tbuckley/cabot-search huggingface dataset:
Utility of CA 27.29 levels at the time of breast cancer diagnosis.
Authors: Pamela Li, Sarah Patricia Cate, David Lucido, Stephen C. Malamud, Paula Klein, Manjeet Chadha, Efat Azizi, Theresa Shao, Alyssa Gillego, Susan K. Boolbol
Journal: Journal of Clinical Oncology (2014)

e22189 Background: CA 27.29 is a marker associated with the MUC-1 gene, which codes for a mucin glycoprotein found to be overexpressed in breast cancer. CA 27.29 has been used in the early detection of recurrent disease and in monitoring the efficacy of treatment in advanced disease. CA 27.29 is not routinely used at the time of breast cancer diagnosis. In this study, we sought to correlate preoperative CA 27.29 levels with various clinical and pathological variables to determine its utility at the time of breast cancer diagnosis. Methods: In this IRB approved retrospective study, we identified 183 new breast cancer patients diagnosed at our institution between November 2011 and December 2013 for whom preoperative CA 27.29 levels were known. Various demographic and clinical variables including age at diagnosis, ethnicity, menopausal status, preoperative CA 27.29 level, tumor size, nodal status, and hormonal status were reviewed. We compared mean CA 27.29 levels for each variable with a student’s T test or single factor analysis of variance (ANOVA). We also examined the probability of the mean difference between characteristics present versus absent versus the mean CA 27.29 level. Results: Among the 183 patients identified, the mean age at diagnosis was 58.9 years. Fifty-four patients (29.5%) had positive lymph nodes. CA 27.29 levels ranged from 4.45 Units/mL to 127.6 Units/ml with a mean value of 23.4 Units/mL. Only fifteen of the 183 patients (8.2%) had an elevated preoperative CA 27.29 level, defined as greater than 37.7 Units/mL at our institution. Of those fifteen patients, only four patients had positive lymph nodes and none had any evidence of distant metastatic disease. There were no differences in CA 27.29 levels in regards to tumor size, nodal status, hormone receptor status, age or race. Conclusions: Preoperative CA 27.29 levels are not a significant predictor of pathologic features such as tumor size, axillary lymph node involvement, and hormone receptor status. Although this is a relatively small sample size, we did not find clinical utility in CA 27.29 levels in the preoperative setting. Based on our results, a change in practice for routinely obtaining CA 27.29 level at diagnosis may not be warranted.
Primary versus interval debulking surgery and the risk to induce platinum resitance.
Authors: Alexandre Andre Balieiro Anastacio da Costa, Camila Vieira Valadares, Augusto Saito, Adriana Regina G. Ribeiro, Milena Tariki, Andrea Paiva G. Guimaraes, Solange Sanches, Celso Lopes Mello, Julio Cesar Prestes, Maria Isabel Waddington Achatz
Journal: Journal of Clinical Oncology (2014)

