tbuckley/cabot-search huggingface dataset:
Клініко-патогенетичні аспекти хронічного панкреатиту в поєднанні з вірусним гепатитом С в амбулаторній практиці
Authors: L.S. Babinets, E.R. Shaygen, G.A. Khomin
Journal: GASTROENTEROLOGY (2018)

Актуальність. Останніми роками зросла увага до інфекційного агента, вплив якого може призвести до розвитку запального процесу в підшлунковій залозі. Значне поширення вірусного гепатиту С серед населення, різноманітність його позапечінкових проявів обумовлюють актуальність проблеми. Недостатність розробки питань первинної й вторинної профілактики хронічного панкреатиту мотивує до глибшого вивчення механізму його розвитку на тлі вірусного гепатиту С. Мета: вивчити клінічний перебіг хронічного панкреатиту у хворих із супутнім вірусним гепатитом С. Матеріали та методи. Обстежено 57 хворих на хронічний панкреатит із супутнім вірусним гепатитом С. Групу порівняння становили 20 осіб, хворих на хронічний панкреатит. Для встановлення клінічного діагнозу хронічного панкреатиту й вірусного гепатиту С усі хворі були обстежені згідно з протоколами, затвердженими наказами МОЗ України № 638 від 10.09.2014 і № 729 від 18.07.2016. Діагноз хронічного панкреатиту й вірусного гепатиту С верифікували на підставі даних анамнезу захворювання, клінічних проявів і результатів досліджень. Загальноклінічні й біохімічні обстеження проводили хворим на хронічний панкреатит у фазі загострення й нестійкої ремісії, хворим із вірусним гепатитом С — у фазі стійкої ремісії. Результати. У клінічному перебігу хронічного панкреатиту із супутнім вірусним гепатитом С провідне місце посідали больовий, диспептичний синдроми й порушення випорожнення, що були більш вираженими, ніж у групі порівняння (вірогідна відмінність від показників II групи, p &lt; 0,05). У хворих на хронічний панкреатит із супутнім вірусним гепатитом С виявили анемію легкого ступеня, зниження рівня загального білка в крові, гіпербілірубінемію, гіперхолестеринемію, підвищення рівня ферментів аланінамінотрансферази й аспартатамінотрансферази, підвищення рівнів амілази крові й діастази сечі (вірогідна відмінність стосовно II групи, p &lt; 0,05). У хворих на хронічний панкреатит із супутнім вірусним гепатитом С показник копрограми становив (5,20 ± 0,82) бала, а у хворих на хронічний панкреатит — (3,10 ± 0,32) бала (виявлено значно гірші показники, більш виражений запальний синдром і дисбактеріоз). У двох досліджуваних групах переважала стеаторея II типу. Глибина структурних змін у підшлунковій залозі за даними ультразвукового дослідження в групі хворих на хронічний панкреатит із супутнім вірусним гепатитом С становила (2,56 ± 1,10) бала, що відповідає процесу середнього ступеня тяжкості. У контрольній групі ступінь ураження становив (1,90 ± 0,60) бала. Висновки. На підставі оцінки даних дослідження встановлено негативний вплив супутнього вірусного гепатиту С на перебіг хронічного панкреатиту.
Systematic review of a personalized strategy in cancer clinical trials leading to FDA approval.
Authors: Denis Leonardo Fontes Jardim, Maria Clemence Schwaederle, J. Jack Lee, David S. Hong, Alexander M. Eggermont, Richard L. Schilsky, John Mendelsohn, Vladimir Lazar, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2014)

