bluuebunny/crossref_metadata_2025 huggingface dataset:
Severity of Oral Mucositis in Children following Chemotherapy and Radiotherapy and Its Implications at a Single Oncology Centre in Durango State, Mexico
Authors: Carreón-Burciaga Ramón G. , Castañeda-Castaneira Enrique , González-González Rogelio , Molina-Frechero Nelly , Gaona Enrique , Bologna-Molina Ronell
Published: May 2018

Background. Mucositis is an adverse effect of chemotherapy (QT) and/or radiotherapy (RT). The purpose of this study was to investigate the occurrence of oral mucositis in children undergoing cancer treatment. Methods. Fifty-one children with cancer who had received QT, RT, or both (QT-RT) underwent clinical evaluations; World Health Organization criteria were used to establish the degree and severity of mucositis. The correlations between the clinical data, type of cancer, and therapy were statistically analysed. Results. Mucositis was present in 88.23% of the patients; 57.78%, 7.78%, and 24.44% received QT, RT, and QT-RT, respectively. Severity scores of 1 and 2 were the most common; scores of 3-4 were observed in patients who received QT-RT or more than 7 treatment cycles. There was a significant association between mucositis, the type of treatment, and the number of cycles received (p<0.05). Conclusion. It is important to implement therapeutic protocols that help maintain excellent oral health and reduce the risk of oral mucositis. Stomatologists should be consulted to assess patients’ oral cavities and provide preventive treatment prior to QT and/or RT administration. It is important to integrate a stomatologist into the oncological working group to focus on preventing and managing oral mucositis.
Remifentanil Preconditioning Attenuates Hepatic Ischemia-Reperfusion Injury in Rats via Neuronal Activation in Dorsal Vagal Complex
Authors: Cui Cui , Yu Fang , Yin Suqing , Yang Yuting , Jiao Yingfu , Cheung Chiwai , Wang Xiaomin , Qi Bo , Liu Yaling , Li Peiying , Yu Weifeng , Xiao Jie , Yang Liqun
Published: May 2018

Remifentanil, an ultra-short acting opiate, has been reported to protect against hepatic ischemia-reperfusion injury, which is a major cause of postoperative liver dysfunction. The objective of this study was to determine whether a central vagal pathway is involved in this protective procedure. Rat models of hepatic ischemia-reperfusion were used in the experimental procedures. The results revealed that intravenous pretreatment with remifentanil decreased serum aminotransferases and hepatic histologic damage; however, an intraperitoneal injection of μ-opioid receptor antagonist did not abolish the protection of remifentanil preconditioning. c-Fos immunofluorescence of the brain stem showed that dorsal motor nucleus of the vagus was activated after remifentanil preconditioning. Moreover, serum alanine aminotransferase, histopathologic damage, and apoptosis decreased in remifentanil preconditioning group compared to vagotomized animals with remifentanil preconditioning, and there was no statistical difference of TNF-α and IL-6 between NS/Va and RPC/Va groups. In addition, remifentanil microinjection into dorsal vagal complex decreased serum aminotransferases, inflammatory cytokines, and hepatic histologic injury and apoptosis, and these effects were also abolished by a peripheral hepatic vagotomy. In conclusion, remifentanil preconditioning conferred liver protection against ischemia-reperfusion injury, which was mediated by the central vagal pathway.
The Implementation of Milstein Scheme in Two-Dimensional SDEs Using the Fourier Method
Authors: Alnafisah Yousef
Published: May 2018

Multiple stochastic integrals of higher multiplicity cannot always be expressed in terms of simpler stochastic integrals, especially when the Wiener process is multidimensional. In this paper we describe how the Fourier series expansion of Wiener process can be used to simulate a two-dimensional stochastic differential equation (SDE) using Matlab program. Our numerical experiments use Matlab to show how our truncation of Itô’-Taylor expansion at an appropriate point produces Milstein method for the SDE.
Periodic Solutions with Minimal Period for Fourth-Order Nonlinear Difference Equations
Authors: Liu Xia , Zhou Tao , Shi Haiping , Long Yuhua , Wen Zongliang
Published: May 2018

A fourth-order nonlinear difference equation is considered. By making use of critical point theory, some new criteria are obtained for the existence of periodic solutions with minimal period. The main methods used are a variational technique and the Linking Theorem.
Severe Maternal Morbidity Associated with Systemic Lupus Erythematosus Flare in the Second Trimester of Pregnancy
Authors: Blitz Matthew J. , Fleischer Adiel
Published: May 2018