5588 Background: Interval debulking surgery (IDS) is an option to treat patients with stage IIIC and IV ovarian carcinoma. Two randomized trials have shown similar survival for primary debulking sugery (PDS) and IDS. One of the concerns with IDS is the potentialy higher risk to induce platinum resistance when treating patients with larger disease volume. At least one retrospective analysis sugest that patients treated with IDS have a higher risk to develop platinum resistance at second relapse. Methods: We did a retroscpective review of medical records from 213 patients with stage IIIC and IV ovarian carcinoma treated at a single institution from 2000 to 2013. We analysed the association of baseline clinical and pathological characteristics with time to first platinum resistant relapse (TTPR), platinum resitant disease at first relapse, defined as a platinum free interval (PFI) after first line chemotherapy less than 6 months, and overall response rate (ORR) to chemotherapy at first platinum sensitive relapse. Results: For a median follow-up time of 58.6 months, the overall survival was 45.2 months and progression free survival was 18.3 months. Factors related to a shorter TTPR in univariate analysis were residual disease (RD) > 10mm after surgery, CA 125>150 before first treatment (chemotheray or surgery) and IDS compared to PDS. In the multivariate cox regression model including these three variables and age and stage (IIIC vs IV), RD>10mm (HR 1.87, CI95% 1.37-2.44, p<0.001) CA 125>150 (HR 3.39, CI95% 1.31-8.81, p=0.012) and IDS (HR 1.79, CI95% 1.02-3.18, p=0.043) remained associated to a shorter TTPR. The only factor associated to a greater risk of a PFI<6 months at first relapse was RD>10mm (OR 1.59, CI95% 1.14-2.20, p=0.005) and the only factor associated to a worse ORR to chemotherapy at first platinum sensitive relapse was IDS (OR 4.32, CI95% 1.15-16.15, p=0.030. Conclusions: IDS may be associated to a greater risk of platinum resistance induction. Some of the bias in choosing PDS or IDS may not have been accounted in this analysis due to its the retrospective nature, but it supports the hypotesis of other papers and suggests that it would be interesting to see this analysis done in patients from PDS vs IDS clincal trials already published.
Rash and diarrhea with afatinib treatment in metastatic adenocarcinoma lung cancer patients (pts) unselected for epidermal growth factor receptor (EGFR) mutations: Retrospective study.
Authors: Maria Rita Migliorino, Stefano De Santis, Alberto Fulvi, Daniela Soregaroli, Antonio Passaro, Serena Ricciardi
Journal: Journal of Clinical Oncology (2014)

e19165 Background: Afatinib (Gilotrif, Giotrif) is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases. The drug is approved from june 2013 as front-line therapy for patients with NSCLC harboring EGFR mutations. The most common toxicities observed with afatinib are diarrhea, stomatitis and skin rash. The aim of the current study is to investigate the incidence of toxicity in a group of unselected for EGFR mutations patients with advanced NSCLC, treated with afatinib. Methods: We conducted a retrospective observational study of Caucasian patients with advanced lung adenocarcinoma, enrolled in compassionate use and treated with afatinib at the daily dose of 40-30 mg in our centre. We excluded the 50 mg dose according to criteria used in the Lux Lung 1. We analized toxicity profile. The gastrointestinal and cutaneous toxicity was recorded and classified according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0;2009). Results: We analysed 15 patients with adenocarcinoma. with PS 0-1, 5 pts had EGFR mutation, 8 pts were men, median age was 66 ( range 58-72). The pts received Afatinib in second-, third-, fourth-, and fifth-line of therapy. No patient experienced G4 toxicities. Skin rash was observed in 80 % of pts, G1=41%,G2= 34%, G3= 25%. Diarrhea was observed in 87% of pts, G1= 69,2%, G2=23,1%, G3= 7,7%. (value lower than that of LL3). No seriuos events requiring hospitalization were reported. No toxic related death was reported. Conclusions: Afatinib at 40-30 mg dose has a manageable toxicity profile. The absence of G4 toxicity and the low G3 toxicity show the tolerability of the drug. It is important for physicians to know how to manage the toxicity in the best way to exploit the benefit of the drug.
Identification of tumor-specific promoters of Salmonella Typhimurium.
Authors: Nabil Arrach, Ming Zhao, Robert Hoffman, Michael Mcclelland
Journal: Cancer Research (2007)

