Background. Acute Ischemic Stroke (AIS) is a common cause of death worldwide and the leading cause of long-term severe disability. Endovascular bridging therapies (EBT), including endovascular thrombectomy (ET) and intra-arterial thrombolytic (IAT), have been recommended to realize a favorable functional outcome for AIS patients. Methods. An overview of meta-analyses of primary randomized controlled trial (RCT) studies was performed evaluating EBT for AIS patients compared with usual care. Results. Ten meta-analyses were included in this overview. ET was associated with a higher incidence of achieving functional outcome improvement, defined as a modified Rankin scale of 0 to 1 (mRS, ), 0 to 2 (), and 0 to 3 (). The risk of symptomatic intracranial hemorrhage (sICH) rate and all-cause mortality were similar between the two groups. Moreover, IAT treatment was also related to significantly improved outcomes in terms of the mRS score (), but no significant difference in rates of sICH and mortality within 90 days. Conclusions. In conclusion, our analysis supports that EBT, regardless of format (e.g., ET or IAT), is superior to the best medical therapy alone (e.g., IVT) in terms of mRS score in patients with AIS. In addition, the safety of EBT is similar to IVT.
http://ift.tt/2FtqQNM
Τρίτη 6 Μαρτίου 2018
An Overview of Meta-Analyses of Endovascular Bridging Therapies for Acute Ischemic Stroke
A prospective injury surveillance study in canyoning
Publication date: Available online 6 March 2018
Source:Injury
Author(s): Lukas Ernstbrunner, Eva Schulz, Matthaeus Ernstbrunner, Thomas Hoffelner, Thomas Freude, Herbert Resch, Maximilian Haas
IntroductionLittle is known about injuries in canyoning. It was the purpose of this study to determine injury rates, patterns, causes and risk factors in canyoning; and to identify targets for future injury prevention strategies.MethodsFrom May to October 2015, 109 participants from 17 different countries were prospectively followed via a monthly e-mail-based questionnaire.ResultsDuring 13,690 hours canyoning, 57 injury-events occurred. The overall injury-rate was 4.2 injuries/1,000 hours of canyoning. The hand (23%) and lower leg and foot (25%) were most frequently involved. Most of the injuries were mild (n = 27, 49%) and limited to the soft-tissue. There were seven severe injuries (12%) with two lateral malleolar fractures, both necessitating surgery. The majority of injuries were due to material failure (44%) and significantly more injury-events were reported when the tour included rappelling (p = 0.037). Canyoning guides suffered from significantly less injuries compared to beginners and advanced canyoneers (p<0.001).ConclusionsThe majority of canyoning injuries are mild. On the other side, roughly one-tenth suffered from severe injury. Canyoning guides are less prone to injury-events and beginners should consider performing tours with experienced guides. Notwithstanding, rappelling was the most common activity associated with an injury and the material used was deemed causative for an injury-event in almost half of all cases. Further improvement in canyoning equipment, frequent equipment service, and instructional courses to ensure adequate employment of equipment might minimize the risk of getting injured.
http://ift.tt/2Hc9q5r
Treatment of Danhong Injection Combined with Naoxintong Capsule in Acute Coronary Syndrome Patients Undergoing PCI Operation: Study for a Randomized Controlled and Double-Blind Trial
Objective. This double-blind and randomized placebo-controlled trial evaluated the safety and efficacy of Danhong injection combined with Naoxintong capsule in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods. ACS patients scheduled to undergo PCI were equally and randomly apportioned to either a treatment or control group. After PCI, the treatment group received Danhong injection combined with Naoxintong capsule for 12 weeks, while the control group was given placebo. Both groups were otherwise treated with conventional secondary prevention of coronary artery disease. The groups were primarily evaluated for clinical efficacy and cardiovascular events. Evaluative indicators of safety included adverse events, platelet count, and liver, renal, and blood coagulation functions. Result. No cardiovascular events or adverse reactions were observed in either group. The treatment group demonstrated better signs of clinical efficacy, including left ventricular ejection fraction, higher nitric oxide levels, and lower levels of endothelin-1 (ET-1) and von Willebrand factor (VWF). Conclusion. ACS patients treated with Danhong injection combined with Naoxintong capsule after PCI demonstrated better improvement with regard to markers associated with atherosclerosis and adverse cardiovascular events, without apparent adverse effects. Thus, Danhong injection combined with Naoxintong capsule was safe and effective for treating ACS patients after PCI.
http://ift.tt/2Hcg3Vq
Update on the Treatment of Anaplastic Large Cell Lymphoma
Abstract
Purpose of Review
Given the rarity of anaplastic large cell lymphoma (ALCL), studies evaluating new therapies have typically grouped ALCL together with other peripheral T cell lymphomas (PTCL). Thus, the treatment paradigm for ALCL largely mirrors that of PTCL in general. In this review, we discuss the current standard of care as well as emerging therapies, including antibody-based drugs, in systemic ALCL as well as primary cutaneous and breast implant-associated ALCL.
Recent Findings
High CD30 expression in ALCL has allowed the use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, in both systemic and primary cutaneous ALCL. Recent clinical trials with brentuximab have shown substantial activity in the relapsed/refractory setting. A randomized phase III study is ongoing comparing brentuximab plus CHP (cyclophosphamide, doxorubicin, prednisone) with standard CHOP in the front-line setting.
Summary
The use of targeted therapies and other novel agents have improved outcomes for ALCL patients and in the future can complement or even replace the current standard of care and front-line treatment options.
http://ift.tt/2G3qKtW
Design and Development of Biomimetic Nanovesicles Using a Microfluidic Approach
Abstract
The advancement of nanotechnology toward more sophisticated bioinspired approaches has highlighted the gap between the advantages of biomimetic and biohybrid platforms and the availability of manufacturing processes to scale up their production. Though the advantages of transferring biological features from cells to synthetic nanoparticles for drug delivery purposes have recently been reported, a standardizable, batch-to-batch consistent, scalable, and high-throughput assembly method is required to further develop these platforms. Microfluidics has offered a robust tool for the controlled synthesis of nanoparticles in a versatile and reproducible approach. In this study, the incorporation of membrane proteins within the bilayer of biomimetic nanovesicles (leukosomes) using a microfluidic-based platform is demonstrated. The physical, pharmaceutical, and biological properties of microfluidic-formulated leukosomes (called NA-Leuko) are characterized. NA-Leuko show extended shelf life and retention of the biological functions of donor cells (i.e., macrophage avoidance and targeting of inflamed vasculature). The NA approach represents a universal, versatile, robust, and scalable tool, which is extensively used for the assembly of lipid nanoparticles and adapted here for the manufacturing of biomimetic nanovesicles.
The microfluidic platform NanoAssemblr is used to synthesize biomimetic nanovesicles. This platform enables the high-throughput, reproducible, and scalable production of nanoparticles, without affecting their pharmaceutical and biological properties. The versatility of this approach makes it suitable for good manufacturing practice-compliant manufacture of biomimetic nanoparticles.
http://ift.tt/2FmSnNs
68Ga–Prostate-Specific Membrane Antigen Expression in Neurocysticercosis Lesions in a Patient With Prostate Carcinoma
68Ga–prostate-specific membrane antigen (PSMA) ligand is a well-known tracer used in prostate cancer. Nevertheless, there are reports of unusual 68Ga-PSMA uptake in variety of benign lesions. We report a case of prostate cancer in which 68Ga-PSMA PET/CT revealed tracer avidity in the enhancing walls of cystic lesions in the brain consistent with the features of neurocysticercosis. The uptake of 68Ga-PSMA in neurocysticercosis is not known and may be attributed to angiogenesis occurring at the periphery of these lesions.http://ift.tt/2D5RA1F
Is There Any Potential of FDG PET/CT in Monitoring Disease Activity in Familial Hemophagocytic Lymphohistiocytosis?
