Adrenocortical carcinoma: clinical, morphologic, and molecular characterization.

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P =.005).The phenotype Ki-67(-)p53(-)mdm-2(+)cyclinD1(-)Bcl-2(-)p21(-)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P =.01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.     

Do recipients of kidneys from donors treated with streptokinase develop anti-streptokinase antibodies?

Streptokinase is used for preflush for non-heart-beating donors (NHBDs) in our center. The aim of this study was to evaluate whether the use of thrombolytic streptokinase results in the production of anti-streptokinase antibodies in the recipients after renal transplantation. Recipient sera taken prior to and at 1 and 6 months posttransplant were tested for the presence of antibodies to streptokinase using an enzyme-linked immunosorbent assay assay. No differences were detected between a group of 18 recipients who had kidneys from thrombolytic-treated NHBDs and a further group of 18 who received NHBD kidneys without such treatment.     

Is detection of asymptomatic recurrence after curative resection associated with improved survival in patients with gastric cancer?

BACKGROUND: It is not clear if more intense surveillance is associated with improved survival after curative resection for cancer. In the context of a followup program after curative gastrectomy, recurrence and survival were investigated for patients presenting with either symptomatic or asymptomatic recurrence. STUDY DESIGN: A prospectively maintained gastric cancer database was used to identify all patients who underwent a curative (R0) gastrectomy from July 1985 to June 2000. Survival curves were generated for patients with either symptomatic or asymptomatic recurrence, and the prognostic variables associated with outcomes were identified. RESULTS: Of 1,172 patients who underwent a curative (R0) gastrectomy, 561 patients (48%) had documented recurrence and 382 patients had complete data about symptoms. Median time to recurrence was 10.8months for asymptomatic patients and 12.4months for symptomatic patients (p = NS). Median postrecurrence survival was 13.5months for asymptomatic patients and 4.8months for symptomatic patients (p < 0.01). Median disease-specific survival was 29.4months for asymptomatic patients and 21.6months for symptomatic patients (p < 0.05). Variables predictive of poor postrecurrence survival included symptomatic recurrence, advanced stage (III/IV), poor differentiation, short disease-free interval (<12months), and multiple sites of recurrence. CONCLUSIONS: Followup did not identify asymptomatic recurrence earlier than symptomatic recurrence. Patients with symptomatic recurrence have more aggressive disease with a shorter postrecurrence survival. The impact of detecting asymptomatic recurrence in the course of followup after curative gastrectomy could not be distinguished from the effects of four powerful biologic variables that also interact to govern outcomes.     

Factors predicting duration of delayed graft function in non-heart-beating donor kidney transplantation

Non-heart-beating donors (NHBDs) are an important potential source of donor organs, but kidneys from such donors are prone to delayed graft function (DGF) and primary nonfunction, which are multifactorial in origin but believed to be mainly due to warm ischemic injury. This retrospective study examined a series of 88 transplants from Maastricht category II and III NHBDs to examine the role of factors to predict the duration of DGF. The main factors affecting duration of DGF were total warm ischemic time, cold ischemic time, product of perfusate GST concentration and donor age, quality of postoperative graft perfusion, incidence of acute rejection, recipient cardiovascular risk score, maximum pressure on machine perfusion, and weight gain during machine perfusion. Primary nonfunction was not accurately predicted from these factors for kidneys that had passed the viability assessment.     

The effect of antioxidants and a caspase inhibitor on cryopreserved rat hepatocytes

Hepatocyte transplantation and use of bioartificial liver support systems have been suggested as potential therapies for fulminant hepatic failure. Cryopreservation in liquid nitrogen is presently the major method of long-term storage of isolated hepatocytes. However, cryopreservation can result in low cell recovery and reduction in differentiated function. Several possible mechanisms of cell death during cryopreservation have been proposed. The most important mechanisms appear to be oxidative stress and apoptosis. In this study, we isolated fresh rat hepatocytes and cryopreserved them in three media: University of Wisconsin (UW) solution, an antioxidant-containing medium, and medium containing a caspase inhibitor. Viability and function of hepatocytes cryopreserved in these media were examined. Cryopreservation conditions had no effect on hepatocyte viability after thawing. However, after culture we found significant improvements in viability and function in both antioxidant- and caspase inhibitor-treated hepatocytes at 6 and 24 h.     

Doublecortin interacts with the ubiquitin protease DFFRX, which associates with microtubules in neuronal processes

Doublecortin (DCX) is a microtubule-associated protein involved in neuronal migration, which causes X-linked lissencephaly and subcortical laminar heterotopia (SCLH) when mutated. Here we show that DCX interacts with the ubiquitin-specific protease Drosophila fat facets related on X chromosome (DFFRX). This interaction was confirmed by targeted mutagenesis, colocalization, and immunoprecipitation studies. DFFRX is thought to deubiquitinate specific substrates including beta-catenin, preventing their degradation by the proteasome. Interestingly, unlike beta-catenin, no ubiquitinated forms of DCX could be detected, and indeed we show that DCX interacts with a novel recognition domain in DFFRX, located outside of its catalytic site. We also show that DFFRX associates with microtubules at specific subcellular compartments, including those enriched in DCX. These results thus suggest that in addition to vesicular trafficking, DCX may play a role in the regulation of cell adhesion via its interaction with DFFRX in migrating and differentiating neurons.     

The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial

A noninvasive method of delivery of parenteral opioids for management of acute pain may offer logistic advantages for patients and nursing staff. A patient-controlled transdermal system (PCTS) under development consists of a preprogrammed, self-contained drug-delivery system that uses electrotransport technology (E-TRANS, ALZA Corp, Mountain View, CA) to deliver 40 micro g of fentanyl HCl over 10 min per on-demand dose for patient-controlled analgesia (PCA). In this randomized, double-blinded, placebo-controlled trial we compared the efficacy and safety of on-demand fentanyl HCl PCTS 40 microg against placebo for postoperative pain up to 24 h after major abdominal, orthopedic, or thoracic surgery in 205 patients. The primary efficacy measurement was the percentage of patients withdrawn from the study because of inadequate analgesia after completing at least 3 h of treatment. Secondary efficacy measures included mean pain intensity (using visual analog scales), patient global assessments, and investigator global assessments. Of 189 patients considered evaluable for efficacy, 25% of patients in the fentanyl HCl PCTS 40 microg group withdrew because of inadequate analgesia, compared with 40.4% of the placebo group (P < 0.05). Use of fentanyl HCl PCTS 40 micro g was associated with lower VAS scores and higher mean patient and investigator global assessment scores compared with placebo. No patient experienced clinically relevant respiratory depression. This study showed that a fentanyl HCl PCTS 40 microg for PCA was superior to placebo and well tolerated for the control of moderate to severe postoperative pain for up to 24 h after major surgery. IMPLICATIONS: This multicenter, randomized, double-blinded, placebo-controlled trial showed that an on-demand fentanyl HCl patient-controlled transdermal system (PCTS) was superior to placebo and well tolerated for the control of moderate to severe postoperative pain for up to 24 h after major surgery. This fentanyl HCl PCTS is a preprogrammed, needle free, self-contained drug-delivery system that uses electrotransport technology (iontophoresis) to deliver 40 microg of fentanyl per on-demand dose.