Cancer by Sfakianakis Alexandros: 07/21/17

Παρασκευή 21 Ιουλίου 2017

Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer

Abstract

Purpose

Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes.

Methods

Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls.

Results

Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79–0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43–0.88).

Conclusions and implications

There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes.

Implications for Cancer Survivors

These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.

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Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

Publication date: Available online 20 July 2017
Source:Cell Stem Cell
Author(s): Martha S. Windrem, Mikhail Osipovitch, Zhengshan Liu, Janna Bates, Devin Chandler-Militello, Lisa Zou, Jared Munir, Steven Schanz, Katherine McCoy, Robert H. Miller, Su Wang, Maiken Nedergaard, Robert L. Findling, Paul J. Tesar, Steven A. Goldman
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment.

Graphical abstract

Teaser

Goldman and colleagues use mice chimerized with human patient-derived glial progenitor cells to find out whether glia contribute to childhood-onset schizophrenia. The defects in cell differentiation, myelination, and behavior they see strongly suggest that glial cells do, in fact, have a previously unappreciated role in the pathogenesis of this disease.

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Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness

Publication date: Available online 20 July 2017
Source:Cell Stem Cell
Author(s): Hitoshi Takizawa, Kristin Fritsch, Larisa V. Kovtonyuk, Yasuyuki Saito, Chakradhar Yakkala, Kurt Jacobs, Akshay K. Ahuja, Massimo Lopes, Annika Hausmann, Wolf-Dietrich Hardt, Álvaro Gomariz, César Nombela-Arrieta, Markus G. Manz
Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction.

Graphical abstract

Teaser

Takizawa et al. show that self-renewing hematopoietic cells directly sense gram-negative bacterial infection through Toll-like receptor 4 (TLR4) activation, which leads to impaired function via proliferative stress. Genetic and pharmacological blockage of the TLR4-TRIF-ROS-p38 axis can maintain HSC function without disrupting emergency granulopoietic responses to infection.

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High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain

Publication date: Available online 20 July 2017
Source:Cell Stem Cell
Author(s): Ting Zhou, Lei Tan, Gustav Y. Cederquist, Yujie Fan, Brigham J. Hartley, Suranjit Mukherjee, Mark Tomishima, Kristen J. Brennand, Qisheng Zhang, Robert E. Schwartz, Todd Evans, Lorenz Studer, Shuibing Chen
Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients.

Graphical abstract

Teaser

Chen, Studer, and colleagues utilize human pluripotent stem cell-derived neural progenitors to perform a high-content screen for anti-ZIKV drug discovery. Hippeastrine hydrobromide was identified and shown to eliminate ZIKV in infected human neural progenitors, rescue a ZIKV-induced microcephaly phenotype in human forebrain organoids, and suppress virus propagation in adult mice with active ZIKV infection.

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Is That Possible to Stop or Cease the NASH to Turn into HCC?

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Isolated Metachronous Splenic Metastasis from Colon Cancer: Possible Explanations for This Rare Entity

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Patient-reported intestinal toxicity from whole pelvis intensity-modulated radiotherapy: First quantification of bowel dose–volume effects

Intestinal toxicity is commonly experienced during whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer. The aim of the current study was to assess bowel dose–volume relationships for acute patient-reported intestinal symptoms of patients treated with WPRT for prostate cancer.

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Tumor heterogeneity determined with a γH2AX foci assay: A study in human head and neck squamous cell carcinoma (hHNSCC) models

This study aimed to analyze the intra-tumoral heterogeneity of γH2AX foci in tumor specimens following ex vivo radiation to evaluate the potential of γH2AX foci as predictors for radiosensitivity.

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Age and Cancer Treatment Are Related to Receiving Treatment Summaries and Survivorship Care Plans in Female Young Adult Cancer Survivors

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.

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Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A

Summary

Chemotherapeutic agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-stabilizing agent used to treat solid tumors of the breast, ovary, and lung and discodermolide, another stabilizing agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-stabilizing agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging agent, paclitaxel, and discodermolide were used as positive controls. Senescence-associated-β-galactosidase activity was increased by peloruside A, similar to paclitaxel, discodermolde, and doxorubicin, with a potency heirarchy of doxorubicin > paclitaxel > discodermolide > peloruside, based on IC₂₅ concentrations that inhibit proliferation. Clonogenic survival was significantly decreased by peloruside A, similar to doxorubicin and the two other microtubule-stabilizing agents. The tumor suppressor protein p53 increased after treatment, whereas pRb decreased in response to all four compounds. It was concluded that in addition to apoptosis, peloruside A causes accelerated senescence in a subpopulation of MCF7 cells that contributes to its potential anticancer activity in a breast cancer cell line.

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Anti-invasive effects of CXCR4 and FAK inhibitors in non-small cell lung carcinomas with mutually inactivated p53 and PTEN tumor suppressors

Summary

Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. At the time of diagnosis, a large percentage of NSCLC patients have already developed metastasis, responsible for extremely high mortality rates. CXCR4 receptor and focal adhesion kinase (FAK) are known to regulate such invasive cancer behavior. Their expression is downregulated by p53 and PTEN tumor suppressors which are commonly co-inactivated in NSCLC patients and contribute to metastasis. Therefore, targeting CXCR4 or FAK seems to be a promising strategy in suppressing metastatic spread of p53/PTEN deficient NSCLCs. In this study, we first examined the invasive characteristics of NSCLC cells with suppressed p53 and PTEN activity using wound healing, gelatin degradation and invasion assays. Further, changes in the expression of CXCR4 and FAK were evaluated by RT-qPCR and Western Blot analysis. Finally, we tested the ability of CXCR4 and FAK inhibitors (WZ811 and PF-573228, respectively) to suppress the migratory and invasive potential of p53/PTEN deficient NSCLC cells, in vitro and in vivo using metastatic models of human NSCLC. Our results showed that cells with mutually inactive p53 and PTEN have significantly increased invasive potential associated with hyperactivation of CXCR4 and FAK signaling pathways. Treatments with WZ811 and PF-573228 inhibitors significantly reduced migratory and invasive capacity in vitro and showed a trend of improved survival in vivo. Accordingly, we demonstrated that p53/PTEN deficient NSCLCs have extremely invasive phenotype and provided a rationale for the use of CXCR4 or FAK inhibitors for the suppression of NSCLC dissemination.

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New developments in the pathology of malignant lymphoma: a review of the literature published from January to April 2017

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A novel functional splice variant of AKT3 defined by analysis of alternative splice expression in HPV-positive oropharyngeal cancers

The incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) has increased more than 200% in the past 20 years. Recent genetic sequencing efforts have elucidated relevant genes in head and neck cancer, but HPV-related tumors have consistently shown few DNA mutations. In this study, we sought to analyze alternative splicing events (ASE) that could alter gene function independent of mutations. To identify ASE unique to HPV-related tumors, RNA sequencing was performed on 46 HPV-positive OPSCC and 25 normal tissue samples. A novel algorithm using outlier statistics on RNA-sequencing junction expression identified 109 splicing events, which were confirmed in a validation set from the Cancer Genome Atlas (TCGA). Because the most common type of splicing event identified was an alternative start site (39%), MBD-seq genome-wide CpG methylation data were analyzed for methylation alterations at promoter regions. ASE in six genes showed significant negative correlation between promoter methylation and expression of an alternative transcriptional start site, including AKT3. The novel AKT3 transcriptional variant and methylation changes were confirmed using qRT-PCR and qMSP methods. In vitro silencing of the novel AKT3 variant resulted in significant growth inhibition of multiple head and neck cell lines, an effect not observed with wild type AKT3 knockdown. Analysis of ASE in HPV-related OPSCC identified multiple alterations likely involved in carcinogenesis, including a novel, functionally active transcriptional variant of AKT3. Our data indicate that ASEs represent a significant mechanism of oncogenesis with untapped potential for understanding complex genetic changes that result in development of cancer.

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MOlecular Screening for CAncer Treatment Optimization (MOSCATO-01) in pediatric patients: A single institutional prospective molecular stratification trial

Purpose: This single institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients in order to select a targeted therapy. Experimental Design: Following treatment failure patients with signed consent and aged above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next generation sequencing for 75 target genes, whole exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board. Results: From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor and 63.0% an extra-cranial solid tumor. Median tumor cell content was 70% (range 0-100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment prior to inclusion. Conclusions: Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART.

