Publication date: Available online 2 March 2018
Source:Injury
Author(s): Megan E. Cain, Job N. Doornberg, Robin Duit, Jock Clarnette, Ruurd Jaarsma, Bhavin Jadav
BackgroundIntramedullary-nails (IMN) are the treatment of choice for most tibial shaft fractures due to their minimally-invasive nature and non-demanding surgical technique. However, a potential iatrogenic pitfall is intra-articular interlocking screw positioning within the proximal (PTFJ) and distal (DTFJ) tibiofibular joints that may go unrecognized.ObjectiveTo evaluate the incidence of intra-articular screw penetration of the PTFJ and DTFJs after interlocking of IMN for tibial fractures.InterventionReamed IMN using modern techniques, including proximal interlocking via standard aiming jig and distal interlocking either freehand or using SureShot®.MethodsProspective series of 165 consecutive patients with a tibial shaft fracture managed with an IMN. Diagnosis and incidence of penetration of the PTFJ and DTFJ was assessed on protocolled low-dose postoperative CT-scans (standardized clinical practice for assessing rotational alignment). The degree of penetration of the TFJ's was graded as: Grade 1–slight breach of the tibial cortex; Grade 2–clear penetration of the tibial cortex with intra-articular screw tip; and Grade 3–penetration of both tibial- and fibular cortices with screw tip in fibula.ResultsOf the 165 tibial shaft fractures, using the AO/OTA classification, 69% were simple, 16% wedge and 15% complex fractures. Following IMN 42% of patients had intra-articular screw penetration of their PTFJ whilst 39% had penetration of their DTFJ. 66% of patients had penetration of either one- or both of their TFJs. The grading of PTFJ violation was distributed as follows: Grade 1 in 24 patients; Grade 2 in 26 patients and Grade 3 in 19 patients. DTFJ violation was graded as: Grade 1 in 21 patients; 40 patients had Grade 2 violation; and four patients had a Grade 3 penetration.ConclusionsThis diagnostic imaging study reports a high rate of intra-articular screw penetration of the PTFJ and DTFJ after interlocking of IMN for tibia shaft fractures. A prospective cohort study is underway to evaluate its clinical significance.Changes to enable alteration in forced angle of interlocking screw trajectory and avoidance of the anteromedial to posterolateral locking screw may reduce the incidence of TJF violation.Level of evidenceLevel II – Diagnostic Imaging Study
http://ift.tt/2tk2Sjp
Παρασκευή 2 Μαρτίου 2018
High incidence of screw penetration in the proximal and distal tibiofibular joints after intramedullary nailing of tibial fractures—A prospective cohort and mapping study
Technical tip: Removal of a broken tri-cortical syndesmotic screw using a “perfect circle” technique
Publication date: Available online 2 March 2018
Source:Injury
Author(s): Matthew D. Riedel, Jorge Briceno, Christopher P. Miller, John Y. Kwon
While broken or loose syndesmotic screws are typically of no clinical consequence, occasionally breakage can result in pain, metal fretting, or bony erosion. Despite quad-cortical syndesmotic screws being relatively easy to remove due to the prominent screw tip penetrating the medial tibial cortex, removal of a broken tri-cortical screw can be technically challenging. The purpose of this manuscript is to describe a safe technique for removing the buried, broken tri-cortical screw fragment via a minimally invasive medial tibial approach by verifying the screw location using intra-operative fluoroscopy.
http://ift.tt/2FiS0a4
Phase I study of taselisib in Japanese patients with advanced solid tumors or hormone receptor-positive advanced breast cancer
Summary
Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. This paper reports the first study of taselisib administration in Japanese patients. The aim of this two-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (Stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (Stage 2). In Stage 1, oral taselisib tablets 2, 4, and 6 mg/day were administered in 28-day cycles. In Stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/day) with intramuscular fulvestrant 500 mg. Nine and six patients were enrolled in Stage 1 and Stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in Stage 1 and Stage 2 were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after administration; its half-life was 12.9–32.0 hours in Stage 1 and 16.1–26.5 hours in Stage 2. Two patients achieved partial response (PR) and five patients had stable disease (SD) in Stage 1, and one patient had PR and five patients had SD in Stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA-mutated solid tumors or HR-positive advanced breast cancer.
This article is protected by copyright. All rights reserved.
http://ift.tt/2oJgb8j
The Role of Measurement Uncertainty in Health Technology Assessments (HTAs) of In Vitro Tests
Abstract
Introduction
Numerous factors contribute to uncertainty in test measurement procedures, and this uncertainty can have a significant impact on the downstream clinical utility and cost-effectiveness of testing strategies. Currently, however, there is no clear guidance concerning if or how such factors should be considered within Health Technology Assessments (HTAs) of tests.
Objective
The aim was to provide an introduction to key concepts in measurement uncertainty for the HTA community and to explore, via systematic review, current methods utilised within HTAs.
Methods
HTAs of in vitro tests including a model-based economic evaluation were identified via the Centre for Reviews and Dissemination (CRD) HTA database and key reimbursement authority websites. Data were extracted to explore the specific components of measurement uncertainty assessed and methods utilised. The findings were narratively synthesised.
Results
Of 107 identified HTAs, 20 (19%) attempted to assess components of measurement uncertainty: 15 did so via some form of pre-model assessment (such as a literature review or laboratory survey); four also included components within the economic model; and one considered measurement uncertainty within the model only. One study quantified the impact of measurement uncertainty on cost-effectiveness and found that this parameter significantly changed the results, but did not impact the overall decision uncertainty.
Conclusion
A minority of HTAs identified from this review used various approaches to assess and/or incorporate the impact of measurement uncertainty, indicating that these assessments are feasible. Uncertainty remains around best practice methodology for conducting such analyses; further research is required to ensure that future HTAs are fit for purpose.
http://ift.tt/2I21yoy
Recombinant Adenovirus-p53 Gene Therapy for Advanced Unresectable Soft-Tissue Sarcomas
Human Gene Therapy , Vol. 0, No. 0.
http://ift.tt/2tcopua
Baricitinib for Previously Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer (Eli Lilly) of baricitinib (BARI; Olumiant®; a Janus kinase inhibitor that is taken orally) to submit evidence of its clinical and cost effectiveness for the treatment of moderate to severe rheumatoid arthritis (RA) after the failure of disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical-effectiveness evidence in the CS for BARI was based predominantly on three randomised controlled trials comparing the efficacy of BARI against adalimumab or placebo, as well as one long-term extension study. The clinical-effectiveness review identified no head-to-head evidence on the efficacy of BARI against all the comparators within the scope. Therefore, the company performed network meta-analyses (NMAs) in two different populations: one in patients who had experienced an inadequate response to conventional DMARDs (cDMARD-IR), and the other in patients who had experienced an inadequate response to tumour necrosis factor inhibitors (TNFi-IR). The company's NMAs concluded BARI had comparable efficacy as the majority of its comparators in both populations. The company submitted a de novo discrete event simulation model that analysed the incremental cost-effectiveness of BARI versus its comparators for the treatment of RA from the perspective of the National Health Service (NHS) in four different populations: (1) cDMARD-IR patients with moderate RA, defined as a 28-Joint Disease Activity Score (DAS28) > 3.2 and no more than 5.1; (2) cDMARD-IR patients with severe RA (defined as a DAS28 > 5.1); (3) TNFi-IR patients with severe RA for whom rituximab (RTX) was eligible; and (4) TNFi-IR patients with severe RA for whom RTX in combination with methotrexate (MTX) is contraindicated or not tolerated. In the cDMARD-IR population with moderate RA, the deterministic incremental cost-effectiveness ratio (ICER) for BARI in combination with MTX compared with intensive cDMARDs was estimated to be £37,420 per quality-adjusted life-year (QALY) gained. In the cDMARD-IR population with severe RA, BARI in combination with MTX dominated all comparators except for certolizumab pegol (CTZ) in combination with MTX, with the ICER of CTZ in combination with MTX compared with BARI in combination with MTX estimated to be £18,400 per QALY gained. In the TNFi-IR population with severe RA, when RTX in combination with MTX was an option, BARI in combination with MTX was dominated by RTX in combination with MTX. In the TNFi-IR population with severe RA for whom RTX in combination with MTX is contraindicated or not tolerated, BARI in combination with MTX dominated golimumab in combination with MTX and was less effective and less expensive than the remaining comparators. Following a critique of the model, the ERG undertook exploratory analyses after applying corrections to the methods used in the NMAs and two programming errors in the economic model that affected the company's probabilistic sensitivity analysis (PSA) results. The ERG's NMA results were broadly comparable with the company's results. The programming error that affected the PSA of the severe cDMARD-IR population had only a minimal impact on the results, while the error affecting the severe TNFi-IR RTX-ineligible population resulted in markedly higher costs and QALYs gained for the affected comparators but did not substantially modify the conclusions of the analysis. The NICE Appraisal Committee concluded that BARI in combination with MTX or as monotherapy is a cost-effective use of NHS resources in patients with severe RA, except in TNFi-IR patients who are RTX-eligible.
