Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp)

Abstract

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4–5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

https://ift.tt/2s87syb

Safety of Polysorbate 80 in the Oncology Setting

Abstract

Polysorbate 80 is a synthetic nonionic surfactant used as an excipient in drug formulation. Various products formulated with polysorbate 80 are used in the oncology setting for chemotherapy, supportive care, or prevention, including docetaxel, epoetin/darbepoetin, and fosaprepitant. However, polysorbate 80, like some other surfactants, is not an inert compound and has been implicated in a number of systemic and injection- and infusion-site adverse events (ISAEs). The current formulation of intravenous fosaprepitant has been associated with an increased risk of hypersensitivity systemic reactions (HSRs). Factors that have been associated with an increased risk of fosaprepitant-related ISAEs include the site of administration (peripheral vs. central venous), coadministration of anthracycline-based chemotherapy, number of chemotherapy cycles or fosaprepitant doses, and concentration of fosaprepitant administered. Recently, two polysorbate 80-free agents have been approved: intravenous rolapitant, which is a neurokinin 1 (NK-1) receptor antagonist formulated with the synthetic surfactant polyoxyl 15 hydroxystearate, and intravenous HTX-019, which is a novel NK-1 receptor antagonist free of synthetic surfactants. Alternative formulations will obviate the polysorbate 80-associated ISAEs and HSRs and should improve overall management of chemotherapy-induced nausea and vomiting.

Funding Heron Therapeutics, Inc.

https://ift.tt/2KOVfFr

A Chronic Glottic Foreign Body Diagnosed by Radiograph after 9 Months of Symptoms

A six-year-old girl presented to an emergency room after describing choking on a rubber band. She was in no distress and was discharged. Over the course of the next 9 months, she had numerous outpatient and emergency room visits due to intermittent stridor, difficulty breathing, and hoarseness. Eventually, dedicated airway films revealed a laryngeal foreign body. During rigid bronchoscopy, a two-centimeter rubber band was discovered in the larynx. It extended from the supraglottis, through the glottis, and into the subglottis. It was successfully removed. The patient was asymptomatic 24 hours later. This case highlights the appropriate evaluation and management of a child with stridor.

https://ift.tt/2ICRI0d

Cancers, Vol. 10, Pages 154: Treating p53 Mutant Aggregation-Associated Cancer

Cancers, Vol. 10, Pages 154: Treating p53 Mutant Aggregation-Associated Cancer

Cancers doi: 10.3390/cancers10060154

Authors: Mathumai Kanapathipillai

p53 is a tumor suppressor protein. Under stressful conditions, p53 tightly regulates cell growth by promoting apoptosis and DNA repair. When p53 becomes mutated, it loses its function, resulting in abnormal cell proliferation and tumor progression. Depending on the p53 mutation, it has been shown to form aggregates leading to negative gain of function of the protein. p53 mutant associated aggregation has been observed in several cancer tissues and has been shown to promote tumor growth. Recent studies show correlation between p53 mutant aggregation, functional loss, and tumor growth. Moreover, p53 aggregation has been observed in biopsies, patient tissues, and in vivo studies. Given the fact that over fifty percent of cancers have p53 mutation and several of them are prone to aggregation, therapeutic strategies are needed for treating p53 mutant aggregation associated cancers. Recent studies using polyarginine analogues and designer peptides for inhibiting p53 aggregation and tumor growth gives further encouragement in treating cancer as a protein aggregation disease. In this review, we highlight the recent efforts in targeting p53 aggregation in cancer and propose the use of small stress molecules as potential p53-antiaggregation drugs.

https://ift.tt/2IGaZOo

Increased DHRS12 expression independently predicts poor survival in patients with high-grade serous ovarian cancer

Future Oncology, Ahead of Print.


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Lenvatinib and its use in the treatment of unresectable hepatocellular carcinoma

Future Oncology, Ahead of Print.


https://ift.tt/2s1eJzr

Fulvestrant in management of hormone receptor-positive metastatic breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2IGe39f

Etiologic and Clinicopathological Correlates of Gastric Carcinoma in the Egyptian Delta

Abstract

We aimed at evaluation of the clinicoepidemiologic data of patients with gastric carcinoma in the Egyptian Delta as regards the etiologic factors, behavior, presenting symptoms, and tumor location, grade, and stage with highlighting of the treatment modalities, survival, and prognostic factors. Three hundred cases with gastric carcinoma were enrolled, diagnosed, and treated in a tertiary oncology center in the Egyptian Delta. Data were collected as regards the etiology, presenting symptoms, family history, comorbid conditions, treatment modalities, responses, recurrences, and survival outcomes. Univariate and multivariate analyses were done to correlate the different clinicopathologic factors with the overall and disease-free survivals. Male to female ratio was 2:1. The median age was 43 years. The main tumor location was in the gastric body. Pain was the commonest presenting symptom (36%). Most of the cases were stage IV (42.0%). Only 49% of cases were operable. On multivariate analysis, age more than 60 years, performance status 3–4, high grade, diffuse type, T4 lesions, N2 and N3, and the presence of metastasis were independently associated with worse OS. We report a clinic-epidemiologic study of gastric carcinoma in the Egyptian delta; the age at presentation was a decade earlier than that recorded in the USA and Europe; most of the cases were sporadic, located mostly at the body. Most of the cases were presented at stage IV with poor response to neoadjuvant therapy with a poorer overall survival than that recorded in the USA and Europe.

https://ift.tt/2x3Jitj

Machine Learning-Based Radiomics for Molecular Subtyping of Gliomas

Purpose: The new classification announced by the World Health Organization in 2016 recognized five molecular subtypes of diffuse gliomas based on isocitrate dehydrogenase (IDH) and 1p/19q genotypes in addition to histological phenotypes. We aim to determine whether clinical magnetic resonance imaging (MRI) can stratify these molecular subtypes to benefit the diagnosis and monitoring of gliomas. Experimental Design: The data from 456 subjects with gliomas were obtained from The Cancer Imaging Archive. Overall, 214 subjects, including 106 cases of glioblastomas and 108 cases of lower-grade gliomas with preoperative MRI, survival data, histology, IDH, and 1p/19q status were included. We proposed a three-level machine-learning model based on multimodal MR radiomics to classify glioma subtypes. An independent dataset with 70 glioma subjects was further collected to verify the model performance. Results: The IDH and 1p/19q status of gliomas can be classified by radiomics and machine-learning approaches, with areas under receiver operating characteristic curves between 0.922 and 0.975 and accuracies between 87.7 and 96.1% estimated on the training dataset. The test on the validation dataset showed a comparable model performance with that on the training dataset, suggesting the efficacy of the trained classifiers. The classification of 5 molecular subtypes solely based on the MR phenotypes achieved an 81.8% accuracy, and a higher accuracy of 89.2% could be achieved if the histology diagnosis is available. Conclusions: The MR radiomics-based method provides a reliable alternative to determine the histology and molecular subtypes of gliomas.

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Perioperative Chemotherapy for Urothelial Carcinoma of the Upper Urinary Tract: A Systematic Review and Meta-Anaysis

Publication date: Available online 22 May 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Richard W. Gregg, Francisco E. Vera-Badillo, Christopher M. Booth, Aamer Mahmud, Michael Brundage, Michael J. Leveridge, Timothy P. Hanna
IntroductionUpper tract urothelial carcinomas are rare malignancies with differences in anatomy and biology requiring therapeutic strategies that differ from bladder cancer. The role of perioperative systemic therapy in this disease remains uncertain with limited data to support its use. A systematic review of the literature and meta-analysis was therefore undertaken to provide more information and guide clinical practiceMethodsA Literature search was performed using Embase and Medline databases with additional searches performed manually using terms associated with upper tract urothelial malignancies. Data was extracted from studies of patients that underwent nephrouretectomy for the management of upper tract urothelial carcinoma and received either neoadjuvant or adjuvant systemic therapy. Overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were summated and analyzed using Cochrane Revman software Version 5.3.ResultsThere were 13 comparative studies and no randomized studies identified for data extraction; 11 adjuvant and 2 neoadjuvant with 1260 patients receiving perioperative systemic therapy and 3567 controls that did not. Perioperative chemotherapy was associated with improved OS (HR 0.75, 95%CI 0.57-0.99), DFS (HR 0.54, 95%CI 0.32-0.92), and CSS (HR 0.6, 95%CI 0.42-1.15).ConclusionsThe available data suggests that perioperative systemic therapy is associated with improved survival in patients with upper tract urothelial cancer.



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Pericytes in the Premetastatic Niche

The premetastatic niche formed by primary tumor–derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 1–8. ©2018 AACR.

https://ift.tt/2s2R9lf

Glycosylation of Recombinant Anticancer Therapeutics in Different Expression Systems with Emerging Technologies

Glycosylation, a posttranslational modification, has a major role in recombinant anticancer therapeutic proteins, as most of the approved recombinant therapeutics are glycoproteins. The constant amino acid sequence of therapeutics determines the enzymatic activity, while the presence of glycans influences their pharmacokinetics, solubility, distribution, serum half-life, effector function, and binding to receptors. Glycoproteins expressed in different expression systems acquire their own oligosaccharides, which increases the protein diversity. The heterogeneity of glycans creates hurdles in downstream processing, ultimately leading to variable anticancer therapeutic efficacy. Therefore, glycoproteins require an appropriate expression system to obtain structurally and functionally identical glycans, as in humans. In many expression systems, the N-glycosylation pathway remains conserved in the endoplasmic reticulum, but divergence is observed when the protein enters the Golgi complex. Hence, in recent decades, numerous approaches have been adopted to engineer the Golgi's N-glycosylation pathway to attain human-like glycans. Several researchers have tried to engineer the N-glycosylation pathway of expression systems. In this review, we examine the glycosylation pattern in various expression systems, along with emerging technologies for glycosylation engineering of anticancer therapeutic drugs. Cancer Res; 78(11); 1–12. ©2018 AACR.

