Prediction of future risk of any and higher-grade prostate cancer based on the PLCO and SELECT trials.

BACKGROUND: A model was built that characterized effects of individual factors on five-year prostate cancer (PCa) risk in the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). This model was validated in a third San Antonio Biomarkers of Risk (SABOR) screening cohort. METHODS: A prediction model for 1- to 5-year risk of developing PCa and Gleason > 7 PCa (HG PCa) was built on PLCO and SELECT using the Cox proportional hazards model adjusting for patient baseline characteristics. Random forests and neural networks were compared to Cox proportional hazard survival models, using the trial datasets for model building and the SABOR cohort for model evaluation. The most accurate prediction model is included in an online calculator. RESULTS: The respective rates of PCa were 8.9%, 7.2%, and 11.1% in PLCO (n = 31,495), SELECT (n = 35,507), and SABOR (n = 1790) over median follow-up of 11.7, 8.1 and 9.0 years. The Cox model showed higher prostate-specific antigen (PSA), BMI and age, and African American race to be associated with PCa and HGPCa. Five-year risk predictions from the combined SELECT and PLCO model effectively discriminated risk in the SABOR cohort with C-index 0.76 (95% CI [0.72, 0.79]) for PCa, and 0.74 (95% CI [0.65,0.83]) for HGPCa. CONCLUSIONS: A 1- to 5-year PCa risk prediction model developed from PLCO and SELECT was validated with SABOR and implemented online. This model can individualize and inform shared screening decisions.

A prospective evaluation of clinical and genetic predictors of weight changes in breast cancer survivors.

BACKGROUND: Postdiagnosis weight gain in patients with breast cancer has been associated with increased cancer recurrence and mortality. This study was designed to identify risk factors for weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: The weight of 393 patients with breast cancer from the Northwestern Robert H. Lurie Cancer Center was measured over a 2-year period from diagnosis, with body mass index (BMI) change over 18 months as the primary endpoint. Demographics, clinical factors, treatment methods, as well as tumor characteristics were also recorded; and a lifestyle questionnaire was conducted. Blood samples were genotyped for 16 single nucleotide polymorphisms in FTO, adiponectin pathway genes (ADIPOQ, ADIPOR1), and FNDC5. Serum leptin, adiponectin, and irisin levels also were measured. RESULTS: Mean ± standard deviation 18-month BMI changes were 0.68 ± 1.42, 0.98 ± 1.62, 0.79 ± 1.74, and -0.44 ± 1.58 kg/m2 for patients ages <40, 40 to 49, 50 to 59, and ≥60 years, respectively. The optimal multivariable model for 18-month BMI change contained the predictors age, height, and endocrine therapy, but only age was statistically significant, with a 0.04 kg/m2 increase in 18-month BMI change per younger year of age. Single nucleotide polymorphisms in ADIPOR1, FTO, and FNDC5 were associated with 18-month BMI change, and the first 2 remained significant after adjusting for the optimal clinical model (all P < .05). CONCLUSIONS: Women age 60 years and younger at the time of breast cancer diagnosis who have an obesity genetic risk model are at increased risk for weight gain after treatment and should be targeted for weight-maintenance interventions. Cancer 2017;123:2413-21. © 2017 American Cancer Society.

Serial Percent Free Prostate Specific Antigen in Combination with Prostate Specific Antigen for Population Based Early Detection of Prostate Cancer.