FDG PET/CT was performed in a 30-year-old woman to detect the source of fever of unknown origin. The images showed widespread abnormal activity, consistent with lymphoma. However, lymph node biopsy revealed only inflammation, and a diagnosis of familial hemophagocytic lymphohistiocytosis was eventually made after familial hemophagocytic lymphohistiocytosis–specific gene was detected. After proper therapy, a follow-up FDG PET/CT examination 2 months later showed resolution of most of the previously seen lesions.http://ift.tt/2FYI977
SPECT/CT MIBG Imaging Is Crucial in the Follow-up of the Patients With High-Risk Neuroblastoma
Background Planar whole-body imaging with 123I-radiolabeled metaiodobenzylguanidine (123I-MIBG) is routinely used in the follow-up evaluation of neuroblastoma. In recent years, SPECT with integrated low-dose CT (SPECT/CT) has become more accessible. We investigated how much SPECT/CT can have additional diagnostic value over planar imaging in detection of residual and recurrent neuroblastoma. Methods A total of 170 planar 123I-MIBG imaging scans with SPECT/CT follow-up scans performed in 147 patients with known high-risk neuroblastoma were retrospectively analyzed. Regions of increased 123I-MIBG uptake on planar images and the findings on SPECT/CT were compared. Results In 61% of the studies, the whole-body planar images and SPECT/CT images yielded the same result. In 39% of the time, however, SPECT/CT images provided additional information. Conclusions In the follow-up of patients with high-risk neuroblastoma, SPECT/CT can significantly improve planar imaging interpretation and impact patient management.http://ift.tt/2FlnTeJ
Superior Pituitary Border Analysis in Immunotherapy-Induced Hypophysitis
Immunotherapy-induced hypophysitis presents with headache, fatigue, and visual disturbances. The diagnosis is supported by imaging findings of pituitary swelling, enhancement, and hypermetabolism and established by low levels of pituitary hormones. A 64-year-old man with metastatic melanoma on nivolumab presented with a severe headache, initially attributed to sinus disease. Contrast CT was interpreted as minor sinus disease and no pituitary abnormality. Hypophysitis was eventually diagnosed and successfully treated based on PET and laboratory findings. Our retrospective analysis demonstrated abnormal convex superior pituitary border visible on contrast and noncontrast CT and PET. This feature may aid diagnosis in the challenging cases.http://ift.tt/2G0nkZ9
The Findings on Bone Scintigraphy in Patients With Suspected Tumor-Induced Osteomalacia Should Not Be Overlooked
PurposeTumor-induced osteomalacia (TIO) is a chronic, devastating disease. The causative tumor is usually a small benign one that is very difficult to localize. Because the presenting symptoms include diffuse bone pain, a bone scintigraphy is commonly performed to determine the cause of the pain before TIO is suspected. In this retrospective investigation, we tried to assess whether bone scintigraphy acquired will be helpful in the eventual identification of the culprit tumor.MethodsThe images of bone scan and clinical charts of total 91 patients with confirmed TIO were retrospectively reviewed. The image findings were compared with the results of other imaging studies, surgical notes, histopathologic examinations and clinical follow-ups.ResultsIn 76.9% (70 of 91) of the patients, the findings of bone scintigraphy did not correspond to the sites of the causative tumors, which were subsequently located. However, in 23.1% of the patients (21 of 91), the sites of the causative tumors corresponded to one of the abnormal technetium 99m-methyl diphosphonate activity on bone scintigraphy. More importantly, 6 tumors corresponded to the dominant activity on bone scintigraphy.ConclusionsAlthough findings of whole-body scintigraphy are nonspecific in patients with TIO, careful evaluation of bone scintigraphy results can be helpful in guiding further evaluation in some patients. Tumor-induced osteomalacia (TIO) is a chronic, devastating disease. The causative tumor is usually a small benign one that is very difficult to localize. Because the presenting symptoms include diffuse bone pain, a bone scintigraphy is commonly performed to determine the cause of the pain before TIO is suspected. In this retrospective investigation, we tried to assess whether bone scintigraphy acquired will be helpful in the eventual identification of the culprit tumor. Methods The images of bone scan and clinical charts of total 91 patients with confirmed TIO were retrospectively reviewed. The image findings were compared with the results of other imaging studies, surgical notes, histopathologic examinations and clinical follow-ups. Results In 76.9% (70 of 91) of the patients, the findings of bone scintigraphy did not correspond to the sites of the causative tumors, which were subsequently located. However, in 23.1% of the patients (21 of 91), the sites of the causative tumors corresponded to one of the abnormal technetium 99m-methyl diphosphonate activity on bone scintigraphy. More importantly, 6 tumors corresponded to the dominant activity on bone scintigraphy. Conclusions Although findings of whole-body scintigraphy are nonspecific in patients with TIO, careful evaluation of bone scintigraphy results can be helpful in guiding further evaluation in some patients.http://ift.tt/2D3YlB7
18F-Choline PET/MR Can Detect and Delineate Local Recurrence After High-Intensity Focused Ultrasound Therapy of Prostate Cancer
Restaging local recurrence after high-intensity focused ultra-sound (HIFU) is based on multiparametric MRI (mpMRI). However, postinterventional changes of the tissue, such as edema or hemorrhage, are limiting tumor detection on mpMRI. We present a case of a rising prostate-specific antigen values, negative mpMRI, and a Gleason score of 4+4 on template biopsy after HIFU. On 18F-choline PET/MR, high focal uptake was detected at the location of positive biopsy. Re-HIFU based on the fused 18F-choline PET/MR images was performed, followed by a recurrence-free period of 11 months. Thus, 18F-choline PET/MR could improve guiding retreatment in patients with recurrence after HIFU.http://ift.tt/2G3dV3a
Quality and Safety in Health Care, Part XXXIV: The PINNACLE Registry
http://ift.tt/2D5V6sL
SPECT/CT With the PSMA Ligand 99mTc-MIP-1404 for Whole-Body Primary Staging of Patients With Prostate Cancer
Background 99mTc-MIP-1404 (Progenics Pharmaceuticals, Inc, New York, NY) is a novel ligand binding to prostate-specific membrane antigen suitable for SPECT. There are, as yet, no data concerning its use in whole-body primary staging and its interobserver variability in patients with prostate cancer (PC) prior to therapy. Methods A search of our clinical database from April 2013 to May 2017 yielded 93 patients with histologically confirmed cancer in whom 99mTc-MIP-1404 SPECT/CT had been performed for primary whole-body staging before therapy. Whole-body planar and SPECT/CT images of the lower abdomen and thorax had been obtained 3 to 4 hours postinjection of 706 ± 72 MBq 99mTc-MIP-1404. Images were visually analyzed for extent and location of abnormal uptake by 2 experienced nuclear physicians. Interobserver agreement for detection of primary tumor and metastatic lesions was assessed. In addition, SUVs of prostate-specific membrane antigen–positive regions of the prostate were determined in all patients, and from these, a variable reflecting total tumor load in the prostate gland was calculated (TUprostate). Follow-up reports of subsequent therapeutic interventions were available in 52 (56%) of all patients with a median follow-up of 18 months. Results In 90 (97%) of 93 patients, prostate uptake above background was detected as correlate of the histologically diagnosed PC. Forty-eight lymph node and 29 bone metastases were detected in 16 and 9 patients, respectively. In addition, 3 patients had disseminated bone metastases. No distant organ metastases were found. Interobserver agreement was high for the overall scan result (97%), as well as for the detection of the primary tumor (97%), of lymph node metastases (97%), and of bone metastases (99%). Recurrence of PC occurred in 5 patients in whom follow-up was available (10%). TUprostate was significantly higher in patients with Gleason scores of 8 or greater compared with patients with Gleason scores of 7 or less and at prostate-specific antigen (PSA) serum levels of 10 ng/mL or greater compared with PSA serum levels of 10 ng/mL or less. TUprostate of greater than 26 in the primary tumor predicted the occurrence of lymph node or bone metastases with a sensitivity of 82% and specificity of 76%. Conclusions MIP-1404 SPECT/CT has a high accuracy and low interobserver variability in the diagnosis of PC and allows detection of lymph node and bone metastases in a significant proportion of as yet untreated PC patients. TUprostate is correlated with Gleason score and PSA serum concentration and allows prediction of the occurrence of lymph node and bone metastases with moderate accuracy at primary staging.http://ift.tt/2FiZUB9
Adenocarcinoma Prostate With Neuroendocrine Differentiation: Potential Utility of 18F-FDG PET/CT and 68Ga-DOTANOC PET/CT Over 68Ga-PSMA PET/CT
68Ga-PSMA PET/CT is the upcoming imaging modality for staging, restaging and response assessment of prostate cancer. However, due to neuroendocrine differentiation in some of patients with prostate cancer, they express somatostatin receptors instead of prostate specific membrane antigen. This can be exploited and other modalities like 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT should be used in such cases for guiding management. We hereby discuss a similar case of 67-year-old man of adenocarcinoma prostate with neuroendocrine differentiation, which shows the potential pitfall of 68Ga-PSMA PET/CT imaging and benefit of 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT in such cases.http://ift.tt/2FlcFaf
Detecting Intestinal Malrotation on Hepatobiliary Scintigraphy: Making a Case for a Better Standardized Reporting Template
