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Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn's Disease and Ulcerative Colitis. - Inflammatory bowel diseases
Optimal levels of adalimumab (ADA) have not been defined according to the ultimate goal of inflammatory bowel disease treatment-histologic and/or endoscopic healing. The aim of this study was to assess the relationship between random serum ADA levels and histologic and endoscopic healing in patients with inflammatory bowel disease.This was a cross-sectional study including 66 patients receiving maintenance therapy with ADA for Crohn's disease or ulcerative colitis. ADA levels and anti-adalimumab antibodies (AAA) were measured at the time of colonoscopy. The primary outcome was histologic healing (lack of endoscopic and histologic inflammation) and the secondary outcomes were endoscopic healing and serum levels of C-reactive protein, tumor necrosis factor, ICAM, VCAM, and interleukins 1Î², 6, and 8.Sixty-six patients (59 with Crohn's disease) were included. Mean random ADA levels were significantly lower in patients with histologic and endoscopic inflammation (9.2 [SD: 8.4] versus 14.1 [6.4] Î¼g/mL, P = 0.03 and 8.5 [SD: 7.8] versus 13.3 [SD: 7.7], P = 0.02, respectively). The ADA level that was best associated with histologic healing was 7.8 Î¼g/mL (receiver operating characteristic: 0.76 [P = 0.04]), whereas the ADA level that was best associated with endoscopic healing was 7.5 Î¼g/mL (receiver operating characteristic: 0.73 [P = 0.02]). The presence of AAA was associated with lower random ADA levels (5.7 versus 12.5 Î¼g/mL, P = 0.002) and higher C-reactive protein levels (30.3 versus 12.0, P = 0.01).Achievement of histologic and endoscopic healing may require higher levels of ADA than previously described for endoscopic remission. The measurement of random ADA levels and anti-drug antibodies may guide therapy and edify the course of incomplete responses.
Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer. - Oncotarget
Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30-40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response.We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment.As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild-type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 (p = 0.0001), 0.5 vs. 9.3 (p = 0.0006) and 1.0 vs. 11.2 months (p = 0.0008), respectively.The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors.
Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. - JAMA
Despite research showing no link between the measles-mumps-rubella (MMR) vaccine and autism spectrum disorders (ASD), beliefs that the vaccine causes autism persist, leading to lower vaccination levels. Parents who already have a child with ASD may be especially wary of vaccinations.To report ASD occurrence by MMR vaccine status in a large sample of US children who have older siblings with and without ASD.A retrospective cohort study using an administrative claims database associated with a large commercial health plan. Participants included children continuously enrolled in the health plan from birth to at least 5 years of age during 2001-2012 who also had an older sibling continuously enrolled for at least 6 months between 1997 and 2012.MMR vaccine receipt (0, 1, 2 doses) between birth and 5 years of age.ASD status defined as 2 claims with a diagnosis code in any position for autistic disorder or other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (International Classification of Diseases, Ninth Revision, Clinical Modification 299.0x, 299.8x, 299.9x).Of 95,727 children with older siblings, 994 (1.04%) were diagnosed with ASD and 1929 (2.01%) had an older sibling with ASD. Of those with older siblings with ASD, 134 (6.9%) had ASD, vs 860 (0.9%) children with unaffected siblings (Pâ€‰<â€‰.001). MMR vaccination rates (â‰¥1 dose) were 84% (nâ€‰=â€‰78,564) at age 2 years and 92% (nâ€‰=â€‰86,063) at age 5 years for children with unaffected older siblings, vs 73% (nâ€‰=â€‰1409) at age 2 years and 86% (nâ€‰=â€‰1660) at age 5 years for children with affected siblings. MMR vaccine receipt was not associated with an increased risk of ASD at any age. For children with older siblings with ASD, at age 2, the adjusted relative risk (RR) of ASD for 1 dose of MMR vaccine vs no vaccine was 0.76 (95% CI, 0.49-1.18; Pâ€‰=â€‰.22), and at age 5, the RR of ASD for 2 doses compared with no vaccine was 0.56 (95% CI, 0.31-1.01; Pâ€‰=â€‰.052). For children whose older siblings did not have ASD, at age 2, the adjusted RR of ASD for 1 dose was 0.91 (95% CI, 0.67-1.20; Pâ€‰=â€‰.50) and at age 5, the RR of ASD for 2 doses was 1.12 (95% CI, 0.78-1.59; Pâ€‰=â€‰.55).In this large sample of privately insured children with older siblings, receipt of the MMR vaccine was not associated with increased risk of ASD, regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.
