A Randomized Multicenter Study of Optimal Circadian Time of Vinorelbine Combined with Chronomodulated 5‐Fluorouracil in Pretreated Metastatic Breast Cancer Patients: EORTC Trial 05971

Studies in animals synchronized with an alternation of 12 h of light and 12 h of darkness have showed that hematological and systemic toxicities could be reduced if vinorelbine were administered 19 or 23 hours after light onset (HALO), corresponding to 17:00 and 21:00 h in diurnally active humans. This trial aimed to define the least toxic time of vinorelbine administration in metastatic breast cancer patients. Initially, the study treatment consisted of three courses of vinorelbine of 30 mg/m²/d on D1 and D6 and chronomodulated 5‐fluorouracil of 850 mg/m² from D2 to D5 every 21 days. Ninety metastatic breast cancer patients were randomized to receive vinorelbine at one of the eight possible dosing times. Further to the recommendations of the Independent Data Monitoring Committee, the vinorelbine dose was reduced to 25 mg/m²/d midway through the study. The primary objective of the study was detection of the least toxic time based on the incidence of grade 3–4 (G3–4) neutropenia. To show a significant result, the 90% confidence interval width of the least toxic time had to be<6 h. The least toxic time detection based on the incidence of other toxicities was also analyzed. The time of least drug toxic was estimated using a logistic regression model assuming that the logit transformation of the toxicity rate follows a sinusoidal distribution over 24 h. The bootstrap technique was used to obtain the 90% confidence interval. The least toxic time of G3–4 neutropenia was observed at 21:00 h with a non‐significant 90% CI. Secondary endpoint analyses indicated the least toxic time could differ when based on other toxicity parameters (e.g., a significant least toxic time of 17:00 h was observed for G3–4 leucopenia), in agreement with animal data. The least toxic time of 10:30 h was estimated for any G3–4 gastrointestinal toxicity. This results of this study do not allow us to recommend an optimal time for vinorelbine administration. It has highlighted, however, the inherent methodological difficulties in the conduct of such a trial in the human setting. It indicates that future optimal time‐finding trials should have tolerability and/or activity as the primary endpoint in place of a particular toxicity. The randomized optimal time‐finding design may be used to identify the best time of chemotherapy administration. (Author correspondence: bcoudert@dijon.fnclcc.fr)     

Clearing the backlog: trichiasis surgeon retention and productivity in northern Ethiopia

Background

In 2006 there were an estimated 645,000 people in Amhara, Ethiopia, with trachomatous trichiasis (TT) who needed surgery. Despite an extensive integrated eye care worker training programme (IECW) and robust support for TT surgical services, productivity has not reached targets. We investigated why surgeon productivity was below target.

Methodology/Principal Findings

Confidential interviews were conducted in person with TT surgeons trained from 24 selected districts in Amhara Region and their supervisors. Determinants of attrition and productivity were investigated. We interviewed 225 people who had received IECW training; 139 (59%) had subsequently changed career/job. Staff retention was associated with good road access to their health centre, mobile telephone network and a shorter time from initial training. Amongst the 94 IECW still working in the programme, the average number of patients operated was 41/year, which was mostly (86%) done through outreach campaigns and only 14% of cases were performed in the static facilities where they routinely worked. Spot checks were made of surgical instruments and consumables: only 3/94 IECW had the minimum instruments and consumables to perform surgery. The main barriers to operating were lack of time, shortage of consumables, lack of patients, lack of support and equipment problems. Very few IECW received ongoing supervision or active management.

Conclusions/Significance

Surgeon attrition rates are high. Vertical surgery campaigns were effective in treating large numbers of cases, whilst static-site service productivity was low. Good health system management is key to building a well-staffed and well-run service.     

Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation

We report crosstalk between three senescence-inducing conditions, DNA damage response (DDR) defects, oxidative stress (OS) and nuclear shape alterations. The recessive autosomal genetic disorder Ataxia telangiectasia (A-T) is associated with DDR defects, endogenous OS and premature ageing. Here, we find frequent nuclear shape alterations in A-T cells, as well as accumulation of the key nuclear architecture component lamin B1. Lamin B1 overexpression is sufficient to induce nuclear shape alterations and senescence in wild-type cells, and normalizing lamin B1 levels in A-T cells reciprocally reduces both nuclear shape alterations and senescence. We further show that OS increases lamin B1 levels through p38 Mitogen Activated Protein kinase activation. Lamin B1 accumulation and nuclear shape alterations also occur during stress-induced senescence and oncogene-induced senescence (OIS), two canonical senescence situations. These data reveal lamin B1 as a general molecular mediator that controls OS-induced senescence, independent of established Ataxia Telangiectasia Mutated (ATM) roles in OIS.     

Bacterial Symbionts of a Devastating Coffee Plant Pest,the Stinkbug Antestiopsis thunbergii (Hemiptera: Pentatomidae)

Stinkbugs of the genus Antestiopsis, so-called antestia bugs or variegated coffee bugs, are notorious pests of coffee plants in Africa. We investigated the symbiotic bacteria associated with Antestiopsis thunbergii, a major coffee plant pest in Rwanda. PCR, cloning, sequencing, and phylogenetic analysis of bacterial genes identified four distinct bacterial lineages associated with A. thunbergii: a gammaproteobacterial gut symbiont and symbionts representing the genera Sodalis, Spiroplasma, and Rickettsia. In situ hybridization showed that the gut symbiont densely occupied the lumen of midgut crypts, whereas the Sodalis symbiont, the Spiroplasma symbiont, and the Rickettsia symbiont sparsely and sporadically infected various cells and tissues. Diagnostic PCR survey of 154 A. thunbergii individuals collected at 8 localities in Rwanda revealed high infection frequencies (100% for the gut symbiont, 51.3% for the Sodalis symbiont, 52.6% for the Spiroplasma symbiont, and 24.0% for the Rickettsia symbiont). These results suggest that the gut symbiont is the primary symbiotic associate of obligate nature for A. thunbergii, whereas the Sodalis symbiont, the Spiroplasma symbiont, and the Rickettsia symbiont are the secondary symbiotic associates of facultative nature. We observed high coinfection frequencies, i.e., 7.8% of individuals with quadruple infection with all the symbionts, 32.5% with triple infections with the gut symbiont and two of the secondary symbionts, and 39.6% with double infections with the gut symbiont and any of the three secondary symbionts, which were statistically not different from the expected coinfection frequencies and probably reflected random associations. The knowledge of symbiotic microbiota in A. thunbergii will provide useful background information for controlling this devastating coffee plant pest.     

Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians

Background  

A close association between Sst I polymorphism in the 3' untranslated region of the apolipoproteinC3 (APOC3 ) gene and levels of plasma triglycerides (TG) had been reported by different investigators. Hypertriglyceridemia(HTG) is a known risk factor for coronary artery disease (CAD) in the context of Asian Indians. We conducted a study on the relationship between APOC3 SstI polymorphism (S1S1, S1S2 and S2S2 genotypes) and plasma TG levels in a group of 139 male healthy volunteers from Northern India.