Molecular Predictors of Long-Term Survival in Glioblastoma Multiforme Patients

Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain cancer, with <10% of patients surviving for more than 3 years. Demographic and clinical factors (e.g. age) and individual molecular biomarkers have been associated with prolonged survival in GBM patients. However, comprehensive systems-level analyses of molecular profiles associated with long-term survival (LTS) in GBM patients are still lacking. We present an integrative study of molecular data and clinical variables in these long-term survivors (LTSs, patients surviving >3 years) to identify biomarkers associated with prolonged survival, and to assess the possible similarity of molecular characteristics between LGG and LTS GBM. We analyzed the relationship between multivariable molecular data and LTS in GBM patients from the Cancer Genome Atlas (TCGA), including germline and somatic point mutation, gene expression, DNA methylation, copy number variation (CNV) and microRNA (miRNA) expression using logistic regression models. The molecular relationship between GBM LTS and LGG tumors was examined through cluster analysis. We identified 13, 94, 43, 29, and 1 significant predictors of LTS using Lasso logistic regression from the somatic point mutation, gene expression, DNA methylation, CNV, and miRNA expression data sets, respectively. Individually, DNA methylation provided the best prediction performance (AUC = 0.84). Combining multiple classes of molecular data into joint regression models did not improve prediction accuracy, but did identify additional genes that were not significantly predictive in individual models. PCA and clustering analyses showed that GBM LTS typically had gene expression profiles similar to non-LTS GBM. Furthermore, cluster analysis did not identify a close affinity between LTS GBM and LGG, nor did we find a significant association between LTS and secondary GBM. The absence of unique LTS profiles and the lack of similarity between LTS GBM and LGG, indicates that there are multiple genetic and epigenetic pathways to LTS in GBM patients.     

Primary Localization and Tumor Thickness as Prognostic Factors of Survival in Patients with Mucosal Melanoma

Background

Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations.

Methodology

116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages.

Principal Findings

We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T₁, T₂, T₃ or T₄ stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas.

Conclusion

Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006). It also depends on T-stage at the time of diagnosis (p<0.0001).     

Long-Term Survival in a Large Cohort of Patients with Venous Thrombosis: Incidence and Predictors

Background

Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis.

Methods and Findings

4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well.736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0–24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0–5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7–4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0–6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories.

Conclusions

Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients. Please see later in the article for the Editors'' Summary     

Clinical Predictors of Survival for Patients with Stage IV Cancer Referred to Radiation Oncology

BackgroundThere is an urgent need for a robust, clinically useful predictive model for survival in a heterogeneous group of patients with metastatic cancer referred to radiation oncology.MethodsFrom May 2012 to August 2013, 143 consecutive patients with stage IV cancer were prospectively evaluated by a single radiation oncologist. We retrospectively analyzed the effect of 29 patient, laboratory and tumor-related prognostic factors on overall survival using univariate analysis. Variables that were statistically significant on univariate analysis were entered into a multivariable Cox regression to identify independent predictors of overall survival.ResultsThe median overall survival was 5.5 months. Four prognostic factors significantly predicted survival on multivariable analysis including ECOG performance status (0–1 vs. 2 vs. 3–4), number of active tumors (1 to 5 vs. ≥6), albumin levels (≥3.4 vs. 2.4 to 3.3 vs. <2.4 and primary tumor site (Breast, Kidney or Prostate vs. Other). Risk group stratification was performed by assigning points for adverse prognostic factors resulting in very low, low, intermediate and high risk groups. The median survival was >31.4 months for very low risk patients compared to 14.5 months for low risk, 4.1 months for intermediate risk and 1.2 months for high risk (p<0.001).ConclusionsThese data suggest that a model that considers performance status, extent of disease, primary tumor site and serum albumin represents a simple model to accurately predict survival for patients with stage IV cancer who are potential candidates for radiation therapy.     

