Procalcitonin Levels Predict Acute Kidney Injury and Prognosis in Acute Pancreatitis: A Prospective Study

Background

Acute kidney injury (AKI) has been proposed as a leading cause of mortality for acute pancreatitis (AP) patients admitted to the intensive care unit (ICU). This study investigated the predictive value of procalcitonin (PCT) for AKI development and relevant prognosis in patients with AP, and compared PCT’s predictive power with that of other inflammation-related variables.

Methods

Between January 2011 and March 2013, we enrolled 305 cases with acute pancreatitis admitted to ICU. Serum levels of PCT, serum amyloid A (SAA), interleukin-6 (IL-6), and C reactive protein (CRP) were determined on admission. Serum PCT was tested in patients who developed AKI on the day of AKI occurrence and on either day 28 after occurrence (for survivors) or on the day of death (for those who died within 28 days).

Results

Serum PCT levels were 100-fold higher in the AKI group than in the non-AKI group on the day of ICU admission (p<0.05). The area under the receiver-operating characteristic (ROC) curve of PCT for predicting AKI was 0.986, which was superior to SAA, CRP, and IL-6 (p<0.05). ROC analysis revealed all variables tested had lower predictive performance for AKI prognosis. The average serum PCT level on day 28 (2.67 (0.89, 7.99) ng/ml) was significantly (p<0.0001) lower than on the day of AKI occurrence (43.71 (19.24,65.69) ng/ml) in survivors, but the serum PCT level on death (63.73 (34.22,94.30) ng/ml) was higher than on the day of AKI occurrence (37.55 (18.70,74.12) ng/ml) in non-survivors, although there was no significant difference between the two days in the latter group (p = 0.1365).

Conclusion

Serum PCT is superior to CRP, IL-6, and SAA for predicting the development of AKI in patients with AP, and also can be used for dynamic evaluation of AKI prognosis.     

A Prospective Stratified Case-Cohort Study on Statins and Multiple Adverse Events in Japan

Purpose

To assess the association between statins and diverse adverse events in Japanese population.

Methods

New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of “switcher”, use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow’s weighting method. Data were also analyzed by the method proposed by Breslow in 2009.

Results

A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009).

Conclusions

Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.     

A Synthesis of Vitamin B6

In the presence of basic catalyst condensation of dehydrolevulinate and cyanoacetamide afforded ethyl 2-methyl-5-cyano-6-pyridone-4-carboxylate [IV]. Starting from [IV], a total synthesis of vitamin B₆ was described.     

Metabolic Syndrome and Breast Cancer Risk: A Case-Cohort Study Nested in a Multicentre Italian Cohort

Background

Metabolic syndrome (defined as at least three among abdominal obesity, high blood triglycerides, low high-density lipoprotein cholesterol, high blood glucose, and high blood pressure) is emerging as a risk factor for breast cancer; however few studies – most confined to postmenopausal women – have investigated associations between breast cancer risk and metabolic syndrome. The purpose of this study was to examine the association between metabolic syndrome and its components, and risk of breast cancer in postmenopausal and premenopausal women.

Methods

We performed a case-cohort study on 22,494 women recruited in 1993-1998 to four Italian centres (Turin, Varese, Naples, Ragusa) of the European Prospective Investigation into Cancer and Nutrition (EPIC) and followed-up for up to 15 years. A random subcohort of 565 women was obtained and 593 breast cancer cases were diagnosed. Hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounders, were estimated by Prentice-weighted Cox proportional hazards models.

Results

Presence of metabolic syndrome was associated with significantly increased breast cancer risk in all women (HR 1.52, 95%CI 1.14-2.02). When the analyses were repeated separately for menopausal status, the association was limited to postmenopausal women (HR 1.80, 95%CI 1.22-2.65) and absent in premenopausal women (HR 0.71, 95%CI 0.43-1.16); P for interaction between metabolic syndrome and menopausal status was 0.001. Of metabolic syndrome components, only high blood glucose was significantly associated with increased breast cancer risk in all women (HR 1.47, 95%CI 1.13-1.91) and postmenopausal women (HR 1.89, 95%CI 1.29-2.77), but not premenopausal women (HR 0.80, 95%CI 0.52-1.22; P interaction=0.004).

Conclusions

These findings support previous data indicating that metabolic syndrome is an important risk factor for breast cancer in postmenopausal women, but not in premenopausal women, and suggest that prevention of metabolic syndrome through lifestyle changes could confer protection against breast cancer.     

