Use of dipyridamole is associated with lower risk of lymphoid neoplasms: a propensity score-matched cohort study.

The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.

The preventable burden of work-related ill-health.

Background: The fraction of ill-health overall attributable to occupational conditions has not been extensively evaluated, thus contributing to the perception of a lesser relevance of education and research in occupational health in respect to other fields of medical research and practice. Aims: To assess the relevance of work-related conditions on the aetiology of human ill-health in different health domains. Methods: We extracted the risk estimates associated with heritability and with occupational risk factors for chronic lymphocytic leukaemia (CLL), major depressive disorder (MDD) and long QT syndrome (LQTS) from 13 published international reports. The selection criteria for the eligible studies were: genome-wide studies, or studies of the occupational risk factors associated with one of the three diseases of interest. We calculated and compared the respective population attributable fraction for the combined occupational risk factors, and for heritability. Results: We estimated that occupational risk factors would account for 12% (95% confidence interval (CI) 4-19) of CLL, 11% (95% CI 7-15) of MDD and 10% (95% CI 2-13) of LQTS burden in the general population. The corresponding figures for heritability would be 16% (95% CI 11-22), 28% (95% CI 20-5) and 17% (95% CI 7-27). Conclusions: More efforts in capacity building and research in occupational health are warranted aiming to prevent ill-health and to preserve a productive life for the ageing work population.

Plasma 25-hydroxyvitamin D concentration and lymphoma risk: results of the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: The relation between vitamin D status and lymphoma risk is inconclusive. OBJECTIVE: We examined the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and lymphoid cancer risk. DESIGN: We conducted a study nested within the European Prospective Investigation into Cancer and Nutrition cohort of 1127 lymphoma cases and 1127 matched controls with a mean follow-up time of 7.1 y. Conditional logistic regression was used to estimate multivariable-adjusted incidence rate ratios of lymphoma risk in relation to plasma 25(OH)D. Season-standardized and season-specific 25(OH)D quartiles were used. We also analyzed 25(OH)D as a continuous variable and used predefined cutoffs. RESULTS: No statistically significant association between plasma 25(OH)D and overall lymphoid cancer risk was observed. A positive association for B-cell non-Hodgkin lymphoma was noted only in those with a diagnosis made during the first 2 y of follow-up (P-heterogeneity = 0.03), which suggests the possibility of reverse causality. Further analysis restricted to participants with ≥2 y of follow-up time showed a significant association between 25(OH)D and chronic lymphocytic leukemia (CLL) (n = 161): adjusted incidence rate ratios were 0.40 (95% CI: 0.18, 0.90; P-trend = 0.05) and 0.31 (95% CI: 0.13, 0.76; P-trend = 0.03) for the top compared with the bottom season-standardized and season-specific quartiles, respectively. Data on dietary vitamin D intake provided further support for the observed association (incidence rate ratio: 0.33; 95% CI = 0.12, 0.89; P-trend = 0.006). CONCLUSIONS: Our findings do not support a protective role of high 25(OH)D concentration in lymphoid cancers overall. However, they suggest that higher concentrations of 25(OH)D are associated with a reduced risk of CLL.

Trans fatty acid intake is associated with increased risk and n3 fatty acid intake with reduced risk of non-hodgkin lymphoma.

We evaluated the association of dietary fat and protein intake with risk of non-Hodgkin lymphoma (NHL) in a clinic-based study in 603 cases (including 218 chronic lymphocytic leukemia/small lymphocytic lymphoma, 146 follicular lymphoma, and 105 diffuse large B-cell lymphoma) and 1007 frequency-matched controls. Usual diet was assessed with a 128-item food-frequency questionnaire. Unconditional logistic regression was used to estimate ORs and 95% CIs, and polytomous logistic regression was used to assess subtype-specific risks. trans Fatty acid (TFA) intake was positively associated with NHL risk [OR = 1.60 for highest vs. lowest quartile (95% CI = 1.18, 2.15); P-trend = 0.0014], n3 (ω3) fatty acid intake was inversely associated with risk [OR = 0.48 (95% CI = 0.35, 0.65); P-trend < 0.0001], and there was no association with total, animal, plant-based, or saturated fat intake. When examining intake of specific foods, processed meat [OR = 1.37 (95% CI = 1.02, 1.83); P-trend = 0.03], milk containing any fat [OR = 1.47 (95% CI = 1.16, 1.88); P-trend = 0.0025], and high-fat ice cream [OR = 4.03 (95% CI = 2.80, 5.80); P-trend < 0.0001], intakes were positively associated with risk, whereas intakes of fresh fish and total seafood [OR = 0.61 (95% CI = 0.46, 0.80); P-trend = 0.0025] were inversely associated with risk. Overall, there was little evidence for NHL subtype-specific heterogeneity. In conclusion, diets high in TFAs, processed meats, and higher fat dairy products were positively associated with NHL risk, whereas diets high in n3 fatty acids and total seafood were inversely associated with risk.

Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are rare, and their standard therapy has not been established. They are Epstein-Barr virus-associated lymphoid malignancies, and tumor cells express P-glycoprotein leading to multidrug resistance of the disease. Patients with stage IV, relapsed or refractory diseases have a dismal prognosis, with survival measured in months only. To develop an efficacious chemotherapeutic regimen, we conducted a dose-escalation feasibility study of a new chemotherapeutic regimen, SMILE, comprising the steroid dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide. The components of SMILE are multidrug resistance-unrelated agents and etoposide. Etoposide shows both in vitro and in vivo efficacy for Epstein-Barr virus-associated lymphoproliferative disorders. Eligible patients had newly diagnosed stage IV, relapsed or refractory diseases after first-line chemotherapy, were 15-69 years of age, and had satisfactory performance scores (0-2). Four dose levels of methotrexate and etoposide were originally planned to be evaluated. At level 1, six patients with extranodal NK/T-cell lymphoma, nasal type, were enrolled. Their disease status was newly diagnosed stage IV (n = 3), first relapse (n = 2), and primary refractory (n = 1). All of the first three patients developed dose-limiting toxicities, and one of them died of sepsis with grade 4 neutropenia. A protocol revision stipulating early granulocyte colony-stimulating factor administration was made. Two out of three additional patients developed dose-limiting toxicities that were all manageable and transient. For the six enrolled patients, the overall response rate was 67% and the complete response rate was 50%. Although its safety and efficacy require further evaluation, we recommend a SMILE chemotherapy dose level of 1 for further clinical studies.

[Life expectancy in the Plock area caused by lymphatic and erythrocyte line leukemia]. / Deficyt zycia z powodu nowotworów zlosliwych tkanki limfatycznej i krwiotwórczej w rejonie Plocka.

Among all specific environmental pollution the chemical compounds released in the oil refine process seem to hold the biggest interest. At Medical University of Warsaw we have been studying the influence of the Plock petroleum refinery plant pollution to citizens' health status for over 30 years. The high amount of hydrocarbons--including benzene--were presented in emission. One of the study objectives was to analyze death causes in Plock and Kutno and in the Plock area--according to environmental criteria. The population of the non-petrochemic polluted city Kutno was chosen as the control group. The previous analysis in 1984-1993 showed increased lymphatic or erythrocyte line leukaemia mortality in Plock population vs Kutno population. Similar situation was observed between the area of increased environmental petrochemical pollution and non-polluted area. In this article the Potential Years of Life Lost ratio was used to estimate the life deficiency as the measure of health needs due to mentioned neoplasms. Data indicate that the health needs are bigger than the mortality analysis has shown.

Effects of selenium supplementation on malignant lymphoproliferative pathologies associated with OF1 mouse ageing.

Low plasma selenium (Se) levels have been shown to correlate with increased cancer incidence in humans and in mice. This study was undertaken to investigate the ability of Se to decrease mortality rate and tumor production in ageing mice. Se (2.5 ppm) given as sodium selenite in drinking water to 8 months old OF1 mice, for 4 consecutive months, reduced significantly the mortality of mice with 6% and 50% mortality rate for Se and control groups, respectively. In addition 80% of control deaths resulted from a lymphoid cell neoplasma, while no one of Se supplemented mice produced tumor. Evaluation of parameters of free radical metabolism showed highly significant reduction of the antioxidant defence system in the liver of cancer mice, with a 78% decrease in GSH-Px activity, a 65% decrease in superoxide dismutase (SOD) activity, a 75% decrease in the GSH/GSSG ratio and a 62% decrease of plasma Se level, as compared to healthy old mice. Nevertheless in the conditions of our experiment, Se didn't really improve the endogenous antioxidant status of ageing mice.