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Detection of Bladder Cancer Via Microfluidic Immunoassay and Single-Cell DNA Copy Number Alteration Analysis of Captured Urinary Exfoliated Tumor Cells

The increasing incidence of bladder cancer (BC) and its high rate of recurrence over a 5-year period necessitate the need for diagnosis and surveillance amelioration. Cystoscopy and urinary cytology are the current tools, and molecular techniques such as BTA stat, NMP22, survivin mRNA, and urovysion FISH have attracted attention, however, they suf-fer from insufficient sensitivity or specificity. We developed a novel microfluidic approach for harvesting intact urinary-exfoliated tumor cells (UETCs), either individually or in clus-ters, in a clean and segregated environment, which is crucial to minimize cross-contamination and misreads. To reliably and accurately identify UETC, our quantitative immunoassay involved concurrent use of two oncoproteins CK20 and CD44v6 antigen. CK20 is an intermediate filament protein overexpressed in urothelial tumors, and CD44v6 is a membrane adhesion molecule closely associated with cell invasion, tumor progression and metastatic spread. Single-cell whole-genome sequencing on 12 captured UETCs and copy number alteration analysis showed that 11/12 (91.7%) of the immunofluorescence-identified UETCs possessed genomic instability. A total of 79 BC patients and 43 age-matched normal controls (NC) were enrolled in the study. We detected considerably high-er UETC counts in BC patients versus the NC group [53.3 (10.7-1001.9) vs. 0.0 (0-3.0) UETCs/10 mL; p < 0.0001]. For BC detection, a stratified 10-fold cross-validation of train-ing data reveals an overall predictive accuracy of 0.84 (95%CI: 0.76-0.93) with a 89.8% (95%CI: 71.5-86.4%) for sensitivity and 71.5% (95%CI: 59.7-83.3%) for specificity. Overall, the microfluidic immunoassay demonstrates increased sensitivity and specificity com-pared to other techniques for the detection of bladder cancer.

https://ift.tt/2s6TMm9

Juxtacrine signaling inhibits antitumor immunity by upregulating PD-L1 expression

Programmed death-ligand 1 (PD-L1) is a well-known immune checkpoint protein that helps cancer cells evade immune response. Anti-PD-L1 immune therapy has been approved for the treatment of several advanced human cancers. Therefore, further understanding of the regulatory mechanisms of PD-L1 is critical to improve PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways may regulate anticancer immunity, highlighting the importance of cell contact-induced signaling in cancer immunity. Here we show that tumor cell contact upregulates PD-L1 expression and reduces T cell-mediated cell killing through the membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is not expressed in normal tissues except testis and is known to mediate cell contact-dependent juxtacrine signaling. Knockout of EphA10 in tumor cells increased T cell-mediated antitumor immunity in syngeneic mouse models. EphA10 expression also correlated positively with PD-L1 in human breast tumor tissues. Together our data reveal that in addition to paracrine/autocrine signaling, cell contact-mediated juxtacrine signaling also promotes PD-L1 expression, implying that tumor cells may escape immune surveillance via this mechanism and that targeting EphA10 to boost antitumor immunity may be a new immune checkpoint blockade strategy for female breast cancer patients.

https://ift.tt/2J1uyQt

Mapping the HLA ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation

Immune cell infiltrates have proven highly relevant for colorectal carcinoma (CRC) prognosis, making CRC a promising candidate for immunotherapy. Since tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here we comprehensively describe the naturally presented HLA-ligandome of CRC and corresponding non-malignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA-class I ligands on CRC and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic CRC-associated pathways including Wnt, TGF-β, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired CRC and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be over-represented merely within the CRC ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T cell repertoire. Overall, these data show that the HLA-ligandome reflects cancer-associated pathways implicated in CRC oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived tumor-antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells might comprise promising candidates for immunotherapeutic applications.

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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor-1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.

https://ift.tt/2kiSb9j

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores, Published online: 23 May 2018; doi:10.1038/s41416-018-0095-9

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

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The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

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Langerhans cell histiocytosis at L5 vertebra treated with en bloc vertebral resection: a case report

Abstract

Background

Langerhans cell histiocytosis (LCH) in adult lumbar spine is extremely rare, and optimal treatments remain unclear. In literature, only a few cases of lumbar spine LCH were treated using surgery but en bloc vertebral resection has not been used.

Case presentation

A 50-year-old man presented with unbearable radiating pain at his right leg. Radiological studies revealed a solitary osteolytic lesion, which was moderately enhanced on contrast MR imaging and hyper-metabolic on PET/CT, at the right L5 vertebral body and arch. In biopsy, Langerhans cells were observed, but findings were insufficient to establish a diagnosis of LCH. A modified L5 en bloc vertebral resection via anterior and posterior approaches was performed to remove the right 2/3 portion of the L5 vertebra. The left 1/3 vertebral body and left pedicle of L5, which were not affected, were kept in situ to allow short instrumentation and reconstruction. His leg pain disappeared after the surgery, and a precise diagnosis of LCH was established after a throughout histological study of the removed vertebra. The patient further accepted 1 cycle of low-dose radiotherapy postoperatively. At 18-month follow-up, the lumbosacral spine was fused and no local reoccurrence was noticed.

Conclusions

For lumbar spine LCH, surgery should be considered if there are neurological symptoms or histological diagnosis is indefinite in biopsy. En bloc vertebral resection can be used to alleviate neurological symptoms and prevent local reoccurrence.

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Outcomes of adjuvant treatments for resectable intrahepatic cholangiocarcinoma: Chemotherapy alone, sequential chemoradiotherapy, or concurrent chemoradiotherapy

Prospective randomized trials have not been used to evaluate the efficacy of adjuvant therapies after intrahepatic cholangiocarcinoma (ICC) resection.

https://ift.tt/2Lo4zBa

Respiratory motion of lymph node stations in pancreatic cancer: Analyses using contrast-enhanced four-dimensional computed tomography

Data regarding respiratory motion of lymph node (LN) stations in pancreatic cancer is limited. Therefore, we assessed their respiratory motion using contrast-enhanced four-dimensional-computed tomography (CE-4DCT).

https://ift.tt/2x27wEv

Can dose outside the PTV influence the risk of distant metastases in stage I lung cancer patients treated with stereotactic body radiotherapy (SBRT)?

In an era where little is known about the "abscopal" (out-of-the-field) effects of lung SBRT, we investigated correlations between the radiation dose proximally outside the PTV and the risk of cancer recurrence after SBRT in patients with primary stage I non-small cell lung cancer (NSCLC).

https://ift.tt/2LmpCnJ

Unmet information needs of patients with melanoma in Germany

There is a scarcity of available data on unmet information needs (UINs) of melanoma patients (MPs) from Germany and of MPs with clinical stage IV. In a multicenter cross-sectional survey, we explored the UINs of 529 MPs by applying a standardized questionnaire. Subgroup differences in scope and contents of UINs were determined by univariate analyses. Predictors of the presence of UINs were identified by binary logistic regression. Overall, 55% of MPs reported UINs. Most MPs felt poorly or not informed about psychosocial support (24–31%). In MPs currently receiving medical treatment [odds ratio (OR): 1.9; P=0.017], MPs aging of at least 55 years (OR: 1.7; P=0.029), and in MPs who generally had a high need for information on their condition (OR: 2.4; P=0.001), the presence of UINs was significantly more likely than in post-treatment MPs, MPs more than 55 years of age, and those whose general information need was low. Most UINs concerned treatment-related information and were reported by MPs with tumor progression. Presence and scope of UINs did not differ significantly between metastatic and nonmetastatic MPs (57 vs. 53%; P=0.436). We highlighted differences in the presence, scope, and contents of UINs between MP subgroups, which should be considered when educating them in medical consultations and providing information via media. In particular, MPs felt insufficiently informed about psychosocial support and desired more treatment information. Other members of the German NVKH supporting group involved in this study are listed in the Appendix. Correspondence to Julia Brütting, MSc, Dresden University Hospital Carl Gustav Carus, Department of Dermatology, Fetscherstr. 74, 01307 Dresden, Germany Tel: +49 176 2078 9627; fax: +49 351 458 4338; e-mail: julia.bruetting@uniklinikum-dresden.de Received December 4, 2017 Accepted April 26, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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A Pilot Study of a Novel Automated Somatosensory Evoked Potential (SSEP) Monitoring Device for Detection and Prevention of Intraoperative Peripheral Nerve Injury in Total Shoulder Arthroplasty Surgery

Introduction: Peripheral nerve injury is a potentially devastating complication after total shoulder arthroplasty (TSA) surgery. This pilot study aimed to assess the feasibility of using an automated somatosensory evoked potential (SSEP) device to provide a timely alert/intervention to minimize intraoperative nerve insults during TSA surgery. Methods: A prospective, single-arm, observational study was conducted in a single university hospital. The attending anesthesiologist monitored the study participants using the EPAD automated SSEP device and an intervention was made if there was an alert during TSA surgery. The median, radial, and ulnar nerve SSEP on the operative arm, as well as the median nerve SSEP of the nonoperative arm were monitored for each patient. All patients were evaluated for postoperative neurological deficits 6 weeks postoperatively. Results: In total, 21 patients were consented and were successfully monitored. In total, 4 (19%) patients developed intraoperative abnormal SSEP signal changes in the operative arm, in which 3 were reversible and 1 was irreversible till the end of surgery. Median and radial nerves were mostly involved (3/4 patients). The mean cumulative duration of nerve insult (abnormal SSEP) was 21.7±26.2 minutes. Univariate analysis did not identify predictor of intraoperative nerve insults. No patients demonstrated postoperative peripheral neuropathy at 6 weeks. Conclusions: A high incidence (19%) of intraoperative nerve insult was observed in this study demonstrating the feasibility of using an automated SSEP device to provide a timely alert and enable an intervention in order to minimize peripheral nerve injury during TSA. Further randomized studies are warranted. The study (IRB #107438) was approved by Lawson Health Research Institute, Western University. Clinical trial registration #: NCT02237599 (www.clinicaltrials.gov). J.C. is the archival author. J.M.M. is member of Scientific Advisory Board of SafeOp Surgical, Hunt Valley, MD. J.C. and D.D. has no conflicts of interest to disclose. Address correspondence to: Jason Chui, MBChB, FANZCA, C3-106, University Hospital, 339 Windermere Road, London, ON, Canada N6A 5A5 (e-mail: Jason.chui@lhsc.on.ca). Received January 31, 2018 Accepted March 29, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