Intestinal malrotation displays classic pattern of the small bowel activity on hepatobiliary scintigraphy that could lead to the diagnosis, but only if an interpreting physician looks for it. Presented are 2 cases, one demonstrates diagnostic findings during the first 60-minute phase, whereas the other reveals the diagnosis only on the later sincalide stimulation phase. The currently recommended structured reporting for hepatobiliary scintigraphy does not include examination of bowel activity pattern, which could result in a missed diagnosis. Including interrogation of the small bowel pattern into the structured reporting checklist would ensure consistent detection of this rare but most consequential diagnosis.http://ift.tt/2FiZE59
Small Lymph Node Metastasis Detected by 68Ga–Prostate-Specific Membrane Antigen But Not 18F-Fluciclovine PET/CT in Low–Prostate-Specific Antigen Biochemical Recurrence of Prostate Cancer
A 58-year-old man with Gleason 4+3 prostate cancer was initially treated by radical prostatectomy followed by salvage radiotherapy to the prostate bed for postoperative biochemical failure. One year later, 18F-fluorocholine PET/CT detected a pelvic lymph node recurrence, which was treated with radiation therapy and 6 months of androgen deprivation. PSA started to rise again 18 months later, but 18F-fluciclovine PET/CT failed to demonstrate the site of recurrence at a PSA of 0.63 ng/mL. However, 68Ga-PSMA PET/CT revealed a single positive 4-mm perirectal lymph node (PSA 0.80 ng/mL at time of scan), in retrospect anatomically apparent but negative on 18F-fluciclovine PET/CT.http://ift.tt/2D5HldR
Amyloid PET Positivity in Different Primary Progressive Aphasia Phenotypes
Purpose Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize 18F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with 18F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" 18F-florbetapir scans. Then, we compare the quantification and distribution of 18F-florbetapir uptake with those of typical, predominantly amnestic AD patients. Methods We conducted a PET study with 18F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic-variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. Results Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was 18F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were 18F-florbetapir positive. A significantly higher 18F-florbetapir uptake was observed in PPA 18F-florbetapir–positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. Conclusions These results suggest that 18F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome.http://ift.tt/2FhpRB4
A Case Series of Molecular Imaging of Glucagonoma After Initial Therapy—68Ga-DOTATATE PET/CT Reveals Similar Results as in Neuroendocrine Tumors of Other Origin in Follow-up and Re-evaluation
Glucagonoma is an extremely rare, glucagon-secreting neuroendocrine tumor of the pancreas. Only sparse data are available about the characteristics of this tumor in somatostatin receptor imaging and only for the situation of initial diagnosis. We present a series of 3 glucagonoma patients who underwent at least 1 68Ga-DOTATATE PET/CT scan. All patients were diagnosed by either histology and/or elevated serum levels of glucagon. The presented cases suggest that somatostatin receptor–based imaging can probably be used for re-evaluation of disease status in patients with glucagonoma in a similar way as it is already established for neuroendocrine tumors of other origin.http://ift.tt/2D7nT04
Pancreatic Malignancy or Not?: Role of 18F-FDG PET/CT in Solving the Diagnostic Dilemma and Evaluating Treatment Response
Immunoglobulin G4–related disease is an autoimmune entity with multisystem involvement. 18F-FDG PET/CT can provide important information about disease extent and severity and also aid in treatment response evaluation. We report a case of a 57-year-old woman presenting with abdominal discomfort, belching, and loss of weight in whom 18F-FDG PET/CT provided valuable information in diagnosis and monitoring treatment response.http://ift.tt/2Ff6Uii
Asthmatic Exacerbation as a Cause of False-Positive Whole-Body Iodine Scan in a Patient With Treated Papillary Thyroid Carcinoma
A 44-year-old woman was found to have new diffuse lung uptake on a follow-up whole-body 131I scan 1 year after being treated with surgery and radioactive iodine for papillary thyroid cancer. However, subsequent CT thorax and thyroglobulin levels were both unremarkable. Shortly after, she presented with respiratory symptoms, exhibiting end-expiratory wheezing on auscultation. Metacholine challenge test confirmed asthma. Symptoms improved under inhaled corticosteroids and beta-2 agonists. Resolution of lung uptake was confirmed on a second 131I imaging 6 months later.http://ift.tt/2D7nsTu
Incidental Detection of Synchronous Lung Melanoma on 18F-FDG PET/CT in a Patient With Parotid Gland Myoepithelial Carcinoma
The detection of synchronous or metachronous malignancies is on the rise with the advent of whole-body 18F-FDG PET/CT. It has shown its utility in detecting second primary carcinoma in patients undergoing imaging for evaluation of primary carcinoma, influencing the management and overall survival. Primary malignant melanoma of the lung is an extremely rare entity, accounting for 0.01% of all lung tumors. It is an even rare occurrence as a synchronous malignancy. We present the case of a 33-year-old woman with primary parotid myoepithelial carcinoma and incidental detection of second primary malignant melanoma of lung during 18F-FDG PET/CT imaging.http://ift.tt/2Fi7qfx
Active Bone Marrow With Focal FDG Accumulation Mimicking Bone Metastasis With a Case of Early Esophageal Cancer
A 68-year-old man underwent 18F-FDG PET/CT for the staging of esophageal carcinoma discovered by a medical checkup. Increased focal accumulation in some vertebrae, right humerus, and right femoral bone was noted on FDG-PET, whereas CT showed relatively high attenuation, and MRI showed hypointense lesions on T1- and T2-weighted imaging. A bone biopsy revealed mildly hypercellular bone marrow in the thoracic spine with FDG accumulation and markedly hypocellular bone marrow in the pelvic bone without an increased uptake. 111InCl scintigraphy showed a similar distribution and confirmed the diagnosis of bone marrow reconversion.http://ift.tt/2FnNTqd
Rare Case of Intratracheal Metastasis Detected on 68Ga–Prostate-Specific Membrane Antigen PET/CT Scan in a Case of Thyroglobulin Elevated Negative Iodine Scan Syndrome
A 64-year-old woman underwent completion thyroidectomy with upper tracheal ring resection and right-sided neck dissection for papillary carcinoma of the thyroid infiltrating the trachea and was given 131I radioiodine treatment. Three years later, she presented with hemoptysis. On evaluation, she had increased serum thyroglobulin and negative iodine scan (TENIS). 18F-FDG PET/CT scan did not identify any site of disease. One year later, 68Ga-PSMA scan done revealed a moderate focal tracer-avid intratracheal soft tissue; biopsy revealed it to be metastatic papillary carcinoma of the thyroid. This case kindles the possibility of using 68Ga-PSMA PET/CT to reveal occult disease in cases of TENIS.http://ift.tt/2FiZquP
Patterns and profiles of Methylphenidate use in both children and adults
Summary
Aim
The aim was to characterize patterns of Methylphenidate (MPH) use in France in both children and adults over a three year period.
Methods
Using the French General Health Insurance database limited to two areas covering approximately 4 million individuals, we made up a cohort of incident MPH users between July 2010 and June 2013. Splitting them into distinct age groups ( [18-24]; [25;49]; >=50 years olds for adults and less than 6 years old, [6-11] and [12;17] for children), we described these populations at MPH initiation and during follow-up according to duration of treatment, quantities dispensed, and co-prescription with Central Nervous System (CNS) drugs.
Results
We included a cohort of 3 534 incident users involving 30 238 dispensations of MPH leading to an annual rate of 29 incident users/ 100 000 in 2013. Children (66% of new users) were characterized by long-term use of MPH with few co-medications. The group of 25-49-year-old patients where more frequently dispensed MPH than other groups, had the highest mean dosage and were more often co-prescribed other CNS drugs. The >=50 years-old group was more often co-prescribed antidepressants and antiparkinsonians.
Conclusions
Our pharmacoepidemiological study involving incident MPH users and a large number of characteristics shows different patterns of MPH use among children and adults. The results among 25-49 years suggest that MPH may be used for medical conditions other than Attention Deficit Hyperactivity Disorder or narcolepsy in adults and that it might be subject to misuse and/or abuse.
http://ift.tt/2tm9bCJ
Retrospective analysis on the clinical outcomes of recombinant human soluble thrombomodulin for disseminated intravascular coagulation syndrome associated with solid tumors
Abstract
Background
Recombinant human soluble thrombomodulin (rTM) has been established and introduced in the clinic as a standard treatment for disseminated intravascular coagulation (DIC). However, the efficacy and safety of rTM for DIC associated with solid tumors (DIC-STs) have not been fully established. Here, we performed a retrospective analysis of the clinical outcomes of rTM for DIC-STs and considered a treatment strategy with rTM for DIC-STs.
Methods
Patients with DIC-STs between November 2009 and March 2016 in 2 cancer core hospitals were retrospectively analyzed. Data, including patient background, treatment course, and clinical outcomes of rTM for DIC-STs, were extracted. The clinical outcomes were evaluated by comparing the DIC score, resolution rate, and overall survival (OS) duration.
Results
The study included 123 patients with DIC-STs. The median OS in all patients was 41 days. The DIC resolution rate was 35.2%. DIC scores and DIC-related blood test data (fibrin degradation product and prothrombin time-international normalized ratio) significantly improved at the end of rTM administration (P < 0.001). The OS duration was longer in patients who were treated with chemotherapy after DIC onset than in those who were not treated with chemotherapy (median, 178 days vs. 17 days, P < 0.001). In both univariate and multivariate analyses, chemotherapy after DIC onset showed the strongest association with OS.