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89Zr-lumretuzumab PET imaging before and during HER3 antibody lumretuzumab treatment in patients with solid tumors

Purpose: We evaluated biodistribution and tumor targeting of ⁸⁹Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody. Experimental design: 20 patients with histologically confirmed HER3-expressing tumors received ⁸⁹Zr-lumretuzumab and underwent Positron Emission Tomography (PET). In Part A, ⁸⁹Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab and scans were performed 2, 4 and 7 days postinjection to determine optimal imaging conditions. In Part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV). Results: Optimal PET conditions were found to be 4 and 7 days after administration of ⁸⁹Zr-lumretuzumab with 100 mg unlabeled lumretuzumab. At baseline using 100 mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days postinjection. SUVmean for normal blood, liver, lung and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n=7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5) and 24.6% (±20.9) at PD-active doses of 400, 800 and 1600 mg, respectively, when compared to baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400 mg lumretuzumab. Conclusions: PET imaging showed biodistribution and tumor specific ⁸⁹Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased ⁸⁹Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses.

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Direct metabolic interrogation of dihydrotestosterone biosynthesis from adrenal precursors in primary prostatectomy tissues

Purpose: A major mechanism of castration-resistant prostate cancer (CRPC) involves intratumoral biosynthesis of dihydrotestosterone (DHT) from adrenal precursors. We have previously shown that adrenal-derived androstenedione (AD) is the preferred substrate over testosterone (T) for 5α-reductase expressed in metastatic CRPC, bypassing T as an obligate precursor to DHT. However, the metabolic pathway of adrenal-derived DHT biosynthesis has not been rigorously investigated in the setting of primary disease in the prostate. Experimental Design: Seventeen patients with clinically localized prostate cancer were consented for fresh tissues after radical prostatectomy. Prostate tissues were cultured ex vivo in media spiked with an equimolar mixture of AD and T, and stable isotopic tracing was employed to simultaneously follow the enzymatic conversion of both precursor steroids into nascent metabolites, detected by liquid chromatography-tandem mass spectrometry. CRPC cell line models and xenograft tissues were similarly assayed for comparative analysis. A tritium-labeled steroid radiotracing approach was used to validate our findings. Results: Prostatectomy tissues readily 5α-reduced both T and AD. Furthermore, 5α-reduction of AD was the major directionality of metabolic flux to DHT. However, AD and T were comparably metabolized by 5α-reductase in primary prostate tissues, contrasting the preference exhibited by CRPC in which AD was favored over T. 5α-reductase inhibitors effectively blocked the conversion of AD to DHT. Conclusions: Both AD and T are substrates of 5α-reductase in prostatectomy tissues, resulting in two distinctly non-redundant metabolic pathways to DHT. Furthermore, the transition to CRPC may coincide with a metabolic switch towards AD as the favored substrate.

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Implementation of a model-based design in a phase 1b study of combined targeted agents

In recent years, investigators have recognized the rigidity of single agent, safety only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and /or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed / refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations.

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Dose Transition Pathways: The missing link between complex dose-finding designs and simple decision-making

The ever increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended Phase II dose compared to conventional rule-based designs such as the 3+3 but despite this, their use remains limited. Here, we propose a useful tool, Dose Transition Pathways (DTP), which helps overcome several commonly-faced practical and methodological challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate or stop early), using all the accumulated information. After specifying a model with favourable statistical properties, we utilise the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgements. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified Continual Reassessment Method is illustrated in an Acute Myeloid Leukaemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose-update. In the illustrated trial, the seamless, clear transition for each dose-recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators.

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Neuraxial drug delivery for the management of cancer pain: cost, updates, and society guidelines.

Purpose of review: The present study discusses the utilization of neuraxial drug delivery (NDD) for the management of cancer pain, based on recent trials, reviews, and guidelines with a focus on cost analysis. Recent findings: Almost all recent publications suggest that more stringent research is needed to improve evidence on NDD, particularly as conflicting reports exist regarding cost effectiveness of drug delivery systems. The combination of local anesthetics and opioids, with or without clonidine, continues to be reported as beneficial with the utilization of patient controlled systems providing an advantage over continuous ones. Interestingly, the use of opioids as an adjunct to local anesthetics may not enhance analgesia but the addition of dexamethasone is useful for incident cancer-related bone pain. Ziconitide remains supported as first-line therapy in districts where it is available - United States and Europe. Although new targeted drugs are being designed for cancer pain management, none have seen human clinical trials in the last year. Summary: The ability to demonstrate cost effectiveness of NDD is variable from region to region. Less expensive externalized systems may pose a viable alternative. With the exception of dexamethasone, no new drugs have been shown to provide any benefit to conventional medications. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Management of complex spine surgery.

Purpose of review: The main objective of this article is to present the updated data regarding the perioperative management of patients undergoing major spine surgery in an era where the surgical techniques are changing and there is a high demand for these surgeries in older and high-risk patients. Recent findings: Preoperative assessment and stabilization is now more structured protocol and it is based on a multidisciplinary approach to the patient. The Enhanced Recovery After Surgery (ERAS) programs and the Perioperative Surgical Home on major spine surgery are not yet fully evidence based but it seems that the use of a perioperative optimization of patients and use of a drugs' bundle is more effective than using single drugs or interventions on the postoperative pain reduction and faster recovery from surgery. Fluid and pain-control protocols combined with an accurate blood management represent the key to success. Summary: A tailored approach to patients undergoing major spine surgeries seems to be effective improving the outcome and quality of life of patients. Future studies should aim to understand which elements of the ERAS can be improved to allow the patient to have a long-term good outcome. Video abstract: http://ift.tt/2vtcsgP Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Thoracic paravertebral block for postoperative pain management after renal surgery: A randomised controlled trial.

BACKGROUND: Thoracic paravertebral block (ThPVB) combined with general anaesthesia is used in thoracic and general surgery. It provides effective analgesia, reduces surgical stress response and the incidence of chronic postoperative pain. OBJECTIVE: To assess the efficacy of ThPVB in reducing opioid requirements and decreasing the intensity of pain after renal surgery. DESIGN: A prospective, randomised, open label study. SETTING: A single university hospital. Study conducted from August 2013 to February 2014. PARTICIPANTS: In total, 68 patients scheduled for elective renal surgery (open nephrectomy or open nephron-sparing surgery). INTERVENTIONS: Preoperative ThPVB with 0.5% bupivacaine combined with general anaesthesia, followed by postoperative oxycodone combined with nonopioid analgesics as rescue drugs. Follow-up period: 48 h. MAIN OUTCOME MEASURES: Total dose of postoperative oxycodone required, pain intensity, occurrence of opioid related adverse events, ThPVB-related adverse events and patient satisfaction. RESULTS: A total of 68 patients were randomised into two groups and, of these, 10 were subsequently excluded from analysis. Patients in group paravertebral block (PVB; n = 27) had general anaesthesia and ThPVB, and those in group general (anaesthesia) (GEN) (n = 31) formed a control group receiving general anaesthesia only. Compared with patients in group GEN, patients who received ThPVB required 39% less i.v. oxycodone over the first 48 h and had less pain at rest (P

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Clinical trial registry use in anaesthesiology systematic reviews: A cross-sectional study of systematic reviews published in anaesthesiology journals and the Cochrane Library.

