Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies

Background

There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM).

Methods and Findings

We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. 6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR = 1.10, 95%CIs: 1.00–1.21; P = 0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR = 1.19, 95%CIs: 1.04–1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR = 1.46, 95%CIs: 1.03–2.08; P = 0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled results suggested that ADT was associated with CVM (HR = 1.17, 95%CIs: 1.04–1.32; P = 0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g. prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR = 1.19, 95%CIs: 1.08–1.30; P<0.001) and CVM (HR = 1.30, 95%CIs: 1.13–1.50; P<0.001) were found in men treated with ADT monotherapy.

Conclusions

ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.     

Diagnosis of Bladder Cancer Recurrence Based on Urinary Levels of EOMES,HOXA9, POU4F2, TWIST1, VIM,and ZNF154 Hypermethylation

Background

Non muscle invasive bladder cancer (NMIBC) has the highest recurrence rate of any malignancy and as many as 70% of patients experience relapse. Aberrant DNA methylation is present in all bladder tumors and can be detected in urine specimens. Previous studies have identified DNA methylation markers that showed significant diagnostic value. We evaluated the significance of the biomarkers for early detection of tumor recurrence in urine.

Methodology/Principal Findings

The methylation levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 in urine specimens were measured by real-time PCR (MethyLight). We analyzed 390 urine sediments from 184 patients diagnosed with NMIBC. Urine from 35 age-matched control individuals was used to determine the methylation baseline levels. Recurrence was diagnosed by cystoscopy and verified by histology. Initially, we compared urine from bladder cancer patients and healthy individuals and detected significant hypermethylation of all six markers (P<0.0001) achieving sensitivity in the range 82%–89% and specificity in the range 94%–100%. Following, we validated the urinary hypermethylation for use in recurrence surveillance and found sensitivities of 88–94% and specificities of 43–67%. EOMES, POU4F2, VIM and ZNF154 were more frequently methylated in urine from patients with higher grade tumors (P≤0.08). Univariate Cox regression analysis showed that five markers were significantly associated with disease recurrence; HOXA9 (HR = 7.8, P = 0.006), POU4F2 (HR = 8.5, P = 0.001), TWIST1 (HR = 12.0, P = 0.015), VIM (HR = 8.0, P = 0.001), and ZNF154 (HR = 13.9, P<0.001). Interestingly, for one group of patients (n = 15) we found that hypermethylation was consistently present in the urine samples despite the lack of tumor recurrences, indicating the presence of a field defect.

Conclusion/Significance

Methylation levels of EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 in urine specimens are promising diagnostic biomarkers for bladder cancer recurrence surveillance.     

Smoking Modifies the Associated Increased Risk of Future Cardiovascular Disease by Genetic Variation on Chromosome 9p21

Aims

Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors.

Methods and results

A total of 24944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13–1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20–1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95–1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94–1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574.

Conclusion

Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.     

Pituitary Stalk Interruption Syndrome in 53 Postpubertal Patients: Factors Influencing the Heterogeneity of Its Presentation

Background

Pituitary stalk interruption syndrome (PSIS) may induce an isolated growth hormone (GH) deficiency or multiple hypothalamic-pituitary (HP) deficiencies. Patients with multiple HP deficiencies, primarily those with adrenocorticotropin (ACTH) deficiency, are at increased risk of morbidity and mortality. Our objective was to identify the factors influencing each symptom and the MRI features of the syndrome to enhance its diagnosis and genetic analysis.

Methods

This study was a retrospective, single-center, case-cohort study of 53 patients with PSIS who had reached pubertal age.

