Diroximel fumarate to treat multiple sclerosis.

On October 29, 2019, the Food and Drug Administration (FDA) of the United States approved diroximel fumarate (DRF) as an oral fumarate for the treatment of relapsing forms of multiple sclerosis. Another oral fumarate, dimethyl fumarate (DMF), was approved for the same indication on March 27, 2013. Prior to its approval, DRF did not undergo rigorous testing to determine its efficacy, as its active metabolite, monomethyl fumarate, is the same as that of DMF (bioequivalency). The efficacy, safety and tolerability of DMF have previously been demonstrated in a number of clinical trials and real-world studies. For DRF, one phase III study has been completed, and another is in progress to determine its safety, tolerability and efficacy. In this paper, we review the pharmacology, pharmacokinetics, metabolism, clinical studies and drug safety of DRF.

Improved Visualization of Cortical Lesions in Multiple Sclerosis Using 7T MP2RAGE.

BACKGROUND AND PURPOSE: Cortical lesions are common and often extensive in multiple sclerosis but are difficult to visualize by MRI, leaving important questions about their clinical implications and response to therapy unanswered. Our aim was to determine whether cortical lesions are better visualized using magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) than T2*-weighted imaging on 7T MR imaging. MATERIALS AND METHODS: Brain MR imaging using T1-weighted MP2RAGE at 500-µm isotropic resolution, T2*-weighted gradient-echo, and T2*-weighted segmented echo-planar imaging sequences were collected for 13 patients with MS and 5 age-matched neurologically healthy controls on a 7T research system. One MS case underwent postmortem MR imaging including gradient-echo and MP2RAGE sequences, after which cortical lesions seen on MR imaging were assessed with immunohistochemistry. RESULTS: MP2RAGE detected 203 cortical lesions (median, 16 lesions/case; interquartile range, 15), compared to 92 with T2*gradient-echo (median, 7; interquartile range, 8; P < .001) and 81 with T2*EPI (median, 7; interquartile range, 5; P < .001). This increase in lesion number detected on MP2RAGE versus T2* was observed for juxtacortical, leukocortical, and intracortical lesions. Forty-three percent of all cortical lesions were identified only on MP2RAGE. White matter lesion volume correlated with total juxtacortical (r = 0.86, P < .001) and leukocortical lesion volume (r = 0.70, P < .01) but not intracortical lesion volume, suggesting that pathophysiology may differ by lesion type. Of 4 suspected lesions seen on postmortem imaging, 3 were found to be true cortical lesions while 1 represented postmortem tissue damage. CONCLUSIONS: A combination of MP2RAGE and T2*-weighted imaging at 7T improved detection of cortical lesions and should enable longitudinal studies to elucidate their spatiotemporal dynamics and clinical implications.

Practice Patterns and Outcomes for Pemetrexed Plus Platinum Doublet as Neoadjuvant Chemotherapy in Adenocarcinomas of Lung: Looking Beyond the Usual Paradigm.

AIMS: Neoadjuvant chemotherapy (NACT) is the standard of care in non-small cell lung cancers (NSCLC) with locally advanced N2 disease. There is a scarcity of data for the pemetrexed-platinum regimen as NACT. Also, apart from N2 disease, the role of NACT in locally advanced NSCLCs for tumour downstaging is unclear. MATERIALS AND METHODS: Non-metastatic adenocarcinomas of lung treated with pemetrexed-platinum-based NACT were analysed. The patients with locoregionally advanced N2 disease and those who were borderline candidates for upfront definitive treatment were planned for NACT after discussion in a multidisciplinary clinic. In total, four cycles of 3-weekly pemetrexed and platinum were delivered in the combined neoadjuvant and adjuvant setting. A response assessment was carried out using RECIST criteria. Progression-free (PFS) and overall survival were calculated using the Kaplan-Meier method. RESULTS: Of 114 patients, 96 evaluable patients received NACT with pemetrexed-platinum. The most common indication for NACT was N2 disease at baseline (46.8%). The objective response rate was 36.4% (95% confidence interval 22-52%), including two complete and 32 partial responses, whereas 12.5% of patients had progressive disease on NACT. The median PFS was 14 months (95% confidence interval 10.7-17.3) and the median overall survival was 22 months (95% confidence interval 15.6-28.4) at a median follow-up of 16 months. There was a significant improvement in the overall survival of patients undergoing definitive therapy versus no definitive therapy (median overall survival 25 months [95% confidence interval 19.6-30.4] versus 12 months [95% confidence interval 3.2-20.7], respectively; P = 0.015, hazard ratio 0.56 [95% confidence interval 0.3-0.9]). Among patients who could not undergo definitive chemoradiation upfront due to dosimetric constraints (n = 34), 24 (70.6%) patients finally underwent definitive therapy after NACT. CONCLUSIONS: Pemetrexed-platinum-based NACT seems to be an effective option and many borderline cases, where upfront definitive therapy is not feasible, may become amenable to the same after incorporation of NACT.