BACKGROUND: Publication bias within systematic reviews may result in incorrect conclusions leading to inappropriate clinical decisions and a decreased quality of patient care. Searching clinical trial registries for unpublished studies is one possible solution to minimise publication bias. OBJECTIVES: To examine rates of clinical trial registry searches in systematic reviews published in respected anaesthesiology journals and whether these searches found trials (or data) eligible for inclusion; to compare rates of registry searches between published reviews and similar reviews within the Cochrane Anaesthesia, Critical and Emergency Care Group; to conduct trial registry searches for a subset of reviews, determining whether eligible studies were overlooked; to investigate whether reporting of results in completed anaesthesia trials on ClinicalTrials.gov followed guidelines. DESIGN: A cross-sectional study of systematic reviews published in 10 anaesthesiology journals and the Cochrane Library. SETTING AND PARTICIPANTS: PubMed and the Cochrane Library were searched for systematic reviews or meta-analyses. MAIN OUTCOME MEASURES: The primary outcome was the number of systematic reviews that searched clinical trial registries for unpublished trials. Secondary outcomes included the number of registered trials in the ClinicalTrial.gov registry and the number of trials reporting trial results which were available on the ClinicalTrials.gov database and which should have been considered in a systematic review. RESULTS: The PubMed search yielded 507 records, and 415 remained after exclusions. Of these, 49 (11.8%) included a search of clinical trial registries. In total, 12 systematic reviews reported finding unpublished data but only five incorporated the data into their analyses. Of the Cochrane reviews, 58.9% (43/73) reported registry searches. Among a sample of 30 systematic reviews that omitted registry searches, we found many studies within the registries that were probably eligible to be included in the systematic reviews. For completed trials within the ClinicalTrials.gov database, only 15.4% reported results. CONCLUSION: The majority of systematic reviews in anaesthesiology did not include data from clinical trial registries. Exclusion of statistically nonsignificant data may lead to a biased interpretation of the data and hence inappropriate clinical interventions. TRIAL REGISTRATION: Registered in University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000021932). (C) 2017 European Society of Anaesthesiology

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History of anaesthesia: the ketamine story - past, present and future.

: Ketamine's history begins in the 1950s in Detroit, Michigan, at Parke-Davis Laboratories. On 26 March 1956, Harold V. Maddox synthesised phencyclidine or PCP. Domino studied PCP effects in animals and in 1958, Greifenstein made the first trials of PCP in humans under the name of Sernyl. Sernyl did not cause depression of cardiovascular and respiratory functions, but elicited severe excitation with a very prolonged postoperative recovery. Because of its psychedelic effects, it became a street drug under the name of 'angel dust' and was placed on schedule II of Federal Controlled Substance Act (CSA) in 1978. Eticyclidine or PCE had no medical career. The chemist Calvin Stevens, consultant to Parke-Davis, synthesised ketamine in 1962. The drug was studied in humans in 1964, by Domino and Corssen. These authors described the so-called 'dissociative anaesthesia'. Ketamine was patented in 1966 under the name of Ketalar for human use and was administered to soldiers during the Vietnam war. Because of abuse, ketamine was placed among the class III substances of CSA in 1999. The psychedelic effects and the arrival of propofol prompted the shelving of ketamine. However, the discovery of the NMDA-receptor and its noncompetitive inhibition by ketamine revolutionized the pathophysiology of hyperalgesia and mental functioning. In early 1990s, the arrival of remifentanil preceded the discovery of opioid-induced hyperalgesia, eliciting a paradigm shift in the management of pain, and a comeback of ketamine, as and antihyperalgesic drug. Ketamine is nowadays under the spotlight in the field of treatment-resistant depression and has been proposed as a potential fast antidepressant in patients with high suicidal risk. In a near future, we may observe new practices like increased S-(+)-ketamine availability, new ultra-short-acting ketamine analogues or the development antagonists. (C) 2017 European Society of Anaesthesiology

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Injectate spread following anterior sub-costal and posterior approaches to the quadratus lumborum block: A comparative cadaveric study.

BACKGROUND: The dermatomal level of analgesia achieved with quadratus lumborum blocks varies according to the location of injection. The most commonly used approaches are either at the postero-lateral aspect or anterior to the quadratus lumborum muscle. The aim of the study was to determine whether the site of injection of contrast dye around the quadratus lumborum muscle of cadavers affects the extent and mechanism of dye spread. METHODS: Six fresh human cadavers received either a posterior quadratus lumborum block or an anterior sub-costal quadratus lumborum block on each side. Cadavers were then dissected to determine the extent of dye spread. RESULTS: The posterior quadratus lumborum block approach revealed consistently deep staining of the iliohypogastric, ilioinguinal, subcostal nerve, T11 to 12 and L1 nerve roots. In addition, staining of the middle thoracolumbar fascia was seen in all specimens but only variable staining of T10 nerve roots. The anterior subcostal quadratus lumborum block approach in all specimens demonstrated predictable deep staining of the iliohypogastric and ilioinguinal nerves, subcostal nerves, T11 to 12 and L1 nerve roots, and in addition traversing the arcuate ligaments to involve T9 to 12 nerve roots with variable staining of higher thoracic nerve roots. CONCLUSION: Our cadaveric study demonstrates that injection of dye on the posterior aspect of quadratus lumborum muscle led to injectate spread through the lateral and posterior abdominal wall but with limited cranial spread, whereas the anterior approach produced broader coverage of the lower to mid-thoracic region. Clinical translation of these findings to determine the practical significance is warranted. (C) 2017 European Society of Anaesthesiology

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Serious game versus online course for pretraining medical students before a simulation-based mastery learning course on cardiopulmonary resuscitation: A randomised controlled study.

BACKGROUND: Although both recorded lectures and serious games have been used to pretrain health professionals before simulation training on cardiopulmonary resuscitation, they have never been compared. OBJECTIVE: The aim of this study was to compare an online course and a serious game for pretraining medical students before simulation-based mastery learning on the management of sudden cardiac arrest. DESIGN: A randomised controlled trial. Participants were pretrained using the online course or the serious game on day 1 and day 7. On day 8, each participant was evaluated repeatedly on a scenario of cardiac arrest until reaching a minimum passing score. SETTING: Department of Simulation in Healthcare in a French medical faculty. PARTICIPANTS: Eighty-two volunteer second-year medical students participated between June and October 2016 and 79 were assessed for primary outcome. INTERVENTIONS: The serious game used was Staying Alive, which involved a 3D realistic environment, and the online course involved a PowerPoint lecture. MAIN OUTCOME MEASURES: The median total training time needed for students to reach the minimum passing score on day 8. This same outcome was also assessed 4 months later. RESULTS: The median training time (interquartile range) necessary for students to reach the minimum passing score was similar between the two groups: 20.5 (15.8 to 30.3) minutes in the serious game group versus 23 (15 to 32) minutes in the online course group, P = 0.51. Achieving an appropriate degree of chest compression was the most difficult requirement to fulfil for students in both groups. Four months later, the median training time decreased significantly in both groups, but no correlation was found at an individual level with the training times observed on day 8. CONCLUSION: The serious game used in this study was not superior to an online course to pretrain medical students in the management of a cardiac arrest. The absence of any correlation between the performances of students evaluated during two training sessions separated by 4 months suggests that elements such as chest compression can only be learned by simulation-based training. TRIAL REGISTRATION: ClinicalTrials.gov-NCT02758119. (C) 2017 European Society of Anaesthesiology

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Erratum to: Predictors of chest wall toxicity after stereotactic ablative radiotherapy using real-time tumor tracking for lung tumors

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Ovarian Cancer in Young Women

Abstract

It is not clear how often epithelial tumours affect young women. This study aimed to evaluate the clinico-pathological pattern and survival outcome of women, 40 years and younger, with cancer ovary. Women 40 years and younger, operated between 2008 and 2012 for ovarian cancer, were retrospectively recruited and followed up. The study design was descriptive as well as a survival analysis. A hybrid of retrospective and prospective cohort design was used for risk factor analysis. Of the 115 women less than 40 years being operated for probable ovarian cancer, 22 were excluded for various reasons. Demographic details, clinical presentations, histopathological features, treatments and survival outcomes were studied. The primary outcomes looked for were death and recurrence. Secondary outcomes were complications of treatment and fertility. The predominant histology in the study population was epithelial tumour (70%), and serous adenocarcinoma was the commonest tumour type. The overall survival rate was 87%, and progression free survival was 63%. Time to death and recurrence were dependent on stage of disease, histology of tumour, primary treatment and residual disease at surgery. In multivariate analysis, the hazard ratio for recurrence in advanced stages was 12.6 (95% CI 3.5 to 45.5; p < 0.001) as compared to early stage disease. Epithelial ovarian cancers are common in young women. Death and recurrence are more likely in women with epithelial cancers, advanced stage disease and in those with residual tumour at cytoreductive surgery.