Pregnancy in women with systemic lupus erythematosus (SLE) is associated with an increased risk of adverse maternal and fetal outcomes. Here, we present a case of severe maternal morbidity in a 23-year-old primigravida with SLE and secondary Sjögren’s syndrome who experienced a life-threatening multisystem flare at 17 weeks of gestational age. She presented to the emergency department complaining of cough with hemoptysis and shortness of breath. She developed hypoxic respiratory failure and was admitted to the intensive care unit. Bronchoscopy confirmed diffuse alveolar hemorrhage. Physical exam and laboratory evaluation were consistent with an active SLE flare, pancytopenia, and new-onset lupus nephritis. After counseling regarding disease severity, poor prognosis, and recommendation for therapy with cytotoxic agents, she agreed to interruption of pregnancy which was achieved by medical induction. Her course was further complicated by thrombotic microangiopathy and generalized tonic-clonic seizures attributable to posterior reversible encephalopathy syndrome versus neuropsychiatric SLE. This case represents one of the most extreme manifestations of lupus disease activity associated with pregnancy that has been reported in the literature and emphasizes the importance of preconception evaluation and counseling and a multidisciplinary management approach in cases with a complex and evolving clinical course.
Identification of Estrogen Receptor α Antagonists from Natural Products via In Vitro and In Silico Approaches
Authors: Pang Xiaocong , Fu Weiqi , Wang Jinhua , Kang De , Xu Lvjie , Zhao Ying , Liu Ai-Lin , Du Guan-Hua
Published: May 2018

Estrogen receptor α (ERα) is a successful target for ER‐positive breast cancer and also reported to be relevant in many other diseases. Selective estrogen receptor modulators (SERMs) make a good therapeutic effect in clinic. Because of the drug resistance and side effects of current SERMs, the discovery of new SERMs is given more and more attention. Virtual screening is a validated method to high effectively to identify novel bioactive small molecules. Ligand‐based machine learning methods and structure‐based molecular docking were first performed for identification of ERα antagonist from in‐house natural product library. Naive Bayesian and recursive partitioning models with two kinds of descriptors were built and validated based on training set, test set, and external test set and then were utilized for distinction of active and inactive compounds. Totally, 162 compounds were predicted as ER antagonists and were further evaluated by molecular docking. According to docking score, we selected 8 representative compounds for both ERα competitor assay and luciferase reporter gene assay. Genistein, daidzein, phloretin, ellagic acid, ursolic acid, (−)‐epigallocatechin‐3‐gallate, kaempferol, and naringenin exhibited different levels for antagonistic activity against ERα. These studies validated the feasibility of machine learning methods for predicting bioactivities of ligands and provided better insight into the natural products acting as estrogen receptor modulator, which are important lead compounds for future new drug design.
Mobilization of Fluids in the Intensive Treatment of Primary and Secondary Lymphedemas
Authors: Godoy Jose Maria Pereira de , Pereira de Godoy Henrique Jose , Gracino de Marqui Thatiany , Spessoto Luis Cesar , Godoy Maria de Fatima Guerreiro
Published: May 2018

Background. Lymphedema is a clinical condition resulting from the accumulation of macromolecules in the interstitial space with a consequent buildup of fluids. Aim. The objective of this study was to compare the therapeutic response to treatment that mobilizes fluids between primary and secondary lymphedemas. Method. Thirty-three patients with severe leg lymphedema who underwent intensive treatment for five consecutive days in 2013 and 2014 at the Clínica Godoy were evaluated in a prospective clinical trial. Diagnosis was based on the patient’s history and physical examination. Treatment consisted of eight hours/day of Mechanical Lymphatic Therapy using an electromechanical device (RAGodoy®) that performs plantar flexion and extension associated with 15 minutes of Cervical Lymphatic Therapy, a technique developed by Godoy and Godoy that involves stimulation in the cervical region and a grosgrain compression stocking alternated with elastic bandages. The unpaired t-test and Fisher’s exact test were used for statistical analysis with an alpha error of 5% (p value < 0.05) being considering acceptable. Secondary lymphedema was more prevalent in women (Fisher exact test p value < 0.01). Results. The age of patients with secondary lymphedema was greater than those with primary lymphedema (unpaired t-test: p value < 0.03). The mean volume losses were 64.62% and 48.35% for the patients with secondary and primary lymphedema, respectively (p value < 0.03). Conclusion. Women are more prevalent and older in the secondary lymphedema group. Volumetric reductions below the knee are faster with intensive treatment for secondary rather than for primary lymphedema.
Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis
Authors: Yu QingAn , Lv XiaoYing , Liu KunPeng , Ma DaKun , Wu YaoHua , Dai WenJie , Jiang HongChi
Published: May 2018

Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas. The purpose of this study was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroid cancer. To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecified fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35; 95% confidence interval [CI] 1.12–1.64; P=0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12–1.88; P=0.005). After pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61–1.58, P=0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.
Histoplasma Peritonitis: An Extremely Rare Complication of Peritoneal Dialysis
Authors: Sardar Asjad , Thajudeen Bijin , Kadambi Pradeep V.
Published: May 2018

Bacterial peritonitis is a common complication of peritoneal dialysis, but fungal peritonitis is unusual and is mostly due to Candida species. Peritonitis due to Histoplasma capsulatum is rare and we report one such case. A 63-year-old female presented with progressively worsening abdominal pain, fever, and altered mental status. She had end-stage renal disease and had been on peritoneal dialysis for 4 years. She had abdominal tenderness without rebound or guarding. Laboratory studies and CT of abdomen were significant for leukocytosis and peritoneal membrane thickening, respectively. Peritoneal dialysis fluid study was consistent with peritonitis and culture of the fluid grew Histoplasma capsulatum. Treatment recommendations include removal of catheter and initiation of antifungal therapy. With the availability of newer antifungals, medical management without removal of PD catheter is possible, but at the same time if there is no response to treatment within a week, PD catheter should be removed promptly.
Calcifying Odontogenic Cyst with Extensive Areas of Dentinoid: Uncommon Case Report and Update of Main Findings
Authors: Santos Hellen Bandeira de Pontes , de Morais Everton Freitas , Moreira Deborah Gondim Lambert , Neto Luis Ferreira de Almeida , Gomes Petrus Pereira , Freitas Roseana de Almeida
Published: May 2018

The calcifying odontogenic cyst (COC) is a benign odontogenic cyst that occurs in the gnathic bones. This cyst is part of a spectrum of lesions characterized by odontogenic epithelium containing “ghost cells,” which may undergo calcification. Areas of an eosinophilic matrix material compatible dentinoid also may present adjacent to the epithelial component. However, these areas of dentinoid commonly do not appear so abundant in COCs. In this study, we report a case of intraosseous COC with extensive areas of dentinoid and perform an update regarding the clinical, radiographical, histopathological, and differential diagnosis, treatment, and prognosis of this cystic lesion.
Alternative Approach of Developing Optical Binary Adder Using Reversible Peres Gates
Authors: Mandal Dhoumendra , Mandal Sumana , Mandal Mrinal Kanti , Garai Sisir Kumar
Published: May 2018

All-optical devices will play a very significant and crucial role in the modern all-optical network by eliminating the bottleneck of opto-electro-opto- (O-E-O-) conversion. Unfortunately, the conventional logic gates lose information at the output, and the states of the outputs cannot give any credible impressions of the states of the inputs. In this article, at first, the authors have proposed a method of designing an optical three-input-three-output reversible Peres gate. Authors have deployed polarization switching characteristic of Semiconductor Optical Amplifier (SOA) for designing this circuit. The authors have also proposed a method of designing an optical reversible full adder, using two such Peres gates and subsequently a data recovery circuit which can recover the input data of the adder. The authors have chosen frequency encoded data for processing the operation. The proposed scheme has been verified by simulation results.
A High Precision Laser-Based Autofocus Method Using Biased Image Plane for Microscopy
Authors: Gu Chao-Chen , Cheng Hao , Wu Kai-Jie , Zhang Liang-Jun , Guan Xin-Ping
Published: May 2018

This study designs and accomplishes a high precision and robust laser-based autofocusing system, in which a biased image plane is applied. In accordance to the designed optics, a cluster-based circle fitting algorithm is proposed to calculate the radius of the detecting spot from the reflected laser beam as an essential factor to obtain the defocus value. The experiment conduct on the experiment device achieved novel performance of high precision and robustness. Furthermore, the low demand of assembly accuracy makes the proposed method a low-cost and realizable solution for autofocusing technique.
Role Participation: A Comparison across Age Groups in a Norwegian General Population Sample
Authors: Bonsaksen Tore
Published: May 2018

