Hepatic transcatheter arterial chemoembolization alternating with systemic protracted continuous infusion 5-fluorouracil for gastrointestinal malignancies metastatic to liver: a phase II trial of the Puget Sound Oncology Consortium (PSOC 1104)

We assessed a regimen of alternating regional and systemic therapy in patients with gastrointestinal malignancies with liver-dominant metastases for feasibility, toxicity, response rate, response duration, patterns of progression, and progression-free and overall survival. Regional therapy comprised selective hepatic transcatheter arterial chemoembolization (TACE) using a suspension of cisplatin and particulate polyvinyl alcohol. This procedure was delivered between cycles of protracted continuous infusion 5-fluorouracil (PCI-5FU) as systemic chemotherapy. Patient eligibility criteria included: (a) having histologically documented adenocarcinoma arising from a gastrointestinal primary site with unresectable liver metastases bidimensionally measurable on computerized tomography scan; (b) age greater than 18 years; and (c) performance status 0-2 (Zubrod). PCI-5FU (250 mg/m2/day) was administered i.v. for 28 days, followed by the first TACE (TACE 1) delivered to the hepatic artery supplying the lobe with the greatest tumor burden. Restaging was performed before TACE 2 and TACE 3, which followed at monthly intervals. PCI-5FU for 21 days was sandwiched between each of the TACE treatments. After the final TACE, maintenance PCI-5FU was given for 28 days of each 35-day cycle until toxicity or progression. Between December 23, 1991, and January 19, 1995, 32 patients were registered in this trial, of whom 27 were eligible; 20 completed one or more treatment cycles and were evaluable for radiographic response. Patients with colorectal liver metastases predominated (74%). Twelve (44%) of 27 patients had failed one or more prior treatment regimens. There were no treatment-related deaths, and hematological and hepatic toxicities were generally manageable and reversible. Two patients, however, developed hepatic abscesses requiring drainage, and one patient developed an infarcted gallbladder, which necessitated cholecystectomy. There were no patients with complete responses; there were 8 (40%) with partial responses, 4 (20%) with minor responses, 2 (10%) with stable disease, and 6 (30%) who progressed on the treatment. The median duration of response for partial responders was 4.2 months (127 days; range, 56-245 days). The median reduction in carcinoembryonic antigen for responders was 87.5%. Two patients underwent subsequent resection of residual metastases; one of them is still alive at 58.4 months follow-up. The predominant site of disease progression was the liver; 25% of the patients progressed in extrahepatic sites. The median overall survival for the whole group is 14.3 months (95% confidence interval, 7.2-16.2). Actuarial overall survival for the whole group at 1 year and 2 years is 57 and 19%, respectively. Alternating systemic PCI-5FU and regional TACE (cisplatin/polyvinyl alcohol) is an active and feasible regimen with manageable toxicities in patients with metastatic gastrointestinal malignancies with liver-dominant disease and merits further investigation. The complications seen were in line with those reported at other specialized centers.     

Prediction of response during interferon alfa 2b therapy in chronic hepatitis C patients using viral and biochemical characteristics: a comparison

Patients with chronic hepatitis C (n = 103) were treated for 24 weeks with interferon alfa 2b and followed up for 24 weeks after cessation of therapy (week 48). When hepatitis C virus (HCV) RNA at week 48 was used to assess interferon response, 15 (14.6%) were virological complete responders, and all have remained HCV RNA negative for a mean of 3 years. At week 48, 3 of 15 virological complete responders had elevated alanine transaminase (ALT) values. When serum ALT level was used at week 48 to determine response to interferon, 20 (19.4%) were biochemical complete responders. However, 8 of the 20 patients with normal ALT levels were HCV RNA positive at week 48, and 7 of these individuals have had a recurrence of elevated ALT levels within 3 years after cessation of treatment. These findings indicate that measurement of HCV RNA was more accurate than ALT in determining true responses to interferon therapy. Identification of nonresponders early during the course of interferon treatment showed that an elevated ALT level at week 12 was 92% predictive (odds ratio 3.7) but misidentified 33% (5 of 15) of the patients who were virological complete responders at week 48. In contrast, a positive HCV RNA at week 12 of treatment was 98% predictive (odds ratio 35.5) and misidentified only 6.7% (1 of 15) of the virological complete responders. Thus, positive HCV RNA at week 12 of therapy was more accurate in identifying eventual virological nonresponders than measurement of ALT at this time. Termination of interferon therapy in patients who were HCV RNA positive at week 12 would result in a 27% reduction in the direct medical costs and keep patients from undergoing unnecessary treatment. Therefore, testing for HCV RNA at week 12 to identify nonresponders and then discontinuing their treatment is practical, cost-efficient and beneficial both to patients and to third-party payers.     

