Small cell carcinoma of prostate

Small cell carcinoma(SCC) of prostate is a very rare and highly aggressive neoplasm which constitutes less than 1 % of all prostate cancers. Half of the small cell carcinomas arising in the prostate are pure without an associated adenocarcinoma. Majority of SCC of prostate present at the advanced stage of disease and a disproportionately low serum PSA levels as compared to adenocarcinoma prostate. Chemotherapy and associated surgery are mainstay of treatment along with palliative radiation. Due its very poor prognosis and high mortality, it is necessary to diagnose it early and treat aggressivel

A National Survey of Hepatocellular Carcinoma Surveillance Practices Following Liver Transplantation

Recurrence of hepatocellular carcinoma (HCC) is an important predictor of survival after liver transplantation (LT). Recent studies show that early diagnosis, aggressive treatment, and surveillance may improve outcomes after HCC recurrence. We sought to determine the current practices and policies regarding surveillance for HCC recurrence after LT. Methods: We conducted a web-based national survey of adult liver transplant centers in the United States to capture center-specific details of HCC surveillance post-LT. Responses were analyzed to generate numerical and graphical summaries. Results: Of 101 eligible adult liver transplant centers, 48 (48%) centers across the United States responded to the survey. Among the participating centers, 79% stratified transplant recipients for HCC recurrence risk, while 19% did not have any risk stratification protocol. Explant microvascular invasion (mVI) was the most common factor used in risk stratification. Use of pretransplant serum biomarkers such as alpha-fetoprotein (AFP) was variable, with only 48% of the participating centers reporting specific "cutoff" values. While a majority of centers (88%) reported having a routine imaging protocol for HCC recurrence surveillance, there was considerable heterogeneity in terms of frequency and duration of such surveillance. Of the centers that did risk stratify patients to identify those at higher risk of HCC recurrence, about 50% did not change their surveillance protocol. Conclusions: Our study affirms significant variability in center practices, and our results reflect the need for high-quality studies to guide risk stratification and surveillance for HCC recurrence

Development and Validation of a Model to Predict Acute Kidney Injury in Hospitalized Patients With Cirrhosis

OBJECTIVES: Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis which contributes to morbidity and mortality. Improved prediction of AKI in this population is needed for prevention and early intervention. We developed a model to identify hospitalized patients at risk for AKI. METHODS: Admission data from a prospective cohort of hospitalized patients with cirrhosis without AKI on admission (n = 397) was used for derivation. AKI development in the first week of admission was captured. Independent predictors of AKI on multivariate logistic regression were used to develop the prediction model. External validation was performed on a separate multicenter cohort (n = 308). RESULTS: In the derivation cohort, the mean age was 57 years, the Model for End-Stage Liver Disease score was 17, and 59 patients (15%) developed AKI after a median of 4 days. Admission creatinine (OR: 2.38 per 1 mg/dL increase [95% CI: 1.47-3.85]), international normalized ratio (OR: 1.92 per 1 unit increase [95% CI: 1.92-3.10]), and white blood cell count (OR: 1.09 per 1 × 10/L increase [95% CI: 1.04-1.15]) were independently associated with AKI. These variables were used to develop a prediction model (area underneath the receiver operator curve: 0.77 [95% CI: 0.70-0.83]). In the validation cohort (mean age of 53 years, Model for End-Stage Liver Disease score of 16, and AKI development of 13%), the area underneath the receiver operator curve for the model was 0.70 (95% CI: 0.61-0.78). DISCUSSION: A model consisting of admission creatinine, international normalized ratio, and white blood cell count can identify patients with cirrhosis at risk for in-hospital AKI development. On further validation, our model can be used to apply novel interventions to reduce the incidence of AKI among patients with cirrhosis who are hospitalized

Liver transplantation for hepatocellular carcinoma: Management after the transplant

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153700/1/ajt15697.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153700/2/ajt15697_am.pd

Improving Outcomes of Bariatric Surgery in Patients With Cirrhosis in the United States: A Nationwide Assessment

