bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baseline factors associated with acute progression of metastatic lesions after primary tumor resection in patients with unresectable colorectal cancer.
Authors: Akashi Momoko , Ando Takayuki , Hosokawa Ayumu , Yoshita Hiroki , Nanjyo Sohachi , Ueda Akira , Mihara Hiroshi , Fujinami Haruka , Kajiura Shinya , Ogawa Kohei , Sugiyama Toshiro 
Published: January 2019

860 Background: In patients with unresectable colorectal cancer, primary tumor resection is expected not only local control but also prolongation of survival time. However, in some cases, metastatic tumors have been known to rapidly progress after primary tumor resection. We examined clinical factors associated with acute metastatic progress after primary tumor resection, and it might lead to worse survival. Methods: We retrospectively analyzed 183 patients who were newly diagnosed with unresectable colorectal cancer in our institution between April 2007 and April 2016. Among all patients, 83 patients received resection of primary tumor without the presence of symptoms. They were divided into progression and non-progression group according to metastatic progression that evaluated CT scan from four to six weeks after surgery. We analyzed clinicopathological factors related to acute progression after primary tumor resection using Cox proportional hazards. Results: After resection of the primary tumor, 25 patients were classified into progression group and 58 patients were classified into non-progression group. In progression group, the median percent change in the sum of the longest diameters of target lesions was 29.6% (10.0-191.7%), and 22 (88.0%) patients showed to have new lesions after resection of the primary tumor. Multivariate analysis revealed LDH (HR 4.44, 95%CI 1.15-18.5, p = 0.02), number of liver metastasis (HR 3.28, 95% CI 1.09-10.0, p = 0.03) and RAS status (HR 3.08, 95% CI 1.05-9.46, p = 0.03) were independent baseline factors associated with acute progression after resection of the primary tumor. The median overall survival (OS) was 12.3 and 27.8 months in progression and non-progression group, respectively. Conclusions: Serum LDH, number of liver metastasis, and RAS mutation were baseline factors associated with acute progression of metastatic tumors after resection of primary tumor in patients with unresectable colorectal cancer. These results indicated that the resection of the primary tumor in patients with these factors might be avoided when they have no clinical symptoms.
Three-year outcomes of two phase II studies of adjuvant chemotherapy with S-1 plus oxaliplatin or capecitabine plus oxaliplatin in patients with stage III gastric cancer after D2 gastrectomy.
Authors: Nakamura Yoshiaki , Yamanaka Takeharu , Chin Keisho , Cho Haruhiko , Katai Hitoshi , Terashima Masanori , Ito Seiji , Hirao Motohiro , Yoshida Kazuhiro , Oki Eiji , Sasako Mitsuru , Emi Yasunori , Bando Hideaki , Kawashima Yoshiyuki , Fukunaga Tetsu , Gotoh Masahiro , Ishibashi Takako , Shitara Kohei 
Published: January 2019

94 Background: Two phase II trials of oxaliplatin-based adjuvant chemotherapy for patients (pts) with gastric cancer (GC) after D2 gastrectomy have been conducted in Japan; the J-CLASSIC study of capecitabine plus oxaliplatin (CAPOX) and the SOXaGC study of S-1 plus oxaliplatin (SOX). In the current study, we evaluated survival outcomes of the two trials. Methods: The J-CLASSIC, enrolling stage II and III pts from 12 centers between July 2012 and July 2013, evaluated eight cycles of CAPOX. The SOXaGC, enrolling stage III pts from 11 centers between July 2013 and February 2014, evaluated seven cycles of SOX after one cycle of S-1 monotherapy. The two studies were conducted sequentially and most centers (9 centers) participated in both trials. In this pooled analysis, we updated relapse-free survival (RFS) and overall survival (OS) information. The median follow-up time was 49 months in the J-CLASSIC and 39 months in the SOXaGC. Results: Fifty-nine stage III pts treated with CAPOX and 62 stage III pts treated with SOX were analyzed. The 3-year RFS and OS rates of SOX were 70.9% (57.8-80.5%) and 75.7% (63.0-84.6%), respectively, whereas the 3-year RFS and OS rates of CAPOX were 67.8% (54.3-78.1%) and 79.3% (66.5-87.7%), respectively. The hazard ratio (HR) of SOX in comparison to CAPOX was 0.925 (0.498-1.720) for RFS, suggesting the efficacy of the two treatments was similar. Trend of a different efficacy was observed in some particular subgroups; the HR for RFS was 1.732 (0.506-5.927) in the intestinal type and 0.735 (0.353-1.528) in the diffuse type, while that was 2.008 (0.447-9.016) in stage IIIA, 0.872 (0.266-2.857) in stage IIIB, and 0.597 (0.258-1.383) in stage IIIC. Conclusions: This is the first report of survival follow-up in Japanese GC pts with oxaliplatin-based adjuvant chemotherapy, which suggests comparable outcomes in both treatments for stage III GC. Different trend in the treatment effect by histologic type or stage warrants further evaluation in a larger cohort. Clinical trial information: UMIN000026883.
Morbidity and mortality of laparoscopic D2 gastrectomy with complete mesogastrium excision (D2+CME) versus conventional D2 gastrectomy for advanced gastric cancer: An interim report of a single-center, prospective, randomized trial (NCT01978444).
Authors: Xie Daxing 
Published: January 2019

