Simvastatin protects against cholestasis-induced liver injury

Background:

Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage.

Experimental approach:

C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg·kg⁻¹) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined.

Key results:

Administration of 0.2 mg·kg⁻¹ simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37–82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg·kg⁻¹ simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation.

Conclusions and implications:

These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.     

Sunitinib efficacy against advanced renal cell carcinoma

PURPOSE: We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). RESULTS: Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months. CONCLUSIONS: The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation.     

A community study of delay in presenting with signs of melanoma to medical practitioners

In the absence of more effective treatment for advanced tumors, early diagnosis and treatment of localized tumors is the most effective way of reducing the burden of illness associated with melanoma. This study examined the following factors: prevalence of signs of melanoma (a mole changing in size, shape, appearance, or color, itching or tingling, bleeding or weeping, becoming raised) in 1344 individuals in a randomly selected sample of 1075 households; the length of delay in seeking medical advice; the factors associated with either going to a medical practitioner or not going/delaying; and the actions of the medical practitioners when first presented with these signs. The results indicate that a large proportion of the sample (11.9%, n = 156) had observed signs of melanoma in the previous 12 months. Of the sample reporting signs that had first appeared in the previous 5 years, only 32% sought medical advice about the signs within the recommended period. Of the sample either not seeking advice at all or delaying, 49% reported that they thought the sign "wasn't serious/would clear up." Furthermore, 30% of the sample either did not known or underrated the importance of early detection and treatment of lesions. These results indicate that there is a deficit in the knowledge of the general public about the signs of melanoma, the severity of the disease, and the possible risks associated with delay.     

Managing multiple myeloma: the emerging role of novel therapies and adapting combination treatment for higher risk settings

Novel therapies have transformed the treatment paradigm for multiple myeloma with significant improvements in survival now seen in both younger and older patients. Nonetheless, the disease is heterogeneous and high‐risk patients in particular continue to have poor outcome. Moreover, the disease remains incurable. Efforts to refine risk stratification and disease characteristics continue with the use of cytogenetics, enhanced imaging techniques and other new technologies, such as genomics. The integration of novel therapies into induction therapy, consolidation and maintenance continues to evolve, and the appropriate use of combination strategies including proteasome inhibition and immunomodulatory treatment is emerging as a platform with application across the disease spectrum. Despite these advances, resistance to novel agents occurs and so the identification of new targets and the recognition of clonal heterogeneity are especially important as improvements to current treatment strategies are developed, with the goal of further improving patient outcome.     

Prevention of post-cone biopsy cervical stenosis using a temporary cervical stent

Stenosis of the residual cervix is not an infrequent complication of cone biopsy which may result in subfertility, problems with adequate follow-up and dysmenorrhoea. In an attempt to minimize this complication a temporary indwelling cervical support stent has been developed. This is sutured into the exposed cone bed immediately after cutting the cone specimen and removed 2 weeks later. A pilot study using this device in 33 cold knife conizations has been performed. There were no primary or secondary haemorrhages and no post-conization pelvic infections. At follow-up, 6 months after cone biopsy two patients (6%) had clinical cervical stenosis, and one patient (3%) complained of dysmenorrhoea (although the cervix was not stenosed). The cervical transformation zone was fully visible in 21/33 patients (64%) (95% CI 48 to 80) and follow-up smears contained endocervical cells in 20/33 patients (61%) (95% CI 44 to 78). These results compare very favourably with historical controls from the same unit and suggest that cone biopsy support stents should now be assessed in a prospective randomized trial.     

A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.     

Delay in consulting a medical practitioner about rectal bleeding.

STUDY OBJECTIVE--The aims were to estimate the incidence of rectal bleeding in the community, and to determine the proportion of individuals who delay or fail to seek medical advice after a first episode of rectal bleeding. DESIGN--The data were collected as part of a large scale general population survey of the health practices and attitudes of individuals in a randomly selected sample of 2121 households. SETTING--The survey was conducted in the Newcastle and Lake Macquarie areas of New South Wales, Australia, during 1987-88. PARTICIPANTS--Information about rectal bleeding was collected from 1213 individuals aged 40 years and over. MEASUREMENTS AND MAIN RESULTS--Of the 1213 people aged 40 years and over, 239 (20%) reported noticing rectal bleeding at some time in their life. However, since an estimated 4.5% had noticed rectal bleeding for the first time in the past year the true lifetime incidence of rectal bleeding is likely to be much higher. Of the 77 individuals who had noticed a first occurrence of rectal bleeding more than three months but less than five years prior to the interview, 23 (30%) had either not sought medical advice or had only done so after a period of delay. The most commonly reported reason for delay or failure to consult was thinking that the bleeding was not serious and would clear up by itself. CONCLUSIONS--The data suggest that prompt investigation of rectal bleeding is not occurring in a relatively large proportion of cases. However, in the absence of firm evidence that early detection improves prognosis, and considering the costs of screening, it would be premature to initiate programmes which encourage people to seek care promptly for this symptom.