Background. Life events, illness, and disability may alter a person’s role participation, in which case occupational therapy may be an appropriate intervention. However, role participation data derived from the general population, which is required for meaningful comparison, is largely missing. This study is aimed at describing past, present, and anticipated role participation in a general population sample from Norway and at examining differences in current role participation between age groups. Methods. In 2015, a sample of 140 persons (age range 19–94 years, 65% females) from the Norwegian general population completed the Role Checklist at one occasion. The data were analyzed descriptively and with chi-square tests and one-way analysis of variance. Results. The most frequent role was a home maintainer (93.6%), and the least frequent was a religious participant (7.1%). Participants aged 65 years and above had fewer roles compared with their younger counterparts and had to a larger extent experienced role loss over the course of their lives. Conclusions. Role continuity was the most prevalent role pattern in the total sample, whereas role loss appeared to be the most prevalent role pattern among those in the oldest age group. Rehabilitation services in general and participation-focused occupational therapy in particular may profit from assessing role participation in clients and potentially target roles through intervention.
A Handy Preterm Infant Incubator for Providing Intensive Care: Simulation, 3D Printed Prototype, and Evaluation
Authors: Zaylaa Amira J. , Rashid Mohamad , Shaib Mounir , El Majzoub Imad
Published: May 2018

Preterm infants encounter an abrupt delivery before their complete maturity during the third trimester of pregnancy. Polls anticipate an increase in the rates of preterm infants for 2025, especially in middle- and low-income countries. Despite the abundance of intensive care methods for preterm infants, such as, but not limited to, commercial, transport, embrace warmer, radiant warmer, and Kangaroo Mother Care methods, they are either expensive, lack the most essential requirements or specifications, or lack the maternal-preterm bond. This drove us to carry this original research and innovative idea of developing a new 3D printed prototype of a Handy preterm infant incubator. We aim to provide the most indispensable intensive care with the lowest cost, to bestow low-income countries with the Handy incubator’s care, preserve the maternal -preterm’s bond, and diminish the rate of mortality. Biomedical features, electronics, and biocompatible materials were utilized. The design was simulated, the prototype was 3D printed, and the outcomes were tested and evaluated. Simulation results showed the best fit for the Handy incubator’s components. Experimental results showed the 3D-printed prototype and the time elapsed to obtain it. Evaluation results revealed that the overall performance of Kangaroo Mother Care and the embrace warmer was 75 ± 1.4% and 66.7 ± 1.5%, respectively, while the overall performance of our Handy incubator was 91.7 ± 1.6%, thereby our cost-effective Handy incubator surpassed existing intensive care methods. The future step is associating the Handy incubator with more specifications and advancements.
A Cascading Failures Perspective Based Mesoscopic Reliability Model of Weighted Public Transit Network considering Congestion Effect and User Equilibrium Evacuation
Authors: Zhang Lin , Lu Jian , Long Man , Li Shu-bin , Zhou Jialin
Published: May 2018

To establish the optimal route layout estimation technology based on reliability optimization, a more accurate and realistic reliability model of a weighted public transit network (PTN) is the indispensable basis. This paper establishes a cascading failures (CFs) perspective based mesoscopic reliability model for measuring PTN survivability. First, a modeling method for abstracting weighted PTN and determining its initial passenger flow and bearing capacity is proposed, making the network passenger flow pattern follow the aggregated flow pattern. Second, three basic concepts (time step, congestion effect of a road section, and CFs judging method) for establishing the CFs model are defined to clarify the overall evolution process of CFs. Furthermore, the aggregated passenger flow evacuation that exists in an emergency occurring at a station (i.e., failure load dynamic redistribution (FLDR)) is considered as a conscious dynamic game process through following the user equilibrium rule. As a result, a novel CFs model that considers congestion effect and user equilibrium evacuation is obtained. Finally, based on the collected data of Jinan’s PTN, a case simulation analysis is conducted to verify the adaptability of this model through showing a significantly different dynamics characteristic with the existing FLDR patterns and to provide optimization direction for effectively controlling PTN survivability, that is, guide the transformation among varying FLDR patterns through some technical measures or traffic policies.
Ahmed Glaucoma Valve Implantation in Vitrectomized Eyes
Authors: Erçalık Nimet Yeşim , İmamoğlu Serhat
Published: May 2018