Results

Patients were classified as having an isolated GH deficiency (n = 24, Group 1) or HP deficiencies (n = 29, Group 2); of these, 19 had complete HP deficiency, and 10 had GH deficiency associated with TSH (n = 4), TSH and ACTH (n = 3), TSH and gonadotropin (n = 1) deficiencies or amenorrhea (n = 2). The following features were less frequent in Group 1 than in Group 2: breech presentation (4% vs 35%, P = 0.008), hypoglycemia (0% vs 59%, P<0.00001), micropenis (13% vs 69%, P<0.003), hypothalamic origin (0% vs 52%, P<0.000001), ophthalmic malformation (8% vs 38%, P<0.02) and psychomotor delay (0% vs 31%, P<0.004). The frequencies of all other malformations were similar in both groups (37% vs 59%). A visible pituitary stalk was characteristic of patients belonging to Group 1 (P<0.0002). The GH peak was greater in Group 1 than in Group 2 (P<0.0003), as was the anterior pituitary height (P = 0.01).

Conclusion

The factors that best discriminate patients with multiple HP deficiencies from those with an isolated GH deficiency are breech presentation, hypoglycemia, and micropenis. No patient with an isolated GH deficiency had psychomotor delay, but associated malformations and/or syndromes, with the exception of ophthalmic disorders, occurred with similar frequencies in both groups. We have also shown that each of the above characteristics is associated with a given HP deficiency and/or malformation/syndrome in the majority of cases.     

Immediate Postmastectomy Breast Reconstruction Showed Limited Advantage in Patient Survival after Stratifying by Family Income

Background

Postmastectomy breast reconstruction is widely used in breast cancer patients for its aesthetic effect. Although several studies have casted suspicion upon the oncological safety of immediate breast reconstruction after mastectomy, the potential impact of different reconstruction methods on patient survival remains unclear.

Patients and Methods

We identified 35,126 female patients diagnosed with breast cancer from January 1, 1998 to December 31, 2002 in the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients who underwent mastectomy with or without immediate breast reconstruction (autologous reconstruction or implant reconstruction) using Cox proportional hazard regression models.

Results

In multivariate analysis unadjusted for family income, patients undergoing immediate postmastectomy reconstruction exhibited improved BCSS [pooled reconstruction (any types of reconstruction): hazard ratio (HR)  =  0.87, 95% confidence interval (CI) 0.80–0.95, P = 0.001] and OS (pooled reconstruction: HR = 0.70, 95% CI 0.65–0.75, P<0.001) compared to patients who underwent mastectomy alone. However, after stratifying by family income, patients receiving reconstruction showed limited advantage in BCSS and OS compared with those undergoing mastectomy alone. When comparing between the two reconstruction methods, no significant differences were observed in either BCSS (implant versus autologous reconstruction: HR = 1.11, 95%CI 0.90–1.35, P = 0.330) or OS (implant versus autologous reconstruction: HR = 1.07, 95% 0.90–1.28, P = 0.424).

Conclusions

Compared to mastectomy alone, immediate postmastectomy reconstruction had limited advantage in survival after adjusting for confounding factor of family income. Our findings, if validated in other large databases, may help to illustrate the actual effect of immediate postmastectomy reconstruction on patient survival.     

Red Blood Cell Distribution Width and Long-Term Outcome in Patients Undergoing Percutaneous Coronary Intervention in the Drug-Eluting Stenting Era: A Two-Year Cohort Study

Background

Previous studies suggest the higher the red blood cell distribution width (RDW) the greater the risk of mortality in patients with coronary artery disease (CAD). However, the relationship between RDW and long-term outcome in CAD patients undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) remains unclear. This study was designed to evaluate the long-term effect of RDW in patients treated with drug-eluting stent for CAD.

Methods

In total of 2169 non-anemic patients (1468 men, mean age 60.2±10.9 years) with CAD who had undergone successful PCI and had at least one drug-eluting stent were included in this study. Patients were grouped according to their baseline RDW: Quartile 1 (RDW<12.27%), Quartile 2 (12.27%≤RDW<13%), Quartile 3 (13%≤RDW<13.5%), and Quartile 4 (RDW≥13.5).

