CT volume of enhancement of disease (VED) can predict the early response to treatment and overall survival in patients with advanced HCC treated with sorafenib.

OBJECTIVES: To analyse the predictive value of the volume of enhancement of disease (VED), based on the CT arterial enhancement coefficient (ΔArt%), in the evaluation of the sorafenib response in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with sorafenib-treated advanced HCC, who underwent a multiphase contrast-enhanced CT before (T0) and after 60-70 days of starting therapy (T1), were included. The same target lesions utilised for the response evaluation according to modified Response Evaluation Criteria in Solid Tumors criteria were retrospectively used for the ΔArt% calculation ([(HUarterial phase - HUunenhanced phase) / HUunenhanced phase] × 100). ΔArt% was weighted for the lesion volume to obtain the VED. We compared VEDT0 and VEDT1 values in patients with clinical benefit (CB) or progressive disease (PD). The impact of VED, ancillary imaging findings, and blood chemistries on survival probability was evaluated. RESULTS: Thirty-two patients (25 men, mean age 65.8 years) analysed between 2012 and 2016 were selected. At T1, 8 patients had CB and 24 had PD. VEDT0 was > 70% in 8/8 CB patients compared with 12/24 PD patients (p = 0.011). Patients with VEDT0 > 70% showed a significantly higher median survival than those with lower VEDT0 (451.5 days vs. 209.5 days, p = 0.032). Patients with VEDT0 > 70% and alpha-fetoproteinT0 ≤ 400 ng/ml had significantly longer survival than all other three combinations. In multivariate analysis, VEDT0 > 70% emerged as the only factor independently associated with survival (p = 0.037). CONCLUSION: In patients with advanced HCC treated with sorafenib, VED is a novel radiologic parameter obtained by contrast-enhanced CT, which could be helpful in selecting patients who are more likely to respond to sorafenib, and with a longer survival. KEY POINTS: • To achieve the best results of treatment with sorafenib in advanced HCC, a strict selection of patients is needed. • New radiologic parameters predictive of the response to sorafenib would be essential. • Volume of enhancement of disease (VED) is a novel radiologic parameter obtained by contrast-enhanced CT, which could be helpful in selecting patients who are more likely to respond to therapy, and with a longer survival.

Alpha-tocopherol pro-vitamins: synthesis, hydrolysis and accumulation in rabbit ear skin.

We synthesized esters of alpha-tocopherol (VE) with the aim to develop new pro-vitamins, easily reconverted by enzymes in the skin and able to release another active moiety such as an amino acid, in order to obtain a synergic effect. In particular, the attention was dedicated to the amino acids glycine and alanine and to pyroglutamic acid. The sensitivity of pro-vitamins to enzymatic hydrolysis was evaluated in vitro using porcine liver esterase. Permeation experiments were performed using rabbit ear skin, for the quantification of pro-vitamins and derived VE in the epidermis and dermis. The new derivatives synthesized, and in particular the glycine and alanine derivatives, accumulated in rabbit skin in a significant extent and originated substantial amounts of alpha-tocopherol. In comparison with the acetate derivative (VEAc), the amounts accumulated are comparable or higher. Moreover, the new derivatives, being more hydrophilic, allow the use of vehicles such as the mixture water/propylene glycol/ethanol widely employed for the preparation of creams and gels. Finally, the enzymatic metabolism of these new derivatives generates not only VE, but also components that can have a further advantageous action on skin.

Successful treatment of multidrug-resistant tuberculosis following drug-induced hepatic necrosis requiring liver transplant.

A 28-year-old female developed multidrug-resistant (MDR) tuberculous lymphadenitis following a trip to India. She was initially treated with a four-drug regimen of first-line anti-tuberculosis medications, but when sensitivities indicated resistance to isoniazid and rifampin, her regimen was altered to ciprofloxacin (CFX), pyrazinamide (PZA) and ethambutol. She subsequently developed a rash, flu-like symptoms and fever, which progressed to acute hepatic necrosis despite discontinuation of medication. The clinical presentation and subsequent investigations suggested a hypersensitivity reaction, possibly related to the quinolone. The patient subsequently had an orthoptic liver transplant; second-line anti-tuberculosis medications were restarted to which she responded clinically and radiologically. Our findings raise the possibility that the CFX and PZA combination was responsible for the hepatic necrosis. The patient also illustrates that active, even MDR tuberculosis is not a contraindication to hepatic transplant.

A cost-effectiveness analysis of pneumococcal vaccination in street-involved, HIV-infected patients.