Purpose. To evaluate the outcomes of Ahmed glaucoma valve (AGV) implantation in vitrectomized eyes.Materials and Methods. The medical records of 13 eyes that developed glaucoma due to emulsified silicon oil or neovascularization following pars plana vitrectomy and underwent AGV implantation were retrospectively reviewed. The main outcome measures were intraocular pressure (IOP), best-corrected visual acuity (BCVA), number of antiglaucoma medications, and postoperative complications. Surgical success was defined as last IOP ≤21 mmHg or ≥6 mmHg and without loss of light perception.Results. The mean follow-up duration was 11.7 ± 5.5 (range, 6–23) months. The mean IOP before the AGV implantation was 37.9 ± 6.7 mmHg with an average of 3.5 ± 1.2 drugs. At the final visit, the mean IOP was 15.9 ± 4.6 mmHg (p=0.001) and the mean number of glaucoma medications decreased to 2.3 ± 1.3 (p=0.021). At the last visit, 11 eyes (84.4%) had stable or improved VA and one eye (7.7%) had a final VA of no light perception. Surgical success was achieved in 11 of the 13 eyes (84.4%). Postoperative complications were bleb encapsulation (69.2%), early hypotony (38.5%), hyphema (23.1%), decompression retinopathy (23.1%), choroidal detachment (15.4%), intraocular hemorrhage (7.7%), and late endophthalmitis (7.7%). One eye (7.7%) was enucleated because of late endophthalmitis.Conclusions. Despite complications necessitating medical and surgical interventions, vitrectomized eyes were effectively managed with AGV implantation.
Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice
Authors: Gulati Pratiksha , Rühl Julia , Kannan Abhilash , Pircher Magdalena , Schuberth Petra , Nytko Katarzyna J. , Pruschy Martin , Sulser Simon , Haefner Mark , Jensen Shawn , Soltermann Alex , Jungraithmayr Wolfgang , Eisenring Maya , Winder Thomas , Samaras Panagiotis , Tabor Annett , Stenger Rene , Stupp Roger , Weder Walter , Renner Christoph , Münz Christian , Petrausch Ulf
Published: May 2018

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.

Experimental Design: Fibroblast activation protein (FAP)–specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.

Results: All the three CARs demonstrated FAP-specific functionality in vitro. Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.

Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981–93. ©2018 AACR.
TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations
Authors: Hasako Shinichi , Terasaka Miki , Abe Naomi , Uno Takao , Ohsawa Hirokazu , Hashimoto Akihiro , Fujita Ryoto , Tanaka Kenji , Okayama Takashige , Wadhwa Renu , Miyadera Kazutaka , Aoyagi Yoshimi , Yonekura Kazuhiko , Matsuo Kenichi
Published: May 2018

Activating mutations in the EGFR gene are important targets in cancer therapy because they are key drivers of non–small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(8); 1648–58. ©2018 AACR.
Tumor-Specific Inhibition ofIn SituVaccination by Distant Untreated Tumor Sites
Authors: Morris Zachary S. , Guy Emily I. , Werner Lauryn R. , Carlson Peter M. , Heinze Clinton M. , Kler Jasdeep S. , Busche Sara M. , Jaquish Abigail A. , Sriramaneni Raghava N. , Carmichael Lakeesha L. , Loibner Hans , Gillies Stephen D. , Korman Alan J. , Erbe Amy K. , Hank Jacquelyn A. , Rakhmilevich Alexander L. , Harari Paul M. , Sondel Paul M.
Published: May 2018

In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the “primary” tumor would induce a systemic antitumor response causing regression of the “secondary” tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated “primary” tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic “DEREG” mice or IgG2a anti–CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti–CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825–34. ©2018 AACR.
The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non–Clear Cell Renal Cell Carcinoma
Authors: McKay Rana R. , Bossé Dominick , Xie Wanling , Wankowicz Stephanie A.M. , Flaifel Abdallah , Brandao Raphael , Lalani Aly-Khan A. , Martini Dylan J. , Wei Xiao X. , Braun David A. , Van Allen Eliezer , Castellano Daniel , De Velasco Guillermo , Wells J. Connor , Heng Daniel Y. , Fay Andre P. , Schutz Fabio A. , Hsu JoAnn , Pal Sumanta K. , Lee Jae Lyun , Hsieh James J. , Harshman Lauren C. , Signoretti Sabina , Motzer Robert J. , Feldman Darren , Choueiri Toni K.
Published: May 2018

Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non–clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, 8 patients (19%) objectively responded, including 4 patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months [95% confidence interval (CI), 2.8–5.5] and median OS was 12.9 months (95% CI, 7.4–not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1–blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Cancer Immunol Res; 6(7); 758–65. ©2018 AACR.
Kibrkegaard e as origens do existencialismo
Authors: Abbagnano Nicola
Published: May 2018

Conferência pronunciada em São Paulo, em 29 de Abril de 1949, na Faculdade de Filosofia, a convite da Reitoria da Universidade de São Paulo. Texto taquigrafado, não revisto pelo autor.
Multifactorial intervention for diabetes control among older users of insulin
Authors: Machry Rafael Vaz , Pedroso Henrique Umpierre , Vasconcellos Luthiele Silva , Nunes Rafaela Ramos , Evaldt Cibelle de Abreu , Yunes Filho Eduardo Bardou , Rodrigues Ticiana da Costa
Published: May 2018

