tbuckley/cabot-search huggingface dataset:
Does cytotoxic chemotherapy (CT) have a role in palliative treatment of hepatocellular carcinoma (HCC)?
Authors: Guilherme Nader Marta, Leonardo Gomes da Fonseca, Maria Ignez Freitas Melro Braghiroli, Paulo Marcelo Hoff, Jorge Sabbaga
Journal: Journal of Clinical Oncology (2018)

10114 Background: Palliative treatment of patients (pts) with HCC after progression to sorafenib represents a clinical challenge due to the usual concomitance with hepatic failure. Although new drugs have recently demonstrated survival benefit in phase III trials after sorafenib therapy, these agents are not widely available and their use is limited by the stringent inclusion criteria of the clinical trials. CT is broadly used as a palliative treatment in this clinical setting, although there is no proof of its efficacy. We analyzed a cohort of HCC pts treated with CT with the aim of evaluating the efficacy and safety of this approach. Methods: A cohort of pts with advanced HCC treated with CT after progression to sorafenib was retrospectively evaluated. Survival (PCS) was calculated from the first day of CT to death or last data record. PCS was estimated using Kaplan-Meier and curves were compared by log-rank test. Results: We analyzed 240 HCC pts treated with sorafenib from Oct-2007 to Jan-2017. At sorafenib discontinuation, best supportive care was the only treatment for 79.2%, while 18.3% received cytotoxic CT and 2.5% were enrolled in clinical trials. For pts treated with CT, median age 60 years (19-74), 75.6% male, 42.2% had HCV, 71.1% Child-Pugh (CP) A, 95.6% had extrahepatic spread, and 55.6% received doxorubicin-based CT. The median PCS was 8.0 months (3.9-12.1) and 53.3% had progressive disease as best response. Survival benefit from CT could not be predicted by CP A (p = 0.66), ECOG PS 0-1 (p = 0.09), CT regimens used (p = 0.97) or α-fetoprotein (p = 0.29). Grade 3 or 4 toxicities occurred in 37.7% of pts and the most common grade 3 or 4 adverse events (AE) were nausea/vomiting (20%), mielotoxicity (18%) and fatigue (11%). CT was most commonly discontinued due to unacceptable AE (44.4%) and disease progression (37.8%). Conclusions: Palliative treatment of HCC pts with CT after sorafenib failure is associated with high rates of toxicity and low efficacy. These data suggest that CT seems to have very limited activity in a group of pts with a very poor prognosis without a clear survival benefit and should only be recommended in very selected cases.
Causal effects of methotrexate reductions/delays in treatment of high-grade resectable osteosarcoma.
Authors: Jakob Klaas Anninga, Carlo Lancia, Cristian Spitoni, Hans Gelderblom, Marta Fiocco
Journal: Journal of Clinical Oncology (2016)

