Paolo Frumento

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

BackgroundMolecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific VEGF polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.MethodsGenomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. VEGF -2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of VEGF polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of VEGF -1498 C/T polymorphism between bevacizumab-and control group.ResultsIn the bevacizumab-group median PFS and OS of patients carrying VEGF -1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). VEGF -1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of VEGF -1498 C/T allelic variants and PFS or OS was found. Interaction between VEGF -1498 C/T variants and treatment effect suggested that the relation of VEGF -1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.ConclusionsThese data suggest a possible role for VEGF -1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data

Importance Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, −3.62; 95% CI, −0.81 to −6.43; P = .01; d = −0.25) but not from pretreatment to midtreatment (mean difference, −1.66; 95% CI, −4.92 to 1.60; P = .32; d = −0.14) or from pretreatment to follow-up (mean difference, −2.98, 95% CI, −5.99 to 0.03; P = .05; d = −0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Evaluating the Effect of Training on Wages in the Presence of Noncompliance, Nonemployment, and Missing Outcome Data

The effects of a job training program, Job Corps, on both employment and wages are evaluated using data from a randomized study. Principal stratification is used to address, simultaneously, the complications of noncompliance, wages that are only partially defined because of nonemployment, and unintended missing outcomes. The first two complications are of substantive interest, whereas the third is a nuisance. The objective is to find a parsimonious model that can be used to inform public policy. We conduct a likelihood-based analysis using finite mixture models estimated by the expectation-maximization (EM) algorithm. We maintain an exclusion restriction assumption for the effect of assignment on employment and wages for noncompliers, but not on missingness. We provide estimates under the “missing at random” assumption, and assess the robustness of our results to deviations from it. The plausibility of meaningful restrictions is investigated by means of scaled log-likelihood ratio statistics. Substantive conclusions include the following. For compliers, the effect on employment is negative in the short term; it becomes positive in the long term, but these effects are small at best. For always employed compliers, that is, compliers who are employed whether trained or not trained, positive effects on wages are found at all time periods. Our analysis reveals that background characteristics of individuals differ markedly across the principal strata. We found evidence that the program should have been better targeted, in the sense of being designed differently for different groups of people, and specific suggestions are offered. Previous analyses of this dataset, which did not address all complications in a principled manner, led to less nuanced conclusions about Job Corps.

An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients.

BACKGROUND Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients. PATIENTS AND METHODS DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients. RESULTS One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05). CONCLUSION An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.BACKGROUND Despite therapeutic innovations, metastatic colorectal cancer (mCRC) is still characterized by poor prognosis and few molecular markers predict the risk of progression. Polycomb group genes (PcGs) are epigenetic modifiers involved in tumor suppressor gene silencing. PcG member EZH2 mediates gene silencing through histone-H3 lysine-27 methylation. In colorectal cancer (CRC), EZH2 overexpression predicts shorter survival. Recently, four EZH2 single-nucleotide polymorphisms (SNPs) have been described. The present study was aimed at evaluating the correlation between EZH2 SNPs and outcome parameters in mCRC patients. PATIENTS AND METHODS DNA was extracted from blood samples of 110 mCRC patients treated with first-line 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) and bevacizumab. Genotyping was carried out by real-time PCR. Genotype was used to predict objective response, progression-free survival (PFS) and overall survival (OS). EZH2 messenger RNA levels were evaluated on lymphocytes of a parallel cohort of 50 CRC patients. RESULTS One allelic variant (rs3757441 C/C versus C/T or T/T) was significantly associated with shorter PFS and OS (P < 0.01 and P < 0.05, respectively). At multivariate analysis, the same variant resulted an independent predictor of PFS and OS (P < 0.05). The C/C variant was associated with significantly higher EZH2 expression (P < 0.05). CONCLUSION An EZH2 SNP may be useful to predict clinical outcome in mCRC patients.

