tbuckley/cabot-search huggingface dataset:
Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment–Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction])
Authors: Sivabaskari Pasupathy, Rosanna Tavella, Suchi Grover, Betty Raman, Nathan E.K. Procter, Yang Timothy Du, Gnanadevan Mahadavan, Irene Stafford, Tamila Heresztyn, Andrew Holmes, Christopher Zeitz, Margaret Arstall, Joseph Selvanayagam, John D. Horowitz, John F. Beltrame
Journal: Circulation (2017)

Background: Contemporary ST-segment–elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. Methods: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging–assessed infarct size. Secondary end points included cardiac magnetic resonance–determined myocardial salvage and creatine kinase kinetics. Results: Of 112 randomized patients with ST-segment–elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance–assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P =0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37–79) compared with placebo (27%; interquartile range, 14–42; P &lt;0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively ( P =0.08). Conclusions: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/ . Unique identifier: 12610000280000.
Prevalence of homologous recombination deficiency among all tumor types.
Authors: Arielle Lutterman Heeke, Tabari Baker, Filipa Lynce, Michael J. Pishvaian, Claudine Isaacs
Journal: Journal of Clinical Oncology (2017)

1502 Background: Triple negative breast and ovarian cancer are known to have a high frequency of homologous recombination deficiencies (HRDef). The prevalence of HRDef among all tumors is unknown. Methods: Molecular profiles of 48,733 tumors obtained from pts with bladder, breast, ovarian, pancreas, prostate, thyroid, cervical, hepatobiliary, colorectal (CRC), endometrial, gastric/esophageal (GE), head/neck, renal, non-small cell lung (NSCLC), small cell lung (SCLC), GIST, glioma, melanoma, sarcoma and unknown 1° cancers were reviewed to identify somatic pathogenic mutations (mut) in HR genes ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, or WRN. Molecular profiles were generated from tumors submitted to Caris Life Sciences using multiple technologies including next generation sequencing (average read depth 500X). Results: Overall frequency of HR mut among all tumors is 11.61% (5658/48733). Cancer lineages with highest frequency of HR mut are endometrial (38.08%, 1956/5137), glioma (15.90%, 265/1667), ovarian (12.99%, 1151/8862), prostate (11.21%, 77/687), cervix (10.06%, 79/785) &amp; breast (9.66%, 562/5818). Least commonly mutated lineages include GIST (1.50%, 3/200), sarcoma (3.12%, 55/1763), head/neck (3.70%, 24/648), hepatobiliary (4.72%, 39/827) &amp; pancreas (5.05%, 102/2022). Frequencies of HR gene mutations are depicted in Table 1. Conclusions: HR mutations were seen in 11.61% of tumors. While the percentage of HRDef in pancreatic cancer pts is lower than what has been seen in other datasets, the percentage in breast and ovarian cancer, as well as the percentage of other tumors with HRDef, provide a path to employ HRDef-directed therapies such as platinums, but especially PARP inhibitors and newer agents such as ATRX inhibitors. [Table: see text]
Suitability factors of core needle biopsies for pharmacodynamic (PD) studies.
Authors: Ralph E. Parchment, Katherine Ferry-Galow, Hala R. Makhlouf, Brad J. Wood, Elliott B. Levy, Venkatash P. Krishnasamy, Richard Chang, Geraldine H. O'Sullivan Coyne, Robert S. Meehan, Robert J. Kinders, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2017)

