Impact of JAK2V617F mutation on thrombosis and myeloid transformation in essential thrombocythemia: a multivariate analysis by Cox regression in 141 patients.

OBJECTIVE: To perform a multivariate analysis by Cox proportional hazard model of the impact of JAK2 V617F mutation on thrombosis and myeloid transformations in patients with essential thrombocythemia (ET). PATIENTS AND METHODS: The clinicopathologic features and outcome of a cohort of Chinese ET patients were retrospectively reviewed. JAK2 V617F mutation was detected by allele-specific polymerase chain reaction. Potential risk factors including JAK2 V617F that might impact on thrombosis and outcome were studied by multivariate analysis with Cox proportional hazard model. RESULTS: Of 141 patients studied, JAK2 V617F was found in 80 cases (57%). JAK2 V617F was positively correlated with hemoglobin and leukocyte count at diagnosis. Univariate analysis showed significant thrombotic risks to be JAK2 V617F (P=0.006), hemoglobin >13 g/dl (P=0.015), and age >55 years (P=0.011). However, in multivariate analysis, only age and hemoglobin were independent risk factors. JAK2 V617F was unrelated to survival or leukemic/myelofibrotic transformation. CONCLUSION: In Chinese patients with ET, JAK2 V617F was positively associated with age, hemoglobin, and leukocyte count, but was not an independent risk for thrombosis.

Epigenetic inactivation of the miR-34a in hematological malignancies.

miR-34a is a transcriptional target of p53 and implicated in carcinogenesis. We studied the role of miR-34a methylation in a panel of hematological malignancies including acute leukemia [acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)], chronic leukemia [chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)], multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). The methylation status of miR-34a promoter was studied in 12 cell lines and 188 diagnostic samples by methylation-specific polymerase chain reaction. miR-34a promoter was unmethylated in normal controls but methylated in 75% lymphoma and 37% myeloma cell lines. Hypomethylating treatment led to re-expression of pri-miR-34a transcript in lymphoma cells with homozygous miR-34a methylation. In primary samples at diagnosis, miR-34a methylation was detected in 4% CLL, 5.5% MM samples and 18.8% of NHL at diagnosis but none of ALL, AML and CML (P = 0.011). In MM patients with paired samples, miR-34a methylation status remained unchanged at progression. Amongst lymphoid malignancies, miR-34a was preferentially methylated in NHL (P = 0.018), in particular natural killer (NK)/T-cell lymphoma. In conclusion, amongst hematological malignancies, miR-34a methylation is preferentially hypermethylated in NHL, in particular NK/T-cell lymphoma, in a tumor-specific manner, therefore the role of miR-34a in lymphomagenesis warrants further study.

Arsenic trioxide in comparison with chemotherapy and bone marrow transplantation for the treatment of relapsed acute promyelocytic leukaemia.

BACKGROUND: The best overall treatment strategy for patients with acute promyelocytic leukaemia (APL) in relapse with chemotherapy, bone marrow transplantation (BMT) or arsenic trioxide (As(2)O(3)) based therapy remains undefined. PATIENTS AND METHODS: We reviewed the clinical course and treatment outcome of 143 APL cases seen in four major hospitals in Hong Kong over a 10-year period. RESULTS: Complete remission (CR) was attained in 113 cases (79%) with all-trans retinoic acid (ATRA) and chemotherapy. Relapse occurred at a median of 16 months in 54 cases, with a 3-year disease free survival of 56%. Post-relapse treatment was successful in 41 cases (76%), giving an actuarial 3-year overall survival (OS) of 81% from CR1. Three different protocols were used: chemotherapy alone (n = 19), allogeneic BMT (n = 14) and an As(2)O(3)-based regimen (n = 21). Chemotherapy was associated with the highest treatment-related mortality (TRM) at 53%, giving a CR2 rate of 47%. TRM was 36% for BMT. The CR2 rate for the As(2)O(3)-based regimen was 100%, with no TRM. However, 38% of As(2)O(3) treated patients had subsequent relapses, which were further salvaged in 75% by combined As(2)O(3) plus ATRA. The actuarial OS for the three protocols leveled off by 2 years at 82% for As(2)O(3), 43% for BMT and 23% for chemotherapy (P = 0.0004). CONCLUSIONS: Our results suggest that As(2)O(3) may be superior to chemotherapy and BMT for the treatment of APL in relapse.

Effect of increasing levels of hard wheat fiber on fecal weight, minerals and steroids and gastrointestinal transit time in healthy young women.