3294  Salmonella serovar Typhimurium has the ability to preferentially grow in solid tumors relative to normal tissues. We have used a high-throughput method to screen for Typhimurium promoters that are selectively activated in tumors in the mouse. A random library of Typhimurium with DNA cloned upstream of a promoterless GFP was injected into subcutaneous human PC-3 prostate tumorsin nude mice and intravenously into control nude mice. GFP-positive Typhimurium clones from tumor, spleen, liver and in vitro growth in LB, were sorted by fluorescence activated cell sorter (FACS). Active promoters in all environments were amplified by PCR and identified by DNA-microarray hybridization. Among promoters identified as preferentially induced in tumors compared to the other environments (spleen, liver, or in vitro) were at least five genes known to be anaerobically regulated by the Fumarate and Nitrate reduction global regulator (FNR). At least five other genes with unknown regulation were also enriched in tumors. The natural tendency of Typhimurium to target tumors preferentially over other tissues, combined with the use of promoters preferentially induced in the tumor environment versus other environments, may allow the exquisitely specific expression of fusion proteins on the surface of Salmonella or secreted only into the tumor for highly selective tumor therapy.
NHLBI-Sponsored Randomized Trial of Postconditioning During Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction
Authors: Jay H. Traverse, Cory M. Swingen, Timothy D. Henry, Jane Fox, Yale L. Wang, Ivan J. Chavez, Daniel L. Lips, John R. Lesser, Wesley R. Pedersen, Nicholas M. Burke, Akila Pai, Jana L. Lindberg, Ross F. Garberich
Journal: Circulation Research (2019)

Rationale: Postconditioning at the time of primary percutaneous coronary intervention (PCI) for ST-segment–elevation myocardial infarction may reduce infarct size and improve myocardial salvage. However, clinical trials have shown inconsistent benefit. Objective: We performed the first National Heart, Lung, and Blood Institute–sponsored trial of postconditioning in the United States using strict enrollment criteria to optimize the early benefits of postconditioning and assess its long-term effects on left ventricular (LV) function. Methods and Results: We randomized 122 ST-segment–elevation myocardial infarction patients to postconditioning (4, 30 seconds PTCA [percutaneous transluminal coronary angioplasty] inflations/deflations)+PCI (n=65) versus routine PCI (n=57). All subjects had an occluded major epicardial artery (thrombolysis in myocardial infarction=0) with ischemic times between 1 and 6 hours with no evidence of preinfarction angina or collateral blood flow. Cardiac magnetic resonance imaging measured at 2 days post-PCI showed no difference between the postconditioning group and control in regards to infarct size (22.5±14.5 versus 24.0±18.5 g), myocardial salvage index (30.3±15.6% versus 31.5±23.6%), or mean LV ejection fraction. Magnetic resonance imaging at 12 months showed a significant recovery of LV ejection fraction in both groups (61.0±11.4% and 61.4±9.1%; P &lt;0.01). Subjects randomized to postconditioning experienced more favorable remodeling over 1 year (LV end-diastolic volume =157±34 to 150±38 mL) compared with the control group (157±40 to 165±45 mL; P &lt;0.03) and reduced microvascular obstruction ( P =0.05) on baseline magnetic resonance imaging and significantly less adverse LV remodeling compared with control subjects with microvascular obstruction ( P &lt;0.05). No significant adverse events were associated with the postconditioning protocol and all patients but one (hemorrhagic stroke) survived through 1 year of follow-up. Conclusions: We found no early benefit of postconditioning on infarct size, myocardial salvage index, and LV function compared with routine PCI. However, postconditioning was associated with improved LV remodeling at 1 year of follow-up, especially in subjects with microvascular obstruction. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01324453.
Phase I multicenter, open-label study to establish the maximum tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin combination in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Antoine Hollebecque, Aitana Calvo, Thierry Andre, Guillem Argiles, Andres Cervantes, Catherine Leger, Aude Valette, Nadia Amellal, Ronan Fougeray, Josep Tabernero
Journal: Journal of Clinical Oncology (2018)