PURPOSE: We characterized the diagnostic properties of serial percent free prostate specific antigen in relation to prostate specific antigen in a multiethnic, multiracial cohort of healthy men. MATERIALS AND METHODS: A total of 6,982 percent free prostate specific antigen and prostate specific antigen measurements were obtained from participants in a greater than 12-year Texas screening study comprising 1,625 men who never underwent biopsy, 497 who underwent 1 or more biopsies negative for prostate cancer and 61 diagnosed with prostate cancer. We evaluated the ROC AUC of percent free prostate specific antigen and the proportion of patients with fluctuating values across multiple visits determined according to 2 thresholds (less than 15% vs 25%). The proportion of cancer cases in which percent free prostate specific antigen indicated a positive test before prostate specific antigen greater than 4 ng/ml did and the number of negative biopsies that would have been spared by negative percent free prostate specific antigen test results were calculated. RESULTS: Percent free prostate specific antigen fluctuated around its threshold of less than 25% (less than 15%) in 38.3% (78.1%), 42.2% (20.9%), and 11.4% (25.7%) of patients never biopsied, and with negative and positive biopsies, respectively. At the same thresholds, percent free prostate specific antigen tested positive earlier than prostate specific antigen in 71.4% and 34.2% of cancer cases, respectively. Among men with multiple negative biopsies and PSA greater than 4 ng/ml, percent free PSA would have tested negative in 31.6% and 65.8%, respectively. CONCLUSIONS: Percent free prostate specific antigen should accompany prostate specific antigen testing to potentially spare unnecessary biopsies or detect cancer earlier. When near the threshold, both tests should be repeated due to commonly observed fluctuation.

Surrogate endpoints in second-line treatment for mCRC: a systematic literature-based analysis from 23 randomised trials.

PURPOSE: To evaluate progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) as potential surrogate endpoints (SEP) for overall survival (OS) in second-line treatment for metastatic colorectal cancer (mCRC). METHODS: A systematic literature search of randomised trials of second-line chemotherapy for mCRC reported from January 2000 to July 2013 was performed. Correlation coefficients weighted by number of patients in the treatment arms between median PFS, ORR and DCR with median OS were estimated. RESULTS: Twenty-three trials reflecting 10 800 patients met the inclusion criteria. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. PFS showed moderate correlation with OS [RPFS = 0.73; 95% confidence interval (CI) 0.61-0.82]. In contrast, ORR only weakly correlated with OS (RORR = 0.58; 95% CI 0.38-0.72, n = 22). Despite a small number of studies (n = 10) reporting on DCR, moderate correlation with OS was observed (RDCR = 0.74; 95% CI 0.56-0.86). CONCLUSION: Based on the available trial-level data, PFS may serve as an appropriate SEP in second-line chemotherapy for mCRC. A small number of studies revealed moderate correlation of DCR with OS that justifies further investigation.

Nutrient status: a missing factor in phenological and pollen research?

Phenology ranks among the best ecosystem processes for fingerprinting climate change since temperature explains a high percentage of the interannual or spatial variation in phenological onset dates. However, roles of other environmental variables, such as foliar nutrient concentrations, are far from adequately understood. This observational study examined the effects of air temperature and 11 nutrients on spring phenology of Betula pendula Roth (birch) along an urban-rural gradient in Munich, Germany, during the years 2010/2011. Moreover, the influence of temperature, nutrients, and air pollutants (NO2 and O3) on the amounts of pollen and catkin biomass in 2010 was evaluated. In addition to the influence of higher temperatures advancing phenological onset dates, higher foliar concentrations of potassium, boron, zinc, and calcium were statistically significantly linked to earlier onset dates. Since flushing of leaves is a turgor-driven process and all the influential nutrients are involved in cell extension, membrane function, and stability, there might be a reasonable physiological interpretation of the observed association. The amounts of pollen were negatively correlated with temperature, atmospheric NO2, and foliar iron concentration, suggesting that these variables restrict pollen production. The results of this study suggested an influence of nutritional status on both phenology and pollen production. The interaction of urbanization and climate change should be considered in the assessment of the impact of global warming on ecosystems and human health.

Angpt2/Tie2 autostimulatory loop controls tumorigenesis.

Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF-PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin-2 (ANGPT2) is elevated in patients with NF-PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF-PitNETs in the GH3 PitNET cell line, primary human NF-PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF-PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF-PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC-specific expands our view on the microenvironmental cues that are essential for tumor progression.

