bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase III trial to confirm the superiority of S-1 adjuvant chemotherapy for vulnerable elderly patients with pathological stage II/III gastric cancer after curative resection: JCOG1507 (BIRDIE).
Authors: Yamaguchi Kazuya , Yoshida Kazuhiro , Mizusawa Junki , Mizutani Tomonori , Ito Seiji , Nishida Yasunori , Yabusaki Hiroshi , Sano Takeshi , Sasako Mitsuru , Katayama Hiroshi , Fukuda Haruhiko , Boku Narikazu , Yoshikawa Takaki , Terashima Masanori 
Published: January 2019

TPS196 Background: Base on the ACTS-GC trial, adjuvant chemotherapy with S-1 at a dose of 80 mg/m2/day (4 weeks on and 2 weeks off, repeated for one year) is the standard care for stage II/III gastric cancer (GC) patients (pts) after D2 gastrectomy. As Japan has the most aged population in the world, the actual number of elderly GC pts is still increasing. While elderly pts population is heterogeneous and is conceptually composed of “fit”, “vulnerable” and “frail” pts, full-dose adjuvant chemotherapy tends to be given to fit elderly pts in clinical practice. However, it has not been determined yet whether S-1 should be administered to vulnerable pts over 80. Actually, according to the questionnaire survey conducted on 58 institutions of Stomach Cancer Study Group of Japan Clinical Oncology Group, S-1 was administered on only 15% to stage II/III pts > = 80 years old suggesting that surgery alone is generally considered as community standard for vulnerable pts. It is an urgent need to establish the standard adjuvant treatment of the vulnerable elderly GC pts. Methods: The study is designed to confirm the superiority of S-1 treatment group over surgery alone group focusing on vulnerable > = 80 years old pts in stage II / III GC after curative resection. The “vulnerable” is defined in this study based on the three factors [creatinine clearance (Ccr), weight loss, type of surgery] considered to have the most influence on compliance of S-1, that is Ccr > = 30ml/min, weight loss < 15% and total gastrectomy, or 80 > Ccr > = 30ml/min, weight loss < 15% and other than total gastrectomy. Initial dose was reduced by 1 rank from the standard dose. The primary endpoint is overall survival (OS) and the secondary endpoints are relapse free survival, time to treatment failure, treatment continuity, relative dose intensity and adverse events. We assume expected 3-year OS in surgery alone arm will be 55% and S-1 treatment will improve the survival by more than 10%. 370 pts are required to provide 75% of power and 5% one-sided alpha error, with 4 years accrual and 3 years of follow up period. The trial has started from January 2017. Clinical trial information: UMIN000025742. Clinical trial information: 000025742.
Phase I open label trial of intraperitoneal paclitaxel (IPP) in combination with intravenous cisplatin (C) and oral capecitabine (X) in patients with advanced gastric cancer and peritoneal metastases.
Authors: Vatandoust Sina , Bright Tim I. , Roy Amitesh Chandra , Klevansky Myron , Bull Jeff , Karapetis Christos Stelios 
Published: January 2019

TPS201 Background: There have been few studies investigating advanced gastric cancer with peritoneal involvement and ascites, showing poor survival in these patients. Researchers from Japan have shown that chemotherapy with IPP and Oral S-1 (tegafur/gimeracil/oteracil) is active in these patients. These results have been achieved in a different genetic pool (Japanese population) compared with Australia, using regimens that are not available here. We have designed this phase I trial to investigate the Maximum Tolerated Dose (MDT) of IPP in combination with a standard chemotherapy combination (C+X) in these patients. Methods: This is an open-label, single centre, phase I trial with 3+3 expanded cohort design. Patients will have an IP catheter placed surgically after trial enrolment. Study was approved by the relevant ethics committee. Chemotherapy: maximum of six 21-day cycles of: X (PO, 1000 mg/m2 BD days 1-14) + C (IV 80mg/m2 day 1) + IPP (day 1 and 8) with the following doses: Cohort-1: 10 mg/m2, Cohort-2: 20 mg/m2 and Cohort-3: 30 mg/m2. Important inclusion criteria: age ≥ 18 years, signed written informed consent, HER-2 non-amplified gastric adenocarcinoma with biopsy or cytology showing peritoneal involvement and/or ascites, adequate organ function and signed consent. Important exclusion criteria: history of another malignancy within 5 years, life expectancy < 3months, peripheral neuropathy, recent ( < 4 weeks) abdominal or pelvic radiation treatment, significant intra-abdominal adhesions or active intra-abdominal sepsis. Cohorts 1 and 2 have been completed. Enrolment to cohort-3 is beginning in October 2017. Clinical trial information: ACTRN12614001063606.
Trans-intra-arterial gemcitabine versus continuation of IV gemcitabine and nab-paclitaxel following radiotherapy for locally advanced pancreatic cancer (TIGeR-PaC).
Authors: Pishvaian Michael J. , Goodman Karyn A. , Zervos Emmanuel E. , Muscarella Peter , Kim Alexander Y. , Bloomston Mark , Nutting Charles W. , Meredith Ken Lee , Lavu Harish , Chuy Jennifer W. , Lee Justin , Matrana Marc Ryan , Lavarias Clifford , Gellert Scott , Agah Ramtin 
Published: January 2019