Results

The incidence of in-hospital mortality and death or myocardial infarction was significantly higher in Quartiles 3 and 4 compared with Quartile 1 (P<0.05). After a follow-up of 29 months, the incidence of all-cause death and stent thrombosis in Quartile 4 was higher than in Quartiles 1, 2, and 3 (P<0.05). The incidence of death/myocardial infarction/stroke and cardiac death in Quartile 4 was higher than in Quartiles 1 and 2 (P<0.05). Multivariate Cox regression analysis showed that RDW was an independent predictor of all-cause death (hazard ratio (HR) = 1.37, 95% confidence interval (CI) = 1.15–1.62, P<0.001) and outcomes of death/myocardial infarction/stroke (HR = 1.21, 95% CI = 1.04–1.39, P = 0.013). The cumulative survival rate of Quartile 4 was lower than that of Quartiles 1, 2, and 3 (P<0.05).

Conclusion

High RDW is an independent predictor of long-term adverse clinical outcomes in non-anemic patients with CAD treated with DES.     

Prognostic Role of MicroRNA-221 in Various Human Malignant Neoplasms: A Meta-Analysis of 20 Related Studies

Background

MicroRNA-221 (miR-221) has been shown to play an important role in cancer prognosis. In order to evaluate the predictive value of miR-221, we compiled the evidence from 20 eligible studies to perform a meta-analysis.

Design

All of relevant studies were identified by searching PubMed, Embase, and Web of Science, and were assessed by further quality evaluation. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of total and stratified analyses, for overall survival (OS) and recurrence-free survival (RFS), were calculated to investigate the association between high miR-221 expression and cancer prognosis.

Results

We found that high miR-221 expression can predict a poor OS in malignant tumors (pooled HR = 1.55, P = 0.017) but has no significant association with RFS (pooled HR = 1.02, P = 0.942). Further in stratified analyses, high miR-221 expression was significantly associated with a poor OS in Asians (pooled HR = 2.04, P = 0.010) or serum/ plasma subgroup (pooled HR = 2.28, P<0.001), and even showed significantly poor OS (pooled HR = 1.80, P<0.001) and RFS (pooled HR = 2.43, P = 0.010) in hepatocellular carcinoma (HCC) subgroup, but was correlated to a favorable RFS in prostate cancer subgroup (pooled HR = 0.51, P = 0.004).

Conclusions

Our findings demonstrate that miR-221 is more suitable to predict cancer prognosis in Asians, and it is a promising prognostic biomarker for HCC. The detection of miR-221 in serum or plasma samples may make it become an effective method for monitoring patients'' prognosis and assessing therapeutic efficacy in the future.     

Mortality among Methadone Maintenance Clients in China: A Six-Year Cohort Study

Objective

To assess the overall mortality of methadone maintenance treatment (MMT) clients in China and its associated factors.

Methods

A total of 1,511 MMT clients, all of whom enrolled in China''s first eight MMT clinics between March and December 2004, were included in this cohort study and followed for approximately six years, until June 2010. Mortality and its predictors were examined using Cox proportional hazards regression models.

Results

A total of 154 deaths were observed within 5,391 person-years (PY) of follow-up for an all-cause mortality rate of 28.6 per 1,000 PY. The leading causes of death were drug overdose (33.8%), HIV/AIDS-unrelated disease (21.4%), and HIV/AIDS (16.9%). The all-cause mortality rate of clients engaged in MMT for one year or less was roughly three times that of clients who stayed in MMT for four years or more (14.0 vs. 4.6, p<0.0001), HIV-positive subjects was nearly four times mortality rate than that of HIV-negative individuals (28.1 vs.6.8, p<0.0001). ART-naive HIV-positive subjects had approximately two times higher mortality rate than those receiving ART (31.2 vs. 17.3, <0.0001). After adjusting for confounding variables, we found that being male (HR = 1.63, CI: 1.03–2.57, p = 0.0355) and being HIV-positive (HR = 5.16, CI: 3.70–7.10, p<0.0001) were both associated with higher risk of death whereas increased durations of methadone treatment were associated with a lower risk of death (HR = 0.26, CI: 0.18–0.38, p<0.0001 for two to three years, HR = 0.08, CI: 0.05–0.14, p<0.0001 for four or more years).