Introduction: With increasing burden of obesity and liver disease in the United States, a better understanding of bariatric surgery in context of cirrhosis is needed. We described trends of hospital-based outcomes of bariatric surgery among cirrhotics and determined effect of volume status and type of surgery on these outcomes. Methods: In this population-based study, admissions for bariatric surgery were extracted from the National Inpatient Sample using International Classification of Diseases, 9th and 10th Revision, Clinical Modification codes from 2004 to 2016 and grouped by cirrhosis status, type of bariatric surgery, and center volume. In-hospital mortality, complications, and their trends were compared between these groups using weighted counts, odds ratios [ORs], and logistic regression. Results: Among 1,679,828 admissions for bariatric surgery, 9,802 (0.58%) had cirrhosis. Cirrhosis admissions were more likely to be in white men, had higher Elixhauser Index, and higher in-hospital complications rates including death (1.81% vs 0.17%), acute kidney injury (4.5% vs 1.2%), bleeding (2.9% vs 1.1%), and operative complications (2% vs 0.6%) (P < 0.001 for all) compared to those without cirrhosis. Overtime, restrictive surgeries have grown in number (12%-71%) and complications rates have trended down in both groups. Cirrhotics undergoing bariatric surgery at low-volume centers (<50 procedures per year) and nonrestrictive surgery had a higher inpatient mortality rate (adjusted OR 4.50, 95% confidence interval 3.14-6.45, adjusted OR 4.00, 95% confidence interval 2.68-5.97, respectively). Discussion: Contemporary data indicate that among admissions for bariatric surgery, there is a shift to restrictive-type surgeries with an improvement in-hospital complications and mortality. However, patients with cirrhosis especially those at low-volume centers have significantly higher risk of worse outcomes (see Visual abstract, Supplementary Digital Content, http://links.lww.com/AJG/B648)

Karnofsky performance status predicts outcomes in candidates for simultaneous liver-kidney transplant

Karnofsky performance status (KPS), a measure of physical frailty, predicts pre-transplant and post-transplant outcomes in liver transplantation, but has not been assessed in simultaneous liver–kidney transplantation (SLKT). We examined the association between KPS and outcomes in SLKT waitlist registrants and recipients (2005-2018) in the UNOS database. KPS was categorized into A (able to work), B (able to provide self-care), and C (unable to provide self-care). Cox regression and competing risk analysis were used to assess the association between KPS groups and outcomes. A total of 10,785 patients were waitlisted (KPS: 19% A, 46% B, 35% C), and 5,516 underwent SLKT (12% A, 36% B, 52% C). One-year waitlist mortality was 17%, 22%, and 32% for KPS A, B, and C, respectively. In adjusted competing risk regression, KPS C was associated with increased waitlist mortality (SHR 1.15, 95%CI 1.04-1.28). One-year post-transplant survival was 92%, 91%, and 87% for KPS A, B, and C, respectively. In adjusted Cox regression, KPS C was associated with increased post-transplant mortality (HR 1.32, 95%CI 1.08-1.61). It was also associated with increased liver and kidney graft losses and with hospital length of stay. Frailty, as assessed by KPS, is associated with poor outcomes in SLKT pre- and post-transplant

Hospital-Acquired Versus Community-Acquired Acute Kidney Injury in Patients with Cirrhosis: A Prospective Study

Introduction: In patients with cirrhosis, differences between acute kidney injury (AKI) at the time of hospital admission (community-acquired) and AKI occurring during hospitalization (hospital-acquired) have not been explored. We aimed to compare patients with hospital-acquired AKI (H-AKI) and community-acquired AKI (C-AKI) in a large, prospective study. Methods: Hospitalized patients with cirrhosis were enrolled (N = 519) and were followed for 90 days after discharge for mortality. The primary outcome was mortality within 90 days; secondary outcomes were the development of de novo chronic kidney disease (CKD)/progression of CKD after 90 days. Cox proportional hazards and logistic regressions were used to determine the independent association of either AKI for primary and secondary outcomes, respectively. Results: H-AKI occurred in 10%, and C-AKI occurred in 25%. In multivariable Cox models adjusting for significant confounders, only patients with C-AKI had a higher risk for mortality adjusting for model for end-stage liver disease-Na: (hazard ratio 1.64, 95% confidence interval [CI] 1.04-2.57, P = 0.033) and adjusting for acute on chronic liver failure: (hazard ratio 2.44, 95% CI 1.63-3.65, P < 0.001). In univariable analysis, community-acquired-AKI, but not hospital-acquired-AKI, was associated with de novo CKD/progression of CKD (odds ratio 2.13, 95% CI 1.09-4.14, P = 0.027), but in multivariable analysis, C-AKI was not independently associated with de novo CKD/progression of CKD. However, when AKI was dichotomized by stage, C-AKI stage 3 was independently associated with de novo CKD/progression of CKD (odds ratio 4.79, 95% CI 1.11-20.57, P = 0.035). Discussion: Compared with H-AKI, C-AKI is associated with increased mortality and de novo CKD/progression of CKD in patients with cirrhosis. Patients with C-AKI may benefit from frequent monitoring after discharge to improve outcomes