2540 Background: There are different requirements of biopsies for diagnosis vs. pharmacologic evaluation of drug mechanism biomarkers. Evaluation of core needle biopsy pairs collected pre-dose and at a defined timepoint post-dose provides insight into the pharmacodynamics of agents in early development. Adequate biopsies are key for quantifying response of the tumor cell population to molecular drug action. Tumor heterogeneity and variable tumor content make many biopsy pairs unsuitable for biomarker evaluation with any assay platform (microscopy, immunoassay, etc.). We analyzed biopsies obtained from the Developmental Therapeutics Clinic (DTC) for suitability for PD assays. Methods: Specimens obtained from 2010-2016 across 4 trials were analyzed. For microscopy measurements, biopsy pairs collected using image guidance are snap-frozen, thawed under fixative, and embedded in paraffin with control tissues. The likelihood of finding optimal regions for analysis is maximized by preparing a series of sections with H&amp;E stained flanking slides, and annotation by an anatomic pathologist. Results: Of 112 biopsies evaluated, 26% were found to contain &lt; 5% tumor, making them inadequate for quantitative microscopy due to a mixture of factors, with the primary factor being predominantly non-neoplastic tissue, followed by extensive mucin content, necrosis, fibrosis, inadequate size and tissue artifact post-collection. Another 20% contained ≤25% tumor, and in this group, tumor segmentation methodology during image analysis increased the rate of evaluable biopsies. 56% of tissues had &gt; 25% tumor and were suitable for analysis. Conclusions: Improved communication between oncologists, radiologists and pathologists is key to a better understanding of factors that affect suitability of biopsies for robust PD biomarker analyses. NCI’s DTC has implemented protocol modifications including increased tissue collection and frequent case reviews by the Phase 1 team, interventional radiologists and PD team aimed at understanding features during image guidance that relate to suitability. Implementation of a scoring system has allowed the assessment of suitability of biopsies for analysis. Funded by NCI Contract No HHSN261200800001E.
Breast cancer recurrence in older patients with clinically node-negative T1-T2 tumors managed without sentinel node biopsy (SNB) and without adjuvant radiation therapy.
Authors: Mervat Nabil Saleh, Bachir Joseph Sakr, Sabrina M. Witherby, Adam J. Olszewski, William M. Sikov
Journal: Journal of Clinical Oncology (2015)

528 Background: Older patients (pts) with small breast cancers who receive endocrine therapy can omit radiation without a survival disadvantage. SNB adds additional burden and may not be necessary for pts who are not planning adjuvant radiation or chemotherapy. The objective of our study was to evaluate recurrence rate with or without SNB in those pts. Methods: We retrospectively reviewed records of pts ≥ 60 years (y) old, diagnosed at our center between 2000 and 2014 with T1-T2, clinically node-negative, estrogen receptor-positive breast cancer, who did not receive adjuvant radiation or chemotherapy. We used Fisher’s exact test to compare characteristics, and Gray’s test for cumulative incidence function (CIF) for cancer recurrence, with 95% confidence intervals. Results: We identified 364 pts. Those managed without SNB were significantly older, more often with apocrine, mucinous or papillary histology and less likely to undergo mastectomy, with no significant differences in other characteristics. There were 5 recurrences (4 local, 1 axillary) in pts without SNB and 16 (11 local, 2 axillary, 3 distant) with SNB. CIF for recurrence at 5 years was 4.8% (CI, 2.6-8.0) for all pts, 6.6% (CI, 1.7-16.3) without SNB and 4.3% (CI, 2.1-7.8) with SNB, not significantly different (P = .80). Positive SNB (in 12%) was not prognostic for recurrence (P = 0.94). CIF for death from competing causes was twice as high in pts without SNB (24.6 vs 11.1%, P = .0001), resulting in lower overall survival (77.5 vs 89.3%). Conclusions: Overall recurrence rate was similar to prior clinical trials. Pts selected for management without SNB have a high risk of death from non-cancer causes, which reflects their advanced age and comorbidities, but they experience no significant increase in the risk of recurrence. Our results, if confirmed in a larger dataset, suggest that SNB does not provide useful prognostic information in older pts who are not planning multimodality adjuvant therapy, and could be omitted. SNB N Median age Low-risk histology High grade HER2- positive LVI† Mastec- tomy Positive margin Yes 283 73 7% 14% 6% 13% 39% 3% No 81 82 * 21% * 10% 3% 7% 7% * 5% * P< .001; † Lymphovascular invasion
Conjugate Vaccine Immunotherapy for Substance Use Disorder
Authors: Paul T. Bremer, Kim D. Janda
Journal: Pharmacological Reviews (2017)