TPS529 Background: Treatment of locally advanced pancreatic cancer (LAPC) remains a challenge, and novel therapy options for local treatment of disease beyond systemic therapy are needed. Recently published data of intra-arterial delivery of gemcitabine (IAG) for local disease control has shown this approach to be safe (J. Pancreatic Cancer 3(1) 58:65). Furthermore, in patients who have received prior radiation for LAPC, there seems to be an effect on the local microvasculature that enhances the clinical efficacy of IAG. TIGeR-PaC is a randomized Phase 3 trial designed to test if the combination of induction systemic chemotherapy plus radiation followed by IAG is superior to systemic chemotherapy plus radiation alone (NCT03257033). Methods: All subjects with biopsy proven, and imaging-confirmed LAPC (by the NCCN guidelines) will receive induction therapy with IV gemcitabine plus nab-paclitaxel, for approximately four months, during which time a course of radiation therapy will also be incorporated. Subjects without evidence of disease progression will then be randomized to receive either IAG (test group); or continue only IV gemcitabine plus nab-paclitaxel (control group). Subjects will receive the randomized treatments for up to 16 weeks or until progression. Non-progressing patients from both groups will then receive, at the discretion of the investigator, either a continuation of IV gemcitabine and nab-paclitaxel, or oral capecitabine until disease progression. The primary endpoint is progression free survival; secondary endpoints will include overall survival, neutropenia, quality of life, and neuropathy assessed over 2 years. Based on an assumed superiority of IAG therapy, which will lead to an increased PFS from 6 months (control group) up to 12 months (IAG group), with an alpha-error of 0.05 and a 90% power, 132 patients will be randomized; assuming a 30% dropout during the induction phase prior to randomization, 200 patients will be recruited. TIGeR-PaC will test the hypothesis that IAG local therapy, after induction systemic chemotherapy plus radiation in patients with LAPC is superior to systemic therapy plus radiation alone. Clinical trial information: NCT03257033.
A pilot study of ponatinib in cholangiocarcinoma patients with FGFR2 fusions.
Authors: DeLeon Thomas , Alberts Steven R. , McWilliams Robert R. , Hubbard Joleen Marie , Ahn Daniel H. , Bekaii-Saab Tanios S. , Mody Kabir , Roberts Lewis R. , Salomao Marcela , Kipp Benjamin , Halfdanarson Thorvardur Ragnar , Murtaza Muhammed , Ramanathan Ramesh K. , Dueck Amylou C. , Borad Mitesh J. 
Published: January 2019

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as > 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.
Phase II open-label, single-center study evaluating safety and efficacy of pembrolizumab following induction with the hypomethylating agent azacitidine in patients with advanced pancreatic cancer after failure of first-line therapy.
Authors: Safyan Rachael A , Gonda Tamas , Tycko Benjamin , Chabot John A. , Manji Gulam Abbas , Schwartz Gary K. , Oberstein Paul Eliezer 
Published: January 2019