TPS190 Background: In our previous research, laparoscopic D2 lymphadenectomy plus Complete Mesogastrium Excision (D2+CME) has been proven to be an optimal surgical approach for advanced gastric cancer (AGC). However, there is a lack of evidence regarding its oncologic safety. Here, we conducted a single-centre, prospective, randomized controlled trial comparing the morbidity and mortality of laparoscopic D2+CME with conventional D2 gastrectomy in AGC. Methods: Patients eligibly criteria were pathologically-proven adenocarcinoma, 18 to 75 years old, cT2-4N0-3M0 at preoperative evaluation, expected curative resection via laparoscopic distal gastrectomy, no history of other cancers, chemotherapy or radiotherapy, no history of upper abdominal operation and perioperative ASA class I, II or III. The primary end-point was 3-year disease-free survival. The morbidity and mortality were compared to evaluate the safety of this trial. We hypothesized that the morbidity of this study was not significantly different from that of previous reports on laparoscopic distal gastrectomy (5.7%-15.5%). This study is registered at ClinicalTrials.gov, ID number is NCT01978444. Clinical trial information: NCT01978444.
A phase II study of durvalumab following multimodality therapy for locally advanced esophageal adenocarcinoma: Big Ten Cancer Research Consortium BTCRC-ESO14-012 study.
Authors: Mamdani Hirva Mansurali , Abushahin Laith I. , Schneider Bryan J. , Chowdhery Rozina A. , Hrinczenko Borys , Lee Ahran , Perkins Susan M. , Kesler Kenneth , Jalal Shadia Ibrahim 
Published: January 2019

TPS194 Background: The standard of care for locally advanced esophageal adenocarcinoma is concurrent chemoradiation (CRT) followed by esophagectomy with lymphadenectomy. Approximately 30% of patients achieve a complete pathologic response (pCR) with this multimodality approach, which has been correlated with improved disease-free survival. The risk of relapse in the remaining 70% of patients who have pathologic evidence of persistent disease in the surgical specimen is extremely high and estimated at 60-70%. Preclinical studies have demonstrated that radiation with or without concurrent chemotherapy upregulates the programmed cell death receptor- 1 (PD-1) pathway by inducing a local inflammatory response, an effect that persists for a number of months after cessation of therapy. Durvalumab is a selective, high affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, and has shown activity in metastatic esophageal cancer. The aim of this study is to evaluate efficacy of post-operative durvalumab with respect to decreasing the relapse rate in patients who do not achieve pCR following CRT. Methods: Patients with esophageal adenocarcinoma who have pathologic evidence of persistent disease in the surgical specimen following neoadjuvant concurrent CRT (carboplatin plus paclitaxel or cisplatin plus 5-FU) and R0 resection are eligible for enrollment on this single arm phase II study. Durvalumab 1500mg IV every 4 weeks is started within 1-3 months of surgery and continued for up to 1 year. The primary endpoint is 1-year relapse free survival (RFS). Secondary endpoint is to assess the incidence and severity of overall and treatment related adverse events. Exploratory endpoints include PDL1 expression in tumor and tumor infiltrating lymphocytes, assessment of Immunoscore within the center and invasive margin of the tumor, and the correlation between changes in circulating tumor cell numbers in response to PD-L1 inhibition. The study is currently open to accrual at 5 sites in the Big Ten Cancer Research Consortium and 17 of the planned 23 patients have been enrolled within the past 14 months. Clinical trial information: NCT02639065.
Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase II precision medicine trial (NCT02213289).
Authors: Joshi Smita Suhas , Maron Steven Brad , Lomnicki S , Polite Blase N. , Sharma Manish , Ibe Jennifer , Allen Kenisha , Racette Christine , Rampurwala Murtuza M. , Amico Andrea Louise , Shergill Ardaman , Kozloff Mark , Phillips Brooke Elizabeth , Suh Grace K. , Narula Sunil , Rayani Shayan , Kipping-Johnson Kristen , Wojak Erin , Kindler Hedy L. , Catenacci Daniel V.T. 
Published: January 2019