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Early response of C-reactive protein as a predictor of survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors

Abstract

Background

Pretreatment C-reactive protein (CRP) has been shown to be an independent prognostic factor for metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs). We further evaluated the early response of CRP after the initiation of TKIs.

Methods

A total of 103 patients (80 men and 23 women) were treated with TKIs for mRCC from 2008−2013. Patients were divided into three groups according to their early CRP kinetics—patients whose baseline CRP levels were <10 mg/L (non-elevated), patients whose baseline CRP levels were ≥10 mg/L and had decreased by >20% at 4 weeks after the initiation of TKIs (early CRP responder), and the remaining patients (non-early CRP responder). The endpoints were progression-free survival (PFS) and overall survival (OS).

Results

The median follow-up period was 21 (interquartile range 10–34) months. The numbers of patients classified as non-elevated, early CRP responder, and non-early CRP responder were 62, 19, and 22, respectively. The 1-year PFS rates of patients in the non-elevated, early CRP responder, and non-early CRP responder groups were 50, 23, and 9.7%, respectively (p < 0.001). The 1-year OS rates of patients in these three groups were 79, 62, and 36%, respectively (p < 0.001). In multivariate analysis, the early CRP kinetics assessment was a significant independent factor for PFS and OS.

Conclusions

Early CRP response at 4 weeks is predictive of survival for patients with mRCC treated with TKI.

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Cerebral magnetic resonance findings during enzyme replacement therapy in mucopolysaccharidosis

Abstract

Background

Although enzyme replacement therapy (ERT) is an effective treatment for mucopolysaccharidosis (MPS) types I, II, IVA and VI, its effectiveness in children with central nervous system (CNS) disorders is said to be poor because the blood–brain barrier cannot be penetrated by ERT drugs.

Objective

To assess CNS involvement in mucopolysaccharidosis at the start of enzyme replacement therapy and to investigate the time course of ERT in the central nervous system.

Materials and methods

We performed brain MRI in 17 children and young adults who underwent ERT. The clinical severity was classified as attenuated or severe by a specialist pediatrician, based on the clinical symptoms and genotypes. At the start of ERT, we scored nine parameters using two- or three-point scales based on the severity of the disease revealed on MRI scans. After the start of ERT, we compared the initial and follow-up MRI scans, and classified the findings as no change, improved or worse. We then compared the results with the changes in clinical findings.

Results

At the start of ERT, comparison of the clinical symptoms and image scores revealed differences between severe and attenuated mucopolysaccharidosis. The scores in patients with severe MPS ranged from 9 to 16 (mean 12.2); for patients with attenuated MPS, they ranged from 2 to 11 (mean 6.4). Images of the four patients with severe MPS showed ventricular dilation and brain atrophy. Such findings were made in only 2 of 13 patients with attenuated MPS. The results after the start of ERT showed that 11/17 (65%) patients manifested improvement or no change. All five patients with MPS I experienced improvement in some regions. There were no new lesions. One patient with MPS II experienced worsening of his CNS symptoms, and his MRI findings revealed more severe ventricular dilation, brain atrophy and white matter lesions.

Conclusion

Ventricular dilation and brain atrophy on imaging studies might represent useful markers in predicting the severity of mucopolysaccharidosis and worsening of CNS symptoms. Enzyme replacement therapy improves CNS images in MPS I and has an inhibitory effect on the occurrence of new lesions in MPS II.

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Motion monitoring during a course of lung radiotherapy with anchored electromagnetic transponders

Abstract

Purpose

Anchored electromagnetic transponders for tumor motion monitoring during lung radiotherapy were clinically evaluated. First, intrafractional motion patterns were analyzed as well as their interfractional variations. Second, intra- and interfractional changes of the geometric transponder positions were investigated.

Materials and methods

Intrafractional motion data from 7 patients with an upper or middle lobe tumor and three implanted transponders each was used to calculate breathing amplitudes, overall motion amount and motion midlines in three mutual perpendicular directions and three-dimensionally (3D) for 162 fractions. For 6 patients intra- and interfractional variations in transponder distances and in the size of the triangle defined by the transponder locations over the treatment course were determined.

Results

Mean 3D values of all fractions were up to 4.0, 4.6 and 3.4 mm per patient for amplitude, overall motion amount and midline deviation, respectively. Intrafractional transponder distances varied with standard deviations up to 3.2 mm, while a maximal triangle shrinkage of 36.5% over 39 days was observed.

Conclusions

Electromagnetic real-time motion monitoring was feasible for all patients. Detected respiratory motion was on average modest in this small cohort without lower lobe tumors, but changes in motion midline were of the same size as the amplitudes and greater midline motion can be observed in some fractions. Intra- and interfractional variations of the geometric transponder positions can be large, so for reliable motion management correlation between transponder and tumor motion needs to be evaluated per patient.

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Motion monitoring during a course of lung radiotherapy with anchored electromagnetic transponders

Abstract

Purpose

Materials and methods

Results

Conclusions

http://ift.tt/2tmSMd1

Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer

Abstract

Background

Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer.

Methods

Immunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models.

Results

CNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017).

Conclusion

CNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.

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Correlation of Transabdominal Ultrasonography and Cystoscopy in Follow-up of Patients with Non-muscle Invasive Bladder Cancer

Abstract

Cystoscopy (CS) is considered to be the gold standard in the follow-up of non-muscle invasive bladder cancer. However, CS is invasive, time-consuming, and expensive. On the other hand, modern sensitive transducers have improved the imaging of urinary tract rendering transabdominal ultrasonography (US) more effective in visualizing intraluminal filling defects in the bladder than it was in the past. Twenty-five follow-up patients of low-risk bladder cancer meeting the inclusion and exclusion criteria were included in study. Ultrasonography of the bladder was performed by a single senior radiologist, and subsequently, these patients were subjected to flexible cystoscopy under local anesthesia. Pain score was calculated for each of the cystoscopies done. Findings of transabdominal ultrasound of the bladder were correlated and compared with those of cystoscopy. Subjects with US and/or CS findings suggestive of recurrence underwent transurethral resection of bladder tumor (TURBT) under general anesthesia and confirmation of the bladder carcinoma was achieved by the histopathological examination. Mean patient age was 60.56 years with range of 29 to 77 years. The sensitivity of modern ultrasonographic techniques was found to be 84.61% with specificity of 91.7% taking flexible cystoscopy as the gold standard for detection of recurrence. The accuracy of US was 88% with positive predictive value of 91.7% and negative predictive value of 84.61%. Technological evolution has improved the accuracy of ultrasonography in diagnosis of bladder carcinoma. It represents a valuable surveillance tool in selected sub group of low risk non-muscle invasive bladder cancer patients.

http://ift.tt/2uJa9Z6

Gatekeepers’ perceptions of the quality and availability of services for breast and cervical cancer patients in the English-speaking Windward Islands: an exploratory investigation

Abstract

Purpose

Although extensive screening services for breast and cervical cancers are available in the Caribbean, these cancers continue to be the leading causes of cancer death among women in this region. The purpose of this study was to determine the quality and availability of breast and cervical cancer treatment care and support services from the perspective of the gatekeepers who provide care for the patients in the Windward Islands of Dominica, Grenada, St Lucia, and St. Vincent.

Methods

A qualitative research design using semi-structured, in-depth interviews was used to gather data from gatekeepers who provided oncology prevention and care services to patients for at least one year. Data were collected on availability and quality of cancer care and treatment services and coded using the themes obtained via thematic analysis of the data.

Results

Twenty-three current providers participated in the study (Dominica, 5; Grenada, 7; St. Lucia, 5; St. Vincent and the Grenadines, 6). The participants' years of work experience ranged from 2 to 45 years. The codes encompassed a range of social ecological factors that influence breast and cervical cancer screening and treatment in the Windward Islands. The emergent themes were availability of resources, cost of care, and social support.