http://ift.tt/2CWFI1H
Ponatinib for Treating Acute Lymphoblastic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig®) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. The clinical-effectiveness evidence in the company's submission was derived from a phase II, single-arm, open-label, non-comparative study. Given the lack of comparative evidence, a naïve indirect comparison was performed against re-induction chemotherapy comparing major cytogenetic response and complete remission. Best supportive care (BSC) was assumed to produce no disease response. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment for patients with Ph+ ALL. The company submitted a state transition model that analysed the incremental cost effectiveness of ponatinib versus re-induction therapy and BSC for the treatment of Ph+ ALL in patients whose disease is resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or who have the threonine-315-isoleucine mutation. This population was further subdivided into those who were suitable for allogeneic stem cell transplant (allo-SCT) and those who were not. The company's revised economic evaluation, following the clarification process, estimated incremental cost-effectiveness ratios (ICERs) in those suitable for allo-SCT of £31,123 per quality-adjusted life-year (QALY) gained for ponatinib compared with re-induction chemotherapy and £26,624 per QALY gained compared with BSC. For those for whom allo-SCT was unsuitable, the company-estimated ICER compared with BSC was £33,954 per QALY gained. Following a critique of the model, the ERG undertook exploratory analyses that, when combined, produced a range in ICERs (due to uncertainty of the most appropriate overall survival function) of dominant (being less expensive and providing more QALYs) to £11,727 per QALY gained compared with re-induction chemotherapy and between £7892 and £31,696 per QALY gained compared with BSC for those in whom allo-SCT was suitable. For those in whom allo-SCT was not suitable, the ERG estimated that ponatinib was dominant. During the consultation period, the company agreed a revised patient access scheme (PAS) that reduced the ICER ranges to £7156 to £29,995 per QALY gained versus BSC and to less than £5000 per QALY gained versus re-induction chemotherapy. In people for whom allo-SCT was unsuitable, ponatinib dominated BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of UK NHS resources in the considered population, subject to the company providing the agreed discount in the PAS.
http://ift.tt/2F6R9tY
Clinical features and treatment outcomes of langerhans cell histiocytosis of the spine
Publication date: Available online 2 March 2018
Source:The Spine Journal
Author(s): XiangYu Xu, SongBo Han, Liang Jiang, ShaoMin Yang, XiaoGuang Liu, HuiShu Yuan, Feng Wei, FengLiang Wu, Lei Dang, Hua Zhou, Hua Zhang, ZhongJun Liu
Background ContextLangerhans cell histiocytosis (LCH) of the spine is a relatively rare condition with unknown etiology. The diagnosis and treatment protocols for spine LCH remain controversial.PurposeIn this study, we evaluated the efficacy and safety of our proposed diagnosis and treatment protocol introduced in 2009.Study DesignThis is a retrospective study.Patient SampleOne hundred and ten patients with spine LCH who had been diagnosed and treated in our hospital from October 1997 to November 2015 were included in this study.Outcome MeasuresThe age, gender, symptoms, neurological function, lesion distribution, radiological features, pathology, treatment, outcome, and treatment complications of the patients were collected. Visual analog scale (VAS) for pain and Frankel scale for neurologic status were also documented.MethodsWe retrospectively reviewed 110 patients with spine LCH who had been diagnosed and treated in our hospital from October 1997 to November 2015. The indications for Computed tomography (CT)-guided biopsy and surgery for spine LCH have become more stringent since 2009. In cases of a solitary spinal lesion, immobilization and/or observation were usually first suggested. Chemotherapy was suggested for cases with multifocal LCH lesions, and low-dosage radiotherapy was restricted to recurrent solitary lesion. This project was supported by our hospital (No. Y71508-01) (¥ 400,000).ResultThis series included 69 male and 41 female patients (age range, 1–52 years). Pain was the most common symptom (93.6%, 103/110). Pathologic diagnosis was achieved in 72 cases (65.5%). CT-guided biopsies were performed in 91.3% (42/46) and 73.2% (41/56) of cases before and after 2009, respectively (P = 0.02). Ninety-eight cases (89.1%) were followed up for a mean 66.3 (range, 24–159) months. Immobilization and/or observation were performed in 25.9% (14/54) and 75.0% (42/56) cases before and after 2009, respectively (P<0.001). Approximately 35.2% (19/54) and 10.7% (6/56) cases had surgery (P = 0.002) before and after 2009, respectively. During the follow-up, no significant difference was found in the outcomes between the two groups treated before and after 2009 (P = 0.64).ConclusionBiopsy is not mandatory for typical spine lesions of LCH. Given the self-healing tendency of spine LCH, immobilization and/or observation remain the first-choice treatments for LCH lesions. Conservative biopsy and treatment protocols might be more appropriate for spinal LCH.
http://ift.tt/2CVlZzB
Synthesis and Evaluation of 2-[18F]Fluoroethyltriazolesuberohydroxamine Acid for Histone Deacetylase in a Tumor Model as a Positron Emission Tomography Radiotracer
Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.
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ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial
Future Oncology, Ahead of Print.
http://ift.tt/2tbCoAe
A regulated multiscale closed-loop cardiovascular model, with applications to hemorrhage and hypertension
Summary
A computational tool is developed for simulating the dynamic response of the human cardiovascular system to various stressors and injuries. The tool couples zero-dimensional models of the heart, pulmonary vasculature, and peripheral vasculature to one-dimensional models of the major systemic arteries. To simulate autonomic response, this multiscale circulatory model is integrated with a feedback model of the baroreflex, allowing control of heart rate, cardiac contractility, and peripheral impedance. The performance of the tool is demonstrated in two scenarios: neurogenic hypertension by sustained stimulation of the sympathetic nervous system, and an acute 10 percent hemorrhage from the left femoral artery. This article is protected by copyright. All rights reserved.
http://ift.tt/2FfJ9pJ
IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma
Purpose: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating GBM have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, Nivolumab (anti-PD-1), which failed to improve recurrent GBM patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for GBM, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents. Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of GBM treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiation therapy (RT), based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human GBM, the previously-described enhancement of immune cell functions after PD-1 blockade, as well as the pro-inflammatory effects of radiation. Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-GBM cells, rather than tumor cells. Timing of effector T cell infiltration, animal subject age and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit. Conclusions: These data highlight a novel and clinically-relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly-initiated phase I/II trial for GBM patients.
http://ift.tt/2F7LjEA
Sequencing pancreatic juice: squeezing the most out of surveillance
Next-generation sequencing of pancreatic juice can detect and quantify tumor-promoting mutations, supporting imaging and cytology findings to predict the degree of dysplasia in patients at high risk for pancreatic cancer. Future studies are needed to optimize this approach and determine how it best fits into clinical practice.
http://ift.tt/2FlICCq
A Phase 1 Clinical Trial of Guadecitabine and Carboplatin In Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic And Pharmacodynamic Analyses
Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase 1 study of guadecitabine and carboplatin (G+C) in patients with recurrent, platinum resistant high-grade serous ovarian cancer (OC), primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC). Experimental Design: Guadecitabine was administered once daily on Days 1-5 followed by carboplatin IV on Day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4. Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72). Median number of prior regimens was 7 (1-14). In the first cohort (N=6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia) leading to dose de-escalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTS were observed in the subsequent 14 patients. Grade ≥3AEs ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR) and six patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene re-expression in paired tumor biopsies/ascites were recorded. Conclusions: G+C was tolerated and induced clinical responses in a heavily pretreated platinum resistant OC population, supporting a subsequent randomized phase 2 trial.
http://ift.tt/2FaIiTS
A Small-Molecule Splicing Modulator Targets Spliceosome-Mutant Cells [Research Watch]
The small molecule H3B-8800 binds to and modulates the SF3b complex to kill spliceosome-mutant cells.
http://ift.tt/2GZfE8K
Umbralisib Inhibits PI3K{delta} with Less Toxicity Than Previous Inhibitors [Research Watch]
Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers.
http://ift.tt/2oECvjj
Oncogenes Induce Replication Stress via Intragenic Replication Origins [Research Watch]
Oncogenes induce premature S phase, resulting in replication–transcription conflicts and replication stress.
http://ift.tt/2F8sLE0
SETD1A Interacts with Cyclin K to Promote Leukemia Cell Survival [Research Watch]
SETD1A enhances leukemic cell growth and survival independent of its methyltransferase activity.
http://ift.tt/2F88anj
Medulloblastoma Circulating Tumor Cells Form Leptomeningeal Metastases [Research Watch]
NCAM+CD45+ medulloblastoma cells were shown to be medulloblastoma circulating tumor cells (CTC).
http://ift.tt/2CUnZIw
Colorectal tumors require NUAK1 for protection from oxidative stress [Research Articles]
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human Cancer and anti-oxidant defences are implicated in resistance to chemo- and radiotherapy. Targeted suppression of anti-oxidant defences could thus broadly improve therapeutic outcomes. Here we identify the AMPK-related kinase NUAK1 as a key component of the anti-oxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the anti-oxidant master regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, while acute depletion of NUAK1 induces regression of pre-existing autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.
http://ift.tt/2F6DT8o
The NCX1/TRPC6 complex mediates TGF{beta}-driven migration and invasion of human hepatocellular carcinoma cells
Transforming growth factor β (TGFβ) plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.
http://ift.tt/2Fa5bqo
Outcome after PSMA PET/CT based radiotherapy in patients with biochemical persistence or recurrence after radical prostatectomy
Abstract
Background
PSMA PET/CT visualises prostate cancer residual disease or recurrence at lower PSA levels compared to conventional imaging and results in a change of treatment in a remarkable high number of patients. Radiotherapy with dose escalation to the former prostate bed has been associated with improved biochemical recurrence-free survival. Thus, it can be hypothesised that PSMA PET/CT-based radiotherapy might improve the prognosis of these patients.