Conclusion

Overall mortality was high among MMT clients in China. Specific interventions aimed at decreasing mortality among MMT clients are needed. Our study supports the need for keeping client at MMT longer and for expanding ART coverage and suggests the potential benefits of integrated MMT and ART services for drug users in China.     

Duration of Thyroid Dysfunction Correlates with All-Cause Mortality. The OPENTHYRO Register Cohort

Introduction and Aim

The association between thyroid dysfunction and mortality is controversial. Moreover, the impact of duration of thyroid dysfunction is unclarified. Our aim was to investigate the correlation between biochemically assessed thyroid function as well as dysfunction duration and mortality.

Methods

Register-based follow-up study of 239,768 individuals with a serum TSH measurement from hospitals and/or general practice in Funen, Denmark. Measurements were performed at a single laboratory from January 1st 1995 to January 1st 2011. Cox regression was used for mortality analyses and Charlson Comorbidity Index (CCI) was used as comorbidity score.

Results

Hazard ratios (HR) with 95% confidence intervals (CI) for mortality with decreased (<0.3 mIU/L) or elevated (>4.0 mIU/L) levels of TSH were 2.22; 2.14–2.30; P<0.0001 and 1.28; 1.22–1.35; P<0.0001, respectively. Adjusting for age, gender, CCI and diagnostic setting attenuated the risk estimates (HR 1.23; 95% CI: 1.19–1.28; P<0.0001, mean follow-up time 7.7 years, and HR 1.07; 95% CI: 1.02–1.13; P = 0.004, mean follow-up time 7.2 years) for decreased and elevated values of TSH, respectively. Mortality risk increased by a factor 1.09; 95% CI: 1.08–1.10; P<0.0001 or by a factor 1.03; 95% CI: 1.02–1.04; P<0.0001 for each six months a patient suffered from decreased or elevated TSH, respectively. Subdividing according to degree of thyroid dysfunction, overt hyperthyroidism (HR_overt 1.12; 95% CI: 1.06–1.19; P<0.0001), subclinical hyperthyroidism (HR_subclinical 1.09; 95% CI: 1.02–1.17; P = 0.02) and overt hypothyroidism (HR_overt 1.57; 95% CI: 1.34–1.83; P<0.0001), but not subclinical hypothyroidism (HR_subclinical 1.03; 95% CI: 0.97–1.09; P = 0.4) were associated with increased mortality.

Conclusions and Relevance

In a large-scale, population-based cohort with long-term follow-up (median 7.4 years), overt and subclinical hyperthyroidism and overt but not subclinical hypothyroidism were associated with increased mortality. Excess mortality with increasing duration of decreased or elevated serum TSH suggests the importance of timely intervention in individuals with thyroid dysfunction.     

A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma

Background

Nasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.

Methods

A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.

Results

Univariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×10⁹/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×10⁹/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR  = 0.558, 95% confidence interval or 95% CI  = 0.417–0.748; P<0.001), DFS (HR  = 0.669, 95% CI  = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI  = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).

Conclusions

The elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.     

Pre-Treatment Anemia Is a Poor Prognostic Factor in Soft Tissue Sarcoma Patients

Background

Anemia refers to low hemoglobin (Hb) levels, represents a common symptom and complication in cancer patients and was reported to negatively influence survival in patients with various malignancies. In the present study, we aimed to explore the prognostic impact of pre-operative Hb levels on clinical outcome in a large cohort of soft tissue sarcoma (STS) patients after curative surgery.

Methods

Retrospective data from 367 STS patients, which were operated between 1998 and 2013, were included in the study. Cut-off levels for anemia were defined as Hb<13 g/dl in males and Hb<12 g/dl in females according to the current WHO guidelines. The impact of pre-operative Hb levels on cancer-specific survival (CSS) and overall survival (OS) was assessed using Kaplan-Meier curves. Additionally, Hb levels were compared for the prognostic influence on CSS and OS applying univariate and multivariate Cox proportional models.