Substance use disorder, especially in relation to opioids such as heroin and fentanyl, is a significant public health issue and has intensified in recent years. As a result, substantial interest exists in developing therapeutics to counteract the effects of abused drugs. A promising universal strategy for antagonizing the pharmacology of virtually any drug involves the development of a conjugate vaccine, wherein a hapten structurally similar to the target drug is conjugated to an immunogenic carrier protein. When formulated with adjuvants and immunized, the immunoconjugate should elicit serum IgG antibodies with the ability to sequester the target drug to prevent its entry to the brain, thereby acting as an immunoantagonist. Despite the failures of first-generation conjugate vaccines against cocaine and nicotine in clinical trials, second-generation vaccines have shown dramatically improved performance in preclinical models, thus renewing the potential clinical utility of conjugate vaccines in curbing substance use disorder. This review explores the critical design elements of drug conjugate vaccines such as hapten structure, adjuvant formulation, bioconjugate chemistry, and carrier protein selection. Methods for evaluating these vaccines are discussed, and recent progress in vaccine development for each drug is summarized.
Traitement endoscopique des sténoses digestives néoplasiques par pose de prothèse métallique auto-expansible avec l'aide d'un overtube
Authors: E Samalin, E Assenat, P Bauret, P Senesse
Journal: Endoscopy (2006)

Evaluer la faisabilité et l'efficacité clinique de la pose endoscopique de prothèses métalliques de type „Wallstent“ à l'aide d'un overtube dans le traitement des sténoses digestives néoplasiques.
Outcomes in Women With Cytology Showing Atypical Squamous Cells of Undetermined Significance With vs Without Human Papillomavirus Testing
Authors: Jack Cuzick, Orrin Myers, Ji-Hyun Lee, Yang Shi, Julia C. Gage, William C. Hunt, Michael Robertson, Cosette M. Wheeler
Journal: JAMA Oncology (2017)

<h3>Importance</h3> Little is known about the long-term yield of high-grade cervical intraepithelial neoplasia (CIN) and the influence on biopsy and treatment rates of human papillomavirus (HPV) triage of cytology showing atypical squamous cells of undetermined significance (hereafter ASC-US cytology). <h3>Objective</h3> To examine 5-year outcomes after ASC-US cytology with vs without HPV testing. <h3>Design, Setting, and Participants</h3> In this observational study, all cervical cytology and HPV testing reports from January 1, 2007, to December 31, 2012, were obtained for women throughout New Mexico and linked to pathology reports. The dates of the analysis were May 4, 2015, to January 13, 2017. <h3>Main Outcomes and Measures</h3> Influence of HPV testing on disease yield, time to histologically confirmed disease, and biopsy or loop electrosurgical excision procedure rates. <h3>Results</h3> A total of 457 317 women (mean [SD] age, 39.8 [12.5] years) with a screening test were recorded between 2008 and 2012, and 20 677 (4.5%) of the first cytology results per woman were reported as ASC-US. CIN grade 3 or more severe (CIN3+) lesions were detected in 2.49% of women with HPV testing vs 2.15% of women without HPV testing (<i>P</i> = .23). Time to CIN3+ detection was much shorter in those with HPV testing vs those without testing (median, 103 vs 393 days;<i>P</i> &lt; .001). CIN grade 1 was detected in 11.6% of women with HPV testing vs 6.6% without testing (relative risk, 1.76; 95% CI, 1.56-2.00;<i>P</i> &lt; .001). Loop electrosurgical excision procedure rates within 5 years were 20.0% higher in those who underwent HPV testing, resulting in more CIN2+ and CIN3+ detection. <h3>Conclusions and Relevance</h3> Human papillomavirus testing led to faster and more complete diagnosis of cervical disease, but 55.8% more biopsies and 20.0% more loop electrosurgical excision procedures were performed. In those tested, virtually all high-grade disease occurred in the 43.1% of women who were HPV positive, allowing clinical resources to be focused on women who need them most. These data provide essential information for cervical screening guidelines and public health policy.
Fréquence des lésions néoplasiques colorectales omises lors de la vidéocoloscopie en 2005: résultats d'une étude prospective multicentrique par doubles coloscopies réalisées par 2 opérateurs différents dans un ordre aléatoire
Authors: D Heresbach, MG Lapalus, T Barrioz, D Coumaros, P Bauret, P Potier, D Sautereau, C Boustière, JC Grimaud, J See, C Barthélémy, PN d'Halluin, I Serraj, B Branger, T Ponchon
Journal: Endoscopy (2006)