TPS534 Background: First-line cytotoxic chemotherapy improves survival for patients with metastatic pancreatic adenocarcinoma (PDA) but the majority will progress after a median of 5-7 months. CD8 T-cells are thought to be the major anti-tumor effector cells and their density in resected pancreatic tumors correlates with survival. Our published pre-clinical data in the KPC-Brca1 mouse model shows that treatment with a hypomethylating agent inhibits tumor growth (Shakya, Gonda et al., Cancer Res, 2013) and, in recent data (B.T. and T.G. in preparation), combining a hypomethylating agent with an immune checkpoint inhibitor leads to slowing of tumor growth and increased survival in KPC mice. We propose a novel approach to improve response rates with immune checkpoint blockade in pancreatic cancer by utilizing a hypomethylating agent to prime the tumor and its microenvironment, thereby increasing the number of intratumoral effector T cells, decreasing the immunosuppressive cell population, and influencing stromal-tumor cell interactions. Methods: Thirty-one evaluable subjects with advanced pancreatic cancer will be enrolled in this phase II study to evaluate the efficacy and safety of pembrolizumab following induction with azacitidine in the second-line setting. All subjects will have received a single line of chemotherapy for locally advanced or metastatic PDA prior to study enrollment. Subjects must have available baseline biopsy or archival tissue for analysis. Low-dose azacitidine (50 mg/m2 subcutaneous) will be given daily for 5 days every 4 weeks, and pembrolizumab 200 mg IV will be administered starting on day 15 and then continued every 3 weeks. Subjects will undergo an on-treatment biopsy during week 8. The primary efficacy endpoint will be PFS according to RECIST v1.1 criteria. There will be an accelerated phase Ib dose determination component with an initial 6 subjects. Secondary endpoints will include safety/tolerability, ORR, DOR, and OS. Multiple correlative analyses utilizing tissue and serum samples will be performed. Clinical trial information: NCT03264404.
Keynote 290: Pembrolizumab (pem) in combination with stereotactic body radiotherapy for resectable liver metastatic colorectal cancer.
Authors: Deming Dustin A. , Kim David H. , Matkowskyj Kristina , Uboha Nataliya Volodymyrivna , Lubner Sam Joseph , LoConte Noelle K. , Mulkerin Daniel , Abbott Daniel , Weber Sharon M. , Winslow Emily , Jeraj Robert , Ritter Mark A. , Perlman Scott , Eickhoff Jens C. , Bassetti Michael Frederick 
Published: January 2019

TPS874 Background: Colorectal cancer (CRC) is one of the few cancers in which aggressive local approaches to treat systemic metastases have resulted in clinical benefit. Despite these approaches 70-80% of patients (pts) with resectable metastatic disease will recur. The one-year recurrence rate for this population is ~40-50%. Immunotherapeutics have yet to be studied in this setting. To sensitize microsatellite stable (MSS) CRCs to immune therapies adjunctive therapies are required. Gross tumor microenvironments suppress systemic anti-cancer immune responses. Stereotactic body radiation therapy (SBRT) is commonly utilized to treat liver metastatic CRC, using very high doses of focused radiation to ablate tumors. This causes localized inflammation, a potential increase in immunogenic intra-tumoral and intra-lymphatic antigen release, and a rapid influx of responding immune cells. We hypothesize that radiotherapy-induced tumor necrosis, and surgical removal of the remaining immunosuppressive gross disease will enhance the immunogenicity of CRC and potentiate the effectiveness of PD-1 blockade. Methods: This is a single arm phase 1b investigator-initiated study (NCT02837263) to evaluate the use of pem in combination with ablative radiotherapy for the treatment of oligometastatic CRC. This study examines the sequential use of SBRT, then pem followed by resection of all known sites of disease and 6 months of adjuvant pem. Pts with MSS CRC with resectable liver metastatic disease who have received prior FOLFOX are eligible. The primary endpoints are safety/tolerability and the rate of cancer recurrence at 1 year. Secondary endpoints include time to disease recurrence, disease free survival and overall survival. This study is currently enrolling with a planned total accrual of 15 patients. Correlative studies examine PD-L1 status, tumor infiltrating lymphocytes, evidence of an abscopal effect, versican proteolysis as a novel immune biomarker, and the ability of multiparametric fluorodeoxyglucose (FDG) PET MR and fluorothymidine (FLT) PET CT to detect immune infiltration. Clinical trial information: NCT02837263.
Potential Roles of CD34+ Fibrocytes Masquerading as Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy
Authors: Smith Terry J 
Published: January 2019

AbstractContextOrbital tissues in thyroid-associated ophthalmopathy exhibit particular reactivity and undergo characteristic remodeling. Mechanisms underlying these changes have remained largely unexplained. Studies have characterized orbital connective tissues and derivative fibroblasts to gain insights into local manifestations of a systemic autoimmune syndrome.Evidence AcquisitionA systematic search of PubMed was undertaken for studies related to thyroid-associated ophthalmopathy (TAO), orbital fibroblasts, and fibrocytes involved in pathogenesis.Evidence SynthesisOrbital tissues display marked cellular heterogeneity. Fibroblast subsets, putatively derived from multiple precursors, inhabit the orbit in TAO. Among them are cells displaying the CD34+CXC chemokine receptor 4+collagen I+ phenotype, identifying them as fibrocytes, derived from the monocyte lineage. Their unique presence in the TAO orbit helps explain the tissue reactivity and characteristic remodeling that occurs in the disease. Their unanticipated expression of several proteins traditionally thought to be thyroid gland specific, including the TSH receptor and thyroglobulin, may underlie orbital involvement in Graves disease. Although no currently available information unambiguously establishes that CD34+ orbital fibroblasts originate from circulating fibrocytes, inferences from animal models of lung disease suggest that they derive from bone marrow. Further studies are necessary to determine whether fibrocyte abundance and activity in the orbit determine the clinical behavior of TAO.ConclusionEvidence supports a role for fibrocytes in the pathogenesis of TAO. Recognition of their presence in the orbit now allows development of therapies specifically targeting these cells that ultimately could allow the restoration of immune tolerance within the orbit and perhaps systemically.
Serum levels of androgens in acne & their role in acne severity
Authors: Iftikhar Usma , Choudhry Nakhshab 
Published: January 2019