OBJECTIVE: To evaluate if the closer follow-up with the supply of insulin pens and the measurement of capillary blood glucose improve the management of older patients with type 2 diabetes without adequate glycemic control despite extensive therapy. METHODS: This is a prospective, non-randomized, quasi-experimental study. We have included 45 patients over 60 years old, from both sexes, with glycated hemoglobin (HbA1c) > 8.5% using oral hypoglycemic agents and insulin. The intervention consisted of monthly medical visits, with the provision of insulin pens and strips for blood glucose measurement. All patients received insulin pen, refills of Neutral Protamine Hagedorn and regular insulin, needles for the pen, blood glucose meter, and capillary blood glucose tests (three tests/day). Treatment was adjusted with the same endocrinologist monthly for six months. Glycated hemoglobin was measured at baseline and 12 and 24 weeks after intervention. RESULTS: Glycated hemoglobin at baseline was 10.34% (SE = 0.22%) and 8.54% (SE = 0.24%, p < 0.001) and 8.09% (SE = 0.21%, p < 0.001) at 12 and 24 weeks after intervention, respectively, with a significant reduction from baseline. CONCLUSIONS: More frequent medical visits, with treatment inputs including the use of insulin pens and self-monitoring, have improved glycemic control (reduction of 2.25% in HbA1C, on average, at 24 weeks of follow-up). Our data support a change in the management and medical behavior of older patients with chronically decompensated diabetes.
School health promotion and use of drugs among students in Southern Brazil
Authors: Paz Fernanda Marques , Teixeira Vanessa Andina , Pinto Raquel Oliveira , Andersen Cristine Scattolin , Fontoura Larissa Prado , Castro Luís César de , Pattussi Marcos Pascoal , Horta Rogério Lessa
Published: May 2018

OBJECTIVE: To analyze the relationship between the health promotion conditions in schools and the consumption of alcohol and other drugs by students. METHODS: This is a cross-sectional study with a probabilistic sample of 3,464 students aged 12 to 17 from all schools of the cities of Lajeado and Sapiranga, state of Rio Grande do Sul, Brazil, and 53 managers from the same schools; the data was collected in 2012. Reports of the use of tobacco, alcohol, and illicit drugs in 2012 were used as outcomes, and the health promotion score in the school environment was used as the exposure of interest. We submitted the data to multilevel analysis. RESULTS: The prevalence of the annual use of tobacco was 9.8% (95%CI 8.8–10.8), alcohol was 46.2% (95%CI 44.5–47.8), and other drugs was 10.9% (95%CI 9.9–12.0). In the crude analysis, only the use of tobacco was associated with less health promoting schools (OR = 1.89, 95%CI 1.16–3.09) when compared to those with better conditions. This association lost statistical significance in the adjusted analysis (OR = 1.27, 95%CI 0.74–2.19). CONCLUSIONS: The effects of the school environment on the use of drugs, especially tobacco and alcohol, are manifested mainly by the individual and family conditions of the adolescents.
Utilization of basic health units of FHS according to private health insurance
Authors: Fontenelle Leonardo Ferreira , Camargo Maria Beatriz Junqueira de , Bertoldi Andréa Dâmaso , Gonçalves Helen , MacielI Ethel Leonor Noia , Barros Aluísio J D
Published: May 2018

OBJECTIVE: To describe the utilization of basic health units according to coverage by discount card or private health insurance. METHODS: Household survey in the area covered by Family Health Strategy in Pelotas, state of Rio Grande do Sul, Brazil, from December 2007 to February 2008, with persons of all age groups. The frequency of (medical or non-medical) healthcare seeking at the basic health units in the last six months and the prevalence of basic health unit utilization for the last medical consultation (in case it had been performed up to six months before, for a non-routine reason) were analyzed by Poisson regression adjusted for the sampling design. RESULTS: Of the 1,423 persons, 75.6% had no discount card or private health insurance. The average frequency of (medical or non-medical) healthcare seeking was 1.6 times in six months (95%CI 1.3–2.0); this frequency was 55.8% lower (p < 0.001) among privately insured persons compared to those with no discount card or private health insurance. Among the last medical consultations, 35.8% (95%CI 25.4–47.7) had been performed at the basic health units; this prevalence was 36.4% lower (p = 0.003) among persons covered by discount card and 87.7% lower (p = 0.007) among privately insured persons compared to those without both coverages. CONCLUSIONS: Private health insurance and, to a lesser degree, discount card coverage, are related to lower utilization of basic health units. This can be used to size the population under the accountability of each Family Health Strategy team, to the extent that community health workers are able to differentiate discount card from PHI during family registration.
Minimally Invasive Delivery of Hydrogel-Encapsulated Amiodarone to the Epicardium Reduces Atrial Fibrillation
Authors: Garcia Jose R. , Campbell Peter F. , Kumar Gautam , Langberg Jonathan J. , Cesar Liliana , Deppen Juline N. , Shin Eric Y. , Bhatia Neal K. , Wang Lanfang , Xu Kai , Schneider Frank , Robinson Brian , García Andrés J. , Levit Rebecca D.
Published: May 2018