Results

Hb level was associated with established prognostic factors, including age, tumor grade, size and depth (p<0.05). Kaplan-Meier curves showed that low Hb levels were significantly associated with decreased CSS and OS in STS patients (p<0.001 for both endpoints, log-rank test). In multivariate analysis, we found an independent association between low Hb levels and poor CSS and OS (HR = 0.46, Cl 95% = 0.25–0.85, p = 0.012; HR = 0.34, Cl 95% = 0.23–0.51, p<0.001).

Conclusion

The present data underline a negative prognostic impact of low pre-operative Hb levels on clinical outcome in STS patients. Thus, Hb levels may provide an additional and cost-effective tool to discriminate between STS patients that are at high risk of mortality.     

Corticosteroids in the Treatment of Community-Acquired Pneumonia in Adults: A Meta-Analysis

Background

The benefit of corticosteroids in community-acquired pneumonia (CAP) remains controversial. We did a meta-analysis to include all the randomized controlled trials (RCTs) which used corticosteroids as adjunctive therapy, to examine the benefits and risks of corticosteroids in the treatment of CAP in adults.

Methods

Databases including Pubmed, EMBASE, the Cochrane controlled trials register, and Google Scholar were searched to find relevant trials. Randomized and quasi-randomized trials of corticosteroids treatment in adult patients with CAP were included. Effects on primary outcome (mortality) and secondary outcomes (adverse events) were accessed in this meta-analysis.

Results

Nine trials involving 1001 patients were included. Use of corticosteroids did not significantly reduce mortality (Peto odds ratio [OR] 0.62, 95% confidence interval [CI] 0.37–1.04; P = 0.07). In the subgroup analysis by the severity, a survival benefit was found among severe CAP patients (Peto OR 0.26, 95% CI 0.11–0.64; P = 0.003). In subgroup analysis by duration of corticosteroids treatment, significant reduced mortality was found among patients with prolonged corticosteroids treatment (Peto OR 0.51, 95% CI 0.26–0.97; P = 0.04; I ² = 37%). Corticosteroids increased the risk of hyperglycemia (Peto OR 2.64, 95% CI 1.68–4.15; P<0.0001), but without increasing the risk of gastroduodenal bleeding (Peto OR 1.67, 95% CI 0.41–6.80; P = 0.47) and superinfection (Peto OR 1.36, 95% CI 0.65–2.84; P = 0.41).

Conclusion

Results from this meta-analysis did not suggest a benefit for corticosteroids treatment in patients with CAP. However, the use of corticosteroids was associated with improved mortality in severe CAP. In addition, prolonged corticosteroids therapy suggested a beneficial effect on mortality. These results should be confirmed by future adequately powered randomized trials.     

The Effect of Age and NT-proBNP on the Association of Central Obesity with 6-Years Cardiovascular Mortality of Middle-Aged and Elderly Diabetic People: The Population-Based Casale Monferrato Study

Background

Among people with type 2 diabetes the relationship between central obesity and cardiovascular mortality has not been definitely assessed. Moreover, NT-proBNP is negatively associated with central obesity, but no study has examined their combined effect on survival. We have examined these issues in a well-characterized population-based cohort.

Methods and Findings

Survival data of 2272 diabetic people recruited in 2000 who had no other chronic disease have been updated to 31 December 2006. NT-proBNP was measured in a subgroup of 1690 patients. Cox proportional hazards modeling was employed to estimate the independent associations between cardiovascular and all-cause mortality and waist circumference. Mean age was 67.9 years, 49.3% were men. Both age and NT-proBNP were negatively correlated with waist circumference (r = −0.11, p<0.001 and r = −0.07, p = 0.002). Out of 2272 subjects, 520 deaths (221 for CV mortality) occurred during a median follow-up of 5.4 years. Central obesity was not associated with CV mortality (hazard ratio, HR, adjusted for age, sex, diabetes duration, 1.14, 95% CI 0.86–1.52). NTproBNP was a negative confounder and age a strong modifier of this relationship (p for interaction<0.001): age<70 years, fully adjusted model HR = 3.52 (1.17–10.57) and age ≥70 years, HR = 0.80 (0.46–1.40). Respective HRs for all-cause mortality were 1.86 (1.03–3.32) and 0.73 (0.51–1.04).