A 2-year study of sertraline in the treatment of obsessive-compulsive disorder

The present study investigated the tolerability, safety profile, and anti-obsessional efficacy of sertraline, a selective serotonin reuptake inhibitor, during long-term treatment of patients with obsessive-compulsive disorder (OCD). Fifty-nine OCD patients who had completed a 1 year double-blind, fixed dose study comparing sertraline and placebo subsequently entered a 1-year open extension. Among the 51 patients who had been treated with sertraline during the double-blind phase, the mean total duration of sertraline treatment was 690 days. Only treatment responders who completed the 52-week double-blind treatment phase were permitted to enter the open extension. The higher rate (p < 0.02) of sertraline patients (51 out of 241) than of placebo patients (eight out of 84), who responded to treatment and entered the open-label phase is therefore consistent with the greater mean improvement observed in the sertraline group during double-blind treatment. Placebo responders differed from sertraline responders in that they were less impaired at baseline of the double-blind study [Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) of 18.5 versus 23.4] and they exhibited less improvement during double-blind treatment (-6.1 versus -11.4). In the open-label phase all patients received sertraline at a starting dose of 50 mg once a day, titrated in 50 mg increments to a maximum dose of 200 mg according to clinical response. At end-point the mean Y-BOCS score for all patients decreased by a further 3.6 points. Patients previously treated with placebo showed greater improvement after being switched to sertraline than those who received continued sertraline treatment. Patients who completed the study and received 2 full years of sertraline treatment (n = 38) exhibited a mean improvement of 15.6 points using the Y-BOCS. Sertraline was well tolerated during both the double-blind phase and the open extension, and the incidence of adverse experiences was generally reduced during the second year of treatment. Three patients discontinued open treatment because of adverse experiences. Long-term sertraline treatment did not appear to be associated with the emergence, increased incidence, or increased severity of adverse experiences or clinically significant abnormalities in laboratory tests, vital signs, or the electrocardiogram. The study supports the long-term safety and tolerability of sertraline over a 2-year treatment course and the sustained efficacy of sertraline in patients with OCD.     

Characterization of Y3 receptor-mediated synaptic inhibition by chimeric neuropeptide Y-peptide YY peptides in the rat brainstem

Archival material from primary and metastatic renal clear cell carcinomas of 25 patients was studied by comparative genomic hybridization. Copy number changes of entire chromosomes or chromosomal subregions were detected in 22 primary and 21 metastatic tumors. Copy number changes affected the following chromosomes in at least 20% of the 25 primary tumors (minimal common region given in parentheses): gains were noted for chromosomes 1 (1q21-->q23), 5 (5q31-->q34), 7 (7p), 8 (8q), 16 (16p), 17 (17q12-->qter), 19, and 22 (22q12-->qter); losses were revealed for chromosomes 3 (3p21-->pter), 8 (8p23-->pter), 14(14q21-->qter), and Y. The same chromosomal regions that were involved in primary renal clear cell carcinomas were also found in the respective metastatic tumors but with strikingly different frequencies for a few regions. Metastatic tumors showed a significantly higher frequency of complete or partial gains of the long arm of chromosome 1, in particular at 1q21-->q23 than primary tumors (16 cases versus 6 cases; P < 0.005). These data suggest a correlation of metastatic events in renal clear cell carcinomas with an increase in the copy number of genes located at 1q, in particular at 1q21-->q23. In contrast, the entire or partial loss of the short arm of chromosome 3 was significantly less frequent in metastatic tumors (8 cases versus 15 cases; P < 0.025). The validity of 1q and 3p copy number changes detected by comparative genomic hybridization was confirmed by interphase cytogenetics with region-specific yeast artificial chromosomes to paraffin-embedded tumor tissue sections.     

Comparison of high-resolution structures of the diphtheria toxin repressor in complex with cobalt and zinc at the cation-anion binding site

The diphtheria toxin repressor (DtxR) from Corynebacterium diphtheriae is a divalent-metal activated repressor of chromosomal genes responsible for siderophore-mediated iron-uptake and of a gene on several corynebacteriophages that encodes diphtheria toxin. Even though DtxR is the best characterized iron-dependent repressor to date, numerous key properties of the protein still remain to be explained. One is the role of the cation-anion pair discovered in its first metal-binding site. A second is the reason why zinc exhibits its activating effect only at a concentration 100-fold higher than other divalent cations. In the presently reported 1.85 A resolution Co-DtxR structure at 100K, the sulfate anion in the cation-anion-binding site interacts with three side chains that are all conserved in the entire DtxR family, which points to a possible physiological role of the anion. A comparison of the 1.85 A Cobalt-DtxR structure at 100K and the 2.4 A Zinc-DtxR structure at room temperature revealed no significant differences. Hence, the difference in efficiency of Co2+ and Zn2+ to activate DtxR remains a mystery and might be hidden in the properties of the intriguing second metal-binding site. Our studies do, however, provide a high resolution view of the cationanion-binding site that has most likely evolved to interact not only with a cation but also with the anion in a very precise manner.     

Ca(2+)-ATPases in the cochlear duct

Differing levels of the Ca(2+)-ATPase enzymes that reside on the plasma membrane (PM) and on the endoplasmic reticulum (ER) were identified in individual rat cochlear tissues by the use of a semi-quantitative enzyme-linked immunosorbent assay (ELISA). Unlike other studies, a specific antibody to PM Ca(2+)-ATPase was used to detect significantly greater levels (about 2x) of PM Ca(2+)-ATPase in the stria vascularis (SV) than that in the spiral ligament (SL) and organ of Corti (OC) tissues. Similarly, levels of ER Ca(2+)-ATPase were also significantly higher in the SV than in the SL and OC tissues. The presence of ER Ca(2+)-ATPase in the tissues of the SV has not been demonstrated previously. Given the importance of Ca2+ homeostasis in the inner ear, the statistically significantly higher densities of both PM and ER Ca(2+)-ATPase measured in the SV relative to the SL and OC regions would indicate tissue-specific responses to fluctuations in systemic and local Ca2+ concentrations.