A phase-2, randomized, multicenter, placebo-controlled, proof-of-concept trial of oral fexinidazole in adults with chronic indeterminate Chagas disease

alexandrossfakianakis shared this article with you from Inoreader A phase-2, randomized, multicenter, placebo-controlled, proof-of-concept trial of oral fexinidazole in adults with chronic indeterminate Chagas disease via Clinical Infectious Diseases Advance Access Abstract Background Chagas disease (CD) has significant global health impact, but safe and effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. Methods This double-blind, randomised, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically-confirmed chronic indeterminate CD and positive PCR were randomly assigned to one of six fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat population (ITT). Follow-up was extended to 12 months. Results Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade-3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients ad ministered >2 weeks. A total of 40 patients received from 3 days to 8 weeks of treatment with fexinidazole. Delayed onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients, versus none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% ("1200mg-2week") and 100.0% ("1800mg-2week"). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (p = 0.0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. Conclusions Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens of <10 days. View on Web

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Clinical and Molecular Analysis of Recurrent Gram-Negative Bloodstream Infections

alexandrossfakianakis shared this article with you from Inoreader Clinical and Molecular Analysis of Recurrent Gram-Negative Bloodstream Infections via Clinical Infectious Diseases Advance Access Abstract Background The causes and clinical characteristics of recurrent gram-negative bacterial bloodstream infections (GNB-BSI) are poorly understood. Methods We used a prospectively ascertained cohort of patients with GNB-BSI to identify clinical characteristics, microbiology, and risk factors associated with recurrent GNB-BSI. Bacterial genotyping (both pulsed field gel electrophoresis [PFGE] and whole genome sequencing [WGS]) was used to define whether these episodes were due to relapse or reinfection. Multivariable logistic regression was used to identify risk factors associated with recurrence. Results Of the 1423 patients with GNB-BSI that met criteria for inclusion in this study, 60 (4%) had recurrent GNB-BSI. Non-white race (OR: 2.35; CI95% 1.38-4.01; p = 0.002), admission to a surgical service (OR: 2.18; CI95% 1.26-3.75; p = 0.005) and presence of an indwelling cardiac device (OR: 2.73; CI95% 1.21-5.58, p =  0.009) were associated with increased risk for recurrent GNB-BSI. Among the 48 patients with recurrent GNB-BSI whose paired bloodstream isolates underwent genotyping, 63% were due to relapse (30/48) and 38% were due to reinfection (18/48) based on WGS. Compared with WGS, PFGE correctly differentiated relapse and reinfection in 98% (47/48) of cases. Median time to relapse and reinfection was similar (113 days [IQR: 35-222 days] vs. 174 days [IQR: 69-599 days], p = 0.13). Presence of a cardiac device was associated with relapse (Relapse: 7/27 [26%]; Non-relapse: 65/988 [7%]; p = 0.002). Conclusions In this study, recurrent GNB-BSI was most commonly due to relapse. PFGE accurately differentiated relapse from reinfection when compared with WGS. Presence of a cardiac device was a risk factor for relapse. View on Web

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Two cases of oral steroid and local tacrolimus combination therapy for oral lichen planus ineffective with local steroid therapy

alexandrossfakianakis shared this article with you from Inoreader Two cases of oral steroid and local tacrolimus combination therapy for oral lichen planus ineffective with local steroid therapy via ScienceDirect Publication: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Publication date: Available online 5 August 2022 Source: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Author(s): Yusuke Aoki, Masaki Minabe, Junichiro Inada, Yurie Akiyama, Kazuhiko Hashimoto, Michiyoshi Kouno, Shinichi Takahashi, Takeshi Nomura View on Web

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Leucovorin (folinic acid) rescue for high‐dose methotrexate: A review

alexandrossfakianakis shared this article with you from Inoreader Leucovorin (folinic acid) rescue for high‐dose methotrexate: A review via Journal of Clinical Pharmacy and Therapeutics Leucovorin rescue is a cornerstone for toxicity prevention in high dose methotrexate treatment. Leucovorin rescue protocols differ greatly across tumor types and medical institutions. Leucovorin rescue protocols were reviewed for patients with ALL, lymphomas, and osteosarcoma. Abstract High-dose methotrexate (HDMTX) is active against various malignancies; it possesses serious toxicities and is associated with patient characteristics, dosage regimens, comedications, and physiological status. There are many strategies to overcome HDMTX-induced toxicities, such as hydration, alkalization, leucovorin rescue, and haemodialysis. Leucovorin rescue is a cornerstone for toxicity prevention in HDMTX treatment. However, the leucovorin dose adjustment and the existence of leucovorin overrescue are still controversial. At present, various methods for calculating leucovorin doses in different tumour types have been proposed, including empirical calculations based on MTX plasma concentration, the Bleyer nomogram, and other methods. Nonetheless, leucovorin rescue protocols differ greatly across tumour types and medical institutions. Further studies are needed to investigate the optimal dosage regimen for leucovorin rescue in various tumours using HDMTX. View on Web

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Angiotensin II-induced miR-31-5p upregulation promotes vascular smooth muscle cell proliferation and migration

alexandrossfakianakis shared this article with you from Inoreader Angiotensin II-induced miR-31-5p upregulation promotes vascular smooth muscle cell proliferation and migration via ScienceDirect Publication: Experimental Cell Research Publication date: Available online 5 August 2022 Source: Experimental Cell Research Author(s): Bing Zhou, Nan Wu, Yuan Yan, Lu-Lu Wu, Guo-Qing Zhu, Xiao-Qing Xiong View on Web