Prediction of Outcome for Patients with Cutaneous Melanoma

Most patients with primary melanoma are cured by local surgery, but a significant minority develop fatal metastases. The ability to identify patients with progressive disease is central to efficient management: permitting optimal deployment of adjunctive therapy and sparing the non-progressing majority the morbidity of aggressive therapy. Accurate prediction on an individual patient basis is the ideal, but the best current prognosticators permit only assignment to risk categories. Formulaic combinations of well tried correlates of outcome (gender, ulceration, depth, thickness, and mitotic rate increase accuracy of prediction, but not to personalised level. The use of large data bases against which the attributes of individual patients may be compared is useful and amalgamation of data bases will increase the availability of this approach. The development of markers of proliferation fraction (PCNA and MIB-1) and of the metastatic phenotype (PNA-receptor status) will further refine the process. Staging of disease is critical. Ac-curacy of staging is improved by mapping the (sentinel) lymph nodes likely to contain early tumor by lymphoscintigraphy and dye/radiomarker localisation. The application of exquisitely sensitive immunohistochemical and molecular biological techniques to biopsies from tissues likely to be the site of metastases permit assessment of clinical stage with a previously impossible degree of accuracy (ultrastaging).     

Clinical Characteristics of 582 Patients with Uveal Melanoma in China

Objective

To assess clinical characteristics, treatment and survival of patients with uveal melanoma in China.

Methods

The retrospective study included all patients with malignant uveal melanoma who were consecutively examined in the study period from January 2005 and June 2015 in the Beijing Tongren hospital.

Results

The mean age of the 582 patients (295(50.7%) women) was 44.6±12.6 years (range:5–77 years). The tumors were located most often in the superior temporal region (in 117(21.5%) patients) and least common in the inferior region (in 31(5.7%) patients). In 548(94.2%) patients, the tumors were located in the choroid, in 33(5.7%) patients in the ciliary body, and in one (0.2%) patient in the iris. Treatment included episcleral brachytherapy (415(71.3%) patients), local tumor resection (48(8.2%) patients) and primary enucleation (119(20.4%) patients). In 53 individuals out of the 415 patients with primary brachytherapy, episcleral brachytherapy was followed by enucleation, due to an increasing tumor size or due to uncontrolled neovascular glaucoma. Median follow-up time was of 30 months (range: 1–124 months; mean: 34.8 ± 24.4 months). Overall survival rate at 5 and 10 years was of 92.7% and 85.1%. Younger age (P = 0.017), tumor location in the nasal meridian(P = 0.004), smaller tumor size (P<0.001), hemispheric tumor shape (P = 0.025), histological tumor cell type (spindle-cell type versus epitheloid cell type;P = 0.014), and type of treatment (episcleral brachytherapy versus local tumor resection and versus primary enucleation; P<0.001) were significantly associated with the overall survival in univariate analysis, while in multivariate analysis only smaller tumor size was significantly (P<0.001; RR: 4.75; 95% confidence interval:2.11,10.7) associated with better overall survival.

Conclusions

In this study on clinical characteristics of uveal melanoma of a larger group of patients from China, the onset age was considerably younger and survival rate better than in studies from Western countries. Tumor size was the most significant factor for survival.     

Predictors of Bacteraemia in Patients with Suspected Community-Acquired Pneumonia

Introduction

The diagnostic yield of blood cultures is limited in patients with community-acquired pneumonia (CAP). Yet, positive blood culture results provide important information for antibiotic treatment and for monitoring epidemiologic trends. We investigated the potential of clinical predictors to improve the cost-benefit ratio of obtaining blood cultures.

Methods

Data from two prospective cohort studies of adults with suspected CAP, admitted to non-ICU wards, were combined. Two models were created, one using readily available parameters and one additionally including laboratory parameters.

Results

3,786 patients were included (2,626 (69%) with X-ray confirmed CAP). Blood cultures were obtained from 2,977 (79%) patients (and from 2,107 (80%) with X-ray confirmed CAP). 266 (8.9%) of the patients with a blood culture had bacteraemia. Clinical predictors of bacteraemia were absence of pre-admission antibiotic treatment, pleuritic pain, gastro-intestinal symptoms, tachycardia, tachypnea, hypotension and absence of hypoxia. After including laboratory results in the model, younger age, C-reactive protein, leukocytosis or leukopenia, low thrombocyte count, low sodium level, elevated urea and elevated arterial pH were added, while gastro-intestinal symptoms and hypotension were no longer significant. The area under the receiver operating characteristics curve was 0.66 (95% confidence interval 0.63–0.70) for the first model and 0.76 (95% confidence interval 0.73–0.79) for the second model.