Conclusion

The findings of this study emphasize the varying social determinants of health that affect breast and cervical cancer prevention and treatment. It also highlights the disparities in availability of treatment within the wider Caribbean. It is necessary to broaden the perspective on health from a purely biomedical paradigm to a social perspective.

http://ift.tt/2uIMtnC

Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells

Abstract

Background

Sub-lethal heat treatment characterizes a transition zone of radiofrequency ablation (RFA) which explains hepatocellular carcinoma (HCC) residual cancer occurrence in this area after RFA treatment. The biochemistry of residual cancer cell recurrence is poorly understood, but long noncoding RNAs (lncRNAs) may have aberrant expression that is associated with diverse cancers. Thus, we measured lncRNA gene expression in sub-lethally heat-treated HCC cells using microarray.

Method

Differentially expressed lncRNA and mRNA were measured with an Agilent Human lncRNA + mRNA Array V4.0 (4 × 180 K format) containing 41,000 lncRNAs and 34,000 mRNAs. Bioinformatics analysis was used to assess differentially expressed lncRNA and mRNA. Seven lncRNA and seven mRNA were validated by qRT-PCR analysis in HCC cells.

Results

Genome-wide lncRNA and mRNA expression data in sub-lethal heat-treated SMMC-7721 HCC cells 558 lncRNA and 250 mRNA were significantly up-regulated and 224 lncRNA and 1031 mRNA down-regulated compared to normal cultured SMMC-7721 cells. We demonstrated for the first time that ENST00000570843.1, ENST00000567668.1, ENST00000582249.1, ENST00000450304.1, TCONS_00015544, ENST00000602478.1, TCONS_00001266 and ARC, IL12RB1, HSPA6 were upregulated, whereas STAT3, PRPSAP1, MCU, URB2 were down-regulated in sub-lethally heat-treated HCC cells.

Conclusions

lncRNA expression data in sub-lethally heat-treated HCC cells will provide important insights about lncRNAs' contribution to HCC recurrence after RFA treatment.

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Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis

Abstract

The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23–1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44–2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.

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FDA Clears Wider Use of Cooling Cap to Reduce Hair Loss during Chemotherapy

The FDA has cleared a cooling cap—a device designed to reduce hair loss during chemotherapy called the DigniCap Scalp Cooling System—for use by patients with any type of solid tumor.

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Crescentic glomerular nephritis associated with rheumatoid arthritis: a case report

Rheumatoid arthritis is a systemic disorder where clinically significant renal involvement is relatively common. However, crescentic glomerular nephritis is a rarely described entity among the rheumatoid nephr...

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Assessment of simplified ratio-based approaches for quantification of PET [ 11 C]PBR28 data

Abstract

Purpose

Kinetic modelling with metabolite-corrected arterial plasma is considered the gold standard for quantification of [¹¹C]PBR28 binding to the translocator protein (TSPO), since there is no brain region devoid of TSPO that can serve as reference. The high variability in binding observed using this method has motivated the use of simplified ratio-based approaches such as standardised uptake value ratios (SUVRs) and distribution volume (V_T) ratios (DVRs); however, the reliability of these measures and their relationship to V_T have not been sufficiently evaluated.

Methods

Data from a previously published [¹¹C]PBR28 test-retest study in 12 healthy subjects were reanalysed. V_T was estimated using a two-tissue compartment model. SUVR and DVR values for the frontal cortex were calculated using the whole brain and cerebellum as denominators. Test-retest reliability was assessed for all measures. Interregional correlations were performed for SUV and V_T, and principal component analysis (PCA) was applied. Lastly, correlations between ratio-based outcomes and V_T were assessed.

Results

Reliability was high for V_T, moderate to high for SUV and SUVR, and poor for DVR. Very high interregional correlations were observed for both V_T and SUV (all R ² > 85%). The PCA showed that almost all variance (>98%) was explained by a single component. Ratio-based methods correlated poorly with V_T (all R ² < 34%, divided by genotype).

Conclusions

The reliability was good for SUVR, but poor for DVR. Both outcomes showed little to no association with V_T, questioning their validity. The high interregional correlations for V_T and SUV suggest that after dividing by a denominator region, most of the biologically relevant signal is lost. These observations imply that results from TSPO PET studies using SUVR or DVR estimates should be interpreted with caution.

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Comparison of RECIST to immune-related response criteria in patients with non-small cell lung cancer treated with immune-checkpoint inhibitors

Abstract

Purpose

Given that immune-related response in non-small cell lung cancer (NSCLC) has not been well evaluated, we assessed tumor response using the response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1) and immune-related response criteria (irRC) to identify atypical responses in patients with advanced NSCLC treated with immunotherapeutic agents.

Methods

Patients received immune-checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, and durvalumab plus tremelimumab) to treat metastatic or recurrent NSCLC after failed platinum-based chemotherapy. Tumor response was assessed according to both RECIST v1.1 and irRC.

Results

Responses by 41 patients were analyzed. The overall response rate (ORR) was 29.2% (95% CI 17.6–44.5) assessed by RECIST v1.1 and 34.1% (95% CI 21.6–49.4) by irRC, showing similar results from the two methods (p = 0.923). Two patients (4.9%) were defined as having progressive disease as assessed by RECIST but not by irRC. The patients eventually experienced tumor regression, suggesting delayed pseudoprogression. For all patients, the median PFS was 5.1 months (95% CI 3.4–6.7) and OS was 18.3 months (95% CI 6.7–29.8). In multivariate analysis, ex- or current smokers (HR 0.34, p = 0.14) and EGFR mutation negativity (HR 0.16, p = 0.05) were associated with significantly longer PFS.

Conclusion

Our study found that pseudoprogression was not frequently observed in NSCLC. Conventional RECIST v1.1 might underestimate the benefit of immune-checkpoint inhibitors. Given the small number of patients studied, further study is warranted on whether treatment with immune-checkpoint inhibitors beyond RECIST progression benefits patients with advanced NSCLC.

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Preoperative Chemoradiation Therapy Does Not Increase Risk of Anastomotic Leak in Patients with Gastric Cancer

Publication date: Available online 20 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Naruhiko Ikoma, Prajnan Das, Mariela Blum, Jeannelyn S. Estrella, Catherine E. Devine, Xuemei Wang, Keith Fournier, Paul Mansfield, Bruce D. Minsky, Jaffer Ajani, Brian D. Badgwell
IntroductionWe sought to determine whether preoperative chemoradiation therapy or chemotherapy increases the risk of anastomotic leak after gastrectomy in gastric cancer patients without gastroesophageal junction involvement.MethodsWe reviewed data from a prospectively maintained database of patients who underwent gastrectomy at our institution between 2001 and 2016. The incidence of anastomotic leak and symptomatic intra-abdominal fluid collection was determined and tested for associations with the type of preoperative therapy. Risk factors for these complications were identified using univariate and multivariable logistic regression models.ResultsOf 346 included patients, 35% had upfront surgery, 44% had preoperative chemoradiation therapy, and 21% had preoperative chemotherapy. Anastomotic leak and intra-abdominal fluid collection were diagnosed in 3.5% and 7.5% of patients, respectively. Multivariable analysis revealed that concomitant organ resection was the only significant risk factor for anastomotic leak or intra-abdominal fluid collection (p = 0.014). The type of preoperative therapy was not a risk factor for anastomotic leak or intra-abdominal fluid collection.ConclusionAnastomotic leak and intra-abdominal fluid collection were rare after gastrectomy, and neither type of preoperative therapy increased the risk of these complications. Our results add to the existing literature that preoperative therapy, including preoperative chemoradiation therapy, is safe for patients with gastric cancer.

Teaser

In this single institutional retrospective cohort study of 346 patients who underwent gastrectomy at our institution 2001-2016, anastomotic leak and intra-abdominal fluid collection were diagnosed in 3.5% and 7.5% of patients, respectively. Multivariable analysis revealed that concomitant organ resection was the only significant risk factor for anastomotic leak or intra-abdominal fluid collection (p = 0.014). Preoperative chemoradiation therapy was not a risk factor for anastomotic leak or intra-abdominal fluid collection.

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Inhibitory effect and mechanism of mesenchymal stem cells on melanoma cells

Abstract

Purpose

To explore the inhibitory effect and mechanism of MSCs on melanoma proliferation.

