Postoperative Liver Dysfunction and Future Remnant Liver: Where Is the Limit?

Background The future remnant liver (FRL) limit for safe major hepatectomy with low risk of postoperative liver failure has not yet been well defined. Methods Between April 2000 and September 2004, every patient scheduled for major hepatectomy in our institution underwent CT-volumetry of FRL. Patients with FRL <25% underwent portal vein embolization (PVE). Exclusion criteria were PVE, associated vascular resection and liver cirrhosis. The FRL was correlated with short-term results in patients with normal liver (group A) and those with impaired liver function secondary to neoadjuvant chemotherapy or cholestasis (bilirubin >2 mg/100 ml) (group B). Liver dysfunction was defined as both PT <50% and serum bilirubin level >5 mg/100 ml for three or more consecutive days. Results A total of 119 patients were analyzed, 72 in group A and 47 in group B. The FRL value was the only significant risk factor for postoperative liver dysfunction in the univariate and multivariate analysis (p = 0.009). The FRL did not correlate with postoperative mortality and morbidity. Bilirubin and prothrombin time (PT) on days 3 and 7 were significantly correlated to FRL in both groups. In group A, patients with postoperative liver dysfunction had a FRL<30% (3 versus 0; p = 0.005). According to receiving operator characteristic (ROC) curve analysis, a FRL value of 26.5% predicted postoperative liver dysfunction with 66.7% sensitivity, 97.1% specificity, 50% positive predictive value (PPV), and 98.5% negative predictive value (NPV). In group B, patients with postoperative liver dysfunction had a FRL <35% (4 versus 0; p = 0.027). According to ROC curve analysis, a FRL value of 31.05% predicted postoperative liver dysfunction with 75% sensitivity, 79.1% specificity, 25% PPV, and 97.1% NPV. Conclusions Hepatectomy can be considered safe when FRL is >26.5% in patients with healthy liver and >31% in patients with impaired liver function.     

Predicting Individual Survival After Hepatectomy for Hepatocellular Carcinoma: a Novel Nomogram from the “HCC East &amp; West Study Group”

Introductions

Different staging systems have been devised for patients undergoing resection for hepatocellular carcinoma (HCC) with disparate results. The aim of this study was to create a new nomogram to predict individual survival after hepatectomy for HCC.

Methods

Based on the “Hepatocellular Carcinoma: Eastern & Western Experiences Network,” data from 2046 patients who underwent HCC resections at ten centers were reviewed. Patient survival was analyzed with Cox-regression analysis to construct a unique nomogram and contour plots to predict survival.

Results

The nomograms built on the multivariate analyses, which showed that the independent predictors were tumor size, tumor number, vascular invasion, cirrhosis, preoperative bilirubin value, and esophageal varices, showed good calibration and discriminatory abilities with C-index value of 0.62 (95 % CI, 0.59–0.69) and 0.61 (95 % CI, 0.56–0.64) for overall and disease-free survival, respectively. The 5-year survival contour plots showed that the presence of vascular invasion was associated with decreased survival, regardless of the tumor number or size. Cirrhosis and varices were equally associated with decreased survival, according to the tumor number or size.

Conclusions

These nomograms accurately predict individual prognosis after HCC resection and support an expansion of the selection criteria for resection. They offer useful guidance to clinicians for individual survival prediction.

     

Analysis of survival after pancreatic resection for oncological pathologies

Surgical treatment of pancreatic cancer is to date the only modality that offers a chance of long-term survival. Potentially curative surgery is an option for only about 15% of patients with pancreatic adenocarcinoma. The aim of this study was to determine the survival and to assess the association of clinical, pathological, and treatment features with survival of patients who underwent resection of pancreatic cancer at the Department of Surgery of Udine University Hospital. From November 1989 to December 2005, 137 consecutive patients, who underwent surgical procedures for pancreatic cancer, were followed in our department. We performed 76 pancreatico-duodenectomy, 26 distal pancreatectomies and 35 total pancreatectomies. The surgical reconstruction after pancreatico-duodenectomy was as follows: 11 closures of the main duct with manual nonabsorbable stitches, 24 closures of the main duct with a linear stapler, 17 occlusions of the main duct with neoprene glue and 24 duct-to-mucosa anastomoses. Mean survival time was 27.7 +/- 26.93 months (mean +/- SD) and mean disease-free survival time was 25.4 +/- 23.06 months (mean +/- SD). 1, 3, 5, 7 and 9-year survival rates were 63.9, 33.7, 21.17, 12.7 and 10.2%, respectively. Significant differences in survival were recorded by the Log-rank test for age > 70 (p = 0.001), surgical procedures (p = 0.00046) and presence of metastases (p = 0.0055) The treatment of pancreatic cancer is undertaken with two different aims. The first is radical surgery for patients with early-stage disease, mainly stage I and partly stage II. In all other cases, the aim of treatment is the palliation of the several distressing symptoms related to this cancer. The standard treatment option for resectable tumours is radical pancreatic resection according to the Whipple procedure or total pancreatectomy.     

