Long-term results of a phase-I/II study of sequential high-dose chemotherapy with autologous stem cell transplantation in the initial treatment of aggressive non-Hodgkin's lymphoma

AIMS AND BACKGROUND: To improve the survival of patients with aggressive non-Hodgkin's lymphoma, we evaluated a risk-adapted therapeutic approach using high-dose (HD) or conventional-dose (CD) chemotherapy (CT) for poor-risk and good-risk patients, respectively. METHODS: Twenty patients were treated in each group. In both groups, the first chemotherapy cycle consisted of dexamethasone, vincristine, ifosfamide, and etoposide. Thereafter, the CD or HD patients received 3 or 2 cycles of dexamethasone, vincristine, epirubicin, and cyclophosphamide, respectively, followed by 1 cycle of dexamethasone, carboplatin, and etoposide. In the HD group cyclophosphamide, epirubicin, carboplatin, and etoposide were dose-escalated by a factor of 6, 3, 3, and 3, respectively, as compared to the CD group, and autologous peripheral blood stem cells were administered after each HD-CT cycle. RESULTS: Grade III-IV toxicities were neutropenia and thrombocytopenia (100%), anemia (55%), and stomatitis (30%) in patients with HD-CT, and neutropenia (90%) in patients with CD-CT. One toxic death occurred in a patient with HD-CT.The overall response rate was 100% in HD-CT patients, including 70% complete remissions, and 80% in CD-CT patients, including 60% complete remissions. The 10-year overall survival was 55% for patients with HD-CT and 80% for patients with CD-CT. CONCLUSIONS: The risk-adapted treatment approach showed tolerable toxicities and was associated with encouraging results.     

Multicenter validation of recursive partitioning analysis classification for patients with squamous cell head and neck carcinoma treated with surgery and postoperative radiotherapy

PURPOSE: To validate the recursive partitioning analysis (RPA) classification system for squamous cell head and neck cancer as recently reported by the VU University Medical Center. METHODS AND MATERIALS: In eight Dutch head and neck cancer centers, data necessary to classify patients according to the RPA system were retrospectively collected from the charts of a group of 780 patients treated between 1989 and 2003. The patients in this validation group were classified according to the RPA classification system. For each endpoint, the 5-year values and hazard ratios were calculated and compared with the results of the VU University Medical Center. The RPA classification system was considered valid if the hazard ratio of the validation population was within the 95% confidence interval of the VU University Medical Center study population. RESULTS: The locoregional control rate was 82%, 75%, and 63% at 5 years for those with class I, II, and III, respectively (p < 0.0001). The hazard ratio for the locoregional control rate relative to class I was 1.44 (95% confidence interval, 0.97-2.16) for class II and 2.37 (95% confidence interval, 1.57-3.57) for class III. Similar results were found for the distant metastasis, overall survival, and disease-free survival rates. CONCLUSION: The RPA classification system for head and neck squamous cell carcinoma in the postoperative setting, which was originally designed at one center, proved to be valid in a multicenter setting among patients included in a national multicenter study. This validated RPA classification scheme can be used to assess standard treatment strategies for head and neck squamous cell carcinoma in the postoperative setting, as well as in the design of future prospective studies.     

Resident care needs and work stressors in special care units versus non-specialized long-term care units

Differences in how elderly residents' care needs affect staff's experiences of work stressors between special care units (SCUs) for dementia and psychiatric residents and non-SCUs were investigated. The data were drawn from 390 staff members in 38 long-term care SCUs, and 587 staff in 53 non-SCUs in Finland. Residents' care needs were based on the Resident Assessment Instrument (RAI) system measured by the Minimum Data Set 2.0. Work stressors (time-pressure and role-conflicts) were assessed with a staff survey questionnaire. Multiple-group regression analysis showed that residents' dependency in activities of daily living (ADL) was related to increased work stressors only in SCUs. A high proportion of behavioral problems was related to fewer work stressors for SCU staff, but more for non-SCU staff. Work stressors may be reduced by specializing, so that residents with similar care needs are placed together and care is focused.     