La coloscopie est l'examen de base pour le dépistage des lésions précancéreuses colorectales mais plusieurs études ont suggéré que sa sensibilité n'était pas parfaite: 9–24% des adénomes et 0–6% des adénomes ≥1cm n'étaient pas visualisés lorsque 2 coloscopies étaient réalisées le même jour. Il est nécessaire de confirmer ce résultat en évitant les biais de ces études (2 fois le même endoscopiste, recrutement monocentrique, endoscopie par fibre optique) avant de proposer le recours systématique à d'autres explorations; chromoendoscopie, autofluorescence, coloscopie virtuelle. Le but de cette étude est de déterminer la valeur prédictive négative de la vidécoloscopie en 2005.
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations.
Authors: Mallika Sachdev Dhawan, Imke Heleen Bartelink, Rahul Raj Aggarwal, Jim Leng, Robin Kate Kelley, Michelle E. Melisko, Charles J. Ryan, Scott Thomas, Pamela N. Munster
Journal: Journal of Clinical Oncology (2017)

2527 Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value &lt; 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874.
Spotlight on measles 2010: A measles outbreak in a Roma population in Pulawy, eastern Poland, June to August 2009
Authors: H Orlikova, J Rogalska, E Kazanowska-Zielinska, T Jankowski, J Slodzinski, B Kess, P Stefanoff
Journal: Eurosurveillance (2010)

We describe a local indigenous outbreak of measles in a susceptible Roma community, which occurred in Pulawy, a town of 50,000 citizens in the Lubelskie province (eastern Poland) during summer 2009. From 22 June to 30 August 2009, 32 measles cases were reported, and additionally nine possible cases were actively identified. A mass immunisation campaign was organised to stop measles transmission in the Roma community. Active surveillance of rash-febrile illnesses allowed documentation of the impact of mass immunisation in preventing further measles spread in the Roma community, and the surrounding population of Pulawy.
FRI0137 Presence of thyroid disease in rheumatoid arthritis patients is predictor of worse initial treatment response: an observational, cohort study
Authors: A Emamifar, R Hviid Larsen, R Asmussen Andreasen, IM Jensen Hansen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid Arthritis (RA) should be treated instantly to prevent further joint destruction. The first few months after treatment initiation are critical for long-term treatment outcome.[1]Patients with RA are at increased risk of thyroid disease with direct effect on initial treatment response.[2] <h3>Objectives</h3> To define the prevalence of thyroid disease among RA patients as well as to evaluate the correlation between presence of thyroid disease in RA patients and initial treatment response. <h3>Methods</h3> All RA patients who were registered in the local part of Danish Danbio registry were included in this study. Patients9 demographic data, serology results including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-ccp) as well as disease activity score in 28 joints-C-reactive protein (DAS28-CRP) at the time of diagnosis and after 4 months (±1–2 months) of treatment initiation were extracted. ΔDAS28 was calculated as follows: DAS28 at the time of diagnosis – DAS28 after 4 months (±1–2 months) of treatment initiation. Patients9 electronic hospital records including laboratory results were reviewed to reveal if they had been diagnosed with thyroid disease. <h3>Results</h3> 1035 patients were included in the study (Table 1). Prevalence of thyroid disease was 11.8% (122/1035). Multiple linear regression analysis showed a negative correlation between ΔDAS28 and presence of thyroid disease adjusted for age, gender, disease duration, RF, anti-ccp and DAS28 at the time of diagnosis (Regression coefficient (95% Confidence Interval): -0,157 (-0.312 to -0.002), P=0.047) (Table 2). RA patients with thyroid disease had significantly poorer initial response to RA treatment compared to patients with isolated RA after 4 months of treatment (P=0.002). <h3>Conclusions</h3> Presence of thyroid disease in RA patients worsens initial treatment response and is suggestive of poor long-term prognosis. The authors propose routine measurement of serum thyroid stimulating hormone (TSH) in all RA patients at the time of diagnosis and with yearly interval. <h3>References</h3> Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388:2023–2038. doi: 10.1016/S0140–6736(16)30173–8. Joshi P, Agarwal A, Vyas S, et al. Prevalence of hypothyroidism in rheumatoid arthritis and its correlation with disease activity. Trop Doct 2017;47:6–10. <h3>Acknowledgements</h3> We thank Mrs. Maryam Mousavi for her contribution to data collection. <h3>Disclosure of Interest</h3> None declared
Multi-gene hereditary cancer testing among men with breast cancer.
Authors: Krystal Brown, Gregory Sampang Calip, Ryan Bernhisel, Brent Evans, Eric Thomas Rosenthal, Jennifer Saam, Johnathan Lancaster, Kent Hoskins
Journal: Journal of Clinical Oncology (2017)