e22502 Background: We analyzed preoperative data from EURAMOS-1, a large study in resectable osteosarcoma where the regimen is MAP (Methotrexate/Adriamycin/Cisplatin), focusing on the effect on Histological Response (HRe) of reducing Methotrexate (MTX) by one dose. In the analysis of chemotherapy data, toxicity requires special care because it is a time-dependent confounder. Toxicity is at the same time a risk factor for HRe and a predictor for the exposure levels in the next cycle. Indeed, both drug doses and starting date of the next chemotherapy cycle are dynamically allocated to each patient depending on the toxicity levels through the end of the previous cycle. Methods: We used Marginal Structural Models (MSMs) based on Inverse Probability-of-Treatment Weigthed (IPTW) estimators, which can estimate the causal effect of therapy modifications in presence of time-dependent confounders such as toxicity. MSMs create a pseudo-population by weighting each subject with the inverse of the probability of observing the allocation of a dose delay/reduction. In this pseudo-population toxicity history no longer predicts the next exposure, and MSMs mimic a randomized trial where the reduction of the exposure intensity is no longer confounded by the toxicity. Using the severity of toxic side-effects and both age and gender, we weighted the original population and then fitted a Marginal Structural Logistic Model for HRe with both cumulative reduction and cumulative delay as explanatory variables. Results: Reducing the courses of MTX has a positive effect on HRe (OR 1.460, p-value 0.216); delaying a cycle by more than a week haa a negative effect (OR 0.564, p-value 0.045). Conclusions: Although no statistical significance supports the positive effect of reducing MTX, in a clinical scenario where a choice must be taken between (i) giving 2 courses of MTX but delaying the cycle because of high toxicity; (ii) skipping one course of MTX and not delaying the end of the cycle; our findings suggest that the latter decision should probably be taken.
<i>Notes from the Field:</i> Responding to an Outbreak of Monkeypox Using the One Health Approach — Nigeria, 2017–2018
Authors: Womi-Eteng Eteng, Anna Mandra, Jeff Doty, Adesola Yinka-Ogunleye, Sola Aruna, Mary G. Reynolds, Andrea M. McCollum, Whitni Davidson, Kimberly Wilkins, Muhammad Saleh, Oladipupo Ipadeola, Lamin Manneh, Uchenna Anebonam, Zainab Abdulkareem, Nma Okoli, Jeremiah Agenyi, Chioma Dan-Nwafor, Ibrahim Mahmodu, Chikwe Ihekweazu
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In September 2018, the first case of an outbreak of monkeypox was reported in Nigeria, which likely resulted from a complex intersection of events and required a robust outbreak response collaboration among human, animal, and environmental health institutions.
TCT-167 In-hospital Outcomes of Using the Hybrid Approach of Percutaneous Coronary Interventions for Chronic Total Occlusions: Update from the PROGRESS-CTO (PROspective Global REgiStry for the Study of Chronic Total Occlusion Intervention) International Registry
Authors: Peter Tajti, Darshan Doshi, Mir Basir, Julianne Longlade, Margaret Fox, Aimee Topacio, None Mary cadigan, Hector Tamez, Abdullah Almasoud, Omid Behnamfar, Belal Al Khiami, Zach Rosol, Clay Barbin, Amanda Bollino, Kristin Miller, Jesse Byrd, Dmitrii Khelimskii, Julie McCracken, Christina Podias, Jennifer Nguyen, Kontopodis Eleftherios, Andreas Tassopoulos, Katsanou Konstantina, Amanda Fiebach, Iosif Xenogiannis, Bavana Rangan
Journal: Journal of the American College of Cardiology (2018)
Dose-adjusted (DA)-EPOCH-R with high-dose methotrexate (HD-MTX) for newly diagnosed stage II-IV CD5-positive diffuse large B-cell Iymphoma (CD5+ DLBCL): Primary analysis of PEARL5 study.
Authors: Kana Miyazaki, Naoko Asano, Tomomi Yamada, Kohta Miyawaki, Hirotaka Takasaki, Tadahiko Igarashi, Momoko Nishikori, Kinya Ohata, Kazutaka Sunami, Isao Yoshida, Yuki Nishimura, Satoshi Tamaru, Masakatsu Nishikawa, Koji Izutsu, Tomohiro Kinoshita, Junji Suzumiya, Koichi Ohshima, Koji Kato, Naoyuki Katayama, Motoko Yamaguchi
Journal: Journal of Clinical Oncology (2018)

7561 Background: CD5+ DLBCL comprises 5-10% of DLBCL and is characterized by various aggressive clinical features and frequent CNS relapse. Our previous retrospective study (Miyazaki et al. Ann Oncol 2011) revealed that the 2-year (yr) PFS and CNS relapse rates in patients (pts) with newly diagnosed stage II-IV CD5+ DLBCL were 51% and 15%, respectively. An interim analysis of our multicenter phase II study for newly diagnosed stage II-IV CD5+ DLBCL (PEARL5 study) revealed that DA-EPOCH-R/HD-MTX provided a high CR rate (91%) with manageable toxicity (Miyazaki et al. ASH 2016). Methods: Pts with newly diagnosed stage II-IV CD5+ DLBCL between 20-75 yrs old and ECOG PS of 0-3 were eligible. Four cycles of DA-EPOCH-R followed by 2 cycles of HD-MTX (3.5 g/m2) and additional 4 cycles of DA-EPOCH-R were planned as the protocol treatment. Cell-of-origin of DLBCL was determined by means of NanoString analysis system. The primary endpoint was 2-yr PFS. Results: From Aug 2012 to Nov 2015, 47 pts were enrolled in the study. AII the pts were eligible and exhibited the following features: age, 37-74 yrs (median 62); M:F = 18:29; ECOG PS > 1, 4%; stage III/IV, 53%; IPI HI/H, 47%; and ABC/GCB/unclassified, 39/4/3 (n = 46). With a median follow-up of 3.1 yrs (range, 2.0-4.9), the 2-yr PFS rate was 79% (95% CI, 64-88%). This compared favorably with the historical control of conventional R-chemotherapy (51%). The 2-yr OS rate was 89%. One pt in CR died in a traffic accident 0.8 yr after enrollment. The 2-yr CNS relapse rate was 9% (95% CI, 3-21%; n = 4). Among the 4 pts, 1 pt had primary testicular DLBCL. The remaining 3 pts experienced CNS relapse before HD-MTX. Two of these pts had high-grade B-cell lymphoma, NOS (WHO 2016) with MYC rearrangement, and the other pt discontinued the protocol treatment after the 1st rituximab due to grade 4 tumor lysis syndrome. The 2-yr PFS and OS rates in CD5+ ABC DLBCL (n = 39) were 77% and 87%, respectively. Conclusions: DA-EPOCH-R/HD-MTX is an effective treatment for newly diagnosed stage II-IV CD5+ DLBCL. Long-term efficacy and toxicity will be evaluated in a 5-yr follow-up in Nov 2021. Clinical trial information: UMIN000008507.
Cetuximab observational study as first-line therapy in patients with metastatic colorectal cancer.
Authors: Michio Itabashi, Kimitaka Tani, Kei Muro, Toshiki Masuishi, Yasuo Ohashi, Kenichi Sugihara
Journal: Journal of Clinical Oncology (2016)