Afamin and apolipoprotein A-IV: novel protein markers for ovarian cancer.

Comparative proteomics identified the vitamin E-binding plasma protein afamin as a potential novel tumor marker for ovarian cancer. In addition, we observed in a previous small study decreased plasma concentrations of apolipoprotein A-IV (apoA-IV) in preoperative patients with kidney cancer. The aim of this study was therefore to analyze afamin and apoA-IV in a large case-control study to evaluate the diagnostic utility of the two potential novel tumor markers in ovarian cancer patients. We measured plasma concentrations of afamin and apoA-IV by means of a specific sandwich-type ELISA using affinity-purified polyclonal and monoclonal antibodies in 181 ovarian cancer patients of various clinical stages, 399 patients with benign gynecologic diseases, including endometriosis, and 177 controls and compared results with those for the conventional ovarian cancer tumor marker cancer antigen 125 (CA125). Afamin concentrations decreased from a median of 70.7 mg/L (range, 34.6-116.1 mg/L) in healthy controls to 65.2 mg/L (range, 20.2-206.6 mg/L) in patients with benign gynecologic diseases to 56.0 mg/L (range, 4.7-96.0 mg/L) in ovarian cancer patients (P < 0.001 for all pairwise comparisons). Similar results were obtained with apoA-IV concentrations decreasing from 13.0 mg/dL (range, 5.5-34.0 mg/dL) in controls to 11.7 mg/dL (range, 2.0-32.3 mg/dL) in benign conditions to 9.4 mg/dL (range, 0.3-29.5 mg/dL) in ovarian cancer (all P < 0.001). Receiver operating characteristic analysis for differentiating ovarian cancer patients from healthy controls revealed for a specificity of 90% sensitivity values of 92.4%, 42.4%, and 40.8% for CA125, afamin, and apoA-IV, respectively. Afamin, but not apoA-IV, added independent diagnostic information to CA125 and age for differentiating ovarian cancer from benign and healthy samples; the odds ratio of ovarian cancer was reduced by 44% for each doubling of afamin (P = 0.032). The relatively low sensitivity, however, clearly indicates that afamin and apoA-IV alone are not sufficiently suitable as diagnostic markers for ovarian cancer. Afamin contributes, however, independent diagnostic information to CA125, thus establishing its potential as an adjunct marker to CA125.

Yearly prostate specific antigen and digital rectal examination fluctuations in a screened population.

PURPOSE: Prostate biopsy is often recommended based on increases in prostate specific antigen and/or abnormal digital rectal examination. We investigated the stability of a single positive test during the next 3 consecutive years. MATERIALS AND METHODS: A total of 2,578 participants in a San Antonio screening cohort with 2 or more consecutive annual prostate specific antigen and digital rectal examination tests were identified. Occurrences of an increased prostate specific antigen (2.5 ng/ml or greater) followed by 1 or more nonincreased prostate specific antigen results were compared with similar fluctuations of digital rectal examination from abnormal to normal. RESULTS: In 2,272 men who did not have a biopsy during the study, in 23.3% of 744 incidences of an increased prostate specific antigen with 1 year of followup, the next prostate specific antigen was not increased. In 19.5% of 462 incidences of an increased prostate specific antigen with 2 years of followup, the next 2 consecutive prostate specific antigen levels were not increased. Finally, in 17.5% of 285 incidences of an increased prostate specific antigen with 3 years of followup, the next 3 consecutive prostate specific antigens were not increased. Rates were similar but lower in 221 men with 1 or more negative biopsies during the study and in 85 men in whom prostate cancer eventually developed during the study. In contrast, approximately 70% of abnormal digital rectal examinations were normal the following year even in patients with prostate cancer, and in the majority of incidences remained normal the next 2 to 3 consecutive years. CONCLUSIONS: Occurrences of reversed prostate specific antigen cut point or abnormal digital rectal examination based decisions to biopsy 1 or more years after the initial test are not uncommon, suggesting repetition of these tests.

