tbuckley/cabot-search huggingface dataset:
A first-in-human study of REGN2810, a monoclonal, fully human antibody to programmed death-1 (PD-1), in combination with immunomodulators including hypofractionated radiotherapy (hfRT).
Authors: Kyriakos P. Papadopoulos, Marka R. Crittenden, Melissa Lynne Johnson, Albert C. Lockhart, Kathleen N. Moore, Gerald Steven Falchook, Silvia Formenti, Richard D. Carvajal, Rom S. Leidner, Aung Naing, Lee S. Rosen, Glen J. Weiss, Wilson Caldwell Iii, Bo Gao, Anne Paccaly, Elizabeth Stankevich, Pamela Trail, Matthew G. Fury, Israel Lowy
Journal: Journal of Clinical Oncology (2016)

3024 Background: Monotherapy with PD-1 pathway blockade is effective in a significant minority of patients with various malignancies. Combination therapy may further augment immune and clinical responses. This phase 1 multicenter study assessed the safety and preliminary anti-tumor activity of REGN2810, an anti-PD-1 antibody, as monotherapy and in combination with other anti-tumor treatments in patients with advanced solid tumors. Methods: REGN2810 was evaluated at 1, 3, or 10 mg/kg IV q 2 weeks (W) as monotherapy, and at 1 and 3mg/kg IV q 2W in combination with hfRT (either 9 Gy X 3 days or 6 Gy X 5 days in cycle 1 week 2), or with (CTX) or CTX + hfRT. A standard 3 + 3 dose escalation design was used, with additional patients (up to 6 total) to confirm safety. DLT monitoring period was 28 days. Tumor response (RECIST 1.1; in non-irradiated lesions) was evaluated every 8 weeks. Results: As of Feb 2016, 58 pts (median age 57.5 yrs, 57% male) have been treated in the dose escalation/safety confirmation portion of study: 18 at 1 mg/kg REGN2810 (mono: n= 6; with RT: n=12); 34 at 3 mg/kg (mono: n=6: with RT: n=12; with CTX: n=6; with RT+CTX: n=10); and 6 at 10 mg/kg alone. There were no DLTs. The most common drug-related adverse events were fatigue (n=14,24.1%), arthralgias (n=7,12.1%), nausea (n=6,10.3%), influenza like illness and rash (each n=5, 8.6%). Drug related adverse events ≥ grade 3 were transaminase elevation (n = 2), anemia (n=1), and anti Hu associated paraneoplastic encephalitis (n=1). Ongoing PK analyses indicate that steady-state is reached within 8 doses of q2W dosing with 2-3 fold accumulation. 43 pts were evaluable for response. Partial/unconfirmed partial responses (uPR) were seen in 9/22 (40.9%) pts who received hfRT and in 2/21(9.5%) pts who received monotherapy. 27/43 (62.8%) pts had disease control (CR/PR/uPR/SD). Multiple expansion cohorts are evaluating REGN2810 at the recommended dose of 3 mg/kg q 2 weeks combined with hfRT and other anti-tumor regimens. Conclusions: REGN2810 has been well-tolerated to date. Responses appear augmented when hfRT is added to REGN2810, suggesting abscopal effects. Clinical trial information: NCT02383212.
Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma
Authors: Daoxiang Zhang, Lin Li, Hongmei Jiang, Brett L. Knolhoff, Albert C. Lockhart, Andrea Wang-Gillam, David G. DeNardo, Marianna B. Ruzinova, Kian-Huat Lim
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC. Experimental Design: We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cells in vitro and in vivo. Results: p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Conclusions: Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. Clin Cancer Res; 23(7); 1748–59. ©2016 AACR.
Increased protoporphyrin IX accumulation does not improve the effect of photodynamic therapy for actinic keratosis: a randomized controlled trial
Authors: C.V. Nissen, I.M. Heerfordt, S.R. Wiegell, C.S. Mikkelsen, H.C. Wulf
Journal: British Journal of Dermatology (2016)