The growth hormone: insulin-like growth factor 1 axis is a mediator of diet restriction-induced inhibition of mononuclear cell leukemia in Fischer rats.

A leukemia cell transplant model and both in situ and in vitro bioassays were used to assess the roles of endogenous factors in mediating diet restriction (DR)-induced inhibition of mononuclear cell leukemia (MNCL) in Fischer 344 rats. DR-treated male rats (n = 35), which were fed 75% of ad libitum (AL) intake of NIH-07 open formula diet, had lower transplanted MNCL incidence (54 versus 77%; P = 0.039) with longer latency (P = 0.015) and decreased severity (P = 0.01) than AL-treated rats 12 weeks after inoculation with MNCL cells. Five-day proliferation rates of cultured MNCL (CRNK-16) cells in diffusion chambers implanted in DR-treated rats were 22% less than in AL-treated rats (P = 0.03), indicating that DR-dependent diffusible factor(s) modulate in situ MNCL cell growth. Serum from DR-treated rats supported lower in vitro CRNK-16 cell proliferation rates relative to serum from AL-treated rats. Serum levels of both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) were over 50% lower in DR- versus AL-treated rats. An evaluation of the in vitro cell proliferative activity of a panel of purified factors showed that GH and IGF-1, but not 15 other growth factors, stimulated thymidine incorporation in CRNK-16 cells. Infusion of either GH or IGF-1 via osmotic minipumps restored in situ and in vitro CRNK-16 cell proliferation in DR-treated rats up to rates measured in AL-treated rats. Splenocytes from DR-treated rats, relative to AL-treated rats, were more sensitive to mitogen stimulation, displayed increased cell surface expression of receptors for class 1 and 2 major histocompatibility complex molecules, and were more cytotoxic to target tumor cells. Infusion of either GH or IGF-1 in DR-treated rats further enhanced mitogen responsiveness and natural cytotoxicity but reversed the DR-induced increase in major histocompatibility complex receptors. We conclude that DR modulates MNCL progression in Fischer 344 rats through both its influence on MNCL cell proliferation via suppression of the GH:IGF-1 axis and its enhancement of host defenses against tumor cells.

Physician compliance and relapse rates of acute lymphoblastic leukemia in children.

We studied the prescription patterns of maintenance therapy for children with acute lymphoblastic leukemia and their association with duration of complete remission. Both 6-mercaptopurine and methotrexate (MTX) were prescribed in doses significantly lower than those recommended (75 mg/m2 daily 6-mercaptopurine; 20 mg/m2 weekly MTX) during maintenance therapy. Of 212 evaluated patients, patients who had relapses (n = 101) received significantly less MTX compared with patients who did not have relapses (n = 111) during the first 2 years of maintenance therapy. In the group of standard-risk patients who received the same induction therapy (n = 92), 11 of 17 who received less than 50% of the recommended MTX dose (64%) and 28 of 75 who received greater than 50% of the dose (37%) had relapses (P less than 0.05). The two groups had comparable periods of interruption of MTX therapy. Further analysis revealed that the lower maintenance dose stemmed from a continuous low prescribed dose and not from more frequent interruption of therapy in relapse. Physicians' inability or failure to adhere to the recommended protocol was associated with a higher relapse rate of acute lymphoblastic leukemia. Improved physicians' compliance may improve the prognosis of the disease.

Effect of trimethoprim/sulfamethoxazole prophylaxis on outcome of childhood lymphocytic leukemia. A Pediatric Oncology Group Study.

The Pediatric Oncology Group (POG) undertook a prospective randomized trial using a single chemotherapy regimen with or without trimethoprim/sulfamethoxazole (TS). In a previous acute lymphocytic leukemia (ALL) study of initial therapy, investigators were free to use TS prophylaxis or not. Analysis of those data seemed to favor TS for duration of continuous complete remission. In the study reported here, of 126 randomized patients with ALL, 63 received TS. There was no effect of TS on disease-free survival after 3 years follow-up. Overall severe toxicity did not differ. However, granulocytopenia was somewhat more severe in the TS group. Hepatic toxicity, measured by enzyme elevation approached significance in the TS group versus controls. Some institutions declined randomization and treated with or without TS as a routine. Outcome and toxicities did not differ from randomized patients. There was no statistically significant effect on severe, life-threatening or fatal infection between the randomized TS versus control groups. Children not receiving TS developed varicella more often, a disease for which one would not expect TS to show a preventative effect. Pneumocystis pneumonias were not reported. The authors conclude that TS prophylaxis did not increase the continuous complete remission rate in children with ALL or decrease the incidence of infection. Toxicity is somewhat higher on TS.

