tbuckley/cabot-search huggingface dataset:
Target lesion selection as a source of variability of response classification by RECIST 1.1.
Authors: Christiane K. Kuhl, Alexandra Barabasch, Tim Dirrichs, Philipp Bruners, Lieven Kennes, Tim Bruemmendorf, Sebastian Keil
Journal: Journal of Clinical Oncology (2013)

11077 Background: Response classification in RECIST is based on manual uni-dimensional quantification of changes of target lesion size. In RECIST 1.1, the maximum number of target lesions was reduced to 5, with a maximum of 2 per organ. We analyzed the importance of different factors (manual vs. automated size measurement, uni- vs. three-dimensional size assessment, and between-reader-variability of target lesion selection) on response categorization. Methods: 41 female patients (58.1±13.2 y) with metastatic breast cancer underwent contrast-enhanced thoraco-abdominal CT for initial staging and first follow-up after systemic chemotherapy. Data were independently and prospectively interpreted by three radiologists. In addition, response was evaluated by a CAD system that allowed automated uni- and three-dimensional assessment of target lesions. Results: Response classification differed between readers in 19/41 patients (46%). In 25/41 patients, readers chose the same target lesions. In 6 of these 25 patients (24%), readers disagreed with regards to response classification. In 16/41 patients, readers chose different target lesions. In 13 of these 16 patients, readers disagreed (81%) (p &lt; 0.001). When dichotomizing response classification according to its therapeutic implication into progressive vs. non-progressive disease, readers disagreed in 11/41 patients (27%). In 9 of these 11 patients, readers had chosen different target lesions. Classification by manual vs. automated uni-dimensional measurement differed in 11/41 of patients (27%). Classification by uni-dimensional vs. volumetric measurements differed in 6/41 of patients (15%). Conclusions: Response classification by RECIST suffers from substantial between-reader variability. Major source of variability is not the manual or uni-dimensional measurement, but the variable choice of target lesions between readers. [Table: see text]
Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma
Authors: Kohei Shigeta, Meenal Datta, Tai Hato, Shuji Kitahara, Ivy X. Chen, Aya Matsui, Hiroto Kikuchi, Emilie Mamessier, Shuichi Aoki, Rakesh R. Ramjiawan, Hiroki Ochiai, Nabeel Bardeesy, Peigen Huang, Mark Cobbold, Andrew X. Zhu, Rakesh K. Jain, Dan G. Duda
Journal: Hepatology (2019)

Background and Aims Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD‐1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and Results We recapitulated these clinical outcomes using orthotopic—grafted or induced—murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR‐2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti‐PD‐1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti‐PD‐1/VEGFR‐2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8–positive (CD8 + ) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor‐associated macrophages and reducing T regulatory cell (Treg) and chemokine (C‐C motif) receptor 2–positive monocyte infiltration in HCC tissue. In these models, VEGFR‐2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD‐ligand 1 expression in HCC cells was induced in a paracrine manner upon anti‐VEGFR‐2 blockade in endothelial cells in part through interferon‐gamma expression. Moreover, we found that VEGFR‐2 blockade increased PD‐1 expression in tumor‐infiltrating CD4 + cells. We also found that under anti‐PD‐1 therapy, CD4 + cells promote normalized vessel formation in the face of antiangiogenic therapy with anti‐VEGFR‐2 antibody. Conclusions We show that dual anti‐PD‐1/VEGFR‐2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti‐PD‐1 therapy–resistant and anti‐PD‐1 therapy–responsive HCC models.
Global burden of atherosclerotic cardiovascular disease in people with hepatitis C virus infection: a systematic review, meta-analysis, and modelling study
Authors: Kuan Ken Lee, Dominik Stelzle, Rong Bing, Mohamed Anwar, Fiona Strachan, Sophia Bashir, David E Newby, Jasmit S Shah, Michael H Chung, Gerald S Bloomfield, Chris T Longenecker, Shashwatee Bagchi, Shyamasundaran Kottilil, Sarah Blach, Homie Razavi, Peter R Mills, Nicholas L Mills, David A McAllister, Anoop S V Shah
Journal: The Lancet. Gastroenterology & hepatology (2019)