Primary malignant melanoma of the esophagus. - Indian journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India
Primary malignant melanoma most commonly originates from the skin; other less common extra cutaneous sites include squamous mucous membranes, uvea, retina, leptomeninges, genitourinary tract, digestive tract, biliary tract, and upper respiratory tract. Primary melanoma of the gastrointestinal tract is exceedingly rare. We are reporting a histo-pathologically proven rare case of primary malignant melanoma of the esophagus and its findings on fluorodeoxyglucose positron emission tomography and computed tomography.
An unusual variation of axillary artery: a case report. - Journal of clinical and diagnostic research : JCDR
An unusual unilateral variation was observed in branching pattern and course of branches of the axillary artery of the left upper limb in an adult male cadaver. The superior thoracic branch of axillary artery had a very unusual course as it passed between the two divisions of the lateral cord of the brachial plexus and then descended down towards the first two intercostal spaces. A common trunk was seen arising from the third part of the axillary artery which divided into anterior and posterior circumflex humeral, subscapular and Profunda brachii artery. The ulnar and radial collaterals arose from the Profunda brachii artery rather than the brachial artery. The knowledge about such variations becomes essential and of utmost significance in various clinical procedures performed by the vascular surgeons, radiologists and clinical anatomists. Moreover, the injuries of the brachial plexus are quite common and require exploration and repair. During such repair surgeries the abnormal arterial branch may be a matter of definite concern if its presence is not kept in mind.
The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. - Gut
The aim of this study was to assess the correlation between serum and intestinal anti-tumour necrosis factor (TNF) levels, and their relationship to endoscopic disease activity and levels of TNF.Cross-sectional study of 30 patients receiving treatment with infliximab or adalimumab for Crohn's disease or UC. For each patient, a sample of serum was matched to tissue biopsies. Endoscopic and histological disease activity was recorded for each tissue sample.There was a significant positive correlation between anti-TNF in serum and tissue (r=0.3920, p=0.002), especially in uninflamed tissue (r=0.50, p<0.001), but not with those samples that had inflammation (r=0.19, p=0.54). Anti-TNF concentration in tissue correlated with degree of endoscopic inflammation, except for tissue with severe inflammation in which anti-TNF levels were again lower (mean normalised anti-TNF in tissue: uninflamed=0.93, mild=2.17, moderate=13.71, severe=2.2 inflammation (p=0.0042)). The ratio of anti-TNF-to-TNF in tissue was highest in uninflamed areas and lowest in severely inflamed areas. Patients with active mucosal disease had a higher rate of serum to tissue drug level mismatch when compared to those in remission (73.3% vs 33.3%, respectively; p=0.03).Our data suggest that local tissue inflammation characterised by high levels of TNF serves as a sink for anti-TNF. We further postulate that some patients with high serum anti-TNF levels have active disease because tissue levels of anti-TNF are insufficient to neutralise local TNF production.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. - Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI).We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI.Levels of 6-TGN correlated with those of infliximab (Ï, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 Ã— 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 Ã— 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01).Although 6-TGN levels of greater than 230 pmol/8 Ã— 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 Ã— 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.Copyright Â© 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
Antimicrobial polymers. - Advanced healthcare materials