11047 Background: Evidence for the hypothesis that personalization of therapy optimizes benefit is a subject of debate. We compared efficacy between US Food and Drug Administration (FDA) approved cancer treatments deploying a personalized strategy vs. those without a biomarker-based rationale. Methods: We reviewed registration trials (based on package inserts from Drugs@FDA) that evaluated new agents receiving FDA approval (Sept. 1998 to June 2013) for cancer. Pooled analysis of response rate (RR), progression-free survival (PFS) and overall survival (OS) for all trials and hazard ratios (HRs) for time-to-event endpoints for randomized trials were compared between personalized (defined as using a drug matched to a biomarker or in a population where > 50% of patients harbor the cognate target) vs. non-personalized trials. Results: A total of 58 approved drugs were included (57 randomized [32% personalized] and 55 non-randomized trials [47% personalized]; N=38,104 patients). Personalized trials more often included oral drugs (68% vs. 35%, P=0.001), single agents (89% vs. 71%, P=0.036) and more frequently allowed crossover to experimental arms than non-personalized trials (67% vs. 28%, P=0.009). RR was significantly higher (49% vs. 25%, P<0.001) and PFS was longer (8.5 vs. 5.5 mos, P=0.001) with a personalized approach. In the multilinear regression analysis, personalized therapy was selected as an independent factor predicting a higher RR (P<0.001) and longer PFS (P=0.002). Median HR for PFS of experimental to control arms was 0.37 for personalized vs. 0.58 for non-personalized trials (P=0.003), indicating that, in randomized trials, the personalized experimental arm had significantly more improvement in PFS. Personalized trials also showed a longer OS (median= 18.2 vs. 13.5 mos, P=0.035 in the multilinear analysis), even though crossover was allowed more frequently in personalized trials. Median treatment-related mortality did not differ (0.4%, personalized vs. 1.0%, non-personalized, P=0.22). Conclusions: Personalized trials were associated with more pronounced clinical benefit, expressed by significantly higher RR and longer PFS and OS, despite the latter being confounded by more frequent crossover.
Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma
Authors: Chuan Xing Wu, Xiao Qi Wang, Siu Ho Chok, Kwan Man, Simon Hing Yin Tsang, Albert Chi Yan Chan, Ka Wing Ma, Wei Xia, Tan To Cheung
Journal: Theranostics (2018)

Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential. Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies. Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation. Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.
Clinical outcomes of endoscopic submucosal dissection for lesions on the proximal location of the stomach
Authors: S. Kim, C. Choi, D. Kang, H. Kim, S. Park, D. Ryu, J. Ko, H. Kim, B. Kwon, K. Lee, J. Lee, J. Lee, H. Nam
Journal: Annals of Oncology (2018)

Introduction: Tumors located on the proximal stomach are associated with the longer procedure time and lower en bloc resection of endoscopic submucosal dissection (ESD). Especially, ESD for lesions after distal gastrectomy is more difficult because of the narrow inner space. We aimed to evaluate the therapeutic outcomes of ESD for lesion on the remnant stomach compared with that on the upper third of whole stomach. Methods: A total of 135 patients with neoplasm located on the proximal stomach who received ESD from Aug 2008 to Dec 2016. We retrospectively reviewed en bloc resection rate, complete resection rate, and complication rate according to the status of stomach whether distal gastrectomy was done or not. Results: The rates of en bloc resection and complete resection showed no significant difference between the remnant stomach and entire stomach in the en bloc (92% [23/25] and 93.6% [103/110], p = 0.674) and complete resection (84% [21/25] and 90.0 [99/110], p = 0.478) rates. In a 1:3 matched data analysis, there was no significant difference in en bloc and complete resection rate. The tumor size and submucosa invasive cancer were associated with incomplete resection. In a multivariable analysis, the submucosa invasive cancer was an independent risk factor for incomplete resection. Conclusion: ESD is feasible treatment for the lesion located on the proximal stomach regardless the operation history of distal gastrectomy. However, the complete resection rate decreases for lesion invade the submucosa.
ATRT-30. INSTITUTIONAL EXPERIENCE OF PEDIATRIC PATIENTS WITH ATYPICAL TERATOID RHABDOID TUMORS TREATED AT PHOENIX CHILDREN’S HOSPITAL FROM 2000–2017
Authors: Elizabeth Eden, Nicole Mis, Lisa Keller, Cynthia Wetmore
Journal: Neuro-Oncology (2018)

