 5-year local recurrence from 6% to 3.5% with RT. Results: Accrual goals for the planned 1790 patients were not met; the study was closed early. From December 1999 to July 2006, 636 women were randomized to receive 50 Gy in 5 weeks vs. OBS. 43 women were ineligible on review and 8 withdrew consent. Median follow-up (F/U) time was 6.46 years. Mean age was 59; TAM was used in 62% of women. There were 2 LF in the RT arm vs. 15 in the OBS arm: at 5 years 0.4% RT vs. 3.2% OBS (p=0.0023, HR [95%CI] = 0.14 [0.03, 0.61]). With limited events, LF is not correlated with size, grade, margin status, or age. The rate of CBF at 5 years was 3.0% for the RT arm vs. 1.9% for the OBS arm (p=0.42, HR [95%CI] = 1.46 [0.59, 3.62]) and does not appear to be influenced by TAM use (3.6 versus 2.7% TAM). The DFS and OS results were excellent. Rate of grade 1-2 toxicity was 76% in the RT arm vs. 30% in the OBS arm, and the rate of ≥ 3 grade toxicities was 4% on both arms. Conclusions: In this “good risk” subset of DCIS, the LF rate was decreased significantly with the addition of RT. Longer follow-up is planned.
PCPNDT seems to benefit India’s birth sex ratios
Authors: A S Ahankari, P R Myles, L J Tata, A W Fogarty
Journal: BMJ (2016)

The possibility of lifting a ban on sex determination is an important ongoing debate in India.1 The introduction of prenatal diagnostic techniques legislation in 1994 and an amendment in 2003 aim to prevent female feticide (sex selective abortion of female fetuses) and represent milestones for the Indian …
Anti-PD1–Induced Pneumonitis: Capturing the Hidden Enemy
Authors: Eduardo Castanon
Journal: Clinical Cancer Research (2016)

Abstract Anti-PD1 antibodies have led to a therapeutic shift in cancer treatment. Although classically described as "well tolerated," these drugs can lead to severe immune-related adverse events. Using CT scan imaging, Nishino and colleagues describe different radiologic patterns and their possible relation to severity of several cases of anti-PD1–induced pneumonitis. Clin Cancer Res; 22(24); 5956–8. ©2016 AACR. See related article by Nishino et al., p. 6051
Fast-Track Zika Vaccine Development — Is It Possible?
Authors: Stephen J. Thomas, Maïna L’Azou, Alan D.T. Barrett, Nicholas A.C. Jackson
Journal: New England Journal of Medicine (2016)