Conclusions
rTM can at least temporarily improve or maintain the state of DIC-STs. It is suggested that prolongation of survival can be expected when control of DIC and treatment of the underlying disease are compatible.
http://ift.tt/2oOC7yD
Head and voice tremor improving with immunotherapy in an anti-NF155 positive CIDP patient
Abstract
Chronic inflammatory demyelinating polyradiculoneuropathy with NF155 antibodies (anti-NF155+) constitutes a specific chronic inflammatory demyelinating polyradiculoneuropathy subset with a high incidence of limb's tremor and poor response to conventional therapies. We report a patient with chronic inflammatory demyelinating polyradiculoneuropathy anti-NF155+ with a severe tremor involving limbs, head and voice that responded very well to rituximab. This response correlated with a sharp decrease in the anti-NF155 titers. This case is the first report associating head and voice tremor to chronic inflammatory demyelinating polyradiculoneuropathy, reinforces the hypothesis of the cerebellar origin of this tremor and provides indirect evidence that the antibodies may be the cause of the tremor in these patients.
http://ift.tt/2FhrAX2
Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury
Abstract
Background
Traumatic cerebrovascular injury (TCVI), a common consequence of traumatic brain injury (TBI), presents an attractive therapeutic target. Because phosphodiesterase-5 (PDE5) inhibitors potentiate the action of nitric oxide (NO) produced by endothelial cells, they are candidate therapies for TCVI. This study aims to: (1) measure cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and change in CVR after a single dose of sildenafil (ΔCVR) in chronic TBI compared to uninjured controls; (2) examine the safety and tolerability of 8-week sildenafil administration in chronic symptomatic moderate/severe TBI patients; and as an exploratory aim, (3) assess the effect of an 8-week course of sildenafil on chronic TBI symptoms.
Methods
Forty-six subjects (31 chronic TBI, 15 matched healthy volunteers) were enrolled. Baseline CBF and CVR before and after administration of sildenafil were measured. Symptomatic TBI subjects then completed an 8-week double-blind, placebo-controlled, crossover trial of sildenafil. A neuropsychological battery and neurobehavioral symptom questionnaires were administered at each study visit.
Results
After a single dose of sildenafil, TBI subjects showed a significant increase in global CVR compared to healthy controls (P < 0.001, d = 0.9). Post-sildenafil CVR maps showed near-normalization of CVR in many regions where baseline CVR was low, predominantly within areas without structural abnormalities. Sildenafil was well tolerated. Clinical Global Impression (CGI) scale showed a trend toward clinical improvement while on sildenafil treatment.
Findings
Single-dose sildenafil improves regional CVR deficits in chronic TBI patients. CVR and ΔCVR are potential predictive and pharmacodynamic biomarkers of PDE5 inhibitor therapy for TCVI. Sildenafil is a potential therapy for TCVI.
http://ift.tt/2FmAVca
Nomograms forecasting long-term overall and cancer-specific survival of patients with oral squamous cell carcinoma
Abstract
Our aim was to establish a "nomogram" model to forecast the overall survival (OS) and cancer-specific survival (CSS) of oral squamous cell carcinoma (OSCC) patients. The clinicopathological data for the 10,533 OSCC patients were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used a credible random split-sample method to divide 10,533 patients into two cohorts: 7046 patients in the modeling cohort and 3487 patients in the external validation cohort (split-ratio = 2:1). The median follow-up period was 32 months (1–119 months). We developed nomograms to predict 5- and 8-year OS and CSS of OSCC patients with a Cox proportional hazards model. The precision of the nomograms was assessed by the concordance index (C-index) and calibration curves through internal and external validation. The C-indexes of internal validation regarding 5- and 8-year OS and CSS were 0.762 and 0.783, respectively. In addition, the external validation's C-indexes were 0.772 and 0.800. Based on a large-sample analysis targeting the SEER database, we established two nomograms to predict long-term OS and CSS for OSCC patients successfully, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.
We successfully established two nomograms predicting overall survival(OS) and cancer-specific survival(CSS) of OSCC patients collected from SEER database. The validation results of the nomograms through the concordance index (C-index) and calibration curves showed that the model were credible, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.
http://ift.tt/2D7aGV3
PAK4 pathway as a potential therapeutic target in pancreatic cancer
Future Oncology, Ahead of Print.
http://ift.tt/2D5Frd3
Background and rationale of the eXalt3 trial investigating X-396 in the treatment of ALK+ non-small-cell lung cancer
Future Oncology, Ahead of Print.
http://ift.tt/2FYvCR7
B cells in multiple sclerosis therapy—A comprehensive review
For decades, B cells were ignored in multiple sclerosis (MS) pathogenesis, and the disease was always regarded as a T cell-mediated disorder. Recent evidence shows that there is an antigen-driven B-cell response in the central nervous system of patients with MS, and memory B cells/plasma cells are detectable in MS lesions. The striking efficacy of B cell-depleting therapies in reducing the inflammatory activity of the disease highlights that B cells may play more pathogenetic roles than expected. B cells express several unique characteristic markers on their surface, for example, CD19, CD20 molecules, that provide selective targets for monoclonal antibodies. In this respect, several B cell-targeted therapies emerged, including anti-CD20 antibodies (rituximab, ocrelizumab, and ofatumumab), anti-CD19 antibody (inebilizumab), and agents targeting the BAFF/APRIL signaling pathway (atacicept, belimumab, and LY2127399). In this review, we discuss, in detail, the immunobiology of B cells and their protective and destructive roles in MS pathogenesis. In the second part, we list the completed and ongoing clinical trials investigating the safety and efficacy of B cell-related monoclonal antibodies in MS.
http://ift.tt/2Fmyark
Discrete-choice experiment to analyse preferences for centralizing specialist cancer surgery services
Background
Centralizing specialist cancer surgery services aims to reduce variations in quality of care and improve patient outcomes, but increases travel demands on patients and families. This study aimed to evaluate preferences of patients, health professionals and members of the public for the characteristics associated with centralization.
Methods
A discrete-choice experiment was conducted, using paper and electronic surveys. Participants comprised: former and current patients (at any stage of treatment) with prostate, bladder, kidney or oesophagogastric cancer who previously participated in the National Cancer Patient Experience Survey; health professionals with experience of cancer care (11 types including surgeons, nurses and oncologists); and members of the public. Choice scenarios were based on the following attributes: travel time to hospital, risk of serious complications, risk of death, annual number of operations at the centre, access to a specialist multidisciplinary team (MDT) and specialist surgeon cover after surgery.
Results
Responses were obtained from 444 individuals (206 patients, 111 health professionals and 127 members of the public). The response rate was 52·8 per cent for the patient sample; it was unknown for the other groups as the survey was distributed via multiple overlapping methods. Preferences were particularly influenced by risk of complications, risk of death and access to a specialist MDT. Participants were willing to travel, on average, 75 min longer in order to reduce their risk of complications by 1 per cent, and over 5 h longer to reduce risk of death by 1 per cent. Findings were similar across groups.
Conclusion
Respondents' preferences in this selected sample were consistent with centralization.
http://ift.tt/2Fgs6EA
Bariatric surgery is associated with increased risk of new-onset inflammatory bowel disease: case series and national database study
Summary
Background
Case series suggest a possible association between bariatric surgery and incident IBD.
Aim
The aim of this study was to evaluate the association between bariatric surgery and new-onset IBD.
Methods
We first conducted a multi-institutional case series of patients with a history of IBD and bariatric surgery. We next conducted a matched case-control study using medical and pharmacy claims from 2008 to 2012 in a US national database from Source Healthcare Analytics LLC. Bariatric surgery was defined by ICD-9 or CPT code. Bariatric surgery was evaluated as recent (code in database timeframe), past (past history V code) or no history. Conditional logistic regression was used to estimate odds ratios (OR) and 95% CI for new-onset IBD, CD and UC.
Results
A total of 15 cases of IBD (10 CD, 4 UC, 1 IBD, type unclassified) with a prior history of bariatric surgery were identified. Most cases were women, had Roux-en-Y surgery years prior to diagnosis and few IBD-related complications. A total of 8980 cases and 43 059 controls were included in our database analysis. Adjusting for confounders, a past history of bariatric surgery was associated with an increased risk of new-onset IBD (OR 1.93, 95% CI 1.34-2.79). However, patients who had recent bariatric surgery did not appear to be at shorter term risk of IBD (OR 0.94, 95% CI 0.58-1.52).
