tbuckley/cabot-search huggingface dataset:
Evaluation of relationship between progression-free survival and overall survival in first-line treatment of advanced non-small cell lung cancer.
Authors: Manuela Buzoianu, Dr Shengyan Hong, Li Shi, Jaye Viner
Journal: Journal of Clinical Oncology (2012)

e18073 Background: There is increasing interest in assessing progression-free survival (PFS) as a potential surrogate for overall survival (OS) in many tumor types. However, such an assessment has yet to be adequately performed for non-small cell lung cancer (NSCLC). We assessed the relationship between 1 st line treatment effects on PFS or OS in advanced NSCLC utilizing published data from clinical trials. Methods: The estimated PFS hazard ratio (HR) and OS HR from 43 randomized trials published between 2000 and 2010 were used to estimate Pearson correlation coefficient and to model the linear relationship between PFS HR and OS HR. Three approaches were considered in fitting the linear model, reflecting different ways of handling the variability of HR estimates used in the model fitting. The analysis was performed on add-on trials and head-to-head trials separately as well as jointly. Results: For add-on trials, the Pearson correlation coefficient r was 0.831 based on the observed HR data weighted by trial size. The R 2 was 0.791 for the linear model after Bayesian adjustment of variability in the observed HR data. All showed strong relationship between PFS HR and OS HR for add-on therapies. The relationship is weak for head-to-head therapy (r=0.288 and R 2 =0.202). The overall relationship, when jointly considering add-on and head-to-head therapies, is moderate (r=0.653 and R 2 =0.577). Conclusions: Our analysis supports the use of PFS as a reasonable surrogate for OS if an add-on therapy is developed, but not if a head-to-head therapy is developed as 1 st line treatment of advanced NSCLC.
Hair transplant in frontal fibrosing alopecia: A multicenter review of 51 patients
Authors: Sergio Vañó-Galván, Emilio Villodres, Ramón Pigem, M.R. Navarro-Belmonte, Manuel Asín-Llorca, Teresa Meyer-González, Rita Rodrigues-Barata, Óscar M. Moreno-Arrones, David Saceda-Corralo, Pierre Bouhanna, Alejandro Camps
Journal: Journal of the American Academy of Dermatology (2019)
Time-Resolved MRI Assessment of Convection-Enhanced Delivery by Targeted and Nontargeted Nanoparticles in a Human Glioblastoma Mouse Model
Authors: Zachary R. Stephen, Peter A. Chiarelli, Richard A. Revia, Kui Wang, Forrest Kievit, Chris Dayringer, Mike Jeon, Richard Ellenbogen, Miqin Zhang
Journal: Cancer Research (2019)