e15022 Background: Cetuximab (Cmab) + chemotherapy is now indicated in various treatment guidelines as a first-line therapy for non-resectable metastatic colorectal cancer (mCRC). The efficacy of Cmab + FOLFIRI has been demonstrated in CRYSTAL, but its efficacy and safety in combination with other regimens is unclear. Few reports have examined Cmab combination therapy as a first-line chemotherapy in Japan. We therefore planned an observational study to evaluate the efficacy and safety of first-line therapy including Cmab, and to clarify treatment results according to ESMO guideline groups 1-3 (G1-3). This study received support from the Public Health Research Foundation’s Comprehensive Support Project for Oncology Research. Methods: Of 590 mCRC patients from 158 institutes who received Cmab as first-line therapy either as combination therapy or monotherapy between January 2012 and June 2013, 577 eligible patients were enrolled in this study. G1 included 174 patients, G2 included 229 patients and G3 included 174 patients. Endpoints were response rate, PFS, and reason for cancelations of first-line treatment. We investigated adverse events to evaluate safety. Concomitant drugs were oxaliplatin/ irinotecan/ Cmab monotherapy/ others in 379/ 173/ 21/ 4 patients. Results: First-line therapy was completed in 91.7% of patients up to November 2015. Response rate was 55.2% (CR 3.8%; PR 51.4%; SD 20.0%; PD 9.8%). Curative resection was performed in 15.2% of patients (G1, 41.8%; G2, 4.2%; G3, 3.4%). Response rates were 72.4% and 52.0% in patients with and without acneiform eruptions at 16 weeks. Infusion reactions occurred in 2.1% at 8 weeks, 0.8% at 16 weeks, 1.1% at 24 weeks and 0.6% at 1 year. The cancelation rate of first-line treatment was 44.4% with PD, with second-line treatments performed for 57.1% of these patients. Overall survival rates at 1 and 2 years were 77.9% (G1, 92.6%; G2, 64.7%; G3, 80.2%), 54.3% (G1, 79.0%; G2, 35.8%; G3, 54.2%). Progression-free survival rates at 1 and 2 years were 42.7% (G1, 62.7%; G2, 32.0%; G3, 37.7%) and 19.3% (G1, 33.2%; G2, 13.1%; G3, 14.5%). Conclusions: We reported treatment results according to ESMO guideline groups on the efficacy and safety of Cmab as first-line therapy. Clinical trial information: 000007275.
Prognostic differences between male and female patients in virus-negative Merkel cell carcinoma.
Authors: Lisa Villabona, Hannah Bjorn-Andtback, Viveca Björnhagen-Säfwenberg, Weng-onn Lui, Giuseppe V. Masucci
Journal: Journal of Clinical Oncology (2018)