Conclusion
New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies.
http://ift.tt/2oPzWLj
Rb is required for retinal angiogenesis and lamination
Rb is required for retinal angiogenesis and lamination
Rb is required for retinal angiogenesis and lamination, Published online: 06 March 2018; doi:10.1038/s41419-018-0411-6
Rb is required for retinal angiogenesis and laminationhttp://ift.tt/2tkQkrP
Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis
Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis
Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis, Published online: 06 March 2018; doi:10.1038/s41419-018-0412-5
Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsishttp://ift.tt/2oNDRbw
High-Resolution Analysis of the Efficiency, Heritability, and Editing Outcomes of CRISPR/Cas9-Induced Modifications of NCED4 in Lettuce (Lactuca sativa)
CRISPR/Cas9 is a transformative tool for making targeted genetic alterations. In plants, high mutation efficiencies have been reported in primary transformants. However, many of the mutations analyzed were somatic and therefore not heritable. To provide more insights into the efficiency of creating stable homozygous mutants using CRISPR/Cas9, we targeted LsNCED4 (9-cis-epoxycarotenoid dioxygenase4), a gene conditioning thermoinhibition of seed germination in lettuce. Three constructs, each capable of expressing Cas9 and a single gRNA targeting different sites in LsNCED4, were stably transformed into lettuce (Lactuca sativa) cvs. Salinas and Cobham Green. Analysis of 47 primary transformants (T1)and 368 T2 plants by deep amplicon sequencing revealed that 57% of T1 plants contained events at the target site: 28% of plants had germline mutations in one allele indicative of an early editing event (mono-allelic), 8% of plants had germline mutations in both alleles indicative of two early editing events (bi-allelic), and the remaining 21% of plants had multiple low frequency mutations indicative of late events (chimeric plants). Editing efficiency was similar in both genotypes, while the different gRNAs varied in efficiency. Amplicon sequencing of 20 T1 and more than 100 T2 plants for each of the three gRNAs showed that repair outcomes were not random, but reproducible and characteristic for each gRNA. Knockouts of NCED4 resulted in large increases in the maximum temperature for seed germination, with seeds of both cultivars capable of germinating >70% at 37°C. Knockouts of NCED4 provide a whole-plant selectable phenotype that has minimal pleiotropic consequences. Targeting NCED4 in a co-editing strategy could therefore be used to enrich for germline-edited events simply by germinating seeds at high temperature.
http://ift.tt/2oOYWlM
Effect of perioperative opioids on cancer-relevant circulating parameters: mu opioid receptor and TLR4 activation potential, and proteolytic profile
Purpose: To investigate the potential interplay between opioid analgesia and tumour metastasis through modulation of μ opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement pre-operatively and at 3, 6 and 24 h after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. AlphascreenTM cyclic AMP (cAMP) assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue™ hTLR4 were utilised to measure TLR4 activation. Circulating matrix metalloprotease (MMP) and Tissue Inhibitor of Matrix Protease (TIMP) activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Post-operative plasma samples displayed the ability to activate MOR and to inhibit LPS-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was neither correlated to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point.
http://ift.tt/2FhcOQ1
Telatinib is an effective targeted therapy for pseudomyogenic hemangioendothelioma
Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1-FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1-FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib. Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells. Results: Truncated FOSB significantly affected tumor growth in 3D on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (4-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1 and FLT4 signaling and down-regulated SERPINE1, thereby affecting the self-regulation of the fusion gene. Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor, could be a highly specific treatment option for patients with multifocal unresectable PHE.
http://ift.tt/2FjthPz
Toxicity and efficacy of a novel GADD34-expressing oncolytic HSV-1 for the treatment of experimental glioblastoma.
Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives. Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in non-dividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neuro-toxicity evaluation of NG34 was tested by intracerebral inoculation. Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose-response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared to rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model. Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM.
http://ift.tt/2Fh9DI8
Tissue transglutaminase regulates interactions between ovarian cancer stem cells and the tumor niche
Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin β1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/β-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target.
http://ift.tt/2FkYJNj
Extracellular citrate affects critical elements of cancer cell metabolism and supports cancer development in vivo
Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.
http://ift.tt/2FiGvjR
Tight junction protein claudin-2 promotes self-renewal of human colorectal cancer stem-like cells
Post-treatment recurrence of colorectal cancer (CRC), the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSCs). The tight junction (TJ) protein claudin-2 is overexpressed in human CRC where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-FU-based chemotherapy, an outcome in which CSC play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted CRC self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSC and increased their proportion in CRC cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSC towards the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine microRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within CRC stem-like cells, suggesting a potential role for this protein as a therapeutic target in CRC.
http://ift.tt/2D5rV9l
Kite, Sangamo Partner on Gene-Edited Cell Therapies [News in Brief]
Firms will use zinc finger nuclease technology to make autologous and allogeneic CAR T-cell and other cellular treatments.
http://ift.tt/2FkKIzl
Cross-cohort analysis identifies a TEAD4 {leftrightarrow} MYCN positive-feedback loop as the core regulatory element of high-risk neuroblastoma [Research Articles]
High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10 protein transcriptional module - centered around a TEAD4 MYCN positive-feedback loop - emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.
http://ift.tt/2FhPVvL
Genetic mechanisms of immune evasion in colorectal cancer [Research Articles]
To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration, and furthermore, that CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.
http://ift.tt/2D51YXs
Sigmoid Colon Cancer in a Juvenile Patient Without a Family History of Colorectal Cancer
An 18-year-old woman presented with intermittent hematochezia. She had no previous history or family history of cancer. A colonoscopy showed a reddish 5-mm polyp in the sigmoid colon (Figure A). Narrow-band imaging showed a brownish area on the head of the polyp (Figure B), suggestive of NICE type 2. However, the surface and vessel pattern were indicative of NICE type 1 (Figure C). Therefore, we suspected a hyperplastic polyp. However, because of the overlapping features of NICE type 1 and type 2, the optical diagnosis of the polyp would be low-confident.
http://ift.tt/2Ib48ss
Endoscopic Therapy of Jejunal Diphyllobothrium nihonkaiense Infection
A 75-year-old man was referred to our hospital with persistent diarrhea. He had a habit of eating raw salmon, although he did not eat raw meat. In laboratory testing, eosinophilia (2232/μL; normal range, 100–300/μL) was detected. Abnormal findings were not observed on computed tomography. A flat creamy-white worm with numerous tile-like proglottides was found at the ileocecal valve by colonoscopy (Figures A and B). Part of the worm was sampled, and it was identified as Diphyllobothrium nihonkaiense.
http://ift.tt/2oV9D5H
Pharmacokinetics of intravenous mycophenolate mofetil in allogeneic hematopoietic stem cell-transplanted Japanese patients
Abstract
Purpose
Mycophenolate mofetil (MMF) is increasingly used among Japanese patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Because pharmacokinetic data for MMF in the Asian population are limited, we conducted this investigation.
Methods
Intravenous MMF (1000 mg/dose) was administered to 10 patients along with cyclosporine or tacrolimus for 10 days after allo-SCT; it was administered every 8 h in peripheral blood stem cell- and bone marrow-transplanted patients, and every 12 h in cord blood-transplanted patients. MMF was administered orally at the same dose from day 11. Plasma concentrations of mycophenolic acid (MPA) were measured by high-performance liquid chromatography.
Results
The MPA AUC0 − tau was 31.9 ± 3.4, 26.2 ± 2.4, and 21.0 ± 2.2 µg*h/mL, the mean Ctrough was 0.25, 0.35, and 0.37 µg/mL, and the Cmax was 10.8, 9.2, and 5.5 µg/mL on days 2, 9, and 16, respectively. The AUC0 − tau and Cmax were significantly higher after intravenous MMF dosing than after oral MMF dosing. All patients exhibited successful neutrophil engraftments in a median time of 18 days. Grade II acute graft-versus-host disease (GvHD) of the skin was observed in two patients, and one patient developed limited chronic GvHD. Individual cases of transient and curable grade III oral mucositis and diarrhea were observed; however, MMF was not discontinued. No other severe complications or infections were observed.
Conclusions
Intravenously administered MMF was safe and possibly effective in achieving higher MPA plasma concentrations for GvHD prophylaxis after allo-SCT in Japanese patients.
http://ift.tt/2Fl8boc
Development of a pelvic exenteration service at a tertiary referral centre
Background
Over one-third of primary rectal cancers are locally advanced at diagnosis, and local recurrence of rectal cancer occurs at a rate of 3–10% following primary curative resection. Extended resectional surgery, including pelvic exenteration, is the only proven therapy with curative potential in the treatment of these cancers along with many other pelvic malignancies. A microscopically clear resection margin (R0 resection) is the predominant prognostic factor affecting overall and disease-free survival. The extent and complexity of surgery required to achieve an R0 resection is associated with significant risk of morbidity and mortality. The aim of this paper is to show that pelvic exenterations can be performed with acceptable oncological and safe perioperative results in an appropriately resourced specialist centre.
Methods
Data was collected retrospectively for 61 consecutive patients treated between June 2012 and February 2017. This included patient demographics, tumour characteristics, operative, clinical and histological data, length of hospital stay, morbidity and mortality data.