Conclusions

In diabetic people aged 70 years and lower, central obesity was independently associated with increased cardiovascular mortality, independently of the negative effect of NT-proBNP. In contrast, no effect on 6-years survival was evident in diabetic people who have yet survived up to 70 years.     

Patient Age and the Prognosis of Idiopathic Membranous Nephropathy

Background

Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients.

Methods

We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65–70 years, and 41 (24.0%) patients ≥71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients.

Results

During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR) = 3.11, 95% confidence interval (CI): 1.45–7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59–242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59–204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51–37.8; P = 0.012).

Conclusions

Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper.     

Outpatient Therapeutic Feeding Program Outcomes and Determinants in Treatment of Severe Acute Malnutrition in Tigray,Northern Ethiopia: A Retrospective Cohort Study

Background

Outpatient Therapeutic feeding Program (OTP) brings the services for management of Severe Acute Malnutrition (SAM) closer to the community by making services available at decentralized treatment points within the primary health care settings, through the use of ready-to-use therapeutic foods, community outreach and mobilization. Little is known about the program outcomes. This study revealed the levels of program outcome indictors and determinant factors to recovery rate.

Methods

A retrospective cohort study was conducted on 628 children who had been managed for SAM under OTP from April/2008 to January/2012. The children were selected using systematic random sampling from 12 health posts and 4 health centers. The study relied on information of demographic characteristics, anthropometries, Plumpy''Nut, medical problems and routine medications intakes. The results were estimated using Kaplan-Meier survival curves, log-rank test and Cox-regression.

Results

The recovery, defaulter, mortality and weight gain rates were 61.78%, 13.85%, 3.02% and 5.23 gm/kg/day, respectively. Routine medications were administered partially and children with medical problems were managed inappropriately under the program. As a child consumed one more sachet of Plumpy''Nut, the recovery rate from SAM increased by 4% (HR = 1.04, 95%-CI = 1.03, 1.05, P<0.001). The adjusted hazard ratios to recovery of children with diarrhea, appetite loss with Plumpy''Nut and failure to gain weight were 2.20 (HR = 2.20, 95%-CI = 1.31, 3.41, P = 0.001), 4.49 (HR = 1.74, 95%-CI = 1.07, 2.83, P = 0.046) and 3.88 (HR = 1.95, 95%-CI = 1.17, 3.23, P<0.001), respectively. Children who took amoxicillin and de-worming had 95% (HR = 1.95, 95%-CI = 1.17, 3.23) and 74% (HR = 1.74, 95%-CI = 1.07, 2.83) more probability to recover from SAM as compared to those who didn''t take them.

Conclusions

The OTP was partially successful. Management of children with comorbidities under the program and partial administration of routine drugs were major threats for the program effectiveness. The stakeholders should focus on creating the capacity of the OTP providers on proper management of SAM to achieve fully effective program.     

Sagittal Abdominal Diameter Is an Independent Predictor of All-Cause and Cardiovascular Mortality in Incident Peritoneal Dialysis Patients

Backgrounds and Aims

Visceral fat has a crucial role in the development and progression of cardiovascular disease, the major cause of death in end-stage renal disease (ESRD). Although sagittal abdominal diameter (SAD), as an index of visceral fat, significantly correlated with mortality in the general population, the impact of SAD on clinical outcomes has never been explored in ESRD patients. Therefore, we sought to elucidate the prognostic value of SAD in incident peritoneal dialysis (PD) patients.

Methods

We prospectively determined SAD by lateral abdominal X-ray at PD initiation, and evaluated the association of SAD with all-cause and cardiovascular mortality in 418 incident PD patients.