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A Case of Primary Intra-abdominal Synovial Sarcoma

Abstract

Synovial sarcomas are relatively common intermediate-to-high-grade malignant soft tissue tumors, often with an initial indolent course. And among the sarcomas primary intra-abdominal synovial sarcoma is a relatively rare entity that may present with an abdominal mass and diagnosis is usually confirmed by immunohistochemistry. The authors report a case of a 46-year-old man who presented with a large palpable abdominal mass. Contrast-enhanced computed tomography (CT) scan showed a large well-defined heterogeneous intra-abdominal mass filling the entire pelvis and extending upwards till the subhepatic region causing displacement of intra-abdominal organs. However, no other focal lesions were seen in the solid organs. The same findings were confirmed on surgery. Histopathology was suggestive of desmoid tumor/hemangiopericytoma. Immunohistochemistry showed positive markers corresponding to synovial sarcoma. The patient was advised to undergo chemotherapy which was refused and follow-up was lost. After 10 months, patient presented for follow-up CT, which showed marked increase in size of the lesion.

https://ift.tt/2x2ikSO

Social Network, Surgeon, and Media Influence on the Decision to Undergo Contralateral Prophylactic Mastectomy

Objectives: The rate of contralateral prophylactic mastectomy (CPM) has risen sharply in the past decade. The current study was designed to examine social network, surgeon, and media influence on patients' CPM decision-making, examining not only who influenced the decision, and to what extent, but also the type of influence exerted. Methods: Patients (N=113) who underwent CPM at 4 Indiana University–affiliated hospitals between 2008 and 2012 completed structured telephone interviews in 2013. Questions addressed the involvement and influence of the social network (family, friends, and nonsurgeon health professionals), surgeon, and media on the CPM decision. Results: Spouses, children, family, friends, and health professionals were reported as exerting a meaningful degree of influence on patients' decisions, largely in ways that were positive or neutral toward CPM. Most surgeons were regarded as providing options rather than encouraging or discouraging CPM. Media influence was present, but limited. Conclusions: Patients who choose CPM do so with influence and support from members of their social networks. Reversing the increasing choice of CPM will require educating these influential others, which can be accomplished by encouraging patients to include them in clinical consultations, and by providing patients with educational materials that can be shared with their social networks. Surgeons need to be perceived as having an opinion, specifically that CPM should be reserved for those patients for whom it is medically indicated.

https://ift.tt/2KMPzLQ

Evaluating Candidacy for Hypofractionated Radiation Therapy, Accelerated Partial Breast Irradiation, and Endocrine Therapy After Breast Conserving Surgery: A Surveillance Epidemiology and End Results (SEER) Analysis

Purpose/Objective(s): After breast conserving surgery, adjuvant radiation therapy represents the standard of care for most patients. However, multiple options exist beyond standard fractionated whole breast irradiation including hypofractionated whole breast irradiation (HFRT), accelerated partial breast irradiation (APBI), and endocrine therapy (ET) alone, which can limit treatment duration, and potentially reduce morbidity and cost. Limited data are available on the percentage of patients eligible for these alternatives; therefore, a Surveillance Epidemiology and End Results (SEER) analysis was performed to assess candidacy for these alternative options in women with early stage breast cancer. Materials and Methods: Women treated for breast cancer between the years of 2010 and 2012 were identified in the SEER database. Patients with unknown staging, metastatic disease, T3/T4 disease, and ≥N1 disease were excluded. Patients were defined as eligible for HFRT based on the American Society for Radiation Oncology (ASTRO) consensus guidelines and randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer (IMPORT LOW) trial criteria, APBI based on the ASTRO, American Brachytherapy Society and the Groupe Européen de Curiethérapie of European Society for Therapeutic Radiotherapy and Oncology (GEC-ESTRO) consensus guidelines, and GEC-ESTRO APBI and IMPORT LOW trial criteria, and ET alone based on the Cancer and Leukemia Group B 9343 and Post-operative Radiotherapy in Minimum Risk Elderly II inclusion criteria. Results: A total of 108,484 women with early stage breast cancer who met the aforementioned inclusion criteria were identified. Of these patients, 86,896 (80.1%) were eligible for HFRT based on ASTRO consensus guidelines and 81,459 (75.0%) based on IMPORT LOW trial criteria. Regarding APBI, 44,797 (41.2%), 81,020 (74.6%), 81,020 (74.6%) were eligible according to ASTRO, ABS, GEC-ESTRO consensus guidelines, respectively, 97,301 (89.7%) patients according to the GEC-ESTRO trial criteria, and 81,459 (75.0%) patients according to the IMPORT LOW trial criteria. For ET alone, 23,006 (21.2%) were eligible according to Cancer and Leukemia Group B 9343 criteria and 42,104 (38.8%) according to Post-operative Radiotherapy in Minimum Risk Elderly II criteria. Conclusions: This SEER analysis demonstrates that a substantial proportion of women with early stage breast cancer are eligible for HFRT, APBI, or ET alone after breast conserving surgery according to consensus guidelines and prospective trial criteria. With incorporation of additional pathologic, dosimetric, and chemotherapy data, quality assurance pathways may use such data to help ensure patients are receiving appropriate risk stratified treatment recommendations.

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Concurrent Radiotherapy and Triweekly Carboplatin for the Definitive Treatment of Locally Advanced Laryngeal Carcinoma

Purpose of the Study: In 2003, our institution adopted triweekly carboplatin (tCb) area under the curve (AUC) 5 as an alternative to high-dose cisplatin (100 mg/m2) for select patients receiving definitive concurrent chemoradiation for locally advanced laryngeal carcinoma (LALC). Here, we present our experience and outcomes with this definitive concurrent chemoradiation regimen. Methods: From January 2003 through December 2013, 53 patients with stage III (60%) or IVA (40%) LALC were treated with tCb AUC 5 and concurrent radiotherapy to 70 Gy without neoadjuvant chemotherapy. Reasons for using carboplatin instead of cisplatin in these patients were: age 70 and older (21%), poor renal function (6%), presence of 1 or more major comorbid condition(s) (36%), and per discretion of the treating medical oncologist (38%). Primary disease site was glottis in 22 (42%) patients and supraglottis in 31 (58%) patients. Results: Median follow-up time was 63 months for surviving patients. Out of the 53 patients, 43 (81%) received all 3 cycles of carboplatin and all patients received their intended dose of radiotherapy. Although 17 (32%) patients required a feeding tube during treatment, only 2 (4%) required it long term. There were no acute treatment-related grade 4 or 5 hematologic toxicities. On last follow-up, 14 (26%) patients had died of intercurrent disease. For the subgroup of "RTOG 9111 eligible" patients in our cohort (n=46), 5-year estimates of overall survival, disease-free survival, laryngectomy-free survival, larynx preservation, and locoregional control were: 49%, 42%, 39%, 80%, and 63%, respectively. Conclusions: In patients with LALC who are suboptimal candidates for high-dose cisplatin, our experience suggests that tCb AUC 5 with concurrent radiotherapy provides acceptable outcomes with tolerable toxicity.

https://ift.tt/2KHA8EI

Prognostic Factors, Treatment, and Outcomes in Early Stage, Invasive Papillary Breast Cancer: A SEER Investigation of Less Aggressive Treatment in a Favorable Histology

Objectives: Invasive papillary breast cancer (IPBCA) represents 0.5% of invasive BCA, and is thought to carry a favorable prognosis. This population-based study reports on prognostic factors, treatment, and outcomes of early-stage IPBCA to explore whether there is any evidence to support less aggressive treatment. Materials and Methods: IPBCA cases from 1990 to 2009 of the recent Surveillance, Epidemiology, and End Results were analyzed. Inclusion criteria included patients with stage T1-2, N0 IPBCA. Univariate and multivariate analyses were performed using the variables of treatment, stage, race, hormone receptor status, grade (G1-3), and age. Treatment modalities included lumpectomy alone (LA), lumpectomy with radiation treatment (LRT), and mastectomy alone (MA). Results: Among 10,485 patients, median follow-up was 56 months. Five and 10-year overall survival (OS) were 93.1% and 76.8%, respectively. Patients treated with LRT had superior mean OS 16.8 versus 14.9 years for MA (P=0.0004) and 14.2 years for LA (P=0.0003). Improved OS also correlated with lower histologic grade (P

https://ift.tt/2s1V16N

Knowledge of Clinical Trial Availability and Reasons for Nonparticipation Among Adolescent and Young Adult Cancer Patients: A Population-based Study

Purpose of the Study: Adolescent and young adult (AYA) cancer patients are underrepresented in clinical trials, but the reasons for this phenomenon are unknown. Patients And Methods: Questionnaire and medical record data from 515 AYA cancer patients (21 acute lymphocytic leukemia [ALL], 201 germ cell tumor, 141 Hodgkin lymphoma, 128 non-Hodgkin lymphoma, 24 sarcoma) from a population-based study were analyzed. We used multivariable models to determine characteristics associated with patient knowledge of the availability of clinical trials for their cancer. Reasons for not participating in a trial were tabulated. Results: In total, 63% of patients reported not knowing whether a relevant clinical trial was available, 20% reported knowing that a clinical trial was not available, and 17% reported that a trial was available. Among patients reporting an available trial, 67% were recommended for enrollment. Knowing about the availability of clinical trials was associated with having ALL (odds ratio=2.9, 95% confidence interval=1.1, 7.8). Reporting that a clinical trial was available was positively associated with having ALL, Hodgkin lymphoma, non-Hodgkin lymphoma and sarcoma (relative to germ cell tumor) and working full-time or in school full-time (odds ratio=2.6, 95% confidence interval=1.0, 6.7). Concerns about involvement in research (57%) and problems accessing trials (21%) were the primary reasons cited for not enrolling among patients who knew that a trial was available. Conclusions: Improvement in AYA cancer patient clinical trial enrollment will require enhancing knowledge about trial availability and addressing this population's concerns about participating in medical research.

https://ift.tt/2KLSODv

Outcomes of Node-positive Breast Cancer Patients Treated With Accelerated Partial Breast Irradiation Via Multicatheter Interstitial Brachytherapy: The Pooled Registry of Multicatheter Interstitial Sites (PROMIS) Experience

