Increased plasma nitric oxide, L-arginine, and arginase-1 in cirrhotic patients with progressive renal dysfunction

Background and Aims:  Increased levels of nitric oxide (NO) are hypothesized to contribute to renal dysfunction in patients with decompensated cirrhosis. In this study, we examined whether splanchnic and/or peripheral NO levels and L-arginine (L-Arg) correlate with progressive renal dysfunction in cirrhotics.
Methods:  Serum NO metabolites (NOx) and L-Arg were measured in: controls ( n  = 10); organ donors ( n  = 12); compensated cirrhotics ( n  = 17), cirrhotics with ascites ( n  = 25), refractory ascites ( n  = 11) or hepatorenal syndrome type II (HRS) ( n  = 11) and chronic renal failure patients ( n  = 18).
Results:  Plasma NOx and L-Arg levels rose progressively with worsening renal function in decompensated cirrhotics. Both NOx and L-Arg levels were highest in patients with HRS ( P  < 0.001 and P  < 0.025, respectively). While there were no differences in NOx levels related to the site of sampling, L-Arg levels were lowest in hepatic venous blood. There were significant relationships of NOx and L-Arg with Model for End-Stage Liver Disease score and Child–Pugh scores ( P  < 0.04 and P  < 0.01, respectively). Multivariate analysis showed a significant relationship between NOx, L-Arg and HRS.
Conclusion:  Worsening renal function in decompensated cirrhosis is accompanied by progressive elevation in plasma NOx and L-Arg. These findings support the hypothesis that NO-mediated vasodilation is probably linked with the mechanism of progressive renal failure in decompensated cirrhotics.     

Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine

OBJECTIVES: To compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. DESIGN: Two multicenter, open-label, randomized 24-week studies. METHODS: Adults HIV-1 infection, HIV-1 RNA greater than 10000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. RESULTS: In Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). CONCLUSION: Three-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug-drug interactions.     

Value of third metastasectomy of colorectal adenocarcinoma

62 year-old woman with a tumour in sigmoid colon invading left ovary and metastases in both hepatic lobes. Posterior pelvic exanteration and metastasectomy of left hepatic lesions were performed in the first surgery, right hepatectomy in the second one and metastasectomy of 2 new metastases in the third one. A new metastases in remanent portal pediculum was considered non-operable. The patient died 29 months after first surgery.     

Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma

Aim: To analyze toxicity, response and outcome of a phase IItrial with intensive chemotherapy plus autologous stem-celltransplantation (ASCT) for young patients with peripheral T-celllymphoma (PTCL). Patients and methods: Forty-one patients [30 males and 11 females,median age 47 years] consecutively diagnosed with PTCL receivedthree courses of high-dose cyclophosphamide 2000 mg/m²/day,adriamycin 90 mg/m²/day, vincristine and prednisone alternatingwith three courses of etoposide, cisplatin, cytarabine and prednisone.Responders were submitted to ASCT. Results: Sixty-eight percent of patients received the plannedtreatment. After chemotherapy, 20 patients reached completeresponse (CR), 4 partial response and 17 failed. ASCT was carriedout in 17 of 24 candidates due to lack of mobilization (threecases), toxicity (two), early relapse and patient decision (oneeach). CR rate after treatment was 51%. With a median follow-upof 3.2 years, 5 of 21 CR patients relapsed and 2 died in CRdue to secondary neoplasms. Four-year progression-free survivalwas 30%. Twenty-two patients have died, with a 4-year overallsurvival of 39%. International Prognostic Index was the mainvariable predicting survival. No differences were seen amongthe 24 candidates according to whether or not they underwentASCT. Conclusion: This intensive regimen resulted in moderate CR rate,with manageable toxicity in PTCL. The contribution of ASCT inpreventing relapse is debatable. Novel strategies to increaseCR warrant investigation. Key words: autologous stem-cell transplantation, peripheral T-cell lymphoma, prognosis Received for publication January 7, 2008. Accepted for publication January 9, 2008.     

The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counseling units in Spain.

PURPOSE: It is not clear that the published estimates of the breast and ovarian cancer penetrances of mutations in BRCA1 and BRCA2 can be used in genetic counseling in countries such as Spain, where the incidence of breast cancer in the general population is considerably lower, the prevalence of BRCA2 mutations seems to be higher, and a distinct spectrum of recurrent mutations exists for both genes. We aimed to estimate these penetrances for women attending genetic counseling units in Spain. EXPERIMENTAL DESIGN: We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from 12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method. RESULTS: The estimated average cumulative risk of breast cancer to age 70 years was estimated to be 52% [95% confidence interval (95% CI), 26-69%] for BRCA1 mutation carriers and 47% (95% CI, 29-60%) for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 22% (95% CI, 0-40%) and 18% (95% CI, 0-35%), respectively. There was some evidence (two-sided P = 0.09) that 330A>G (R71G) in BRCA1 may have lower breast cancer penetrance. CONCLUSIONS: These results are consistent with those from a recent meta-analysis of practically all previous penetrance studies, suggesting that women with BRCA1 and BRCA2 mutations attending genetic counseling services in Spain have similar risks of breast and ovarian cancer to those published for other Caucasian populations. Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy.     

Endotracheal metastases from colon adenocarcinoma

Endotracheal metastases (ETM) from non-lung cancer are seldom seen. Their main clinical symptoms are cough, haemoptysis and dyspnoea, although occasionally an incidental finding is made during a bronchoscopy. Breast, colon and kidney adenocarcinoma might be associated with ETM, lung cancer being the most frequent cause. Its finding is associated with advanced disease but survival will depend on the primary origin, patient status and comorbidity. Therefore, treatment should be individual for each patient. In our centre we recommend pre-surgery bronchoscopy to exclude metastatic endotracheal lesions in patients with metastatic colon adenocarcinoma disease, as this might affect the final outcome and therefore management of the disease.     

Prognostic value of Bcl‐2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy

We have analyzed the predictive/prognostic value of Bcl‐2 protein in breast cancer patients treated with neoadjuvant chemotherapy. One hundred and ten patients were submitted to two different chemotherapeutic regimens: a) 5‐fluorouracil, adriamycin or epirubicin, and cyclophosphamide (FAC/FEC) during 2–6 cycles before surgery and 3 or 4 additional cycles of FAC/FEC after surgery (n=40) and b) doxorubicin (D) 75mg/m2 or epirubicin (E) 120mg/m2 during 4 cycles before surgery, and 6 cycles of cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) after surgery (n=70). Bcl‐2 expression, evaluated by immunohistochemistry, did not change significantly after chemotherapy and was not related to clinical/pathological response. In FAC/FEC group, Bcl‐2 positive expression after chemotherapy correlated with better disease free survival (DFS) and overall survival (OS) (P=0.008 and P=0.001). In D/E group, Bcl‐2 also correlated with better DFS and OS (P=0.03 and P=0.054) in the post‐chemotherapy biopsies. An unusual nuclear localization of Bax was observed in some biopsies, but this localization did not correlate with the tumor response or outcome of the patients. We found that a high Bcl‐2 expression had no predictive value but had prognostic value in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.