tbuckley/cabot-search huggingface dataset:
Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with oral S-1 for advanced gastric cancer with macroscopic peritoneal metastasis.
Authors: Hironori Yamaguchi, Hironori Ishigami, Shigenobu Emoto, Hiroharu Yamashita, Joji Kitayama
Journal: Journal of Clinical Oncology (2012)

e14530 Background: This phase II study was performed to evaluate the efficacy and the tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) combined with oral S-1 in gastric cancer patients with macroscopic peritoneal metastasis. We previously reported a phase I and II study with the same regimen in gastric cancer patients with peritoneal metastasis, including patients with positive peritoneal washing cytology but negative macroscopic peritoneal metastasis. This trial was scrutinized and approved by a committee appointed by the Ministry of Health, Labour, and Welfare in Japan and performed under the special interim system for Advanced Medical Technology so as to generate an evidence for future approval of the treatment by the Ministry. Methods: Gastric cancer patients with primary tumors with macroscopic peritoneal metastasis confirmed by staging laparoscopy were enrolled. PTX was administered intravenously at 50 mg/m 2 , and intraperitoneally through a subcutaneous implanted access port at 20 mg/m 2 on days 1 and 8. S-1 was administered orally twice daily at 80 mg/m 2 /day for 14 consecutive days followed by 7 days rest, repeated every 3 weeks. The primary endpoint was the one-year overall survival rate. Secondary endpoints were the response rate, efficacy against malignant ascites and safety. Results: In total, 35 patients were enrolled. All patients had several to numerous metastases to the distant peritoneum. The median number of administration course was 11 (range 2-29). The one-year overall survival rate was 77.1%. Massive malignant ascites decreased in 6 of 9 (66.7%) patients. Peritoneal washing cytology turned negative in 28 of 29 (96.7%) patients. The incidences of grade 3/4 hematological and non-hematological toxicities were 34% and 9%, respectively, all of which were reversible. Grade 3/4 toxicity was observed for neutropenia (34%), leukopenia (23%), anemia (9%). There were no treatment-related deaths. Conclusions: The combination chemotherapy regimen of weekly intravenous and intraperitoneal PTX combined with oral S-1 was well tolerated and active in gastric cancer patients with macroscopic peritoneal metastasis.
Quantitative Analysis of NAD Synthesis-Breakdown Fluxes
Authors: Ling Liu, Xiaoyang Su, William J. Quinn, Sheng Hui, Kristin Krukenberg, David W. Frederick, Philip Redpath, Le Zhan, Karthikeyani Chellappa, Eileen White, Marie Migaud, Timothy J. Mitchison, Joseph A. Baur, Joshua D. Rabinowitz
Journal: Cell Metabolism (2018)
Placenta-specific drug delivery by trophoblast-targeted nanoparticles in mice
Authors: Baozhen Zhang, Lunbo Tan, Yan Yu, Baobei Wang, Zhilong Chen, Jinyu Han, Mengxia Li, Jie Chen, Tianxia Xiao, Balamurali K Ambati, Lintao Cai, Qing Yang, Nihar R Nayak, Jian Zhang, Xiujun Fan
Journal: Theranostics (2018)