Molecular analysis of chromosomal rearrangements in mammalian cells after phiC31-mediated integration

Reports on insertional mutagenesis due to integration of gene therapy vectors into the host genome have raised concerns about the genetic manipulation of somatic cells. Previously, it was demonstrated that integrase phiC31 derived from a Streptomyces phage mediates site-specific integration into the host genome of mammalian cells in vitro and in vivo by recombining the attB recognition site in an episomal plasmid and one or more pseudoattP sites in the host chromosomes. In the present study we investigated whether cryptic phiC31 recognition sites in the host genome may result in chromosomal rearrangements. Of 69 independent integration events analyzed in human cells, 6 (8.7%) integrated into human chromosome 19 (19q13.31) and 10 (14.49%) integrated into human chromosome 12 (12q22). Most importantly, of all integration sites analyzed, 15% were found to contain an integrated transgene that was flanked by DNA sequences originating from two different chromosomes. To confirm chromosomal translocations we performed a polymerase chain reaction analysis of chromosomal DNA flanking the transgene and also performed limited studies to determine the genotype of single-cell clones. Although the mechanism responsible for chromosomal translocations needs to be further characterized, we speculate that cryptic phiC31 attachment sites flanking the transgene and cryptic phiC31 attachment sites in the host genome recombine with each other.     

Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli

OBJECTIVES: 1-(1-Naphthylmethyl)-piperazine (NMP) has been shown to reverse multidrug resistance (MDR) in Escherichia coli overexpressing resistance-nodulation-cell division type efflux pumps, but there is no data on its activity in clinical isolates of E. coli. METHODS: The antimicrobial susceptibility of 60 clinical isolates of E. coli to a variety of antimicrobial agents was determined in the absence and presence of NMP and, for comparison, of Phe-Arg-beta-naphthylamide (PAbetaN), another putative efflux pump inhibitor (EPI). The intracellular accumulation of ethidium bromide was measured to confirm efflux pump inhibition as the likely mechanism of action of NMP. RESULTS: Based on a 4-fold or greater reduction of the MIC after the addition of NMP in >50% of the isolates, significant effects of NMP at a concentration of 100 mg/L were seen for levofloxacin, linezolid and ethidium bromide. The ethidium bromide MIC changes after NMP addition correlated with differences in the ethidium bromide intracellular accumulation as measured by fluorometry in whole cell accumulation experiments. The activity of PAbetaN was different from that of NMP, in particular regarding macrolide resistance reversal, suggesting different modes of action of the two putative EPIs. CONCLUSIONS: NMP is moderately active in reversing MDR in clinical isolates of E. coli and can partially restore fluoroquinolone susceptibility through inhibition of efflux pumps.     

Reduction in fluoroquinolone susceptibility among non-typhoidal strains of Salmonella enterica isolated from Finnish patients

OBJECTIVES: The proportion of Salmonella isolates with reduced susceptibility to fluoroquinolones has increased during recent years in many countries, especially in South-east Asia. The present study was performed to evaluate the incidence of and changes in quinolone resistance in Salmonella isolates of either foreign or domestic origin in Finland. METHODS: A total of 1004 Salmonella isolates collected from Finnish patients between 2000 and 2004 were analysed for ciprofloxacin susceptibility. Of these isolates, 504 were of domestic origin and 500 were of foreign origin, collected from travellers to 43 different countries. The Salmonella collection consisted of 89 different serotypes. All isolates belonged to non-typhoidal Salmonella enterica. RESULTS: Of all isolates, 3 (0.3%) were ciprofloxacin-resistant (MIC > or = 4 mg/L) and 214 (21.3%) exhibited reduced susceptibility to ciprofloxacin (MIC > or = 0.125-2 mg/L). The annual proportion of reduced susceptibility varied between 3 and 15% among the domestic Salmonella isolates (P = 0.123). Between 2000 and 2004, the annual proportion of reduced susceptibility increased significantly (from 23 to 39%; P = 0.001) among all foreign isolates as well as among those from Spain alone (from 4 to 73%; P < 0.001). Among the isolates from Thailand, reduced ciprofloxacin susceptibility remained at a constantly high level (52-66%) throughout the study. CONCLUSIONS: Our results show that reduced fluoroquinolone susceptibility in S. enterica is not restricted to South-east Asia alone but continues to grow rapidly in many parts of the world including countries of the European Union.