Objectives: To report outcomes for breast-conserving therapy using adjuvant accelerated partial breast irradiation (APBI) with interstitial multicatheter brachytherapy in node-positive compared with node-negative patients. Materials and Methods: From 1992 to 2013, 1351 patients (1369 breast cancers) were treated with breast-conserving surgery and adjuvant APBI using interstitial multicatheter brachytherapy. A total of 907 patients (835 node negative, 59 N1a, and 13 N1mic) had >1 year of data available and nodal status information and are the subject of this analysis. Median age (range) was 59 years old (22 to 90 y). T stage was 90% T1 and ER/PR/Her2 was positive in 87%, 71%, and 7%. Mean number of axillary nodes removed was 12 (SD, 6). Cox multivariate analysis for local/regional control was performed using age, nodal stage, ER/PR/Her2 receptor status, tumor size, grade, margin, and adjuvant chemotherapy/antiestrogen therapy. Results: The mean (SD) follow-up was 7.5 years (4.6). The 5-year actuarial local control (95% confidence interval) in node-negative versus node-positive patients was 96.3% (94.5-97.5) versus 95.8% (87.6-98.6) (P=0.62). The 5-year actuarial regional control in node-negative versus node-positive patients was 98.5% (97.3-99.2) versus 96.7% (87.4-99.2) (P=0.33). The 5-year actuarial freedom from distant metastasis and cause-specific survival were significantly lower in node-positive versus node-negative patients at 92.3% (82.4-96.7) versus 97.8% (96.3-98.7) (P=0.006) and 91.3% (80.2-96.3) versus 98.7% (97.3-99.3) (P=0.0001). Overall survival was not significantly different. On multivariate analysis age 50 years and below, Her2 positive, positive margin status, and not receiving chemotherapy or antiestrogen therapy were associated with a higher risk of local/regional recurrence. Conclusions: Patients who have had an axillary lymph node dissection and limited node-positive disease may be candidates for treatment with APBI. Further research is ultimately needed to better define specific criteria for APBI in node-positive patients.

https://ift.tt/2s0qG8C

Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma

Objectives: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. Methods: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. Results: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. Conclusions: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease.

https://ift.tt/2IDESe8

A Phase II Study to Prevent Radiation-induced Rectal Injury With Lovastatin

Purpose: Physician reported symptomatic late rectal injury occurs in about 5% to 25% of patients treated with radiation therapy for prostate cancer, depending on the treatment technique. Patients, however, report clinically meaningful declines in bowel/rectal function regardless of the technique used. Lovastatin has been shown to protect mice from late radiation injury. This study was designed to determine if lovastatin might reduce the incidence of late rectal injury in patients receiving radiation therapy for prostate cancer. Materials and Methods: Patients with adenocarcinoma of the prostate receiving radiotherapy with curative intent were eligible. A portion of the rectum had to receive at least 60 Gy. Gastrointestinal functioning was assessed using both physician-reported and patient-reported instruments at baseline and at prescribed intervals during and after treatment. Lovastatin (20 to 80 mg/d) was started on day 1 of radiation and continued for 12 months. Patients were followed for an additional 12 months. The primary endpoint was physician-reported rectal toxicity ≥grade 2 during the first 2 years after treatment. Results: A total of 20/53 (38%) patients developed grade 2 or higher toxicity during the 2-year follow-up period. Seventeen patients had 1 or more unresolved gastrointestinal symptom at the end of 2 years, 3 (6%) of which were grade 2 and none were of higher grade. Conclusions: The primary endpoint of the study was not met. Lovastatin, as administered in this trial, did not reduce the incidence of grade 2 or higher rectal toxicity compared with historical controls.

https://ift.tt/2s0pbap

Decreased Risk of Radiation Pneumonitis With Coincident Concurrent Use of Angiotensin-converting Enzyme Inhibitors in Patients Receiving Lung Stereotactic Body Radiation Therapy

Objectives: Angiotensin-converting enzyme inhibitors (ACEi) have demonstrated decreased rates of radiation-induced lung injury in animal models and clinical reports have demonstrated decreased pneumonitis in the setting of conventionally fractionated radiation to the lung. We tested the role of ACEi in diminishing rates of symptomatic (grade ≥2) pneumonitis in the setting of lung stereotactic body radiation therapy (SBRT). Methods: We analyzed patients treated with thoracic SBRT to 48 to 60 Gy in 4 to 5 fractions from 2006 to 2014. We reviewed pretreatment and posttreatment medication profiles to document use of ACEi, angiotensin receptor blockers, bronchodilators, aspirin, PDE-5 inhibitors, nitrates, and endothelin receptor antagonists. Pneumonitis was graded posttreatment based on Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed and time to development of pneumonitis was evaluated by the Kaplan-Meier method. Results: A total of 189 patients were evaluated with a median follow-up of 24.8 months. The overall 1-year rate of symptomatic pneumonitis was 13.2%. The 1-year rate of symptomatic pneumonitis was 4.2% for ACEi users versus 16.3% in nonusers (P=0.03). On univariate analysis, the odds of developing grade 2 or greater pneumonitis were significantly lower for patients on ACEi (P=0.03). On multivariate analysis, after controlling for clinicopathologic characteristics and dosimetric endpoints, there was a significant association between ACEi use and decreased risk of clinical pneumonitis (P=0.04). Angiotensin receptor blockers or other bronchoactive medications did not show significant associations with development of pneumonitis. Conclusions: Incidental concurrent use of ACEi demonstrated efficacy in diminishing rates of symptomatic pneumonitis in the setting of lung SBRT.

https://ift.tt/2KNX45v

Does Specialty Bias Trump Evidence in the Management of High-risk Prostate Cancer?

Objective: The objective was to query how specialty influences treatment recommendations for high-risk prostate cancer in 3 clinical settings: upfront management, postoperative management, and management of biochemical recurrences (BCRs) after radiotherapy (RT). We hypothesized that specialty bias would manifest in all settings, trumping available evidence. Methods: A survey of practicing urologists and radiation oncologists was distributed through electronic mail. Questions pertained to upfront management, postoperative treatment, and local salvage for postradiation BCRs. The associations between 26 selected categorical responses and specialty were assessed using multivariate logistic regression. Training level/expertise, practice setting, percentage of consultation caseload consisting of prostate cancer, and nationality were set as effect modifiers. Results: One thousand two hundred fifty-three physicians (846 radiation oncologists and 407 urologists) completed the survey. Radiation oncologists were more likely to recommend adjuvant RT and consider it to be underutilized, and more likely to recommend salvage RT at lower prostate-specific antigen thresholds (P

https://ift.tt/2s0Aqjj

Preradiation Chemotherapy for Adult High-risk Medulloblastoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4397)

Objectives: To assess the long-term outcomes and objective response (OR) to preradiation chemotherapy and radiation in adult high-risk medulloblastoma. Materials and Methods: In this prospective phase II trial, adults with high-risk medulloblastoma were treated with 3 cycles of preradiation cisplatin, etoposide, cyclophosphamide, and vincristine followed by craniospinal radiation (CSI). OR, progression-free survival (PFS), overall survival (OS), and toxicities were assessed. Results: Eleven patients were enrolled over a 6-year period. Six (55%) had subarachnoid metastases. Two (18%) had an OR to preradiation chemotherapy. Two (18%) progressed while on chemotherapy. Completion of CSI was not compromised. The OR rate after chemotherapy and radiation was 45% (5/11). Nonevaluable patients at both time-points weakened the response data conclusions. Median PFS was 43.8 months. Five-year PFS was 27%. Five-year OS was 55%. Nonmetastatic (M0) and metastatic (M+) patients had similar outcomes. Conclusions: The OR to this preradiation chemotherapy regimen is lower than anticipated from the adult and pediatric literature raising a question about comparative efficacy of chemotherapy in different age groups. The OS achieved is similar to retrospective adult series, but worse than pediatric outcomes. Although this regimen can be administered without compromising delivery of CSI, our results do not provide support for the use of this neoadjuvant chemotherapy for adult medulloblastoma.

https://ift.tt/2IFlZHF

Patient-reported Urinary, Bowel, and Sexual Function After Hypofractionated Intensity-modulated Radiation Therapy for Prostate Cancer: Results From a Randomized Trial

Objectives: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy. Methods: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment. Results: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains. Discussion: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

https://ift.tt/2rZL6Pg

Pretreatment Tumor Thickness as a Predictor of Pathologic Complete Response to Neoadjuvant Chemoradiation Therapy for Stage II/III Rectal Adenocarcinoma

Objectives: To evaluate pretreatment tumor thickness in predicting pathologic complete response (pCR) of stage II/III rectal adenocarcinoma to neoadjuvant chemoradiation (chemoradiotherapy [CRT]). Methods: We retrospectively analyzed 185 patients who were diagnosed with stage II or III rectal adenocarcinoma from January 2011 to July 2013 and treated with neoadjuvant intensity-modulated radiation therapy (45 Gy in 1.8-Gy fractions to pelvis and 50 Gy in 2-Gy fractions to rectal tumor as an integrated boost) or 3 dimensionally conformal radiation therapy (45 Gy in 1.8-Gy fractions to pelvis followed by an additional 5.4-Gy to rectal tumor) concurrently with two 3-week cycles of chemotherapy (oxaliplatin 130 mg/m2 on day 1 and capecitabine 825 mg/m2, twice per day from day 1 to 14, cycle 2 starts on week 4). One week after CRT, 36% patients received 1 more cycle of the above chemotherapy and 55% received 1 to 2 cycles of FOLFOX6. Tumor response was categorized as pCR and non-pCR. Tumor thickness measured on magnetic resonance imaging was collected. A multivariate logistic regression model was used to evaluate the association of potential predictors and pCR. Results: Thirty-eight patients (20.5%) reached pCR. Multivariate analysis found the pretreatment tumor thickness to be associated with higher probability of pCR after adjusting for radiation therapy-surgery interval time and pretreatment carcino-embryonic antigen level. The pretreatment carcino-embryonic antigen level was associated with pCR in the univariate analysis but lost the association in the multivatiate model. The pretreatment T or N stage, tumor volume, distance from tumor to anal verge, craniocaudal length of tumor, radiation therapy technique, and patient age and sex were not associated with pCR. Conclusions: We concluded that pretreatment tumor thickness is an independent predictor for pCR of stage II/III rectal adenocarcinoma to the neoadjuvant CRT.