TPS198 Background: Targeted therapies (tx) in GEA have had limited efficacy despite recognition of numerous ‘targetable’ molecular events. This may be due to the molecular heterogeneity (MH) that exists between patients (pts), within the primary tumor (PT), between PT and synchronous metastatic lesions (MLs), and in lesions over time. Current biomarker profiling (BP) is performed on one site, usually the PT, yet this fails to capture the MH of GEA, with likely major clinical implications. Classic trial designs are challenged by MH, low frequency oncogenic drivers, and scarcity of tissue. There is need for novel trial designs and BP technologies that address these concerns, provide tx algorithms for pts with multiple aberrations, and have access to several txs. Methods: This phase IIa, open-label, non-randomized ‘platform trial’ enrolls pts with newly diagnosed metastatic GEA or recurrent disease after curative-intent surgery. Baseline tumor BP is performed on PT/ML along with circulating free (cf)DNA. Pts receive first line (1L) mFOLFOX6 + biologic tx based on BP of the ML using a prioritized tx algorithm (HER2+: trastuzumab; MET+: none; FGFR2+: none; EGFR+: ABT806; MSI-H: nivolumab; ‘RAS-like’: ramucirumab). MET/FGFR2 arms (~10% of all pts) are tx’d with cytotoxics only and followed for natural outcome until/if tx becomes available on study. At first progression (PD1), pts undergo biopsy of growing ML and change to 2L FOLFIRI + biologic agent as assigned in 1L tx. Upon results of PD1 biopsy, pts change to a new biologic tx if the molecular category evolves. At PD2, pts change to 3L FOLTAX + biologic as determined after PD1, and switch biologic tx from PD2 biopsy result. All PD1/PD2 tumor/cfDNA samples undergo BP to assess evolution and resistance mechanisms. Co-primary endpoints: safety, feasibility, and overall survival (OS) of this personalized treatment strategy (excluding MET/FGFR2) compared to historical controls (HR 0.66). Secondary endpoints include rate of baseline MH between PT and ML leading to new treatment assignment; utility of cfDNA; overall progression-free survival (PFS)/response rate (RR); OS/PFS/RR in each targetable group. Since 8/2015, 38 of 68 planned pts have been accrued. Clinical trial information: NCT02213289.
Personalized vaccine for advanced HCC.
Authors: Lausoontornsiri Wirote , Har-Noy Michael , Wongwiwatcha Jitraporn , Bloch Miriam , Suparak Supaporn , Ahooja Anucha , Bishop Michael , Sukeepaisarnjaroen Wattana 
Published: January 2019

TPS527 Background: The chronic inflammation and viral infection associated with HCC combined with liver tolerogenic mechanisms creates a profoundly immunosuppressive microenvironment. Modulating the microenvironment with checkpoint blockade benefits ~20% of patients. The non-responders and those with poor liver function are an unmet need. Checkpoint blockade requires effector cells to be resident within tumors. However, the majority of HCC lesions lack effector cells. Therefore, a strategy for amplifying the tumor-specific immune response, while counteracting the immunosuppressive mechanisms may provide an improved immunotherapy. Endogenous heat shock proteins (HSP) chaperone tumor neoantigens. A concentrated composition of calreticulin, hsp70, hsp90 and gr94/gp96 (CRCL) is purified from biopsy samples. In addition, a bioengineered allograft (BAG) derived from healthy blood donors with a Th1 memory phenotype, CD3/CD28-coated microbeads and high expression of CD40L has potent immunomodulatory and counter-regulatory properties. The combination of CRCL with BAG is being evaluated as a strategy to amplify tumor-specific immunity and counter-regulate the immunosuppressive microenvironment. Methods: An open-label Phase II clinical trial evaluating the safety and efficacy of CRCL+BAG vaccine in Child-Pugh A/B advanced/metastatic HCC w/o Sorafenib. Approximately 6-10 cores of tumor are collected at baseline. The tumor is lysed and CRCL purified using an isoelectric focusing technique. Subjects are primed with multiple intradermal injections of BAG cells alone to increase the titer of allo-specific Th1/Tc1 cells. Next, multiple intradermal injections of BAG+CRCL are administered to elicit increased titers of tumor-specific Th1/Tc1 cells. Subsequent intravenous infusions of BAG cells activate allo- and tumor-specific memory cells, enabling their infiltration into tumor lesions. The BAG allo-rejection response creates a type I cytokine storm which serves to down-regulate suppressor circuits. Response is evaluated by mRECIST and experimental biomarkers. Longitudinal CT scans with concurrent biopsies as well as multiple collections of PBMC and plasma permits immunomonitoring of these immune mechanisms. Clinical trial information: NCT02409524.
A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer.
Authors: Sahai Vaibhav , Griffith Kent A. , Zalupski Mark 
Published: January 2019