Abstract Convection-enhanced delivery (CED) provides direct access of infusates to brain tumors; however, clinical translation of this technology has not been realized because of the inability to accurately visualize infusates in real-time and lack of targeting modalities against diffuse cancer cells. In this study, we use time-resolved MRI to reveal the kinetics of CED processes in a glioblastoma (GBM) model using iron oxide nanoparticles (NP) modified with a glioma-targeting ligand, chlorotoxin (CTX). Mice bearing orthotopic human GBM tumors were administered a single dose of targeted CTX-conjugated NP (NPCP-CTX) or nontargeted NP (NPCP) via CED. High-resolution T2-weighted, T2*-weighted, and quantitative T2 MRI were utilized to image NP delivery in real time and determined the volume of distribution (VD) of NPs at multiple time points over the first 48 hours post-CED. GBM-specific targeting was evaluated by flow cytometry and intracellular NP localization by histologic assessment. NPCP-CTX produced a VD of 121 ± 39 mm3 at 24 hours, a significant increase compared with NPCP, while exhibiting GBM specificity and localization to cell nuclei. Notably, CED of NPCP-CTX resulted in a sustained expansion of VD well after infusion, suggesting a possible active transport mechanism, which was further supported by the presence of NPs in endothelial and red blood cells. In summary, we show that time-resolved MRI is a suitable modality to study CED kinetics, and CTX-mediated CED facilitates extensive distribution of infusate and specific targeting of tumor cells. Significance: MRI is used to monitor convection-enhanced delivery in real time using a nanoparticle-based contrast agent, and glioma-specific targeting significantly improves the volume of distribution in tumors.
Reply to Lee and Strek: Occupational Burden in Chronic Respiratory Disease: Call for Recognition, Training, and Data Capture
Authors: Paul D. Blanc, Carrie A. Redlich
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Respiratory Society Statement."Indeed, those were implicit goals that led our international taskforce members to undertake this in-depth review (1).From the onset, we recognized that in focusing on selected nonmalignant respiratory conditions, there would be other occupational associations that we would not be able to address in depth.For example, Table E2 in the online supplement of Reference 1 describes a number of other pulmonary disorders associated with occupational exposures (with supporting citations in the main publication).These include acute eosinophilic pneumonia, bronchiolitis (obliterative, proliferative, and lymphocytic), cryptogenic organizing pneumonia, desquamative interstitial pneumonia, diffuse pulmonary hemorrhage, lipoid pneumonia, nonspecific interstitial pneumonia, and respiratory bronchiolitis interstitial lung disease (1).Many of these disorders fall into the interstitial lung disease group emphasized in the letter by Dr. Lee and Dr. Strek.The authors also raise the important point that autoimmune conditions such as rheumatoid arthritis may not be appreciated as occupationally triggered by silica and other workplace exposures.In that context, it is important to note that concomitant lung disease may not be overt in such syndromes (2).It is our hope that further research and in-depth reviews will continue to shed light on underappreciated occupational contributors to disease and prioritize a reduction in the burden of these preventable conditions.
Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion
Authors: M. Kathryn Brewer, Annette Uittenbogaard, Grant L. Austin, Dyann M. Segvich, Anna DePaoli-Roach, Peter J. Roach, John J. McCarthy, Zoe R. Simmons, Jason A. Brandon, Zhengqiu Zhou, Jill Zeller, Lyndsay E.A. Young, Ramon C. Sun, James R. Pauly, Nadine M. Aziz, Bradley L. Hodges, Tracy R. McKnight, Dustin D. Armstrong, Matthew S. Gentry
Journal: Cell Metabolism (2019)

Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a-/- mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a-/- mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy.
A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with carboplatin in patients with advanced solid tumors.
Authors: Wen Wee Ma, Elaine Tat Lam, Grace K. Dy, Jennifer Robinson Diamond, Yujie Zhao, Lynne A. Bui, Gerald J. Fetterly, Wattanaporn Abramowitz, Ronald Harning, Pepi Pencheva, Shravanti Bhowmik, Ganesh Harishchandra Divekar, Ann Marie DiRaddo, S. Gail Eckhardt, Alex A. Adjei, Antonio Jimeno
Journal: Journal of Clinical Oncology (2013)

