Irinotecan (CPT-11) as first-line monotherapy in patients with advanced, metastatic colorectal cancer refractory to 5-fluorouracil adjuvant chemotherapy: a multicenter phase II study

Irinotecan (CPT-11) is active against colorectal cancer (CRC) refractory to 5-fluorouracil. Further information is needed to confirm whether CPT-11 monotherapy is more effective against tumors than 5-FU monotherapy or if there is cross-resistance of CPT-11 with 5-FU. This study assessed the efficacy and toxicity of CPT-11 350 mg/m² iv, once every 3 weeks, in patients with unsuccessfully pretreated advanced CRC. Thirty-two patients were enrolled and overall 152 cycles were administered. The total objective response rate was 17.9% and the disease stabilized in 11 patients (39.3%). Median time to progression was 3.8 months and me-dian survival was 8.2 months. Grade 3/4 diarrhea was observed in 9 cycles (5.9%) and 6 patients (18.8%), and grade 3/4 neutropenia in 5 cycles (3.3%) and 4 patients (12.5%). CPT-11 monotherapy is an active and well-tolerated first-line chemotherapy for CRC in 5-FU pretreated patients.     

Manometric study of the anal sphincter during haemorrhoidectomy using posterior perineal block

Minor anorectal diseases affect 4-5% of the adult western population. Operations are performed on an ambulatory or 24-hour-stay basis. The aim of our study was to assess the physiology of anal sphincter relaxation by anal manometry after posterior perineal block during haemorrhoidectomy. We recruited 15 patients with third and fourth degree hemorrhoids in a manometric study of the anal sphincter during haemorrhoidectomy with regional anaesthesia. The patients underwent anal manometry before and 15 minutes after the posterior perineal block to determine the resting and squeeze anal pressures. Differences were considered significant at p < 0.05. We observed mean reductions of 34.6% and 37.1% in resting and squeeze pressure values, respectively, after posterior perineal block (p < 0.005). Our manometric study demonstrated that anal sphincter relaxation after posterior perineal block correlates with a significant reduction in resting and squeeze pressures because the block anaesthesia not only the somatic, but also the sympathetic fibres. We believe that posterior perineal block allows the surgeon to perform radical haemorrhoidectomy in the overnight stay setting with optimal intra- and postoperative analgesia, safe sphincter relaxation, lower postoperative complications, and lower costs to the public health service.     

Spread of T lymphocyte immune responses to myelin epitopes with duration of multiple sclerosis

Although the primary cause of multiple sclerosis (MS) is unclear, evidence supports a role for autoimmune attack of myelin by T lymphocytes. However, it has been difficult to relate patterns of autoimmunity to pathogenesis. In mouse models, the case has been made for relapsing and remitting disease driven by epitope spread: an initial lesion leads to presentation of central nervous system antigens, in turn triggering the next wave of autoimmune T cells of different specificity, the response thus broadening. Few studies have been done to determine whether these events could be important over the longer time scale of human disease. We compared T cell responses with a panel of myelin epitopes in clinically isolated syndrome patients with a first attack, patients with MS with a mean disease duration of 0.95 years, and patients with MS having a mean disease duration of 15.9 years. T cells from patients with long-term disease recognize more myelin epitopes than patients with recent-onset disease. The epitope myelin basic protein 131-149, in particular, was more commonly recognized by patients with long-term disease. The data support the notion that the T cell response in MS broadens with time and is thus implicated in the ongoing pathogenic process. However, there was no clear correlation between disease severity and number of epitopes recognized. This may argue against a simple causal role of epitope spread in driving progression, as has been suggested in experimental allergic encephalomyelitis.     

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine

BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.     

Dilated perivascular spaces: hallmarks of mild traumatic brain injury

BACKGROUND AND PURPOSE: Recent animal and human studies have shown an increased frequency of enlarged, high-convexity Virchow-Robin spaces (VRS) in several neurologic diseases, suggesting their role as neuroradiologic markers of inflammatory changes. The aim of this study was to determine the prevalence of high-convexity dilated VRS in mild traumatic brain injury (TBI). METHODS: T2-weighted, T1-weighted, fluid-attenuated inversion recovery, and T2*-weighted gradient-echo brain MR images were acquired in 24 patients with TBI (10 women, 14 men; mean age, 33.6; range, 18.1-50.8 years) and 17 age- and sex-matched healthy control subjects (nine women, eight men; mean age, 32.8; range, 18.4-47.8 years). The mean interval after TBI was 3.6 days (range, 1-9 days) in 15 patients and 3.7 years (range, 0.6-13.4 years) in nine patients. Axial T2-weighted images were used to identify dilated VRS and to measure CSF volume; T1-weighted images were used to measure brain volume. Dilated VRS were identified as punctuate areas with CSF-like signal intensity in the high-convexity white matter. RESULTS: Mean (+/- standard deviation) number of VRS was significantly higher in patients (7.1 +/- 4.6) than in controls (3.0 +/- 3.0, P = 0.002) [corrected] In controls, VRS were associated with age (R = 0.69, P < .001) whereas in patients, they neither correlated with brain and CSF volumes nor with age and the elapsed time from injury. CONCLUSION: Our results suggest that the increased number of dilated VRS is a radiologic marker of mild head injury that is readily detectable on T2-weighted images. Because their number does not vary with time from injury, VRS probably reflect early and permanent brain changes.     