Photodynamic therapy (PDT) with methyl aminolaevulinate (MAL) is highly effective for treating actinic keratosis (AK) on the face/scalp, but less effective on the extremities. Insufficient accumulation of protoporphyrin IX (PpIX) may cause these inferior efficacy rates. However, it is possible to increase PpIX accumulation by extending the MAL application time and/or pretreating the skin with curettage. To investigate whether increased PpIX accumulation improves the effect of MAL‐PDT for AKs in a randomized intra‐individual study. Twenty‐two patients with 533 AKs on both hands were treated with MAL‐PDT. To obtain different concentrations of PpIX, four symmetrical areas on each patient were randomly allocated to different regimens: (i) 3‐h MAL application without prior curettage (3hC−); (ii) 3 h with curettage (3hC+); (iii) 21 h without curettage (21hC−); and (iv) 21 h with curettage (21hC+). Treatment efficacy was evaluated after 3 months, whereas PpIX fluorescence, pain and erythema were assessed during and after PDT. Extended MAL application with and without curettage increased PpIX accumulation significantly compared with the standard 3hC+ regimen (P = 0·001 and P = 0·002, respectively). However, the median total clearance rates did not improve accordingly: 3hC+ (55·0%), 21hC− (55·0%) and 21hC+ (53·6%). Conversely, insufficient PpIX accumulation in the 3hC− regimen led to a significantly lower clearance rate (33·3%) than the other regimens (P < 0·045). Furthermore, pain and erythema were correlated to PpIX accumulation. Increased PpIX accumulation does not improve the effect of MAL‐PDT for AKs on the hands, but leads to worse adverse events. Different strategies are needed to improve PDT on the extremities.
miR-125b controls monocyte adaptation to inflammation through mitochondrial metabolism and dynamics
Authors: Isabelle Duroux-Richard, Christine Roubert, Meryem Ammari, Jessy Présumey, Joachim R. Grün, Thomas Häupl, Andreas Grützkau, Charles-Henri Lecellier, Valérie Boitez, Patrice Codogno, Johanna Escoubet, Yves-Marie Pers, Christian Jorgensen, Florence Apparailly
Journal: Blood (2016)
Prescription Trends—Brand-Name Drugs vs Generic—Reply
Authors: Aaron S. Kesselheim, Joshua J. Gagne
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
BRCA1 mRNA expression in patients (p) with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy
Authors: A. Font, M. Tarón, C. Costa, L. Layos, L. Pérez-Roca, J. Sánchez, I. Chaib, M. Mora, J. Gago, R. Rosell
Journal: Journal of Clinical Oncology (2008)