Better health is basic requirement of human being, but the rapid growth of harmful pathogens and their serious health effects pose a significant challenge to modern science. Infections by pathogenic microorganisms are of great concern in many fields such as medical devices, drugs, hospital surfaces/furniture, dental restoration, surgery equipment, health care products, and hygienic applications (e.g., water purification systems, textiles, food packaging and storage, major or domestic appliances etc.) Antimicrobial polymers are the materials having the capability to kill/inhibit the growth of microbes on their surface or surrounding environment. Recently, they gained considerable interest for both academic research and industry and were found to be better than their small molecular counterparts in terms of enhanced efficacy, reduced toxicity, minimized environmental problems, resistance, and prolonged lifetime. Hence, efforts have focused on the development of antimicrobial polymers with all desired characters for optimum activity. In this Review, an overview of different antimicrobial polymers, their mechanism of action, factors affecting antimicrobial activity, and application in various fields are given. Recent advances and the current clinical status of these polymers are also discussed.Â© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Activated cMET and IGF1R-driven PI3K signaling predicts poor survival in colorectal cancers independent of KRAS mutational status. - PloS one
Oncogenic mutational analysis provides predictive guidance for therapeutics such as anti-EGFR antibodies, but it is successful only for a subset of colorectal cancer (CRC) patients.A comprehensive molecular profiling of 120 CRC patients, including 116 primary, 15 liver metastasis, and 1 peritoneal seeding tissue samples was performed to identify the relationship between v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) WT and mutant CRC tumors and clinical outcomes. This included determination of the protein activation patterns of human epidermal receptor 1 (HER1), HER2, HER3, c-MET, insulin-like growth factor 1 receptor (IGF1R), phosphatidylinositide 3-kinase (PI3K), Src homology 2 domain containing (Shc), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) kinases using multiplexed collaborative enzyme enhanced reactive (CEER) immunoassay.KRAS WT and mutated CRCs were not different with respect to the expression of the various signaling molecules. Poor prognosis in terms of early relapse (<2 years) and shorter disease-free survival (DFS) correlated with enhanced activation of PI3K signaling relative to the HER kinase pathway signaling, but not with the KRAS mutational status. KRAS WT CRCs were identified as a mixed prognosis population depending on their level of PI3K signaling. KRAS WT CRCs with high HER1/c-MET index ratio demonstrated a better DFS post-surgery. c-MET and IGF1R activities relative to HER axis activity were considerably higher in early relapse CRCs, suggesting a role for these alternative receptor tyrosine kinases (RTKs) in driving high PI3K signaling.The presented data subclassified CRCs based on their activated signaling pathways and identify a role for c-MET and IGF1R-driven PI3K signaling in CRCs, which is superior to KRAS mutational tests alone. The results from this study can be utilized to identify aggressive CRCs, explain failure of currently approved therapeutics in specific CRC subsets, and, most importantly, generate hypotheses for pathway-guided therapeutic strategies that can be tested clinically.
Variations in innervation of muscles in anterior compartment of arm - a cadaveric study. - Journal of clinical and diagnostic research : JCDR
Study was undertaken to observe the variation in the innervation of muscles in the front of arm. The results were compiled. Embryological basis and clinical applications of encountered variations were tried to explain with the help of available literature.Thirty upper limbs from fifteen cadavers were dissected to observe the contents of front of arm. Musculocutaneous nerve, median nerve and innervation of the muscles of front of arm were observed.Variations were observed in 13% of cases. Commonly seen variation was the absence of musculocutaneous nerve and innervation of muscles of front of arm by branches of median nerve. This variation was seen bilaterally in 3.3% of cases and unilaterally in 6.6% cases. Bilateral presence of this variation in one out of fifteen cadavers is rare finding. Variation is more common on right side as compared to the left side.Bilateral absence of musculocutaneous nerve and innervation of muscles of front of arm from the branches of median nerve is a rare variation. Knowledge of such anatomical variations is of interest to the anatomist and clinician alike. Variations assume significance during surgical exploration of the axilla and can even fail nerve block of infraclavicular part of brachial plexus. Surgeons who perform procedures involving neoplasm or repairing trauma need to be aware of these variations.
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