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.

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.

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.

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.

Optic atrophy following prophylactic chemotherapy and cranial radiation for acute lymphocytic leukemia.

Two patients with acute lymphocytic leukemia developed progressive optic nerve and chiasmal lesions eight to nine months after the initiation of identical chemotherapy protocols that included intrathecal medication and prophylactic radiation of only 2,400 rads to the central nervous system. Both patients eventually lost all vision despite additional radiotherapy, and there was no evidence of leukemia involving the central nervous system after acute lymphocytic leukemia was diagnosed. Optic nerve biopsy in one case showed changes consistent with radiation necrosis.

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.

Alien-driven diversity and alien-selected escape: a rationale for allogeneic cancer immunotherapy.

We have presented two theories relating to the function of histocompatibility antigens and their presence as alien antigens on tumor cells. The theory of alien-driven diversity suggests that the ability to effectively recognize pathogens in the form of "altered-self" derives from prior exposure to antigens cross-reactive with "altered-self" during development. Furthermore, these cross-reactive antigens are alloantigens that are expressed on autologous cells during somatic development. These somatically generated alloantigens could be the result of the same genetic alterations that produced the polymorphism of these antigens within the species. Second, the theory of alien-selected escape suggests that a tumorigenic pathogen selects a cell bearing an alien H* antigen so that the alien-infected cell is recognized as self rather than altered-self by the tumor host. We than summarized data from mouse and man consistent with these theories and with the concept that clinically evident tumors have escaped the host's immune system. Finally, we have discussed potential directions for devising immunotherapy with allogeneic cells that might circumvent the apparent unresponsiveness of the patient's immune system to his own tumor.

[Effects of prophylactic treatment of central nervous system leukemia in children. Analysis of CNS prophylactic treatment with cyclic high dose multichemotherapy, craniospinal irradiation, and high dose infusion of MTX].

Thirty-five children with previously untreated ALL or AUL who received CNS prophylactic therapy with 8 treatment regiments were analyzed. After eutering complete remission, patients received CNS-prophylaxis with one of the following regimens: Group A- cyclic high dose multichemotherapy plus intermittent intrathecal methotrexate (MTX); Group B-craniospinal irradiation plus intermittent intrathecal MTX; Group C-intermittent high dose intravenous MTX. Incidence of CNS-leukemia and bone marrow relapse was less frequent in Group B. EEG abnormalities were seen in 38.5% of Group A, 40% of Group B, and 28.6% of Group C respectively, but the abnormalities were transient. IQs of three groups were above 100, but IQs of CNS-leukemia patients, especially VIQs had a tendency to be low.

[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.

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.