Methods
One hundred twenty-nine patients underwent PSMA PET/CT due to biochemical persistence (52%) or recurrence (48%) after radical prostatectomy without evidence of distant metastases (February 2014–May 2017) and received PSMA PET/CT-based radiotherapy. Biochemical recurrence free survival (PSA ≤ 0.2 ng/ml) was defined as the study endpoint.
Results
Patients with biochemical persistence were significantly more often high-risk patients with significantly shorter time interval before PSMA PET/CT than patients with biochemical recurrence. Patients with biochemical recurrence had significantly more often no evidence of disease or local recurrence only in PSMA PET/CT, whereas patients with biochemical persistence had significantly more often lymph node involvement. Seventy-three patients were started on antiandrogen therapy prior to radiotherapy due to macroscopic disease in PSMA PET/CT. Cumulatively, 70 (66–70.6) Gy was delivered to local macroscopic tumor, 66 (63–66) Gy to the prostate fossa, 61.6 (53.2–66) Gy to PET-positive lymph nodes and 50.4 (45–52.3) Gy to lymphatic pathways. Median PSA after radiotherapy was 0.07 ng/ml with 74% of patients having a PSA ≤ 0.1 ng/ml. After a median follow-up of 20 months, median PSA was 0.07 ng/ml with ongoing antiandrogen therapy in 30 patients. PET-positive patients without antiandrogen therapy at last follow-up (45 patients) had a median PSA of 0.05 ng/ml with 89% of all patients, 94% of patients with biochemical recurrence and 82% of patients with biochemical persistence having a PSA ≤ 0.2 ng/ml. Post-radiotherapy PSA ≤ 0.1 ng/ml and biochemical recurrence vs. persistence were significantly associated with a PSA ≤ 0.2 ng/ml at last follow-up.
Conclusions
PSMA PET/CT-based radiotherapy is an effective local salvage treatment option with significant PSA response in patients with biochemical recurrence or persistence after radical prostatectomy leading to deferral of long-term ADT or systemic therapy.
http://ift.tt/2HYXC7L
Worming Your Way Through the Gastrointestinal Tract: A Case of Strongyloidiasis
A 45-year-old man originally from Peru was referred for endoscopic evaluation for ongoing symptoms of generalized abdominal pain and bloating. His symptoms had been present for more than 20 years but had worsened recently. His last travel to Peru was 4 years ago. Stool examination for ova and parasite were negative. Stool cultures for Salmonella, Shigella, Campylobacter, Escherichia coli O157, and Yersinia infections also were negative. Esophagogastroduodenoscopy showed normal-appearing stomach and duodenum.
http://ift.tt/2H0n0Jb
Radial nerve injury following dry needling
Robin McManus<br />Jan 26, 2018; 2018:bcr-2017-221302-bcr-2017-221302<br />Case report
http://ift.tt/2oNOha7
FDA Warns of Fraudulent and Unapproved Flu Products
March 2, 2018 -- As part of the U.S. Food and Drug Administration's ongoing efforts to protect consumers from health fraud, the agency is reminding consumers to be wary of unapproved products claiming to prevent, treat or cure influenza, or flu....
http://ift.tt/2HZdIyz
Cellular Composition of the B- and T-Cell-Dependent Areas in the Small Intestine during the Post-Stress Period (Experimental Study)
A quantitative study of lymphoid cells in the B- and T-cell-dependent areas of intestinal lymphoid nodules and mesenteric lymph nodes in behaviorally passive and active rats was performed at various periods after acute stress on the model of 1-h immobilization with simultaneous electrocutaneous stimulation. Stress exposure is accompanied by a decrease in the number of lymphoid cells in immunogenic structures of the gastrointestinal tract. Post-stress changes in the cytoarchitectonics of B- and T-cell-dependent areas in mesenteric lymph nodes of animals are less pronounced than in lymphoid nodules. Quantitative changes in lymphoid cells of B-cell-dependent areas in the small intestine of rats are greater than in T-cell-dependent areas. Changes in the cellular composition of immunogenic structures in the digestive system are most significant at the early stages of the post-stress period (1st week). Passive rats are characterized by significant changes in the cytoarchitectonics of B- and Tcell-dependent areas in the small intestine after extreme exposure, which illustrates functional exhaustion of the lymphoid tissue in stress-predisposed specimens.
http://ift.tt/2tdgCvV
Sex Differences in the Production of SLC5A5, Thyroid Peroxidase, and Thyroid Hormones in Pubertal Rats Exposed to Endocrine Disruptor Dichlorodiphenyltrichloroethane (DDT) during Postnatal Ontogeny
Sex differences in the expression of iodide transporter SLC5A5 and thyroid peroxidase in thyroid follicular epithelium and thyroid serum profile were assessed in pubertal rats exposed to endocrine disruptor DDT starting from the first postnatal day. It was found that exposure to DDT reduced expression of SLC5A5 in peripheral regions of thyroid lobes in males and in central regions in females. The most pronounced sex differences were observed in thyroid peroxidase expression that remained sensitive to thyroid stimulating hormone regulation in males and lost sensitivity to pituitary stimulation in females after exposure to disruptor, which determines more pronounced hypothyroidism in females.
http://ift.tt/2FNQWc6
Pumping Function of Heart Ventricles in Different Mammalian Species under Conditions of Electrical Cardiostimulation
Pumping function of the heart ventricles under conditions of electrical stimulation was examined in adult dogs and rabbits. Pacing induced different changes in intracardiac hemodynamics manifested in impairment of pumping function of the right ventricle, which is largely determined by the functional state of the left ventricle. Initially high HR in rabbits more deeply limited functional reserve of the myocardium in response to electrical stimulus and was accompanied by more pronounced disturbances of pumping function of both ventricles.
http://ift.tt/2F746Qh
Effect of Physical Rehabilitation on Echocardiographic Parameters in Patients with Acute Coronary Syndrome
Echocardiographic parameters were assessed in patients with non-ST segment elevation acute coronary syndrome, who underwent emergency percutaneous coronary intervention followed by various outpatient physical cardiac rehabilitation programs. The patients underwent physical rehabilitation for 3 months under conditions of diagnostic centre in the rehabilitation unit according to the standard program including in treadmill or bicycle exercise in the exercise therapy room or with Nordic walking in the main training block. After rehabilitation course, the left ventricular mass index significantly decreased and systolic volume and left ventricular ejection fraction significantly increased in both groups. Nordic walking training for 3 months non-ST segment elevation acute coronary syndrome induced similar positive shifts in the parameters of intracardiac hemodynamics, as standard treadmill or bicycle training program, which allows considering it as an alternative cardiac rehabilitation method.
http://ift.tt/2FKJ7DX
Nootropic Activity of a Novel (-)-Cytisine Derivative (3a R ,4 S ,8 S ,12 R , 12a S ,12b R )-10-Methyl-2-Phenyloctahydro-1 H -4,12a-Etheno-8,12-Methanopyrrolo[3’,4’:3,4]Pyrido[1,2- a ] [1,5]Diazocine-1,3,5(4 H )-Trione
We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with β-endo stereochemistry were more active than α-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3',4':3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively.
http://ift.tt/2teJ3tH
α-Tocopherol Reduces Morphological Changes and Oxidative Stress during Gentamicin-Induced Acute Renal Failure
We studied the effect of α-tocopherol on gentamicin-induced morphological and functional changes in the kidneys of Wistar rats. Special attention was paid to the ability of α-tocopherol administered in combination with gentamicin to correct ultrastructural changes in the glomerular basal membrane and tubules. Combined treatment with α-tocopherol (100 mg/kg) and gentamicin (100 mg/kg) led to correction of histopathological and biochemical changes and oxidative injury to the kidneys induced by this antibiotic.
http://ift.tt/2FMpk7h
Changes in Activity of Cysteine Cathepsins B and L in Brain Structures of Mice with Aggressive and Depressive-Like Behavior Formed under Conditions of Social Stress
We studied activity of lysosomal cysteine proteases, cathepsins B and L, in brain structures (frontal cortex, caudate nucleus, hippocampus, and hypothalamus) of C57Bl/6J mice with aggressive and depressive-like behavior formed under conditions of chronic social stress (repeated experience of victories and defeats within 20 days). Mice with depressive-like behavior showed increased activity of cathepsin В in the hypothalamus and nucleus caudatus and increased activity of cathepsin L in the hippocampus compared to control animals not subjected to agonistic confrontations. In mice with aggressive behavior, protease activity in the studied brain structures was not changed. In 4 h after immune system activation with LPS (250 μg/kg), cathepsin L activity in the hippocampus of control mice increased in comparison with mice receiving saline. In contrast to control animals, LPS caused a decrease in activity of the enzyme in the caudate nucleus and frontal cortex of aggressive mice and in the hippocampus of mice with depressive-like behavior.