816 Background: Preclinical evidence suggests improved efficacy when combining trifluridine/tipiracil with oxaliplatin compared to each monotherapy (Nukatsuka, 2015). The primary objective was to determine the MTD and the safety profile of the doublet among mCRC pts who have progressed after at least one prior line of treatment. Methods: Using a 3+3 design, eligible pts received escalating trifluridine/tipiracil doses from 25, 30 to 35 mg/m² bid, days 1–5 q14, together with a fixed dose of oxaliplatin 85 mg/m² (day 1). An intermediate cohort with a lower dose of oxaliplatin (65 mg/m²) plus 35 mg/m² of trifluridine/tipiracil was also tested. Results: Fifteen of 17 enrolled pts were evaluable for DLTs. Median age was 61 years (range 32-74), 11 and 6 pts had an ECOG PS of 0 and 1, respectively; 76% received ≥2 lines including for 10 pts previous line with oxaliplatin. Pts received a median of four cycles (range 1–23). The MTD was defined at the maximal planned dose: trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m². Combination was well tolerated and only one DLT was observed (grade 3 febrile neutropenia). The most common ( &gt; 20%) non-hematologic adverse drug reactions (ADRs) included nausea, asthenia, vomiting, diarrhea and decreased appetite. Moderate-to-severe neutropenia occurred in 5 pts and thrombocytopenia in 4 pts (all grade 1); 1 pt experienced a grade 4 anemia at Cycle 4. Oxaliplatin-related neurotoxicity grade ≥2 was observed in 2 pts. ADRs were manageable with basic supportive care, with treatment delays or temporary interruptions. Best overall response includes partial response (n = 1, unconfirmed), stable disease (n = 7). Conclusions: At the MTD (trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m²), incidence and severity of bone marrow suppression as well as gastrointestinal toxicities were similar to previously published data. A cohort of 6 additional pts will confirm the MTD. An expansion part combining the doublet with either nivolumab or bevacizumab evaluating the safety and preliminary antitumor activity of each triplet will start soon. Clinical trial information: NCT02848443.
US National Trends in Pediatric Deaths From Prescription and Illicit Opioids, 1999-2016
Authors: Julie R. Gaither, Veronika Shabanova, John M. Leventhal
Journal: JAMA Network Open (2018)

It is not yet known how many children and adolescents die each year from opioid poisonings and how mortality rates have changed over time.To examine national trends in pediatric deaths from prescription and illicit opioids.Cross-sectional in which serial mortality data from the Centers for Disease Control and Prevention were analyzed. The population included 8986 children and adolescents (age, <20 years) who died in all US settings from opioid poisonings between 1999 and 2016. Data were collected and analyzed between June 1 and October 31, 2018.All opioids.Age-specific mortality rates per 100 000 were estimated with smoothing spline Poisson regression.Of the 8986 children and adolescents who died between 1999 and 2016 from prescription and illicit opioid poisonings, 6567 (73.1%) were male, 7921 (88.1%) were among adolescents aged 15 to 19 years, and 605 (6.7%) were among children aged 0 to 4 years. The overall pediatric mortality rate increased from 0.22 (95% CI, 0.19-0.25) to 0.81 (95% CI, 0.76-0.88) per 100 000, an increase of 268.2% (P for time effect <.001). The highest annual rates were among adolescents aged 15 to 19 years, but time trends revealed a steady linear increase among children aged 0 to 4 years and those aged 5 to 9 years as well as a steady linear increase until 2008 among the cohorts aged 10 to 14 years and 15 to 19 years, when rates briefly declined before rising again. Among adolescents aged 15 to 19 years, heroin was implicated in 1872 deaths: rates increased from 0.21 (95% CI, 0.17-0.25) to 1.06 (95% CI, 0.97-1.17), an increase of 404.8%, whereas rates for prescription opioids increased by 94.7% from 0.57 (95% CI, 0.49-0.66) to 1.11 (95% CI, 0.99-1.25) (all P for time effect <.001). Between 2014 and 2016, there were 1508 opioid deaths among adolescents aged 15 to 19 years; of these, 468 (31.0%) were attributed to synthetic opioids. Across time, 7263 (80.8%) of all pediatric deaths were unintentional, 5537 (61.6%) occurred outside of a medical facility, and 3419 (38.0%) children died at home or another residential setting. Among children younger than 5 years, 148 (24.5%) deaths were attributed to homicide.Over 18 years, nearly 9000 children and adolescents died from opioid poisonings, and the mortality rate increased nearly 3-fold. These findings suggest that the opioid epidemic is likely to remain a growing public health problem in the young unless legislators, public health officials, clinicians, and parents take a wider view of the opioid crisis and implement protective measures that are pediatric specific and family centered.
Randomized, double-blind, placebo-controlled study of tremelimumab for second- and third-line treatment of unresectable pleural or peritoneal mesothelioma.
Authors: Michele Maio, Arnaud Scherpereel, Alessandra Di Pietro, Paul Vasey, Anne S. Tsao, Luana Calabrò, Dongyue Fu, Paul B. Robbins, Ramy A. Ibrahim, Hedy Lee Kindler
Journal: Journal of Clinical Oncology (2014)