BACKGROUND: Delivery of the pneumococcal vaccine (PCV) to street-involved, HIV patients in British Columbia is low due to poor compliance. Since the use of PCV is expected to reduce morbidity and mortality, it may be more cost-effective to provide the vaccine directly to clinics. METHODS: Three strategies were compared for a cohort of 5000 patients: 1) administering PCV at the clinics; 2) giving a prescription for PCV and expecting patients to fill it at a pharmacy and return for administration; and 3) no administration of vaccine. Decision analysis was utilized to map the costs and outcomes of the patients over 5 years and conduct an incremental cost-effectiveness analysis from the perspective of the Ministry of Health. RESULTS: The average cost per patient was the lowest in Strategy 1 ($549) compared to Strategy 2 ($702) and Strategy 3 ($714). For the cohort, Strategy 1 prevented 269 and 299 additional cases of pneumococcal disease and resulted in a cost savings of $535,000 and $595,000 in direct medical costs when compared to Strategies 2 and 3, respectively. The model was robust to extensive sensitivity analyses. CONCLUSIONS: The Ministry of Health should supply PCV to clinics involved in the care of street-involved HIV patients as this is the most cost-effective strategy.

A new ciprofloxacin stepdown program in the treatment of high-risk febrile neutropenia: a clinical and economic analysis.

STUDY OBJECTIVE: To determine treatment outcomes and economic impact of a ciprofloxacin stepdown program for high-risk febrile neutropenic adults from the hospital's perspective. DESIGN: Unblinded, two-phase, single-center study. SETTING: Adult leukemia and stem cell transplant unit. PATIENTS: High-risk adults with febrile neutropenia. INTERVENTION: Two conditions were analyzed: a multidisciplinary ciprofloxacin stepdown program involving a reduction in parenteral ciprofloxacin dose from 400 to 200 mg (i.v.-i.v.) and conversion to oral ciprofloxacin (i.v.-p.o.) when criteria were met; and no i.v.-i.v. stepdown program. MEASUREMENTS AND MAIN RESULTS: Forty-six sequential treatment courses were compared with 42 treatment course from 6-month periods in preintervention (P1) and postintervention (P2) phases. Assessed parameters were clinical and microbiologic outcomes, adverse drug reactions (ADRs), and direct medical resource use and costs (1998 $Canadian) for the episode of febrile neutropenia. A decision analytic model was used to map probabilities and costs and to conduct sensitivity analyses. To supplement standard statistical testing, 1,000 bootstrap samples were created, and the mean cost difference was calculated between phases for each sample. Patient demographics, percentage i.v.-p.o. stepdown, and duration of therapy were similar between phases. Clinical success (83% P1, 81% P2), microbiologic eradication (15% P1, 24% P2), and possible ADRs (6% P1, 9% P2) did not differ. Intravenous-to-intravenous dose stepdown occurred in 33% of P2 and no P1 treatment courses (p<0.001). Resource use and costs were similar between phases, although a reduction was seen in the drug's mean total cost/day ($58 P1, $52 P2, p=0.04). There was also a trend toward a decrease in mean total treatment costs ($4,843 P1, $3,493 P2, p=0.08). In 1,000 bootstrap samples, 99.8% showed a cost advantage for P2. The model was robust to sensitivity analyses. CONCLUSION: This intervention influenced administration of ciprofloxacin without apparent compromise of patient outcomes and resulted in a reduction in total costs of treating febrile neutropenia.

Piperacillin/tazobactam versus imipenem: a double-blind, randomized formulary feasibility study at a major teaching hospital.