https://ift.tt/2ICOmGq

Stereotactic Ablative Radiotherapy (SABR) for Large Renal Tumors: A Retrospective Case Series Evaluating Clinical Outcomes, Toxicity, and Technical Considerations

Objectives: Metastatic renal cell carcinoma represents a clinical scenario where aggressive treatment to the primary tumor (ie, cytoreductive nephrectomy) is associated with a survival benefit. We hypothesized that stereotactic ablative radiotherapy (SABR) could be a safe alternative local modality for inoperable metastatic renal cell carcinoma patients. Our study objectives were to report on technical considerations, toxicity, and clinical outcomes of our institutional experience with renal SABR. Materials and Methods: Patients who underwent renal SABR at our institution between January 2008 and June 2015 were reviewed. Toxicity was quantified using the Common Terminology Criteria for Adverse Events version 4.0. Radiographic response was evaluated using the Response Evaluation Criteria in Solid Tumors classification. Median overall survival and follow-up were calculated using the Kaplan-Meier and reverse Kaplan-Meier methods, respectively. Results: We identified 11 patients that met study criteria. SABR was directed to the tumor or whole kidney in 5 fractions to a dose of 25 to 40 Gy. Median tumor diameter and planning target volume were 9.5 cm (range, 7.5 to 24.4) and 819.3 cm3 (range, 313.4 to 5704.3), respectively. Median follow-up was 3.9 years (95% confidence interval, 0.6-4.9). Five cases of grade 1 toxicity were reported. In the patient with the largest target, grade 2 diarrhea and probable grade 3 nausea were observed. In patients with available follow-up imaging (7/11), stable disease (n=5), partial response (n=1), and progressive disease (n=1) were observed. Median overall survival was 20.4 months (95% confidence interval, 2.30-N/A). Conclusions: In this small cohort, renal SABR was delivered with minimal toxicity. A prospective study is underway at our institution to determine maximum tolerable and optimal dosing (NCT02264548).

https://ift.tt/2s2qoOw

Molecular Predictors of Response to Neoadjuvant Chemoradiation for Rectal Cancer

Objectives: To determine whether the expression of specific molecular markers in the rectal cancer biopsies prior to treatment, can correlate with complete tumor response to chemoradiotherapy (CRT) as determined by the pathology of the surgical specimen. Methods: We retrospectively examined pretreatment rectal biopsies of patients aged 18 years or older with locally advanced rectal cancer who had been treated with neoadjuvant CRT and surgical resection in our tertiary-care, university-affiliated medical center, between January 2001 and December 2011. Samples were analyzed for expression of B-cell lymphoma 2, P53, Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, and the tumor regression grade after CRT and radical surgery. Results: Forty-seven patients were included in the final analysis. Main outcome measures were the correlation between the expression of the molecular markers tested in the pretreatment biopsy, and complete tumor response. Complete pathologic response after CRT was attained in 27% of the patients. Percentage of cells expressing EGFR in the pretreated biopsies of patients having complete pathologic response after CRT and surgery was 33.08±7.87% compared to 19±15.36% (P=0.38), 6.66±2.83% (P

https://ift.tt/2IEPXLP

Under the Knife: The History of Surgery in 28 Remarkable Operations

No abstract available

https://ift.tt/2KNX0mh

Identifying Barriers to Implementation of the National Partnership for Maternal Safety Obstetric Hemorrhage Bundle at a Tertiary Center: Utilization of the Delphi Method

BACKGROUND: In 2015, the National Partnership for Maternal Safety (NPMS) developed an obstetric hemorrhage consensus bundle to provide birthing facilities in the United States with consistent, validated practice guidelines for postpartum hemorrhage management. The process of implementing each bundle element at a large tertiary labor and delivery unit has not been described; we sought to identify practice deficiencies and perceived barriers to bundle implementation among multidisciplinary providers. METHODS: We conducted a prospective, cross-sectional, consensus-building study based on the Delphi method. A multidisciplinary expert panel comprised of anesthesiologists, obstetricians, nurses, and surgical technicians was assembled and participated in 4 sequential questionnaires. The first round identified bundle elements that experts determined as not currently adequate and perceived barriers to implementation. The second round established prioritization of elements within each professional group; and the third round ranked the elements with at least 60% agreement on feasibility of implementation and positive impact on patient care. The last round revealed responses across all 4 professional groups to derive a final consensus. Descriptive statistics were performed. RESULTS: A total of 38 experts completed the study (11 anesthesiologists, 11 obstetricians, 10 nurses, and 6 surgical technicians). While all 13 (100%) NPMS obstetric bundle elements were described as deficient in our labor and delivery unit by a provider in at least 1 discipline, consensus among at least 3 of the 4 disciplines was achieved for 6 element deficiencies. Barriers to implementation were determined. The initiatives that achieved consensus as possessing high patient impact and implementation feasibility were protocol-driven management, unit-based simulation drills, blood loss quantification, and team huddles and debriefings. CONCLUSIONS: The NPMS obstetric hemorrhage bundle was created to help guide practice and systems improvement for US birthing facilities. The Delphi method enabled identification of deficient elements and perceived barriers to element implementation, as well as group consensus on elements with highest patient impact and feasibility. Multidisciplinary group consensus can identify deficiencies and promote tangible, quality improvements in a large, tertiary-care labor and delivery unit. Institutions may utilize our described technique to guide implementation of future care bundles. Accepted for publication April 12, 2018. Funding: Departmental. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Institutional Research Ethics Board: Partners HealthCare Institutional Review Board, Partners Human Research Committee, 116 Huntington Ave, Suite 1002, Boston, MA 02116. Clinical trial number and registry URL: NCT03018119 https://ift.tt/2IIP98H. Reprints will not be available from the authors. Address correspondence to Annemaria De Tina, MD, FRCPC, Department of Anesthesiology, McMaster University, Third Floor, 237 Barton St E, Hamilton, ON L8L 2X2, Canada. Address e-mail to detinaa@mcmaster.ca. © 2018 International Anesthesia Research Society

https://ift.tt/2s0UBOd

Organ Donation After Circulatory Death: Ethical Issues and International Practices

Donation after circulatory death (DCD) is an increasingly utilized practice that can contribute to reducing the difference between the supply of organs and the demand for organs for transplantation. As the number of transplanted organs from DCD donors continues to increase, there is an essential need to address the ethical aspects of DCD in institutional DCD protocols and clinical practice. Ethical issues of respecting the end-of-life wishes of a potential donor, respecting a recipient's wishes, and addressing potential conflicts of interest are important considerations in developing policies and procedures for DCD programs. Although there may be diversity among DCD programs in Europe, Australia, Israel, China, the United States, and Canada, addressing ethical considerations in these DCD programs is essential to respect donors and recipients during the altruistic and generous act of organ donation. Accepted for publication April 12, 2018. Funding: None. The author declares no conflicts of interest. Reprints will not be available from the author. Address correspondence to Barbara G. Jericho, MD, FASA, Department of Anesthesiology, University of Illinois Hospital and Health Sciences System, 1740 W Taylor St, Suite 3200, M\C 515, Chicago, IL 60612. Address e-mail to jericho@uic.edu. © 2018 International Anesthesia Research Society

https://ift.tt/2rZKY2e

“Modified Dynamic Needle Tip Positioning” Short-Axis, Out-of-Plane, Ultrasound-Guided Radial Artery Cannulation in Neonates: A Randomized Controlled Trial

BACKGROUND: Radial artery cannulation is extremely challenging in neonatal patients. Herein, we compared the success rate of the modified dynamic needle tip positioning short-axis, out-of-plane, ultrasound-guided technique with that of the traditional palpation technique in neonatal radial artery cannulation. METHODS: Sixty term neonates undergoing major abdominal surgery were randomized into the ultrasound or palpation group via the sealed-envelope method. The ultrasound group underwent radial artery cannulation using an ultrasonic apparatus, while traditional palpation of arterial pulsation was used in the palpation group. The arterial diameter and depth were measured on ultrasound before the puncture. We recorded age, weight, sex, and other background characteristics. The primary outcomes included the first-attempt, total success rates, and the total puncture procedure duration. Secondary outcomes included the incidence of complications (hematoma and thrombosis). Data were compared between the 2 groups. RESULTS: Sixty term neonates were enrolled in the study. The success rates of the first attempt in the ultrasound and palpation groups were 40% (n = 30) and 10% (n = 30), respectively (P = .007; relative risk, 4.0; 95% confidence interval, 1.3–12.8). The total success rate was 96.7% in the ultrasound group and 60.0% in the palpation group (P = .001; relative risk, 1.61; 95% confidence interval, 1.19–2.17). The average time to accomplish radial artery cannulation in the ultrasound and palpation groups was 91.4 ± 55.4 and 284.7 ± 153.6 seconds, respectively (P

https://ift.tt/2KLu0vb

The Effect of Dexmedetomidine on Propofol Requirements During Anesthesia Administered by Bispectral Index-Guided Closed-Loop Anesthesia Delivery System: A Randomized Controlled Study