Rationale: The availability of therapeutics to treat pregnancy complications is severely lacking, mainly due to the risk of harm to the fetus. In placental malaria, Plasmodium falciparum-infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) on the surfaces of trophoblasts. Based on this principle, we have developed a method for targeted delivery of payloads to the placenta using a synthetic placental CSA-binding peptide (plCSA-BP) derived from VAR2CSA, a CSA-binding protein expressed on IEs. Methods: A biotinylated plCSA-BP was used to examine the specificity of plCSA-BP binding to mouse and human placental tissue in tissue sections in vitro. Different nanoparticles, including plCSA-BP-conjugated nanoparticles loaded with indocyanine green (plCSA-INPs) or methotrexate (plCSA-MNPs), were administered intravenously to pregnant mice to test their efficiency at drug delivery to the placenta in vivo. The tissue distribution and localization of the plCSA-INPs were monitored in live animals using an IVIS imaging system. The effect of plCSA-MNPs on fetal and placental development and pregnancy outcome were examined using a small-animal high-frequency ultrasound (HFUS) imaging system, and the concentrations of methotrexate in fetal and placental tissues were measured using high-performance liquid chromatography (HPLC). Results: plCSA-BP binds specifically to trophoblasts and not to other cell types in the placenta or to CSA-expressing cells in other tissues. Moreover, we found that intravenously administered plCSA-INPs accumulate in the mouse placenta, and ex vivo analysis of the fetuses and placentas confirmed placenta-specific delivery of these nanoparticles. We also demonstrate successful delivery of methotrexate specifically to placental cells by plCSA-BP-conjugated nanoparticles, resulting in dramatic impairment of placental and fetal development. Importantly, plCSA-MNPs treatment had no apparent adverse effects on maternal tissues. Conclusion: These results demonstrate that plCSA-BP-guided nanoparticles could be used for the targeted delivery of payloads to the placenta and serve as a novel placenta-specific drug delivery option.
Publisher Correction: The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning
Authors: Zikai Zhou, An Liu, Shuting Xia, Celeste Leung, Junxia Qi, Yanghong Meng, Wei Xie, Pojeong Park, Graham L. Collingridge, Zhengping Jia
Journal: Nature Neuroscience (2018)
Association of COX-2 expression with lymphocyte infiltration in colorectal cancer.
Authors: Zehua Wu, Jianwei Zhang, Yue Cai, Liu Yang, Yanhong Deng
Journal: Journal of Clinical Oncology (2018)

716 Background: It is proved that in colorectal cancer, Tumor infiltrating lymphocytes is associated with good prognosis. Someone pointed out that COX inhibitors act with anti-PD-1 antibody in pre-clinical models. This study aims to investigate whether COX-2 expression is associated with lymphocyte infiltration, and to know how they affect the survival. Methods: We collected specimens of resected tumor from patients who received surgery and pathological staging II and III from May 2007 to Jan 2012. These patients received surgery and adjuvant therapy with FOLFOX regimen. Tissue microarrays were made by resected tumor. Immunohistochemical staining was performed with COX-2, CD3 and CD8, PD-1 and PD-L1 antibody. Staining result of COX-2 was measured by two degrees of high and low. For CD3 and CD8, stained lymphocytes in and around tumor tissue were defined stained positive. For PD-1 and PD-L1, more 1% cells stained were defined positive stained. Results: COX-2 expression was correlated with CD3 and CD8.There were more CD3 (63.0% vs. 48.5% p=0.028) and CD8 (95.5% vs. 83.5% p=0.002) expression in the COX-2 high expression group. However, there was no significant difference in PD-1 and PD-L1 expression between COX-2 high and low expression group. As for CD3, PD-1 expression was higher in CD3 positive group than in the negative group (27.6% vs. 10.3% p=0.001). similarly, PD-L1 expression was higher in the CD3 positive group (47.3% vs. 15.2% p &lt; 0.001). but PD-1 and PD-L1 expression was not significantly different between in the CD8 positive and negative group. Three years DFS for the whole group patient was 77.6%. There was a better tendency for 3 years DFS in the CD3 positive group (80.6% vs. 73.7%), but it was not significantly different (p=0.216). Conclusions: CD3 and CD8 expression were more in the COX-2 high expression group, which indicated COX-2 inhibitor use may act with tumor infiltrating lymphocytes. But neither PD-1 nor PD-L1 expression was correlated with COX-2 expression. Infiltrating CD3 lymphocytes may be associated with better DFS for adjuvant chemotherapy colorectal cancer patients. [Table: see text]
Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer
Authors: Elysia C. Saputra, Lu Huang, Yihui Chen, Lisa Tucker-Kellogg
Journal: Cancer Research (2018)