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a malignant embryonal tumor of the central nervous system (CNS) that presents most often in patients 3 to 6 years of age. Most pediatric oncology centers have employed a multimodal approach to treatment though no standard of care exists. Phoenix Children’s Hospital (PCH) has provided treatment following “Boston Protocol.” This 53-week protocol includes surgical resection and intensive mutiagent chemotherapy followed by radiation, if indicated. This retrospective chart review analyzed historical data of patient demographics, treatment and outcomes for children undergoing therapy per the Boston protocol at PCH. Data collected included age, sex, date of diagnosis, race and molecular classifications. We analyzed location of tumor, extent of surgical resection, and treatment modalities utilized. We evaluated the toxicity profiles, as well as intervals of progression free and overall survival. Our cohort of 11 patients had a median age of 21 months (range: 3–54 mos). All of the patients had gross total resection and underwent chemotherapy. In addition, 58% also received radiation therapy. The most prevalent side effect was ototoxicity. Three patients (27%) are deceased and 73% under surveillance with a 2-year progression-free survival of 7.72 months.
DIPG-57. A COMPREHENSIVE GENE/PROTEIN INVESTIGATION OF THE TUMOUR MICROENVIRONMENT IN DIFFUSE MIDLINE GLIOMA IN CHILDREN
Authors: Katie Loveson, Helen Fillmore
Journal: Neuro-Oncology (2018)

