Common infection-related conditions and risk of lymphoid malignancies in older individuals

Background: Chronic antigenic stimulation may initiate non-Hodgkin (NHL) and Hodgkin lymphoma (HL) development. Antecedent, infection-related conditions have been associated, but evidence by lymphoproliferative subtype is limited. Methods: From the US SEER-Medicare database, 44 191 NHL, 1832 HL and 200 000 population-based controls, frequency-matched to all SEER cancer cases, were selected. Logistic regression models, adjusted for potential confounders, compared infection-related conditions in controls with HL and NHL patients and by the NHL subtypes diffuse large B-cell, T-cell, follicular and marginal zone lymphoma (MZL). Stratification by race was undertaken. Results: Respiratory tract infections were broadly associated with NHL, particularly MZL. Skin infections were associated with a 15–28% increased risk of NHL and with most NHL subtypes, particularly cellulitis with T-cell lymphoma (OR 1.36, 95%CI 1.24–1.49). Only herpes zoster remained associated with HL following Bonferroni correction (OR 1.55, 95% CI 1.28–1.87). Gastrointestinal and urinary tract infections were not strongly associated with NHL or HL. In stratified analyses by race, sinusitis, pharyngitis, bronchitis and cellulitis showed stronger associations with total NHL in blacks than whites (P<0.001). Conclusions: Infections may contribute to the aetiologic pathway and/or be markers of underlying immune modulation. Precise elucidation of these mechanisms may provide important clues for understanding how immune disturbance contributes to lymphoma.

Mortality among 24,865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: a ten-year update.

The objective of this analysis was to evaluate mortality among a cohort of 24,865 capacitor-manufacturing workers exposed to polychlorinated biphenyls (PCBs) at plants in Indiana, Massachusetts, and New York and followed for mortality through 2008. Cumulative PCB exposure was estimated using plant-specific job-exposure matrices. External comparisons to US and state-specific populations used standardized mortality ratios, adjusted for gender, race, age and calendar year. Among long-term workers employed 3 months or longer, within-cohort comparisons used standardized rate ratios and multivariable Poisson regression modeling. Through 2008, more than one million person-years at risk and 8749 deaths were accrued. Among long-term employees, all-cause and all-cancer mortality were not elevated; of the a priori outcomes assessed only melanoma mortality was elevated. Mortality was elevated for some outcomes of a priori interest among subgroups of long-term workers: all cancer, intestinal cancer and amyotrophic lateral sclerosis (women); melanoma (men); melanoma and brain and nervous system cancer (Indiana plant); and melanoma and multiple myeloma (New York plant). Standardized rates of stomach and uterine cancer and multiple myeloma mortality increased with estimated cumulative PCB exposure. Poisson regression modeling showed significant associations with estimated cumulative PCB exposure for prostate and stomach cancer mortality. For other outcomes of a priori interest--rectal, liver, ovarian, breast, and thyroid cancer, non-Hodgkin lymphoma, Alzheimer disease, and Parkinson disease--neither elevated mortality nor positive associations with PCB exposure were observed. Associations between estimated cumulative PCB exposure and stomach, uterine, and prostate cancer and myeloma mortality confirmed our previous positive findings.

PRDM1 is a tumor suppressor gene in natural killer cell malignancies.

Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methylation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression-in particular, PRDM1α-in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-Cl9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathogenetic mechanism for NKCL.

Étude de l'activité anti-cancéreuse du PCK3145, un peptide dérivé de PSP-94, sur les cancers hématologiques

Le PCK3145 est un peptide de 15 acides aminés inhibant la sécrétion de MMP-9 et démontrant une activité anti-tumorale contre le cancer de la prostate. Comme les cancers hématologiques sécrètent MMP-9, nous avons donc évalué l’effet du PCK3145 sur ces cancers. Nous avons démontré que les lignées humaines de lymphome non- Hodgkinien (LNH) SR et de myélome multiple RPMI-8226 ainsi que la lignée murine de mastocytome P815 ont une prolifération réduite suite à une exposition au PCK3145. Ce peptide diminue également la clonogénicité de ces cellules. In vivo, le PCK3145 diminue significativement la croissance des tumeurs sous-cutanées P815 comparativement au PBS (p<0.001) et aux peptides contrôles (« scrambled peptide » (p<0.05) et PCK5266 (p<0.01)). De plus, le traitement au PCK3145 diminue le nombre de métastases au niveau du foie par rapports aux contrôles (p<0.05). Les niveaux de MMP-9 dans le sang des souris traitées au PCK3145 sont similaires à ceux dans le sang des souris sans tumeur. Par contre, chez les souris recevant le PBS ou le « scrambled peptide », les niveaux de MMP-9 étaient significativement plus élevés que dans les souris sans tumeur et les souris traitées au PCK3145 (p<0.05). De surcroît, dans un modèle de xénogreffe, le PCK3145 diminue significativement la croissance des lymphomes SR par rapport au PBS (p<0.01) et au « scrambled peptide » (p<0.001). Ces résultats indiquent que le PCK3145 possède une activité anti-tumorale et pourrait représenter un agent intéressant pour le traitement de plusieurs cancers hématologiques.

