Anorectal function in Crohn's disease.

Anorectal function was assessed in 63 patients with Crohn's disease and in 10 controls. Eleven patients with Crohn's disease (17%) were partially and three (5%) totally incontinent. The results of anal sphincter function studies of continent patients with Crohn's disease were similar to those of partially incontinent patients and controls. Incontinent patients had significantly lower maximal basal pressure (P less than 0.01) and significantly lower maximal squeeze pressure (P less than 0.05) as compared to controls. There was no significant difference in rectal capacity between continent, partially incontinent and totally incontinent patients and controls. There were significantly more patients with symptoms of anal incontinence in the group of patients with anal Crohn's disease as compared to the Crohn's group with normal anorectum (P less than 0.001). Risk factors for total anal incontinence in Crohn's disease were severe anorectal stenosis and previous surgery for anal abscesses. The most important reason for partial incontinence was diarrhoea. In conclusion, Crohn's disease without macroscopic lesions in the anorectum and without diarrhoea does not affect anorectal function.     

Anal dilatation, lateral subcutaneous sphincterotomy and haemorrhoidectomy for the treatment of second and third degree haemorrhoids. A prospective randomized study.

Patients with second or third degree haemorrhoids were randomized for treatment by anal dilatation, lateral subcutaneous sphincterotomy or haemorrhoidectomy. The patients were studied by means of proctoscopy, anal manometry and symptom grading preoperatively, two months and one year after the procedure. After one year, more than half of the patients were symptomless in each treatment group. Both anal dilatation and sphincterotomy gave poor results in 25% of the patients, compared with 9% after haemorrhoidectomy. Young age was related to good results in anal dilatation or sphincterotomy, but not in haemorrhoidectomy. Results of anal dilatation and sphincterotomy in treating haemorrhoids are unpredictable, so they cannot be recommended as routine procedures. Maximal basal pressure was reduced after all three procedures, but neither the preoperative nor postoperative anal pressures were able to predict the result of the different treatment techniques.     

Immature dense granules in platelets from mice with platelet storage pool disease

Mepacrine uptake into platelets and bone marrow megakaryocytes was analyzed to further characterize the dense granule defects in a group of seven mouse pigment mutants that have characteristics of platelet storage pool disease (SPD). In contrast to our previous studies using electron microscopy, this method revealed that all mutants had normal numbers of dense granules. However, total mepacrine uptake in all mutant platelets was significantly diminished to less than 50% of normal uptake. Also, the flashing phenomenon observed when normal dense granules are irradiated with ultraviolet light was either greatly diminished or absent when platelets of individual mutants were similarly irradiated. Therefore the principal defect in the mutant platelets is an inability to accumulate dense granule contents rather than an absence of the granules. Mepacrine uptake into megakaryocytes was indistinguishable in normal and mutant mice. This indicates the mutant dense granule defects appear either very late in megakaryocyte development or early in platelet formation in correlation with development of the mature dense granule. By standard transmission electron microscopy we have not been able to detect gross structural or subcellular abnormalities in either platelets or megakaryocytes of mutant mice. It appears all seven mutants produce immature or functionally abnormal dense granules.     

Modified LSA2-L2 treatment in 53 children with E-rosette-positive T- cell leukemia: results and prognostic factors (a Pediatric Oncology Group Study)

In an attempt to improve the poor outlook for children with T-cell leukemia (T-ALL), the Southwest Oncology Group, Pediatric Division, used a modified LSA2-L2 multidrug regimen to treat 53 patients with E- rosette-positive T-ALL. This regimen was chosen because of its demonstrated efficacy in T-cell (mediastinal) non-Hodgkin's lymphoma. Complete remission (CR) rate was 88%. Range of follow-up for those patients remaining in CR is 24-49 mo (median 39 mo). Life table analysis estimates that 40% (SE 8.3%) of all patients who started induction therapy will remain failure-free at 3 yr. For patients achieving CR, 46% (SE 9%) are projected to remain in both marrow and extramedullary CR at 3 yr. Median failure-free duration was 13 mo, but only 1 patient has relapsed beyond 16 mo. Twenty-nine percent of initial relapses were isolated CNS relapses. The following presenting factors did not relate significantly to outcome: hemoglobin, platelet count, uric acid, race, and mediastinal mass. Age greater than 10 yr was a poor prognosis indicator only in the less than 50,000/microliter WBC group. Sex was not a significant factor after adjusting for WBC. WBC was the most important prognostic factor: 19% (SE 8%) of patients with WBC greater than 50,000/microliter are projected to remain failure- free at 3 yr as compared to 67% (SE 11%) of patients with WBC less than 50,000/microliter. Although the overall results are better than those previously reported for pediatric patients with T-ALL, the long-term failure-free rate remains low for patients presenting with greater than 50,000/microliter WBC.     

Clinical and histopathological characteristics of familial prostate cancer in Finland

Study Type – Aetiology (cohort) Level of Evidence 2b

OBJECTIVE

? To describe clinical and histopathological characteristics of Finnish familial prostate cancer (PCa) through a detailed analysis of cases in families.

PATIENTS AND METHODS

? In total, 202 Finnish families with 617 histopathologically confirmed PCa cases of confirmed genealogy were collected. ? Complete clinical data, including age and prostate‐specific antigen (PSA) at diagnosis, stage, grade and primary treatment, were gathered. The mean (range) number of affected men per family was 3 (2–8). ? All the available diagnostic biopsy samples (n= 323) were collected and regraded by the same uropathologist. ? A population‐based cohort of 3011 hospital district Pirkanmaa PCa patients was used as a control group.

