Orthotopic Liver Transplantation in Familial Amyloidotic Polyneuropathy Is Associated with Long-Term Progression of Renal Disease

Orthotopic liver transplantation has become the treatment of choice for familial amyloidotic polyneuropathy. The aims of this study were to evaluate the renal complications post orthotopic liver transplantation in familial amyloidotic polyneuropathy and their impact. We retrospectively studied 185 recipients who underwent 217 orthotopic liver transplants. Mean age 36.8±9.5 years, 59% males, 14.3% with renal dysfunction pre orthotopic liver transplantation. Mean follow-up 3.6±3.7 years. Thirty-two patients died. Univariate and multivariate analysis were performed, and p<0.05 was considered significant. Acute kidney injury occurred in 57 patients and renal replacement therapy was needed in 16/57. In multivariate analysis, acute kidney injury was correlated with development of chronic kidney disease (p<0.001). Relating to development of chronic kidney disease, 23.5% had progress to stage 3, 6% to stage 4 and 5.1% to stage 5d. According to Spearmen correlation, risk factors for chronic kidney disease development were age (p<0.001), renal dysfunction pre orthotopic liver transplantation (p<0.001) and acute kidney injury post orthotopic liver transplantation (p<0.001). Mortality was correlated with age (p<0.001), retransplantation need (p=0.004), renal dysfunction pre orthotopic liver transplantation (p<0.001), acute kidney injury post orthotopic liver transplantation (p=0.04), and chronic kidney disease stage 5 (p<0.001). Using binary regression, mortality was correlated with chronic kidney disease development (p=0.02). In conclusion, familial amyloidotic polyneuropathy patients are disposed to renal complications that have a negative impact on the survival of these patients.

Continuous Infusion of Piperacillin/Tazobactam in Septic Critically Ill Patients - a Multicenter Propensity Matched Analysis

The clinical efficacy of continuous infusion of piperacillin/tazobactam in critically ill patients with microbiologically documented infections is currently unknown. We conducted a retrospective multicenter cohort study in 7 Portuguese intensive care units (ICU). We included 569 critically ill adult patients with a documented infection and treated with piperacillin/tazobactam admitted to one of the participating ICU between 2006 and 2010. We successfully matched 173 pairs of patients according to whether they received continuous or conventional intermittent dosing of piperacillin/tazobactam, using a propensity score to adjust for confounding variables. The majority of patients received 16g/day of piperacillin plus 2g/day of tazobactam. The 28-day mortality rate was 28.3% in both groups (p = 1.0). The ICU and in-hospital mortality were also similar either in those receiving continuous infusion or intermittent dosing (23.7% vs. 20.2%, p = 0.512 and 41.6% vs. 40.5%, p = 0.913, respectively). In the subgroup of patients with a Simplified Acute Physiology Score (SAPS) II>42, the 28-day mortality rate was lower in the continuous infusion group (31.4% vs. 35.2%) although not reaching significance (p = 0.66). We concluded that the clinical efficacy of piperacillin/tazobactam in this heterogeneous group of critically ill patients infected with susceptible bacteria was independent of its mode of administration, either continuous infusion or intermittent dosing.

The HIF1A Functional Genetic Polymorphism at Locus +1772 Associates with Progression to Metastatic Prostate Cancer and Refractoriness to Hormonal Castration

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

The HIF1A Functional Genetic Polymorphism at Locus +1772 Associates with Progression to Metastatic Prostate Cancer and Refractoriness to Hormonal Castration

The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

Locally Advanced and Metastatic Prostate Cancer Treated with Intermittent Androgen Monotherapy or Maximal Androgen Blockade: Results from a Randomised Phase 3 Study by the South European Uroncological Group

BACKGROUND: Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). OBJECTIVE: To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. INTERVENTION: During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. RESULTS AND LIMITATIONS: We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. CONCLUSIONS: Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.

Iron Overload in a Murine Model of Hereditary Hemochromatosis Is Associated with Accelerated Progression of Osteoarthritis Under Mechanical Stress

OBJECTIVE: Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress. DESIGN: OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery. RESULTS: Hfe-KO mice showed a systemic iron overload and an increased iron accumulation in the knee synovial membrane following surgery. The histological OA score was significantly higher in the Hfe-KO mice at 8 weeks after surgery. Micro CT study of the proximal tibia revealed increased subchondral bone volume and increased trabecular thickness. Gene expression and immunohistochemical analysis showed a significant increase in the expression of matrix metallopeptidase 3 (MMP-3) in the joints of Hfe-KO mice compared with control mice at 8 weeks after surgery. CONCLUSIONS: HH was associated with an accelerated development of OA in mice. Our findings suggest that synovial iron overload has a definite role in the progression of HH-related OA

A Comparative Study of Cardiovascular Tolerability with Slow Extended Dialysis Versus Continuous Haemodiafiltration in the Critical Patient

Background: In the haemodynamically unstable patient the method of treatment of acute renal failure is still largely controversial. The purpose of our study was to compare slow extended dialysis with continuous haemodiafiltration in the critical patient with indication for renal replacement therapy and haemodynamic instability. Patients and Methods: This is a cohort study comparing in 63 ventilated critical patients a 12 month period when only continuous haemodiafiltration was used (n=25) with an equal period of slow extended dialysis (n=38). Our primary objective was to evaluate the impact of the dialytic procedure on cardiovascular stability in those patients. As secondary aims we considered system coagulation/thrombosis and predictors of mortality. In the two groups we analysed the first session performed, the second session performed and the average of all the sessions performed in each patient. Results: In these patients, mortality in the intensive care unit was high (68% in the continuous haemodiafiltration group and 63% in the slow extended dialysis group). We did not find any association between the dialytic technique used and death; only the APACHE score was a predictor of death. Slow extended dialysis was a predictor of haemodynamic stability, a negative predictor of sessions that had to be interrupted for haemodynamic instability, and a predictor of achieving the volume removal initially sought. Slow extended dialysis was also associated with less coagulation of the system. Conclusions: Our data suggested that slow extended dialysis use was not inferior to continuous haemodiafiltration use in terms of cardiovascular tolerability.