Suppressor of cytokine signaling-3 is affected in T-cells from tuberculosisTB patients.

T-cells and T-cell-derived cytokines are crucial mediators of protection against Mycobacterium tuberculosis infection, but these factors are insufficient as biomarkers for disease susceptibility. In order to define T-cell molecules involved in tuberculosis (TB), we compared gene expression profiles of T-cells from patients with active TB, healthy donors with latent M. tuberculosis infection (LTBIs) and non-infected healthy donors (NIDs) by microarray analysis. Pathway-focused analyses identified a prevalent subset of candidate genes involved in the Janus kinase (JAK)-signal transducer and activator of transcription signalling pathway, including those encoding suppressor of cytokine signalling (SOCS) molecules, in the subset of protection-associated genes. Differential expression was verified by quantitative PCR analysis for the cytokine-inducible SH2-containing protein (CISH), SOCS3, JAK3, interleukin-2 receptor α-chain (IL2RA), and the proto-oncogene serine/threonine protein kinase (PIM1). Classification analyses revealed that this set of molecules was able to discriminate efficiently between T-cells from TB patients and those from LTBIs, and, notably, to achieve optimal discrimination between LTBIs and NIDs. Further characterization by quantitative PCR revealed highly variable candidate gene expression in CD4(+) and CD8(+) T-cells from TB patients and only minor differences between CD4(+) and CD8(+) T-cell subpopulations. These results point to a role of cytokine receptor signalling regulation in T-cells in susceptibility to TB.

CD26/dipeptidyl peptidase 4-deficiency alters thymic emigration patterns and leukcocyte subsets in F344-rats age-dependently.

As CD26 (dipeptidyl peptidase 4/DPP4) rapidly truncates incretins N-terminally, including glucagon-like peptide-1, DPP4-inhibitors have been developed for treatment of diabetes type 2. To some extent this is surprising, as CD26/DPP4 is also deeply involved in immune regulation. Long-term pharmacological studies are hampered by off-target inhibition of DPP4-homologues. Therefore, we studied the effects of genetic CD26/DPP4-deficiency by investigating blood, spleen and thymus leucocyte subpopulations of wild-type and CD26-deficient F344-rats at different ages. In young animals at 1 and 3 months of age, there were no differences in leucocyte subsets, while in older animals the T cell composition was changed significantly. From the age of 6 months onwards, reduced numbers of recent thymic emigrants and memory T cells, and consequently an increased amount of naive T cells were observed in CD26-deficient rats. In addition, the architecture of the thymus was altered, as observed by a reduced density of lymphocytes in the medulla. Furthermore, the number of proliferating cells in the thymus was decreased in CD26-deficient rats at a higher age. Moreover, CD26-deficiency resulted in markedly reduced numbers of B cells in later life. Additionally, an age- but not CD26-dependent increase of regulatory T cells and a decrease of natural killer cell numbers were detected in the blood and spleen. Our findings indicate an important role of CD26 in maintaining lymphocyte composition, memory T cell generation and thymic emigration patterns during immunosenescence, with possible implications for using DPP4-inhibitors.

T-cell responses against tuberculin and sensitin in children with tuberculosis and non-tuberculosis mycobacterial lymphadenopathy.

Multi-colour flow cytometry was applied to determine T-cell-specific interferon-gamma, interleukin-2 and tumour necrosis factor-alpha expression in children with tuberculosis and non-tuberculosis mycobacterial lymphadenopathy (NTM-L). In vitro stimulation of peripheral blood mononuclear cells with purified protein derivative from Mycobacterium tuberculosis (tuberculin) and M. avium (sensitin) revealed differential recognition of tuberculin and sensitin in both study groups. Ratios of tuberculin-specific and sensitin-specific T-cell proportions in individual patients discriminated between children with tuberculosis or NTM-L. These findings have the potential to improve the differential diagnosis of mycobacterial infections.

Exacerbation of rheumatoid arthritis after termination of chemotherapy for breast carcinoma.

Three women with breast carcinoma were treated with combination chemotherapy, including cyclophosphamide, 5-fluorouracil, and methotrexate, after mastectomy. Within two months of termination of chemotherapy, all 3 patients developed florid synovitis. Two patients had prior clinical manifestations consistent with rheumatoid arthritis; one patient had no antecedent history of arthritis. We suggest that this presentation may represent exacerbation of mild or subclinical rheumatoid arthritis as a consequence of withdrawal of methotrexate therapy.