In-Situ Growth of CoS Nanoparticles Onto Electrospun Graphitized Carbon Nanofibers as an Efficient Counter Electrode for Dye-Sensitized Solar Cells.

One-dimensional graphitized carbon nanofibers (G-CNFs) were prepared by employing facile electrospinning technique using 10 wt% of polyacrylonitrile (PAN) solution in N,N-dimethyl formamide (DMF) as precursor followed by successive stabilization, carbonization and purification processes. Cobalt sulfide (CoS) nanoparticles were grown onto G-CNFs by hydrothermal method using cobalt chloride and L-cysteine as precursors. The results of X-ray diffraction (XRD) and Raman spectroscopy confirmed the phase formation and degree of graphitization, respectively. Field-emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM) images confirmed the morphology, growth and distribution of CoS nanoparticles over G-CNFs (CoS/G-CNFs). The electrochemical studies such as cyclic voltammetry (CV), electrochemical impedance and Tafel polarization revealed that CoS/G-CNFs have lower overpotential, low charge transfer resistance and higher exchange current density for triiodide (I− 3 reduction reaction. The superior electrocat- alytic activity of CoS/G-CNFs than std. Pt is due to combined contribution of interconnected pore structure with high surface area of G-CNFs and excellent electrocatalytic activity of CoS. In addition, the dye sensitized solar cell (DSSC) based on platinum-free CoS/G-CNFs has exhibited higher photo-conversion efficiency (PCE) under a simulated solar light irradiation of 100 mW cm−2 when compared to standard platinum (std. Pt) which is attributed to the synergistic effect of CoS with G-CNFs.

Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis.

AIM: Patterns of care for metastatic renal cell carcinomas (mRCC) have seen tremendous reform in the last decade. Here, we present our pattern of care in second-line targeted therapy for mRCC. METHODS: Patients with mRCC treated with second-line therapy were included from a prospective database. Demographics, risk stratification, and treatment details were noted. Event-free survival (EFS) and overall survival (OS) was calculated using Kaplan-Meier method. Log-rank test was used to identify factors affecting EFS and OS. Multivariate analysis was performed using cox regression. RESULTS: Nearly 21.7% (46/212) of patients received second-line targeted treatment. Heng score for risk stratification showed 21.7% of patients in low risk, 36.9% in intermediate, and 34.8% in high risk group. Everolimus followed by pazopanib were the most common second-line therapies used in 65.2% and 13% of patients, respectively. The estimated median EFS was 3.5 months (95% confidence interval [CI] 2.7-4.26 months) and estimated median OS from the start of second-line therapy was 6.2 months (95% CI 3.4-9.0 months) with a median follow-up of 4.3 months. On univariate log-rank analysis, EFS of more than 6 months with first-line therapy was associated with improvement in EFS with second-line therapy (9.5 vs. 2.0 months; hazard ratio (HR) 0.364; P = 0.002). There was no factor independently associated with EFS or OS on multivariate analysis. CONCLUSION: Patterns of care for second line targeted therapy tend to vary with setting. A longer EFS with first-line therapy predicts improved outcomes with second-line treatment.

Novel therapies for memory cells in autoimmune diseases.

Autoimmune diseases are a major cause of morbidity, and their incidence and prevalence continue to rise. Treatments for these diseases are non-specific and result in significant adverse effects. Targeted therapies may help in improving the risk : benefit ratio associated with treatment. Immunological memory is an important feature of the vertebrate immune system that results in the production of cells that are long-lived and able to respond to antigens in a more robust manner. In the setting of autoimmunity this characteristic becomes detrimental due to the ongoing response to a self-antigen(s). These memory cells have been shown to play key roles in various autoimmune diseases such as type 1 diabetes, multiple sclerosis and psoriasis. Memory T cells and B cells can be identified based on various molecules expressed on their surface. Memory T cells can be divided into three main categories - central memory, effector memory and resident memory cells. These subsets have different proliferative potential and cytokine-producing abilities. Utilizing differentially expressed surface molecules or downstream signalling pathway proteins in these cells it is now possible to target memory cells while sparing naive cells. We will discuss the various available options for such a strategy and several potential strategies that may yield successful therapies in the future.

Composite liver tumors: a radiologic-pathologic correlation.

Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi-phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis.

Cleidocranial dysplasia with autosomal dominant inheritance pattern.

Cleidocranial dysplasia (CCD) is an autosomal dominant disease with a wide range of expression, characterized by clavicular hypoplasia, retarded cranial ossification, delayed bone and teeth development, supernumerary teeth, stomatognathic, craniofacial and skeletal abnormalities. This paper presents a case of CCD in a female with brachycephalic skull, depressed frontal bone and nasal bridge, hypoplastic middle one-third of face with mandibular prognathism and hyper mobility of both shoulders with associated radiographic features. Odontologist is often the first professional who patient of CCD approaches, since there is a delay in the eruption or absence of permanent teeth. The premature diagnosis allows a scope for proper treatment modalities, offering a better life quality for patient.

Metagenomic approach for understanding microbial population from petroleum muck.