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

Repeated injection of botulinum toxin a in patients with neurogenic bladder: our experience

Background: In literature, the majority of data about treatment with botulinum toxin A are based on the results of a single treatment. We evaluate the safety and effectiveness in the medium term of the use of botulinum toxin type A in patients with neurogenic bladder, taking into consideration the clinical and urodynamic parameters, particularly in cases with repeated injections. Methods: 25 patients were divided into 2 groups: a first group of patients with detrusor overactivity, and a second with overactive sphincter. We performed 20-30 injections (Dysport), at a dose ranging between 500 and 1000 U. The first group was treated with infiltration in the detrusor and in the detrusor and trigone. The second group received injections in the perisphinteric zone, and in the?perisphinteric zone and bladder neck. Of the 25 patients, 12 received a retreatment: the first group of patients kept a daily voiding diary to record the number of bladder emptying, incontinence episodes, nycturia and urgency of urination. The urodynamic parameters and symptoms pre-treatment and 4 months after the treatment were compared in both groups. Results: In the first group there were significant changes in the cystometric capacity, maximum detrusor pressure, and in the post-void residual urine 4 months after treatment. These patients were satisfied with the treatment because of the improvement of incontinence and episodes of urgency. In 9 out of 15 retreated patients, the therapeutic results were similar to the first treatment. The second group reported significant improvements in maximum urinary flow rate, post-void residual urine and maximum detrusor pressure. 3 out of 10 patients were retreated even in this group; the new therapeutic results were similar to the first treatment. Conclusions: Our results in 25 patients with neurogenic bladder showed a concordance with the literature data. The treatment of detrusor and sphincter neurogenic overactivity with botulinum toxin A is effective and safe. Also in the 12 patients with repeated injection treatment, it has been proven safe and effective.     

Combined therapy with bevacizumab and photodynamic therapy for myopic choroidal neovascularization:A one-year follow-up controlled study

AIM: To evaluate the efficacy and safety of a combined treatment for myopic choroidal neovascularization (CNV) using photodynamic therapy (PDT) and intravitreal bevacizumab and to compare it with intravitreal bevacizumab monotherapy.METHODS: Thirty-four eyes with angiographic evidence of myopic CNV were randomly divided into two groups:17 were treated with one intravitreal bevacizumab injection (1.25 mg) and low-fluence-rate PDT within seven days of the injection (Group A). The other 17 received monotherapy with bevacizumab injections (Group B). Clinical evidence of complications, best corrected visual acuity (BCVA) and fluorescein leakage were evaluated. BCVA and optical coherence tomography (OCT) were evaluated monthly. The timepoints follow-up was established at 6 and 12mo. All patients were retreated following a PRN protocol.RESULTS:A total of 34 eyes of 34 patients (26 women and 8 men) with a mean age of 62.35 years were included. In Group A (17 eyes) the mean BCVA increased from 0.55±0.13 logMAR before the treatment to 0.40±0.09 logMAR at the 12mo follow-up (P<0.01). In Group B (17 eyes) the mean BCVA increased from 0.60±0.11 logMAR before the treatment to 0.55±0.12 logMAR at the 12mo follow-up (P<0.01). There was no statistically significant difference between the two groups in terms of LogMar visual acuity. In Group A the mean number of combined treatments was 1.8±0.11 per patient; in Group B the mean number of intravitreal bevacizumab injections was 3.1±0.08 per patient. The number of treatments was significantly fewer in Group A (P<0.01). No local or systemic side effects occurred among any of the patients treated in this study.CONCLUSION:The combination of anti-angiogenic injections and PDT appears to be a safe and effective option for myopic CNV treatment and allows for a significant reduction of intravitreal injections.     

The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances, or psychosis, such as Alzheimer’s disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI), and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally active dose of the M1/M4-preferring muscarinic agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high-frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high-frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.Subject terms: Schizophrenia, Translational research, Preclinical research