Association between Body Mass Index and Prognosis of Colorectal Cancer: A Meta-Analysis of Prospective Cohort Studies

Studies have reported conflicting results on the association between body mass index (BMI) and prognosis of colorectal cancer. Therefore, we have conducted a meta-analysis of prospective studies, which examined the association of pre- and post-diagnostic BMI with colorectal cancer-specific mortality and all-cause mortality in patients with colorectal cancer. We searched Medline and EMBASE database published between 1970 and September 2014. A total of 508 articles were identified, of which 16 prospective cohort studies were included for the current meta-analysis. The analysis included 58,917 patients who were followed up over a period ranging from 4.9 to 20 years (median: 9.9 years). We found that being underweight before cancer diagnosis was associated with increased all-cause mortality (Relative risk [RR]: 1.63, 95% CI: 1.18–2.23, p < 0.01) and being obese (BMI ≥ 30 kg/m²) before cancer diagnosis was associated with increased colorectal cancer-specific mortality (RR: 1.22, 95% CI: 1.003–1.35, p < 0.01) and all-cause mortality (RR: 1.25, 95% CI: 1.14–1.36, p < 0.01). On the other hand, being underweight (RR: 1.33, 95% CI: 1.20–1.47, p < 0.01), obese (RR: 1.08, 95% CI: 1.03–1.3, p < 0.01), and class II/III obese (BMI ≥ 35 kg/m²; RR: 1.13, 95% CI: 1.04–1.23, p < 0.01) after diagnosis were associated with significantly increased all-cause mortality. Being obese prior to diagnosis of colorectal cancer was associated with increased colorectal cancer-specific mortality and all-cause mortality, whereas being obese after diagnosis was associated with increased all-cause mortality. The associations with being underweight may reflect reverse causation. Maintaining a healthy body weight should be discussed with colorectal cancer survivors.     

A Prospective Study of Adiposity and All‐Cause Mortality: The Malmö Diet and Cancer Study

Objective: This study aims to examine the association between various measures of adiposity and all‐cause mortality in Swedish middle‐aged and older men and women and, additionally, to describe the influences of age and sex on these associations. Research Methods and Procedures: A prospective analysis was performed in a cohort of 10,902 men and 16,814 women ages 45 to 73 years who participated in the Malmö Diet and Cancer Study in Sweden. Baseline examinations took place between 1991 and 1996, and 982 deaths were documented during an average follow‐up of 5.7 years. All‐cause mortality was related to the following variables measured at baseline: body mass index (BMI), percentage of body fat, lean body mass (LBM), and waist‐to‐hip ratio (WHR), with adjustment for age and selected covariates. Body composition data were derived from bioelectrical impedance analysis. Results: The association between percentage of body fat and mortality was modified by age, particularly in women. For instance, fatness was associated with excess mortality in the younger women but with reduced mortality in the older women. Weaker associations were seen for BMI than for percentage of body fat in both sexes. Placement in the top quintiles of waist‐to‐hip ratio, independent of overall body fat, was a stronger predictor of mortality in women than in men. The observed associations could not be explained by bias from early death or antecedent disease. Discussion: The findings reveal sex and age differences for the effects of adiposity and WHR on mortality and indicate the importance of considering direct measures of adiposity, as opposed to BMI, when describing obesity‐related mortality risks.     

Risk Models and Scoring Systems for Predicting the Prognosis in Critically Ill Cirrhotic Patients with Acute Kidney Injury: A Prospective Validation Study

Background

Cirrhotic patients with acute kidney injury (AKI) admitted to intensive care units (ICUs) show extremely high mortality rates. We have proposed the MBRS scoring system, which can be used for assessing patients on the day of admission to the ICU; this new system involves determination of mean arterial pressure (MAP) and bilirubin level and assessment of respiratory failure and sepsis. We had used this scoring system to analyze the prognosis of ICU cirrhotic patients with AKI in 2008, and the current study was an external validation of this scoring system.

Methods

A total of 190 cirrhotic patients with AKI were admitted to the ICU between March 2008 and February 2011. We prospectively analyzed and recorded the data for 31 demographic parameters and some clinical characteristic variables on day 1 of admission to the ICU; these variables were considered as predictors of mortality.

Results

The overall in-hospital mortality rate was 73.2% (139/190), and the 6-month mortality rate was 83.2% (158/190). Hepatitis B viral infection (43%) was observed to be the cause of liver disease in most of the patients. Multiple logistic regression analysis indicated that the MBRS and Acute Physiology and Chronic Health Evaluation III (ACPACHE III) scores determined on the first day of admission to the ICU were independent predictors of in-hospital mortality in patients. In the analysis of the area under the receiver operating characteristic (AUROC) curves, the MBRS scores showed good discrimination (AUROC: 0.863±0.032, p<0.001) in predicting in-hospital mortality.

Conclusion

On the basis of the results of this external validation, we conclude that the MBRS scoring system is a reproducible, simple, easy-to-apply evaluation tool that can increase the prediction accuracy of short-term prognosis in critically ill cirrhotic patients with AKI.     

Carboplatin with Decitabine Therapy,in Recurrent Platinum Resistant Ovarian Cancer,Alters Circulating miRNAs Concentrations: A Pilot Study

Objective

Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study—consisting of patients with recurrent, platinum-resistant ovarian cancer—was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration.

Methods

We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS).

Results

Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p<0.05), in recurrent platinum resistant ovarian cancer patients, that were associated with response to decitabine followed by carboplatin chemotherapy. Furthermore, lower concentrations of miR-148b-5p after this chemotherapy regimen were associated (P<0.05) with the PFS.