Results

The mean SAD was 24.5±4.3 cm, and during a mean follow-up of 39.4 months, 97 patients (23.2%) died, and 49.4% of them died due to cardiovascular disease. SAD was a significant independent predictor of all-cause [3rd versus 1st tertile, HR (hazard ratio): 3.333, 95% CI (confidence interval): 1.514–7.388, P = 0.01; per 1 cm increase, HR: 1.071, 95% CI: 1.005–1.141, P = 0.03] and cardiovascular mortality (3rd versus 1st tertile, HR: 8.021, 95% CI: 1.994–32.273, P = 0.01; per 1 cm increase, HR: 1.106, 95% CI: 1.007–1.214, P = 0.03). Multivariate fractional polynomial analysis also showed that all-cause and cardiovascular mortality risk increased steadily with higher SAD values. In addition, SAD provided higher predictive value for all-cause (AUC: 0.691 vs. 0.547, P<0.001) and cardiovascular mortality (AUC: 0.644 vs. 0.483, P<0.001) than body mass index (BMI). Subgroup analysis revealed higher SAD (≥24.2 cm) was significantly associated with all-cause mortality in men, women, younger patients (<65 years), and patients with lower BMI (<22.3 kg/m²).

Conclusions

SAD determined by lateral abdominal X-ray at PD initiation was a significant independent predictor of all-cause and cardiovascular mortality in incident PD patients. Estimating visceral fat by SAD could be useful to stratify mortality risk in these patients.     

Factors Impacting Early Mortality in Tuberculosis/HIV Patients: Differences between Subjects Na?ve to and Previously Started on HAART

Background

Mortality among patients with tuberculosis (TB)/HIV is highest during the first few months of antituberculous therapy. The objective of this study was to assess the factors associated with early mortality among TB/HIV patients and whether these factors are similar for HAART naïve and those with prior HAART initiation.

Methods

Prospective cohort study including HIV patients with tuberculosis confirmed by culture, cared for at a referral center in Rio de Janeiro, Brazil. Multivariable Cox analysis was used to assess predictors of mortality within 3 months of antituberculous therapy.

Results

Among 227 patients included, 90 (40%) started HAART before TB diagnosis. The median time to TB diagnosis after ARV initiation was 5.9 months (interquartile range [IQR] 3.0–8.9 months). Fourteen patients (6%) died within the first 3 months. Mortality was not different between patients previously started on HAART and those who were naïve to it. In the overall adjusted analysis, HAART use during TB treatment (hazard ratio [HR] = 0.21, 95% confidential interval [CI] = 0.06–0.72) and CD4 lymphocyte count >100 cells/mm3 (HR = 0.21, 95% CI = 0.04–0.99) were associated with lower mortality, while subjects with unknown baseline CD4 lymphocyte count (HR = 9.39, 95% CI = 2.56–34.5) had higher mortality. In subgroup analysis, among HAART naïve subjects, disseminated TB (HR = 5.32, 95% CI = 1.09–25.8) and unknown baseline CD4 lymphocyte count (HR = 13.2, 95% CI = 2.71–64.5) were associated with significantly higher mortality, while HAART (HR = 0.14, 95% CI = 0.03–0.69) predicted a better outcome. Among subjects previously started on HAART, mortality was significantly associated with duration of TB symptoms >120 days (HR = 6.15, 95% CI = 1.15–32.9).

Conclusions

Predictors of early mortality among TB/HIV patients may vary according to the timing of HAART initiation. Among HAART naïve patients, mortality was influenced by baseline clinical severity, HAART use and, possibly, the quality of care preceding TB diagnosis. For patients with prior HAART initiation, longer delays in TB diagnosis predicted a significantly higher mortality.     

Downregulated E-Cadherin Expression Indicates Worse Prognosis in Asian Patients with Colorectal Cancer: Evidence from Meta-Analysis

Background

Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression and aggressiveness of colorectal carcinoma. E-cadherin is the best-characterized molecular marker of EMT, but its prognostic significance for patients with CRC remains inconclusive.