Evolution of chronic renal impairment and long-term mortality after de novo acute kidney injury in the critically ill; a Swedish multi-centre cohort study

IntroductionAcute Kidney Injury (AKI) is common in critical ill populations and its association with high short-term mortality is well established. However, long-term risks of death and renal dysfunction are poorly understood and few studies exclude patients with pre-existing renal disease, meaning outcome for de novo AKI has been difficult to elicit. We aimed to compare the long-term risk of Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and mortality in critically ill patients with and without severe de novo AKI.MethodThis cohort study was conducted between 2005 and 2011 in Swedish intensive care units (ICU). Data from 130134 adult patients listed on the Swedish intensive care register-database was linked with other national registries. Patients with pre-existing CKD (4192) and ESRD (1389) were excluded, as were cases (26771) with incomplete data. Patients were classified according to AKI exposure during ICU admission. Outcome in the de novo AKI group was compared to the non-exposed (no-AKI) intensive care control group. Primary outcome was all-cause mortality. Follow-up ranged from one to seven years (median 2.1 years). Secondary outcomes were incidence of CKD and ESRD and median follow-up was 1.3 years.ResultsOf 97 782 patients, 5273 (5.4%) had de novo AKI. These patients had significantly higher crude mortality at one (48.4% vs. 24.6%) and five years (61.8% vs. 39.1%) compared to the control group. The first 30% of deaths in AKI patients occurred within 11 days of ICU admission whilst the 30-centile in the no-AKI group died by 748 days. CKD was significantly more common in AKI survivors at one year (6.0% vs. 0.44%) than in no-AKI group (adjusted incidence rate ratio (IRR) 7.6). AKI patients also had significantly higher rates of ESRD at one (2.0% vs. 0.08%) and at five years (3.9% vs. 0.3%) than those in the comparison group (adjusted IRR 22.5).ConclusionThis large cohort study demonstrated that de novo AKI is associated with increased short and long-term risk of death. AKI is independently associated with increased risk of CKD and ESRD as compared to an ICU control population. Severe de novo AKI survivors should be routinely followed-up and their renal function monitored.

Age- and health-related quality of life after total hip replacement: Decreasing gains in patients above 70 years of age

Background — While age is a common confounder, its impact on health-related quality of life (HRQoL) after total hip replacement is uncertain. This could be due to improper statistical modeling of age in previous studies, such as treating age as a linear variable or by using age categories. We hypothesized that there is a non-linear association between age and HRQoL. Methods — We selected a nationwide cohort from the Swedish Hip Arthroplasty Register of patients operated with total hip replacements due to primary osteoarthritis between 2008 and 2010. For estimating HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group that consits or 2 parts: the EQ-5D index and the EQ VAS estimates. Using linear regression, we modeled the EQ-5D index and the EQ VAS against age 1 year after surgery. Instead of using a straight line for age, we applied a method called restricted cubic splines that allows the line to bend in a controlled manner. Confounding was controlled by adjusting for preoperative HRQoL, sex, previous contralateral hip surgery, pain, and Charnley classification. Results — Complete data on 27,245 patients were available for analysis. Both the EQ-5D index and EQ VAS showed a non-linear relationship with age. They were fairly unaffected by age until the patients were in their late sixties, after which age had a negative effect. Interpretation — There is a non-linear relationship between age and HRQoL, with improvement decreasing in the elderly.

Association of interleukin 8 with myocardial infarction: Results from the Stockholm Heart Epidemiology Program