Conclusion

In conclusion, in patients hospitalized with CAP, bacteraemia was moderately predictable using clinical parameters only. We recommend against the use of a risk prediction model for the decision to obtain blood cultures.     

Predictors of Viral Pneumonia in Patients with Community-Acquired Pneumonia

Background

Viruses are increasingly recognized as major causes of community-acquired pneumonia (CAP). Few studies have investigated the clinical predictors of viral pneumonia, and the results have been inconsistent. In this study, the clinical predictors of viral pneumonia were investigated in terms of their utility as indicators for viral pneumonia in patients with CAP.

Methods

Adult patients (≥18 years old) with CAP, tested by polymerase chain reaction (PCR) for respiratory virus, at two teaching hospitals between October 2010 and May 2013, were identified retrospectively. Demographic and clinical data were collected by reviewing the hospital electronic medical records.

Results

During the study period, 456 patients with CAP were identified who met the definition, and 327 (72%) patients were tested using the respiratory virus PCR detection test. Viral pneumonia (n = 60) was associated with rhinorrhea, a higher lymphocyte fraction in the white blood cells, lower serum creatinine and ground-glass opacity (GGO) in radiology results, compared to non-viral pneumonia (n = 250) (p<0.05, each). In a multivariate analysis, rhinorrhea (Odd ratio (OR) 3.52; 95% Confidence interval (CI), 1.58–7.87) and GGO (OR 4.68; 95% CI, 2.48–8.89) were revealed as independent risk factors for viral pneumonia in patients with CAP. The sensitivity, specificity, positive- and negative-predictive values (PPV and NPV) of rhinorrhea were 22, 91, 36 and 83%: the sensitivity, specificity, PPV and NPV of GGO were and 43, 84, 40 and 86%, respectively.

Conclusion

Symptom of rhinorrhea and GGO predicted viral pneumonia in patients with CAP. The high specificity of rhinorrhea and GGO suggested that these could be useful indicators for empirical antiviral therapy.     

Quantitative Measurement of Melanoma Spread in Sentinel Lymph Nodes and Survival

Background

Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival.

Methods and Findings

We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3–123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61–2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02–2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories.

Conclusions

Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically. Please see later in the article for the Editors'' Summary     

Survival of Patients with Oral Cavity Cancer in Germany

The purpose of the present study was to describe the survival of patients diagnosed with oral cavity cancer in Germany. The analyses relied on data from eleven population-based cancer registries in Germany covering a population of 33 million inhabitants. Patients with a diagnosis of oral cavity cancer (ICD-10: C00-06) between 1997 and 2006 are included. Period analysis for 2002–2006 was applied to estimate five-year age-standardized relative survival, taking into account patients'' sex as well as grade and tumor stage. Overall five-year relative survival for oral cavity cancer patients was 54.6%. According to tumor localization, five-year survival was 86.5% for lip cancer, 48.1% for tongue cancer and 51.7% for other regions of the oral cavity. Differences in survival were identified with respect to age, sex, tumor grade and stage. The present study is the first to provide a comprehensive overview on survival of oral cavity cancer patients in Germany.     

Natural Killer T Cells in Advanced Melanoma Patients Treated with Tremelimumab

A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-1_26–35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8⁺ cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.     