RESULTS

? The mean (range) year of diagnosis of PCa was 1993 (1962–2006) and the mean (range) age at diagnosis was 68 (43–98 years). ? The median (range) primary PSA level was 12.0 (0.8–11 000) ng/mL. After regrading, the Gleason score was ≤6 in 38%, 7 in 37% and ≥8 in 25% of men. ? The subset of familial PCa men diagnosed after 1995 had higher PSA levels (P= 9.9 × 10^?6) and an earlier age of onset (P= 1.7 × 10^?6) than men in the control group, although there were no differences in cancer‐specific survival.

CONCLUSIONS

? We observed an earlier age of onset and higher PSA in familial PCa. ? However, differences between sporadic and familial or hereditary PCa cannot be truly solved until genetic testing of high‐risk genes in addition to family history is used to define PCa families. ? We also emphasize that, when histological samples are collected over a longer study period, reanalysis of the samples by the same experienced uropathologist should be considered. What’s known on the subject? and What does the study add? Previous hospital‐ or population‐based cross‐sectional studies comparing the clinical and histopathological features of hereditary, familial and sporadic PCa either reported weak trends or no differences in features measured except the age of onset. In present study we observed higher PSA and earlier age of onset in the subset of 257 familial PCa menin Finnish PCa families.     

The Tie receptor tyrosine kinase is expressed by human hematopoietic progenitor cells and by a subset of megakaryocytic cells

Growth factor receptors in human hematopoietic progenitor cells have become the focus of intense interest, because they may provide tools for the monitoring, enrichment, and expansion of stem cells. We have shown earlier that the Tie receptor tyrosine kinase is expressed in erythroid and megakaryoblastic human leukemia cell lines, in the blood islands of the yolk sac, and in endothelial cells starting from day 8.0 of mouse development. Here, the expression of Tie was studied in human hematopoietic cells of various sources. Peripheral blood mononuclear cells were Tie-. However, a large fraction of CD34+ cells from umbilical cord blood (UCB) and bone marrow (BM) expressed tie protein and mRNA. On average, 64% of the fluorescence-activated cell sorting- gated UCB CD34+ cells including CD38- cells and a fraction of cells expressing low levels of c-Kit were Tie+. Also, 30% to 60% of BM CD34+ cells were Tie+, including most of the BM CD34+CD38-, CD34+Thy-1+, and CD34+HLA-DR- cells. Under culture conditions allowing myeloid, erythroid, and/or megakaryocytic differentiation, purified UCB CD34+ cells lost Tie mRNA and protein expression concomitantly with that of CD34; however, a significant fraction of cells expressed Tie during megakaryocytic differentiation. These data suggest that, in humans, the Tie receptor and presumably its ligand may function at an early stage of hematopoietic cell differentiation.     

Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells

Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs showing strong in vitro activity against the human immunodeficiency virus type-1 (HIV-1). Each drug, however, has significant toxicity against normal marrow progenitor cells that frequently proves dose-limiting in patients. In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested as single agents and in combination against normal myeloid (CFU-GM) and erythroid (BFU- E) colony forming cells in a standard methylcellulose culture assay. The data were analyzed using a quantitative computerized analysis based on the median-effect principle and the isobologram equation as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for BFU-E and CFU-GM inhibition was then compared with previously measured in vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in vitro. We demonstrate that (a) the drugs are strongly synergistic in inhibiting marrow progenitor cell growth and that this synergism occurs at drug levels that are within the range of measured plasma levels in phase I clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug concentrations in combination that synergistically inhibit bone marrow progenitors are much higher than those required to inhibit HIV-1 replication in vitro, and (d) the anti- HIV-1 effect for the combination of AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or rIFN-alpha 2a alone as indicated by the combination index and the dose-reduction index. These data suggest that substantially lower doses of AZT and rIFN-alpha than those currently being tested in clinical trials might not only maintain a strong synergistic anti-HIV-1 effect but might also avoid significant hematologic toxicity.     

Cytogenetic and immunophenotypic analysis of cell lines established from patients with T cell leukemia/lymphoma

Cell lines were established from five patients with T cell malignancies. Two patients had T cell lymphoblastic lymphoma (T-LL), whereas three patients had T cell acute lymphoblastic leukemia (T-ALL). Both T-LL cell lines expressed cell surface antigens characteristic of midthymocytes (Leu 2, 3, 6+). One T-ALL cell line also expressed this immunophenotype, one expressed suppressor/cytotoxic antigens (Leu 2+; Leu 3, 6-), and one expressed antigens of a mature but uncommitted T cell (Leu 4+; Leu 2, 3, 6-). Cytogenetic analysis showed that each cell line had 46 chromosomes with pseudodiploidy. The three T-ALL cell lines had only a few chromosome changes; one cell line had one deletion, another had two deletions, and the third had a translocation and two deletions (including loss of part of 9p). In comparison, both T-LL cell lines had complex chromosome changes, including most notably a rearrangement of band 14q11.2. The immunophenotypes and chromosome breakpoints showed patterns of interlock between the T-LL and T-ALL cell lines because common abnormalities occurred at six distinct chromosome sites. Cell lines with limited and specific chromosomal abnormalities are important because they can provide the basic material for molecular genetic studies that could elucidate the genetic mechanisms involved in neoplasia.