e21601 Background: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer. The pathogenesis is linked to the immune system and immunocompromised patients have an increased risk of developing MCC. With the discovery of Merkel cell polyoma virus (MCPyV), which is present in about 80% of MCC (Feng et al 2008) the suggestion of a connection with the immune system has been strengthened. Previous reports (Moshiri et al 2016) has shown that patients with a virus-negative disease have a worse prognosis. Our aim is to analyze clinical variables and their prognostic impact in a Swedish cohort of MCC-patients, in order to better understand possibilities to personalize treatment in the future. Methods: 106 MCC patients referred to the plastic surgery unit at Karolinska University Hospital from 1989-2017 were included and retrospective data was collected. 65 (61%) was identified as female, 41 (39%) as male. Mean age at operation was 75,5 years, mean overall survival (OS) was 4.2±0.5 years. MCPyV status was available in 42 patients, 5 of these were excluded due to lacking retrospective data. Out of the 37 patients, 24 (65%) patients were MCPyV positive, 13 (35 %) MCPyV negative. Results: Survival analysis did not show any significant difference between MCPyV positive and negative patients. When gender was added into multivariate analysis we found that female patients with virus negative disease had a significant better outcome than virus negative male patients (p = 0.02) whereas virus positive MCC did not show any significant difference in OS between female and male patients. Conclusions: Female patients with negative MCPyV MCC had a better outcome than the male patients. This finding indicates that MCPyV positive and negative MCC act as two different diseases. It also raises questions if there is a difference in the disease or immune response between male and female patients.
Prognostic significance of alterations of pathways regulating autophagy in acute myeloid leukemia.
Authors: Giovanni Marconi, Maria Chiara Fontana, Cristina Papayannidis, Antonella Padella, Silvia Lo Monaco, Maria Chiara Abbenante, Chiara Sartor, Luca Bertamini, Jacopo Nanni, Andrea Ghelli Luserna di Rorà, Valentina Robustelli, Elena Tenti, Elena Tenti, Eugenio Fonzi, Giorgia Simonetti, Emanuela Ottaviani, Carmen Baldazzi, Nicoletta Testoni, Giovanni Martinelli
Journal: Journal of Clinical Oncology (2017)

7038 Background: Nowadays, science is debating if autophagy in cancer can lead to therapy resistance or it can favor apoptosis. Autophagy pathways are involved pro-apoptotic mechanism, or they can improve stresses survival eliminating damaged mitochondria and proteins. Levels and activity of pro-apoptotic and anti-apoptotic proteins (eg. bcl-2 and p53), high levels of cAMP, and a pink/park complex could play as fulcrum on this lever. Our study aims to define the role of autophagy in AML. Methods: We analyzed 148 consecutive non M3 AML with Affymetrix SNP array. We screened all patients for TP53, FLT3, NMP1 mutations. Patients was treated with intensive induction chemotherapy regimens. Survival data were collected prospectively, with a median follow-up of 18 months. Results: Autophagy alteration (gene group 1: ULK1 CHR11; ULK1 CHR17; BECN1; ATG14; AMBRA1; UVRAG; ATG9A; ATG9B; PIK3C3; PIK3R4) was related to lower Complete Remission rate (CR%) after induction in univariate (p &lt; .001) and multivariable regression model with age, karyotype, secondary AML, TP53 mutation (p = .014); autophagy alteration shown to confer worst Overal Survival (OS) (p &lt; .001) and was significantly associated with complex karyotype and TP53 mutation (p &lt; .001). We detected significant differences in term of survival independently both in gain and loss in group 1 genes (p &lt; .001). Alterations in genes in cAMP pathway (group 2: SESN1; PRKAA1 CHR 3; PRKAB1: PRKAA1 CHR 1: PRKAG1 CHR11; PRKAG1 CHR 7; PRKAG3; PRKAB1) and in genes that could be related to a switch from a physiological role of autophagy to a resiliency mechanism (group 3: CCND1; BCL2; PINK1; PARK2; TP53; MDM1; MDM4) showed to confer worst OS (p &lt; .001 in both groups); Alteration in group 2 and group 3 were related to lower CR% after induction (p &lt; .001 in both groups). Whole Exome Sequencing on 56 patients in our set did not found any significant mutation in genes we analyzed with the exception of TP53. Conclusions: Alterations in autophagy regulator genes are associated with poor prognosis and therapy resistance. A loss in autophagy could block apoptosis, a gain could confer cell resiliency. Acknowledgements: ELN, AIL, AIRC, Progetto Regione-Università 2010-12,FP7 NGS-PTL, HARMONY
Clinical evaluation of HER2 molecular diagnostic assay with internal quality controls in breast cancer.
Authors: Lin-Kang Hsu, Rong Yu, Yuan-Chil Liu, Kung Y. Chiu, Wu-Chi Hsu, Yen-Ting Lin, Yu-Ming Yeh
Journal: Journal of Clinical Oncology (2016)