Objectives: To correlate acne severity with elevated androgen levels and to compare androgen levels between cases and controls.
Methods: This case-control study was carried out in the Department of Dermatology, Mayo Hospital, Lahore from March 2016 – March 2017. Two hundred and seventy patients and eighty age and gender-matched controls were recruited after ethical approval and informed consent and categorized into mild, moderate and severe acne. Severity was correlated with serum Testosterone, Dihydrotestoststerone and Dihydroepiandrosterone Sulphate levels. Quantitative variables were expressed as median and percentiles, comparisons done by Mann-Whitney and correlations by Spearman correlation. P-value of <0.05 was considered statistically significant.
Results: There were 142 (41%) males and 208 (59%) females. Ninety-Seven patients had mild, 108 moderate and 65 had severe disease. Median hormonal levels were 3.5ng/ml, 184pg/ml and 0.82ug/dl for Testosterone, Dihydrotestosterone and Dihydroepiandrosterone Sulphate respectively which differed significantly between cases and controls. There was no correlation with severity but the levels differed significantly between the different grades in case of Testosterone and DHEAS.
Conclusion: Androgens are not directly correlated with acne severity, but affect acne severity as seen in difference between their levels in different grades of acne. Anti-androgens may be initiated early in acne resistant to conventional therapy.
How to cite this:Iftikhar U, Choudhry N. Serum levels of androgens in acne & their role in acne severity. Pak J Med Sci. 2019;35(1):146-150. doi: https://doi.org/10.12669/pjms.35.1.131
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Challenges in the use of atomistic simulations to predict solubilities of drug-like molecules
Authors: Duarte Ramos Matos Guilherme , Mobley David L. 
Published: January 2019

Background: Solubility is a physical property of high importance to the pharmaceutical industry, the prediction of which for potential drugs has so far been a hard task. We attempted to predict the solubility of acetylsalicylic acid (ASA) by estimating the absolute chemical potentials of its most stable polymorph and of solutions with different concentrations of the drug molecule.Methods: Chemical potentials were estimated from all-atom molecular dynamics simulations. We used the Einstein molecule method (EMM) to predict the absolute chemical potential of the solid and solvation free energy calculations to predict the excess chemical potentials of the liquid-phase systems.Results: Reliable estimations of the chemical potentials for the solid and for a single ASA molecule using the EMM required an extremely large number of intermediate states for the free energy calculations, meaning that the calculations were extremely demanding computationally. Despite the computational cost, however, the computed value did not agree well with the experimental value, potentially due to limitations with the underlying energy model. Perhaps better values could be obtained with a better energy model; however, it seems likely computational cost may remain a limiting factor for use of this particular approach to solubility estimation. Conclusions: Solubility prediction of drug-like solids remains computationally challenging, and it appears that both the underlying energy model and the computational approach applied may need improvement before the approach is suitable for routine use.
An interpretable machine learning model of biological age
Authors: Wood Thomas , Kelly Christopher , Roberts Megan , Walsh Bryan 
Published: January 2019

Background: Assessments of biological (rather than chronological) age derived from patient biochemical data have been shown to strongly predict both all-cause and disease-specific mortality. However, these population-based approaches have yet to be translated to the individual. As well as using biological age as a research tool, by being able to better answer the question “why did we get this result?”, clinicians may be able to apply personalised interventions that could improve the long-term health of individual patients. Methods: Here, the boosted decision tree algorithm XGBoost was used to predict biological age using 39 commonly-available blood test results from the US National Health and Nutrition Examination Survey (NHANES) database. Results: Interrogation of the algorithm produced a description of how each marker contributed to the final output in a single individual. Additive explanation plots were then used to determine biomarker ranges associated with a lower biological age. Importantly, a number of markers that are modifiable with lifestyle changes were found to have a significant effect on biological age, including fasting blood glucose, lipids, and markers of red blood cell production. Conclusions: The combination of individualised outputs with target ranges could provide the ability to personalise interventions or recommendations based on an individual’s biochemistry and resulting predicted age. This would allow for the investigation of interventions designed to improve health and longevity in a targeted manner, many of which could be rooted in targeted lifestyle modifications.