http://ift.tt/2tg7DKO
Experimental Simulation of the Effects of Essential and Toxic Trace Elements on Thyroid Function
The effects of essential (I, Se, and Zn) and toxic (Pb and Cd) trace elements on the thyroid function were studied experimentally. The protective effects of iodine, zinc, and selenium on thyroid tissue and antithyroid effects of toxic trace elements promoting a decrease in the levels of thyroid hormones (T3, T4) and imbalance of pituitary hormones (TSH) were detected. Addition of toxic trace elements to the ration of experimental rats led to their accumulation in the thyroid (0.051 μg/g Pb and 0.190 μg/g Cd). Negative correlations between the levels of toxic and essential trace element accumulation in the organ were detected. Essential trace elements zinc and selenium involved in thyroid hormone metabolism promoted normalization of the thyroid function. A complex of essential trace elements (I, Se, and Zn) was recommended for correction of mineral metabolism under conditions of iodine deficiency and thyroid hypofunction and in exposure to toxic trace elements.
http://ift.tt/2FLSXp1
Outcomes of Endoscopic Balloon Dilation vs Surgical Resection for Primary Ileocolic Strictures in Patients with Crohn’s Disease
Few studies have compared endoscopic balloon dilation (EBD) with ileocolic resection (ICR) in the treatment of primary ileocolic strictures in patients with Crohn's disease (CD).
http://ift.tt/2F9c2AG
Associations Among Mucosal and Transmural Healing and Fecal Level of Calprotectin in Children With Crohn’s Disease
Bowel healing is an important goal of therapy for patients with Crohn's disease (CD). Although there have been many studies of mucosal healing, transmural healing (in the bowel wall) has not been investigated in children. We analyzed data from the ImageKids study to determine associations among mucosal and transmural healing and levels of calprotectin and c-reactive protein in children with CD.
http://ift.tt/2tjf3Np
Effects of Treatment of Chronic HBV Infection on Patient-reported Outcomes
Chronic infection with hepatitis B virus (HBV) causes liver disease and cirrhosis. It is not clear how treatment of chronic HBV infection affects patient-reported outcomes (PROs). We aimed to assess changes in PROs in patients treated for chronic HBV infection.
http://ift.tt/2FMM8Uq
KSHV/HHV8-Associated Extracavitary Primary Effusion Lymphoma Presenting as Multiple Lymphomatous Polyposis
Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity usually characterized by presentation as a lymphomatous body cavity effusion in the absence of solid tumor mass or dissemination during its clinical course. PEL can also rarely occur as a solid lymphoma involving nodal and extranodal sites and is referred to as extracavitary PEL. Here we report a unique case of extracavitary PEL in a 49year-old HIV-seropositive patient, who presented with vague abdominal pain and 20 pound weight loss.
http://ift.tt/2GXE7ex
A Case of Syphilitic Hepatitis in an HIV-Infected Patient
While the incidence of syphilis has been persistently on the rise in the United States, hepatitis as a complication of early syphilis is relatively uncommon. We present a case of a 51-year-old homosexual, HIV-positive male who presented with acute cholestatic hepatitis with a predominantly elevated alkaline phosphatase. After lab studies and imaging were unrevealing, a liver biopsy was performed that showed expanded portal tracts with a predominantly lymphoplasmacytic infiltrate and prominent bile ductular proliferation with periductal neutrophils.
http://ift.tt/2FjZmdu
Psychoeducational Intervention for Symptom Management of Fatigue, Pain and Sleep Disturbance Cluster among Cancer Patients: A Pilot Quasi-experimental Study
To assess the feasibility of conducting a trial of a psycho-educational intervention involving the provision of tailored information and coaching to improve management of a cancer-related symptom cluster (fatigue, pain and sleep disturbance) and reduce symptom cluster impacts on patient health outcomes in the Vietnamese context, and to undertake a preliminary evaluation of the intervention.
http://ift.tt/2GZ3UmA
Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma
Distant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)–related oropharyngeal cancers (OPCs); yet, there are few reliable predictors of DM in this disease. The role of quantitative imaging (ie, radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that are associated with a higher risk of DM developing.
http://ift.tt/2FNCTn1
Specialist Advice Support for Management of Severe Hereditary Angioedema Attacks: A Multicenter Cluster-Randomized Controlled Trial
Hereditary angioedema is a rare disease associated with unpredictable, recurrent attacks of potentially life-threatening edema. Management of severe attacks is currently suboptimal because emergency medical teams are often unaware of new specific treatments. The objective of this trial is to test whether a dedicated national telephone care-management strategy would reduce resource use during severe hereditary angioedema attacks.
http://ift.tt/2CVAhAd
Isolation and Characterization of Neutrophil-derived Microparticles for Functional Studies
http://ift.tt/2Fio6Tb
Dissection and Staining of Drosophila Pupal Ovaries
The Drosophila ovary is an excellent model system for studying stem cell niche development. Though methods for dissecting larval and adult ovaries have been published, pupal ovary dissections require different techniques that have not been published in detail. Here we outline a protocol for dissecting, staining, and mounting pupal ovaries.
http://ift.tt/2H0LguS
Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer
BACKGROUND
To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP).
METHODS
Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival.
RESULTS
For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment.
CONCLUSIONS
The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption. Cancer 2018. © 2018 American Cancer Society.
http://ift.tt/2HXouoM
Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research
The incidence and burden of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) is expected to increase for decades, thus motivating discussions regarding possibilities for screening. This article addresses issues related to the validity and timeliness of screening for HPV-driven OPC, and raises important questions, highlights deficits and confusion in the existing literature, and proposes needed steps in the research agenda.
http://ift.tt/2oLKPNv
Neural and behavioral effects of subordinate-level training of novel objects across manipulations of color and spatial frequency
Abstract
Perceptual expertise is marked by subordinate-level recognition of objects in the expert domain. In the present study, participants learned one family of full-color, artificial objects at the subordinate (species) level and another family at the basic (family) level. Discrimination of trained and untrained exemplars was tested before and after training across several image manipulations (full-color, greyscale, low spatial frequency (LSF), and high spatial frequency (HSF)) while event-related potentials (ERPs) were recorded. Regardless of image manipulation, discrimination (indexed by d') of trained and of untrained exemplars was enhanced after subordinate-level training, but not after basic-level training. Enhanced discrimination after subordinate-level training generalized to untrained exemplars and to greyscale images and images in which LSF or HSF information was removed. After training, the N170 and N250, recorded over occipital and occipitotemporal brain regions, were both more enhanced after subordinate-level training than after basic-level training. However, the topographic distribution of enhanced responses differed across components. The N170 latency predicted reaction time after both basic- and subordinate-level training, highlighting an association between behavioral and neural responses. These findings further elucidate the role of the N170 and N250 as ERP indices of subordinate-level expert object processing and demonstrate how low-level manipulations of color and spatial frequency impact behavior and the N170 and N250 components independent of training or expertise.
This article is protected by copyright. All rights reserved.
http://ift.tt/2HXQIQj
Programmed death ligand 1 testing in non–small cell lung carcinoma cytology cell block and aspirate smear preparations
BACKGROUND
Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) receptor and its ligand, programmed death ligand 1 (PD-L1), have emerged as a therapeutic approach for patients with non–small cell lung carcinoma (NSCLC). PD-L1 expression, assessed by immunohistochemistry (IHC), is used to select patients for PD-1/PD-L1 inhibitor therapy. Most studies have been performed with histology specimens, with limited data available on the performance in cytology specimens. This study evaluated PD-L1 in cytology specimens and compared the results with those from paired core-needle biopsy for concordance.
METHODS
Forty-one NSCLC fine-needle aspiration cases that had paired core-needle biopsy specimens with PD-L1 IHC were selected. A Papanicolaou-stained direct smear and a cell block section from each case were stained with a Dako PD-L1 pharmDx antibody (clone 22C3). Only slides with 100 or more tumor cells (37 smears and 38 cell blocks) were evaluated. Tumor proportion scores (TPS) were assessed on the basis of the partial/complete membranous staining of tumor cells and were correlated with those of paired core-needle biopsy.
RESULTS
All 9 smears that were negative for PD-L1 staining showed 100% concordance with the paired core-needle biopsy, whereas 28 smears with PD-L1 expression showed a similar TPS, except for 1 smear that was discordant. In contrast, 10 negative paired core-needle biopsy cases corresponded to 9 concordant negative cell blocks, whereas 1 cell block had a TPS of 1% to 5%. The remaining 28 cell blocks demonstrated PD-L1 expression, with 22 cases showing a TPS similar to that of the paired core-needle biopsy, whereas 6 cell blocks were discordant, likely because of intratumoral heterogeneity.