Population immunity to polioviruses among preschool children from four urban underserved low income communities, United States, 1997-2001

BACKGROUND: In 1997, the Advisory Committee for Immunization Practices (ACIP) recommended a change in polio vaccination policy, the first in 30 years, from the oral poliovirus vaccine (OPV) to a combined OPV/inactivated poliovirus vaccine (IPV) sequential schedule for routine childhood vaccination. To evaluate the impact of the change in polio vaccination schedule on population immunity, we conducted a seroprevalence survey among low income preschool children from selected urban areas. METHODS: A repeat cross-sectional serosurvey was conducted during 1997-2001. Children 19-35 months of age receiving well-child care were recruited from outpatient clinics of academic medical centers. Serum samples were obtained and tested for neutralizing antibodies to polioviruses types 1, 2 and 3. A standardized questionnaire was administered to the parents or guardians of enrolled children. RESULTS: Seroprevalence remained high and stable during the study period. Among children sampled in the last study year (initiating their vaccinations from August 1997 through September 2000), seroprevalence was >/=95% to poliovirus serotypes 1 and 2 and >/=94% to serotype 3. Overall coverage with >/=3 doses of polio vaccine was 82-95% across sites during this period. The proportion initiating their vaccination schedule with IPV increased from 2.6% in study year 1 (children born October 1994-January 1997) to 80% in study year 4 (children born October 1997-January 2000). CONCLUSIONS: Children in these underserved low income communities are well-protected against the spread of polioviruses; the introduction of IPV did not adversely impact coverage or seroprevalence. Continued monitoring is needed to evaluate population immunity in the absence of OPV circulation.     

MDCT in Pancreatic adenocarcinoma: prediction of vascular invasion and resectability using a multiphasic technique with curved planar reformations

OBJECTIVE: The objective of our study was to determine the negative predictive value of MDCT with curved planar reformations for detecting vascular invasion and predicting overall resectability in patients with pancreatic adenocarcinoma. MATERIALS AND METHODS: Imaging findings related to vascular invasion and overall tumor resectability in 25 patients who underwent contrast-enhanced biphasic MDCT evaluation were correlated with actual vessel invasion and overall resectability determined at surgery and pathologic examination. The presence of vascular invasion was assessed in 110 major peripancreatic vessels in 22 patients who underwent resection. RESULTS: On MDCT, 23 (92%) of 25 patients were deemed to have resectable pancreatic adenocarcinoma. The tumors in the remaining two (8%) were considered not resectable because of the presence of vascular invasion (which was confirmed in only one patient at surgery). Of those 23 patients deemed to be candidates for curative resection on the basis of MDCT results, 20 were found to have resectable adenocarcinoma at time of surgery, yielding a negative predictive value for MDCT of 87% (20/23 patients) for overall resectability. In the other three patients, adenocarcinoma was deemed to be unresectable because of small metastases to the liver (two patients) or to the peritoneum (one patient) discovered at surgery. For detection of vascular invasion, MDCT yielded a negative predictive value of 100% (108/108 vessels) with no false-negative findings and an accuracy of 99% (109/110 vessels) with 108 true-negative findings, one true-positive finding, and one false-positive finding. CONCLUSION: Our preliminary data on MDCT show that the technique has excellent negative predictive value for vascular invasion and good negative predictive value for overall tumor resectability in patients with pancreatic adenocarcinoma, suggesting an improvement over previous results reported using single-detector CT. The problem of undetected micrometastases to the liver and peritoneum remains.     

High incidence of extended-spectrum beta-lactamases among outpatient clinical isolates of Escherichia coli: a phenotypic assessment of NCCLS guidelines and a commercial method

The production of extended-spectrum beta-lactamases (ESBLs) among 357 clinical isolates of Escherichia coli and 175 of Klebsiella spp. was studied using both the National Committee for Clinical Laboratory Standards disk diffusion method and the semiautomated Wider system. We highlight the predominance of E. coli (50, 92.6%) among positive samples and the largely outpatient origin of these (40, 80%), including 39 samples of urine (97.5%) and one of urethral exudate. There were only four ESBL-producing isolates of Klebsiella spp. (7.4%), and three were in outpatient urine samples (75%, 2 K. oxytoca and 1 K. pneumoniae). The positive and negative predictive values for the Wider system were 81% and 98.5%, respectively. We stress the high incidence of ESBL in our setting, the predominance of cases in the outpatient setting, and the acceptable detection of ESBL by means of the Wider system in E. coli and Klebsiella spp.