Hard red wheat bran (HRWB) baked in a yeast-leavened bread was fed to 36 healthy young college women consuming a basal diet of traditional foods, which contained 15 +/- 3 g/d dietary fiber (DF). Three levels of HRWB were added supplying, respectively, 5.7, 17.1 and 28.5 g/d DF; an additional treatment group did not receive any HRWB. Fecal collections were carried out in the last 5 d of treatment. Fecal wet weight, fecal dry weight and fecal ash increased significantly for each increase in HRWB (P less than 0.05). Fecal dry matter percent changed significantly only at the highest level of HRWB (P less than 0.05). After accounting for the minerals in the HRWB, there was an increased fecal loss of Ca, but not of Zn, Cu, Fe or Mg compared to the women fed no HRWB. HRWB at a level of 17.2 g/d induced faster transit times (TT) than no HRWB and 66 g/d HRWB induced faster TT than either 17.2 or 39.6 g/d HRWB (P less than 0.05). Total daily fecal steroids were not altered by changes in HRWB. Daily total bile acid excretion increased significantly (P less than 0.05) at the two higher levels of HRWB due primarily to higher excretion of chenodeoxycholic acid.

Hodgkin's lymphoma in a patient treated for Wegener's granulomatosis with cyclophosphamide and azathioprine.

Only 5 neoplasms have been reported associated with the use of cytotoxic drugs in the treatment of Wegener's granulomatosis. Described here for the first time, to our knowledge, is a patient with Wegener's granulomatosis treated with cyclophosphamide and azathioprine who later developed Hodgkin's lymphoma.

Multivitamin-mineral supplementation: effects on blood chemistries of college-age women.

Forty-two female college students, age 18-29 yr. and consuming nutritionally balanced meals in the college cafeteria participated. Subjects discontinued all vitamin-mineral supplements (VMS) for 17 days and were randomly assigned to one of two treatments, either a placebo, or VMS supplying the United States Recommended Daily Allowance (USRDA) of all vitamins, zinc, iron, iodine, copper, and 60% of the USRDA of calcium, 50% of magnesium and 45% of phosphorus. Treatments were consumed for 77 days. Fasting pre-and post-treatment blood chemistries were compared. VMS yielded significant increases (p less than 0.05) in serum vitamin B-12 (+25.05 pg/ml), vitamin C (+0.35 mg/dl) and folate (+7.40 ng/ml). No significant changes (p greater than 0.05) in hematological or other blood chemistries were observed. Significant decreases in the number of below-normal serum indicators of vitamin status (p less than 0.05) and iron status (p less than 0.005) were seen with VMS. No significant changes were seen with placebo (p greater than 0.05).

Eliminating the effect of water vapor in respiratory gas analysis.

An apparatus is described that removes water vapor from expired gas samples. By humidifying and cooling the sampled gas, the final water vapor partial pressure becomes independent of initial water content. The system has particular application to oxygen measurements.

Effect of methylprednisolone on the production of neutrophil migration inhibition factor by T lymphocytes (NIF-T).

Glucocorticoids may suppress cell-mediated immunity by inhibiting lymphocyte mediator production or reducing the responsiveness of target cells to these mediators. Our laboratory recently described a newly recognized T-lymphocyte mediator, neutrophil migration inhibition factor from T-lymphocytes (NIF-T). In this report we assessed the effect of glucocorticoids on NIF-T activity. Methylprednisolone (MP) at concentrations as low as 10-7 M inhibited NIF-T activity from peripheral blood lymphocytes (PBL) in response to staphylococcal protein A (SPA) and concanavalin A (Con A). However, MP at concentrations as high as 10-4 M did not after the responsiveness of neutrophils to NIF-T. Therefore, the effect of MP on NIF-T activity was due to inhibition of mediator production. The effect of MP on NIF-T production was reversible in 24 hours. This finding is consistent with the clinical observation that alternate day therapy does not suppress cell-mediated immunity. Serum taken from a patient as early as one hour after oral administration of 100 mg of prednisone inhibited NIF-T production in vitro; serum obtained at 48 hr after prednisone had no measurable effect on NIF-T activity, In addition. MP inhibited NIF-T production by previously activated lymphocytes.

Effect of immunoglobulin G on the responsiveness of human neutrophils to soluble staphylococcal protein A-induced neutrophil migration inhibition factor from T-lymphocytes.

Staphylococcal protein A is a bacterial cell wall product that binds human immunoglobulin G and thereby interferes with opsonization and phagocytosis of Staphylococcus aureus by neutrophils. Phagocytic cells are also responsive to various non-immunoglobulin lymphocyte mediators. We utilized the detection of a newly recognized mediator, a neutrophil migration inhibition factor from T-lymphocytes (NIF-T), to show that aggregates of staphylococcal protein A and immunoglobulins G could inhibit the responsiveness of neutrophils to NIF-T. That such aggregates may alter the responsiveness of neutrophils to lymphocyte mediators that amplify or modulate phagocytic functions may have important pathogenetic implications in staphylococcal infection.