CONCLUSIONS
The results show that NSCLC cytology samples evaluated for PD-L1 have high concordance with paired core-needle biopsy samples and can be used for assessing PD-L1 expression. Cancer Cytopathol 2018. © 2018 American Cancer Society.
http://ift.tt/2F6F8o1
Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung
Abstract
Background
Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC.
Methods
Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis.
Results
TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively).
Conclusions
The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.
http://ift.tt/2oLevKz
The C-Reactive Protein/Albumin Ratio is a Novel Significant Prognostic Factor in Patients with Malignant Pleural Mesothelioma: A Retrospective Multi-institutional Study
Abstract
Background
Malignant pleural mesothelioma (MPM), a devastating neoplasm, is traditionally considered to be resistant to antitumor therapy. Identification of clinical prognostic indicators is therefore needed. Although the C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis of many types of malignancy, its utility in patients with MPM is unknown.
Methods
The data of 100 patients diagnosed as having MPM from 1995 to 2015 at the National Kyushu Cancer Center and Kyushu University were analyzed. The CAR was calculated as serum C-reactive protein concentration divided by albumin concentration. A cutoff for CAR was set at 0.58 according to a receiver operating characteristics curve for 1-year survival.
Results
Thirty-five of the 100 (35.0%) patients were classified as having a high CAR. A high CAR was significantly associated with advanced clinical stage (p < 0.001) and chemotherapy alone (p = 0.002). Patients with a high CAR had significantly shorter overall survival (OS) (p < 0.001) and disease- or progression-free survival (DFS/PFS) (p < 0.001). These associations between CAR and prognosis remained significant after propensity score-matching. In multivariate analysis, a high CAR was an independent predictor of shorter OS and DFS/PFS (p = 0.003 and p = 0.008, respectively). Multivariate analyses of the subgroups of patients who had received chemotherapy and of patients who had undergone surgery also showed that a high CAR was an independent predictor of shorter OS and DFS/PFS.
Conclusions
CAR is an independent predictor of prognosis in MPM patients. This prognostic index contributes to clinicians' ability to predict benefit from treatment. Further larger, prospective studies are necessary to validate these findings.
http://ift.tt/2FibWtu
The Rationale and Emerging Use of Neoadjuvant Immune Checkpoint Blockade for Solid Malignancies
Abstract
Unprecedented advances in the treatment of cancer have occurred through the use of immunotherapy, with several agents currently approved by the Food and Drug Administration (FDA) for the treatment of widespread metastatic disease across cancer types. Immune checkpoint blockade represents a particularly promising class of agents that block inhibitory molecules on the surface of T cells, resulting in their activation and propagation of an immune response. Treatment with these agents may re-invigorate anti-tumor immunity, resulting in therapeutic responses, and use of these agents currently is being studied in the adjuvant setting. Additionally, a strong rationale exists for their use in the neoadjuvant setting for high-risk resectable disease (e.g., regional nodal disease in the case of melanoma). This rationale is based on the relatively high risk of relapse for these patients, as well as on scientific evidence suggesting that long-term immunologic memory and tumor control may be superior in the setting of treatment for an intact tumor (i.e., neoadjuvant therapy) as opposed to treatment in the setting of micrometastatic disease (e.g., adjuvant treatment). The potential advantages of this approach and the current landscape for neoadjuvant immune checkpoint blockade is discussed in this report, as well as caveats that should be considered by clinicians contemplating this strategy.
http://ift.tt/2F4YzcT
Impact of Micro- and Macroscopically Positive Surgical Margins on Survival after Resection of Adrenocortical Carcinoma
Abstract
Purpose
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer; complete surgical resection offers the best chance for long-term survival. The impact of surgical margin status on survival is poorly understood. Our objective was to determine the association of margin status with survival.
Methods
Patients with ACC were identified from the National Cancer Data Base, 1998–2012, and stratified based on surgical margin status (negative vs. microscopically positive [+] vs. macroscopically [+]). Univariate/multivariate regression/survival analyses were utilized to determine factors associated with margin status and overall survival (OS).
Results
A total of 1553 patients underwent surgery at 589 institutions: 86% had negative, 12% microscopically (+), and 2% macroscopically (+) margins. Those with microscopically (+) and macroscopically (+) margins more often received adjuvant chemotherapy (39.4% macroscopically (+) vs. 38.5% microscopically (+) vs. 25.2% negative margins, p < 0.001). For unadjusted analysis, there was a significant difference in OS between the groups (log-rank p < 0.001), with median survival times of 58 months (95% confidence interval [CI] 49–66) for those with negative margins, 22 months (95% CI 18–34) microscopically (+), and 14 months (95% CI 6–27) macroscopically (+) margins. After adjustment, both microscopically (+) (HR 1.76, p < 0.001) and macroscopically (+) (HR 2.10, p = 0.0019) margin status were associated with compromised survival.
Conclusions
Having micro- or macroscopically (+) margin status after ACC resection is associated with dose-dependent compromised survival. These results underscore the importance of achieving negative surgical margins for optimizing long-term patient outcomes.
http://ift.tt/2FitG8o
Posterior Semicircular Canal Approach for Inner Ear Gene Delivery in Neonatal Mouse
In this study, we describe the posterior semicircular canal approach as a reliable method for inner ear gene delivery in neonatal mice. We show that gene delivery through the posterior semicircular canal is able to perfuse the entire inner ear.
http://ift.tt/2CUpIxg
Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells (NPCs)
http://ift.tt/2F8uT2P
Sleep quality at 3 months postpartum considering maternal age: A comparative study
Publication date: Available online 2 March 2018
Source:Women and Birth
Author(s): Shih-Yi Wen, Yi-Li Ko, Hei-Jen Jou, Li-Yin Chien
BackgroundPoor sleep quality is related to old age among the general population, but few studies have focused on postpartum women of advanced maternal age. The present study aimed to describe and compare sleep quality between women younger or older than 35 years of age at 3 months postpartum, and to examine the related factors.MethodsA cross-sectional survey was conducted with 160 postpartum women who had given birth at a teaching hospital in Taiwan. The participants were assigned to two groups according to age (≥35 years, n=80; and 20–34 years, n=80). Sleep quality was measured using the Pittsburgh Sleep Quality Index with a cut-off score of 5.ResultsThe prevalence of poor sleep quality at 3 months postpartum was higher in older mothers (61.6%) than in younger mothers (38.4%, p<0.01). Multiple logistic regression revealed that poor sleep quality was positively correlated with the severity of postpartum physical symptoms, lack of exercise, and room-sharing with infants. After adjustment for those variables, older mothers were three times more likely to have poor sleep quality than younger mothers (odds ratio=3.08; 95% confidence interval 1.52–6.23).ConclusionHealth care providers should pay attention to sleep problems among postpartum women, especially mothers of advanced maternal age. In particular, health care providers should evaluate sleep quality among postpartum women, instruct them not to share the bed with their infants at night, perform exercise, and manage their postpartum physical symptoms to improve the sleep quality.
http://ift.tt/2CUpx54
Who owns the baby? A video ethnography of skin-to-skin contact after a caesarean section
Publication date: Available online 2 March 2018
Source:Women and Birth
Author(s): Jeni Stevens, Virginia Schmied, Elaine Burns, Hannah G. Dahlen
ProblemProviding skin-to-skin contact in the operating theatre and recovery is challenging.BackgroundBarriers are reported in the provision of uninterrupted skin-to-skin contact following a caesarean section.AimTo explore how health professionals' practice impacts the facilitation of skin-to-skin contact within the first 2h following a caesarean section.MethodsVideo ethnographic research was conducted utilising video recordings, observations, field notes, focus groups and interviews.FindingsThe maternal body was divided in the operating theatre and mothers were perceived as 'separate' from their baby in the operating theatre and recovery. Obstetricians' were viewed to 'own' the lower half of women; anaesthetists were viewed to 'own' the top half and midwives were viewed to 'own' the baby after birth. Midwives' responsibility for the baby either negatively or positively affected the mother's ability to 'own' her baby, because midwives controlled what maternal-infant contact occurred. Mothers desired closeness with their baby, including skin-to-skin contact, however they realised that 'owning' their baby in the surgical environment could be challenging.DiscussionHealth professionals' actions are influenced by their environment and institutional regulations. Further education can improve the provision of skin-to-skin contact after caesarean sections. Skin-to-skin contact can help women remain with their baby and obtain a sense of control after their caesarean section.ConclusionProviding skin-to-skin contact in the first 2h after caesarean sections has challenges. Despite this, health professionals can meet the mother's desire to 'own' her baby by realising they are one entity, encouraging skin-to-skin contact and avoiding maternal and infant separation.