Predictors of recurrence for patients with small (one centimeter or less) localized breast cancer (T1a,b N0 M0).

BACKGROUND: The frequency of small (< or = 1 cm) axillary lymph node negative invasive breast cancers (T1a,b N0 M0) is increasing because of wider implementation of breast cancer screening. Identification of prognostic factors for these patients has been based largely on retrospective pathology review. The authors analyzed histologic factors recorded in the original pathology reports to determine predictors of recurrence for patients with T1a,b N0 M0 breast cancer. METHODS: Two hundred eighteen patients were studied. Potential prognostic factors including measured millimeter tumor size in three dimensions, histologic grade, nuclear grade, and presence or absence of lymphatic vessel invasion were documented prospectively in routine surgical pathology reports of a large community (nonuniversity based) hospital. Follow-up was performed annually by the tumor registry. RESULTS: With a median follow-up of 6.9 years (range, 3-15.8 years), overall recurrence free survival was 93%. Poor nuclear grade (hazard ratio, 5.8; 95% confidence interval, 1.70-19.82; P = 0.004) and lymphatic vessel invasion (hazard ratio, 4.6; 95% confidence interval, 1.34-15.61; P = 0.01) were independent predictors of recurrence. Only 10% of patients had cancers with both poor nuclear grade and lymphatic vessel invasion and their 67% 7-year recurrence free survival (RFS) rate was significantly lower than the 92% RFS rate observed for patients with one of these two factors (P = 0.007) and the 99% RFS for patients with neither poor risk factor (P = 0.0001). CONCLUSIONS: The combination of poor nuclear grade and lymphatic vessel invasion identifies a very small subset (10%) of patients with T1a,b N0 M0 breast cancer with a significant relapse risk that warrants consideration of adjuvant systemic therapy. However, the majority of patients with T1a,b N0 M0 breast cancer have an exceptionally good prognosis.

A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors.

Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynaud's phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm, the total, relapse-free, and event-free survival distributions were similar in the two arms. Patients receiving EP experienced less emesis (P = .05), higher nadir WBC (P = .06) and platelet counts (P = .01), less magnesium wasting (P = .0001), less mucositis (P = .09), and no pulmonary toxicity. No treatment-related mortality was observed. EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT.

Abnormal colony formation and prostaglandin E responsiveness of myeloid progenitor cells in patients cured of germ cell neoplasms after combination chemotherapy.

Myelopoiesis was evaluated in 16 patients in complete remission for a minimum of 9 months after treatment with cisplatin-based combination chemotherapy for metastatic germ cell tumors. None had overt hematopoietic abnormalities. Bone marrow aspirates were obtained for routine morphologic evaluation in seven patients, and myeloid precursor cells were studied for both colony/cluster formation and sensitivity to prostaglandin E-(PGE) mediated growth inhibition in 13 patients. Routine stained marrow smears appeared normal. Six of 13 patients demonstrated abnormal colony/cluster formation. Four patients had no colony formation at all. Ten of 12 patients showed decreased sensitivity of granulocyte-macrophage colony-forming cells (CFU-GM) to PGE inhibition. The studies suggest that defects in myelopoiesis are detectable in patients treated for germ cell tumors with combination chemotherapy. The clinical significance of these findings requires long-term follow-up and surveillance for overt hematopoietic abnormalities in survivors of testicular cancer.

Altered renin and aldosterone excretion in patients treated for metastatic germ cell tumours.

Twenty-four patients with metastatic germ cell tumours were studied for abnormalities in the renin-aldosterone axis and for persistent abnormalities of renal function 9+ to 54+ months following completion of cisplatin based chemotherapy. Increased plasma renin activity and aldosterone were identified in fourteen of nineteen (79%) patients. The mean serum magnesium was subnormal. Statistically lower serum phosphorus levels, and higher urea and creatinine levels were also observed. No patients was hypertensive or on diuretics at the time of study. Since vascular toxicity has been reported after cisplatin based chemotherapy and hypomagnesaemia and increased plasma renin activity have been linked to cardiovascular events, these data imply that germ cell tumour patients treated with cisplatin based chemotherapy should be carefully observed for delayed cardiovascular toxicity.