Multiclass Classification of SRBCTs

A novel approach to multiclass tumor classification using Artificial Neural Networks (ANNs) was introduced in a recent paper cite{Khan2001}. The method successfully classified and diagnosed small, round blue cell tumors (SRBCTs) of childhood into four distinct categories, neuroblastoma (NB), rhabdomyosarcoma (RMS), non-Hodgkin lymphoma (NHL) and the Ewing family of tumors (EWS), using cDNA gene expression profiles of samples that included both tumor biopsy material and cell lines. We report that using an approach similar to the one reported by Yeang et al cite{Yeang2001}, i.e. multiclass classification by combining outputs of binary classifiers, we achieved equal accuracy with much fewer features. We report the performances of 3 binary classifiers (k-nearest neighbors (kNN), weighted-voting (WV), and support vector machines (SVM)) with 3 feature selection techniques (Golub's Signal to Noise (SN) ratios cite{Golub99}, Fisher scores (FSc) and Mukherjee's SVM feature selection (SVMFS))cite{Sayan98}.

Comparación farmacoeconómica (costo – utilidad / beneficio / efectividad) del Rituximab, con el tratamiento convencional para pacientes con Linfoma No Hodgkins

El Linfoma no Hodgkin es un cáncer maligno que tiene baja incidencia a nivel nacional pero altos costos en la atención catalogándose por su manejo como enfermedad de alto costo. El tratamiento de acuerdo a fase de tratamiento, clasificación histológica y respuesta a tratamiento se consideran las alternativas de tratamiento determinadas en guías clínicas en este trabajo se revisará el tratamiento con quimioterapia (CHOP) y el tratamiento con Rituximab + CHOP Objetivo: Evaluar comparativamente el tratamiento con quimioterapia y el Rituximab en cuanto a costo beneficio / utilidad /efectividad y el efecto de ambas terapias sobre la calidad de vida y carga de enfermedad, desde la perspectiva del marco normativo vigente y la aplicación del mismo en una EPS Resultados: en los análisis de costo beneficio, utilidad y efectividad, se evidenció que los costos del tratamiento del Rituximab superan los de quimioterapia, pero al comparar los resultados obtenidos mediante AVISA, y QALY, confirmaron los resultados evidenciados en literatura, siendo estas las variables más sensibles para determinación de protocolos de manejo de Linfoma No Hodgkin. Conclusiones: aunque el Rituximab es una buena opción terapéutica para el Linfoma No Hodgkin, los costos que se ocasionan por este medicamento sobrepasan la compensación recibida por estos usuarios, es necesario que las políticas públicas relacionen este tipo de análisis para adecuar los ingresos a los egresos y permitir el equilibrio económico de la atención, no permitir que por cuestiones de economía empresarial se tomen alternativas equivocas que pueden ir el menos cabo de la salud de los usuarios.

Evaluación de la exposición a solventes orgánicos en pintores de carros de la ciudad de Bogotá

Introducción. Los pintores de vehículos automotores están expuestos a solventes puros o mezclas de estos, los cuales se han asociado con efectos neurológicos y mutacarcinogénicos. Materiales y Métodos. Se realizó un estudio descriptivo de corte transversal para caracterizar las condiciones de salud y trabajo de individuos expuestos a solventes orgánicos en talleres de lámina y pintura en Bogotá. Se comparó un grupo de expuestos a solventes orgánicos con un grupo no expuestos. Se determinaron concentraciones de benceno, tolueno y xileno (BTX) en aire, se aplicó una encuesta individual y se midieron en orina, los ácidos fenil mercaptúrico, hipúrico, orto-para metilhipúrico como metabolitos de benceno, tolueno y xileno. Los resultados de las mediciones y de la encuesta se correlacionaron para establecer el panorama de exposición. Resultados: hubo diferencias estadísticamente significativas entre la población expuesta y la población no expuesta a solventes (p = 0,00) para los tres metabolitos de BTX. Se encontraron correlaciones positivas entre el tolueno en aire y ácido hipúrico en orina de los expuestos, (Spearman de 0,82) y entre el xileno en aire y el ácido o-metilhipúrico (Spearman de 0,76). Se encontraron valores de ácido hipúrico por encima de los límites permisibles en 11 2 trabajadores y de ácido p-metilhipúrico en 8 de ellos. No hubo valores para ácido fenilmercapturico fuera de límite. Discusión: los pintores de carros se encuentran expuestos a niveles altos de solventes orgánicos en sus sitios de trabajo y no cuentan con condiciones adecuadas de higiene y seguridad industrial para realizar sus labores.