5021 Background: In p with locally-advanced bladder cancer, neoadjuvant chemotherapy followed by cystectomy improves survival compared to surgery alone, especially in p attaining a pathological response (pT0–1N0M0). However, at present no clinical markers are available to predict response to chemotherapy in bladder cancer. BRCA1 mRNA expression has been associated with chemosensitivity and survival in lung and ovarian cancer p (Taron et al. 2004; Quinn et al. 2007) and could be a useful predictive marker in bladder cancer as well. Methods: We analyzed BRCA1 mRNA expression by quantitative PCR in tumor biopsies obtained by transurethral resection from 51 p with locally-advanced bladder cancer. 44 p were clinically staged as cT3–4N0M0, 5 p had regional lymph nodes (cTxN+), and 2 p had distant lymph nodes. 35 p received cisplatin, methotrexate plus vinblastine; 16 p were treated with gemcitabine plus cisplatin. Results: After a median of 3 cycles of chemotherapy, cystectomy was performed in 49 p (96%). A significant pathological response (pT0 or T1) was attained in 25 p (50%). A close correlation was found between BRCA1 levels and pathological response. 21 p (65%) with low/intermediate BRCA1 levels but only 4 p (26%) with high BRCA levels obtained a pathological response (P=0.01). Median disease-free survival (DFS) was 120 months (m) in 17 p with low BRCA1 levels, 184 m in 17 p with intermediate BRCA1 levels, and only 14 m in 17 p with high BRCA1 levels (P=0.02). In the multivariate analysis of DFS, only BRCA1 levels and lymphatic invasion emerged as independent prognostic markers (table). Conclusions: Low levels of BRCA1 can predict response to neoadjuvant cisplatin-based chemotherapy and longer DFS in p with bladder cancer. Clinical trials of customized chemotherapy based on BRCA1 levels are warranted. The prognostic role of BRCA1 in p with bladder cancer merits further investigation. Hazard Ratio 95% CI p BRCA1 mRNA levels Low 1 (ref.) Intermediate 1.16 0.4–3.36 0.77 High 3.1 1.15–8.40 0.02 Lymphatic invasion Yes 7.8 2.54–23.90 <0.0001 No 1 (ref.) No significant financial relationships to disclose.
P3.03-045 Treatment of Malignant Pleural Mesothelioma beyond First-Line among Hispanics (MeSO-CLICaP)
Authors: Luis Corrales, Andrés Cardona, Oscar Arrieta, George Oblitas, Leonardo Rojas, Ludwing Bacon, Claudio Martin, Beatriz Wills, Mauricio Cuello, Luis Alberto Mas Lopez, Carlos Vargas, Hernan Carranza, Jorge Otero, Maria Perez, Lisde González, Luis Chirinos, Pilar Archila, Rafael Rosell
Journal: Journal of Thoracic Oncology (2017)
Mutant IDH1 Expression Drives <i>TERT</i> Promoter Reactivation as Part of the Cellular Transformation Process
Authors: Shigeo Ohba, Joydeep Mukherjee, Tor-Christian Johannessen, Andrew Mancini, Tracy T. Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E. Marshall, Pavithra Viswanath, Kyle M. Walsh, Arie Perry, Robert J.A. Bell, Joanna J. Phillips, Joseph F. Costello, Sabrina M. Ronen, Russell O. Pieper
Journal: Cancer Research (2016)

Abstract Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo. Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680–9. ©2016 AACR.
GP leader attacks CCGs for £30m underspend
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

The chair of the Royal College of General Practitioners has lambasted those in charge of transforming primary care in England for failing to lay down plans to improve services for patients.

Maureen Baker described clinical commissioning groups (CCGs) as a “national disgrace” for underspending their budgets by more than £30m ($38m; €34m) and ignoring the needs of primary care. She also attacked those in charge of the NHS’s new sustainability and transformation plans (STPs) for marginalising general practice and diverting funds to plug the deficits in acute care hospital trusts.

Speaking at the royal college’s annual conference in Harrogate, Yorkshire, on 6 October, Baker said that an analysis by the college had found that CCGs were on course …
Long term follow up of survival in a randomised trial of wide or narrow excision margins in high risk primary melanoma.
Authors: Andrew J Hayes, Lauren Maynard, Roger A'Hern, Gillian Coombes, Julia Newton-Bishop, Michael Timmons, Martin Cook, Jeffery Theaker, Judith Bliss, Joseph Meirion Thomas
Journal: Journal of Clinical Oncology (2015)