Multiparametric Analysis of Cell-Free DNA in Melanoma Patients

Cell-free DNA in blood (cfDNA) represents a promising biomarker for cancer diagnosis. Total cfDNA concentration showed a scarce discriminatory power between patients and controls. A higher specificity in cancer diagnosis can be achieved by detecting tumor specific alterations in cfDNA, such as DNA integrity, genetic and epigenetic modifications.The aim of the present study was to identify a sequential multi-marker panel in cfDNA able to increase the predictive capability in the diagnosis of cutaneous melanoma in comparison with each single marker alone. To this purpose, we tested total cfDNA concentration, cfDNA integrity, BRAF^V600E mutation and RASSF1A promoter methylation associated to cfDNA in a series of 76 melanoma patients and 63 healthy controls. The chosen biomarkers were assayed in cfDNA samples by qPCR. Comparison of biomarkers distribution in cases and controls was performed by a logistic regression model in both univariate and multivariate analysis. The predictive capability of each logistic model was investigated by means of the area under the ROC curve (AUC). To aid the reader to interpret the value of the AUC, values between 0.6 and 0.7, between 0.71 and 0.8 and greater than 0.8 were considered as indicating a weak predictive, satisfactory and good predictive capacity, respectively. The AUC value for each biomarker (univariate logistic model) was weak/satisfactory ranging between 0.64 (BRAF^V600E) to 0.85 (total cfDNA). A good overall predictive capability for the final logistic model was found with an AUC of 0.95. The highest predictive capability was given by total cfDNA (AUC:0.86) followed by integrity index 180/67 (AUC:0.90) and methylated RASSF1A (AUC:0.89).An approach based on the simultaneous determination of three biomarkers (total cfDNA, integrity index 180/67 and methylated RASSF1A) could improve the diagnostic performance in melanoma.     

Expression of BAFF and BAFF-R in Follicular Lymphoma: Correlation with Clinicopathologic Characteristics and Survival Outcomes

Background

B-cell activation factor (BAFF) and BAFF-receptor (BAFF-R) play crucial roles in the viability and proliferation of malignant lymphoma cells. Limited information exists regarding expression profiles and the prognostic role of BAFF and BAFF-R in follicular lymphoma (FL). We sought to determine the expression profiles of BAFF and BAFF-R in FL and to evaluate the correlation of BAFF and BAFF-R expression with clinicopathologic characteristics and outcome of FL. Correlation between expression levels of BAFF detected by immunohistochemical (IHC) and serum levels of BAFF was also evaluated.

Methods

Paraffin-embedded specimens from 115 patients were immunohistochemically examined for BAFF and BAFF-R expression. Expression levels were dichotomized into low versus high categories based on immunostaining intensity. The correlation of BAFF and BAFF-R expression with clinicopathologic characteristics and patient outcome was assessed. Serum levels of BAFF in 35 of the 115 patients with IHC data were measured by Enzyme-linked Immunosorbent assay (ELISA).

Results

BAFF and BAFF-R were expressed in 88.7% (102/115) and 87.8% (101/115) of the cases, respectively. BAFF expression was significantly correlated with only one clinicopathologic feature: Ann Arbor stage. No significant correlation was found between expression levels of BAFF detected by IHC and serum levels of BAFF detected by ELISA. High expression of BAFF-R, but not BAFF, was significantly correlated with inferior progression-free survival (PFS; P = 0.013) and overall survival (OS; P = 0.03). High expression of BAFF-R, bulky disease, and elevated lactate dehydrogenase were correlated with inferior PFS and OS in multivariate analysis. A prognostic scoring system incorporating these 3 risk factors identified 3 distinct prognostic groups with 5-year PFS of 59.4%, 41.9%, and 10.7% and OS of 91.3%, 79.7%, and 45.8%, respectively.

Conclusions

Most patients with FL variably express BAFF and BAFF-R. High expression of BAFF-R, but not BAFF, may be an independent risk factor for PFS and OS in FL.     

Predictors of Acute Respiratory Distress Syndrome in Patients with Paraquat Intoxication

Introduction

Paraquat poisoning is characterized by acute lung injury, pulmonary fibrosis, respiratory failure, and multi-organ failure, resulting in a high rate of mortality and morbidity. The objectives of this study were to identify predictors of acute respiratory distress syndrome (ARDS) in cases of paraquat poisoning and determine the association between these parameters.

Materials and Methods

In total, 187 patients were referred for management of intentional paraquat ingestion between 2000 and 2010. Demographic, clinical, and laboratory data were recorded. Sequential organ failure assessment (SOFA) and Acute Kidney Injury Network (AKIN) scores were collected, and predictors of ARDS were analyzed.