2557 Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using Nanotecton Technology. The MTD of PICN alone was previously determined to be 295 mg/m 2 iv every 3 weeks in a South Asian population. This study aimed to determine the pharmacokinetic (PK) profile of PICN alone and with carboplatin (C), and the MTD of PICN plus C. Methods: Patients (pt) with advanced solid malignancies and ECOG PS 0-1 were eligible. Part A was a PK study designed to examine cohorts of 3 pts, receiving PICN over 30 min at dose levels of 175, 260, and 295 mg/m 2 every 3 weeks; PK were performed at pre-determined time-points. Part B used a ‘3+3’ dose escalation scheme, designed to determine the MTD of PICN (220, 260, and 295 mg/m 2 ) when combined with C at AUC 6. Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1. Results: A total of 18 evaluable pts (9 in Part A, 9 in Part B) were enrolled from 2 US academic centers. No infusion reactions were observed with PICN. No dose limiting toxicity (DLT) was observed in Part A. In Part B, the DLTs were G3 febrile neutropenia and G4 thrombocytopenia requiring platelet transfusion at PICN 260/C AUC 6. A total of 6 pts were treated at PICN 220/C AUC 6 with no DLT. G3 or worse AEs for all cycles were as follow: Part A, bilateral lower extremity weakness, neuropathy, anorexia and neutropenia; Part B, anemia, thrombocytopenia, neutropenia and empyema. Partial responses were observed in biliary(Part A; PICN 260 mg/m 2 ), breast (Part B 220/6) and anal cancers (Part B 260/6). PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: PICN alone was tolerable in the dose range evaluated. When administered with C AUC 6, the MTD of PICN was 220 mg/m 2 administered every 3 weeks. Anti-cancer activity was observed in biliary, breast, and anal cancers. Final PK, toxicity and efficacy data of PICN alone and with C will be presented at the conference. Clinical trial information: NCT01304303.
Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma
Authors: Nicholas D. Klemen, Melinda Wang, Paul L. Feingold, Kirsten Cooper, Sabrina N. Pavri, Dale Han, Frank C. Detterbeck, Daniel J. Boffa, Sajid A. Khan, Kelly Olino, James Clune, Stephan Ariyan, Ronald R. Salem, Sarah A. Weiss, Harriet M. Kluger, Mario Sznol, Charles Cha
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Checkpoint inhibitors (CPI) have revolutionized the treatment of metastatic melanoma, but most patients treated with CPI eventually develop progressive disease. Local therapy including surgery, ablation or stereotactic body radiotherapy (SBRT) may be useful to manage limited progression, but criteria for patient selection have not been established. Previous work has suggested progression-free survival (PFS) after local therapy is associated with patterns of immunotherapy failure, but this has not been studied in patients treated with CPI. <h3>Methods</h3> We analyzed clinical data from patients with metastatic melanoma who were treated with antibodies against CTLA-4, PD-1 or PD-L1, either as single-agent or combination therapy, and identified those who had disease progression in 1 to 3 sites managed with local therapy. Patterns of CPI failure were designated by independent radiological review as growth of established metastases or appearance of new metastases. Local therapy for diagnosis, palliation or CNS metastases was excluded. <h3>Results</h3> Four hundred twenty-eight patients with metastatic melanoma received treatment with CPI from 2007 to 2018. Seventy-seven have ongoing complete responses while 69 died within 6 months of starting CPI; of the remaining 282 patients, 52 (18%) were treated with local therapy meeting our inclusion criteria. Local therapy to achieve no evidence of disease (NED) was associated with three-year progression-free survival (PFS) of 31% and five-year disease-specific survival (DSS) of 60%. Stratified by patterns of failure, patients with progression in established tumors had three-year PFS of 70%, while those with new metastases had three-year PFS of 6% (<i>P</i> = 0.001). Five-year DSS after local therapy was 93% versus 31%, respectively (<i>P</i> = 0.046). <h3>Conclusions</h3> Local therapy for oligoprogression after CPI can result in durable PFS in selected patients. We observed that patterns of failure seen during or after CPI treatment are strongly associated with PFS after local therapy, and may represent a useful criterion for patient selection. This experience suggests there may be an increased role for local therapy in patients being treated with immunotherapy.
The prognostic impact of epidermal growth factor receptor (EGFR) in patients with metastatic gastric cancer.
Authors: Dominique Werner, Akin Atmaca, Claudia Pauligk, Kristina Steinmetz, Havva Colak, Hans-Michael Altmannsberger, Elke Jäger, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2012)

