Alessio Farcomeni

MicroRNA profiling in human medulloblastoma

Medulloblastoma is an aggressive brain malignancy with high incidence in childhood. Current treatment approaches have limited efficacy and severe side effects. Therefore, new risk‐adapted therapeutic strategies based on molecular classification are required. MicroRNA expression analysis has emerged as a powerful tool to identify candidate molecules playing an important role in a large number of malignancies. However, no data are yet available on human primary medulloblastomas. A high throughput microRNA expression profiles was performed in human primary medulloblastoma specimens to investigate microRNA involvement in medulloblastoma carcinogenesis. We identified specific microRNA expression patterns which distinguish medulloblastoma differing in histotypes (anaplastic, classic and desmoplastic), in molecular features (ErbB2 or c‐Myc overexpressing tumors) and in disease‐risk stratification. MicroRNAs expression profile clearly differentiates medulloblastoma from either adult or fetal normal cerebellar tissues. Only a few microRNAs displayed upregulated expression, while most of them were downregulated in tumor samples, suggesting a tumor growth‐inhibitory function. This property has been addressed for miR‐9 and miR‐125a, whose rescued expression promoted medulloblastoma cell growth arrest and apoptosis while targeting the proproliferative truncated TrkC isoform. In conclusion, misregulated microRNA expression profiles characterize human medulloblastomas, and may provide potential targets for novel therapeutic strategies.

Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: A systematic review and meta-analysis. Part 2: Patients treated with therapeutic hypothermia

AIMS AND METHODS To systematically review the accuracy of early (≤7 days) predictors of poor outcome, defined as death or vegetative state (Cerebral Performance Categories [CPC] 4-5) or death, vegetative state or severe disability (CPC 3-5), in comatose adult survivors from cardiac arrest (CA) treated using therapeutic hypothermia (TH). Electronic databases were searched for eligible studies. Sensitivity, specificity, and false positive rates (FPR) for each predictor were calculated. Quality of evidence (QOE) was evaluated according to the GRADE guidelines. RESULTS 37 studies (2403 patients) were included. A bilaterally absent N20 SSEP wave during TH (4 studies; QOE: Moderate) or after rewarming (5 studies; QOE: Low), a nonreactive EEG background (3 studies; QOE: Low) after rewarming, a combination of absent pupillary light and corneal reflexes plus a motor response no better than extension (M≤2) (1 study; QOE: Very low) after rewarming predicted CPC 3-5 with 0% FPR and narrow (<10%) 95% confidence intervals. No consistent threshold for 0% FPR could be identified for blood levels of biomarkers. In 6/8 studies on SSEP, in 1/3 studies on EEG reactivity and in the single study on clinical examination the investigated predictor was used for decisions to withdraw treatment, causing the risk of a self-fulfilling prophecy. CONCLUSIONS in the first 7 days after CA, a bilaterally absent N20 SSEP wave anytime, a nonreactive EEG after rewarming or a combination of absent ocular reflexes and M≤2 after rewarming predicted CPC 3-5 with 0% FPR and narrow 95% CIs, but with a high risk of bias.

Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts

BACKGROUND AND AIMS:The aim of this study was to assess the incidence, natural history, and risk factors of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) with the new polytetrafluoroethylene (PTFE)-covered stent grafts in cirrhotic patients.PATIENTS AND METHODS:Seventy-eight cirrhotic patients treated by TIPS with PTFE-covered stent grafts and followed by the same medical team—according to a prospective protocol for diagnostic workup and surveillance strategy—were reviewed. The follow-up was 19.9 ± 20.6 months.RESULTS: At least one episode of HE occurred in 35 of 78 (44.8%) patients. The probability of remaining free of HE was 53.8% (95% confidence interval [CI] 41.4–66.2] at 1 yr and 50.9% at 2 yr (95% CI 38.2–63.8%). The total number of HE episodes was 89. Fifty-five percent of the episodes were grades III–IV. The occurrence of HE tended to be constant during the follow-up, probably because of the very low incidence of shunt dysfunction (13.6% at 2 yr). Moreover, in six patients, a refractory HE required the reduction of the shunt diameter. One patient died due to variceal bleeding after this procedure. At a multivariate analysis, an older age, high creatinine levels, and low serum sodium and low albumin values were shown to be independent factors for the occurrence of HE. Serum creatinine level was the only variable related to the development of refractory HE at the logistic multivariate analysis.CONCLUSIONS: HE after TIPS with PTFE-covered stent grafts is frequent; its incidence is not confined to the first post-TIPS period, but it has the tendency to be frequent over time. Refractory HE occurred in 8% of patients and may be successfully managed by reducing the stent diameter. The selection of patients undergoing TIPS placement should be very accurate, especially for those subjects with abnormal creatinine level.