Background:

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although treatment options for AF exist, many patients cannot be maintained in normal sinus rhythm. Amiodarone is an effective medication for AF but has limited clinical utility because of off-target tissue toxicity.

Methods:

Here, we use a pig model of AF to test the efficacy of an amiodarone-containing polyethylene glycol–based hydrogel. The gel is placed directly on the atrial epicardium through the pericardial space in a minimally invasive procedure using a specially designed catheter.

RESULTS:

Implantation of amiodarone-containing gel significantly reduced the duration of sustained AF at 21 and 28 days; inducibility of AF was reduced 14 and 21 days post-delivery. Off-target organ drug levels in the liver, lungs, thyroid, and fat were significantly reduced in animals treated with epicardial amiodarone gel compared with systemic controls in small-animal distribution studies.

Conclusions:

The pericardium is an underutilized therapeutic site and may be a new treatment strategy for AF and other cardiovascular diseases.
Independent Prognostic Value of Serum Soluble ST2 Measurements in Patients With Heart Failure and a Reduced Ejection Fraction in the PARADIGM-HF Trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure)
Authors: O’Meara Eileen , Prescott Margaret F. , Claggett Brian , Rouleau Jean L. , Chiang Lu-May , Solomon Scott D. , Packer Milton , McMurray John J.V. , Zile Michael R.
Published: May 2018

Background:

Soluble ST2 (sST2) is associated with cardiac remodeling and fibrosis. In chronic heart failure, the predictive value of sST2 has not been evaluated in a model that includes both NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity cardiac troponin T), in a trial in which treatment had a major impact. Therefore, the effects of treatment on sST2 levels in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the relationships between sST2 and outcomes, and the prognostic utility of various sST2 partition values were examined.

Methods and Results:

Baseline (n=2002), 1-month (n=1936), and 8-month postrandomization (n=1758) sST2 levels were compared between treatment groups (sacubitril/valsartan versus enalapril). Relationships between baseline sST2 and (1) heart failure hospitalization, (2) cardiovascular death, and (3) combined heart failure hospitalization and cardiovascular death were assessed using restricted cubic spline models. Adjusted Cox proportional hazards models were used to examine the impact of sST2 change from baseline to 1 month on the hazard of experiencing each outcome. Sacubitril/valsartan led to more reductions and fewer increases in sST2 levels versus enalapril. After adjusting for other predictors, including NT-proBNP and hs-TnT, baseline sST2 remained an independent predictor of outcomes. Associations between baseline sST2 and outcomes were linear. sST2 increases at 1 month were associated with worse subsequent outcomes and decreased with better outcomes (
P
=0.001, 0.012, and 0.009 for the 3 outcomes, respectively).

Conclusions:

Sacubitril/valsartan resulted in greater reductions and less increases in sST2 levels than enalapril. No specific threshold was associated with risk, as linear relationships between baseline sST2 and outcomes were observed. Changes in sST2 from baseline to 1 month were independently associated with the risk of outcomes.

Clinical Trial Registration

: URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01035255.
Prognostic Significance of Creatinine Increases During an Acute Heart Failure Admission in Patients With and Without Residual Congestion
Authors: Metra Marco , Cotter Gad , Senger Stefanie , Edwards Christopher , Cleland John G. , Ponikowski Piotr , Cursack Guillermo C. , Milo Olga , Teerlink John R. , Givertz Michael M. , O’Connor Christopher M. , Dittrich Howard C. , Bloomfield Daniel M. , Voors Adriaan A. , Davison Beth A.
Published: May 2018

Background:

The importance of a serum creatinine increase, traditionally considered worsening renal function (WRF), during admission for acute heart failure has been recently debated, with data suggesting an interaction between congestion and creatinine changes.

