Added Value of Deep Sequencing Relative to Population Sequencing in Heavily Pre-Treated HIV-1-Infected Subjects.

OBJECTIVE: To explore the potential of deep HIV-1 sequencing for adding clinically relevant information relative to viral population sequencing in heavily pre-treated HIV-1-infected subjects. METHODS: In a proof-of-concept study, deep sequencing was compared to population sequencing in HIV-1-infected individuals with previous triple-class virological failure who also developed virologic failure to deep salvage therapy including, at least, darunavir, tipranavir, etravirine or raltegravir. Viral susceptibility was inferred before salvage therapy initiation and at virological failure using deep and population sequencing genotypes interpreted with the HIVdb, Rega and ANRS algorithms. The threshold level for mutant detection with deep sequencing was 1%. RESULTS: 7 subjects with previous exposure to a median of 15 antiretrovirals during a median of 13 years were included. Deep salvage therapy included darunavir, tipranavir, etravirine or raltegravir in 4, 2, 2 and 5 subjects, respectively. Self-reported treatment adherence was adequate in 4 and partial in 2; one individual underwent treatment interruption during follow-up. Deep sequencing detected all mutations found by population sequencing and identified additional resistance mutations in all but one individual, predominantly after virological failure to deep salvage therapy. Additional genotypic information led to consistent decreases in predicted susceptibility to etravirine, efavirenz, nucleoside reverse transcriptase inhibitors and indinavir in 2, 1, 2 and 1 subject, respectively. Deep sequencing data did not consistently modify the susceptibility predictions achieved with population sequencing for darunavir, tipranavir or raltegravir. CONCLUSIONS: In this subset of heavily pre-treated individuals, deep sequencing improved the assessment of genotypic resistance to etravirine, but did not consistently provide additional information on darunavir, tipranavir or raltegravir susceptibility. These data may inform the design of future studies addressing the clinical value of minority drug-resistant variants in treatment-experienced subjects.

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

Background. A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. METHODS: Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN beta1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years. RESULTS: We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m - last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m - last visit; CH: 0.29, NCH: 0.13). CONCLUSION: Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.

The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer

Background: We aim to investigate the possibility of using 18F-positron emission tomography/computer tomography (PET-CT) to predict the histopathologic response in locally advanced rectal cancer (LARC) treated with preoperative chemoradiation (CRT). Methods: The study included 50 patients with LARC treated with preoperative CRT. All patients were evaluated by PET-CT before and after CRT, and results were compared to histopathologic response quantified by tumour regression grade (patients with TRG 1-2 being defined as responders and patients with grade 3-5 as non-responders). Furthermore, the predictive value of metabolic imaging for pathologic complete response (ypCR) was investigated. Results: Responders and non-responders showed statistically significant differences according to Mandard's criteria for maximum standardized uptake value (SUVmax) before and after CRT with a specificity of 76,6% and a positive predictive value of 66,7%. Furthermore, SUVmax values after CRT were able to differentiate patients with ypCR with a sensitivity of 63% and a specificity of 74,4% (positive predictive value 41,2% and negative predictive value 87,9%); This rather low sensitivity and specificity determined that PET-CT was only able to distinguish 7 cases of ypCR from a total of 11 patients. Conclusions: We conclude that 18-F PET-CT performed five to seven weeks after the end of CRT can visualise functional tumour response in LARC. In contrast, metabolic imaging with 18-F PET-CT is not able to predict patients with ypCR accurately

Angiogenesis-related gene expression profile with independent prognostic value in advanced ovarian carcinoma.

BACKGROUND Ovarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies. Despite the improved median overall survival in patients receiving chemotherapy regimens such as paclitaxel and carboplatin combination, relapse still occurs in most advanced diseased patients. Increased angiogenesis is associated with rapid recurrence and decreased survival in ovarian cancer. This study was planned to identify an angiogenesis-related gene expression profile with prognostic value in advanced ovarian carcinoma patients. METHODOLOGY/PRINCIPAL FINDINGS RNAs were collected from formalin-fixed paraffin-embedded samples of 61 patients with III/IV FIGO stage ovarian cancer who underwent surgical cytoreduction and received a carboplatin plus paclitaxel regimen. Expression levels of 82 angiogenesis related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays. A 34-gene-profile which was able to predict the overall survival of ovarian carcinoma patients was identified. After a leave-one-out cross validation, the profile distinguished two groups of patients with different outcomes. Median overall survival and progression-free survival for the high risk group was 28.3 and 15.0 months, respectively, and was not reached by patients in the low risk group at the end of follow-up. Moreover, the profile maintained an independent prognostic value in the multivariate analysis. The hazard ratio for death was 2.3 (95% CI, 1.5 to 3.2; p<0.001). CONCLUSIONS/SIGNIFICANCE It is possible to generate a prognostic model for advanced ovarian carcinoma based on angiogenesis-related genes using formalin-fixed paraffin-embedded samples. The present results are consistent with the increasing weight of angiogenesis genes in the prognosis of ovarian carcinoma.