Extra-hepatic comorbidity burden significantly increases 90-day mortality in patients with cirrhosis and high model for endstage liver disease

Background We examined how extra-hepatic comorbidity burden impacts mortality in patients with cirrhosis referred for liver transplantation (LT). Methods Adults with cirrhosis evaluated for their first LT in 2012 were followed through their clinical course with last follow up in 2019. Extra-hepatic comorbidity burden was measured using the Charlson Comorbidity Index (CCI). The endpoints were 90-day transplant free survival (Cox-Proportional Hazard regression), and overall mortality (competing risk analysis). Results The study included 340 patients, mean age 56 ± 11, 63% male and MELD-Na 17.2 ± 6.6. The CCI was 0 (no comorbidities) in 44%, 1–2 in 44% and > 2 (highest decile) in 12%, with no differences based on gender but higher CCI in patients with fatty and cryptogenic liver disease. Thirty-three (10%) of 332 patients not receiving LT within 90 days died. Beyond MELD-Na, the CCI was independently associated with 90-day mortality (hazard ratio (HR), 1.32 (95% confidence interval (CI) 1.02–1.72). Ninety-day mortality was specifically increased with higher CCI category and MELD ≥18 (12% (CCI = 0), 22% (CCI = 1–2) and 33% (CCI > 2), (p = 0.002)) but not MELD-Na ≤17. At last follow-up, 69 patients were alive, 100 underwent LT and 171 died without LT. CCI was associated with increased overall mortality in the competing risk analysis (Sub-HR 1.24, 95%CI 1.1–1.4). Conclusions Extra-hepatic comorbidity burden significantly impacts short-term mortality in patients with cirrhosis and high MELD-Na. This has implications in determining urgency of LT and mortality models in cirrhosis and LT waitlisting, especially with an ageing population with increasing prevalence of fatty liver disease

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Background: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). Methods: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. Results: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. Conclusion:GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.</p

Flip-Flop of Phospholipids in Proteoliposomes Reconstituted from Detergent Extract of Chloroplast Membranes: Kinetics and Phospholipid Specificity

Eukaryotic cells are compartmentalized into distinct sub-cellular organelles by lipid bilayers, which are known to be involved in numerous cellular processes. The wide repertoire of lipids, synthesized in the biogenic membranes like the endoplasmic reticulum and bacterial cytoplasmic membranes are initially localized in the cytosolic leaflet and some of these lipids have to be translocated to the exoplasmic leaflet for membrane biogenesis and uniform growth. It is known that phospholipid (PL) translocation in biogenic membranes is mediated by specific membrane proteins which occur in a rapid, bi-directional fashion without metabolic energy requirement and with no specificity to PL head group. A recent study reported the existence of biogenic membrane flippases in plants and that the mechanism of plant membrane biogenesis was similar to that found in animals. In this study, we demonstrate for the first time ATP independent and ATP dependent flippase activity in chloroplast membranes of plants. For this, we generated proteoliposomes from Triton X-100 extract of intact chloroplast, envelope membrane and thylakoid isolated from spinach leaves and assayed for flippase activity using fluorescent labeled phospholipids. Half-life time of flipping was found to be 6±1 min. We also show that: (a) intact chloroplast and envelope membrane reconstituted proteoliposomes can flip fluorescent labeled analogs of phosphatidylcholine in ATP independent manner, (b) envelope membrane and thylakoid reconstituted proteoliposomes can flip phosphatidylglycerol in ATP dependent manner, (c) Biogenic membrane ATP independent PC flipping activity is protein mediated and (d) the kinetics of PC translocation gets affected differently upon treatment with protease and protein modifying reagents