TPS541 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis with a median overall survival (OS) less than 12 months. This randomized, multi-institutional, phase 2, two-arm study is designed to investigate the role of combinational immunotherapy, using nivolumab with chemotherapy (gemcitabine/cisplatin) or as dual immunotherapy (nivolumab and ipilimumab) in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intrahepatic or extrahepatic and gallbladder) without prior systemic treatment, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease and/or chronic steroid use. Primary objective is to evaluate the progression-free survival (PFS) rate at 6 months. Secondary objectives include evaluation of overall response rate (ORR), median PFS and OS and safety in this patient population. Exploratory objectives include identification of biomarker predictors of response and mechanisms of resistance through serial (before, on and post therapy) biopsies and blood collection, including sequential whole exome/transcriptomic analysis and immune cell subset analysis (tissue and blood). Arm A therapy provides gemcitabine 1000 mg/m2, cisplatin 25 mg/m2 on days 1, 8 with nivolumab 360 mg on day 1 every 3 weeks for 6 months. In the absence of disease progression, pts may continue single agent nivolumab for up to 2 years. Arm B therapy includes nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks for up to 2 years in absence of disease progression. Accrual goal is 32 evaluable pts per arm. Using a null hypothesis value of 59% median PFS at 6 months, and an 80% alternative hypothesis, this ongoing study has > 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in one or both study arms. Clinical trial information: NCT03101566.
PI3Kβ—A Versatile Transducer for GPCR, RTK, and Small GTPase Signaling
Authors: Bresnick Anne R , Backer Jonathan M 
Published: January 2019

AbstractThe phosphoinositide 3-kinase (PI3K) family includes eight distinct catalytic subunits and seven regulatory subunits. Only two PI3Ks are directly regulated downstream from G protein–coupled receptors (GPCRs): the class I enzymes PI3Kβ and PI3Kγ. Both enzymes produce phosphatidylinositol 3,4,5-trisposphate in vivo and are regulated by both heterotrimeric G proteins and small GTPases from the Ras or Rho families. However, PI3Kβ is also regulated by direct interactions with receptor tyrosine kinases (RTKs) and their tyrosine phosphorylated substrates, and similar to the class II and III PI3Ks, it binds activated Rab5. The unusually complex regulation of PI3Kβ by small and trimeric G proteins and RTKs leads to a rich landscape of signaling responses at the cellular and organismic levels. This review focuses first on the regulation of PI3Kβ activity in vitro and in cells, and then summarizes the biology of PI3Kβ signaling in distinct tissues and in human disease.
Monopolatic motion vision in the butterfly Papilio xuthus
Authors: Stewart Finlay J. , Kinoshita Michiyo , Arikawa Kentaro 
Published: January 2019