Total prostate specific antigen stability confirmed after long-term storage of serum at -80C.

PURPOSE: We characterized the long-term stability of total prostate specific antigen in serum samples after storage at -80C from 2001 until 2007. MATERIALS AND METHODS: From the San Antonio Biomarkers of Risk biorepository we chose serum samples from white men 55.2 to 80.5 years old (median age 63.3) in which prostate specific antigen was measured in 2001. These men were not diagnosed with prostate cancer by 2007. A blocked randomization scheme was used to randomly select 47 serum samples with prostate specific antigen values spread over the reference ranges 0.0 to 0.4 (10), 0.5 to 0.9 (10), 1.0 to 1.9 (10), 2.0 to 3.9 (11) and 4.0 to 10.0 ng/ml (6) for repeat measurement by the same assay in 2007. Spearman's correlation coefficient was used to calculate the correlation and the paired t test was used to test the null hypothesis of no average difference between prostate specific antigen measured in 2001 and 2007. RESULTS: Median prostate specific antigen values were 1.20 ng/ml (range 0.20 to 7.20) in 2001 and 1.30 (range 0.20 to 6.70) in 2007. In 2001 and 2007 mean +/- SD prostate specific antigen was 1.76 +/- 1.59 and 1.84 +/- 1.64 ng/ml, and the coefficient of variation was 0.91 and 0.89, respectively. The correlation between prostate specific antigen values in 2001 and 2007 was high (0.995). Prostate specific antigen values in 2007 were consistently and statistically significantly higher than in 2001 (mean 0.08 ng/ml, p = 0.005). Systematic and random error increased slightly with increasing prostate specific antigen. CONCLUSIONS: Agreement between total prostate specific antigen values measured from serum samples in 2001, stored at -80C for 7 years and then remeasured was highly correlative.

Predicting prostate cancer risk through incorporation of prostate cancer gene 3.

PURPOSE: The online Prostate Cancer Prevention Trial risk calculator combines prostate specific antigen, digital rectal examination, family and biopsy history, age and race to determine the risk of prostate cancer. In this report we incorporate the biomarker prostate cancer gene 3 into the Prostate Cancer Prevention Trial risk calculator. MATERIALS AND METHODS: Methodology was developed to incorporate new markers for prostate cancer into the Prostate Cancer Prevention Trial risk calculator based on likelihood ratios calculated from separate case control or cohort studies. The methodology was applied to incorporate the marker prostate cancer gene 3 into the risk calculator based on a cohort of 521 men who underwent prostate biopsy with measurements of urinary prostate cancer gene 3, serum prostate specific antigen, digital rectal examination and biopsy history. External validation of the updated risk calculator was performed on a cohort of 443 European patients, and compared to Prostate Cancer Prevention Trial risks, prostate specific antigen and prostate cancer gene 3 by area underneath the receiver operating characteristic curve, sensitivity and specificity. RESULTS: The AUC of posterior risks (AUC 0.696, 95% CI 0.641-0.750) was higher than that of prostate specific antigen (AUC 0.607, 95% CI 0.546-0.668, p = 0.001) and Prostate Cancer Prevention Trial risks (AUC 0.653, 95% CI 0.593-0.714, p <0.05). Although it was higher it was not statistically significantly different from that of prostate cancer gene 3 (AUC 0.665, 95% CI 0.610-0.721, p >0.05). Sensitivities of posterior risks were higher than those of prostate cancer gene 3, prostate specific antigen and Prostate Cancer Prevention Trial risks. CONCLUSIONS: New markers for prostate cancer can be incorporated into the Prostate Cancer Prevention Trial risk calculator by a novel approach. Incorporation of prostate cancer gene 3 improved the diagnostic accuracy of the Prostate Cancer Prevention Trial risk calculator.

Assessment of 54 biomarkers for biopsy-detectable prostate cancer.