With the introduction of piperacillin/tazobactam to the North American market, hospitals have been faced with the task of making a decision regarding its formulary role. In view of its broad spectrum of activity, piperacillin/tazobactam could be considered as a formulary alternative to imipenem. To evaluate the formulary feasibility of substituting piperacillin/tazobactam for imipenem, a comparative assessment of these agents in the empiric treatment of serious bacterial infections was undertaken at this tertiary care hospital. This trial was conducted as a randomized, double-blind, single-center study. Consenting adult patients (>16 years of age) who were prescribed imipenem were randomized to receive either 4 g of i.v. piperacillin/tazobactam or imipenem 500 mg of i.v. Q6H with or without concurrent antibiotics. Doses were adjusted according to renal function. There were no restrictions regarding the use of nonstudy antibiotics before and during the study period. Patients with beta-lactam allergies or meningitis or who had received greater than 72 h of previous imipenem therapy were excluded. Patients were evaluated at the end of treatment, at discharge, and at 30 days postdischarge. Endpoints included both clinical and microbiologic efficacy as well as drug toxicity. Over the 433-day study period, 360 imipenem treatment courses were initiated. Of these, 150 treatment courses (75 piperacillin/tazobactam courses and 75 imipenem courses) met study criteria and were subsequently randomized. The distribution of prescriber services for enrolled patients was similar to that for all patients receiving imipenem during the study period (p = 0.15). Also, there were no statistically significant differences in demographic parameters between enrolled and excluded patients. For those patients enrolled in the study, demographic characteristics, treatment course indication(s), and accompanying antibiotics were similar across treatment arms. The mean duration of study drug therapy was 7.7 days (SD, 6.2) for imipenem and 7.5 days (SD, 6.7)for piperacillin/tazobactam (p = 0.84). In the majority of cases, treatment discontinuation occurred as a result of a favorable treatment course outcome, stepdown to a narrower spectrum parenteral agent, or stepdown to an oral agent and did not differ between study drugs (p = 0.73). Clinical and microbiologic treatment course outcomes were also similar across treatment arms. Clinical outcome was deemed successful or improved for 68% of imipenem and 70% of the piperacillin/tazobactam treatment courses (p = 0.54). Fifty-three percent of treatment courses were microbiologically confirmed. Of the 58 courses that were assessed for microbiological outcome, 93% demonstrated successful eradication of the causative pathogens. There was no difference between study drugs (96% imipenem; 90% piperacillin/tazobactam; p = 0.61). The proportion of treatment courses with at least one adverse event was similar between the study drugs (p = 1.0). Nausea and/or vomiting were/was observed more commonly in the imipenem arm (p = 0.03). Discontinuation of therapy due to drug toxicity occurred in 16% of imipenem and 5% of piperacillin/tazobactam treatment courses (p = 0.06). There was no statistically significant difference between the mean treatment course cost for imipenem ($762; range, $55-$3192) versus piperacillin/tazobactam ($696; range, $79-$2967; p = 0.59). In summary, piperacillin/tazobactam seems to represent a suitable alternative to imipenem for several clinical indications including intraabdominal infections, pneumonia, febrile neutropenia, and skin/soft tissue infections in which the causative pathogens are susceptible. However, in view of the prevalence of multiresistant Gram-negative aerobic pathogens at this institution, we do not believe that imipenem can be removed from the drug formulary. In addition, at the currently studied dosing regimen, there seems to be no evidence of a direct cost advantage associated with

Effects of supplementation with unsaturated fatty acids on plasma and membrane lipid composition and platelet function in patients with cirrhosis and defective aggregation.

BACKGROUND/AIMS: Defective platelet aggregation and reduced platelet production of thromboxane A2, a metabolite of arachidonic acid, are common findings in patients with cirrhosis. We evaluated the effects of dietary supplementation with two combinations of unsaturated fatty acids on platelet function and plasma and membrane fatty acids in patients with liver cirrhosis. METHODS: In a double-blind study, 15 patients with cirrhosis and defective aggregation were randomized to receive a 6-week supplementation with gamma-linolenic and linoleic acid (1 g/day of each fatty acid) or with oleic acid and linoleic acid (groups GLA and OA, respectively). RESULTS: Under baseline conditions, patients showed elevated concentrations of monounsaturated fatty acids and a reduction in polyunsaturated fatty acids. The product/precursor ratios for delta6 and delta5 desaturases, two key enzymes in the pathway leading to arachidonic acid, were significantly reduced in the group of patients. In the GLA group, a significant increase in the levels of dihomo-gamma-linolenic acid (20:3omega6) was observed in plasma and membranes, together with a parallel decrease in the 20:4/20:3omega6 ratio after supplementation. No significant changes were observed in the OA group. The levels of arachidonic acid did not change significantly in either group of patients. Platelet aggregation to collagen was unchanged in the GLA group, but significantly improved in the OA group. CONCLUSIONS: These results show that supplementation with precursors of arachidonic acid is ineffective in elevating plasma or membrane arachidonate levels and does not improve platelet aggregation, suggesting that synthesis of arachidonic acid through the delta5 desaturase cannot be correspondingly activated or that incorporation/retention of the produced fatty acid into lipids is impaired. The increased platelet aggregation in the OA group is likely to be explained by the effect of oleic acid contained in the diet, the effects of which may have been counteracted by the elevation in 20:3omega6, a source of anti-aggregatory prostanoids, in the GLA group.