Ex vivo expansion of CD8+CD56+ and CD8+CD56- natural killer T cells specific for MUC1 mucin

Prostate cancers express MUC1, but nearly all metastatic cells lack HLA class I molecules. Thus, a lymphocyte population that can sense its antigenic environment, while also able to react to stimuli of natural killer (NK) cells, may be a more versatile effector cell population for antitumor immune responses. Herein, we report that tumor-specific MUC1 peptide, interleukin 2, and interleukin 12 act synergistically to stimulate the ex vivo expansion of CD8(+)CD56(-) T cells and CD8(+)CD56(+) natural killer T (NKT) cells from the peripheral blood mononuclear cells of prostate cancer patients, as well as healthy male and female donors. Both the CD56(+) NKT cells and CD56(-) T cells lysed allogeneic mucin-bearing target cells, as well as NK target cells, but not lymphokine-activated killer target cells. However, the CD56(+) NKT cells displayed a 2-fold greater cytolytic activity than the CD56(-) T cells. The mucin-specific cytolytic activity and NK cytolytic activities for both lymphocyte populations were independent of HLA class I and CD1 molecules. The CD56(-) T cells up-regulated CD56 with continued antigenic stimulation in the presence of interleukin 12, suggesting that CD8(+)CD56(-) T cells are NKT cells. However, CD56(+) NKT cells expand poorly to continued stimulation. All mucin-stimulated NKT cells exhibited the activated/memory CD45RO phenotype. The NKT cell lines express the alpha/beta T-cell receptor (TCR). The TCR repertoire was limited and varied with cell line, but was not the V alpha 24V beta 11 TCR typically associated with NKT cells. Whereas CD161 is generally considered a marker of NKT cells, the mucin-stimulated NKT cells did not express this marker. Thus, we have described two phenotypically distinct NKT types that do not display a biased TCR repertoire, but do display specificity for a tumor-specific peptide antigen (CTL-like activity), as well as HLA class I-deficient target cells (NK-like activity).     

Taking off the white coat: can family members who are physicians be good surrogate decision-makers?

The challenges inherent in physicians treating members of their own families are well known. However, the issues related to physicians acting as surrogate decision-makers on behalf of relatives have not been addressed. The growing number of older persons will increase the need not only for healthcare resources, but also for physicians to act on behalf of incapacitated family members as surrogate decision-makers. In this paper, some of the clinical and ethical tensions evoked by physicians serving as surrogate decision-makers for family members are explored. Some recommendations for managing these tensions are suggested.     

Conductometric and indirect AAS determination of antimalarials

Two methods are described for the determination of amodiaquine hydrochloride, chloroquine phosphate and primaquine phosphate, based on the formation of their ion-associates with [Cd(2+), Co(2+), Mn(2+) and Zn(2+)] thiocyanate, ammonium reineckate and/or sodium cobaltinitrite. The molar combining ratio reveal that (1:1) (drug:reagent) ion associates are formed for all reagents except for ammonium reineckate which form (1:2) ion associates with all studied drugs. The optimum conditions for the ion-association have been studied. Conductometric method was applied for the direct determination of the suggested drugs in bulk powders, whereas indirect atomic absorption spectrometric method, depending on the measurement of the excess metal ion present in supernatant solutions after precipitation of the ion associates is used to calculate the drug concentration. Optimum concentration ranges for the determination of aminoquinoline antimalarial drugs under consideration were 0.46-12.90 and 0.155-3.87 mg using conductometric and indirect atomic absorption spectral methods, respectively. The proposed procedures have been applied successfully to the analysis of these drugs in certain formulations and the results are favourably comparable to the official methods.     

Nonosseous abnormalities on bone scans

Although bone scanning is a test primarily concerned with skeletal abnormalities, important nonosseous findings are occasionally present on the images. To gauge the significance of such nonosseous uptake and, in particular, to determine whether these findings contain useful diagnostic information, the technical and medical staff in nuclear medicine must recognize the various patterns of nonbony uptake and understand their causes. The objectives of this article are to demonstrate the appearances of nonosseous uptake on bone scans, to categorize the forms of soft-tissue uptake, to emphasize technical artifacts leading to soft-tissue uptake, and to highlight the clinical significance of pathologic soft-tissue uptake.     

Risk factors of thyroid abnormalities in bipolar patients receiving lithium: a case control study

Background

Lithium-induced thyroid abnormalities have been documented in many studies. They may occur despite normal plasma lithium levels. The objectives of this study were: 1) to determine possible relationship between lithium ratio, defined as erythrocyte lithium concentrations divided by plasma lithium concentrations, and thyroid abnormalities in bipolar patients receiving lithium and 2) to find other possible risk factors for developing thyroid abnormalities in the subjects.