BACKGROUND: Dexmedetomidine, a selective α2-adrenergic agonist currently approved for continuous intensive care unit sedation, is being widely evaluated for its role as a potential anesthetic. The closed-loop anesthesia delivery system (CLADS) is a method to automatically administer propofol total intravenous anesthesia using bi-spectral index (BIS) feedback and attain general anesthesia (GA) steady state with greater consistency. This study assessed whether dexmedetomidine is effective in further lowering the propofol requirements for total intravenous anesthesia facilitated by CLADS. METHODS: After ethics committee approval and written informed consent, 80 patients undergoing elective major laparoscopic/robotic surgery were randomly allocated to receive GA with propofol CLADS with or without the addition of dexmedetomidine. Quantitative reduction of propofol and quality of depth-of-anesthesia (primary objectives), intraoperative hemodynamics, incidence of postoperative adverse events (sedation, analgesia, nausea, and vomiting), and intraoperative awareness recall (secondary objectives) were analyzed. RESULTS: There was a statistically significant lowering of propofol requirement (by 15%) in the dexmedetomidine group for induction of anesthesia (dexmedetomidine group: mean ± standard deviation 0.91 ± 0.26 mg/kg; nondexmedetomidine group: 1.07 ± 0.23 mg/kg, mean difference: 0.163, 95% CI, 0.04–0.28; P = .01) and maintenance of GA (dexmedetomidine group: 3.25 ± 0.97 mg/kg/h; nondexmedetomidine group: 4.57 ± 1.21 mg/kg/h, mean difference: 1.32, 95% CI, 0.78–1.85; P

https://ift.tt/2rZKPvI

Interviewing in Social Science Research: A Relational Approach

No abstract available

https://ift.tt/2KO2GwG

Perianesthetic and Anesthesia-Related Mortality in a Southeastern United States Population: A Longitudinal Review of a Prospectively Collected Quality Assurance Data Base

BACKGROUND: Perianesthetic mortality (death occurring within 48 hours of an anesthetic) continues to vary widely depending on the study population examined. The authors study in a private practice physician group that covers multiple anesthetizing locations in the Southeastern United States. This group has in place a robust quality assurance (QA) database to follow all patients undergoing anesthesia. With this study, we estimate the incidence of anesthesia-related and perianesthetic mortality in this QA database. METHODS: Following institutional review board approval, data from 2011 to 2016 were obtained from the QA database of a large, community-based anesthesiology group practice. The physician practice covers 233 anesthetizing locations across 20 facilities in 2 US states. All detected cases of perianesthetic death were extracted from the database and compared to the patients' electronic medical record. These cases were further examined by a committee of 3 anesthesiologists to determine whether the death was anesthesia related (a perioperative death solely attributable to either the anesthesia provider or anesthetic technique), anesthetic contributory (a perioperative death in which anesthesia role could not be entirely excluded), or not due to anesthesia. RESULTS: A total of 785,467 anesthesia procedures were examined from the study period. A total of 592 cases of perianesthetic deaths were detected, giving an overall death rate of 75.37 in 100,000 cases (95% CI, 69.5–81.7). Mortality judged to be anesthesia related was found in 4 cases, giving a mortality rate of 0.509 in 100,000 (95% CI, 0.198–1.31). Mortality judged to be anesthesia contributory were found in 18 cases, giving a mortality of 2.29 in 100,000 patients (95% CI, 1.45–3.7). A total of 570 cases were judged to be nonanesthesia related, giving an incidence of 72.6 per 100,000 anesthetics (95% CI, 69.3–75.7). CONCLUSIONS: In a large, comprehensive database representing the full range of anesthesia practices and locations in the Southeastern United States, the rate of perianesthestic death was 0.509 in 100,000 (95% CI, 0.198–1.31). Future in-depth analysis of the epidemiology of perianesthetic deaths will be reported in later studies. Accepted for publication April 20, 2018. Funding: Departmental. The authors declare no conflicts of interest. This study was presented in part at the International Anesthesia Research Society Annual Meeting, Washington, DC, May 6, 2017. Reprints will not be available from the authors. Address correspondence to Richard Pollard, MD, FASA, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. Address e-mail to rpollard@bidmc.harvard.edu. © 2018 International Anesthesia Research Society

https://ift.tt/2s0Xmiv

Does Respiratory Variation in Inferior Vena Cava Diameter Predict Fluid Responsiveness in Mechanically Ventilated Patients? A Systematic Review and Meta-analysis

BACKGROUND: We performed a systematic review and meta-analysis of studies investigating the diagnostic accuracy of respiratory variation in inferior vena cava diameter (ΔIVC) for predicting fluid responsiveness in patients receiving mechanical ventilation. METHODS: MEDLINE, EMBASE, the Cochrane Library, and Web of Science were screened from inception to February 2017. The meta-analysis assessed the pooled sensitivity, specificity, diagnostic odds ratio, and area under the receiver operating characteristic curve. In addition, heterogeneity and subgroup analyses were performed. RESULTS: A total of 12 studies involving 753 patients were included. Significant heterogeneity existed among the studies, and meta-regression indicated that ventilator settings were the main sources of heterogeneity. Subgroup analysis indicated that ΔIVC exhibited better diagnostic performance in the group of patients ventilated with tidal volume (TV) ≥8 mL/kg and positive end-expiratory pressure (PEEP) ≤5 cm H2O than in the group ventilated with TV 5 cm H2O, as demonstrated by higher sensitivity (0.80 vs 0.66; P = .02), specificity (0.94 vs 0.68; P 5 cm H2O, this threshold was 14% ± 5%. CONCLUSIONS: ΔIVC shows limited ability for predicting fluid responsiveness in distinct ventilator settings. In patients with TV ≥8 mL/kg and PEEP ≤5 cm H2O, ΔIVC was an accurate predictor of fluid responsiveness, while in patients with TV 5 cm H2O, ΔIVC was a poor predictor. Thus, intensivists must be cautious when using ΔIVC. Accepted for publication April 16, 2018. Funding: This study was supported by the grants from Sun Yat-Sen University Clinical Research 5010 Program (2007015). The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). X. Si and H. Xu contributed equally and share first authorship. Reprints will not be available from the authors. Address correspondence to Xiangdong Guan, PhD, MD, Department of Surgical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan No. 2 Rd, Guangzhou, People's Republic of China. Address e-mail to guanxiangdong1962@163.com. © 2018 International Anesthesia Research Society

https://ift.tt/2ICOpC6

Halving the Volume of AnaConDa: Evaluation of a New Small-Volume Anesthetic Reflector in a Test Lung Model

BACKGROUND: Volatile anesthetics are increasingly used for sedation in intensive care units. The most common administration system is AnaConDa-100 mL (ACD-100; Sedana Medical, Uppsala, Sweden), which reflects volatile anesthetics in open ventilation circuits. AnaConDa-50 mL (ACD-50) is a new device with half the volumetric dead space. Carbon dioxide (CO2) can be retained with both devices. We therefore compared the CO2 elimination and isoflurane reflection efficiency of both devices. METHODS: A test lung constantly insufflated with CO2 was ventilated with a tidal volume of 500 mL at 10 breaths/min. End-tidal CO2 (EtCO2) partial pressure was measured using 3 different devices: a heat-and-moisture exchanger (HME, 35 mL), ACD-100, and ACD-50 under 4 different experimental conditions: ambient temperature pressure (ATP), body temperature pressure saturated (BTPS) conditions, BTPS with 0.4 Vol% isoflurane (ISO-0.4), and BTPS with 1.2 Vol% isoflurane. Fifty breaths were recorded at 3 time points (n = 150) for each device and each condition. To determine device dead space, we adjusted the tidal volume to maintain normocapnia (n = 3), for each device. Thereafter, we determined reflection efficiency by measuring isoflurane concentrations at infusion rates varying from 0.5 to 20 mL/h (n = 3), for each device. RESULTS: EtCO2 was consistently greater with ACD-100 than with ACD-50 and HME (ISO-0.4, mean ± standard deviations: ACD-100, 52.4 ± 0.8; ACD-50, 44.4 ± 0.8; HME, 40.1 ± 0.4 mm Hg; differences of means of EtCO2 [respective 95% confidence intervals]: ACD-100 − ACD-50, 8.0 [7.9–8.1] mm Hg, P

https://ift.tt/2IFlOft

Perioperative Peripheral Nerve Injury After General Anesthesia: A Qualitative Systematic Review

Perioperative peripheral nerve injury (PNI) is a well-recognized complication of general anesthesia that continues to result in patient disability and malpractice claims. However, the multifactorial etiology of PNI is often not appreciated in malpractice claims given that most PNI is alleged to be due to errors in patient positioning. New advances in monitoring may aid anesthesiologists in the early detection of PNI. This article reviews recent studies of perioperative PNI after general anesthesia and discusses the epidemiology and potential mechanisms of injury and preventive measures. We performed a systematic literature search, reviewed the available evidence, and identified areas for further investigation. We also reviewed perioperative PNI in the Anesthesia Closed Claims Project database for adverse events from 1990 to 2013. The incidence of perioperative PNI after general anesthesia varies considerably depending on the type of surgical procedure, the age and risk factors of the patient population, and whether the detection was made retrospectively or prospectively. Taken together, studies suggest that the incidence in a general population of surgical patients undergoing all types of procedures is

https://ift.tt/2rZci0s

Anesthesia and Neurotoxicity

No abstract available

https://ift.tt/2KI4SFN

Delayed presentation of severe rhabdomyolysis leading to acute kidney injury following atorvastatin-gemfibrozil combination therapy: a case report

Rhabdomyolysis is a rare but serious complication of lipid-lowering therapy. Statin and fibrate combination increases the risk of rhabdomyolysis possibly by pharmacodynamic interactions. Advanced age, diabetes...

https://ift.tt/2x5JgRO

Successful resection of a slow-growing synchronous pulmonary metastasis from distal cholangiocarcinoma resected 3.5 years after initial surgery: a case report

A few reports have described the effectiveness of resection for recurrent cholangiocarcinoma. However, none have described resection of synchronous pulmonary metastasis from distal cholangiocarcinoma. We repor...

https://ift.tt/2IZyPDV

Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events

Abstract

Background

Immune checkpoint inhibiting antibodies were introduced into routine clinical practice for cancer patients. Checkpoint blockade has led to durable remissions in some patients, but may also induce immune-related adverse events (irAEs). Lung cancer patients show an increased risk for complications, when infected with influenza viruses. Therefore, vaccination is recommended. However, the efficacy and safety of influenza vaccination during checkpoint blockade and its influence on irAEs is unclear. Similarly, the influence of vaccinations on T cell-mediated immune reactions in patients during PD-1 blockade remains poorly defined.

Methods

We vaccinated 23 lung cancer patients and 11 age-matched healthy controls using a trivalent inactivated influenza vaccine to investigate vaccine-induced immunity and safety during checkpoint blockade.