9001 Background: Our randomized trial of 1 versus 3 cm clinical excision margins for high risk melanoma showed that narrow margins were associated with an increase in loco-regional relapse, but with no significant difference in melanoma-specific survival (MSS). We now report long-term melanoma-specific and overall survival from that trial. Methods: Patients with primary cutaneous melanoma two mm or more in Breslow thickness were randomized to a 1 or 3 cm excision. Results: Four hundred and fifty-three patients were randomized to a 1 cm margin and 447 patients to a 3 cm margin. Median age was 58.7 (IQR 47.2-69.2), median tumour thickness and percentage ulceration were similar in both groups (1 cm group: 3.0 mm and 31.8%, 3 cm group: 3.1 mm and 34.5%) . At a median follow-up of 8.8 years (IQR 6.3-11.3), 494 patients have died, with 359 of these deaths from melanoma. There were 194 melanoma deaths in the 1 cm group and 165 in the 3 cm group. Relative rate of melanoma death was estimated to be 24% higher in the 1 cm group than the 3 cm group on univariable analysis (hazard ratio (HR) 1.24; 95% confidence interval (CI) 1.00 to 1.52; p = 0.05). This effect was similar in multivariable analysis, adjusting for known prognostic factors (table).While there was an increase in the number of overall deaths in the 1 cm group compared to the 3 cm group (253 versus 241), this difference was not statistically significant in univariable analysis (HR 1.14: 95% CI 0.96 to 1.36, p = 0.14). Conclusions: With longer follow up, the previously reported increase in loco-regional relapse associated with narrow excision margins has translated into a significant increase in melanoma specific mortality. Overall Survival Melanoma-Specific Survival N (%) HR (95% CI) p value HR (95% CI) p value Margin 3cm 387 (50.2) 1.00 1.00 1cm 384 (49.8) 1.19 (0.99-1.45 ) 0.07 1.27 (1.02-1.59) 0.036 Sex Female 419 (54.3) 1.00 1.00 Male 352 (45.7) 1.38 (1.11-1.71) 0.003 1.38 (1.07-1.17) 0.013 Thickness 771 (100) 1.18 (1.10-1.27) < 0.001 1.23 (1.13-1.3) < 0.001 Ulceration Absent 475 (61.6) 1.00 Present 296 (38.4) 1.68 (1.38-2.04) < 0.001 1.75 (1.39-2.20) < 0.001 Site Distal limb 244 (31.6) 1.00 1.00 Proximal limb 173 (22.4) 1.23 (0.93-1.63) 0.03 1.44 (1.03-2.03) 0.003 Trunk 354 (45.9) 1.41 (1.09-1.81) 1.69 (1.24-2.29)
United Kingdom back pain exercise and manipulation (UK BEAM) randomised trial: cost effectiveness of physical treatments for back pain in primary care
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To assess the cost effectiveness of adding spinal manipulation, exercise classes, or manipulation followed by exercise ("combined treatment") to "best care" in general practice for patients consulting with low back pain. <b>Design</b> Stochastic cost utility analysis alongside pragmatic randomised trial with factorial design. <b>Setting</b> 181 general practices and 63 community settings for physical treatments around 14 centres across the United Kingdom. <b>Participants</b> 1287 (96%) of 1334 trial participants. <b>Main outcome measures</b> Healthcare costs, quality adjusted life years (QALYs), and cost per QALY over 12 months. <b>Results</b> Over one year, mean treatment costs relative to "best care" were £195 ($360; €279; 95% credibility interval £85 to £308) for manipulation, £140 (£3 to £278) for exercise, and £125 (£21 to £228) for combined treatment. All three active treatments increased participants9 average QALYs compared with best care alone. Each extra QALY that combined treatment yielded relative to best care cost £3800; in economic terms it had an "incremental cost effectiveness ratio" of £3800. Manipulation alone had a ratio of £8700 relative to combined treatment. If the NHS was prepared to pay at least £10 000 for each extra QALY (lower than previous recommendations in the United Kingdom), manipulation alone would probably be the best strategy. If manipulation was not available, exercise would have an incremental cost effectiveness ratio of £8300 relative to best care. <b>Conclusions</b> Spinal manipulation is a cost effective addition to "best care" for back pain in general practice. Manipulation alone probably gives better value for money than manipulation followed by exercise.
CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer.
Authors: Andrew Louis Himelstein, Rui Qin, Paul J. Novotny, Drew K. Seisler, James L. Khatcheressian, John D. Roberts, Stephen S. Grubbs, Tracey O'Connor, Douglas Weckstein, Charles L. Loprinzi, Charles L. Shapiro
Journal: Journal of Clinical Oncology (2015)