Pediatric diffuse midline glioma (pDMG) is a rare aggressive childhood malignancy. While much is known concerning molecular genomics, our focus is on understanding the tumour microenvironment and how this influences cancer growth. We hope to learn how interaction and communication between host cells, tumour cells and extracellular matrix proteins (ECM) promote the pDMG growth. We conducted bioinformatic analysis using data obtained from R2: Genomics Analysis and Visualization Platform of pDMG tissue samples (GSE26576). In parallel, fixed-formalin paraffin embedded tissue (FFPE) was obtained from post-mortem brain. RNA was extracted from tumour core, adjacent and ‘normal’ tissue. Following quality control experiments to ensure RNA integrity, RNA was then used for a focused ECM array. Eighty ECM related genes were chosen for bioinformatics analyses to make indirect comparisons to the ECM focused RT2 profiler. Preliminary bioinformatic analyses indicate that 15 of the 80 genes were significantly up-regulated in pDMG tumours compared to normal brainstem (p<0.05). The most significantly differentially expressed include, Matrix Metalloproteinase1 (MMP1), Collagen type XI alpha 1 (COL11A1), and Matrix Metalloproteinase 16 (MMP16) (p<0.0001). In preliminary analyses of data obtained from FFPE tissue, tumour adjacent RNA was compared to ‘normal’ brain. Out of 80 genes, 7 were differentially expressed and include COL11A1, Collagen type VI alpha 2 (COL6A2) and Laminin alpha 3 (LAMA3). We believe that by identifying key host/tumour interactions that drive pDMG growth, this knowledge will help lead to improved therapeutics for this devastating childhood brain cancer.
OP0014 Serum urate, gout, and cardiovascular disease in a randomised controlled trial of canakinumab: a cantos secondary analysis
Authors: D. Solomon, R.J. Glynn, J.G. MacFadyen, P. Libby, T. Thuren, B.M. Everett, P.M. Ridker
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Serum urate is a risk marker for both gout and cardiovascular disease, but trial data demonstrating that drugs which reduce gout also reduce cardiovascular event rates is scarce. It is also uncertain if any such effects are mediated through urate levels. <h3>Objectives</h3> We examined the relationships between serum urate (SUA), canakinumab, and incidence rates for gout and cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised double-blind placebo controlled trial of IL-1β inhibition. <h3>Methods</h3> 10 061 patients with stable atherosclerosis (prior myocardial infarction) and hsCRP ≥2 mg/L were randomly allocated to placebo or to one of three doses of canakinumab (50 mg, 150 mg, or 300 mg), administered subcutaneously once every three month. Serum urate and hsCRP were tested at baseline and every 3 months for the first year and then annually. A physician diagnosed history of gout was ascertained at baseline and subsequent attacks were assessed during follow-up as part of the systematic adverse event reporting. The rates of gout and major adverse cardiovascular events (myocardial infarction, stroke, re-vascularisation, and cardiovascular death) were compared across different baseline SUA levels and by randomised treatment assignment. <h3>Results</h3> The groups were well balanced with respect to baseline characteristics with a median follow-up of 3.7 years. Median age was 61 years, 74% were male, median BMI was 29.8kg/m<sup>2</sup>, and median SUA at baseline was 6.1 mg/dl (IQR: 5.2, 7.2). In the placebo group, rates for both gout and major adverse cardiovascular events increased across baseline SUA strata. Rates were 0.28, 1.36, and 5.94 per 100 person years for gout and 4.1, 5.3, and 5.6 for major adverse cardiovascular events per 100 person years for SUA levels of &lt;6.9, 6.9–8.9, and ≥9.0 mg/dL, respectively. Random allocation to all dosages of canakinumab reduced rates of incident gout (see figure 1). This reduction in gout by canakinumab was observed at all baseline SUA levels (see table 1), and canakinumab had no effect on SUA levels over time but did reduce hsCRP. <h3>Conclusions</h3> The CANTOS trial confirms that serum urate is a risk marker for both gout and cardiovascular events and demonstrates that IL-1β inhibition is effective in preventing both of these inter-related conditions. However, canakinumab had no effects on serum urate itself. <h3>Reference</h3> [1] Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med2017;377:1119. <h3>Disclosure of Interest</h3> D. Solomon Grant/research support from: Astra Zeneca, R. Glynn: None declared, J. MacFadyen: None declared, P. Libby: None declared, T. Thuren Employee of: Novartis, B. Everett: None declared, P. Ridker: None declared
Effects of Donor and Host Lymphoid and Myeloid Tissue Injections in Lethally X-irradiated Mice Treated with Rat Bone Marrow&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: George W. Santos, Leonard J. Cole
Journal: JNCI Journal of the National Cancer Institute (1958)
Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche
Authors: Shokichi Tsukamoto, Marianne B. Løvendorf, Jihye Park, Karma Z. Salem, Michaela R. Reagan, Salomon Manier, Oksana Zavidij, Mahshid Rahmat, Daisy Huynh, Satoshi Takagi, Yawara Kawano, Katsutoshi Kokubun, Charlotte Albæk Thrue, Kenichi Nagano, Andreas Petri, Aldo M. Roccaro, Marzia Capelletti, Roland Baron, Sakari Kauppinen, Irene M. Ghobrial
Journal: Leukemia (2018)
Nano-delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in desmoplastic melanoma
Authors: Lin Hou, Qi Liu, Limei Shen, Yun Liu, Xueqiong Zhang, Fengqian Chen, Leaf Huang
Journal: Theranostics (2018)

Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy.To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of desmoplastic melanoma.Methods: Frax NE was prepared by an ultrasonic emulsification method.The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis.Immune cell populations in tumor and LNs were detected by flow cytometry.Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells.A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME.In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced.Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced.Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped.Therefore, a tumor-specific peptide vaccine was combined with Frax NEs.The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death.Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced desmoplastic melanoma.
EMBR-11. TANDEM HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR INFANTS WITH EMBRYONAL BRAIN TUMORS
Authors: Asmik Gevorgian, Polina Tolkunova, Tatiana Iukhta, Elena Morozova, Ilya Kazantsev, Tatiana Andreeva, Andrew Kozlov, Svetlana Safonova, Yury Punanov, Ludmila Zubarovskaya, Olga Zheludkova, Boris Afanasyev
Journal: Neuro-Oncology (2018)