The enigma of testicular leukemia: a critical review.

Isolated testicular relapse (T.R.) in acute lymphoblastic leukemia (ALL) has an overall incidence of 10% and affects mainly patients off therapy. Multivariate analysis of pretreatment characteristics has shown that lymphadenopathy and splenomegaly are independently associated with increased risk of T.R. during maintenance and off therapy, respectively. Sequential biopsy studies have demonstrated that testicular biopsies are unable to detect scanty infiltrates and have no practical utility. Prophylactic gonadal irradiation produced equivocal results and should not be used because of its sterilizing effect. Intensive multi-drug regimens or prolonged maintenance were unable to substantially reduce T.R. rate. On the contrary, intermediate-dose methotrexate (IDM) early in remission has almost abolished T.R. These findings strongly support the hypothesis that testicular interstitium is a very peculiar site where blasts are partially protected from the drug action; high drug concentrations are required for the optimal cytocidal effect. There are sufficient clues of a link between the excess of late marrow relapse in male sex and the capacity of testes of harboring blasts. Therefore IDM early in remission should be routinely adopted for prevention of testicular leukemia and its potential of late spread.

The sensitivity to methylnitrosourea-induced T-cell leukemogenesis in mice is modified by the injection of hydrocortisone.

T-cell leukemias were induced in adult BDF1 mice by a single i.v. injection of methylnitrosourea (MNU). Leukemogenesis was delayed by a single or repeated injections of hydrocortisone (HC) after MNU and also when HC was given one day before MNU. Enhancement of leukemogenesis was seen in experiments with 10 and 14 days' intervals between HC and MNU. The T-cell subset composition of the thymus after HC treatment was studied at these time intervals, but a specific target cell for the action of MNU, reduced one day after HC and increased in number during the thymic regeneration at 10 and 14 days could not be defined. HC did not prohibit the toxic action of MNU as measured by hemopoietic stem cell numbers in the femur.

To the question of leukaemia transmission from man to man by means of parenteral application of leukaemic blood: report of a case and survey of the literature.

During a diagnostic collection, leukaemic blood was applied intramuscularly to a nurse. She has been in full clinical health for more than two years. The reported accidents or intentional attempts at human leukaemia transmission are discussed and it is concluded that until now human leukaemia has not been transmitted by any way.

Failed central nervous system prophylaxis in children with acute lymphoblastic leukaemia: treatment and outcome.

Isolated CNS relapse occurred as a first event in 23 (6%) of 354 children with acute lymphoblastic leukaemia (ALL) who shortly after achieving remission had been treated with craniospinal irradiation or cranial irradiation and intrathecal methotrexate. CNS relapse occurred at a median time of 79 weeks from diagnosis and in three cases was asymptomatic, being diagnosed on routine lumbar puncture at completion of maintenance therapy. CNS remission was achieved with weekly intrathecal methotrexate in all but two cases who died in relapse. A second course of radiotherapy was given in 12 cases; at the time of relapse in three and delayed from 14-170 weeks later in nine. Intensified systemic chemotherapy was used in 13 patients and all but three continued on regular maintenance intrathecal methotrexate. Disease free remission following CNS relapse ranged from 9 to 366 weeks (median 76 weeks) with subsequent relapses occurring in the testis, CNS and in particular the bone marrow. Survival after relapse ranged from 11 to 476 weeks (median 92); seven patients are alive; four in continued remission, two with recurrent but controlled CNS disease, and one in remission following bone marrow transplant after subsequent marrow relapse. Recurrent CNS disease was significantly less frequent in patients who were reirradiated. It appears that long-term survival is possible after isolated CNS relapse but that further intensification of systemic chemotherapy and possibly chemo-radiotherapy and bone marrow transplant will be required to reduce the high risk of subsequent bone marrow relapse.

Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children.

We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other "sanctuary" areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P = 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P = 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.