Petroleum products play a major role in fueling the economy of the world but the pollution they create has become a critical issue. Understanding the diversity present in pipeline muck will help with the exploration of new microbial strains with better hydrocarbon degrading capacities for bioremediation of polluted sites. This study provides an analysis of petroleum muck using next generation sequencing.

Metagenomes from the saline desert of kutch.

We provide the first report on the metagenomic approach for unveiling the microbial diversity in the saline desert of Kutch. High-throughput metagenomic sequencing of environmental DNA isolated from soil collected from seven locations in Kutch was performed on an Ion Torrent platform.

Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma.

BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

A study of tubercular lymphadenitis: a comparison of various laboratory diagnostic modalities with a special reference to tubercular polymerase chain reaction.

OBJECTIVE: The purpose of our study was to compare various laboratory diagnostic methods, namely histopathological examination, Ziehl-Neelsen (ZN) stain, AFB culture by conventional Lowenstein-Jensen (LJ) method and fluorescence-based mycobacterial growth indicator tube (MGIT) technique and polymerase chain reaction (PCR) in clinically suspected cases of tubercular lymphadenitis. MATERIALS AND METHODS: A total of 65 lymph nodes biopsied from patients clinically suspected of having tubercular lymph nodes were included. Specimens were processed for AFB culture after NaOH-NALC concentration and inoculation on LJ medium and using the MGIT system. PCR was performed on all specimens using a commercial nested PCR kit targeting IS6110 insertion element of Mycobacterium tuberculosis complex. All lymph node specimens were subjected to histopathological examination. RESULTS: Of the 65 lymph nodes, 37 (56.9%) were positive on MGIT culture and 45 (69.2%) were positive by PCR. Histopathology showed maximum sensitivity (96%) but with compromised specificity (78.5%). PCR showed 90.1% sensitivity and 100% specificity. The mean turnaround time for mycobacterial growth in smear negative specimens was 30 days determined by LJ and 20 days by MGIT techniques. CONCLUSION: PCR is a rapid and useful method for diagnosis of TB lymphadenitis and definitely increases the positive predictive value of a positive histopathology report. MGIT is better than LJ culture as regards time to positivity and higher yield.

Pictorial review. Hepatic vascular shunts: embryology and imaging appearances.

The purpose of this pictorial review is to understand the embryological basis of the development of congenital hepatic vascular shunts and to review the multimodality imaging appearances of congenital and acquired hepatic vascular shunts. Hepatic vascular shunts are commonly seen in imaging. Familiarity with their characteristic appearances is important in order to accurately characterise these shunts and diagnose the underlying disorders.

Chronic hepatic artery occlusion with collateral formation: imaging findings and outcomes.

OBJECTIVE: The imaging findings, clinical presentation, and outcome in post liver transplantation patients with hepatic arterial collaterals are reviewed. MATERIALS AND METHODS: Adult post orthotopic liver transplantation patients who underwent an angiography at our institution for suspected hepatic arterial abnormality during an approximately 10-year period were included in our study. A retrospective review of all cases that had hepatic arterial collaterals detected on angiography was then performed. Angiographic findings were correlated with the findings on ultrasound and other imaging studies. Liver function at the time of angiography was recorded. Clinical outcomes were reviewed. RESULTS: Of the 129 angiographies performed in the approximately 10-year period, 24 (19.4%) were found to have collaterals on angiography. Maximum size of the collaterals seen on angiography was 3 mm. Twenty patients (83%) with collaterals are currently alive. Twelve patients (50%) had a normal outcome and did not develop any complications on follow-up; however, the rest developed complications. Eleven patients (41.7%) had complication related to the liver ischemia and 2 patients (8.3%) developed malignancy (posttransplant lymphoproliferative disease). CONCLUSION: Collaterals seen in patients with chronic hepatic artery occlusion are usually small in caliber and their significance is unclear. Recognition and understanding of this phenomenon is important as this subset of patients may not need urgent surgical re-exploration/vascular intervention.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS: Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS: Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION: Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

Janibacter hoylei sp. nov., Bacillus isronensis sp. nov. and Bacillus aryabhattai sp. nov., isolated from cryotubes used for collecting air from the upper atmosphere.

Three novel bacterial strains, PVAS-1(T), B3W22(T) and B8W22(T), were isolated from cryotubes used to collect air samples at altitudes of between 27 and 41 km. Based on phenotypic characteristics, chemotaxonomic features, DNA-DNA hybridization with the nearest phylogenetic neighbours and phylogenetic analysis based on partial 16S rRNA gene sequences (PVAS-1(T), 1196 nt; B3W22(T), 1541 nt; B8W22(T), 1533 nt), the three strains were identified as representing novel species, and the names proposed are Janibacter hoylei sp. nov. (type strain PVAS-1(T) =MTCC 8307(T) =DSM 21601(T) =CCUG 56714(T)), Bacillus isronensis sp. nov. (type strain B3W22(T) =MTCC 7902(T) =JCM 13838(T)) and Bacillus aryabhattai sp. nov. (type strain B8W22(T) =MTCC 7755(T) =JCM 13839(T)).