Results

We did not observe significant differences between patients and healthy controls in vaccine-induced antibody titers against all three viral antigens. Influenza vaccination resulted in protective titers in more than 60% of patients/participants. In cancer patients, the post-vaccine frequency of irAEs was 52.2% with a median time to occurrence of 3.2 months after vaccination. Six of 23 patients (26.1%) showed severe grade 3/4 irAEs. This frequency of irAEs might be higher than the rate previously published in the literature and the rate observed in a non-study population at our institution (all grades 25.5%, grade 3/4 9.8%).

Conclusions

Although this is a non-randomized trial with a limited number of patients, the increased rate of immunological toxicity is concerning. This finding should be studied in a larger patient population.

https://ift.tt/2s48WZk

An offline technique to evaluate residual motion of the diaphragm during deep inspiratory breath-hold from cone-beam CT datasets

Abstract

Purpose

In radiation therapy, the computer-assisted deep inspiration breath-hold (DIBH) technique is one approach to deal with respiratory motion of tumors in the lung, liver, or upper abdomen. However, inter- and intra-breath-hold deviations from an optimal static tumor position might occur. A novel method is presented to noninvasively measure the diaphragm position and thus estimate its residual deviation (as surrogate for the tumor position) based on cone-beam computed tomography (CBCT) projection data using active breathing control during acquisition.

Methods

The diaphragm dome (DD) position relative to the isocenter of a linear accelerator is known from the static (DIBH) planning CT. A ball-bearing phantom (BB) is placed at this position, a CBCT dataset is acquired, and in each projection the position of the projected BB is determined automatically based on thresholding. The position of the DD is determined manually in CBCT projections of a patient. The distance between DD and BB (ideal static setting) in craniocaudal direction is calculated for a given angle based on the distance in the projection plane and the relative position of the BB referring to the source and the detector. An angle-dependent correction factor is introduced which takes this geometrical setting into account. The accuracy of the method is assessed.

Results

The method allows a CBCT projection-based estimation of the deviation between the DD and its optimal position as defined in the planning CT, i.e., the residual motion of the DD can be assessed. The error of this estimation is 2.2 mm in craniocaudal direction.

Conclusions

The developed method allows an offline estimation of the inspiration depth (inter- and intra-breath-hold) over time. It will be useful as a reference for comparison to other methods of residual motion estimation, e.g., surface scanning.

https://ift.tt/2kfuyyd

Epidermal growth factor receptor ( EGFR ) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non-small cell lung cancer progression during first-generation tyrosine kinase inhibitor therapy: a prospective observational study

Abstract

Introduction

Plasma circulating tumor DNA (ctDNA) is an ideal approach to detecting the epidermal growth factor receptor (EGFR) T790M mutation, which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor (TKI) therapy. The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer (NSCLC) patients.

Methods

Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited (CF), brain limited (BF) and other (OF). Amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) were used to identify the T790M mutation in ctDNA. Prognosis was analyzed with Kaplan–Meier methods.

Results

Overall concordance between the two methods was 78.3%. According to both ARMS and ddPCR, patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups (P < 0.001), and a significantly higher T790M mutation rate was also observed in OF-group patients than in those in the CF and BF groups (P < 0.001). AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+ patients in all groups who had progressed on EGFR-TKIs; for other treatments, the prognosis of T790M− patient subgroups varied.

Conclusions

The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR-TKI therapy and indicates that both failure site and T790M mutational status greatly influence treatment selection and prognosis.

https://ift.tt/2s22WjR

Alterations in NO- and PGI 2 - dependent function in aorta in the orthotopic murine model of metastatic 4T1 breast cancer: relationship with pulmonary endothelial dysfunction and systemic inflammation

Abstract

Background

Patients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. The aim of the present work was to examine changes in nitric oxide (NO)- and prostacyclin (PGI₂)-dependent endothelial function in the systemic conduit artery (aorta), in relation to the formation of lung metastases and to local and systemic inflammation in a murine orthotopic model of metastatic breast cancer.

Methods

BALB/c female mice were orthotopically inoculated with 4T1 breast cancer cells. Development of lung metastases, lung inflammation, changes in blood count, systemic inflammatory response (e.g. SAA, SAP and IL-6), as well as changes in NO- and PGI₂-dependent endothelial function in the aorta, were examined 2, 4, 5 and 6 weeks following cancer cell transplantation.

Results

As early as 2 weeks following transplantation of breast cancer cells, in the early metastatic stage, lungs displayed histopathological signs of inflammation, NO production was impaired and nitrosylhemoglobin concentration in plasma was decreased. After 4 to 6 weeks, along with metastatic development, progressive leukocytosis and systemic inflammation (as seen through increased SAA, SAP, haptoglobin and IL-6 plasma concentrations) were observed. Six weeks following cancer cell inoculation, but not earlier, endothelial dysfunction in aorta was detected; this involved a decrease in basal NO production and a decrease in NO-dependent vasodilatation, that was associated with a compensatory increase in cyclooxygenase-2 (COX-2)- derived PGI₂ production.

Conclusions

In 4 T1 metastatic breast cancer in mice early pulmonary metastasis was correlated with lung inflammation, with an early decrease in pulmonary as well as systemic NO availability. Late metastasis was associated with robust, cancer-related, systemic inflammation and impairment of NO-dependent endothelial function in the aorta that was associated with compensatory upregulation of the COX-2-derived PGI₂ pathway.

https://ift.tt/2IDlptV

Galectin-3 activates TLR4/NF-κB signaling to promote lung adenocarcinoma cell proliferation through activating lncRNA-NEAT1 expression

Abstract

Background

Lung cancer remains the top contributor to cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) have been reported to participate in normal development and tumorigenesis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is highly expressed in lung cancer and promotes lung cancer cell proliferation and migration. However, the upstream regulatory mechanism still needs investigation.

Methods

In the present study, we investigated the upstream regulators and mechanisms of NEAT1 expression disorders. We first examined NEAT1 expression in lung adenocarcinoma tissues and its correlation with clinic features in patient with lung adenocarcinoma; next, the detailed function of NEAT1 in lung cancer cell proliferation and migration was assessed. To investigate whether NF-κB acts as a transcription factor of NEAT1 to activate its expression, we validated the combination between NF-κB and NEAT1, and NF-κB regulation of NEAT1 upon LPS stimulation. Further, the effect of NF-κB upstream regulator, TLR4, on NEAT1 expression upon LPS stimulation was examined. Galectin-3 reportedly serves as a ligand of TLR4 and promotes TLR4, MyD88 and p-p65 expression; we investigated whether Galectin-3 could modulate lung adenocarcinoma cell proliferation and migration through TLR4/NF-κB/NEAT1. Finally, the expression and correlation of the above factors in lung adenocarcinoma tissues was validated.

Results

NEAT1 is highly expressed in lung adenocarcinoma tissues and promotes lung cancer cell proliferation and migration. NF-κB binds to NEAT1 promoter to activate NEAT1 expression after LPS-stimulated p65 nucleus translocation. LPS stimulation activates TLR4 signaling, followed by downstream NF-κB activation, and ultimately NEAT1 expression activation. Galectin-3 activates TLR4 signaling thus affecting lung cancer cell proliferation and migration through TLR4/NF-κB/NEAT1. Galectin-3 and TLR4 expression are abnormally up-regulated in lung adenocarcinoma tissues, and positively correlated with NEAT1 expression.

Conclusion

We confirmed that Galectin-3 as a ligand of TLR4 induced TLR4 signaling activation in lung adenocarcinoma cells, thereby activating downstream p65 nucleus translocation, promoting NEAT1 expression, and finally affecting lung adenocarcinoma cell proliferation and migration. Inhibiting Galectin-3-induced TLR4 signaling activation, thus to reduce p65-activated NEAT1 expression might be a promising strategy of suppressing lung adenocarcinoma cell proliferation and migration.

https://ift.tt/2ICTtKZ

Resveratrol induces autophagy-dependent apoptosis in HL-60 cells

Abstract

Background

All known mechanisms of apoptosis induced by resveratrol act through cell cycle arrest and changes in mitochondrial membrane potential. It is currently unknown whether resveratrol-induced apoptosis is associated with other physiological processes, such as autophagy.

Methods

Apoptosis-related markers involved in the intrinsic and extrinsic apoptotic pathways, and autophagic markers were detected by using western blotting and immunofluorescence. Mitochondrial membrane potential was assayed by flow cytometry. Pharmaceutical or genetic inhibition of autophagy involved were carried by 3- methyladenine or knockdown of autophagy-related (Atg) genes by siRNA. Differences between two values were tested by Student's unpaired t test.

Results

We show that resveratrol-induced apoptosis occurs through both the intrinsic and extrinsic apoptotic pathways. Mitochondrial membrane potential and apoptosis-related markers, such as an increased Bax/Bcl-2 ratio, and cleaved forms of caspase-8 and caspase-3, arise following resveratrol addition. Moreover, we find that resveratrol increases both the levels of microtubule-associated protein 1 light chain 3-II and the number of autophagosomes, and further demonstrate that resveratrol-induced autophagy depends on the LKB1-AMPK-mTOR pathway. We next reveal that some apoptosis-related markers induced by resveratrol are further attenuated by the inhibition of autophagy with 3-methyladenine or knockdown of autophagy-related (Atg) genes by siRNA.

Conclusions

These results suggest that resveratrol induced apoptotic cell death of HL-60 cells depends on the autophagy activated through both the LKB1-AMPK and PI3K/AKT-regulated mTOR signaling pathways.

https://ift.tt/2x0kRwZ

Measurement of 68 Ga-DOTATOC Uptake in the Thoracic Aorta and Its Correlation with Cardiovascular Risk

Abstract

Purpose

⁶⁸Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-d-Phe¹-Tyr³-octreotide (⁶⁸Ga-DOTATOC) is taken up by activated macrophages, which accumulate in active inflammatory lesions. The purpose of this study was to investigate the feasibility of ⁶⁸Ga-DOTATOC PET/CT for assessment of vulnerable plaque, by evaluating correlation between aortic uptake of ⁶⁸Ga-DOTATOC and cardiovascular risk factors.