A review of modern multiple hypothesis testing, with particular attention to the false discovery proportion

In the last decade a growing amount of statistical research has been devoted to multiple testing, motivated by a variety of applications in medicine, bioinformatics, genomics, brain imaging, etc. Research in this area is focused on developing powerful procedures even when the number of tests is very large. This paper attempts to review research in modern multiple hypothesis testing with particular attention to the false discovery proportion, loosely defined as the number of false rejections divided by the number of rejections. We review the main ideas, stepwise and augmentation procedures; and resampling based testing. We also discuss the problem of dependence among the test statistics. Simulations make a comparison between the procedures and with Bayesian methods. We illustrate the procedures in applications in DNA microarray data analysis. Finally, few possibilities for further research are highlighted.

A multivariate extension of the dynamic logit model for longitudinal data based on a latent markov heterogeneity structure

For the analysis of multivariate categorical longitudinal data, we propose an extension of the dynamic logit model. The resulting model is based on a marginal parameterization of the conditional distribution of each vector of response variables given the covariates, the lagged response variables, and a set of subject-specific parameters for the unobserved heterogeneity. The latter ones are assumed to follow a first-order Markov chain. For the maximum likelihood estimation of the model parameters, we outline an EM algorithm. The data analysis approach based on the proposed model is illustrated by a simulation study and an application to a dataset, which derives from the Panel Study on Income Dynamics and concerns fertility and female participation to the labor market.

Prognostic value of circulating tumor cells in nonmuscle invasive bladder cancer: a CellSearch analysis

BACKGROUND Circulating tumor cells (CTCs) provide prognostic information in patients with metastatic tumors. Recent studies have shown that CTCs are released in circulation in an early phase of cancer disease so that their presence is under investigation in the adjuvant setting. Few studies investigated the prognostic significance of CTCs enumeration in patients with metastatic and advanced bladder cancer. The current study has analyzed the presence of CTC in patients with nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS Forty-four NMIBC patients were enrolled and included in a 24-month follow-up program. Blood drawings were carried out in all patients at the first diagnosis. CellSearch system (Veridex; LLC, Raritan, NJ) was used for CTCs enumeration. RESULTS CTC were detectable in 8/44 patients (18%). Presence of CTC was found significantly associated to shorter time to first recurrence (6.5 versus 21.7 months, P < 0.001). Median time to progression was not reached, due to the short follow-up period. CTC presence was found associated to concomitant carcinoma in situ and higher T category. CONCLUSION The detection of CTC in this setting of disease may allow to distinguish patients with high risk of recurrence from those with high risk of progression, as well as to early identify patients candidate for adjuvant treatment.BACKGROUND Circulating tumor cells (CTCs) provide prognostic information in patients with metastatic tumors. Recent studies have shown that CTCs are released in circulation in an early phase of cancer disease so that their presence is under investigation in the adjuvant setting. Few studies investigated the prognostic significance of CTCs enumeration in patients with metastatic and advanced bladder cancer. The current study has analyzed the presence of CTC in patients with nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS Forty-four NMIBC patients were enrolled and included in a 24-month follow-up program. Blood drawings were carried out in all patients at the first diagnosis. CellSearch system (Veridex; LLC, Raritan, NJ) was used for CTCs enumeration. RESULTS CTC were detectable in 8/44 patients (18%). Presence of CTC was found significantly associated to shorter time to first recurrence (6.5 versus 21.7 months, P<0.001). Median time to progression was not reached, due to the short follow-up period. CTC presence was found associated to concomitant carcinoma in situ and higher T category. CONCLUSION The detection of CTC in this setting of disease may allow to distinguish patients with high risk of recurrence from those with high risk of progression, as well as to early identify patients candidate for adjuvant treatment.