TPS7609^ Background: Mesothelioma is an uncommon cancer principally caused by asbestos exposure. After 1st-line pemetrexed/platinum, there are no approved or active agents. Novel approaches are clearly needed. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is expressed upon T-cell activation, modulating and eventually inhibiting the T-cell immune response. Tremelimumab is a fully human anti-CTLA-4 antibody that has been investigated in more than 1000 patients (pts) with various tumor types. A single-center, single-arm phase 2 trial of tremelimumab in 29 mesothelioma pts who progressed on 1 prior line of platinum-based therapy demonstrated encouraging activity, including durable partial responses lasting 6 and 18 mos, disease control in 31% of pts, median overall survival (OS) of 10.7 mos, and 1- and 2-y survival rates of 48% and 37%, respectively (Maio, Lancet Oncol 2013). Methods: This multicenter, international, phase 2b, randomized, double-blind, placebo-controlled study (NCT01843374) enrolls pts with unresectable pleural or peritoneal mesothelioma who progressed after 1–2 lines of treatment that must have included a prior anti-folate-platinum-based regimen. Pts, stratified by EORTC status (low vs. high risk), line of therapy (2nd vs. 3rd), and anatomical site (pleural vs. peritoneal) are randomized 2:1 to tremelimumab or placebo. The primary endpoint is OS; secondary efficacy end points include OS rate at 18 mos, patient-reported outcomes, disease control rate (DCR), progression-free survival (PFS), overall response rate (ORR), and duration of response, based on modified RECIST criteria for pleural mesothelioma and RECIST criteria v1.1 for peritoneal mesothelioma. Exploratory objectives include clinical outcomes (DCR, PFS, ORR, and duration of response) based on immune-related response criteria; health-related quality of life, disease-related symptoms, pain, and health status in pts with durable clinical activity; and biomarkers (cellular, protein, and nucleic acid) and their association with tremelimumab treatment and clinical outcome. Recruitment is ongoing to a total of 564 pts at approximately180 centers globally. Clinical trial information: NCT01843374.
Clinical impact of programmed cell death ligand 1 (PD-L1), programmed cell death 1 (PD-1), and CD8 expression in pancreatic cancer.
Authors: Hyun-Jeong Shim, Jun-Eul Hwang, Sook-In Jung, Kyung-Hwa Lee, Ik-Joo Chung, Sang-Hee Cho
Journal: Journal of Clinical Oncology (2014)