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Oncologic outcomes of salvage surgery and immune checkpoint inhibitor therapy in recurrent head and neck squamous cell carcinoma: A single‐institution retrospective study

alexandrossfakianakis shared this article with you from Inoreader Oncologic outcomes of salvage surgery and immune checkpoint inhibitor therapy in recurrent head and neck squamous cell carcinoma: A single‐institution retrospective study via Head & Neck Abstract Background Survival outcomes in recurrent head and neck squamous cell carcinoma (HNSCC) are poor. This study aimed to compare survival outcomes between salvage surgery and immunotherapy in patients with recurrent advanced HNSCC. Methods Patients with advanced stage (stage III or IV) recurrent HNSCC following treatment with platinum-based chemotherapy were included. Survival was estimated using the Kaplan–Meier method, and Cox regression was used for multivariate logistic regression. Results Two-year overall survival after salvage surgery was 68.6% and after immunotherapy patients was 24.6%. Multivariate logistic regression showed that salvage surgery was associated with improved survival without statistical significance (hazard ratio [HR] 0.12, p = 0.25). Subgroup analysis of patients with oral cavity/oropharyngeal cancer noted improved survival with salvage surgery over immunotherapy (HR 0.006, p = 0.01) and decreased survival with neutrophil-to-lymphocyte ratio (NLR) > 5 (HR 6.4, p = 0.02). Conclusion Our retrospective single-institutional data suggest that resectable advanced stage recurrent HNSCC may have improved survival with salvage surgery in appropriately selected patients, but larger prospective studies are required. View on Web

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Characterizing the epithelial–mesenchymal transition status of circulating tumor cells in head and neck squamous cell carcinoma

alexandrossfakianakis shared this article with you from Inoreader Characterizing the epithelial–mesenchymal transition status of circulating tumor cells in head and neck squamous cell carcinoma via Head & Neck Abstract Background Circulating tumor cells (CTCs), in particular those undergoing an epithelial–mesenchymal transition (EMT), are a promising source of biomarkers in head and neck squamous cell carcinoma (HNSCC). Our aim was to validate a protocol using microfluidic enrichment (Parsortix platform) with flow-cytometry CTC characterization. Method Blood samples from 20 treatment naïve HNSCC patients underwent Parsortix enrichment and flow cytometry analysis to quantify CTCs and identify epithelial or EMT subgroups—correlated to clinical outcomes and EMT gene-expression in tumor tissue. Results CTCs were detected in 65% of patients (mean count 4 CTCs/ml). CTCs correlated with advanced disease (p = 0.0121), but not T or N classification. Epithelial or EMT CTCs did not correlate with progression-free or overall survival. Tumor mesenchymal gene-expression did not correlate with CTC EMT expression (p = 0.347). Discussion Microfluidic enrichment and flow cytometry successfully characterizes EMT CTCs in HNSCC. The lack of association between tumor and CTC EMT profile suggests CTCs may undergo an adaptive EMT in response to stimuli within the circulation. View on Web

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Excessive mechanical stress induced temporomandibular joint osteoarthritis via osteoclasts‐mediated osteogenic differentiation of BMSCs

alexandrossfakianakis shared this article with you from Inoreader Excessive mechanical stress induced temporomandibular joint osteoarthritis via osteoclasts‐mediated osteogenic differentiation of BMSCs via Journal of Oral Rehabilitation Abstract Background Bone homeostasis is a dynamic process maintained by osteoblasts and osteoclasts, which may be regulated by excessive mechanical stress (EMS). Objectives Our study aims to explore the relationship between osteogenic differentiation of BMSCs and EMS-activated osteoclast differentiation of RAW 264.7 cells in order to optimize orthodontic treatment. Methods We established the model of EMS in vivo and in vitro. In vivo, HE, Safranin-O staining, micro-CT, and immunofluorescence double-labeling were utilized to assess the changes in condylar, the distributions of osteoblasts, osteoclasts and MAPKs. In vitro, the effects of EMS-activated osteoclast differentiation exerting on osteogenic differentiation of BMSCs were observed by Western Blot, qRT-PCR and Alizarin Red staining. Furthermore, the role of MAPKs in this progress was explored by using inhibitors of MAPKs and co-culture supernatants. Results In vivo, EMS led to the degradation of condylar cartilage and destruction of subchondral bone, diagnosed as temporomandibular joint osteoarthritis (TMJ OA). Osteoclasts and osteoblasts were both enriched in subchondral bone, but osteoclast predominated. The expressions of p-JNK, p-ERK1/2, and p-p38 were all activated in vitro and in vivo, which were localized mainly in the Trap+ area in subchondral bone. Interestingly, only the inactivation of p-ERK1/2 in osteoclasts significantly inhibited the osteogenic differentiation of BMSCs in vitro. This revealed that p-ERK1/2 played a key role in the osteoclasts-induced osteogenic differentiation of BMSCs. Conclusion Our results proved that EMS led to TMJ OA, in which up-regulated p-ERK1/2 in osteoclasts was mechanosensitive and facilitated the osteogenic differentiation of BMSCs. View on Web

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