The ongoing Zika epidemic and its consequences demand rapid development of a safe, efficacious vaccine. As preclinical studies of vaccine candidates continue in parallel with human trials, we need to determine which questions will inform short-term development plans.
S105 Microdroplet digital PCR for the longitudinal monitoring of circulating tumour DNA biomarkers in unselected patients with advanced lung cancer: Abstract S105 Table 1
Authors: E Karampini, A Muhith, H Farah, J King, P Cane, J Spicer, F McCaughan
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Circulating cell-free tumour DNA (cfDNA) can be detected in patients with solid organ malignancies and has the potential to be used as a non-invasive biomarker. Specific mutational events can be identified in biopsies using targeted next-generation sequencing and individualised microdroplet digital PCR (mdPCR) assays designed to detect and monitor the individualised biomarker in plasma. This can inform the timing (and sometimes mechanism) of disease progression or treatment failure. To date this has been demonstrated in patients with EGFR and KRAS mutations. Our objective was to determine if this approach could be applied to an unselected cohort of patients with advanced non-small cell lung cancer (adenocarcinoma subtype). <h3>Methods</h3> Unselected treatment-naive patients with lung cancer were recruited from thoracic oncology clinics. Paired DNA from tumour biopsies and baseline/longitudinal plasma samples was obtained. Targeted next-generation sequencing (NGS) was performed using a 26-gene panel on biopsy-derived DNA. Primer sets and probes for identified mutations were optimised and validated on a the BioRad-QX100 mdPCR system. <h3>Results</h3> The NGS data is summarised in Table 1. 20 patients in our test cohort had stage IIIB/IV lung adenocarcinoma. These included cytology specimens – EBUS, lymph node FNA and pleural effusion, percutaneous biopsies, pleural biopsies and a brain biopsy. The mean quantity of DNA used for targeted resequencing was 23 ng. The lowest read depth for the identified mutations was 1639; in general coverage was &gt;10,000. 19/20 patients had mutations identified in their diagnostic specimen. 12 of 20 samples had &gt;1 mutation detected and 8 had more than 2 mutations detected at a mutant allele frequency (MAF) &gt;10%. CtDNA from plasma has been tested for specific mutations including in <i>PIK3CA</i>, <i>TP53</i>, and <i>BRAF</i> as well as <i>KRAS</i> and <i>EGFR</i> in these patients. In 16 of the 19 patients in which mutations were identified the mutation has also been detected in the plasma. The range of detected MAFs was between &lt;0.1–49.6%. It was noteworthy that there was discordance between the biomarker response and RECIST1.1 criteria in some patients. <h3>Conclusion</h3> It is feasible to perform a targeted NGS analysis on DNA from standard fixed diagnostic lung adenocarcinoma specimens and then validate and use individualised molecular biomarkers for use in a microdroplet digital PCR assay of cell-free circulating tumour DNA. There is potential for this approach to inform clinical decision-making. This is a robust and low cost means of monitoring treatment response non-invasively and merits further evaluation in a clinical trial.
Clinical, Laboratory, and Treatment Outcome Characteristics of Chronic Lymphocytic Leukemia (CLL) Patients with p53 Mutations or del(17p) Enrolled on a Prospective Phase III Clinical Trial: Short Progression Free Survival, Irrespective of Fludarabine-Based Treatment Used.
Authors: David M. Lucas, Gordon W. Dewald, Donna S. Neuberg, John C. Byrd, Gerard Lozanski, Jennifer Harbison, Kammy D. Cunningham, Ian W. Flinn, Martin S. Tallman, Michael R. Grever
Journal: Blood (2004)
Is High Blood Pressure Self-Protection for the Brain?
Authors: Esther A.H. Warnert, Jonathan C.L. Rodrigues, Amy E. Burchell, Sandra Neumann, Laura E.K. Ratcliffe, Nathan E. Manghat, Ashley D. Harris, Zoe Adams, Angus K. Nightingale, Richard G. Wise, Julian F.R. Paton, Emma C. Hart
Journal: Circulation Research (2016)

Rationale: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients. Objective: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. Methods and Results: We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126). Conclusions: Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.
Pembrolizumab for advanced papillary or follicular thyroid cancer: preliminary results from the phase 1b KEYNOTE-028 study.
Authors: Janice M. Mehnert, Andrea Varga, Marcia Brose, Rahul Raj Aggarwal, Chia-Chi Lin, Amy Prawira, Filippo de Braud, Kenji Tamura, Toshihiko Doi, Sarina Anne Piha-Paul, Jill Gilbert, Sanatan Saraf, Pradeep Thanigaimani, Jonathan D. Cheng, Bhumsuk Keam
Journal: Journal of Clinical Oncology (2016)