Results

The overall mortality rate for the entire population was 54% (101/187). Furthermore, the mortality rate was higher in the ARDS patients than in the non-ARDS patients (80% vs. 43.80%, P<0.001). Additionally, the ARDS patients not only had higher AKIN_48-h scores (P<0.009), SOFA_48-h scores (P<0.001), and time to ARDS/nadir PaO₂ (P=0.008) but also suffered from lower nadir PaO₂ (P<0.001), nadir AaDO₂ (P<0.001), and nadir eGFR (P=0.001) compared to those in the non-ARDS patients. Moreover, pneumomediastinum episodes were more frequent in the ARDS patients than in the non-ARDS patients (P<0.001). A multivariate Cox regression model revealed that blood paraquat concentrations (P<0.001), SOFA_48-h scores (P=0.001), and steroid and cyclophosphamide pulse therapies (P=0.024) were significant predictors of ARDS. The cumulative survival rates differed significantly (P<0.001) between patients with SOFA_48-h scores <3 and SOFA_48-h scores ≥3, with a sensitivity of 95.8%, specificity of 58.4%, and overall correctness of 67.6%. Finally, the area under the receiver operating characteristic (AUROC) analysis showed that SOFA_48-h scores (P<0.001) had a better discriminatory power than blood paraquat concentrations (P=0.01) for predicting ARDS.

Conclusions

The analytical results indicate that SOFA_48-h scores, blood paraquat concentrations, and steroid and cyclophosphamide pulse therapies are significantly associated with ARDS complications after paraquat intoxication.     

Genetic Polymorphisms in Endothelin-1 as Predictors for Long-Term Survival and the Cardiac Index in Patients Undergoing On-Pump Cardiac Surgery

Genetic variants within the endothelin-1 gene (EDN1) have been associated with several cardiovascular diseases and may act as genetic prognostic markers. Here, we explored the overall relevance of EDN1 polymorphisms for long-term survival in patients undergoing on-pump cardiac surgery. A prospectively collected cohort of 455 Caucasian patients who underwent cardiac surgery with cardiopulmonary bypass was followed up for 5 years. The obtained genotypes and inferred haplotypes were analyzed for their associations with the five-year mortality rate (primary endpoint). The EDN1 T-1370G and K198N genotype distributions did not deviate from Hardy–Weinberg equilibrium and the major allele frequencies were 83% and 77%, respectively. The cardiovascular risk factors were equally distributed in terms of the different genotypes and haplotypes associated with the two polymorphisms. The five-year mortality rate did not differ among the different EDN1 T-1370G and K198N genotypes and haplotypes. Haplotype analysis revealed that carriers of the G-T (compound EDN1 T-1370G G/K198N T) haplotype had a higher cardiac index than did non-carriers (p = 0.0008); however, this difference did not reach significance after adjusting for multiple testing. The results indicate that common variations in EDN1 do not act as prognostic markers for long-term survival in patients undergoing on-pump cardiac surgery.     

Predictors of Osteodystrophy in Patients with Chronic Nonalcoholic Pancreatitis with or without Diabetes

ObjectiveTo study bone mineral content (BMC), bone mineral density (BMD), vitamin D status, and bone mineral variables in patients with chronic nonalcoholic pancreatitis and to determine the relationship between pancreatic dysfunction and these variables.MethodsThirty-one eligible nonalcoholic men with proven chronic pancreatitis and 35 male control subjects were studied. Biochemical data, variables of malabsorption, and BMD of the lumbar spine were evaluated.ResultsIn patients with chronic pancreatitis, the mean body mass index (BMI) was 18.46 kg/m² and the median 25-hydroxyvitamin D value was 15.5 (range, 5.0 to 52.0) ng/mL. A T-score of less than -2.5 was found in a higher proportion of study patients (9 of 31, 29%) than of control subjects (3 of 35, 9%). BMI correlated significantly with BMC (r = 0.426; P = .017). There was an inverse correlation between stool fat and BMC (r = -0.47; P = .03) in patients with chronic pancreatitis and steatorrhea. There was no significant correlation between serum 25-hydroxyvitamin D or biochemical variables and BMD. Patients with steatorrhea had a significantly lower BMC than did those without steatorrhea, and this difference could not be accounted for by differences in BMI, presence of diabetes, or hypovitaminosis D.ConclusionPancreatic osteodystrophy is a novel entity consisting of osteopenia, osteoporosis, and osteomalacia in patients with chronic pancreatitis. The inverse correlation between stool fat and BMC in patients with chronic pancreatitis, the strong positive correlation between BMI and BMC, and the lack of difference in BMC between subjects with vitamin D sufficiency and those with vitamin D deficiency suggest that long-standing malabsorption with attendant chronic undernutrition is the major factor contributing to the changes in BMC. (Endocr Pract. 2011;17:897-905)     