e14557 Background: The prognostic role of the epidermal growth factor receptor (EGFR) in metastatic gastric cancer has not been established. Methods: EGFR was analyzed by immunohistochemistry (IHC) in a total of 357 patients (formalin-fixed, paraffin-embedded samples) and by real-time quantitative PCR (RTqPCR) in 130 patients with esophagogastric cancer. Staining intensity on IHC was scored in EGFR 0, 1+, 2+ and 3+. Staining intensity (alternatively intensity x % positive cells or the H-Score) and quantitative mRNA expression were correlated with progression-free (PFS) and overall survival (OS) and pathological and clinical characteristics. Results: On IHC, EGFR was negative, 1+, 2+, and 3+ in 205 (57%), 50 (14%), 62 (17%), and 40 (11%) patients, respectively. EGFR 3+ status correlated positively with intestinal type histology (p=.05) but no other correlations between baseline criteria such as age, sex, ECOG, tumor location, type of metastatic sites, and type of sampling and EGFR status were found. PFS and OS were similar in patients with EGFR-positive vs. those with EGFR negative gastric cancer, regardless whether positivity was defined as ≥1+ (PFS, 5.3 vs. 5.7 months, p=.185; OS, 10.6 vs. 10.9 months, p=.463) or as 3+ (PFS, 5.7 vs. 4.9 months, p=.159; OS, 8.6 vs. 10.8 months, p=.377) or when alternative scores were used such as the H-score. The multivariate overall survival analysis indicated that EGFR status is not an independent prognostic factor (hazard ratio 0.84, 0.56 to 1.12, p=.227). There were also no significant differences in progression-free or overall survival when patients were categorized according to median (PFS p=.173, OS p=.116) or quartile (PFS p=.634, OS p=.767) distribution of EGFR mRNA expression or when the cut-off with the highest predictive value was calculated (PFS p=.148, OS p=.189). Conclusions: EGFR status is not prognostic of patient’s outcome in metastatic gastric cancer.
GMC will regulate physician associates, government announces
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The General Medical Council will regulate physician associates (PAs) and anaesthesia associates (AAs) across the UK, the Department of Health and Social Care has announced.1

The GMC said it was working with the department to determine when it will begin regulating the two professions, as well as how the process will be funded. The regulator said the move would ensure all trainees get the support they need to provide safe care.

The announcement follows lengthy discussions over who should regulate the associates.

The BMA has opposed the move,2 with members at its …
First do no harm: the impossible oath
Authors: Kamran Abbasi
Journal: BMJ (2019)

Discussions about patient safety describe healthcare as an industry. If that’s the case then what is healthcare’s business? What does it manufacture? Health and wellbeing? Possibly. But we know for certain that healthcare manufactures harm. Look at the data from our new research paper on the prevalence, severity, and nature of preventable harm (doi:10.1136/bmj.l4185). Maria Panagioti and colleagues find that the prevalence of overall harm, preventable and non-preventable, is 12% across medical care settings. Around half of this is preventable.

These data make something of a mockery of our principal professional oath …
Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation
Authors: Hiroyuki Nagashima, Tanel Mahlakõiv, Han-Yu Shih, Fred P. Davis, Francoise Meylan, Yuefeng Huang, Oliver J. Harrison, Chen Yao, Yohei Mikami, Joseph F. Urban, Kathleen M. Caron, Yasmine Belkaid, Yuka Kanno, David Artis, John J. O’Shea
Journal: Immunity (2019)
Impact of response shift on time to quality-of-life scores deterioration in patients with breast cancer.
Authors: Zeinab Hamidou, Tienhan Sandrine Dabakuyo, Françis Guillemin, Thierry Conroy, Michel Velten, Damien Jolly, Mariette Mercier, Sylvain Causeret, Jean Cuisenier, Olivier Graesslin, Mélanie Gauthier, Franck Bonnetain
Journal: Journal of Clinical Oncology (2012)