BackgroundMore than 70 million people worldwide are estimated to have hepatitis C virus (HCV) infection. Emerging evidence indicates an association between HCV and atherosclerotic cardiovascular disease. We aimed to determine the association between HCV and cardiovascular disease, and estimate the national, regional, and global burden of cardiovascular disease attributable to HCV.MethodsFor this systematic review and meta-analysis, we searched MEDLINE, Embase, Ovid Global Health, and Web of Science databases from inception to May 9, 2018, without language restrictions, for longitudinal studies that evaluated the risk ratio (RR) of cardiovascular disease in people with HCV compared with those without HCV. Two investigators independently reviewed and extracted data from published reports. The main outcome was cardiovascular disease, defined as hospital admission with, or mortality from, acute myocardial infarction or stroke. We calculated the pooled RR of cardiovascular disease associated with HCV using a random-effects model. Additionally, we calculated the population attributable fraction and disability-adjusted life-years (DALYs) from HCV-associated cardiovascular disease at the national, regional, and global level. We also used age-stratified and sex-stratified HCV prevalence estimates and cardiovascular DALYs for 100 countries to estimate country-level burden associated with HCV. This study is registered with PROSPERO, number CRD42018091857.FindingsOur search identified 16 639 records, of which 36 studies were included for analysis, including 341 739 people with HCV. The pooled RR for cardiovascular disease was 1·28 (95% CI 1·18–1·39). Globally, 1·5 million (95% CI 0·9–2·1) DALYs per year were lost due to HCV-associated cardiovascular disease. Low-income and middle-income countries had the highest disease burden with south Asian, eastern European, north African, and Middle Eastern regions accounting for two-thirds of all HCV-associated cardiovascular DALYs.InterpretationHCV infection is associated with an increased risk of cardiovascular disease. The global burden of cardiovascular disease associated with HCV infection was responsible for 1·5 million DALYs, with the highest burden in low-income and middle-income countries.FundingBritish Heart Foundation and Wellcome Trust.
Active epidermal growth factor (EGFR) level is a predictive factor for response and survival in patients with lung cancer
Authors: I. Tek, H. Akbulut, B. Yalcin, A. Buyukcelik, G. Utkan, A. Demirkazik, F. Icli
Journal: Journal of Clinical Oncology (2006)

20058 Background: Over expression of epidermal growth factor receptor (EGFR) has been reported as a poor prognostic factor in patients with cancer. However, active EGFR released from the apoptotic tumor cells could serve as a marker for the prediction of clinical outcome in cancer patients. In this study we aimed to study the role of the level of serum active epidermal growth factor receptor in patients with non-small cell lung cancer as a predictive parameter for response and survival. Methods: Thirty-three consecutive patients with advanced non-small cell lung cancer patients (12 with stage IIIB and 21 stage IV or relapsed disease) were included. The median age was 52 (range: 35–69). The patients were given cisplatinum and docetaxel combination regimen as first line treatment. The serum samples were collected before the first cycle of the chemotherapy and every 2 cycles and kept at -80 C. Response to treatment was evaluated every 2 cycles according to the WHO criteria. Serum active EGFR levels were measured by ELISA (BioSource, Camarillo Ca, USA). Results: Median 4 cycles of chemotherapy (range: 2–6) were administered. Median follow-up time was 11 months. Objective response rate was 18.2%. One-year estimated survival rate was 65.9%. There were no significant differences between the extend of the disease and basal active EGFR levels. Likewise, there was no difference between the basal active EGFR levels of responders and non-responders (0,19 ± 0.09 vs 0.21 ± 0,11 fmol/mL, p = 0.899, respectively). However, the patients responded to the treatment had significantly higher level of active EGFR than the non-responders after 2 cycles (3,74 ± 3,65 vs. 0,174 ± 0,13 fmol/mL, p = 0.028, respectively). While the patients with positive basal EGFR levels (higher than the cutoff level of 0.080 fmol/mL) had lower survival rates than that of negative patients (1 yr survival rate: 62.8% vs. 75%, respectively), active EGFR positive patients after 2 cycles of chemotherapy had longer survival than the negative patients (1 yr survival rate: 70.6% vs. 60%, respectively). Conclusions: Our preliminary results show that serum active EGFR levels could be a predictive marker for response evaluation and survival in patients with non-small cell lung cancer treated with chemotherapy. No significant financial relationships to disclose.
<i>FGFR1</i> Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor–Positive (HR+) Breast Cancer
Authors: Joshua Z. Drago, Luigi Formisano, Dejan Juric, Andrzej Niemierko, Alberto Servetto, Seth A. Wander, Laura M. Spring, Neelima Vidula, Jerry Younger, Jeffrey Peppercorn, Megan Yuen, Giuliana Malvarosa, Dennis Sgroi, Steven J. Isakoff, Beverly Moy, Leif W. Ellisen, A. John Iafrate, Carlos L. Arteaga, Aditya Bardia
Journal: Clinical Cancer Research (2019)