6091 Background: Treatment options are limited for patients (pts) with advanced thyroid cancer. PD-L1 expression in thyroid cancer tumors has been shown to correlate with poor prognosis. Pembrolizumab (pembro), an anti–PD-1 antibody, blocks the interaction between PD-1 and PD-L1 and PD-L2. We assessed the safety and efficacy of pembro in PD-L1+ advanced (unresectable and/or metastatic) thyroid cancer. Methods: KEYNOTE-028 (NCT02054806) is a nonrandomized trial of pembro in 20 types of advanced solid tumors. Key eligibility criteria for this cohort included papillary or follicular subtypes of advanced thyroid cancer, failure of standard therapy, ECOG PS 0-1, and PD-L1 expression in ≥ 1% of tumor or stroma cells by IHC. Pembro 10 mg/kg was given every 2 wk for up to 24 mo or until confirmed progression, intolerable toxicity, death, or withdrawal of consent. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by investigator review. Results: Of the 22 pts enrolled, median age was 60.5 y; 40.9% were male; 68.2% vs 31.8% had papillary vs follicular carcinoma; 36.4% had an ECOG PS of 1; 50.0% received ≥ 2 prior therapies for metastatic disease (18 pts were radioactive iodine refractory; 7 pts received prior sorafenib; 1 pt received prior lenvatinib). Median follow-up duration as of Dec 10, 2015, was 73.5 wk (range, 29.4-87.0). 18 (81.8%) pts had treatment-related adverse events (TRAEs); those occurring in ≥ 15% of pts were diarrhea (n = 7) and fatigue (n = 4). 1 TRAE of grade ≥ 3 (grade 3 colitis) occurred; no pts died or discontinued pembro because of a TRAE. 2 pts had a PR for an ORR (confirmed) of 9.1% (95% CI, 1.1-29.2); median duration of response was not yet reached (range, 35.3-44.1+ wk) by the data cutoff. The stable disease rate was 54.5% (n = 12, 95% CI, 32.2-75.6). The 6-mo OS rate was 100%; the 6-mo PFS rate was 58.7%. At the data cutoff, 6 pts remained on treatment. Conclusions: Pembro shows promising antitumor activity in advanced papillary or follicular thyroid cancer which progressed on standard therapies. The clinical benefit of pembrolizumab in advanced thyroid cancer will be further investigated in the phase 2 KEYNOTE-158 trial (NCT02628067). Clinical trial information: NCT02054806.
Cost-effectiveness analysis of radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) in patients with isolated hepatic metastases from colorectal cancer (CRC).
Authors: Vladimir Kirichenko, Ngoc Thai, William Morris, Amy Heenan, David S. Parda
Journal: Journal of Clinical Oncology (2016)

639 Background: Systemic therapy combined with surgery may prolong survival of patients with isolated hepatic metastases from CRC, however, only 10-25% are resectable. We applied a Markov model to estimate and compare cost effectiveness for the two competing treatments of SBRT and RFA in management of unresectable isolated hepatic metastases. Methods: We developed a multistate Markov decision model with probabilistic sensitivity analysis to simulate a randomized controlled trial for SBRT and RFA and compare respective cost effectiveness (in dollars per quality adjusted life years, or QALY). Model assumptions were based on extensive literature search of utilities and recurrence risks, including published data from our institution. Costs were taken from the 2013 Medicare reimbursement tables. In order to reflect reported patient selection variability across literature, two mortality rates due to hepatic metastases were considered for both treatment modalities: 50% probability of death in 1.5 years and 60% in 5 years. Sensitivity analysis was performed to model uncertainty in these parameters. Results: For patients with 5-year life expectancy, Markov cohort analysis demonstrated QALY-adjusted survival advantage of SBRT over RFA with QALY 4.35 vs. 3.89 respectively. This difference was marginal for patients with 1.5-year life expectancy. Physician-hour involvement was less in SBRT group. The incremental cost adjusted effectiveness (Cost/QALY) for SBRT over RFA was $2,379 in the 5-year life expectancy cohort, and $2,216 for SBRT over RFA in the 1.5-year cohort. Sensitivity analysis demonstated robustness of these results across a range of utility values, costs, recurrence rates, and procedure-related morbidity. Conclusions: In comparison to RFA, SBRT was more cost-effective modality for unresectable or potentially resectable hepatic metastases over a wide range of treatment and disease assumptions, including recurrence rates, and procedure-related morbidity. Additionally, SBRT is a relatively fast outpatient procedure requiring less physician-hour involvement.