Trans-fatty acids and cancer: the evidence reviewed

The present review comes from the authors of the recent Scientific Advisory Committee on Nutrition (SACN) review Update on Trans Fatty Acids and Health, and focuses on assessing the strength of the evidence for a link between trans-fatty acid (trans-FA) intake and cancer. It evaluates a range of human ecological, case-control and prospective studies with trans-FA exposure assessed using either dietary assessment methods or trans-FA levels in tissues. Relevant animal studies are also presented in order to elucidate potential mechanisms. It concludes that there is weak and inconsistent evidence for a relationship between trans-FA and breast or colorectal cancer. Evidence for an association between trans-FA and prostate cancer is limited, but a recent large case-control study has shown a strong interaction between risk and trans-FA intake for the RNASEL QQ/RQ genotype that is present in about 35% of the population. This potential association requires further investigation. The single study on non-Hodgkin's lymphoma reported a strong positive association, but out), used a single assessment of dietary trans-FA made at the start of the study in 1980, and the significant changes it) trans-FA intakes between then and the end Of follow-up in 1994 limit the reliability of this observation. There is insufficient evidence to allow any differentiation between the effects of trans-FA from animal or vegetable origin on cancer risk.

Balanoposthitis caused by Pseudomonas aeruginosa co-producing metallo-beta-lactamase and 16S rRNA methylase in children with hematological malignancies

Balanoposthitis is defined as the inflammation of the glans penis and its foreskin. In the presence of other underlying medical conditions, this localized infection may spread systemically, serving as a source of fever and bacteremia in neutropenic males. Two rare cases of balanoposthitis caused by a clonally related Pseudomonas aeruginosa isolate co-producing the SPM-1 metallo-beta-lactamase and the novel 16S rRNA methylase RmtD are described. Four multidrug-resistant (MDR) P. aeruginosa isolates were successively recovered from glans/foreskin swabs and urine cultures from two uncircumcised pediatric patients, one with Burkitt`s non-Hodgkin`s lymphoma and one with acute lymphoblastic leukemia. Clinically, preputial colonization by MDR P. aeruginosa evolved to severe balanoposthitis with glans/foreskin lesions as a source of fever. Combination therapy of ciprofloxacin and/or aztreonam (systemic) plus polymyxin B (topical) was effective once reversion of the neutropenic condition was achieved. Although P. aeruginosa remains an unusual cause of balanoposthitis, these cases should alert the physician to the potential pathogenicity of this bacterium. Furthermore, co-production of metallo-beta-lactamase and 16S rRNA methylase has a potential impact on the empirical management of complicated infections caused by P. aeruginosa. Crown Copyright (C) 2009 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. All rights reserved.

Leukemia risk associated with low-level benzene exposure

Background: Men who were part of an Australian petroleum industry cohort had previously been found to have an excess of lympho-hematopoietic cancer. Occupational benzene exposure is a possible cause of this excess.

Methods: We conducted a case-control study of lympho-hematopoietic cancer nested within the existing cohort study to examine the role of benzene exposure. Cases identified between 1981 and 1999 (N = 79) were age-matched to 5 control subjects from the cohort. We estimated each subject's benzene exposure using occupational histories, local site-specific information, and an algorithm using Australian petroleum industry monitoring data.

Results: Matched analyses showed that the risk of leukemia was increased at cumulative exposures above 2 ppm-years and with intensity of exposure of highest exposed job over 0.8 ppm. Risk increased with higher exposures; for the 13 case-sets with greater than 8 ppm-years cumulative exposure, the odds ratio was 11.3 (95% confidence interval = 2.85-45.1). The risk of leukemia was not associated with start date or duration of employment. The association with type of workplace was explained by cumulative exposure. There is limited evidence that short-term high exposures carry more risk than the same amount of exposure spread over a longer period. The risks for acute nonlymphocytic leukemia and chronic lymphocytic leukemia were raised for the highest exposed workers. No association was found between non-Hodgkin lymphoma or multiple myeloma and benzene exposure, nor between tobacco or alcohol consumption and any of the cancers.

