Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia

Five patients with sickle cell anemia were treated with hydroxyurea (HU), in hopes of augmenting their production of fetal hemoglobin. Laboratory responses in two patients treated for more than 2 years were encouraging and there were suggestions of clinical improvement. Long- term HU therapy should be considered for severely affected adults with sickle cell anemia who are willing to accept what is probably a small risk of carcinogenesis. Preliminary chromosomal analysis and knowledge of the clastogenic properties of HU suggest that conception and pregnancy should be avoided. Pharmacokinetic studies will probably be necessary to adjust individual dosage schedules so that cytotoxicity is avoided. F cell responses can be seen in 2 to 3 weeks if the HU dose is optimal, but establishment of a large number of F cells in the circulation may take a month or longer.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

Quality control of multidrug resistance assays in adult acute leukemia: correlation between assays for P-glycoprotein expression and activity

We have compared multiple assays for the P-glycoprotein (Pgp/MDR1) phenotype in fresh and thawed adult acute leukemia to validate and quantitate measures for the expression and function of Pgp. The results are related to the Pgp-expressing KB8 and KB8-5 call lines. The most sensitive assay was the measurement of modulation of the rhodamine 123 (R123) fluorescence by 2 micromol/L PSC833, followed by the modulation of the probe calcein-AM. We also found a good intralaboratory and interlaboratory correlation between the values of the R123/PSC833 assay for fresh as well as thawed samples. In addition, the affects of PSC833 on 3H-daunorubicin (DNR) accumulation, DNR fluorescence, and 3H- vincristine accumulation were very similar. The correlation between the DNR/PSC833 and R123/PSC833 test was r = .86 (N = 51). The modulation of drug accumulation by 8 micromol/L verapamil was the some as the PSC833 effect for DNR (117%, N = 21), but was higher for vincristine in every single case (161% v 121%, N = 22; P< .001), indicating additional verapamil effects, not related to Pgp. The correlation of the staining of viable cells for Pgp with the monoclonal antibody MRK16 was r = .77 (N = 52) for the R123/PSC833 functional test and r = .84 (N = 50) for the DNR/PSC833 test. From these results it could be calculated that a maximal increase of the mean DNR accumulation of about 50% can be achieved by blocking Pgp pump activity with PSC833 in leukemic blast samples with the highest mean Pgp expression. Subpopulations of blast calls with higher Pgp activity are likely to be present. Their relevance has to be studied further. The methods outlined here allow the reliable, quantitative monitoring of the Pgp/MDR1 phenotype in leukemias in multicentered, clinical Pgp modulation studies.     

Splenectomy versus medical treatment for idiopathic thrombocytopenic purpura

BACKGROUND: Treatment strategies for idiopathic thrombocytopenic purpura (ITP) are still uncertain and its management is primarily empirical. The aim of this study was to investigate the role of splenectomy in the therapy of ITP and to evaluate whether medical or surgical treatment is superior. METHODS: Ninety-two patients with ITP were included in the study. All of these patients had medical therapy and 38 of them underwent splenectomy subsequently. Follow-up was completed in 91 patients after a median of 64 months. RESULTS: Side effects of medical therapy were noticed in 32 patients (35%), whereas after surgery only 2 patients (5%) had minor complications. A complete or partial remission was achieved in 35 patients (92%) after splenectomy, whereas this was achieved in only 27 patients (30%) after medical therapy. On multivariate analysis splenectomy and age were the only significant independent factors for complete and partial remission. CONCLUSIONS: Splenectomy is highly effective and safe in the treatment of ITP and is superior over medical therapy. These results should stimulate the discussion about splenectomy for ITP, possibly establishing evidence-based guidelines for surgical treatment in hematology.     

Currarino triad: Characteristic appearances on magnetic resonance imaging and plain radiography

The Currarino triad is a complex anomaly consisting of an anorectal malformation, a sacral bone defect and a presacral mass. It was first described in 1981 and since then, approximately 250 cases have been reported. Radiology has an important part to play in the diagnosis of this entity, as the imaging features are characteristic. We report a case of Currarino triad in an infant who presented with intractable constipation and discuss relevant MRI and plain radiography findings.     

Loss of tumor-promoting activity of unleaded gasoline in N- nitrosodiethylamine-initiated ovariectomized B6C3F1 mouse liver