BACKGROUND Interleukin 8 (IL8) has been contradictorily associated with the risk of myocardial infarction (MI). AIM To investigate the association of IL8 serum levels with the risk of MI and the association of the IL8 (IL8) and IL8 receptors (CXCR1 and CXCR2) genetic variants with IL8 levels and MI risk in a large case control study, the Stockholm Heart Epidemiology Program. METHODS AND RESULTS IL8 levels (pg/mL) were divided into quartiles and the MI risk was calculated by logistic regression and expressed as odds ratio (OR) and 95% CI. Two IL8 SNPs (rs4073A/T, rs2227306C/T) and three SNPs tagging CXCR1 and CXCR2 (rs4674258C/T, rs1008563C/T, rs6723449T/C) were analyzed for association with IL8 levels and with MI risk. Multivariate adjusted ORs for MI risk by IL8 levels in the highest quartiles indicated reduced point estimates in both women (OR 0.37; 95% CI 0.2-0.8) and men when compared to the lowest quartile. In female cases, IL8 levels decreased progressively in the six months after MI (p=0.03). IL8, CXCR1 and CXCR2 genetic variants were not associated with IL8 levels. In men, the T allele at the IL8 SNP rs4073 was associated with a slight increase in the MI risk under an additive and a recessive model of inheritance. CONCLUSIONS IL8 serum levels were associated with a reduced occurrence of MI among women, whereas IL8 was associated with a slightly increased risk among men, possibly through different mechanisms. These data suggest that the biological effects of IL8 on MI risk may vary over time and warrant further cohort studies with repetitive IL8 measurements.

Women in Charnley class C fail to improve in mobility to a higher degree after total hip replacement

Background— The Charnley comorbidity classification organizes patients into 3 classes: (A) 1 hip involved, (B) 2 hips involved, and (C) other severe comorbidities. Although this simple classification is a known predictor of health-related quality of life (HRQoL) after total hip replacement (THR), interactions between Charnley class, sex, and age have not been investigated and there is uncertainty regarding whether A and B should be grouped together. Methods — We selected a nationwide cohort of patients from the Swedish Hip Arthroplasty Register operated with THR due to primary osteoarthritis between 2008 and 2010. For estimation of HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group. This consists of 2 parts: the EQ-5D index and the EQ VAS estimates. We modeled the EQ-5D index and the EQ VAS against the self-administered Charnley classification. Confounding was controlled for using preoperative HRQoL values, pain, and previous contralateral hip surgery. Results — We found that women in class C had a poorer EQ-5D outcome than men. This effect was mostly due to the fact that women failed to improve in the mobility dimension; only 40% improved, while about 50% of men improved. Age did not interact with Charnley class. We also found that the classification performed best without splitting or aggregating classes. Interpretation — Our results suggests that the self-administered Charnley classification should be used in its full capacity and that it may be interesting to devote special attention to women in Charnley class C.

Temporal trends in extreme rainfall intensity and erosivity in the Mediterranean region: a case study in southern Tuscany, Italy

Worldwide climate is likely to become more variable or extreme with increases in intense precipitation. In Mediterranean areas, climate change will increase the risks of droughts, flash floods and soil erosion. Despite rainfall intensity being a key factor in erosive processes, in these areas information on extreme rainfall intensity and the associated erosivity, based on high-temporal resolution data, is either non homogeneous or scarce. These parameters thus need to be assessed in order to highlight suitable adaptation strategies. In this paper, an hourly rainfall intensity (RI) data series is analyzed together with the corresponding 1-min rainfall intensity maximum (RIm) of 23 rainfall gauges located in Tuscany, Italy, in an area highly vulnerable to erosion. The aim is to look for temporal trends (1989–2010) in extreme rainfall intensity and erosivity. Fixed effect logistic regression shows statistically significant temporal increases in the number of RI and RIm exceedances over the 95th percentile threshold. Winter is shown to be the season with the strongest increasing trend in coastal and inland rainfall gauge groups, followed by spring for the coastal group and autumn for the inland group. Linear regressions show that in the inland group there is a temporal increase in rainfall erosivity and on a seasonal basis, the highest increase is observed in autumn. By contrast, for the coastal group this increasing trend is only detectable for spring and winter. Such an increase in rainfall erosivity and its potential continuation could have a strong adverse effect on Mediterranean land conservation.

Integrated analysis of the prostate cancer small-nucleolar transcriptome reveals SNORA55 as a driver of prostate cancer progression

Metastasis is the primary cause of death in prostate cancer (PCa) patients. Small nucleolar RNAs (snoRNAs) have long been considered “housekeeping” genes with no relevance for cancer biology. Emerging evidence has challenged this assumption, suggesting that snoRNA expression is frequently modulated during cancer progression. Despite this, no study has systematically addressed the prognostic and functional significance of snoRNAs in PCa.