Conclusions

This is the first report demonstrating altered circulating miRNA concentrations following a combination platinum plus HMA chemotherapy regiment. In addition, circulating miR-148b-5p concentrations were associated with PFS and may represent a novel biomarker of therapeutic response, with this chemotherapy regimen, in women with recurrent, drug-resistant ovarian cancer.     

Association of Diabetes and Prognosis of Minor Stroke and Its Subtypes: A Prospective Observational Study

BackgroundThe association between diabetes mellitus (DM) and prognosis of minor stroke is unclear. The aim of this study is to investigate whether DM contributes to the prognosis of minor stroke or its specific subtype.MethodsAll minor ischemic stroke patients were derived from the China National Stroke Registry and classified into 5 subtypes according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. DM was defined as either self-reported physician diagnosis of diabetes or use of hypoglycemic medications during hospitalization or at discharge. Patients were followed up for 1 year for clinical outcomes of recurrent stroke, death and functional outcome. Poor functional outcomes were defined as a score of 2–6 for modified Rankin Score. Associations between DM and prognosis of minor stroke and its subtypes were analyzed by univariable and multivariable logistic regression.ResultsOf 4,548 patients with minor stroke, 1,230(27.0%) patients had DM, 1,038(22.8%) had poor outcomes and 570(13.0%) of 4,401 patients had recurrent stroke at 1 year. In multivariable analyses, DM were significantly associated with 1-year stroke recurrence (Odds Ratio [OR], 1.31; 95% confidence interval [CI]: 1.08–1.59) and poor outcome (OR, 1.51; 95%CI: 1.28–1.77). Among the subtypes of minor stroke, DM was only significantly associated with 1-year stroke recurrence (OR, 1.63; 95%CI: 1.07–2.50) and poor outcome (OR, 1.73; 95%CI: 1.22–2.45) in the small-artery occlusion subtype.ConclusionsDM significantly increased the risk of stroke recurrence and poor outcome in the small-artery occlusion subtype, but not in other subtypes of minor stroke.     

Interactions between Diet,Lifestyle and IL10, IL1B,and PTGS2/COX-2 Gene Polymorphisms in Relation to Risk of Colorectal Cancer in a Prospective Danish Case-Cohort Study

Background & Aims

Diet contributes to colorectal cancer development and may be potentially modified. We wanted to identify the biological mechanisms underlying colorectal carcinogenesis by assessment of diet-gene interactions.

Methods

The polymorphisms IL10 C-592A (rs1800872), C-rs3024505-T, IL1b C-3737T (rs4848306), G-1464C (rs1143623), T-31C (rs1143627) and PTGS2 (encoding COX-2) A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) were assessed in relation to risk of colorectal cancer (CRC) and interaction with diet (red meat, fish, fibre, cereals, fruit and vegetables) and lifestyle (non-steroid-anti-inflammatory drug use and smoking status) was assessed in a nested case-cohort study of nine hundred and seventy CRC cases and 1789 randomly selected participants from a prospective study of 57,053 persons.

Results

IL1b C-3737T, G-1464C and PTGS2 T8473C variant genotypes were associated with risk of CRC compared to the homozygous wildtype genotype (IRR=0.81, 95%CI: 0.68-0.97, p=0.02, and IRR=1.22, 95%CI: 1.04-1.44, p=0.02, IRR=0.75, 95%CI: 0.57-0.99, p=0.04, respectively). Interactions were found between diet and IL10 rs3024505 (P-value for interaction (P_int); meat=0.04, fish=0.007, fibre=0.0008, vegetables=0.0005), C-592A (P_int; fibre=0.025), IL1b C-3737T (P_int; vegetables=0.030, NSAID use=0.040) and PTGS2 genotypes G-765C (P_int; meat=0.006, fibre=0.0003, fruit 0.004), and T8473C (P_int; meat 0.049, fruit=0.03) and A-1195G (P_int; meat 0.038, fibre 0.040, fruit=0.059, vegetables=0.025, and current smoking=0.046).

Conclusions

Genetically determined low COX-2 and high IL-1β activity were associated with increased risk of CRC in this northern Caucasian cohort. Furthermore, interactions were found between IL10, IL1b, and PTGS2 and diet and lifestyle factors in relation to CRC. The present study demonstrates that gene-environment interactions may identify genes and environmental factors involved in colorectal carcinogenesis.     

Circulating Carnosine Dipeptidase 1 Associates with Weight Loss and Poor Prognosis in Gastrointestinal Cancer

Background

Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia.

Design/Subjects

Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer.

Results

Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results.

Conclusions

In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC.     

Studies on the Biosynthesis of Vitamin B6

The production of vitamin B₆ (B₆) compounds with a cell-suspension of Achromobacter cycloclastes A.M.S. 6201 under various conditions were examined. An obvious accumulation of B₆ compounds in the incubation medium with a cell-suspension of the organism harvested at the middle to later part of exponential phase of growth was observed. γ-Aminobutyric acid or β-alanine was found to stimulate the B₆ production markedly, when they were added to the incubation mixture together with glycerol. Some discussion on the implication of these compounds as precursors of B₆ was presented.