No evidence of association between blastocyst aneuploidy and morphokinetic assessment in a selected population of poor-prognosis patients: a longitudinal cohort study

Recent studies involving a limited number of patients have indicated a correlation between aneuploidy and various morphokinetic parameters during preimplantation development. The results among different groups, however, have been inconsistent in identifying the parameters that are able to predict chromosomal abnormalities. The aim of this study was to investigate whether aneuploidy of human blastocysts was detectable by specific morphokinetic parameters in patients at increased risk of aneuploidy because of advanced maternal age, history of unsuccessful IVF treatments, or both. A longitudinal cohort study was conducted using 455 blastocysts from 138 patients. Morphokinetic features of preimplantation development were detected in a timelapse incubator. Blastocysts were subjected to trophectodermal biopsy and comprehensive chromosomal screening. Analyses were conducted by means of logistic mixed-effects models, with a subject-specific intercept. No statistical correlation between 16 commonly detected morphokinetic characteristics of in-vitro embryo development and aneuploidy was found. Results suggest that morphokinetic characteristics cannot be used to select euploid blastocysts in poor-prognosis patients regarded as candidates for pre-implantation genetic screening.

Quantile regression for longitudinal data based on latent Markov subject-specific parameters

We propose a latent Markov quantile regression model for longitudinal data with non-informative drop-out. The observations, conditionally on covariates, are modeled through an asymmetric Laplace distribution. Random effects are assumed to be time-varying and to follow a first order latent Markov chain. This latter assumption is easily interpretable and allows exact inference through an ad hoc EM-type algorithm based on appropriate recursions. Finally, we illustrate the model on a benchmark data set.

Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.

Background Sarcopenia evaluated by computed tomography (CT) scan at the lumbar site has been identified as a risk factor for morbidity and mortality in cirrhosis. Aim The aim of this study was to compare the measurement of muscle mass through CT scan, considered the gold standard, with other reliable techniques to evaluate the rate of agreement between different available methods for the assessment of muscle mass in cirrhosis. The correlation between measurements of muscle mass and of muscle strength was also investigated. Patients and methods Adult patients eligible for liver transplantation were studied. Lumbar skeletal muscle cross-sectional area was measured by CT and muscle depletion was defined using previously published cut-offs. Mid-arm muscle circumference was calculated following anthropometric measures. The Fat-Free Mass Index and the Appendicular Skeletal Muscle Index were calculated using dual-energy X-ray absorptiometry. Muscle strength was evaluated using the Hand Grip test. Results Fifty-nine patients with cirrhosis were included. Sarcopenia was diagnosed in 76% of the patients according to CT evaluation. A significant reduction in Fat-Free Mass Index and Appendicular Skeletal Muscle Index was observed in 42–52% of the patients, whereas 52% showed a mid-arm muscle circumference less than 10th percentile. Skeletal muscle mass evaluation through CT was only weakly correlated with dual-energy X-ray absorptiometry and anthropometry evaluation. No correlation was observed between CT measurement of muscle mass and Hand Grip test. Conclusion CT scan can identify the highest percentage of sarcopenia in cirrhosis and no other techniques are actually available as a replacement. Future efforts should focus on approaches for assessing both skeletal muscle mass and function to provide a better evaluation of sarcopenia in cirrhotic patients.

Distribution and assessment of marine debris in the deep Tyrrhenian Sea (NW Mediterranean Sea, Italy).

Marine debris is a recognized global ecological concern. Little is known about the extent of the problem in the Mediterranean Sea regarding litter distribution and its influence on deep rocky habitats. A quantitative assessment of debris present in the deep seafloor (30-300 m depth) was carried out in 26 areas off the coast of three Italian regions in the Tyrrhenian Sea, using a Remotely Operated Vehicle (ROV). The dominant type of debris (89%) was represented by fishing gears, mainly lines, while plastic objects were recorded only occasionally. Abundant quantities of gears were found on rocky banks in Sicily and Campania (0.09-0.12 debris m(-2)), proving intense fishing activity. Fifty-four percent of the recorded debris directly impacted benthic organisms, primarily gorgonians, followed by black corals and sponges. This work provides a first insight on the impact of marine debris in Mediterranean deep ecosystems and a valuable baseline for future comparisons.