Methods

The inhibitory effect of MSCs on melanoma A375 cells was detected by co-culture and conditioned medium (CM) experiments using MTT method. The cell cycle was analyzed by flow cytometry. Then, Western Blot experiment detected the expression of proteins related to NF-κB signaling in A375 cells. The expression of IL-1Ra in MSCs was proved by RT-PCR. The over-expression and silencing vector pcDNA3.1-EGFP-IL-1Ra and pGPH1-IL-1R were constructed and transfected into MSCs cells. After that, the changes of inhibitory effect and cell cycle from MSCs-S and MSCs-O CM on A375 cells were explored. The expression of proteins related to NF-κB signaling in A375 cells after MSCs-S or MSCs-O CM treatment was detected by Western Blot. MSCs, MSCs-S, or MSCs-O and A375 cells were co-injected into nude mice under the arms, the growth of tumor was observed, the frozen sections were made, and H&E staining of tumor tissue was performed.

Results

The proliferation of A375 cells was inhibited and the cell cycle of A375 was arrested by MSCs. The expressions of cytokines related to NF-κB signaling were down-regulated. Over-expression and silence of Interleukin 1 receptor antagonist (IL-1Ra), specifically blocking activation of NF-κB signaling, indicated that inhibitory effect from MSCs was enhanced or weakened respectively, which suggested that IL-1Ra was involved in the inhibitory effect. In vivo, tumor initiation and growth were significantly inhibited when A375 cells were co-injected with MSCs into nude mice, which were related to the expression level of IL-1Ra.

Conclusion

MSCs could inhibit the proliferation and tumor initiation of melanoma A375 cells through NF-κB signaling. MSCs could secret IL-1Ra and inhibit expressions of NF-κB signaling-related factors of tumor cells, and cause cell cycle arrest in G1 phase.

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Erratum

Case Rep Ophthalmol 2017;8:389

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Catheter Ablation of Atrial Fibrillation: An Overview for Clinicians

Abstract

Catheter ablation (CA) of atrial fibrillation (AF) is currently one of the most commonly performed electrophysiology procedures. Ablation of paroxysmal AF is based on the elimination of triggers by pulmonary vein isolation (PVI), while different strategies for additional AF substrate modification on top of PVI have been proposed for ablation of persistent AF. Nowadays, various technologies for AF ablation are available. The radiofrequency point-by-point ablation navigated by electro-anatomical mapping system and cryo-balloon technology are comparable in terms of the efficacy and safety of the PVI procedure. Long-term success of AF ablation including multiple procedures varies from 50 to 80%. Arrhythmia recurrences commonly occur, mostly due to PV reconnection. The recurrences are particularly common in patients with non-paroxysmal AF, dilated left atrium and the "early recurrence" of AF within the first 2–3 post-procedural months. In addition, this complex procedure can be accompanied by serious complications, such as cardiac tamponade, stroke, atrio-esophageal fistula and PV stenosis. Therefore, CA represents a second-line treatment option after a trial of antiarrhythmic drug(s). Good candidates for the procedure are relatively younger patients with symptomatic and frequent episodes of AF, with no significant structural heart disease and no significant left atrial enlargement. Randomized trials demonstrated the superiority of ablation compared to antiarrhythmic drugs in terms of improving the quality of life and symptoms in AF patients. However, nonrandomized studies reported additional clinical benefits from ablation over drug therapy in selected AF patients, such as the reduction of the mortality and stroke rates and the recovery of tachyarrhythmia-induced cardiomyopathy. Future research should enable the creation of more durable ablative lesions and the selection of the optimal lesion set in each patient according to the degree of atrial remodeling. This could provide better long-term CA success and expand indications for the procedure, especially among the patients with non-paroxysmal AF.

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Inhibitory effect and mechanism of mesenchymal stem cells on melanoma cells

Abstract

Purpose

To explore the inhibitory effect and mechanism of MSCs on melanoma proliferation.

Methods

Results

Conclusion

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Erratum to: Predictors of chest wall toxicity after stereotactic ablative radiotherapy using real-time tumor tracking for lung tumors

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PTENP1 inhibits the growth of esophageal squamous cell carcinoma by regulating SOCS6 expression and correlates with disease prognosis

Abstract

PTEN pseudogene (PTENP1) has a tumor suppressive role in multiple cancers. However, its involvement in esophageal squamous cell carcinoma (ESCC) remains largely unknown. In this study, we set out to identify the role of PTENP1 in the development of ESCC. Gene Expression Omnibus database was employed to investigate the expression of PTENP1 in ESCC. sRNA target Database(StarBase v2.0) was used to query the downstream of PTENP1. Next, both in vitro and in vivo experiments were employed to explore the function. Cell proliferation was evaluated by CCK-8, soft agar and colony formation assays. Expression of relative genes was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. 3'UTR luciferase assay was used to confirm the miRNA binding. The clinical significance of PTENP1 was further validated by immunohistochemistry (IHC) and correlation with clinicopathological indicators in additional samples (n = 93). We found expression of PTENP1 in ESCC was lower than that in the corresponding adjacent normal tissues (n = 17). Overexpression of PTENP1 in Eca109 and TE-1 cells resulted in inhibited proliferation and altered expression of SOCS6-p-STAT3-HIF-1α pathway both in vitro and in vivo. Subsequent IHC reported a similar trend in human ESCC samples. 3'UTR luciferase assay demonstrated that PTENP1 3'UTR decoyed miR-17-5p from binding to SOCS6. Moreover, PTENP1 expression was correlated with clinicopathological indicators to varying degrees, including histological grade, TNM stage, infiltration depth, lymph node metastasis and overall survival. Taken together, these results suggested an anti-oncogenic role of PTENP1. Meanwhile, PTENP1 may also serve as a candidate of prognostic indicator for ESCC patients. This article is protected by copyright. All rights reserved

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The RNA-binding protein HuR inhibits expression of CCL5 and limits recruitment of macrophages into tumors

ABSTRACT

The RNA-binding protein HuR promotes tumor growth by affecting proliferation, metastasis, apoptosis, and angiogenesis. Although immune cells, especially tumor-associated macrophages, are critical components of the tumor stroma, the influence of HuR in tumors on the recruitment of immune cells remains poorly understood. In the present study, we therefore aimed to elucidate the impact of tumor cell HuR on the interaction between tumor cells and macrophages. To this end, we stably depleted HuR in human MCF-7 breast cancer cells. We found that HuR-deficient cells not only showed reduced proliferation, they further expressed elevated levels of the chemokine CCL5. HuR-dependent repression of CCL5 was neither caused by altered CCL5 mRNA stability, nor by changes in CCL5 translation. Instead, loss of HuR augmented transcription of CCL5, which was mediated via an interferon-stimulated response element in the CCL5 promoter. Furthermore, HuR depletion enhanced macrophage recruitment into MCF-7 tumor spheroids, an effect which was completely lost upon neutralization of CCL5. HuR expression further negatively correlated with CCL5 expression and macrophage appearance in a cohort of breast tumors. Thus, while HuR is well-characterized to support various pro-tumorigenic features in tumor cells, we provide evidence that it limits the recruitment of macrophages into tumorsby repressing CCL5. As macrophage infiltration is associated with poor prognosis, our findings underline the highly cell-type and context specific role of HuR in tumorigenesis. This article is protected by copyright. All rights reserved

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Adenocarcinoma of the Lung Acquiring Resistance to Afatinib by Transformation to Small Cell Carcinoma: A Case Report

A 65-year-old woman visited our hospital due to right chest pain and dyspnea on exertion. Chest radiography revealed decreased permeability of the right lung. Computed tomography demonstrated a huge mass in the right upper lobe and right pleural effusion. Right pleural effusion cytology yielded a diagnosis of adenocarcinoma and was positive for mutation of epidermal growth factor receptor (EGFR; exon 21 L858R). Afatinib was selected for the initial treatment. Multiple tumors regressed remarkably, but then rapidly progressed 3 months later. We performed re-biopsy to detect the mechanism of resistance to afatinib. Histopathology revealed a mixture of small cell carcinoma (SCC) and adenocarcinoma harboring same EGFR mutation. To the best of our knowledge, this is the first report of transformation to SCC after treatment with afatinib.
Case Rep Oncol 2017;10:666–670

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An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging

Abstract

Aim

The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity.