Frequency and Clinicopathological Profile Associated with Braf Mutations in Patients with Advanced Melanoma in Spain

Real-world data on BRAF mutation frequency in advanced melanoma are lacking in Spain. Moreover, data available on clinicopathological profile of patients with advanced BRAF-mutant melanoma are currently limited. This study aimed to assess the frequency of BRAF V600 mutations in Spanish patients with advanced or metastatic melanoma and to identify clinical and histopathological features associated with BRAF-mutated tumors. A multicenter, cross-sectional epidemiological study was conducted in 33 Spanish hospitals in adult patients with stage IIIc/IV melanoma. A total of 264 patients were included. The median age was 68 years and 57% were male. Melanoma mainly involved skin with intermittent (40.4%) and low or no sun exposure (43.5%). Most patients (85.6%) had stage IV disease (M1a: 19.3%; M1b: 13.3%; M1c: 22.7%). Serum lactate dehydrogenase levels were elevated in 20% of patients. Superficial spreading melanoma was the most frequent histological type (29.9%). Samples were predominantly obtained from metastases (62.7%), mostly from skin and soft tissues (80%). BRAF mutation analysis was primarily performed using the Cobas 4800 BRAF V600 Mutation Test (92.8%) on formalin-fixed, paraffin-embedded tissue (95.8%). BRAF mutations were detected in 41.3% of samples. Multivariate analysis identified age (odd ratio [OR] 0.975) and stage IV M1a (OR 2.716) as independent factors associated with BRAF mutation. The frequency of BRAF mutations in tumor samples from patients with advanced or metastatic melanoma in Spain was 41.3%. BRAF mutations seem to be more frequent in younger patients and stage M1a patients.This study provides the basis for further investigation regarding BRAF-mutated advanced melanoma in larger cohorts.     

Analysis of the Relationships between Clinicopathologic Factors and Survival in Gallbladder Cancer following Surgical Resection with Curative Intent

Background

This study elucidated the relationships between various clinicopathologic factors and the outcome of patients with gallbladder cancer (GBC) treated by surgical resection with curative intent.

Methods

Between January 2003 and January 2011, 76 patients with GBC underwent surgical resection with curative intent at our department. We then conducted a retrospective analysis of clinicopathologic data. Fourteen clinicopathological variables were selected for univariate and multivariate analysis to evaluate their influence on the outcome.

Results

The actuarial 1-, 3-, and 5-year survival rates in the 76 resected cases were 56.6%, 32.7%, and 23.8%, respectively. The univariate analysis revealed that curative resection (P<0.001), lymph node metastasis (P<0.001), AJCC stage (P = 0.030), tumor location (P = 0.008), histologic differentiation (P = 0.028), intraoperative blood loss (P = 0.011), and preoperative jaundice (P = 0.012) were significant risk factors for survival. Multivariate analysis revealed that noncurative resection and tumor location on gallbladder neck were significant risk factors for poor outcome. Among jaundiced patients, we discovered that gallbladder carcinoma with tumor thrombus in common bile duct (CBD) was very rare but with relatively special clinical manifestation and characteristic radiography manifestation. The prognosis of gallbladder carcinoma with tumor thrombus in CBD after surgical procedure was apparently better than gallbladder carcinoma with invasion of hilar tissues.

Conclusions

Curative surgical resection remains the only effective approach to the treatment of GBC. This series confirm that jaundice is a poor prognostic factor. However, the presence of jaundice does not preclude resection, especially in highly selected patients (when R0 resection is achievable). Gallbladder carcinoma with tumor thrombus in CBD has special clinical characteristics, which need to be awared by radiologists and clinicians.