OBJECTIVE: We analyzed the association of 54 biomarkers from seven classes including adipokines, immune response metalloproteinases, adhesion molecules, and growth factors with prostate cancer risk adjusting for the Prostate Cancer Prevention Trial (PCPT) risk score. METHODS: A total of 123 incident prostate cancer cases and 127 age-matched controls were selected from subjects in the San Antonio Center for Biomarkers of Risk of Prostate Cancer cohort study. Prediagnostic serum concentrations were measured in the sample collected at baseline using LabMAP technology. The odds ratios (OR) of prostate cancer risk associated with serum concentrations of 54 markers were estimated using univariate conditional logistic regression before and after adjustment for the PCPT risk score. Two-way hierarchical unsupervised clustering techniques were used to evaluate whether the 54-marker panel distinguished cases from controls. RESULTS: Vascular endothelial growth factor, resistin, interleukin 1Ra (IL-1Ra), granulocyte colony-stimulating factor, matrix metalloproteinase-3, plasminogen activator inhibitor, and kallikrein-8 were statistically significantly (P < 0.05) underexpressed in prostate cancer cases, and alpha-fetoprotein was statistically significantly overexpressed in prostate cancer cases, but all had area underneath the receiver-operating characteristic curve <60%; none were statistically significant adjusting for multiple comparisons (P < 0.0008) or after adjustment for the PCPT risk score. Statistical clustering of patients by the marker panel did not distinguish a separate group of cases from controls. CONCLUSIONS: This age-matched case-control study did not support findings of increased diagnostic potential from a 54-marker panel when compared with the conventional risk factors incorporated in the PCPT risk calculator. Future discovery of new biomarkers should always be tested and compared against conventional risk factors before applying them in clinical practice.

Biomarkers for prostate cancer detection.

PURPOSE: The limitations of prostate specific antigen as a biomarker for prostate cancer screening, characterized by low sensitivity for acceptable false-positive rates, are well known. New markers that differentiate indolent from aggressive cancers to decrease potential the over treatment of prostate cancer are needed. We reviewed current and potential biomarkers for prostate cancer detection. MATERIALS AND METHODS: A literature search was performed to identify established and emerging biomarkers for prostate cancer detection. Recent suggested guidelines by the Early Detection Research Network for phases of biomarker studies were interpreted for use in prostate cancer and the existing status of marker studies were reviewed with respect to these phases of study. RESULTS: Advances in high throughput bench research, including high dimensional genomic, proteomic and autoantibody signatures, have the potential to improve the operating characteristics of prostate specific antigen but they are undergoing reproducibility and multicenter validation studies. None of the prostate specific antigen derivatives or isoforms, such as prostate specific antigen density, velocity or percent complexed prostate specific antigen, improve operating characteristics enough to likely replace prostate specific antigen. Prostate stem cell antigen, alpha-methyl coenzyme-A racemase, PCA3, early prostate cancer antigen, human kallikrein 2 and hepsin are promising markers that are currently undergoing validation. CONCLUSIONS: The process of discovering novel biomarkers to replace or augment the existing best marker, prostate specific antigen, requires standardized phases of evaluation and validation. Several biomarkers are currently on the cusp of initial validation studies.

The role of adjuvant chemotherapy for patients with resected pancreatic cancer: systematic review of randomized controlled trials and meta-analysis.