Results
A total of 61 patients underwent surgery. Median age was 57 years (range 27–78 years). Median length of stay was 41 days (range 6–288 days). Median operative time was 624 min (range 239–1035 min); 30-day mortality was 3.3% (n = 2). Resection rates were 91.5% – R0, 6.8% – R1 and 1.7% – R2 resections. Histologically, 86.9% – adenocarcinomas, 3.3% – squamous cell carcinomas and 9.8% – represented by leiomyosarcoma, melanoma, myxoid chondrosarcoma, non-neoplastic processes and undifferentiated carcinoma.
Conclusion
Our experience confirms that radical resectional pelvic surgery can be safely performed with acceptable results during the establishment phase of a dedicated tertiary service.
http://ift.tt/2Fn2Jx1
The impact of ischemia-reperfusion injuries on skin resident murine dendritic cells
Abstract
Pressure ulcers are a chronic problem for patients or the elderly who require extended periods of bed rest. The formation of ulcers is due to repeated cycles of ischemia-reperfusion (IR), which initiates an inflammatory response. Advanced ulcers disrupt the skin barrier, resulting in further complications. To date, the immunological aspect of skin IR has been understudied, partly due to the complexity of the skin immune cells. Through a combination of mass cytometry, confocal imaging and intravital multiphoton imaging, this study establishes a workflow for multidimensionality single cell analysis of skin myeloid responses in the context of IR injury with high spatiotemporal resolution. The data generated has provided us with previously uncharacterized insights into the distinct cellular behavior of resident dendritic cells (DCs) and recruited neutrophils post IR. Of interest, we observed a drop in DDC numbers in the IR region, which was subsequently replenished 48h post IR. More importantly, in these cells, we observe an attenuated response to repeated injuries, which may have implications in the subsequent wound healing process.
This article is protected by copyright. All rights reserved
http://ift.tt/2H8GKdu
Impact of Health Education on Knowledge and Behaviors toward Infectious Diseases among Students in Gansu Province, China
Objectives. Infectious disease knowledge and behaviors are key elements that ensure student health and safety. This study explores the impact of health education on student knowledge and behaviors toward infectious diseases and determines the factors affecting infectious diseases knowledge and behaviors among students in Gansu, China. Methods. A cross-sectional study and three sampling methods were used in two counties, 12 schools, and 32 classes in Gansu, China, from 2012 to 2013. Collected data included the following: (1) sociodemographic characteristics of 2002 students (1001 participants in the intervention group and 1001 in the control group); (2) accuracy of student knowledge and behaviors toward infectious diseases based on comparison of intervention and control groups through test; and (3) mean scores on knowledge and behavior of students with different characteristics toward infectious diseases, as analyzed through analysis of variance (ANOVA). Multiple linear regression was conducted to analyze factors affecting student knowledge and behaviors toward infectious diseases. Results. Statistically significant differences were observed among eight items of infectious disease transmission and treatment knowledge between intervention and control groups . Average accuracies of knowledge and behaviors toward infectious diseases reached 72.23% and 60.03%. Significant differences were observed in six items on student behavior in rural and urban areas . Health education, household register, and county affected scores of student knowledge and behaviors toward infectious diseases . Gender and education level also affected scores of student behaviors toward infectious diseases . Conclusions. Health education contributes to student knowledge and behaviors toward infectious diseases. Students in the control group need intensified health education on infectious diseases. Health education needs to pay particular attention to rural students, all male students, and students at senior high school level living on campus.
http://ift.tt/2FiOOMy
PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC
PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC
PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC, Published online: 06 March 2018; doi:10.1038/bjc.2018.9
PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLChttp://ift.tt/2Fk8rQb
Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition
Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition
Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition, Published online: 06 March 2018; doi:10.1038/bjc.2018.11
Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predispositionhttp://ift.tt/2Fj8yzL
A method for automatic selection of parameters in NTCP modelling
In this study we present a fully automatic method to generate multiparameter normal tissue complication probability (NTCP) models and compare its results with a published model of the same patient cohort.
http://ift.tt/2tlskEX
Scholarly Impact of Student Participation in Radiation Oncology Research
Student authorship rates over time are ill defined. This is an analysis of the effects of student authorship on scholarly impact in radiation oncology by comparing the H-indices of corresponding authors in IJROBP that published with and without student authors in 2006-2014. Students are not a detriment to scholarly productivity; student authorship rates increased and corresponding authors publishing with student authors had higher H-indices compared to those that did not publish with student authors.
http://ift.tt/2tlsfB9
Dock2 in the development of inflammation and cancer
Abstract
An atypical guanine exchange factor, Dock2 is specifically expressed in hematopoietic cells and regulates activation and migration of immune cells through activating Ras-related C3 botulinum toxin substrate (Rac). Dock2 was shown to be critical in the development of various inflammatory diseases, including allergic diseases, HIV infection, and graft rejection in organ transplantation. DOCK2 mutation in infants was recently identified to be associated with T and B cell combined immunodeficiency. Furthermore, Dock2 is involved in host protection during enteric bacterial infection and is also associated with the proliferation of cancer cells. It was also shown that patients with digestive tract cancer had high frequency mutation of DOCK2. This review summarizes the latest research progresses on the role of Dock2 for the development of various inflammatory diseases and cancers, and discusses the potential application of Dock2 modulators for patient treatment.
This article is protected by copyright. All rights reserved
http://ift.tt/2Fnn5Gf
Methylprednisolone Sodium Succinate for Injection 40mg, 125mg, and 1g by Sagent Pharmaceuticals: Recall - High Out of Specification Impurity Results
[Posted 03/06/2018] AUDIENCE: Pharmacy, Risk Manager ISSUE: Sagent Pharmaceuticals, Inc. announced the voluntary nationwide recall of ten lots of Methylprednisolone Sodium Succinate for Injection, USP, 40mg, 125mg, and 1g. A detailed listing of...
http://ift.tt/2FlZAO7
Autonomic Dysfunction in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia Impairs Physiological Responses to Routine Care Events
To evaluate whether infants with hypoxic-ischemic encephalopathy and evidence of autonomic dysfunction have aberrant physiological responses to care events that could contribute to evolving brain injury.
http://ift.tt/2oNUyU9
Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial
To evaluate in a randomized, double-blind, placebo-controlled trial the effect of early caffeine on the age of first successful extubation in preterm infants.
http://ift.tt/2ttgGIr
Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis
To establish baseline trends in fecal calprotectin, a protein excreted into the stool when there is neutrophilic inflammation in the bowel, in infants at risk for necrotizing enterocolitis (NEC).
http://ift.tt/2tjlTlZ
Questions regarding relative merit of ultrasonography compared with chest radiograph to detect pneumonia
We read with great interest the report by Ambroggio et al on the role of lung ultrasonography compared with chest radiograph for detecting pneumonia in children with respiratory symptoms.1 This adds interesting data to increasing evidence2-5 showing that ultrasonography can provide a viable alternative to chest radiograph for assessing pediatric pneumonia.
http://ift.tt/2oNuJn7
Methylprednisolone Sodium Succinate for Injection 40mg, 125mg, and 1g by Sagent Pharmaceuticals: Recall - High Out of Specification Impurity Results
[Posted 03/06/2018] AUDIENCE: Pharmacy, Risk Manager ISSUE: Sagent Pharmaceuticals, Inc. announced the voluntary nationwide recall of ten lots of Methylprednisolone Sodium Succinate for Injection, USP, 40mg, 125mg, and 1g. A detailed listing of...
http://ift.tt/2FlZAO7
Characterization of Immune Cells in Human Adipose Tissue by Using Flow Cytometry
This article describes a method to analyze immune cell content of adipose tissue by isolation of immune cells from adipose tissue and subsequent analysis using flow cytometry.
http://ift.tt/2I6mMla
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
http://ift.tt/2oUww9k
Opportunities for Prevention and Intervention of Opioid Overdose in the Emergency Department
Consider "Jane," a 30-year-old female patient brought in by emergency medical services (EMS) to the emergency department (ED), reflecting just one of more than 100,000 opioid overdose patients treated in EDs each year. Naloxone, an opioid antagonist and overdose reversal drug, was administered in the field by EMS; however, additional rounds of naloxone were required in the ED because of high opioid potency. Once she was stabilized, a quick review of her chart revealed several recent visits for opioid-related overdoses.
http://ift.tt/2I7iVV5
Sampling Strategies and Processing of Biobank Tissue Samples from Porcine Biomedical Models
The practical application and performance of methods for generation of representative tissue samples of porcine animal models for a broad spectrum of downstream analyses in biobank projects are demonstrated, including volumetry, systematic random sampling, and differential processing of tissue samples for qualitative and quantitative morphologic and molecular analyses types.
