Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

Background: Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia. Methods: In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2–8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809. Findings: Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5–6 g resulted in a sustained and significant (p<0·0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes. Interpretation: Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted

Client Acceptability for Integrating Antiretroviral Therapy in Methadone Maintenance Therapy Clinics in Sichuan, China.

BackgroundUsing methadone maintenance therapy (MMT) clinics to deliver antiretroviral therapy (ART) has proven to be effective for promoting treatment initiation and adherence in drug users living with HIV.ObjectivesThe objective of this study was to investigate the HIV-positive client acceptability of integrated ART services and to identify the reasons for and factors associated with service acceptability.MethodsA total of 86 HIV-positive MMT clients were recruited from 12 MMT clinics in Sichuan Province, China. They participated in a cross-sectional survey that queried their willingness to receive seven different types of MMT-based ART services. The reasons for their willingness/unwillingness to accept these services were documented. The association between service acceptability and background characteristics was examined.ResultsThe most accepted integrated services were ART-related counseling (75.6%) and referral (73.2%). Concerns regarding the provider's lack of ART expertise and confidentiality issues were common barriers for the acceptance of MMT-based ART services. A trust relationship with MMT providers was a reason for service acceptance. Service acceptability was associated with a poorer perceived health status. Conclusions/Importance: ART-related services, based on the client perspective, can be delivered at MMT clinics. However, service provider training and the protection of confidentiality must be strengthened for the effective implementation of integrated service delivery

Focal Spot, Spring 1979

https://digitalcommons.wustl.edu/focal_spot_archives/1023/thumbnail.jp

Gastric Cancer at a University Teaching Hospital in Northwestern Tanzania: A Retrospective Review of 232 Cases.

Despite marked decreases in its incidence, particularly in developed countries, gastric cancer is still the second most common tumor worldwide. There is a paucity of information regarding gastric cancer in northwestern Tanzania. This study was undertaken to describe our experience, in our local setting, on the management of gastric cancer, outlining the clinicopathological and treatment outcome of these patients and suggesting ways to improve the treatment outcome. This was a retrospective study of histologically confirmed cases of gastric cancer seen at Bugando Medical Centre between January 2007 and December 2011. Data were retrieved from patients' files and analyzed using SPSS computer software version 17.0. A total of 232 gastric cancer patients were enrolled in the study, representing 4.5% of all malignancies. The male to female ratio was 2.9:1. The median age of patients was 52 years. The majority of the patients (92.1%) presented late with advanced gastric cancer (Stages III and IV). Lymph node and distant metastasis at the time of diagnosis was recorded in 31.9% and 29.3% of cases, respectively. The antrum was the most frequent anatomical site (56.5%) involved and gastric adenocarcinoma (95.1%) was the most common histopathological type. Out of 232 patients, 223 (96.1%) patients underwent surgical procedures for gastric cancer of which gastro-jejunostomy was the most frequent performed surgical procedure, accounting for 53.8% of cases. The use of chemotherapy and radiotherapy was documented in 56 (24.1%) and 12 (5.1%) patients, respectively. Postoperative complication and mortality rates were 37.1% and 18.1%, respectively. According to multivariate logistic regression analysis, preoperative co-morbidity, histological grade and stage of the tumor, presence of metastases at the time of diagnosis was the main predictors of death (P <0.001). At the end of five years, only 76 (32.8%) patients were available for follow-up and the overall five-year survival rate was 6.9%. Evidence of cancer recurrence was reported in 45 (19.4%) patients. Positive resection margins, stage of the tumor and presence of metastasis at the time of diagnosis were the main predictors of local recurrence (P <0.001). Gastric cancer in this region shows a trend towards relative young age at diagnosis and the majority of patients present late with an advanced stage. Lack of awareness of the disease, poor accessibility to health care facilities and lack of screening programs in this region may contribute to advanced disease at the time of diagnosis. There is a need for early detection, adequate treatment and proper follow-up to improve treatment outcome

Impact on clinical practice of the preoperative screening of Covid-19 infection In surgical oncological patients. Prospective Cohort Study

Background In the oncological patient, an COVID-19-Infection, whether symptomatic or asymptomatic, a surgical procedure may carry a higher postoperative morbidity and mortality. The aim of this study was to describe the impact on clinical practice of sequential preoperative screening for COVID-19-infection in deciding whether to proceed or postpone surgery. Methods Prospective, cohort study, based on consecutive patients’ candidates for an oncological surgical intervention. Sequential preoperative screening for COVID-19-infection: two-time medical history (telematic and face-to-face), PCR and chest CT, 48 h before of surgical intervention. COVID-19-infection was considered positive if the patient had a suggestive medical history and/or PCR-positive and/or CT of pneumonia. Results Between April 15th and May 4th, 2020, 179 patients were studied, 97 were male (54%), mean (sd) age 66.7 (13,6). Sequential preoperative screening was performed within 48 h before to surgical intervention. The prevalence of preoperative COVID-19-infection was 4.5%, 95%CI:2.3–8.6% (8 patients). Of the operated patients (171), all had a negative medical history, PCR and chest CT. The complications was 14.8% (I-II) and 2.5% (III-IV). There was no mortality. The hospital stay was 3.1 (sd 2.7) days. In the 8 patients with COVID-19-infection, the medical history was suggestive in all of them, 7 presented PCR-positive and 5 had a chest CT suggestive of pneumonia. The surgical intervention was postponed between 15 and 21 days. Conclusion Preoperative screening for COVID-19-infection using medical history and PCR helped the surgeon to decide whether to go ahead or postpone surgery in oncological patients. The chest CT may be useful in unclear cases

Translation and validation of EORTC QLQ-C30 into Indonesian version for cancer patients in Indonesia.

The Indonesian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 can be used as a questionnaire to assess quality of life in Indonesian cancer patients with high-emetogenic treatments

AUGMENT : a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma

PURPOSE Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab. METHODS A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review. RESULTS A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively. CONCLUSION Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile

Qualitative study of Chinese widows in Hong Kong: Insights for psycho-social care in hospice settings

In an exploratory, phenomenological study of seven Chinese widows in Hong Kong, five major themes are identified: relationship with the deceased, relationship with others, grief reactions, coping and emotional expression. This paper focuses on the first theme: the widows' relationship with the deceased husband along a timeline from the time of diagnosis to after death. The experiences in the final days with the deceased were frequently referred to when the informants talked about this theme. This paper aims to give added voice, based on the experience of Chinese widows, to the possible role of hospice and palliative care on influencing the bereavement experience. Issues of awareness and acceptance of death, the supportive environment and support for family carers, the moment of death, creation of legacies, and sensitivity towards cultural embedded practices, are discussed. It is hoped that the experiences of these bereaved widows will stimulate new research to elucidate and verify the findings reported in this paper. © 2006 Edward Arnold (Publishers) Ltd.postprin