BACKGROUND: In patients undergoing surgery for resectable pancreatic cancer prognosis still remains poor. The role of adjuvant treatment strategies (including chemotherapy and chemoradiotherapy) following resection of pancreatic cancer remains controversial. METHODS: A Medline-based literature search was undertaken to identify randomized controlled trials that evaluated adjuvant chemotherapy after complete macroscopic resection for cancer of the exocrine pancreas. Five trials of adjuvant chemotherapy were eligible and critically reviewed for this article. A meta-analysis (based on published data) was performed with survival (median survival time and 5-year survival rate) being the primary endpoint. RESULTS: For the meta-analysis, 482 patients were allocated to the chemotherapy group and 469 patients to the control group. The meta-analysis estimate for prolongation of median survival time for patients in the chemotherapy group was 3 months (95% CI 0.3-5.7 months, p = 0.03). The difference in 5-year survival rate was estimated with 3.1% between the chemotherapy and the control group (95% CI -4.6 to 10.8%, p > 0.05). CONCLUSION: Currently available data from randomized trials indicate that adjuvant chemotherapy after resection of pancreatic cancer may substantially prolong disease-free survival and cause a moderate increase in overall survival. In the current meta-analysis, a significant survival benefit was only seen with regard to median survival, but not for the 5-year survival rate. The optimal chemotherapy regimen in the adjuvant setting as well as individualized treatment strategies (also including modern chemoradiotherapy regimens) still remain to be defined.

Obesity, adipokines, and prostate cancer in a prospective population-based study.

BACKGROUND: The purpose of this investigation was to examine the association of obesity and the adipokines leptin, adiponectin, and interleukin-6 (IL-6) with prostate cancer risk and aggressiveness. METHODS: One hundred twenty-five incident prostate cancer cases and 125 age-matched controls were sampled from among participants in the original San Antonio Center for Biomarkers of Risk of Prostate Cancer cohort study. The odds ratios (OR) of prostate cancer and high-grade disease (Gleason sum >7) associated with the WHO categories of body mass index (kg/m(2)) and with tertiles of serum concentrations of adiponectin, leptin, and IL-6 were estimated using multivariable conditional logistic regression models. RESULTS: Body mass index was not associated with either incident prostate cancer [obese versus normal; OR, 0.75; 95% confidence interval (95% CI), 0.38-1.48; P(trend) = 0.27] or high-grade versus low-grade disease (OR, 1.17; 95% CI, 0.39-3.52; P(trend) = 0.62). Moreover, none of the three adipokines was statistically significant associated with prostate cancer risk or high-grade disease, respectively: leptin (highest versus lowest tertile; OR, 0.77; 95% CI, 0.28-1.37; P(trend) = 0.57; OR, 1.20; 95% CI, 0.48-3.01; P(trend) = 0.85); adiponectin (OR, 0.87; 95% CI, 0.46-1.65; P(trend) = 0.24; OR, 1.93; 95% CI, 0.74-5.10; P(trend) = 0.85); IL-6 (OR, 0.84; 95% CI, 0.46-1.53; P(trend) = 0.98; OR, 0.84; 95% CI, 0.30-2.33; P(trend) = 0.17). CONCLUSIONS: Findings from this nested case-control study of men routinely screened for prostate cancer and who had a high prevalence of overweight and obesity do not provide evidence to support that prediagnostic obesity or factors elaborated by fat cells strongly influence prostate cancer risk or aggressiveness. However, due to the small sample population, a small or modest effect of obesity and adipokines on these outcomes cannot be excluded.

Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings.

OBJECTIVE: To perform systematic analysis of current proton magnetic resonance spectroscopy ((1)H MRS) findings in bipolar disorder (BD). METHOD: We grouped the (1)H MRS studies documenting data on the metabolites of N-acetylaspartate (NAA), Choline (Cho), myo-inositol (mI), Glutamate (Glu)/Glutamine (Gln) and Creatine (Cr) separately, for each of the euthymic, manic, depressed adult and child/adolescent bipolar patients. RESULTS: For NAA resonance, 22 studies involving 328 adult bipolar and 349 control subjects were identified. NAA levels were lower in euthymic bipolar patients in the frontal lobe structures and hippocampus. Lithium seems to have an increasing effect on NAA in those brain regions. Available data in children indicates lower NAA levels in euthymic bipolar patients in dorsolateral prefrontal cortex (DLPFC) and cerebellar vermis. Existing data over 25 studies on 366 adult bipolar and 393 control subjects, although inconsistent, may suggest higher Cho/Cr ratios in the basal ganglia (BG) of euthymic bipolar patients. The metabolite mI seems to be increased both in euthymic and manic bipolar children, while most of the available data does not support such alteration in adults. Glu/Gln levels in adult bipolar patients were higher in all mood states compared to controls. Limited data in children supports such an alteration only in the euthymic state. CONCLUSION: The studies reviewed in this paper suggest regional abnormalities of NAA, Cho and Glu/Gln in BD, with the DLPFC, prefrontal and anterior cingulate cortices, hippocampus, and BG being specifically implicated. Systematic analysis of (1)H MRS findings so far helps to define future strategies in this field for delineation of actual neurochemical framework in BD.

Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: a meta-analysis.

In a review of the current literature, we identified (1)H MRS studies of major depressive disorder (MDD) that examined the metabolites N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), glutamate/glutamine/gamma-aminobutyric acid-GABA (Glx), and creatine (Cr). Separate meta-analyses comparing adult and pediatric MDD patients with healthy controls were performed. For adults, 14 studies with 227 patients/246 controls for NAA, 15 studies with 240 patients/261 controls for Cho, seven studies with 96 patients/104 controls for mI, six studies with 86 patients/109 controls for Glx, and nine studies with 146 patients/173 controls for Cr were identified. There were six studies containing a total of 79 pediatric depressed patients. We performed 15 separate meta-analyses to combine results from studies with similar characteristics. Adult MDD patients had higher Cho/Cr values than controls in the basal ganglia. In contrast, three studies on Glx levels indicated significantly lower Glx levels in the frontal lobe of MDD patients. The review indicated increased Cho/Cr in the basal ganglia in MDD and no alteration of NAA, suggesting an increased membrane turnover in MDD without a neurodegenerative outcome. Lower Glx levels in depressed patients in contrast to a likely hyperglutamatergic state in bipolar disorder may implicate a different pathophysiological ground in MDD.

Sensitivity and specificity of prostate-specific antigen for prostate cancer detection with high rates of biopsy verification.

In this article we explain findings from the Prostate Cancer Prevention Trial (PCPT) concerning the operating characteristics of PSA for biopsy-detectable prostate cancer, with special emphasis on a subpopulation of men with PSA less than 4 ng/ml, what is often regarded as the "normal" level of PSA in healthy men. The PCPT enrolled 18,882 healthy men 55 years of age or older, with a PSA value less than 3 ng/mL and a normal digital rectal exam (DRE); 9,459 of these men were randomized to the placebo arm and 9,423 to the finasteride arm In this report we summarize the operating characteristics of PSA only for the placebo arm of the PCPT; operating characteristics of PSA on the finasteride arm are more complicated to assess since finasteride approximately halves the PSA value and will be reported only briefly. In our first analysis, we focused on a group of 2,950 men on the placebo arm who had had an end-of-study biopsy and a normal DRE and PSA < 4 ng/mL for all 7 years of the study. For prostate cancer, the standard PSA cut-off of 4 ng/mL has low sensitivity: with this cut-off only 20.5% of the prostate cancer cases test positive-nearly 80% of prostate cancer cases are missed. The specificity at this cut-off is high (93.6%) meaning only 6.2% of men who do not have prostate cancer falsely test positive. Lowering the PSA threshold for screening increases detection of aggressive cancer at an earlier stage, but has the unavoidable tradeoff of increased detection of the biologically irrelevant cancers.

Merging digital rectal exam, family history, age and prostate-specific antigen to create a decision-making tool.