e15258 Background: Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a key role in the evasion of the host immune system by tumor cells via inhibition of T-cells. PD-L1 expression was detected in various human cancers. The objective of this analysis was to investigate the expression and prognostic significance (overall survival, progression free survival and response to chemotherapy) of PD-1, PD-L1 and CD8 in pancreatic cancer. We also examined the correlation between PD-L1 expression on tumor cells and PD-1 and CD8 expression on tumor-infiltrating lymphocytes (TILs). Methods: In this study we evaluated the expression of PD-L1, PD-1 and CD8 in pancreatic tissue obtained from 80 patients with unresectable advanced pancreatic adenocarcinoma (stage III-IV) who are treated with chemotherapy by immunohistochemistry. Results: No relationship was found between the expression of PD-L1 and both OS and PFS. PD-1 expression was not associated with OS whereas high tumor PD-1 expression was associated with favorable outcome for PFS (P=0.042). CD8 expression was also not related to the OS and but high CD8 expression trended towards prolonged PFS (P=0.06). There was no correlation between the expression of PD-1, PD-L1 and CD8 and response to chemotherapy. No correlation was found between PD-L1 and CD8 expression whereas significant positive correlations were detected between PD-L1 and PD-1 expression(p=0.035) and also CD8 and PD-1 expression (p<0.00). Conclusions: Our results showed no significant relation between the expression of PD-1, PD-L1 and CD8 and OS in pancreatic cancer. High PD-1 expression was only associated with prolonged PFS. Recent reports have shown that not all tumor PD-L1 or PD-1 expression confers a worse prognosis. So further investigation will be needed to determine whether PD-1/PD-L1 targeted therapy induces tumor regression in pancreatic cancer.
AR-Variant–Positive CTC: A Surrogate for a Surrogate for Taxane Therapy Outcome?
Authors: Scott M. Dehm, Bruce Montgomery, Stephen R. Plymate
Journal: Clinical Cancer Research (2018)

Circulating tumor cells' (CTC) biomarkers may become indicators for selection of therapy. The presence of androgen receptor (AR)-variant-positive CTCs may be markers indicating the need for switching therapy. Methods for AR-variant mRNA isolation from CTCs and confirmation of expression are critical factors needed for these techniques to be clinically applicable.See related article by Tagawa et al., p. 1880.
Abstract 18093: Unleashing the Role of Speckle Tracking Echocardiography in Detection of Left Atrial Fibrosis
Authors: Ahmed Saleh, Mathias Forkmann, Konstantin Zintl, Johannes Brachmann, Christian Mahnkopf
Journal: Circulation (2017)

Introduction: Atrial fibrillation (AF) is the most common arrhythmia in the clinical setting. Structural atrial remodeling has been observed in clinical and experimental AF models and proved to play a major role in the AF substrate. The relationship between left atrial (LA) structure and function is not fully elucidated. Patients and methods: Thirty four patients with AF who underwent pulmonary vein isolation (cryo- or radiofrequency ablation) were included between April 2016 and May 2017. They were subjected prior to the Ablation to a 3-dimensional delayed-enhancement MRI and the degree of LA wall fibrosis was detected and quantified using a semi-automated quantification algorithm (Marrek). All patients underwent an echocardiography with tissue Doppler measurements as well as left atrial strain rate obtained by speckle tracking. Results: Five patients were excluded due to suboptimal echocardiographic images. 29 eligible patients with mean age of 62± 11 years old (42% women) were enrolled for further anal...
Very Early Adoptive Transfer of Ex Vivo Generated Multi-Virus Specific T Cells Is a Safe Strategy for Prevention of Viral Infection after Allogeneic T Cell Depleted Stem Cell Transplantation
Authors: Pawel Muranski, Sarah I Davies, Sawa Ito, Eleftheria Koklanaris, Jeanine Superata, Quan Yu, Steven L Highfill, Marianna Sabatino, David F. Stroncek, Minoo Battiwalla, Austin John Barrett
Journal: Blood (2018)
Biomarkers and personalised medicine for asthma
Authors: Michael Roth, Daiana Stolz
Journal: European Respiratory Journal (2019)

<b>Precision medicine and personalised therapy are major goals for chronic inflammatory diseases such as asthma. These two aims can only be achieved when the different subtypes of asthma can be precisely defined by robust diagnostic criteria.</b>http://ow.ly/2rsy30mODVS