Patients and methods

A total of 13 patients with stage II–III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary turmor and affected lymph nodes). The fraction dose was increased within the individual PET-based PTV (PTV_PET) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method.

Results

The average dose to PTV_PET reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis.

Conclusion

These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe late toxicity.

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Mismatch repair deficient metastatic colon cancer and urothelial cancer: a case report of sequential immune checkpoint therapy.

Mismatch repair deficient metastatic colon cancer and urothelial cancer: a case report of sequential immune checkpoint therapy.

Cancer Biol Ther. 2017 Jul 20;:0

Authors: Ghatalia P, Nagarathinam R, Cooper H, Geynisman DM, El-Deiry WS

Abstract
A major recent advance in cancer therapy involves the use of immune checkpoint therapy for tumors with mismatch repair deficiency, as they have a high tumor mutation load and neoantigen burden. Approximately 4% of advanced colorectal cancer harbors a mismatch repair deficiency. When mismatch repair deficiency exists in the germline, there is increased susceptibility to a variety of cancers including colorectal cancer, uterine cancer, urothelial carcinoma, and skin cancer. Herein we report the case of a 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a history of sebaceous carcinomas. As the patient in 2016 was ineligible for clinical trials he received immune checkpoint anti-PD-1 therapy with pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the failure of second-line treatment. The patient's CEA initially responded to pembrolizumab for 4 months and then kept rising for 5 months before mildly declining again. His treatment was then switched to anti-PD-L1 therapy with atezolizumab as it was approved for urothelial carcinoma at that time, and his CEA declined again. This case raises interesting questions about caring for patients with mismatch repair deficient colorectal cancer, including the role of PD-L1 therapy, sequencing of immunotherapy, relying on CEA trends and determining future therapies after progression on pembrolizumab.

PMID: 28726535 [PubMed - as supplied by publisher]

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An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging

Abstract

Aim

Patients and methods

Results

Conclusion

http://ift.tt/2uhgeuZ

Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer

Abstract

Background

Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor − 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa.

Methods

METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/− 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London.

Discussion

This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place.

Trial registration

EudraCT number 2014–005193-11. Registered on September 09, 2015.

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Reply to: radioiodine ablation necessary for patients with low-risk papillary thyroid carcinoma and tumor > 4 cm?

Publication date: Available online 21 July 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Jennifer L. Marti, Luc G.T. Morris, Allen S. Ho

http://ift.tt/2gPI6BS

Complications following completion lymphadenectomy versus therapeutic lymphadenectomy for melanoma - A systematic review of the literature

Publication date: Available online 21 July 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): J.A. Moody, S.J. Botham, K.E. Dahill, D.L. Wallace, J.T. Hardwicke
PurposeCompletion lymph node dissection (CLND) following a positive sentinel lymph node biopsy (SLNB) has been reported to be less morbid than lymphadenectomy for palpable disease (therapeutic lymph node dissection; TLND). The reporting of morbidity data can be heterogeneous, and hence no 'average' surgical complication rates of these procedures has been reported. This review aims to determine complications rates to inform patients undergoing surgery for metastatic melanoma.MethodsA systematic review of English-language literature from 2000-2017, reporting morbidity information about CLND and TLND for melanoma, was performed. The methodological quality of the included studies was performed using the methodological index for non-randomised studies (MINORS) instrument and Detsky score. Pooled proportions of post-operative complications were constructed using a random effects statistical model.ResultsAfter application of inclusion and exclusion criteria, 18 articles progressed to the final analysis. In relation to TLND (1627 patients), the overall incidence of surgical complications was 39.3% (95% CI 32.6-46.2); including wound infection/breakdown 25.4% (95% CI: 20.9-30.3); lymphoedema 20.9% (95% CI: 13.8-29.1); and seroma 20.4% (95% CI: 15.9-25.2). For CLND (1929 patients), the overall incidence of surgical complications was 37.2% (95% CI 27.6-47.4); including wound infection/breakdown 21.6% (95% CI: 13.8-30.6); lymphoedema 18% (95% CI: 12.5-24.2); and seroma 17.9% (95% CI: 10.3-27). The complication rate was marginally lower for CLND but not to statistical significance.

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Combined detection of dickkopf-1 subtype classification autoantibodies as biomarkers for the diagnosis and prognosis of non-small cell lung cancer

http://ift.tt/2tNkXkB

Targeted TPX2 increases chromosome missegregation and suppresses tumor cell growth in human prostate cancer

http://ift.tt/2tweI9C

IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model

Abstract

Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.

http://ift.tt/2ugTObA

Cancers, Vol. 9, Pages 93: Seed-in-Soil: Pancreatic Cancer Influenced by Tumor Microenvironment

Cancers, Vol. 9, Pages 93: Seed-in-Soil: Pancreatic Cancer Influenced by Tumor Microenvironment

Cancers doi: 10.3390/cancers9070093

Authors: Huey-Jen Lin Jiayuh Lin

Pancreatic ductal adenocarcinoma is a fatal malignancy with a five-year survival rate lower than 7%, and most patients dying within six months of diagnosis. The factors that contribute to the aggressiveness of the disease include, but are not limited to: late diagnosis, prompt metastasis to adjacent vital organs, poor response, and resistance to anticancer treatments. This malignancy is uniquely associated with desmoplastic stroma that accounts for 80% of tumor mass. Understanding the biology of stroma can aid the discovery of innovative strategies for eradicating this lethal cancer in the future. This review highlights the critical components in the stroma and how they interact with the cancer cells to convey the devastating tumor progression.

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IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model

Abstract

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Prognosis Prediction for Postoperative Esophageal Cancer Patients Using Onodera's Prognostic Nutritional Index.

Prognosis Prediction for Postoperative Esophageal Cancer Patients Using Onodera's Prognostic Nutritional Index.

Nutr Cancer. 2017 Jul 20;:1-6

Authors: Matsumoto H, Okamoto Y, Kawai A, Ueno D, Kubota H, Murakami H, Higashida M, Hirai T

Abstract
PURPOSE: Preoperative nutritional status may impact surgical outcome and prognosis. We evaluated the predictive value of Onodera's prognostic nutritional index (O's-PNI) of surgical outcome following esophagectomy in esophageal cancer patients.
PATIENTS AND METHODS: In total, 144 patients undergoing esophagectomy for esophageal cancer from April 2010 to May 2015 were evaluated, retrospectively. Eighty-four patients were enrolled in this study. O's-PNIs were calculated before surgery, discharge, and 1, 2, and 6 mo after discharge. The relationship between O's-PNI and occurrence of complications as classified by the Clavien-Dindo (C-D) classification, length of hospital stay, and survival time was investigated.
RESULTS: The mean O's-PNI for patients with complications of more than Grade 2 by the C-D classification was 37.4, which was significantly lower than that for Grades 0 or 1 (40.5, P = 0.0094). A negative correlation was obtained between O's-PNI and hospital stay length (P = 0.0006), whereas a positive correlation was obtained for O's-PNI at 6 mo postsurgery and overall survival (P = 0.0171, P = 0.0201).
CONCLUSION: O's-PNI may represent a useful indicator of the occurrence of complications and length of hospital stay, and may influence overall survival at 6 mo postsurgery. Nutritional management during the perioperative period could therefore contribute to satisfactory outcomes following esophagectomy in esophageal cancer patients.

PMID: 28726497 [PubMed - as supplied by publisher]

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Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G 2 /M arrest and cell survival in cells with p53 defects under heat stress

Abstract

Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G₂/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt-4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G₂/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia.