1532 Background: All men with a personal diagnosis of breast cancer (BC) are candidates for BRCA1/2 genetic testing, as pathogenic variants (PVs) in these genes have a known association with BC risk in both men and women. As additional genes with known BC risk in women are now routinely included in multi-gene panel testing, we evaluated the outcomes of multi-gene panel testing in a large cohort of men with BC. Methods: This analysis includes the results of commercial genetic testing for 1,358 men with BC usinga multi-gene pan-cancer panel between September 2013 and January 2017. Clinical information was obtained from provider-completed test request forms. Age at diagnosis, personal, and family history were compared for men with PVs in BRCA1/2 versus non- BRCA1/2 genes. Results: Overall, 207 (15.2%) men with BC were found to carry a PV, where 147 (10.8%) men had a PV in BRCA1/2 ( BRCA1, 0.7%; BRCA2, 10.2%) and 60 (4.4%) men had a PV in a non- BRCA1/2 gene ( CHEK2, 2.0%; ATM, 1.0%; PALB2, 1.0%; BARD1, 0.2%; NBN, 0.2%; MSH6, 0.1%; BRIP1, 0.1%; CDH1, 0.1%; CDKN2A, 0.1%; MLH1, 0.1%, TP53, 0.1%). There were no substantial differences in the median age-at-diagnosis for men without a PV (65) compared to those with a BRCA1/2 PV (66) or a non- BRCA1/2 PV (63). Prostate cancer was the most common additional malignancy among all men with BC (9.0%), with a similar incidence among men with a BRCA1/2 PV (9.2%) and a non- BRCA1/2 PV (8.3%). In addition, 1.4% of men with a BRCA1/2 PV and 3.3% of men with a non- BRCA1/2 PV had a second BC. A family history of breast and/or ovarian cancer was present in 44.4% of the testing cohort, 66.7% of men with a BRCA1/2 PV, and 48.3% of men with a non- BRCA1/2 PV. This is consistent with the relative penetrance of BRCA1/2 and other genes included here. There were no other substantial differences in family history among BRCA1/2 PV carriers versus non- BRCA1/2 PV carriers. Conclusions: Close to a third of all PVs identified here in men with BC were in a gene other than BRCA1/2. There were no obvious differences in the clinical presentation of men with a BRCA1/2 PV compared to men with a PV in another gene or no PV at all. Collectively, this suggests that multi-gene panel testing is appropriate for all men with BC, regardless of other personal or family history.