Methodology

Eligible studies were searched from the PubMed, Embase and Web of Science databases. Correlation between E-cadherin expression and clinicopathological features and prognosis was analyzed. Subgroup analysis was also performed according to study location, number of patients, quality score of studies and cut-off value.

Principal Findings

A total of 27 studies comprising 4244 cases met the inclusion criteria. Meta-analysis suggested that downregulated E-cadherin expression had an unfavorable impact on overall survival (OS) of CRC (n = 2730 in 14 studies; HR = 2.27, 95%CI: 1.63–3.17; Z = 4.83; P = 0.000). Subgroup analysis indicated that low E-cadherin expression was significantly associated with worse OS in Asian patients (n = 1054 in 9 studies; HR = 2.86, 95%CI: 2.13–3.7, Z = 7.11; P = 0.000) but not in European patients (n = 1552 in 4 studies; HR = 1.14, 95%CI: 0.95–1.35, Z = 1.39; P = 0.165). In addition, reduced E-cadherin expression indicated an unfavorable OS only when the cut off value of low E-cadherin expression was >50% (n = 512 in 4 studies; HR = 2.08, 95%CI 1.45–2.94, Z = 4.05; P = 0.000). Downregulated E-cadherin expression was greatly related with differentiation grade, Dukes'' stages, lymphnode status and metastasis. The pooled OR was 0.36(95%CI: 0.19–0.7, Z = 3.03, P = 0.002), 0.34(95%CI: 0.21–0.55, Z = 6.61, P = 0.000), 0.49(95%CI: 0.32–0.74, Z = 3.02, P = 0.002) and 0.45(95%CI: 0.22–0.91, Z = 3.43, P = 0.001), respectively.

Conclusions

This study showed that low or absent E-cadherin expression detected by immunohistochemistry served as a valuable prognostic factor of CRC. However, downregulated E-cadherin expression seemed to be associated with worse prognosis in Asian CRC patients but not in European CRC patients. Additionally, this meta-analysis suggested that the negative threshold of E-cadherin should be >50% when we detected its expression in the immunohistochemistry stain.     

Cancer Incidence and Mortality in Patients with Type 2 Diabetes Treated with Human Insulin: A Cohort Study in Shanghai

Aim

The aim was to investigate the association between human insulin and cancer incidence and mortality in Chinese patients with type 2 diabetes.

Methods

We recruited 8,774 insulin-naïve diabetes patients from the Shanghai Diabetes Registry (SDR). The follow-up rate was 85.4%. All subjects were divided into the insulin use cohort (n = 3,639) and the non-insulin use cohort (n = 5,135). The primary outcome was the first diagnosis of any cancer. The secondary outcome was all-cause mortality. Cox proportional hazards model was used to estimate the relative risk (RR) of cancer and mortality.

Results

We observed 98 cancer events in the insulin use cohort and 170 in the non-insulin use cohort. Cancer incidence rates were 78.6 and 74.3 per 10,000 patients per year in the insulin users and the non-insulin users, respectively. No significant difference in cancer risk was observed between the two cohorts (adjusted RR = 1.20, 95% CI 0.89–1.62, P = 0.228). Regarding site-specific cancers, only the risk of liver cancer was significantly higher in the insulin users compared to that in the non-insulin users (adjusted RR = 2.84, 95% CI 1.12–7.17, P = 0.028). The risks of overall mortality (adjusted RR = 1.89, 95% CI 1.47–2.43, P<0.0001) and death from cancer (adjusted RR = 2.16, 95% CI 1.39–3.35, P = 0.001) were all significantly higher in the insulin users than in the non-insulin users.

Conclusion

There was no excess risk of overall cancer in patients with type 2 diabetes who were treated with human insulin. However, a significantly higher risk of liver cancer was found in these patients. Moreover, insulin users showed higher risks of overall and cancer mortality. Considering that individuals treated with insulin were more likely to be advanced diabetic patients, caution should be used in interpreting these results.