Abstract The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them “proefficacy” strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them “antiresistance” strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy. Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 2419–31. ©2018 AACR.
The easy Liver Fibrosis Test (eLIFT) avoids unnecessary specialized evaluations of liver fibrosis in NAFLD and ALD patients
Authors: B. Thomas, L. Adrien, S. Bertrais, P. Etienne, Frédéric Oberti, I.F. Hubert, P. Cales, J. Boursier
Journal: Journal of Hepatology (2018)
Patient-reported Outcomes for the Detection, Quantification, and Evaluation of Chronic Obstructive Pulmonary Disease Exacerbations
Authors: Alex J. Mackay, Konstantinos Kostikas, Lindsey Murray, Fernando J. Martinez, Marc Miravitlles, Gavin Donaldson, Donald Banerji, Francesco Patalano, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Section:ChooseTop of pageAbstract <<The Many Faces of HCRU-de...Regulatory GuidanceSymptom Diary CardsElectronic Symptom Diary ...The Exacerbations and Sym...Exacerbations of Chronic ...Health Status MeasuresChronic Respiratory Disea...Interpreting HCRU and PRO...Future DevelopmentsConclusionsReferencesCITING ARTICLES
Outcome of metastases resection from gastric cancer: A Spanish multicenter retrospective study.
Authors: Pablo Reguera Puertas, Ainhoa Madariaga Urrutia, Federico Longo, Maria Alsina, Cinta Hierro, Raquel Guardeño, Ana B. Custodio, Jorge Adeva Alfonso, Javier Medina, Maria Gion Cortés, Alfonso Cortés Salgado, Jacobo Muñoz del Toro, Silvia Patricia Cortez Castedo, Julio Galindo, Pedro Lopez Hervas, Mercedes Rodríguez Garrote, Reyes Ferreiro Monteagudo, Vanessa Pachón Olmos, Carmen Guillén Ponce, Alfredo Carrato
Journal: Journal of Clinical Oncology (2015)

e15069 Background: The current standard treatment for metastatic gastric cancer (MGC) is systemic chemotherapy. A small number of retrospective series have reported long-term survival in selected MGC patients (pts) treated with metastasectomy (MS), although most of the studies are focused in Asiatic population. Prognostic factors and indications for surgery are still unclear. Methods: We retrospectively analyzed the internal database of six Spanish hospitals, identifying 39 MGC pts who underwent surgery for primary GC and MS from October 1997 to August 2014. Clinicopathological and treatment related characteristics were collected in order to find potential prognostic factors. A score was performed to predict survival. Results: Median age at diagnosis was 59 years, with male predominance (72%). Median overall survival (OS) since diagnosis was 37 months (m) (95%CI 27-46m). Median OS and progression free survival (PFS) since MS were 20m (95%CI 7-33m) and 9m (95%CI 4-14m), respectively. Type of resection and complementary treatment (CT) had a significant effect on PFS, while prognostic factors for prolonged OS were R0 resection and metachronous metastases (MM), with a slight trend for CT use (Table 1). In the proposed score we included the prognostic criteria MM, R0 MS and use of CT; median PFS/OS for patients who met 3, 2, 1 and none of the factors were 18m/not reached, 15m/63m, 6m/15m and 3m/12m respectively (Log-rank: PFS p = 0.002, OS p = 0.042). Conclusions: Patients with MM who are fit for systemic treatment may benefit from a MS if R0 resection is feasible. Multidisciplinary evaluation is mandatory for this approach. The results of our exploratory analysis and prognostic score need to be confirmed in prospective studies. Surgery, complementary treatment and synchronicity as prognostic factors for PFS and OS. Factor Median (m) HR CI 95% Log rank PFS Primary tumor resection R0 R1-2 12 2 0.18 0.06-0.52 < 0.001 MS R0 R1-2 15 5 0.39 0.16-0.91 0.025 CT Neoadjuvant and/or Adjuvant No 18 5 0.27 0.12-0.63 0.001 OS Primary tumor resection R0 R1-2 36 7 0.32 0.11-0.94 0.03 MS R0-R1 R2 36 11 0.26 0.09-0.76 0.008 Synchronicity Synchronous Metachronous 16 NR 0.27 0.08-0.94 0.028 CT Neoadjuvant and/or Adjuvant No 37 18 0.46 0.18-1.18 0.1
Positron Emission Tomography–Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial
Authors: Ulrich Dührsen, Stefan Müller, Bernd Hertenstein, Henrike Thomssen, Jörg Kotzerke, Rolf Mesters, Wolfgang E. Berdel, Christiane Franzius, Frank Kroschinsky, Matthias Weckesser, Dorothea Kofahl-Krause, Frank M. Bengel, Jan Dürig, Johannes Matschke, Christine Schmitz, Thorsten Pöppel, Claudia Ose, Marcus Brinkmann, Paul La Rosée, Martin Freesmeyer, Andreas Hertel, Heinz-Gert Höffkes, Dirk Behringer, Gabriele Prange-Krex, Stefan Wilop, Thomas Krohn, Jens Holzinger, Martin Griesshammer, Aristoteles Giagounidis, Aruna Raghavachar, Georg Maschmeyer, Ingo Brink, Helga Bernhard, Uwe Haberkorn, Tobias Gaska, Lars Kurch, Daniëlle M.E. van Assema, Wolfram Klapper, Dieter Hoelzer, Lilli Geworski, Karl-Heinz Jöckel, André Scherag, Andreas Bockisch, Jan Rekowski, Andreas Hüttmann
Journal: Journal of Clinical Oncology (2018)