e23130 Background: Determination of HER2 status before taking therapeutic regimens plays an essential role in breast cancer. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently working assays for HER2 testing. With the advantages of cost-effectiveness and high accuracy for IHC and FISH respectively, these two assays have been recommended as the routinely-used diagnostic tool. However, several studies has been reported that false signals and lab-to-lab variations are major unsolved issues for HER2 testing. Moreover, both IHC and FISH assays do not have the internal quality control mechanism, which might be the root-causes of the issues that we’re facing. Methods: Here, we developed and evaluated a novel HER2 testing assay with built-in internal quality control mechanisms by the principle of multiplex real-time PCR. Results: Fifty FFPE samples were collected and analyzed for the evaluation. The result showed that the agreement between the developed assay and FDA certified FISH assay is over 90%, suggesting the developed Real-Time PCR is accurate and reliable for HER2 testing. Furthermore, the quality of FFPE samples can be distinguished simultaneously, which can prevent false signals or lab-to-lab variations that resulted from poor qualified samples. Conclusions: To sum up, the clinical efficacy of the developed HER2 molecular diagnostic assay shows great quality control ability and high analytical consistency with current assays for HER2 testing.
Prognosis of brain metastasis (BM) in metastatic renal cell carcinoma (mRCC): Experience from Gustave Roussy (IGR).
Authors: Annalisa Guida, Laurence Albiges, Lisa Derosa, Luigi Marcheselli, Guillaume Louvel, Frederic Dhermain, Bernard J. Escudier
Journal: Journal of Clinical Oncology (2016)

4561 Background: BM occur in 2-16% of patients (pts) with mRCC and are associated with a poor outcome. However, BM appear at different stage of the disease, and various therapies can be proposed. The aim of this study was to find out potential prognostic factors in this heterogeneous group of pts. Methods: Metastatic RCC pts with radiological evidence of BM, followed at IGR from 1997 to 2015 were analyzed. Pts characteristics, treatments and outcome data were collected. Tumor burden (TB) at the time of BM was defined according to RECIST 1.1. OS was calculated from date of BM diagnosis to death for any cause or last follow-up using the Kaplan-Maier method and modelled with the Cox-regression model. Results: 162 pts were included in this retrospective study. Most pts (95%) had clear-cell histology. Half pts (54%) had synchronous metastatic disease. In 36% of cases BM occurred before the start of 1-line therapy, in 37% before the start of 2-line. The most common metastatic sites at the time of BM diagnosis were: lung 79%, lymph nodes 54% and bones 34%. Using International Metastatic Renal Cancer Database Consortium (IMDC) prognostic score, pts were classified as good 24%, intermediate 54% and poor 22% risk when BM was diagnosed. Two third of pts (66%) were diagnosed of a single BM, while 14% had ≥ 3. Neurological symptoms (NS) were present in 61% of cases. Local treatments (LT) were: surgery 28%, stereotaxic radiotherapy (SRT) 30%, whole-brain radiotherapy (WBRT) 24%, while 25% did not receive local treatment. With a median follow up of 44 months (mo), median OS for pts with BM was 12 mo. In multivariate analysis (table), NS, TB, time to BM (TTBM), number of line of therapy, and the use of a local therapy appear significantly correlated with OS. Conclusions: This is the largest series of BM from mRCC. In this series, characteristics of the disease appear to be more important than the type of local treatment of BM in terms of prognosis. Covariate HR (95CI) p TTBM yr < 1 1 1 - 5 0.45 (0.26-0.78) 0.004 > 5 0.36 (0.19-0.71) 0.003 TB mm > 100 2.32 (1.44-3.76) < 0.001 Line 0 1 1 2.05 (1.18-3.56) < 0.01 ≥ 2 2.64 (1.34-5.20) < 0.005 NS Yes 1.8 (1.10-2.96) 0.018 LT No 1 Surgery 0.09 (0.04-0.20) < 0.001 SRT 0.17 (0.09-0.32) < 0.001 WBRT 0.36 (0.20-0.65) 0.001
Abstract 15949: Activation of Adipose Tissue TACE/ADAM17 Leads to Coronary Microvascular Dysfunction in Older Obese Patients
Authors: Huijuan Dou, Alec Davila, Vijay Patel, Vinayak Kamath, Neil Weintraub, Zsolt Bagi
Journal: Circulation (2016)

Elevated inflammatory cytokine and adipokine levels, including tumor necrosis factor-α (TNF) and interleukin-6 (IL-6) is a hallmark of obesity- and aging-related cardiovascular pathologies. A disintegrin and metalloproteinase ADAM17 (TNF-α converting enzyme or TACE) regulates soluble TNF and IL-6 receptor levels. Here, we examined whether age-related changes in adipose tissue (AT)-expressed ADAM17 contributes to coronary microvascular dysfunction. Coronary arterioles (CA, ~100 μm in diameter) from right atrial appendages and AT from mediastinal fat depots were examined ex vivo in 68 consecutive patients who underwent open-heart surgery. CA and AT was also studied in 3-month (young) and 24-month (aged) mice fed a high-fat diet (HFD). We found that bradykinin-induced dilation in human CA significantly declines with age in obese, but not in lean patients. CA dilation was reduced in aged, but not in young HFD mice, which was accompanied by elevated plasma TNF and IL-6 levels and increased ADAM17 activity in A...