While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic breast cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR+)/HER2- MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro.In the clinical cohort (N = 110), we identified that patients with FGFR1+ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P = 0.005), coexisting TP53 mutations (41% vs. 21%; P = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1+ HR+/HER2- MBC. In preclinical models, estrogen receptor-positive (ER+)/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER+ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition.Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER+/FGFR1+ MBC.
Effect of germline polymorphisms of DNA repair genes on chemotherapy outcome in advanced non-small cell lung cancer (NSCLC) patients.
Authors: Ivana Sullivan, Margarita Majem, David Páez, Cinta Pallares, Laia Paré, Elisabeth Del Rio, Teresa Ramon Y Cajal, Agust Barnadas, Montserrat Baiget
Journal: Journal of Clinical Oncology (2012)

e18057 Background: The identification of predictors of efficacy of chemotherapy in NSCLC could help in the selection of patients who are more likely to benefit from a particular scheme and the avoidance of undue toxicity in poor responders. We examined the role of several polymorphisms in DNA repair and DNA synthesis genes as pharmacogenetic markers in the outcome of NSCLC patients. Methods: A blood sample was collected from 117 patients with NSCLC and genomic DNA was isolated from the peripheral blood nucleated cells. Polymorphisms were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were excision repair cross-complementing-1 (ERCC1 Asn118Asn), xeroderma pigmentosum group D (XPD Lys751Gln), thymidylate synthase (TS) (VNTR/5’UTR, 2R G&gt;C SNP, 3R G&gt;C SNP) and Methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were eligible (14 patients with stage I-II were excluded). The median PFS was significantly longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months (m) and 10 m, respectively, as compared to 6 m for the C/C patients (p=0.034). Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) than those C/C (10.5 m; p=0.1). Subgroup analysis revealed that ERCC1 C/T or T/T genotypes were associated with increased PFS in male (p=0.005), smokers (p=0.036) and age &lt;70 years (p=0.012). Patients with A/A or A/C genotypes in codon 751 in XPD had a trend to longer median OS than those C/C (p=0.09). No differences in median PFS were observed. No association between TS and MTHFR polymorphisms and outcome was found in overall population. Conclusions: ERCC1 C/T or T/T genotype in codon 118 might be useful for predicting the outcome of NSCLC patients treated with platinum-based chemotherapy specially in male, smokers and age &lt;70 subgroups.
Induction in locally advanced uterine cervix carcinoma with cisplatin, paclitaxel, and capecitabine: Response and tolerability.
Authors: Juan J. Rodriguez-Riao, George Oblitas, Virgilio Colon
Journal: Journal of Clinical Oncology (2013)

e16521 Background: Cervix cancer is a public health problem in developing countries, and the locally advanced disease is the most common stage and patiente with complete response after concurrent radiotherapy and cisplatin is low. In this study we use induction chemotherapy in orden to reduce the tumor before radiotherapy administration. Methods: 47 patients with pathological confirmed cervix cancer stage Ib2 to IVa received induction chemotherapy for three cycles with cisplatin, paclitaxel and capecitabine prior to treatment with concurrent chemotherapy-radiotherapy. The primary end points were clinical response rate, pathological response and imaging after induction and secondary end point was safety (NCI toxicity version 3.0). Results: A total of 47 patients found that the average age was 45 years, stage IIB was the most common, squamous histology representing 89.4% of the patients. The clinical response rate was 100%, without disease progression during the period of following. Pathological complete response was 48.9%. The most common hematologic toxicity was anemia (55%) and grade 3 neutropenia (14.8%) but both were manageable, all patients had hand-foot syndrome and alopecia. Neuropathy grade 3 was 12.7%. Conclusions: Induction chemotherapy whith cisplatin, paclitaxel and capecitabine for three cycles prior to standard treatment offers an effective and safety alternative in patients with locally advanced cervical carcinoma.
Effects of Conventional Uric Acid–Lowering Therapy on Monosodium Urate Crystal Deposits
Authors: Hanna Ellmann, Sara Bayat, Elizabeth Araujo, Bernhard Manger, Arnd Kleyer, Alexander Cavallaro, Michael Lell, Hannah Schenker, David Simon, Koray Tascilar, Herbert S. B. Baraf, Georg Schett, Jürgen Rech
Journal: Arthritis & Rheumatology (2019)