http://ift.tt/2FjvPAD
gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML
gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML
gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML, Published online: 02 March 2018; doi:10.1038/s41419-018-0387-2
gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CMLhttp://ift.tt/2FjAYsn
Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells
Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells
Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cells, Published online: 02 March 2018; doi:10.1038/s41419-018-0396-1
Epigenetic modifiers promote mitochondrial biogenesis and oxidative metabolism leading to enhanced differentiation of neuroprogenitor cellshttp://ift.tt/2CUkQZ0
Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr system
Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr system
Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the <i>agr</i> system, Published online: 02 March 2018; doi:10.1038/s41419-018-0398-z
Inhibiting PSMα-induced neutrophil necroptosis protects mice with MRSA pneumonia by blocking the agr systemhttp://ift.tt/2F4ju3Q
5th International Multithematic Scientific Bio-Medical Congress (IMBMC), Nicosia, Cyprus, 2–4 November 2017
5th International Multithematic Scientific Bio-Medical Congress (IMBMC), Nicosia, Cyprus, 2–4 November 2017
5th International Multithematic Scientific Bio-Medical Congress (IMBMC), Nicosia, Cyprus, 2–4 November 2017, Published online: 02 March 2018; doi:10.1038/s41419-018-0393-4
5th International Multithematic Scientific Bio-Medical Congress (IMBMC), Nicosia, Cyprus, 2–4 November 2017http://ift.tt/2CVzCyD
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice, Published online: 02 March 2018; doi:10.1038/s41419-018-0381-8
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in micehttp://ift.tt/2F6yVZh
Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages
Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages
Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of <i>Fusobacterium nucleatum</i> in THP-1-derived macrophages, Published online: 02 March 2018; doi:10.1038/s41419-018-0389-0
Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophageshttp://ift.tt/2FjADpB
Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy
Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy
Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophy, Published online: 02 March 2018; doi:10.1038/s41419-018-0355-x
Systemic inflammation induced by lipopolysaccharide aggravates inherited retinal dystrophyhttp://ift.tt/2CSOwWA
Left hippocampal dosimetry correlates with visual and verbal memory outcomes in survivors of pediatric brain tumors
BACKGROUND
Radiotherapy (RT) in the pediatric brain tumor population causes late neurocognitive effects. In the current study, the authors investigated associations between clinical and dosimetric risk factors and memory outcomes in a cohort of patients treated with proton radiotherapy (PRT).
METHODS
A total of 70 patients (median age at PRT, 12.1 years [range, 5.0-22.5 years]) who were treated with PRT were identified with baseline and follow-up evaluations of visual and verbal memory (Children's Memory Scale and the third edition of the Wechsler Memory Scale). Whole-brain as well as bilateral hippocampal and temporal lobe contours were delineated for the calculation of dosimetric indices. Multivariate analyses were performed to assess associations of score changes over time with clinical factors and dosimetric indices.
RESULTS
The median neurocognitive follow-up was 3.0 years (range, 1.1-11.4 years). For the entire cohort, delayed and immediate verbal memory scaled scores demonstrated small declines. The mean decline for delayed verbal memory scores was 0.6 (P = .01), and that for immediate verbal memory scores was 0.5 (P = .06). Immediate and delayed visual memory scores were not found to change significantly (+0.1 and -0.3, respectively; P>.30). A higher left hippocampal V20GyE (percentage of the volume of a particular anatomical region receiving at least a 20 gray equivalent) was correlated with a score decline in all 4 measures. Female sex was found to be predictive of lower delayed verbal memory follow-up scores (P = .035).
CONCLUSIONS
Only delayed verbal memory scores were found to have declined statistically significantly at follow-up after PRT, reflecting some weakness in verbal memory retrieval. Given a correlation of left hippocampal dosimetry and memory outcomes after PRT, left hippocampal-sparing PRT plans may assist patients with pediatric brain tumors in preserving memory-retrieval abilities. Cancer 2018. © 2018 American Cancer Society.
http://ift.tt/2oPfQQH
Dose-intensified hypofractionated stereotactic body radiation therapy for painful spinal metastases: Results of a phase 2 study
BACKGROUND
The objective of this study was to prospectively evaluate dose-intensified hypofractionated stereotactic body radiation therapy (SBRT) in patients with painful spinal metastases in a multicenter, single-arm, phase 2 study.
METHODS
Patients with 2 or fewer distinct, noncontiguous, painful, mechanically stable, unirradiated spinal metastases from a solid tumor with a Karnofsky performance status ≥ 60 were eligible. Patients with a long (Mizumoto score ≤ 4) or intermediate overall survival expectancy (Mizumoto score = 5-9) received 48.5 Gy in 10 fractions or 35 Gy in 5 fractions, respectively, with SBRT. The primary outcome was the overall (complete and partial) pain response as measured with international consensus guidelines 3 months after SBRT.
RESULTS
There were 57 patients enrolled between 2012 and 2015, and 54 of these patients with 60 painful vertebral metastases were analyzed. The 3-month pain response was evaluated in 42 patients (47 lesions). An overall pain response was observed in 41 lesions (87%), and the pain response remained stable for at least 12 months. The mean maximum pain scores on a visual analogue scale significantly improved from the baseline of 6.1 (standard deviation, 2.5) to 2.0 (standard deviation, 2.3) 3 months after treatment (P < .001). The 5-level EuroQol 5-Dimension Questionnaire quality-of-life (QOL) dimensions (self-reported mobility, usual activities, and pain/discomfort) significantly improved from the baseline to 3 months after treatment. The 12-month overall survival and local control rates were 61.4% (95% confidence interval [CI], 48%-74.8%) and 85.9% (95% CI, 76.7%-95%), respectively. Grade 3 toxicity was limited to acute pain in 1 patient (2%). No patient experienced radiation-induced myelopathy. Six patients (11%) developed progressive vertebral compression fractures (VCFs), and 8 patients (15%) developed new VCFs.
CONCLUSIONS
Dose-intensified SBRT achieved durable local metastasis control and resulted in pronounced and long-term pain responses and improved QOL. Cancer 2018. © 2018 American Cancer Society.
http://ift.tt/2I0ac74
Breast cancer-specific survival by age: Worse outcomes for the oldest patients
BACKGROUND
Although breast cancer often is perceived to be indolent in older women, breast cancer outcomes in the oldest patients are variable. In the current study, the authors examined breast cancer-specific death by age, stage, and disease subtype in a large, population-based cohort.
METHODS
Using Surveillance, Epidemiology, and End Results data, a total of 486,118 women diagnosed with American Joint Committee on Cancer stage I to IV breast cancer between 2000 and 2012 were identified. Using a series of Fine and Gray regression models to account for competing risk, the authors examined the risk of breast cancer-specific death by age and stage (I-IV) for subcohorts with hormone receptor (HR)-positive, HR-negative, human epidermal growth factor receptor 2-positive, and triple-negative disease, adjusting for demographic and clinical variables.
RESULTS
Overall, 18% of women were aged 65 to 74 years, 13% were aged 75 to 84 years, and 4% were aged ≥85 years. Regardless of stage of disease within the HR-positive and HR-negative cohorts, patients aged ≥75 years (vs those aged 55-64 years) experienced a higher adjusted hazard of breast cancer-specific death, which was particularly evident for those with early-stage, HR-positive disease (hazard ratio for those aged 75-84 years, 1.88 [95% confidence interval, 1.68-2.09] and hazard ratio for those aged ≥85 years, 3.59 [95% confidence interval, 3.12-4.13] [both for stage I disease]). In the cohorts with human epidermal growth factor receptor 2-positive and triple-negative disease, women aged ≥70 years had a consistently higher risk of breast cancer-specific death across disease stages (vs those aged 51-60 years), with the exception of stage IV triple-negative disease.
CONCLUSIONS
Older patients experience worse breast cancer outcomes, regardless of disease subtype and stage. With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority. Cancer 2018. © 2018 American Cancer Society.
http://ift.tt/2oJlp2I
Cancer pain management and the opioid crisis in America: How to preserve hard-earned gains in improving the quality of cancer pain management
Cancer pain remains a feared consequence of the disease and its treatment. Although prevalent, cancer pain can usually be managed through the skillful application of pharmacologic and nonpharmacologic interventions. Unfortunately, access to these therapies has been hampered by interventions designed to contain another serious public health problem: the opioid misuse epidemic. This epidemic and the unintended consequences of efforts to control this outbreak are leading to significant barriers to the provision of cancer pain relief. Oncologists and other professionals treating those with cancer pain will require new knowledge and tools to provide safe and effective pain control while preventing additional cases of substance use disorders (SUDs), helping patients in recovery to maintain sobriety, and guiding those not yet in recovery to seek treatment. How do these 2 serious epidemics intersect and affect oncology practice? First, oncology professionals will need to adopt practices to prevent SUDs by assessing risk and providing safe pain care. Second, oncology practices are likely to see an increased number of patients with a current or past SUD, including opioid misuse. Few guidelines exist for the direct management of pain when opioids may be indicated in these individuals. Third, modified prescribing practices along with the education of patients and families are warranted to prevent the exposure of these medications to unintended persons. Finally, advocacy on behalf of those with cancer pain is imperative to avoid losing access to essential therapies, including opioids, for those who might benefit. Cancer 2018. © 2018 American Cancer Society.