http://ift.tt/2FlD1sF
Imaging Intermediate Filaments and Microtubules with 2-dimensional Direct Stochastic Optical Reconstruction Microscopy
The overall goal of this methodology is to give the optimal experimental conditions from sample preparation to image acquisition and reconstruction in order to perform 2D dual color dSTORM images of microtubules and intermediate filaments in fixed cells
http://ift.tt/2FXPBPS
Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 305-319
http://ift.tt/2oV7arL
Interaction of the middle domains stabilizes Hsp90α dimer in a closed conformation with high affinity for p23
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 337-345
http://ift.tt/2oUj5pU
How human serum albumin recognizes DNA and RNA
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 347-360
http://ift.tt/2I7AaoU
In vitro reconstitution and biochemical characterization of human phospholipid scramblase 3: phospholipid specificity and metal ion binding studies
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 361-374
http://ift.tt/2oYMXSb
LncRNA KCNQ1OT1 ameliorates particle-induced osteolysis through inducing macrophage polarization by inhibiting miR-21a-5p
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 375-386
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LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 387-395
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High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3
Journal Name: Biological Chemistry
Volume: 399
Issue: 4
Pages: 397-406
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Ustekinumab for Treating Moderately to Severely Active Crohn’s Disease after Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
Abstract
As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Janssen to submit evidence on the clinical and cost effectiveness of their drug ustekinumab, an interleukin-12/23 inhibitor, for treating moderate-to-severe active Crohn's disease (CD). The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the Company's submission, the ERG's critical review of submitted evidence, and the resulting NICE guidance. The main supporting clinical evidence was derived from four well conducted, randomised controlled trials, comparing ustekinumab with placebo in two sub-populations (conventional care failure and anti-TNFα failure patients) of adults with moderate-to-severe CD. Three trials assessed treatment induction over 8 weeks, while the fourth recruited successfully induced patients into a maintenance trial for 1 year. These trials showed ustekinumab to be more effective than placebo in terms of its ability to induce and maintain clinical response and remission. In the absence of any direct head-to-head data, the Company conducted a network meta-analysis (NMA), which synthesised induction trial data on ustekinumab and relevant comparators (vedolizumab, adalimumab and infliximab) using placebo data as a common comparator. This analysis found ustekinumab to be of comparable efficacy to previously approved biologics in treatment induction. A 'treatment sequence analysis' compared long-term treatment efficacy, finding ustekinumab to be comparable in maintaining treatment response and remission to the three other biologic therapies. However, the ERG had identified many limitations and potential bias in this analysis, and urged caution when interpreting the results. The Company's economic model estimated ustekinumab to be dominant in both sub-populations compared with conventional care; however, the ERG's preferred base-case estimated an incremental cost-effectiveness ratio of £109,279 in the conventional care failure sub-population, and £110,967 in the anti-TNFα failure sub-population when compared with conventional care. However, the ERG identified significant failings in both the model structure and data inputs, which could not be addressed without complete restructuring. The ERG considered that the economic analysis presented by the Company failed to adequately address the decision problem specified in NICE's scope. The NICE Appraisal Committee recommended ustekinumab within its market authorisation, on the grounds of sufficiently similar efficacy and costs to previously recommended biologic therapies. However, the ERG's analyses demonstrated that all currently recommended biologics are unlikely to be cost effective relative to conventional care, raising broader questions regarding the appropriateness of cost-comparison exercises for decision making.
http://ift.tt/2FrOJW7
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Exposure to environmental toxicants can acutely impact development with long-term effects. Detailed protocols are provided to illustrate a strategy using an effective lab model to study the effect of early embryonic exposure to bisphenol A. We provide fecundity and behavioral assays to monitor the effectiveness of our toxicant exposure bio-assays.
http://ift.tt/2FkVMwq
Surgical Treatment for Benign Prostatic Hyperplasia: Holmium Laser Enucleation of the Prostate (HoLEP).
Here we present a safe and efficient protocol, holmium laser enucleation of the prostate, to treat benign prostatic hyperplasia.
http://ift.tt/2FjZ4E0
Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers
Abstract
Purpose
It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy.
Experimental design
Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients' primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor-specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration.
Results
There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005).
Conclusions
Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy.
http://ift.tt/2Flq81L
Abracadabra
The hallways of the Emergency Department are filled with patients during influenza season. Our patient is rushed to imaging with work-boots left-behind as his placeholder.
This article is protected by copyright. All rights reserved.
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Development of an anesthetized rat model of exercise hyperpnoea: An integrative model of respiratory control using an equilibrium diagram
New Findings
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What is the central question of this study?
The lack of useful small animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states.
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What is the main finding and its importance?
We developed an anesthetized rat model for studying exercise hyperpnoea, using respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models.
Abstract
Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of the respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiologic basis in various disease models, the lack of integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anesthetized rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data, and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO2 pressure (PETCO2) and minute ventilation (VE), and the plant by the hyperbolic relationship between VE and PETCO2. During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen output. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points (VE and PETCO2) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anesthetized rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models.
This article is protected by copyright. All rights reserved
http://ift.tt/2G1ykVW
A short-term in vivo model for Merkel Cell Carcinoma
Abstract
In vivo tumour models are essential for studying the biology of cancer, identifying tumour targets and evaluating anti-tumour drugs. Considering the request for the minimization of animal experiments and following the „3R"-rule („replacement", „refinement", „reduction"), it has become crucial to develop alternative experimental models in cancer biology. Several studies have already described the avian chorioallantoic membrane (CAM) model as an alternative to rodents, suitable to investigate growth, progression and metastasis of various types of cancer. In the present work, we grafted three Merkel Cell Carcinoma (MCC) cell lines onto the avian CAM and monitored tumour growth and development of solid tumour nodules. Morphology of xenograft was characterized histologically and immunohistochemically. Our results demonstrate CAM assay as a useful tool to study MCC pathophysiology.
This article is protected by copyright. All rights reserved.
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Myosin 10 is involved in murine pigmentation
Abstract
Myosins are molecular motors that are well known for their role in cell movement and contractile functions. Although extensively studied in muscle physiology, little is known about the function of myosins in mammalian skin. As part of the Sanger Institute Mouse Genetic Project, we have identified a role for Myo10 in pigmentation, with a phenotype unlike those of Myo5a or Myo7a. Adult mice homozygous for a disrupted Myo10 allele on a C57BL/6N background displayed a high degree of penetrance for white patches on their abdomen and dorsal surface. Fore- and hind paw syndactyly was also observed in these mice. Tail epidermal wholemounts showed a complete lack of melanocytes in the hair follicles and interfollicular epidermis. Myo10 previously been implicated in human pigmentation. Our current study reveals involvement of Myo10 in murine pigmentation.
This article is protected by copyright. All rights reserved.
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Capsaicin induces atopic dermatitis-like manifestations through dysregulation of proteolytic system and alteration of filaggrin processing in rats
Abstract
Atopic dermatitis (AD) is a complex disease featuring pruritic skin inflammation. Many animal models have been developed. In a rat model, subcutaneous capsaicin injection within 48 hours after birth induces AD-like skin manifestations of dermatitis and scratching behavior 3 weeks after the injection. When 2-4-week-old rats were injected with capsaicin, the lag period was shortened and the severity of skin manifestations was significantly reduced, suggesting influences of postnatal development. Lgr6 is an epidermal stem cell marker that is normally restricted to the isthmus area of hair follicles at postnatal 2 weeks. Lgr6 persisted in the interfollicular epidermis of capsaicin-injected rats beyond 3 weeks after birth, indicating that capsaicin-induced skin manifestations were influenced by postnatal epidermal development. Capsaicin injection induced alteration of proteolytic processing of filaggrin and corneodesmosin, suggesting epidermal barrier dysfunction. Inappropriate degradation of matriptase was observed. Degrees of proteolysis of these proteins were co-related with the severity of manifestations, suggesting that inappropriate proteolysis might be a possible cause of the skin manifestations. The results strongly suggest that capsaicin may dysregulate the protease system, resulting in alteration of profilaggrin and corneodesmosin proteolysis and skin manifestations. These events may be influenced by postnatal epidermal development.
This article is protected by copyright. All rights reserved.
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Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs that Orchestrate the Rapid Recall Response of Memory CD8+ T Cells
How glucose metabolism enables rapid acquisition of effector function in memory CD8+ T cells remains poorly understood. Bantug et al. demonstrate that mitochondria-endoplasmic reticulum contact sites are signaling hubs that enable the metabolic reprogramming required for rapid CD8+ T cell recall responses.
http://ift.tt/2G07yxw
Predictors for Use of Sentinel Node Biopsy and the Association with Improved Survival in Melanoma Patients Who Have Nodal Staging
Abstract
Background
It is unknown how many patients with localized melanoma undergo sentinel lymph node biopsy (SLNB) or if there is a therapeutic effect from performing nodal staging. We evaluated predictors for SLNB use and assessed if there was an association with improved survival in melanoma patients who had SLNB.