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Radiation Dose and Cardiac Risk in Breast Cancer Treatment: An Analysis of Modern Radiotherapy Including Community Settings

Publication date: Available online 20 July 2017
Source:Practical Radiation Oncology
Author(s): Julian C. Hong, Elham Rahimy, Cary P. Gross, Timothy Shafman, Xin Hu, James B. Yu, Rudi Ross, Steven E. Finkelstein, Arie Dosoretz, Henry S. Park, Pamela R. Soulos, Suzanne B. Evans
PurposeAdjuvant radiotherapy (RT) for breast cancer improves outcomes, but prior studies have documented substantive cardiac dose and cardiac risk. We assessed mean heart dose (MHD) of RT, and estimated risk of RT-associated cardiac toxicity in women undergoing adjuvant RT for breast cancer in contemporary (predominantly) community practice.Methods and MaterialsWe identified women with left-sided breast cancer receiving adjuvant RT during 2012 through 2014 from 94 centers across 16 states. We used bivariate analyses and multivariable linear regression to assess associations between RT techniques and MHD. Excess RT-related cardiac risk by age 80 was estimated for women diagnosed at age 60 using previously reported relationship between MHD and cardiac risk.ResultsAmong 1161 women, 77.3% were treated in community practice and with breast-conservation (77.8%). The most common techniques were free-breathing (92.2%), supine (94.8%), and fixed gantry intensity modulated RT (FG-IMRT; 46.9%). Median MHD was 2.76Gy (IQR 1.47–5.03). In multivariable analyses, predicted median MHD with deep inspiration breath hold was 2.41Gy compared to 3.86Gy with free-breathing (p<0.001). Three-dimensional conformal RT (3D–CRT) was associated with lower predicted median MHD (2.78Gy) than FG-IMRT (4.02Gy) or rotational IMRT (R-IMRT, 6.60Gy, p<0.001). For 60-year old women with the median MHD of the study population (2.76Gy) and no cardiovascular risk factors, the 20-year predicted excess risk of death from ischemic heart disease attributable to radiation was 3.5 excess events/1000 patients, in contrast to estimates of 8 events/1000 from prior analyses. The predicted risk of cardiac events varied based on radiation technique, with 4 excess events/1000 with 3D–CRT, 5 excess events/1000 with FG-IMRT, and 8 excess events/1000 with R-IMRT.ConclusionsMHD varies substantially across patients and is influenced by technique in predominantly community settings. Overall risk of cardiac toxicity is modest.SummaryWe assessed mean heart dose of radiotherapy (RT), and estimated risk of RT-associated cardiac toxicity in women undergoing adjuvant RT for left-sided breast cancer in a large contemporary cohort. For 60-year old women without cardiovascular risk factors, the predicted excess risk of death from ischemic heart disease 20years post-radiation was 3.5 excess events/1000 patients, lower than estimates derived in prior studies (8 per 1000). Mean heart dose varied substantially and was influenced by technique.

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Prostate Cancer-Specific PET Radiotracers: A Review on the Clinical Utility in Recurrent Disease

Publication date: Available online 20 July 2017
Source:Practical Radiation Oncology
Author(s): Jaden D. Evans, Krishan R. Jethwa, Piet Ost, Scott Williams, Eugene D. Kwon, Val J. Lowe, Brian J. Davis
Prostate cancer-specific positron emission tomography (pcPET) has been shown to detect sites of disease recurrence at serum prostate specific antigen (PSA) levels that are lower than those levels detected by conventional imaging. Commonly used pcPET radiotracers in the setting of biochemical recurrence are reviewed including C-11/F-18 choline, Ga-68/F-18 PSMA, and F-18 fluciclovine. Review of the literature generally favors PSMA-based agents for the detection of recurrence as a function of low PSA levels. Positive Ga-68/F-18 PSMA PET/CT scans detected potential sites of recurrence in a median 51.5% of patients when PSA level is <1.0ng/mL, 74% of patients when PSA level is 1.0–2.0ng/mL, and 90.5% of patients when PSA level is >2.0ng/mL. Review of C-11/F-18 choline and F-18 fluciclovine data commonly demonstrated lower detection rates for each respective PSA cohort, although with some important caveats, despite having similar operational characteristics to PSMA-based imaging. Sensitive pcPET imaging has provided new insight into the early patterns of disease spread, which has prompted judicious re-consideration of additional local therapy either after prostatectomy, definitive radiotherapy or post-prostatectomy radiotherapy. This review discusses the literature, clinical utility, availability and fundamental understanding of pcPET imaging needed to improve clinical practice.

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Standardization of Nodal Radiation Therapy through Changes to a Breast Cancer Clinical Pathway throughout a Large, Integrated Cancer Center Network

Publication date: Available online 20 July 2017
Source:Practical Radiation Oncology
Author(s): Brian J. Gebhardt, Joel Thomas, Zachary D. Horne, Colin E. Champ, Gretchen M. Ahrendt, Emilia Diego, Dwight E. Heron, Sushil Beriwal
BackgroundStudies demonstrate safety of omitting axillary nodal dissection (ALND) for early-stage breast cancer with positive sentinel lymph node (+SLN) biopsy, though trial designs differed in radiotherapy (RT) fields. Regional nodal irradiation (RNI) was separately shown to improve outcomes in high-risk patients. This led to lack of consensus in RT volumes. Clinical pathways (CP) standardize care where practice varies unnecessarily. We evaluated the impact of changes to a CP guiding post-operative RT in women with +SLNs on practice patterns throughout a network.Methods/MaterialsWe implemented a CP for management of breast cancer with post-operative RT designed to promote uniform nodal treatment. The CP recommended modified tangents (MT) including level I/II nodes for women with micrometastases (pN1mi). For women with macrometastases (pN1a), CP recommended including level I/II LN in MT and a third supraclavicular (SCN) LN +/− internal mammary nodes for women with adverse factors present.ResultsRT fields of 233 women undergoing breast conserving surgery with +SLN but not ALND were retrospectively reviewed: 25% had pN1mi disease, and 75% pN1a. Of 127 women treated before CP changes, 35% with pN1mi and 22% with pN1a were treated with whole-breast irradiation (WBI) alone. Following CP changes, 106 women were treated: 5% with WBI alone, 58% with MT, and 38% with MT+SCN field. Utilization of MT was associated with CP changes. Utilization of a 3rd SCN field was associated with CP changes, pN-Stage, extracapsular extension, and total number of adverse factors.ConclusionCP's translate published data and institutional experience into management plans that promote evidence-based care and eliminate unnecessary practice variations. Recognizing that post-operative RT treatment volumes were heterogeneous, we modified the CP based upon the latest evidence for RNI, after which we found increased compliance and consistency with quality guidelines, which will also aid in tracking outcomes in future investigations.

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Recurrent triploid digynic conceptions and mature ovarian teratomas: Are they different manifestations of the same genetic defect?

Abstract

Miscarriages affect 15% of clinically recognized pregnancies. Recurrent miscarriage (RM) is defined by the occurrence of at least two consecutive pregnancy losses and affects 1% to 5% of couples trying to conceive. In an attempt to categorize patients with RM and identify the mechanisms leading to their miscarriages, we first used flow cytometry to assess the ploidy of 93 products of conception (POCs) from 53 patients with RM (≥ 3 miscarriages). We identified a single patient with four triploid POCs. We then used fluorescent in situ hybridization to confirm the triploidies and fluorescent microsatellite genotyping with distal and pericentromeric markers to determine their parental origin and the mechanisms leading to their formation. We found that all four triploidies were digynic and due to a failure in meiosis II (MII) suggesting a genetic predisposition. Upon further investigation into the family, we found a remarkable history of ovarian cysts and dysfunctions on the maternal side. Notably, one maternal cousin had a mature ovarian teratoma that we analyzed and found an identical mechanism at its origin, a failure in MII. The identification of two patients in the same family with two different manifestations, digynic triploid conceptions and mature ovarian teratomas, both resulting from the failure of MII, suggests an inherited genetic susceptibility towards an error in MII segregating in the family that may manifest in the form of a triploid digynic miscarriage as well as a mature ovarian teratoma. Our findings may facilitate the future identification of causative mutations for MII defects. This article is protected by copyright. All rights reserved.

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Analysis of clinical characteristics and efficacy of chronic myeloid leukemia onset with extreme thrombocytosis in the era of tyrosine kinase inhibitors

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Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer

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Circ-104916 is downregulated in gastric cancer and suppresses migration and invasion of gastric cancer cells

http://ift.tt/2gPlQbg

Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck

Summary

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck. Thirty-five patients were enrolled in this prospective study. The primary endpoint was the 3-year local control rate, while secondary endpoints included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and 3 patients received 64.0 Gy (RBE) and 57.6 Gy (RBE) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and 5 patients died. The 3-year local control and overall survival rates were 93% and 88%. Acute grade 2 to 3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, 1, and 0 patients. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. (UMIN000007886)

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