ABSTRACT
The swallowtail butterfly Papilio xuthus can perceive the linear polarization of light. Using a novel polarization projection system, we recently demonstrated that P. xuthus can detect visual motion based on polarization contrast. In the present study, we attempt to infer via behavioural experiments the mechanism underlying this polarization-based motion vision. Papilio xuthus do not perceive contrast between unpolarized and diagonally polarized light, implying that they cannot unambiguously estimate angle and degree of polarization, at least as far as motion detection is concerned. Furthermore, they conflate brightness and polarization cues, such that bright vertically polarized light resembles dim unpolarized light. These observations are consistent with a one-channel ‘monopolatic’ detector mechanism. We extend our existing model of motion vision in P. xuthus to incorporate these polarization findings, and conclude that the photoreceptors likely to form the basis for the putative monopolatic polarization detector are R3 and R4, which respond maximally to horizontally polarized green light. R5–R8, we propose, form a polarization-insensitive secondary channel tuned to longer wavelengths of light. Consistent with this account, we see greater sensitivity to polarization for green-light stimuli than for subjectively equiluminant red ones. Somewhat counter-intuitively, our model predicts greatest sensitivity to vertically polarized light; owing to the non-linearity of photoreceptor responses, light polarized to an angle orthogonal to a monopolatic detector's orientation offers the greatest contrast with unpolarized light.
Accounting for aetiology: can regional surveillance data alongside host biomarker-guided antibiotic therapy improve treatment of febrile illness in remote settings?
Authors: Chandna Arjun , White Lisa J. , Pongvongsa Tiengkham , Mayxay Mayfong , Newton Paul N. , Day Nicholas P. J. , Lubell Yoel 
Published: January 2019

Background: Across Southeast Asia, declining malaria incidence poses a challenge for healthcare providers, in how best to manage the vast majority of patients with febrile illnesses who have a negative malaria test. In rural regions, where the majority of the population reside, empirical treatment guidelines derived from central urban hospitals are often of limited relevance. In these settings, relatively untrained health workers deliver care, often without any laboratory diagnostic support. In this paper, our aim was to model the impact on mortality from febrile illness of using point-of-care C-reactive protein testing to inform the decision to prescribe antibiotics and regional surveillance data to inform antibiotic selection, rooted in the real-world context of rural Savannakhet province, southern Laos. Methods: Our model simulates 100 scenarios with varying quarterly incidence of six key pathogens known to be prevalent in rural Laos. In the simulations, community health workers either prescribe antibiotics in-line with current practice as documented in health facilities in rural Laos, or with the aid of the two interventions. We provide cost-effectiveness estimates for each strategy alone and then for an integrated approach using both interventions. Results: We find that each strategy alone is predicted to be highly cost-effective, and that the combined approach is predicted to result in the biggest reduction in mortality (averting a predicted 510 deaths per year in rural Savannakhet, a 28% reduction compared to standard practice) and is highly cost-effective, with an incremental cost-effectiveness ratio of just $66 per disability-adjusted life year averted. Conclusions: Substantial seasonal variation in the predicted optimal empirical antibiotic treatment for febrile illness highlights the benefits of up-to-date information on regional causes of fever. In this modelling analysis, an integrated system incorporating point-of-care host biomarker testing and regional surveillance data appears highly cost-effective, and may warrant piloting in a real-life setting.
Robust Optimization of Dose-Volume Metrics for Prostate HDR-Brachytherapy Incorporating Target and OAR Volume Delineation Uncertainties
Authors: Balvert Marleen , den Hertog Dick , Hoffmann Aswin L. 
Published: January 2019

In radiation therapy planning, uncertainties in the definition of the target volume yield a risk of underdosing the tumor. The traditional corrective action in the context of external beam radiotherapy (EBRT) expands the clinical target volume (CTV) with an isotropic margin to obtain the planning target volume (PTV). However, the EBRT-based PTV concept is not directly applicable to brachytherapy (BT) since it can lead to undesirable dose escalation. Here, we present a treatment plan optimization model that uses worst-case robust optimization to account for delineation uncertainties in interstitial high-dose-rate BT of the prostate. A scenario-based method was developed that handles uncertainties in index sets. Heuristics were included to reduce the calculation times to acceptable proportions. The approach was extended to account for delineation uncertainties of an organ at risk (OAR) as well. The method was applied on data from prostate cancer patients and evaluated in terms of commonly used dosimetric performance criteria for the CTV and relevant OARs. The robust optimization approach was compared against the classical PTV margin concept and against a scenario-based CTV margin approach. The results show that the scenario-based margin and the robust optimization method are capable of reducing the risk of underdosage to the tumor. As expected, the scenario-based CTV margin approach leads to dose escalation within the target, whereas this can be prevented with the robust model. For cases where rectum sparing was a binding restriction, including uncertainties in rectum delineation in the planning model led to a reduced risk of a rectum overdose, and in some cases, to reduced targetcoverage. The online supplement is available at https://doi.org/10.1287/ijoc.2018.0815 .