AIM: Embryonal brain tumors (EBTs) are the most common solid malignancy in children younger than 48 months. They are characterized by similar morphology (undifferentiated small round cell tumor), aggressive clinical course with a tendency to disseminate throughout central nervous system, and very poor prognosis. We tried to assess the effectiveness of tandem high-dose chemotherapy (HDCT) with autologous hematopoietic stem-cell transplantation (auto-HSCT) in these patients. A consecutive cohort of 39 infants under 48 months with different primary EBTs such as medulloblastoma, PNET NOS, pineoblastoma, ATRT, ETMR receiving tandem HDCT with auto-HSCT in 2010 to 2017. All patients underwent prior surgical resection and induction chemotherapy. The conditioning regimens for tandem auto-HSCT were carboplatin-etoposide for the first, and thiotepa-cyclophosphamide for the second one. All high-dose regimens were accompanied by intraventricular methotrexate injections. Most patients finished the therapy program, in 9 cases the second auto-HSCT was cancelled due to toxic HDCT complications (N=4) or early disease progression (N=5). The median follow-up is currently 24 (range 8–83) months. Two-year overall survival (OS) was 70% and disease free survival (DFS) was 59%. DFS was significantly better among patients in CR (75%) in compared to children in PR (51%) at the moment of HDCT (p=0.043). DFS in patients completing treatment program was 72%. Employment of tandem HDCT with auto-HSCT in infants with primary embryonal brain tumors may be a feasible option for patients in CR or PR after induction treatment. All conditioning regimens used had acceptable toxicity.
Next-generation point-of-care immunoassay system for rapid and accurate determination of cancer markers in the physician office.
Authors: Stephen M Zappala, John A Libertino, Alan J. Wein, E. Darracott Vaughan, Peter T. Scardino
Journal: Journal of Clinical Oncology (2012)

e15196 Background: Claros Diagnostics (Woburn, MA) has developed a novel multiplex immunoassay system designed to transition diagnostic tests performed at the centralized laboratory to the point-of-care (POC). The credit card-sized microfluidics disposable analyzes a fingerstick drop of whole blood with laboratory-quality results in 10 minutes, with significant ease-of-use. Total PSA was selected as an initial test to validate that this platform technology can achieve equivalent sensitivity, absence of interferences, etc. as compared to the reference laboratory. Further, the need to clinically validate the use incentives of such a POC system in optimizing the patient-physician encounter, practice efficiency, and overall quality of care were explored. Methods: We completed two consecutive studies measuring PSA in whole blood with the Claros system against the laboratory results in a matching serum sample. The first study entailed 72 patients from two sites and compared fingerstick samples against the laboratory Siemens Centaur serum assay, while the second study compared PSA results from 34 patients’ whole blood against the laboratory Roche E-170 serum assay. All studies were conducted under IRB approved protocols. Results: The PSA values measured in the 72 patients ranged from &lt;0.1 to 8.3 ng/mL. Linear regression yielded a slope of 1.05 and a R 2 value of 0.94. Range of PSA values in the second study on 34 patients were &lt;0.1 to 13.5 ng/mL, from which the linear regression analysis yielded a slope of 1.04 and a R 2 value of 0.98. In addition, specific data obtained between 0.1 and 1 ng/mL yielded an excellent correlation with a slope of 0.93 and a R 2 value of 0.94. Overall (n=106) 7 patients were measured &lt;0.1ng/mL by both assays. Conclusions: Quantitative results obtained with the Claros POC system using a fingerstick of whole blood correlated extremely well with laboratory assays over the clinically relevant range of PSA, including at very low PSA concentrations (essential to detect cancer recurrence post-intervention). Overall ease of use, the ability to use fingerstick blood and short time-to-result converge in improving physician practice efficiency and patient-physician interactions.