Methods
The Surveillance, Epidemiology, and End Results database was queried for clinically node-negative melanoma cases ≥ 0.75 mm in thickness treated from 2010 to 2012. Clinicopathologic factors were correlated with SLNB use, overall survival (OS), and melanoma-specific survival (MSS).
Results
Overall, 13,703 cases were included. SLNB was performed in 1479 of 3439 thin cases (43.0%), 5810 of 8522 intermediate-thickness cases (68.2%), and 916 of 1742 thick cases (52.6%). On multivariable analysis, age ≥ 70 years, thickness < 1 or > 4 mm, head/neck or trunk tumor location, being unmarried, African American race, and residing in a county with a lower level of education were significantly associated with a lower likelihood of performing SLNB (p < 0.05). Patients with intermediate-thickness or thick melanoma who had a SLNB had significantly improved OS and MSS compared with patients who did not have a SLNB (p < 0.05). On multivariable analysis, SLNB use significantly predicted for improved OS and MSS (p < 0.01).
Conclusions
Only 68.2% of intermediate-thickness and 52.6% of thick melanomas are treated with SLNB. Age, thickness, tumor location, race, marital status, and socioeconomic factors appear to influence the performance of SLNB. This data becomes more relevant with the finding that SLNB use is potentially associated with improved survival.
http://ift.tt/2I8Dr7u
Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas
Abstract
Background
The optimal treatment of high-risk soft tissue sarcomas (STS) of the extremities remains controversial. We report follow-up from a phase II study of dose-intense chemotherapy with preoperative hypofractionated radiation in this population supplemented with subsequent data from an extensive institutional experience using this regimen.
Methods
Patients with localized, intermediate- or high-grade STS of the extremity or body wall measuring > 5 cm were treated with epirubicin 30 mg/m2/day and ifosfamide 2.5 g/m2/day on days 1–4 every 21 days for 3 preoperative and 3 postoperative cycles. During cycle 2 of preoperative therapy, epirubicin was omitted, and a total of 28 Gy of radiation (8 fractions) was delivered. Twenty-five patients were treated on the phase II study (2002–2005). Fifty-one additional patients were identified from a retrospective chart review (2005–2014).
Results
The 5-year rates for overall survival, distant disease-free survival, and freedom from local regional failure were 70.4% (95% CI 59.2–83.7%), 55.9% (95% CI 44.5–70.2%), and 87.2% (95% CI 77.9–96.5%) respectively. Thirty-eight percent of tumors (29/76) demonstrated ≥ 90% pathologic response. Wound complications occurred in 32% (24/76) of patients.
Discussion
Treatment with preoperative radiation and pre- and post-operative epirubicin and ifosfamide was associated with favorable clinical outcomes. Survival and recurrence rates were comparable to those reported with other preoperative chemotherapy regimens in high-risk extremity sarcomas. Use of trimodality therapy should be considered for appropriate high-risk STS patients.
http://ift.tt/2oTpJwx
Dialysis Increases the Risk of Bladder Recurrence in Patients with Upper Tract Urothelial Cancer: A Population-Based Study
Abstract
Background
The relation of dialysis to tumor recurrence in patients with upper tract urothelial cancer (UTUC) is unknown; however, a limited number of small-scale studies suggest that patients with renal diseases prior to UTUC are more likely to exhibit bladder recurrence. We performed a population-based analysis to determine the effect of dialysis on bladder recurrence for patients with UTUC.
Methods
This retrospective cohort study included patients diagnosed with UTUC (2002–2007) from the Taiwan National Cancer Registry and divided them into two groups—dialysis and non-dialysis groups. These patients were followed up until bladder recurrence, death, or the end of 2010. Competing risk analyses adjusting covariates and death were applied to determine the relation of dialysis and bladder recurrence.
Results
Of the 5141 eligible patients, 548 (10.7%) were undergoing dialysis. The cumulative bladder recurrence was significantly higher in the dialysis group than in the non-dialysis group (29% vs. 21%, modified log-rank p < 0.001). In the multivariable analysis, the dialysis group exhibited a 64% increased bladder recurrence risk (cause-specific hazard ratio 1.64, 95% confidence interval 1.34–2.01, p < 0.001), which was confirmed using stratification and propensity score weighting methods. The other prognostic factors for bladder recurrence were sex, diabetes, cardiac disorder, Charlson Comorbidity Index, and tumor grade.
Conclusions
Despite unknown reasons, approximately one-tenth of patients with UTUC have experienced dialysis treatment. Patients undergoing dialysis have a higher risk of bladder recurrence. Various treatment and screening strategies should be developed for dialysis and non-dialysis patients.
http://ift.tt/2I7jkGL
Laparoscopic-Assisted Modified Intersphincter Resection for Ultralow Rectal Cancer
Abstract
Background
Intersphincter resection (ISR) is considered to be a superior technique offering sphincter preservation in patients with ultralow rectal cancer.1 Because high-definition laparoscopy offers wider and clearer vision into the narrow pelvic cavity and intersphincteric space, ISR has been further refined.2 However, functional outcome after ISR has not been optimal. More than half of patients receiving ISR suffer partial or even complete anal incontinence.3 We therefore propose a laparoscopic-assisted modified ISR, with the aim of improving sphincter function following ISR.
Methods
The video describes the technique for performing such laparoscopic-assisted modified ISR in a 62-year-old woman with ultralow rectal cancer (3 cm from anal verge). Preoperative staging by endorectal ultrasound and pelvic magnetic resonance imaging revealed stage I rectal cancer (cT2N0M0). The operation consisted of an abdominal and a perineal phase. The abdominal phase routinely involved colonic mobilization with high ligation of inferior mesenteric vessels, total mesorectal excision (TME), as well as transabdominal intersphincteric dissection. The procedure for laparoscopic TME was performed according to our published method.4 Along the TME dissection plane, the puborectalis could be reached and the intersphincteric space was entered posterolaterally. The hiatal ligament at the posterior side of the rectum was transected afterwards. The dissection of the intersphincteric space was continued caudally at the anterior side of the rectum. The distal bowel wall was mobilized for 2 cm from the lower edge of the tumor to obtain adequate distal margin. At this point, circular dissection of the intersphincteric space was completed. After the abdominal phase, perineal dissection was performed with wide exposure by use of a hooked self-retaining retractor. The lower margin of the tumor was identified under direct vision. We developed a modified ISR technique. Resection of the mucosa and internal sphincter was initiated 2 cm distal to the lower edge of the tumor at the tumor side to obtain the necessary distal margin. Meanwhile, at the opposite side of the tumor, the resection line was just above the dentate line so that partial dentate line could be preserved. After removal of the specimen en bloc per anus, the pelvic cavity was generously irrigated with diluted povidone iodine solutions. The distal margin of the specimen was then examined by frozen section for presence of cancer. If clear, coloanal anastomosis was performed using a handsewn technique. The colon was rotated 90° and anastomosed to the anal canal with interrupted absorbable 3–0 sutures. Finally, a pelvic suction drain was placed, and a temporary diverting stoma made in the terminal ileum.
Results
There were no intraoperative complications. The operating time was 180 min. Blood loss was 50 mL. The distal margin was clear, and the final pathology was pT2N0M0. The patient underwent an uneventful recovery. She began sphincter-strengthening exercises 2 weeks after surgery. The stoma was closed after examinations 3 months later. No local recurrence or distant metastasis was found. At 12-month follow-up, in terms of sphincteric function, the patient was continent to solids, liquids, and flatus.
Conclusions
Laparoscopic-assisted modified intersphincter resection for ultralow rectal cancer is safe and feasible. This technique should be considered whenever possible as a means to offer sphincter preservation and improve sphincter function in patients with ultralow rectal cancer.
http://ift.tt/2oUoXzd
Chemotherapy with or Without Definitive Radiation Therapy in Inoperable Pancreatic Cancer
Abstract
Background
The LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC.
Methods
Using the NCDB, patients with American Joint Committee on Cancer (AJCC) clinical stage T2–4, N0–1, M0 adenocarcinoma of the pancreas from 2004 to 2014 were analyzed. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions or ≥ 5 Gy per fraction [i.e., stereotactic body radiation therapy (SBRT)] were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively.
Results
13,004 patients met inclusion criteria, of whom 7034 (54%) received CT and 5970 (46%) received CRT. After PSM, 5215 patients remained in each cohort. The CRT cohort demonstrated better overall survival (OS) compared with CT alone, with median and 1-year OS of 12 versus 10 months, and 50% and 41%, respectively (p < 0.001). On multivariable analysis, CRT was associated with superior OS with hazard ratio of 0.79 (95% confidence interval 0.76–0.83) compared with CT alone.
Conclusions
In our series, addition of definitive radiotherapy to CT was associated with better OS when compared with CT alone in LAPC. Definitive radiotherapy should remain a treatment option for LAPC, but optimal selection criteria remain unclear.
http://ift.tt/2I7jaPF
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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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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