Methods

Fifty patients with neuroendocrine tumors who underwent ⁶⁸Ga-DOTATOC PET/CT were retrospectively enrolled. The uptakes in the thoracic aorta were measured by two methods: multi-sample region-of-interest (ROI) method and single volume-of-interest (VOI) method. TBR_max-avg, TBR_mean-avg, TBR_max-VOI, and TBR_mean-VOI were defined by maximum and mean target-to-background ratio (TBR) from the multi-sample ROI method and the single VOI method, respectively.

Results

Framingham risk score (FRS) exhibited significant correlations with TBR_max-avg and TBR_mean-avg, as well as TBR_max-VOI (r = 0.3389–0.4593, P < 0.05 for all). TBR_max-avg and TBR_max-VOI were significantly higher in high FRS group than in low FRS group (1.48 ± 0.21 vs. 1.70 ± 0.17, P < 0.001 for TBR_max-avg and 1.90 ± 0.33 vs. 2.25 ± 0.36, P = 0.002 for TBR_max-VOI). TBR exhibited high correlations between the two measuring methods (r = 0.9684, P < 0.001 for TBR_mean-avg and TBR_mean-VOI and r = 0.8681, P < 0.001 for TBR_max-avg and TBR_max-VOI).

Conclusions

⁶⁸Ga-DOTATOC uptake in the thoracic aorta exhibited a significant correlation with cardiovascular risk factors, which suggests the feasibility of ⁶⁸Ga-DOTATOC PET for vulnerable plaque imaging, with a simple measurement of the single VOI method that is comparable to the multi-sample ROI-based approach.

https://ift.tt/2J0dE4A

Neuroimaging findings in Menkes disease: a rare neurodegenerative disorder

Menkes disease is a rare neurodegenerative metabolic disease with a reported incidence of 1 per 300 000 live births. It occurs due to mutations in ATP7A gene located on X-chromosome leading to deficiency of several copper-containing enzymes. The patient presents with history of neuroregression with characteristic kinky hair. MRI is the imaging modality of choice. Characteristic imaging findings are: bilateral subdural hygromas, cerebral and cerebellar atrophy, white matter changes and tortuous intracranial vessels on angiography. The rarity of this condition prompted us to report this case of Menkes disease along with the characteristic neuroimaging findings and brief review of literature.

https://ift.tt/2GEb2UR

Ro-positive interstitial lung disease treated with cyclophosphamide

Interstitial lung disease (ILD) comprises a spectrum of conditions involving inflammation and/or fibrosis of the alveolar wall causing limitation in gaseous exchange. Treatment varies depending on the underlying ILD. We describe the case of a woman presenting with a productive cough who was diagnosed with community-acquired pneumonia. While on the ward she developed type-1 respiratory failure requiring continuous positive airway pressure and intensive care unit admission. Failing to respond to targeted antimicrobials she was investigated by chest high-resolution CT and autoantibody screen to identify non-infective causes of her respiratory signs and symptoms. These demonstrated diffuse ground-glass change with peripheral honeycombing in keeping with fibrosis and alveolitis alongside high titres of anti-SS-A/Ro antibodies. She was managed with reducing course of steroids and immunosuppression with cyclophosphamide. The rational of long-term immunosuppression was based on a presumed diagnosis of lung-dominant connective tissue disease, a disease concept proposed in contemporary medical literature.

https://ift.tt/2khIxnq

Chronic Madura foot: mycetoma and/or Actinomyces spp or actinomycosis

A 58-year-old agricultural worker from a remote Western province farming community in Saudi Arabia presented with a 2-year history of right plantar foot soft tissue mass. According to the patient, the swelling had gradually increased in size over a few years, but it was painless and thus had not restricted him from continuing to farm until the lesion started to affect mobility. An MRI, microbiology and histopathology reported a rare infectious agent—Actinomyces spp, otherwise referred to as Madura foot. Three-dimensional CT aided in a preoperative surgical plan which included mass excision/debulking for this challenging lesion. Full eradication was not possible, and the patient required prolonged anti-infective therapy (>6 months) along with close surveillance to map resolution of infective symptoms.

https://ift.tt/2s1ApuF

New Formulation, New Drug? The Importance of Assessing the Safety of New Supportive Care Formulations in Oncology

https://ift.tt/2KLR5hy

PARPi related toxicities: do we need more appropriate instruments to evaluate it?

https://ift.tt/2rZCoAh

Advances in the systemic treatment of melanoma brain metastases

Abstract

Of the solid tumor types that metastasize to the brain, melanoma has the highest propensity to form brain metastases. In addition, much remains unknown regarding the pathophysiology involved in melanoma cell extravasation through the blood-brain barrier, which enables interactions with the microenvironment, and melanoma cell transcriptomic responses to brain-specific cues. However, recent developments in targeted therapy and immunotherapy have generated considerable optimism regarding the treatment of metastatic melanoma. Although robust efficacy data exist on systemic therapy treatment of extracranial melanoma, data in the setting of melanoma brain metastases (MBM) are limited, primarily because patients with MBM are typically excluded from clinical trials. However, several clinical trials focusing on patients with MBM are now complete, and more are underway. Clinical evaluation of serine/threonine-protein kinase B-Raf (BRAF) inhibition in combination with MEK inhibition for MBM produced intracranial response rates of close to 60%, suggesting that inhibition of the mitogen-activated protein kinase pathway has the potential to further improve MBM outcomes. For immunotherapy, there is now increasing evidence that checkpoint inhibitors may also be effective in MBM with a high rate of durable intracranial responses observed with combination therapy. Furthermore, radiotherapy—particularly MBM treatment with mainstay stereotactic radiosurgery—appears to be safe and effective when combined with systemic therapy. Finally, evolving magnetic resonance imaging capabilities have inspired new approaches to the measurement of tumor burden and treatment responses. This review evaluates current published evidence describing MBM as a multifaceted disease and presents an overview of currently available and investigational treatments for patients with MBM.

https://ift.tt/2IC5tIA

Artificial intelligence for melanoma diagnosis: How can we deliver on the promise?

https://ift.tt/2rYWaMo

The hard road to patient-centered care: 3 or 6 months of adjuvant chemotherapy for patients with stage III colon cancer?

https://ift.tt/2KLE8nY

Six cycles of R-CHOP-21 are not inferior to eight cycles for treatment of diffuse large B-cell lymphoma - A Nordic Lymphoma Group population-based study

https://ift.tt/2rYW07K

FDA Approves Second CAR T-Cell Therapy for Lymphoma

FDA has approved tisagenlecleucel (Kymriah) for certain kinds of non-Hodgkin lymphoma. Read about the trial that led to the approval and what the approval means for people with lymphoma.

https://ift.tt/2KIC28i

Dexamethasone Implant as Sole Therapy in Sympathetic Ophthalmia

We present the case of a 46-year-old woman with sympathetic ophthalmia occurring 27 years after complicated juvenile cataract surgeries. The patient declined systemic immunosuppressive therapy. Dexamethasone implant in the sympathizing eye allowed good visual recovery up to 18 months of follow-up with a total of 6 implants. Intraocular pressure rise was controlled medically. This is a unique report of sympathetic ophthalmia treated solely with slow-release dexamethasone implant without systemic therapies.
Case Rep Ophthalmol 2018;9:256–262

https://ift.tt/2IAIX6J

Dairy Consumption and Risk of Testicular Cancer: A Systematic Review.

Related Articles

Dairy Consumption and Risk of Testicular Cancer: A Systematic Review.

Nutr Cancer. 2018 May 21;:1-27

Authors: Signal V, Huang S, Sarfati D, Stanley J, McGlynn KA, Gurney JK

Abstract
Dairy consumption has been studied extensively in terms of its relationship with testicular cancer (TC), yet this relationship remains unclear. In this systematic review, we aimed to answer whether TC development is associated with (a) high amounts of dairy product consumption, (b) the type of dairy product consumed, (c) increasing levels of dairy product consumption, and (d) dairy consumption during certain periods during the lifecourse. Following a systematic review of the literature, eight studies (all case-control studies) were included in our review. The included studies varied in terms of the dairy product(s) investigated (milk, cheese, cream, butter, and yoghurt) as well as the type of exposure to dairy consumption (e.g., high vs. low exposure, dose-response, and timing during lifecourse). We found that there was no strong evidence that high levels of dairy consumption are associated with risk of TC, conflicting evidence of a dose-response relationship, inconsistent evidence on whether certain types of dairy are more strongly associated with TC than others, and conflicting evidence that exposure during certain life-course periods affects TC risk more than other periods. There is no consistent evidence to support the premise that dairy product consumption is associated with the risk of TC development.

PMID: 29781734 [PubMed - as supplied by publisher]

https://ift.tt/2kjymhT

In-Vitro Analysis of Glucose and Quercetin Effects on m-TOR and Nrf-2 Expression in HepG2 Cell Line (Diabetes and Cancer Connection).

Related Articles

In-Vitro Analysis of Glucose and Quercetin Effects on m-TOR and Nrf-2 Expression in HepG2 Cell Line (Diabetes and Cancer Connection).

Nutr Cancer. 2018 May 21;:1-6

Authors: Yarahmadi A, Khademi F, Mostafavi-Pour Z, Zal F

Abstract
Some types of cancers show a strong relationship with diabetes and play a central role in mortality in the patient population suffering from diabetes mellitus. In this study, HepG2 cells have been used to investigate the toxic effects of hyperglycemia and/or quercetin (Q) on mammalian target of rapamycin (m-TOR) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression as central molecules involved in cancer. HepG2 cells were cultured with different concentrations of glucose (5.5, 30, and 50 mM) and/or Q (25 µM) for 48 and 72 h. Effects of glucose and/or Q on m-TOR and Nrf-2 expression were assayed by quantitative real-time PCR (qRT-PCR). qRT-PCR results revealed that 30 and 50 mM of glucose increased m-TOR expression at 48 h, although after 72 h, only 30 mM had an increasing effect. At 50 mM, glucose-induced Nrf-2 gene expression after both 48 and 72 h. The results also showed that 25 µM of Q reduced m-TOR and Nrf-2 expression at both 30 and 50 mM after 48 and 72 h incubation. Q has potential effects on reducing oxidative stress caused by hyperglycemia and during diabetes may be able to modulate some carcinogenic signaling pathways.

PMID: 29781726 [PubMed - as supplied by publisher]

https://ift.tt/2s120Mx