Proceso INFORNUT: validación de la fase de filtro-FILNUT--y comparación con otros métodos de detección precoz de desnutrición hospitalaria.

INTRODUCTION According to several series, hospital hyponutrition involves 30-50% of hospitalized patients. The high prevalence justifies the need for early detection from admission. There several classical screening tools that show important limitations in their systematic application in daily clinical practice. OBJECTIVES To analyze the relationship between hyponutrition, detected by our screening method, and mortality, hospital stay, or re-admissions. To analyze, as well, the relationship between hyponutrition and prescription of nutritional support. To compare different nutritional screening methods at admission on a random sample of hospitalized patients. Validation of the INFORNUT method for nutritional screening. MATERIAL AND METHODS In a previous phase from the study design, a retrospective analysis with data from the year 2003 was carried out in order to know the situation of hyponutrition in Virgen de la Victoria Hospital, at Malaga, gathering data from the MBDS (Minimal Basic Data Set), laboratory analysis of nutritional risk (FILNUT filter), and prescription of nutritional support. In the experimental phase, a cross-sectional cohort study was done with a random sample of 255 patients, on May of 2004. Anthropometrical study, Subjective Global Assessment (SGA), Mini-Nutritional Assessment (MNA), Nutritional Risk Screening (NRS), Gassull's method, CONUT and INFORNUT were done. The settings of the INFORNUT filter were: albumin < 3.5 g/dL, and/or total proteins <5 g/dL, and/or prealbumin <18 mg/dL, with or without total lymphocyte count < 1.600 cells/mm3 and/or total cholesterol <180 mg/dL. In order to compare the different methods, a gold standard is created based on the recommendations of the SENPE on anthropometrical and laboratory data. The statistical association analysis was done by the chi-squared test (a: 0.05) and agreement by the k index. RESULTS In the study performed in the previous phase, it is observed that the prevalence of hospital hyponutrition is 53.9%. One thousand six hundred and forty four patients received nutritional support, of which 66.9% suffered from hyponutrition. We also observed that hyponutrition is one of the factors favoring the increase in mortality (hyponourished patients 15.19% vs. non-hyponourished 2.58%), hospital stay (hyponourished patients 20.95 days vs. non-hyponourished 8.75 days), and re-admissions (hyponourished patients 14.30% vs. non-hyponourished 6%). The results from the experimental study are as follows: the prevalence of hyponutrition obtained by the gold standard was 61%, INFORNUT 60%. Agreement levels between INFORNUT, CONUT, and GASSULL are good or very good between them (k: 0.67 INFORNUT with CONUT, and k: 0.94 INFORNUT and GASSULL) and wit the gold standard (k: 0.83; k: 0.64 CONUT; k: 0.89 GASSULL). However, structured tests (SGA, MNA, NRS) show low agreement indexes with the gold standard and laboratory or mixed tests (Gassull), although they show a low to intermediate level of agreement when compared one to each other (k: 0.489 NRS with SGA). INFORNUT shows sensitivity of 92.3%, a positive predictive value of 94.1%, and specificity of 91.2%. After the filer phase, a preliminary report is sent, on which anthropometrical and intake data are added and a Nutritional Risk Report is done. CONCLUSIONS Hyponutrition prevalence in our study (60%) is similar to that found by other authors. Hyponutrition is associated to increased mortality, hospital stay, and re-admission rate. There are no tools that have proven to be effective to show early hyponutrition at the hospital setting without important applicability limitations. FILNUT, as the first phase of the filter process of INFORNUT represents a valid tool: it has sensitivity and specificity for nutritional screening at admission. The main advantages of the process would be early detection of patients with risk for hyponutrition, having a teaching and sensitization function to health care staff implicating them in nutritional assessment of their patients, and doing a hyponutrition diagnosis and nutritional support need in the discharge report that would be registered by the Clinical Documentation Department. Therefore, INFORNUT would be a universal screening method with a good cost-effectiveness ratio.