Few studies have systematically and quantitatively addressed the impact of urate-lowering therapy on monosodium urate (MSU) deposits. This study was undertaken to analyze the effect of lifestyle measures and conventional urate-lowering therapy on MSU deposits in patients with gout.In this prospective study, subjects with gout according to the American College of Rheumatology/European League Against Rheumatism classification criteria and presence of MSU deposits seen on dual-energy computed tomography (DECT) scans received either lifestyle intervention or conventional urate-lowering therapy for a mean period of 18 months before a follow-up DECT scan. Detected MSU deposits were quantified by volumetric measurement and validated by semiquantitative scoring, and baseline and follow-up measurements were compared.Baseline and follow-up DECT scans were available for all 83 subjects. Six subjects discontinued treatment, and 77 subjects underwent a lifestyle intervention (n = 24) or were treated with allopurinol (n = 29), febuxostat (n = 22), or benzbromarone (n = 2) over the entire observation period. The mean serum uric acid (UA) level decreased from 7.2 to 5.8 mg/dl in the overall population. In patients who discontinued treatment, no change in MSU deposits or serum UA levels was observed. The burden of MSU deposits significantly decreased in patients undergoing lifestyle intervention (MSU volume P = 0.007; MSU score P = 0.001), and in patients treated with allopurinol (MSU volume and score P < 0.001) or febuxostat (MSU volume P < 0.001; MSU score P = 0.001). No significant decline in MSU deposits was noted in patients who discontinued treatment.These data show that lifestyle intervention and xanthine oxidase inhibitors significantly decrease the MSU deposit burden. Hence, conventional gout therapy not only lowers serum UA levels, but also reduces pathologic MSU deposits.
HIV Infection, Cancer Treatment Regimens, and Cancer Outcomes Among Elderly Adults in the United States
Authors: Anna E. Coghill, Gita Suneja, Anne F. Rositch, Meredith S. Shiels, Eric A. Engels
Journal: JAMA Oncology (2019)

<h3>Importance</h3> HIV-infected patients with cancer have an elevated cancer-specific mortality rate compared with HIV-uninfected patients with cancer. However, to our knowledge, studies describing this association have not adjusted in detail for cancer treatment, despite evidence of suboptimal cancer treatment in the setting of HIV. <h3>Objective</h3> To compare cancer-specific mortality in HIV-infected and HIV-uninfected patients with cancer after adjusting for available data on receipt of specific cancer treatments. <h3>Design, Setting, and Participants</h3> We used Surveillance, Epidemiology, and End Results–Medicare linked data to identify 308 268 patients in the United States (age, ≥65 years), including 288 with HIV infection, with nonadvanced cancers of the colorectum, lung, prostate, or breast diagnosed between 1996 and 2012 who received standard, stage-appropriate cancer treatment during the year after cancer diagnosis. Data analysis was done from August 2016 to September 2018. <h3>Exposures</h3> HIV infection identified by the presence of Medicare claims. <h3>Main outcomes</h3> Overall mortality, cancer-specific mortality, and relapse or cancer-specific mortality after initial treatment. <h3>Results</h3> In this database study of 308 268 patients with nonadvanced cancer (168 998 men and 139 270 women; age, ≥65 years), HIV-infected patients (n = 288) had significant elevations in the overall mortality rate compared with HIV-uninfected patients for cancers of the colorectum (hazard ratio [HR], 1.73; 95% CI, 1.11-2.68;<i>P</i> = .02), prostate (HR, 1.58; 95% CI, 1.23-2.03;<i>P</i> &lt; .01), and breast (HR, 1.50; 95% CI, 1.01-2.24;<i>P</i> = .05). Cancer-specific mortality was elevated for prostate (HR, 1.65; 95% CI, 0.98-2.79;<i>P</i> = .06) and breast cancer (HR, 1.85; 95% CI, 0.96-3.55;<i>P</i> = .07). Compared with their HIV-uninfected counterparts, HIV-infected men with prostate cancer also experienced significantly higher rates of relapse or death (HR, 1.32; 95% CI, 1.03-1.71;<i>P</i> = .03) as did HIV-infected women with breast cancer (HR, 1.63; 95% CI, 1.09-2.43;<i>P</i> = .02). <h3>Conclusions and Relevance</h3> In the United States, elderly HIV-infected patients with cancer, particularly prostate and breast cancers, have worse outcomes than HIV-uninfected patients with cancer. This disparity persists even after adjustment for administered first-course cancer treatments and will become increasingly relevant as the HIV population in the United States continues to age.
Cardiac Arrest during Competitive Sports
Authors: Nicole Karam, Eloi Marijon, Xavier Jouven
Journal: New England Journal of Medicine (2018)

Cardiac Arrest during Competitive SportsTo the Editor: The suggestion by Landry et al. that the value of preparticipation screening is in question is premature.The conclusions of their study are limited by its retrospective nature and the multiple assumptions made, particularly relating to the diagnosis of causative conditions.The study results are not generalizable to the wider population of competitive athletes.The overall incidence of sudden cardiac arrest of 0.76 cases per 100,000 athlete-years was driven large-The New England Journal of Medicine Downloaded from nejm.