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DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells
DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells
DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells, Published online: 02 March 2018; doi:10.1038/s41416-018-0025-x
DNMTi/HDACi combined epigenetic targeted treatment induces reprogramming of myeloma cells in the direction of normal plasma cells
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Pooled shRNA Screen for Reactivation of MeCP2 on the Inactive X Chromosome
We report a small hairpin RNA (shRNA) and next generation sequencing-based protocol for identifying regulators of X-chromosome inactivation in a murine cell line with firefly luciferase and hygromycin resistance genes fused to the methyl CpG binding protein 2 (MeCP2) gene on the inactive X chromosome.
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Piezo High Accuracy Surgical Osteal Removal (PHASOR): A Technique for Improved Cranial Window Surgery in Mice
Piezoelectric surgery has led to improvements in human maxillofacial and dental surgery. We have developed a protocol to optimize piezoelectric surgery for cranial window surgery in mice.
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Ultra-early occlusion of the normal bile duct after uncovered self-expandable metallic stent placement in unresectable perihilar bile duct cancer
Abstract
Uncovered self-expandable metallic stents (USEMS) are superior to plastic stents in patients with unresectable malignant perihilar biliary obstruction (UMHBO) 1. The causes of SEMS occlusion include: tumor ingrowth/mucosal hyperplasia, tumor overgrowth, sludge with/without stone, hemobilia, food impaction, bile duct kinking, ulceration, perforation, and fibrin clots 2-3. We present a rare case of ultra-early occlusion of the normal bile duct after USEMS placement for UMHBO.
This article is protected by copyright. All rights reserved.
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Overt gastrointestinal bleeding caused by hookworm infection, diagnosed by capsule endoscopy
Abstract
A 60-year-old man was admitted due to a chronic anaemia and intermittent melena since two months ago. Laboratory data revealed: haemoglobin 9.4 g/dl, haematocrit 26%, mean corpuscular volume 78 μm3, white cell count 9500/mm3 with 4% eosinophils. Esophagogastroduodenoscopy and colonoscopy were realized without identifying the bleeding cause.
This article is protected by copyright. All rights reserved.
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Modern Treatments of Haemophilia: Review of Cost-Effectiveness Analyses and Future Directions
Abstract
Background
Cost is currently one of the most important aspects in haemophilia care. Factor concentrates absorb more than 90% of healthcare direct costs of haemophilia care, and the debate regarding the high cost of haemophilia treatments and their different use across different countries is increasing.
Objective
The objective of this study was to review cost-effectiveness analyses conducted on treatment options in haemophilia, focusing on their results and their strengths and limitations; to highlight the possible issues associated with economic evaluations of new treatment options.
Methods
Electronic searches in PubMed and EMBASE were performed to retrieve papers published between November 2015 and September 2017 to update the previous review of economic evaluations of haemophilia treatments by Drummond et al. Reference lists of included articles and reviews were examined for relevant studies, which were assessed for their quality and their empirical results.
Results
Twenty-six relevant economic analyses were identified; 15 (57.7%) were conducted in patients with haemophilia with inhibitors while 11 (42.3%) involved patients without inhibitors. There were methodological variations among the included studies, and differences in the treatment schemes make a comparative assessment of interventions for patients with haemophilia difficult. Only immune tolerance induction showed consistent results in its cost-saving profile compared with the treatment with bypassing agents.
Conclusions
Economic evaluations of haemophilia treatments are increasing, but the identification of general cost-effectiveness trends is still difficult in these studies. We are now facing a new era in haemophilia management with a soaring need for high-quality economic evaluations, performed through proactive collaboration between clinical experts, budget holders and health economists.
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Trifluridine–Tipiracil for Previously Treated Metastatic Colorectal Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf®), to submit evidence for the clinical and cost effectiveness of T/T compared with best supportive care (BSC) for metastatic colorectal cancer (third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company's submission (CS), the ERG report and the development of the NICE guidance for the use of this drug in England and Wales by the appraisal committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of T/T based upon the CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE) showed that T/T resulted in a significant increase in overall survival [OS; hazard ratio (HR) 0.67, 95% CI 0.58–0.78] and progression-free survival (PFS; HR 0.46, 95% CI 0.40–0.53). The AC considered the survival benefit of T/T clinically meaningful although relatively small. The ERG highlighted that none of the participants in the phase II trial and approximately half of the RECOURSE participants (394 of 800) were from Europe, which might limit the applicability of the study findings to the NHS. Moreover, the ERG's critical assessment of the company's economic evaluation highlighted a number of concerns that resulted in 11 adjustments to the company's base-case analysis. The ERG adjustments that had the largest impact were using the RECOURSE trial data only (instead of the pooled evidence), fixing errors and violations and using the utilities from the CORRECT trial (identified in the literature review) only. The ERG preferred to use the RECOURSE trial data only given the suboptimal methodology used by the company to pool the evidence. However, since there were no fundamental arguments to prevent the two trials from being pooled, the ERG also presented its base-case analysis based on the pooled effectiveness estimates. The company base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032 per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392 per QALY gained based on the RECOURSE trial only and pooled evidence, respectively. Since the AC concluded that the most plausible ICER was £49,392 per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as a cost effective use of NHS resources.
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Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.
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IPMNs with co-occurring invasive cancers: neighbours but not always relatives
Objective
Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated.
DesignWe analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient.
ResultsWe analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes.
ConclusionThis study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.
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SLAM family member 8 is involved in oncogenic KIT-mediated signaling in human mastocytosis
Abstract
The signaling lymphocytic activation molecule family member 8 (SLAMF8)/CD353 is a member of the CD2 family of proteins. Its ligand has not been identified. SLAMF8 is expressed by macrophages and suppresses cellular functions. No study has yet explored SLAMF8 expression or function in human mastocytosis, which features oncogenic KIT-mediated proliferation of human mast cells. SLAMF8 protein was expressed in human mastocytosis cells, immunohistochemically. SLAMF8 expression was also evident in the human mast cell lines, HMC1.2 (expressing oncogenic KIT) and LAD2 (expressing wild-type KIT) cells. SLAMF8-knockdown significantly reduced the KIT-mediated growth of HMC1.2 cells but not that of LAD2 cells. SLAMF8-knockdown HMC1.2 cells exhibited significant attenuation of SHP-2 activation and oncogenic KIT-mediated RAS–RAF–ERK signaling. An interaction between SLAMF8 and SHP-2 was confirmed in HMC1.2 cells and all pathological mastocytosis specimens examined (19 of 19 cases, 100%). Thus, SLAMF8 is involved in oncogenic KIT-mediated RAS–RAF–ERK signaling and the subsequent growth of human neoplastic mast cells mediated by SHP-2. SLAMF8 is a possible therapeutic target in human mastocytosis patients.
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IL-26 in allergic contact dermatitis: resource in a state of readiness
Abstract
In this study, we investigated the role of IL-26 in allergic contact dermatitis (ACD), highlighting its contribute in the cytotoxic mechanism responsible of the tissue injury. IL-26 is a signature Th17 cytokine, and immune cells are its predominant sources. Recently, it has shown that Th17 cell-derived-IL-26 functions like an antimicrobial peptide. Here, we hypothesized that IL-26 could be involved in cytotoxicity mechanism, that underlies ACD. Indeed, we have attributed a role to IL-26 in this context, through PBMC cytotoxicity assays versus Hacat. In order to demonstrate that IL-26 was effectively involved in this activity, we performed the assay using transfected ACD PBMCs by siRNA for IL-26. Indeed, we demonstrated that these cells were less able to kill keratinocytes compared to ACD PBMC (p<0.01). In conclusion, our findings support the idea that this emergent cytokine, IL-26, is implicated in the killing mechanisms of KC observed during ACD.
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Dermal fibroblasts can activate matrix metalloproteinase-1 independent of keratinocytes via plasmin in a 3D collagen model
Abstract
Photoaging of the skin is marked by obvious wrinkles and mainly depends on degradation of the extracellular matrix (ECM) in the dermis. Matrix metalloproteinase (MMP)-1 is one of the most important factors involved in degradation of the ECM, however, its mechanism of activation is not fully understood. It has been thought that MMP-1 is expressed by dermal fibroblasts as an inactive precursor protein that is activated by proteinases produced by keratinocytes in the epidermis. In this study, we constructed a 3D model of the dermis using collagen-embedded fibroblasts with or without ultraviolet (UV)-A exposure to mimic photoaging in the dermis. Collagen lattices embedded with UV-A irradiated fibroblasts miniaturized and collagen was degraded to a greater extent than collagen lattices embedded with non-irradiated fibroblasts. The results demonstrate that fibroblasts in this 3D model express activated-MMP-1 in the absence of keratinocytes. Moreover, the results confirm that activation of MMP-1 depends on increased plasmin activity in this model and lattice miniaturization was inhibited by the plasmin inhibitor tranexamic acid. Our results suggest that plasmin acts as an activator of MMP-1 and the inhibition of plasmin prevents collagen degradation.