9501 Background: Zoledronic acid (ZA) given monthly for 24 months (mo) reduces bone pain and skeletal-related events (SRE) in patients (pts) with bone metastases. We tested whether ZA every 3 mo would be non-inferior to monthly for 24 mo, with less toxicity, in a randomized trial in 1822 pts: breast (n = 833), prostate (n = 674), myeloma (n = 270), and other (n = 45). Methods: SRE were defined as radiation therapy (RT) to bone, fractures, spinal cord compression or surgery to bone within 24 mo. ZA doses were adjusted for creatinine clearance. The primary endpoint was the proportion of pts in each group who had ≥ 1 SRE; secondary endpoints included skeletal morbidity rates, performance status, pain using the Brief Pain Inventory, and incidences of jaw osteonecrosis and renal dysfunction. The trial design was non-inferiority (NI) with stratification and pre-planned analyses by disease. The NI margin was 7% absolute difference. With 1,230 pts (planned sample size 1758 with 30% allowance for inevaluable pts), the power was > 82% when the NI margin was < 0 using a 1-sided test at a 5% significance level. Results: Between May 1, 2009 and April 13, 2012, 1822 pts were randomized. Baseline characteristics of the 2 groups were comparable. Dose delays were more common with ZA monthly. The 2-year cumulative incidences of SRE and selected toxicities are presented in the Table. The proportions of SRE were 29.5% vs 28.6% (95% CI for margin: -3.3% to 5.1%, Cochran-Maentel-Hanzel p = 0.79) for monthly and every 3 mo, respectively. Conclusions: ZA administered every 3 mo is non-inferior to ZA administered monthly for 24 mo in breast cancer, prostate cancer and multiple myeloma. Bone turnover markers in a subset of pts and a cost analysis will be presented. Clinical trial information: NCT00869206. Q Month N = 911 Q 3 Months N = 911 HR (P-value) Total ZA dose (median) 56 mg 24 mg — ( < 0.01) Dose delays 62% 37% — ( < 0.01) Any SRE 260 253 1.05 (0.60) Any SRE – breast pts (N = 820) 113 119 0.90 (0.43) Any SRE – prostate pts (N = 660) 107 101 1.15 (0.31) Any SRE – myeloma pts (N = 265) 35 30 1.30 (0.29) Bone RT 185 163 1.16 (0.18) Bone fractures 62 79 0.78 (0.13) Spinal cord compression 23 30 0.75 (0.30) Bone surgery 22 42 0.51 (0.01) Jaw osteonecrosis 18 9 — (0.08) Grade 2-4 creatinine increase 11 5 — (0.46)
Could the neutrophil to lymphocyte ratio be a poor prognostic factor for lung cancers?
Authors: Turgut Kacan, Nalan Babacan, Mehmet Metin Seker, Birsen Yucel, Aykut Bahceci, Mustafa Asim Gedikli, Saadettin Kilickap
Journal: Journal of Clinical Oncology (2014)

e19145 Background: Although many prognostic factors have been identified for lung cancers, new ones are needed to determine the course of the disease. Recently, high neutrophil to lymphocyte ratio prior to surgery or treatment has been shown to be an indicator of prognosis for cancer. The aim of this study is to investigate the value of blood neutrophil to lymphocyte ratio as a prognostic factor in non small cell lung cancer patients prior to treatment. Methods: Patients data who were diagnosed with non-small cell lung cancer in our institution were retrospectively reviewed. Demographic and clinicopathologic characteristics of the patients were recorded. Neutrophil to lymphocyte ratios were calculated before the application of any treatment. Results: A total of 299 patients, 270 (90%) males and 29 (10%) females, were included in the study. There was a positive correlation between the ECOG performance status and neutrophil to lymphocyte ratio (p = 0.001). No significant correlation was calculated between patients’ gender, disease stage, the presence of anemia, histopathologic type, lactate dehydrogenase and carcinoembryonic antigen levels. A positive correlation had observed between the C-reactive protein levels and neutrophil to lymphocyte ratio (r = 0.33, p = 0.016). Median overall survival was 13.2 months in patients whose NLR was <5 and 6.3 months whose NLR was ≥5. ECOG performance status (p <0.001), high lactate dehydrogenase (p <0.001), the presence of anemia at diagnosis (p <0.001) and neutrophil to lymphocyte ratio ≥ 5 (p = 0.029) were found to be the prognostic factors for survival. Conclusions: Prior to treatment,high neutrophil to lymphocyte ratio may be a prognostic factor for non-small cell lung cancer.