Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer: the TNT trial.

BACKGROUND: In the TNT trial of triple negative breast cancer (NCT00532727), germline BRCA1/2 mutations were present in 28% of carboplatin responders. We assessed quantitative measures of structural chromosomal instability (CIN) to identify a wider patient subgroup within TNT with preferential benefit from carboplatin over docetaxel. PATIENTS AND METHODS: Copy number aberrations (CNAs) were established from 135 formalin-fixed paraffin-embedded primary carcinomas using Illumina OmniExpress SNP-arrays. Seven published [allelic imbalanced CNA (AiCNA); allelic balanced CNA (AbCNA); copy number neutral loss of heterozygosity (CnLOH); number of telomeric allelic imbalances (NtAI); BRCA1-like status; percentage of genome altered (PGA); homologous recombination deficiency (HRD) scores] and two novel [Shannon diversity index (SI); high-level amplifications (HLAMP)] CIN-measurements were derived. HLAMP was defined based on the presence of at least one of the top 5% amplified cytobands located on 1q, 8q and 10p. Continuous CIN-measurements were divided into tertiles. All nine CIN-measurements were used to analyse objective response rate (ORR) and progression-free survival (PFS). RESULTS: Patients with tumours without HLAMP had a numerically higher ORR and significantly longer PFS in the carboplatin (C) than in the docetaxel (D) arm [56% (C) versus 29% (D), PHLAMP,quiet = 0.085; PFS 6.1 months (C) versus 4.1 months (D), Pinteraction/HLAMP = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), PNtAI,intermediate = 0.03; 62% (C) versus 33% (D), PAiCNA,intermediate = 0.076]. Patients with high AiCNA and PGA had shorter PFS in the carboplatin arm [3.4 months (high) versus 5.7 months (low/intermediate); and 3.8 months (high) versus 5.6 months (low/intermediate), respectively; Pinteraction/AiCNA = 0.027, Padj.interaction/AiCNA = 0.125 and Pinteraction/PGA = 0.053, Padj.interaction/PGA = 0.176], whilst no difference was observed in the docetaxel arm. CONCLUSIONS: Patients with tumours lacking HLAMP and demonstrating intermediate CIN-measurements formed a subgroup benefitting from carboplatin relative to docetaxel treatment within the TNT trial. This suggests a complex and paradoxical relationship between the extent of genomic instability in primary tumours and treatment response in the metastatic setting.

Prevalence of malnutrition in medical and surgical gastrointestinal outpatients.

BACKGROUND: UK NICE guidelines, state that patients attending an outpatient clinic for the first time, should be screened for malnutrition. AIMS: To determine the prevalence of malnutrition in the medical and surgical gastroenterology outpatient department (OPD) using body mass index (BMI) and % weight loss (%WL) and to assess the physicians'/surgeons' response to malnutrition being detected. METHODS: The BMI and the %WL were determined for every patient over a 2 week period before the clinician saw the patient. The BMI and %WL were scored as in the Malnutrition Universal Screening Tool (MUST). RESULTS: 605 patients (316 females) of mean age 54 years were included. 150 (25%) were new patients. 519 (86%) had a normal BMI and %WL. 86 (14%) had a BMI <20 kg/m2 or had 5% WL. 61 (10%) were in MUST "medium risk" and 25 (4%) were in MUST "high risk" of malnutrition. 15 (60%) of the "high risk" patients were under the care of or had been referred to a dietitian compared to 19 (28%) of "medium risk" patients. The prevalence of malnutrition was independent of sex, age, history of previous surgery or underlying comorbidities. There was no difference in the prevalence of malnutrition between new and follow up patients. Malnutrition was more common in patients with IBD (38, 18%) vs non-IBD (48, 12%) and patients with cancer (11, 25%) vs non cancer (75, 13%) (p < 0.05). CONCLUSIONS: The prevalence of malnutrition in medical and surgical gastrointestinal outpatients was 14%. IBD and cancer patients had the highest prevalence. Most patients with malnutrition (52, 61%) were not being seen by a dietitian.

Occurrence of viral pathogens in Penaeus monodon post-larvae from aquaculture hatcheries.

Viral pathogens appear to exert the most significant constraints on the growth and survival of crustaceans under culture conditions. The prevalence of viral pathogens White Spot Syndrome Virus (WSSV), Hepatopancreatic Parvo Virus (HPV), Monodon Baculo Virus (MBV) and Infectious Hypodermal and Hematopoietic Necrosis Virus (IHHNV) in Penaeus monodon post-larvae was studied. Samples collected from different hatcheries and also samples submitted by farmers from Kerala were analyzed. Out of 104 samples collected, WSSV was detected in 12.5% of the post-larvae samples. Prevalence of concurrent infections by HPV, MBV and WSSV (either dual or triple infection) was present in 60.6% of the total post-larvae tested. Out of the 51 double positives, 98% showed either HPV or IHHNV infection. HPV or IHHNV was detected in 11 post-larval samples showing triple viral infection. This is the first report of IHHNV from India. Result of this study reveals the lack of efficient screening strategies to eradicate viruses in hatchery reared post-larvae.

Dynamic changes in dna methylation status in peripheral blood Mononuclear cells following an acute bout of exercise: Potential impact of exercise-induced elevations in interleukin-6 concentration.