Methods and Results:

In post hoc analyses, we analyzed the association of WRF with length of hospital stay, 30-day death or cardiovascular/renal readmission and 90-day mortality in the PROTECT study (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Daily creatinine changes from baseline were categorized as WRF (an increase of 0.3 mg/dL or more) or not. Daily congestion scores were computed by summing scores for orthopnea, edema, and jugular venous pressure. Of the 2033 total patients randomized, 1537 patients had both available at study day 14. Length of hospital stay was longer and 30-day cardiovascular/renal readmission or death more common in patients with WRF. However, these were driven by significant associations in patients with concomitant congestion at the time of assessment of renal function. The mean difference in length of hospital stay because of WRF was 3.51 (95% confidence interval, 1.29–5.73) more days (
P
=0.0019), and the hazard ratio for WRF on 30-day death or heart failure hospitalization was 1.49 (95% confidence interval, 1.06–2.09) times higher (
P
=0.0205), in significantly congested than nonsignificantly congested patients. A similar trend was observed with 90-day mortality although not statistically significant.

Conclusions:

In patients admitted for acute heart failure, WRF defined as a creatinine increase of ≥0.3 mg/dL was associated with longer length of hospital stay, and worse 30- and 90-day outcomes. However, effects were largely driven by patients who had residual congestion at the time of renal function assessment.

Clinical Trial Registration

: URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT00328692 and NCT00354458.
Remote Left Ventricular Hemodynamic Monitoring Using a Novel Intracardiac Sensor
Authors: Mondritzki Thomas , Boehme Philip , White Jason , Park Jin Woo , Hoffmann Jessica , Vogel Julia , Kolkhof Peter , Walsh Stuart , Sandner Peter , Bischoff Erwin , Dinh Wilfried , Hüser Jörg , Truebel Hubert
Published: May 2018

Background—

Heart failure (HF) remains the most common reason for hospital admission in patients aged >65 years. Despite modern drug therapy, mortality and readmission rates for patients hospitalized with HF remain high. This necessitates further research to identify early patients at risk for readmission to limit hospitalization by timely adjustment of medical therapy. Implantable devices can monitor left ventricular (LV) hemodynamics and remotely and continuously detect the early signs of decompensation to trigger interventions and reduce the risk of hospitalization for HF. Here, we report the first preclinical study validating a new batteryless and easy to implant LV-microelectromechanical system to assess LV performance.

Methods and Results—

A miniaturized implantable wireless pressure sensor was adapted for implantation in the LV apex. The LV-microelectromechanical system sensor was tested in a canine model of HF. The wireless pressure sensor measurements were compared with invasive left heart catheter-derived measurements at several time points. During different pharmacological challenge studies with dobutamine or vasopressin, the device was equally sensitive compared with invasive standard procedures. No adverse events or any observable reaction related to the implantation and application of the device for a period of 35 days was observed.

Conclusions—

Our miniaturized wireless pressure sensor placed in the LV (LV-microelectromechanical system) has the potential to become a new telemetric tool to earlier identify patients at risk for HF decompensation and to guide the treatment of patients with HF.
Gastrointestinal Bleeding With Edoxaban Versus Warfarin
Authors: Aisenberg James , Chatterjee-Murphy Prapti , Friedman Flack Kathryn , Weitz Jeffrey I. , Ruff Christian T. , Nordio Francesco , Mercuri Michele F. , Choi Youngsook , Antman Elliott M. , Braunwald Eugene , Giugliano Robert P.
Published: May 2018

Background:

The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21 105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail.

Methods and Results:

This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin. During 2.8 years mean follow-up, there were 579 MGIB (1.22% per year), of which 63 were life-threatening or fatal (0.13% per year). Male sex, increased age, prior GIB, concomitant aspirin, lower baseline hemoglobin, renal dysfunction, and higher HAS-BLED and CHADS
2
scores were independently associated with the risk of MGIB. Whereas the annual rate of MGIB was higher with HD-ER than with warfarin (1.53% and 1.25%, respectively; hazard ratio, 1.23; 95% confidence interval, 1.02–1.48;
P
=0.033), the annual rates of life-threatening or fatal GIB were similar (0.15% and 0.18%, respectively). Several indicators of more severe GIB, including hemodynamic instability, hospitalization, ≥ 4 U transfusion, and hemoglobin loss ≥5 g/dL, were similar with HD-ER and warfarin, whereas surgery required to manage bleeding was less frequent with HD-ER. Lower-dose edoxaban regimen, which achieved 50% lower trough edoxaban levels, was associated with significantly less MGIB than warfarin.

Conclusions:

MGIB occurred more frequently with HD-ER than warfarin. The rates of life-threatening or fatal GIB were low and similar with both HD-ER and warfarin. Clinical outcomes were generally favorable. The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00781391.