Unleaded gasoline (UG) vapor (2056 ppm) increased the incidence of liver tumors in a chronic bioassay and exhibited tumor-promoting activity in N-nitrosodiethylamine (DEN)-initiated female mouse liver. Estrogen inhibited mouse liver tumor development and the hepatocarcinogenic and tumor-promoting dose of UG produced uterine changes suggestive of estrogen antagonism. To directly test the hypothesis that UG-induced tumor-promoting ability is secondary to its interaction with the mouse liver tumor inhibitor, estrogen, we compared the tumor-promoting ability of UG in ovariectomized (Ovex) mice with the hepatic tumor-promoting ability of UG in intact mice. Ovaries were surgically removed at 4 weeks of age. Exposure to wholly vaporized UG (2018 ppm) under bioassay and tumor-promoting conditions began at 8 weeks of age. After 4 months of exposure, UG increased relative liver weight and hepatic microsomal cytochrome P450 pentoxyresourfin-O- dealkylase and ethoxyresorufin-O-deethylase activity to a similar extent in intact and Ovex mice. Non-focal hepatocyte proliferation, as measured by the incorporation of bromo-deoxyuridine, was not changed by UG exposure and was similar in all treatment groups. After 4 months of exposure to DEN-initiated mice, UG significantly increased the volume fraction of liver occupied by foci (three-fold) as compared to control intact mice. As expected, volume of foci was elevated in DEN/Ovex/control mice as compared to DEN/intact/control mice. In DEN/Ovex mice UG did not significantly increase the focal volume fraction. Thus, the tumor promoting activity of UG, as demonstrated by increased volume fraction of liver occupied by hepatic foci in intact mice, is greatly attenuated in Ovex mice. The volume fraction data in Ovex mice support the hypothesis that the tumor promoting activity of UG is dependent upon the interaction of UG with ovarian hormones. These data also indicate that hepatic microsomal cytochrome P450 PROD and EROD induction, hepatomegaly and non-focal hepatic LI are not specific markers of hepatic tumor promoting activity of UG.      

Prognostic indicators for breast cancer patients with one to three regional lymph node metastases, with special reference to alterations in expression levels of bcl-2, p53 and c-erbB-2 proteins

Patients with primary breast carcinoma with one to three axillary lymph node metastases but without distant metastases (n1-3) in Japan have been shown to have a 10-year disease-free survival rate of > 60%. It would be reasonable to divide n1-3 Japanese breast cancer patients into groups with high- or low-risk for recurrence and to consider post-operative adjuvant therapy. In the present study, we analyzed 228 consecutive Japanese patients with n1-3 breast cancer who underwent radical mastectomy and were followed up for a median time of 11.0 years. The expression of bcl-2, p53 and c-erbB-2 proteins in the primary tumors was examined immunohistochemically and their prognostic roles were also analyzed along with conventional clinicopathologic indicators. bcl-2 expression was correlated with positive estrogen receptor status and inversely correlated with p53, c-erbB-2 and histologic grade. Univariate analysis showed that bcl-2, p53 and c-erbB-2 expression were prognostic indicators of the patient's group as well as node status, histologic grade, tumor size, age at diagnosis, menopausal status and estrogen receptor status. Cox's regression analysis demonstrated that the number of nodes involved, menopausal status, p53 and bcl-2 were independent predictors for overall survival and that histologic grade and the number of nodes involved were independent predictors for disease-free survival. These results suggest that bcl-2 expression in combination with p53 and c-erbB-2 expression, the number of lymph node metastases, histologic grade and menopausal status are useful in selecting subgroups of n1-3 breast cancer patients with good or poor prognoses.      

Risk factors for deaths in under-age-five children attending a diarrhoea treatment centre

Few case-control studies have examined possible risk factors for diarrhoeal deaths in under-age-five children in the developing countries. We analysed data from the surveillance system of our diarrhoea treatment centre/hospital for the period 1990-94 on 928 children less than 5 years of age. In univariate analysis, 11 factors were significantly associated with death: lack of breastfeeding, severe malnutrition, complicated diarrhoea, pneumonia, xerophthalmia, duration of diarrhoea 7-14 days, moderate or severe dehydration, recent history of measles, Shigella flexneri infection, maternal illiteracy, and very low household income. Rotavirus diarrhoea was negatively associated with fatal outcome. In the assessment of severe malnutrition, weight-for-height measurement discriminated mortality risk better than weight-for-age or height-for-age indices. Only two factors retained their significance, severe malnutrition and non-breastfeeding in the multivariate analysis with adjusted odds ratio (95% confidence interval) of 84.2 (9.1, 775.9) and 4.2 (1.3, 13.2) respectively.     

Short stay facilities: the future of efficient paediatric emergency services

OBJECTIVE: To assess the reactions of parents and their children to the request for a blood sample and an attempt to take blood. METHODS: 1859 children aged 1.5-4.5 years took part in a national survey of diet and nutrition. A retrospective inquiry of the parents' and children's reported reactions was carried out six to 18 months later by postal questionnaire sent only to the 1157 who had given consent for an attempt to take blood. RESULTS: 866 questionnaires were returned; 790 were from parents of children in whom an attempt to take blood had been successful. Thirteen per cent said that their child had given blood previously. About 30% discussed the request with the family doctor or nurse. Some 90% said that they were given enough information and that the phlebotomist was sympathetic. Attempting to take blood caused upset in over 50%, which, in most, lasted for less than five minutes. A substantial minority were upset for up to 30 minutes and a few much longer. Bruising or bleeding occurred in 20-27%. Degree and duration of upset were both adversely associated with a failed attempt to obtain blood. CONCLUSION: The majority of preschool children experienced no more than a little upset of short duration after an attempt to take blood, but a substantial minority exhibited a greater degree of upset. These responses should be taken into account when assessing the benefits and risks of the procedure. The best equipment and expertise should be employed for taking blood as successful attempts are less upsetting.