1584 Background: Time to quality of life (QoL) score deterioration (TD) is a method of longitudinal QoL data analysis that has been proposed for breast cancer (BC) patients (Hamidou et al Oncologist 2011). As for RECIST criteria, the optimal definitions dealing with reference should be explored. This study aims to study the impact of changes in internal standards (CIS) of response-shift (RS) and the influence of baseline QoL expectancies on TD. Methods: A prospective multicenter study including all women hospitalized for a primary BC was conducted. The EORTC-QLQ-C30 and BR-23 questionnaires were used to assess the QoL at baseline, at the end of 1 st hospitalization, and 3 and 6 months after. CIS was investigated by the then-test method. QoL expectancy was assessed at baseline using Likert scale. Deterioration was defined as a decrease in QoL scores reaching at least the mean difference identified as minimal clinically important difference (MCID) using Jaeschke’s transition question. Sensitivity analyses were done using the then-test score as reference score, and considering 5 and 10 points as MCID. TD was estimated using Kaplan-Meier method. Cox regression analyses were used to identify factors influencing TD. Results: From February 2006 to February 2008, 381 women were included. For role functioning dimension, the median TD increased from 3.2 months [95% CI: 3.1-3.36] to 4.76 months [3.3-6.2] when adjusting on CIS. For body image when adjusting on CIS, sentinel lymph node biopsy became significantly associated with longer TD (HR: 0.64[0.43-0.94]) as compared to axillary lymph node dissection, radiotherapy to a shorter TD (HR: 0.63[0.42-0.95] and the type of surgery had no effect on TD. For global health, cognitive and social functioning dimensions, patients expecting deterioration in their QoL had a significantly shorter TD. For fatigue and breast symptom scales, patients expecting no change had a significantly shorter TD, as compared to patients expecting an improvement. Sensitivity analyses using a MDCS of 5 or 10 confirmed these results. Conclusions: Our results suggest that it would be more accurate to take into account CIS component of RS as well as QoL expectancies to estimate TD of QoL scores in patient with BC.
Hepatitis B and C prevalence and incidence in key population groups with multiple risk factors in the EU/EEA: a systematic review
Authors: Lauren MK Mason, Erika Duffell, Irene K Veldhuijzen, Uarda Petriti, Eveline M Bunge, Lara Tavoschi
Journal: Eurosurveillance (2019)

Background People living with HIV (PLHIV) and people in prison are population groups with a potentially high risk and/or prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Aim We conducted a systematic review in order to find prevalence and incidence estimates in these populations in the European Union/European Economic Area (EU/EEA). Methods Original research articles published between January 2005 and February 2017 were retrieved from PubMed and Embase in February 2017. Results Fifty-two articles were included, providing 97 estimates of HBV/HCV infection prevalence or incidence. Estimates of HBV infection prevalence ranged between 2.9% and43.4% in PLHIV and 0.0% and 25.2% in people in prison. Estimates of HCV infection prevalence ranged from 2.9% to 43.4% in PLHIV and 0.0% to 25.2% in people in prison. Incidence estimates ranged between 0.0 and 2.5 cases per 100 person-years for HBV infection in PLHIV. No such data was available for people in prison. HCV infection incidence ranged between 0.3 and 0.9 cases per 100 person-years in PLHIV and between 1 and 1.2 cases per 100 person-years in people in prison. Prevalence estimates were generally higher than in the general population, especially for HCV infection and among groups with multiple risk factors. Conclusions PLHIV, people in prison and groups with multiple risk factors, have a high prevalence of HBV and HCV and may be at ongoing risk of infection. These groups should be among the populations prioritised and targeted for active case finding and prevention programmes in the EU/EEA.
Phase 1 Results of ZUMA-3: KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)
Authors: Bijal D. Shah, Wendy Stock, William G Wierda, Olalekan Oluwole, Houston Holmes, Gary J. Schiller, Max S. Topp, Marie José Kersten, Roch Houot, Nicolas Boissel, Michelle Mojadidi, Allen Xue, Armen Mardiros, Yizhou Jiang, Tong Shen, Jeff S. Aycock, Shanna Stout, Jeffrey S. Wiezorek, Rajul Jain
Journal: Blood (2017)
Longevity Among Major League Baseball Players—Play Ball!
Authors: John W. Waterbor, Glenn Fleisig
Journal: JAMA Internal Medicine (2019)

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