Methods

Sixty-eight bipolar patients receiving lithium therapy were enrolled in a cross-sectional evaluation of thyroid function test and thyroid size. Patients were divided into two groups based on their thyroid function tests and thyroid sizes. Erythrocyte and plasma lithium concentrations were determined by atomic absorption spectrometry for each patient. Lithium ratio was then calculated.

Results

No significant differences were found between age, positive family history of affective disorder, plasma lithium concentration, erythrocyte lithium concentration, and lithium ratio comparing the two groups. Thyroid abnormalities was significantly higher in women than in men (p < 0.05).

Conclusions

Lithium ratio does not appear to have a predictive role for thyroidal side effects of lithium therapy. Female gender was the main risk factor. We suggest more frequent thyroid evaluation of bipolar women who are treated with lithium.

     

Long-term follow-up of a phase I study of high-dose decitabine,busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias

BACKGROUND: Decitabine is a hypomethylating agent that has activity in patients with leukemia. The authors combined decitabine with busulfan and cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. METHODS: Patients with high-risk acute myeloid leukemia (AML) (n = 12 patients); chronic myelomonocytic leukemia (CMML) (n = 1 patient); acute lymphocytic leukemia (ALL) (n = 1 patient); or late chronic phase, accelerated, or blastic phase chronic myelogenous leukemia (n = 9 patients) were eligible for the study. The treatment plan was comprised of busulfan, 12 mg/kg orally; cyclophosphamide, 100 mg/kg (n = 4 patients) or 120 mg/kg (n = 19 patients); and decitabine, intravenously at 3 dose levels: 400 mg/m(2) (n = 10 patients), 600 mg/m(2) (n = 8 patients), and 800 mg/m(2) (n = 5 patients). Donors were human leukocyte antigen-identical siblings in all cases, and all but one patient received peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus based in all but one patient. RESULTS: The median time to neutrophil and platelet engraftment was 12.5 days and 17.5 days, respectively. Twenty-one patients were engrafted and achieved disease remission. At a median of 3.3 years posttransplantation, 26% of patients (40% of patients with AML) were alive and disease free. The median survival for the group was 17.2 months, and the disease free survival for the group was 8.9 months. Causes of death were disease recurrence (nine patients), chronic GVHD (four patients), infections (three patients), and acute GVHD (one patient). The 100-day mortality rate was 9%. No decitabine dose-limiting toxicity was documented. The treatment-related mortality rate at 3 years was 35%. Responders were treated at all three decitabine dose levels, and no dose-response correlation was observed. CONCLUSIONS: There was a high response rate with low treatment-related mortality, with 26% of patients alive in remission 3.3 years after transplantation.     

Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia

BACKGROUND: General and site-specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti-CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML. METHODS: One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML. Decitabine was given at 100 mg/m(2) over 6 hours every 12 hours x 5 days (1000 mg/m(2) per course) in the first 13 patients, 75 mg/m(2) in the subsequent 33 patients, and 50 mg/m(2) in the remaining 84 patients. RESULTS: A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph-negative CML, four (57%) had objective responses. There was no evidence of a dose-response effect. The estimated 3-year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50-75 mg/m(2), the median time to granulocyte recovery above 0.5 x 10(9)/L was about 4 weeks. Myelosuppression-associated complications included febrile episodes in 37% and documented infections in 34%. CONCLUSIONS: Decitabine appears to have significant anti-CML activity. Future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases.     

Epidemiological features of tumors of the skin and mucosal membranes in the department of dermatology at the Yalgado Ouedraogo National Hospital, Ouagadougou, Burkina Faso

We conducted a retrospective study of the files of all patients seen from 1 January 1992 through 31 December 1996 with tumors of the skin and mucosal membranes at the Yalgado Ouédraogo National Hospital in order to determine the epidemiologic features of this disease. The records revealed 988 patients presented 1024 tumors, which could be classified into 33 categories. Most of the patients (60.6%) were in the age bracket of 20 to 39 years. Nearly all cases (988 or 96.5%) were benign skin tumors, mainly of infectious origin, especially viral (51.7%). We observed a substantial number of sexually transmissible infections, such as condylomata. We also found 36 cases (3.5%) of malignant tumors, including 29 cases of Kaposi sarcoma, five skin carcinoma (13.8%), three spinocellular and two basocellular; we also noted two borderline malignant tumors: a dermatofibrosar-coma protuberans and a nodular hidradenoma. The elevated prevalence of condyloma (151 cases) may explain the predominance of the 20-39 year age group, which is the most sexually active. Our series also confirmed the relative rarity (3.5%) of cutaneous cancers among African blacks. The predominance of Kaposi sarcoma may be explained by the high prevalence of HIV infection in our country.