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.
Effectiveness and safety of direct-acting antiviral therapies in chronic hepatitis C infections patients with cirrhosis in Turkey
Authors: F. Tabak, N.O. Cuvalci, B. Kurtaran, Y. Onlen, N.D. Sari, S. Kaya, N. Ince, S. Esen, I. Dokmetas, M. Namiduru, A. Batirel, T. Yamazhan
Journal: Journal of Hepatology (2018)
Abstract 16224: Stroke Volume Recovery Impact on Outcomes Following Surgical Aortic Valve Replacement for Severe Aortic Stenosis
Authors: Anthony Poulin, Maxime Berthelot-Richer, Lionel Tastet, Louis Simard, Dimitri Kalavrouziotis, Philippe Pibarot, Marie-Annick Clavel
Journal: Circulation (2016)

Background:  In patients with aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF), pre-operative indexed stroke volume (SVi) is a predictor of short-term mortality following surgical aortic valve replacement (SAVR). However, long-term predictors of mortality remain controversial. The aim of this study was to assess the impact of postoperative SVi on outcomes in patients with AS and preserved LVEF.   Methods:  We examined 1,865 patients with AS and preserved LVEF who underwent SAVR. A total of 341 patients were excluded due to absent post-operative echocardiography or without reliable stroke volume measurement.   Results:  Among these patients, 502 (33%) were in Paradoxical Low Flow (PLF) AS as defined by preoperative SVi of ≤35 mL/m 2 ; and 1022 (67%) were in Normal Flow (NF) AS as defined by preoperative SVi of >35 mL/m 2 . Groups were subdivided according to post-operative SVi at discharge (SViD): 363 (24%) had PLF and low SViD (Persisting Low Flow); 129 (9%) had PLF and normal SViD (Normalized Flow); 597 (39%) had NF and low SViD (New Onset LF); and 435 (28%) had NF and normal SViD (Maintained NF). There were 169 deaths (11%) occurring at a mean follow-up of 33 months. After comprehensive adjustment, patients with persisting low flow have a higher late postoperative mortality (HR: 1.33; p=0.047; Table 1) and persistent echocardiographic features of low flow state (Figure 1).   Conclusion:  Patients with AS showing no recovery of SVi after SAVR have a higher rate of mortality and persistent low flow state, which may be related to the pre-existing ventricular dysfunction. When PLF AS is present, early referral for SAVR must be considered as this could improve SAVR outcomes.
Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas
Authors: Antonio Omuro, Kathryn Beal, Katharine McNeill, Robert J. Young, Alissa Thomas, Xuling Lin, Robert Terziev, Thomas J. Kaley, Lisa M. DeAngelis, Mariza Daras, Igor T. Gavrilovic, Ingo Mellinghoff, Eli L. Diamond, Andrew McKeown, Malbora Manne, Andrew Caterfino, Krishna Patel, Linda Bavisotto, Greg Gorman, Michael Lamson, Philip Gutin, Viviane Tabar, Debyani Chakravarty, Timothy A. Chan, Cameron W. Brennan, Elizabeth Garrett-Mayer, Rashida A. Karmali, Elena Pentsova
Journal: Journal of Clinical Oncology (2018)

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.