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The Highly Divergent Mitochondrial Genomes Indicate That the Booklouse, Liposcelis bostrychophila (Psocoptera: Liposcelididae) Is a Cryptic Species
The booklouse, Liposcelis bostrychophila is an important storage pest worldwide. The mitochondrial (mt) genome of an asexual strain (Beibei, China) of the L. bostrychophila comprises two chromosomes; each chromosome contains approximate half of the 37 genes typically found in bilateral animals. The mt genomes of two sexual strains of L. bostrychophila, however, comprise five and seven chromosomes, respectively; each chromosome contains one to six genes. To understand mt genome evolution in L. bostrychophila, and whether L. bostrychophila is a cryptic species, we sequenced the mt genomes of six strains of asexual L. bostrychophila collected from different locations in China, Croatia, and the United States. The mt genomes of all six asexual strains of L. bostrychophila have two chromosomes. Phylogenetic analysis of mt genome sequences divided nine strains of L. bostrychophila into four groups. Each group has a distinct mt genome organization and substantial sequence divergence (48.7–87.4%) from other groups. Furthermore, the seven asexual strains of L. bostrychophila, including the published Beibei strain, are more closely related to two other species of booklice, L. paeta and L. sculptilimacula, than to the sexual strains of L. bostrychophila. Our results revealed highly divergent mt genomes in the booklouse, L. bostrychophila, and indicate that L. bostrychophila is a cryptic species.
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Base-Resolution Analysis of DNA Methylation Patterns Downstream of Dnmt3a in Mouse Naive B Cells
The DNA methyltransferase, Dnmt3a, is dynamically regulated throughout mammalian B cell development and upon activation by antigenic stimulation. Dnmt3a inactivation in hematopoietic stem cells has been shown to drive B cell-related malignancies, including chronic lymphocytic leukemia, and associates with specific DNA methylation patterns in transformed cells. However, while it is clear that inactivation of Dnmt3a in hematopoietic stem cells has profound functional effects, the consequences of Dnmt3a inactivation in cells of the B lineage are unclear. To assess whether loss of Dnmt3a at the earliest stages of B cell development lead to DNA methylation defects that might impair function, we selectively inactivated Dnmt3a early in mouse B cell development and then utilized whole genome bisulfite sequencing to generate base-resolution profiles of Dnmt3a+/+ and Dnmt3a–/– naïve splenic B cells. Overall, we find that global methylation patterns are largely consistent between Dnmt3a+/+ and Dnmt3a–/– naïve B cells, indicating a minimal functional effect of DNMT3A in mature B cells. However, loss of Dnmt3a induced 449 focal DNA methylation changes, dominated by loss-of-methylation events. Regions found to be hypomethylated in Dnmt3a–/– naïve splenic B cells were enriched in gene bodies of transcripts expressed in B cells, a fraction of which are implicated in B cell-related disease. Overall, the results from this study suggest that factors other than Dnmt3a are the major drivers for methylome maintenance in B cell development.
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Unintended Side Effects of Transformation Are Very Rare in Cryptococcus neoformans
Received wisdom in the field of fungal biology holds that the process of editing a genome by transformation and homologous recombination is inherently mutagenic. However, that belief is based on circumstantial evidence. We provide the first direct measurement of the effects of transformation on a fungal genome by sequencing the genomes of 29 transformants and 30 untransformed controls with high coverage. Contrary to the received wisdom, our results show that transformation of DNA segments flanked by long targeting sequences, followed by homologous recombination and selection for a drug marker, is extremely safe. If a transformation deletes a gene, that may create selective pressure for a few compensatory mutations, but even when we deleted a gene, we found fewer than two point mutations per deletion strain, on average. We also tested these strains for changes in gene expression and found only a few genes that were consistently differentially expressed between the wild type and strains modified by genomic insertion of a drug resistance marker. As part of our report, we provide the assembled genome sequence of the commonly used laboratory strain Cryptococcus neoformans var. grubii strain KN99α.
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Genomic Understanding of an Infectious Brain Disease from the Desert
Rhinocladiella mackenziei accounts for the majority of fungal brain infections in the Middle East, and is restricted to the arid climate zone between Saudi Arabia and Pakistan. Neurotropic dissemination caused by this fungus has been reported in immunocompromised, but also immunocompetent individuals. If untreated, the infection is fatal. Outside of humans, the environmental niche of R. mackenziei is unknown, and the fungus has been only cultured from brain biopsies. In this paper, we describe the whole-genome resequencing of two R. mackenziei strains from patients in Saudi Arabia and Qatar. We assessed intraspecies variation and genetic signatures to uncover the genomic basis of the pathogenesis, and potential niche adaptations. We found that the duplicated genes (paralogs) are more susceptible to accumulating significant mutations. Comparative genomics with other filamentous ascomycetes revealed a diverse arsenal of genes likely engaged in pathogenicity, such as the degradation of aromatic compounds and iron acquisition. In addition, intracellular accumulation of trehalose and choline suggests possible adaptations to the conditions of an arid climate region. Specifically, protein family contractions were found, including short-chain dehydrogenase/reductase SDR, the cytochrome P450 (CYP) (E-class), and the G-protein β WD-40 repeat. Gene composition and metabolic potential indicate extremotolerance and hydrocarbon assimilation, suggesting a possible environmental habitat of oil-polluted desert soil.
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Genome-Wide Screen for New Components of the Drosophila melanogaster Torso Receptor Tyrosine Kinase Pathway
Patterning of the Drosophila embryonic termini by the Torso (Tor) receptor pathway has long served as a valuable paradigm for understanding how receptor tyrosine kinase signaling is controlled. However, the mechanisms that underpin the control of Tor signaling remain to be fully understood. In particular, it is unclear how the Perforin-like protein Torso-like (Tsl) localizes Tor activity to the embryonic termini. To shed light on this, together with other aspects of Tor pathway function, we conducted a genome-wide screen to identify new pathway components that operate downstream of Tsl. Using a set of molecularly defined chromosomal deficiencies, we screened for suppressors of ligand-dependent Tor signaling induced by unrestricted Tsl expression. This approach yielded 59 genomic suppressor regions, 11 of which we mapped to the causative gene, and a further 29 that were mapped to <15 genes. Of the identified genes, six represent previously unknown regulators of embryonic Tor signaling. These include twins (tws), which encodes an integral subunit of the protein phosphatase 2A complex, and α-tubulin at 84B (αTub84B), a major constituent of the microtubule network, suggesting that these may play an important part in terminal patterning. Together, these data comprise a valuable resource for the discovery of new Tor pathway components. Many of these may also be required for other roles of Tor in development, such as in the larval prothoracic gland where Tor signaling controls the initiation of metamorphosis.
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Functional Analysis of Cancer-Associated DNA Polymerase {varepsilon} Variants in Saccharomyces cerevisiae
DNA replication fidelity relies on base selectivity of the replicative DNA polymerases, exonucleolytic proofreading, and postreplicative DNA mismatch repair (MMR). Ultramutated human cancers without MMR defects carry alterations in the exonuclease domain of DNA polymerase (Pol). They have been hypothesized to result from defective proofreading. However, modeling of the most common variant, Pol-P286R, in yeast produced an unexpectedly strong mutator effect that exceeded the effect of proofreading deficiency by two orders of magnitude and indicated the involvement of other infidelity factors. The in vivo consequences of many additional Pol mutations reported in cancers remain poorly understood. Here, we genetically characterized 13 cancer-associated Pol variants in the yeast system. Only variants directly altering the DNA binding cleft in the exonuclease domain elevated the mutation rate. Among these, frequently recurring variants were stronger mutators than rare variants, in agreement with the idea that mutator phenotype has a causative role in tumorigenesis. In nearly all cases, the mutator effects exceeded those of an exonuclease-null allele, suggesting that mechanisms distinct from loss of proofreading may drive the genome instability in most ultramutated tumors. All mutator alleles were semidominant, supporting the view that heterozygosity for the polymerase mutations is sufficient for tumor development. In contrast to the DNA binding cleft alterations, peripherally located variants, including a highly recurrent V411L, did not significantly elevate mutagenesis. Finally, the analysis of Pol variants found in MMR-deficient tumors suggested that the majority cause no mutator phenotype alone but some can synergize with MMR deficiency to increase the mutation rate.
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An Overexpressed Q Allele Leads to Increased Spike Density and Improved Processing Quality in Common Wheat (Triticum aestivum)
Spike density and processing quality are important traits in modern wheat production and are controlled by multiple gene loci. The associated genes have been intensively studied and new discoveries have been constantly reported during the past few decades. However, no gene playing a significant role in the development of these two traits has been identified. In the current study, a common wheat mutant with extremely compact spikes and good processing quality was isolated and characterized. A new allele (Qc1) of the Q gene (an important domestication gene) responsible for the mutant phenotype was cloned, and the molecular mechanism for the mutant phenotype was studied. Results revealed that Qc1 originated from a point mutation that interferes with the miRNA172-directed cleavage of Q transcripts, leading to its overexpression. It also reduces the longitudinal cell size of rachises, resulting in an increased spike density. Furthermore, Qc1 increases the number of vascular bundles, which suggests a higher efficiency in the transportation of assimilates in the spikes of the mutant than that of wild type. This accounts for the improved processing quality. The effects of Qc1 on spike density and wheat processing quality were confirmed by analyzing nine common wheat mutants possessing four different Qc alleles. These results deepen our understanding of the key roles of Q gene, and provide new insights for the potential application of Qc alleles in wheat quality breeding.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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