In this paper, we report on risk factors for prostate cancer detection on biopsy as found in the Prostate Cancer Prevention Trial (PCPT), with special emphasis on the independent contribution of prostate-specific antigen (PSA) velocity to prostate cancer risk over that provided by PSA. For this study, we used a subset of PCPT placebo arm participants who had had at least one prostate biopsy and a digital rectal examination (DRE) and PSA measured within 1 year prior to biopsy. In order to evaluate PSA velocity, we also required an additional PSA measurement within 3 years prior to biopsy, yielding 5,519 PCPT placebo arm participants for inclusion in the analysis. The risk of prostate cancer rose from 11.1% for PSA values less than 1 ng/mL to 43.3% for PSA values greater than 6 ng/mL and the risk of high-grade disease rose from 1.0% to 22.0% across these two PSA intervals. It was in fact no longer statistically significant as soon as the single predictor PSA was added to the risk equation, whereas PSA remained statistically significant even when velocity was in the risk equation. Furthermore, in a head-to-head comparison of predictive strength as a single predictor in a model, assessed by maximized log likelihood, PSA was more predictive than PSA velocity. These findings occurred for every definition of velocity that was considered and hence we concluded that velocity did not add independent prognostic information to prostate cancer risk over that provided by PSA. Similarly, age, which is also a predictor of prostate cancer in the absence of other factors, did not add independent prognostic information to PSA, DRE, family history, and prior biopsy.

New answers from the Prostate Cancer Prevention Trial on the chemoprevention of prostate cancer.

In this paper, we report ongoing investigations concerning the increased number of high-grade (Gleason grade > or = 7) prostate cancer, despite a reduction in all prostate cancer, found on the finasteride arm of the Prostate Cancer Prevention Trial (PCPT). There was a statistically significant 24.8% reduction in prostate cancer found on biopsy on the finasteride arm compared to placebo, and the reduction was also observed in both groups of end-of-study and for-cause biopsies. However, when the prostate cancers were examined by Gleason score, there was an increased number of high-grade prostate cancers found on the finasteride arm than on the placebo arm. This observation was emphasized in the editorial to the first publication of PCPT results and has dampened enthusiasm for recommendation of finasteride for chemoprevention. So, what are the potential reasons for increased grade on the finasteride arm? The number of high-grade cancers that are detected following a PSA prompt is directly proportional to the sensitivity of PSA for high-grade disease times the actual but unknown number of high-grade disease cases. So the higher the sensitivity the more likely one is to detect more of the existing high-grade cases irrespective of the true number of cases, i.e., there is an ascertainment bias. We are currently performing a quantitative investigation of whether or not this ascertainment bias could explain the higher number of high-grade disease cases observed on the finasteride arm.

Perioperative transfusion of leukocyte depleted blood products in gastric cancer patients negatively influences oncologic outcome: A retrospective propensity score weighted analysis on 610 curatively resected gastric cancer patients.

The influence of perioperative transfusion (PT) on outcome following surgery for gastric cancer (GC) remains controversial, with randomized trials lacking and observational series confounded by patient risk factors. This analysis determines the association between reception of leukocyte-depleted blood products and post-operative survival for GC.Data from 610 patients who underwent curative surgery for GC in a German tertiary care clinic from 2001 to 2013 were included. Kaplan-Meier survival curves and Cox proportional hazards regression were applied to determine the association of PT and clinical and patient risk factors for overall and relapse-free survival. Propensity score analysis was performed to adjust for observational biases in reception of PT.Higher Union International Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC)-stages (P <0.001), postoperative complications and severity according to the Clavien-Dindo (CD) classification (P <0.001), PT (P = 0.02), higher age (P <0.001), and neoadjuvant chemotherapy (P <0.001) were related to increased mortality rates. Higher UICC-stages (P <0.001), neoadjuvant chemotherapy (P <0.001), and type of surgery (P = 0.02) were independently associated with increased relapse rates. Patients were more likely to receive PT with higher age (P = 0.05), surgical extension to adjacent organs/structures (P = 0.002), tumor location (P = 0.003), and female gender (P = 0.03). In the adjusted propensity score weighted analysis, PT remained associated with an increased risk of death (hazard ratio (HR): 1.31, 95% CI: 1.01-1.69, P = 0.04).Because of the association of PT with negative influence on patient survival following resection for GC, risks from application of blood products should be weighed against the potential benefits.