The aim of the present study was to examine the relationship between interleukin (IL)-6 concentrations and DNA methylation in the peripheral blood mononuclear cells (PBMCs) of trained runners after a bout of prolonged, strenuous exercise. Eight healthy trained males completed a treadmill run at 60% vVO(2max) for 120 min followed by a 5-km time trial in a fasted condition. Whole blood samples were taken prior to, immediately before and 24 h following exercise. From these samples, PBMCs were isolated for analysis and plasma IL-6 concentrations were measured. The methylation status of DNA extracted from PBMCs was analysed using the Illumina 27k methylation beadchip platform. Global DNA methylation status was unaltered immediately and up to 24 hours following a bout of prolonged exercise in comparison to pre-exercise. Despite no change in global DNA methylation, plasma IL-6 concentrations were significantly related to the DNA methylation status of 11 genes. Our study demonstrates that the methylome is stable, while discovering a novel link between exercise-induced increases in circulating IL-6 and the DNA methylation status of 11 individual genes. Based on our preliminary findings, the mechanisms by which changes in plasma IL-6 concentrations and DNA methylation in response to exercise interact require further study.

Characterization of the mouse Ron/Stk receptor tyrosine kinase gene.

In an effort to understand the mechanisms governing the regulation of the mouse Ron receptor gene, a mouse genomic library was screened and overlapping clones coding for the Ron gene and flanking DNA were identified. Continuous DNA sequence was obtained for approximately 16.4 kilobases. The gene, from the initiator methionine to the polyadenylation site, is contained within 13 244 basepairs and contains 19 exons. Primer extension analyses were performed to determine the transcription start site of the mouse Ron transcript. Multiple transcription start sites were found which also appear to be used in transfected reporter constructs containing Ron 5' flanking DNA. To determine the location of sites which may be critical for the function of the Ron gene promoter, a series of chimeric genes containing serial deletions of the Ron gene promoter fused to the coding sequences for the chloramphenicol acetyl-transferase gene were constructed. Transient transfection analyses of these hybrid genes into various cell lines demonstrated that two regions of the Ron gene promoter, encompassing nucleotides -585 to -465 and from -465 to -285, are important for expression of this transcript in CMT-93 cells. Further analysis of the Ron promoter utilizing gel mobility shift analyses suggests that regions encompassing nucleotides -585 to - 508 and nucleotides -375 to -285 appear to bind specific proteins which may be involved in the negative and positive regulation, respectively, of the mouse Ron gene.

The practical implications of recent trials comparing thrombolytic therapy with surgery for lower extremity ischemia.

UNLABELLED: Catheter-based thrombolysis for lower extremity ischemia is a well-accepted and frequently used technique. Three prospective randomized trials, Rochester, STILE, and TOPAS, which compared thrombolytic therapy with traditional surgical revascularization for lower limb ischemia, have recently been published. METHODS: These three trials are reviewed with the intent of assessing the relative of value of thrombolytic therapy and surgical revascularization for lower limb ischemia. RESULTS: As an initial therapy, thrombolysis reduces the magnitude of any subsequent surgical procedure in approximately 40% to 60% of patients. However, recurrent ischemia is frequent, and the subsequent need for surgical revascularization is common for any native artery occlusion or chronic (> 14 days) bypass graft occlusion. In the patient with an acute bypass graft occlusion, the incidence of recurrent ischemia is less and limb salvage at 1 year is enhanced when treated initially by thrombolysis. A possible survival benefit after thrombolysis was suggested in the Rochester trial and in the STILE trial for diabetics with femoral-popliteal occlusions. CONCLUSIONS: Surgical revascularization remains the optimal therapy for most patients with lower limb ischemia. However, thrombolysis as an initial therapy does reduce the magnitude of any subsequent surgical procedure and provides improved limb salvage for patients with acute bypass graft occlusions.

Relationship between intraoperative color-flow duplex findings and early restenosis after carotid endarterectomy: a preliminary report.

PURPOSE: This study was undertaken to examine the relationship between intraoperative color-flow duplex (CFD) findings and the development of restenosis in patients undergoing carotid endarterectomy (CEA). METHODS: Seventy-eight patients (43 male and 35 female; mean age, 65 years) underwent 86 CEAs (eight staged bilateral) and intraoperative CFD during a 31-month period. Three patients (three CEAs, 3%) underwent both CFD and a completion arteriographic scan. Patients were observed in a postoperative protocol using CFD surveillance. The follow-up interval ranged from 6 to 24 months (average, 12 months). RESULTS: After undergoing CEA, 10 patients (10 CEAs, 11%) had an abnormality detected by intraoperative CFD; one was confirmed with a completion arteriographic scan. These abnormalities consisted of elevated peak systolic velocities (PSV) with a mosaic color pattern suggesting turbulence seen in six CEAs, including one internal carotid artery (ICA) with abnormal hemodynamics and an unremarkable completion arteriogram. Intimal defects on B-mode were seen in another four CEAs. These carotid arteries were reexplored, defects (intimal flaps with platelet thrombus) were confirmed by direct examination, and all were repaired with or without a patch (six ICAs, three external carotid arteries, and one common carotid artery). No cerebrovascular events occurred in the perioperative period. No carotid restenosis (> or = 50% diameter reduction) was identified during follow-up of 43 patients (48 CEAs, 56%). Two patients had recurrent neurologic symptoms. CONCLUSION: Intraoperative CFD is an effective test for detecting flow abnormalities or intimal defects in patients undergoing CEA. Ensuring normal intraoperative hemodynamics after CEA may be a major factor associated with decreased incidence of perioperative cerebrovascular events and subsequent carotid artery restenosis.