Increased plasma renin and aldosterone in patients treated with cisplatin-based chemotherapy for metastatic germ-cell tumors.

Twenty-four normotensive males in complete remission (CR) for 9+ to 54+ months after cisplatin-based chemotherapy for metastatic germ-cell tumors were evaluated for evidence of alterations in the renin-aldosterone axis and renal function. Abnormally high ambulatory plasma renin activity was seen in 14 of 19 patients with 24-hour urine sodium excretion greater than 50 mEq. This was correlated with elevated ambulatory plasma aldosterone (P = .009) and 24-hour urinary aldosterone excretion (P = .01). The mean serum magnesium value (1.34 +/- .05 mEq/L) was subnormal. Therapy resulted in an increase in serum creatinine during treatment (P less than .0001), an increase in BUN (P less than .01), and decrease in serum phosphorus (P less than .001). The relationship between the alterations in the renin-aldosterone axis and abnormal renal tubular function remains to be determined. In view of reports of cardiovascular toxicity after treatment for germ-cell tumors, and evidence individually linking both magnesium deficiency and increased plasma renin activity (PRA) to cardiovascular consequences, these abnormalities in renin and magnesium metabolism suggest that patients treated with cisplatin-based chemotherapy should be carefully observed for the development of delayed cardiovascular toxicities.

Gonadal dysfunction in patients treated for metastatic germ-cell tumors.

The effects of chemotherapy on endocrine function were assessed in 22 previously treated patients with germ-cell tumors and compared with the endocrine function of six previously untreated patients. Baseline and stimulated serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, thyroid-stimulating hormone (TSH), prolactin, and thyroxine (T4) were obtained. Baseline LH levels were elevated in both groups of patients, whereas basal FSH levels were significantly elevated only in treated patients (P less than .001). Following gonadotropin-releasing hormone (GnRH), levels of LH (P = .051) and FSH (P = .003) were greater in treated patients than in untreated control patients. No abnormalities of thyroid function or prolactin responsiveness were observed. Patients younger than 25 years of age at the time of treatment had lower serum levels of LH and FSH following chemotherapy than patients older than 25. Evidence for partial recovery of gonadal function was present with patients treated more than 18 months before study having lower levels of LH and FSH than those patients studied less than 18 months after treatment. These data demonstrate that frequent gonadal dysfunction exists in untreated patients with germ-cell tumors and that chemotherapy induces additional injury to both Leydig cells and the germinal epithelium. Further studies with long-term follow-up are necessary to define the pattern of gonadal recovery and to assess the potential sequelae of endogenous gonadotropin hypersecretion.

A pilot study of cisplatin-vinblastine as the initial treatment of advanced head and neck cancer.

Twenty patients with Stage IV and five patients with Stage III carcinoma of the head and neck were treated with the combination of cisplatin and vinblastine before locoregional therapy. Among 24 patients evaluable for response after chemotherapy, there were four complete responders and 16 partial responders for an overall major response rate of 83%. No complete responses were observed in patients with T4 primary lesions or N3a nodal disease. Toxicity was limited primarily to nausea and vomiting (76%) and myelosuppression (72%). Four patients, all treated at the higher vinblastine dose, required hospitalization for fever associated with neutropenia. Two patients had a transient increase in the serum creatinine clearance to greater than 3 mg/dl. The combination of high-dose cisplatin and frequent vinblastine has significant activity in locally advanced squamous cell carcinoma of the head and neck, has mild and reversible toxicity, and does not require prolonged hospitalizations for continuous intravenous infusions.

Phase II trial of 4'-deoxydoxorubicin in patients with advanced breast cancer.

4'Deoxydoxorubicin (25 mg/m2 iv every 3 weeks) was evaluated in 20 patients with advanced breast cancer. The patients had good performance status and had not been heavily pretreated. Although all patients experienced leukopenia, no major therapeutic responses were observed. Nonhematologic toxicity was mild. Further evaluation of 4'-deoxydoxorubicin at this dose and schedule is not warranted in patients with advanced breast cancer.