Conclusions: We found an excess risk of leukemia associated with cumulative benzene exposures and benzene exposure intensities that were considerably lower than reported in previous studies. No evidence was found of a threshold cumulative exposure below which there was no risk.

Health watch exposure estimates:do they underestimate benzene exposure

A nested case–control study found that the excess of leukemia, identified among the male members of the Health Watch cohort, was associated with benzene exposure. Exposure had been retrospectively estimated for each individual occupational history using an algorithm in a relational database. Benzene exposure measurements, supplied by Australian petroleum companies, were used to estimate exposure for specific tasks. The tasks carried out within each job, the products handled, and the technology used, were identified from structured interviews with contemporary colleagues. More than half of the subjects started work after 1965 and had an average exposure period of 20 years. Exposure was low; nearly 85% of the cumulative exposure estimates were at or below 10 ppm-years. Matched analyses showed that leukemia risk increased with increasing cumulative benzene exposures and with increasing exposure intensity of the highest-exposed job. Non-Hodgkin lymphoma and multiple myeloma were not associated with benzene exposure. A reanalysis reported here, showed that for the 7 leukemia case-sets with greater than 16 ppm-years cumulative exposure, the odds ratio was 51.9 (5.6–477) when compared to the 2 lowest exposed categories combined to form a new reference category. The addition of occasional high exposures, e.g. as a result of spillages, increased exposure for 25% of subjects but for most, the increase was less than 5% of total exposure. The addition of these exposures reduced the odds ratios. Cumulative exposures did not range as high as those in comparable studies; however, the recent nature of the cohort and local handling practices can explain these differences.

The health watch case - control study of leukemia and benzene:the story so far

A case–control study nested in the Health Watch cohort of petroleum industry workers, investigated whether the excess of lymphohematopoetic cancers, identified among male members of the Health Watch cohort, was associated with benzene exposure. Cases of non-Hodgkin’s lymphoma (n=31),multiple myeloma (n=15), and leukemia (n=33)were identified between 1981 and 1999. Cases were age-matched to five controls. Exposure was retrospectively estimated for each occupational history using an algorithm in a relational database. Benzene exposure measurements, supplied by Australian petroleum companies, were used to estimate exposure for specific tasks. The tasks carried out within the job, the products handled, and the technology used,were identified from interviews with contemporary colleagues. More than half of the subjects started work after 1965 and had an average exposure period of 20 years. Exposure was low, 85% of the cumulative exposure estimates were<10 ppm years. Matched analyses showed that non-Hodgkin’s lymphoma and multiple myeloma were not associated with benzene exposure. Leukemia risk, however, was significantly increased for the subjects with greater than 16 ppm years cumulative exposure, odds ratio (OR) 51.9 (5.6–477) or with greater than 0.8 ppm intensity of highest exposed job. Cumulative exposures were similar to those found in comparable studies.The inclusion of occasional high exposures, for example, as a result of spillages, reduced the ORs, when the exposure was treated as either a continuous or a categorical variable. Our data demonstrate a strong association between leukemia and modest benzene exposure. The choice of cut-point and reference group has a marked effect on the ORs, but does not change the overall conclusions.

Cancer survival in Australia 1992–1997 : geographic categories and socioeconomic status

Cancer Survival in Australia 1992-1997 is the first national analysis of how cancer survival varies by socioeconomic status and geographic region. It presents an analysis of five-year relative survival proportions by geographic category and socioeconomic status for persons diagnosed with cancer during the years 1992-1997.This analysis is presented by age and sex for all cancers (Excluding non-melanocytic skin cancers) combined and for the following National Health Priority Area cancers - colorectal cancer, cancer of the lung, melanoma, cancer of the breast (females only), cancer of the cervix, cancer of the prostate, and non-Hodgkin's lymphoma.This report is the third in a series of three reports on relative survival after being diagnosed with cancer. It is an important reference for all those interested in the health of Australians.

Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation

 OBJECTIVE: Evidence indicates an increased risk of certain cancers among people with type 2 diabetes. Evidence for rarer cancers and for type 1 diabetes is limited. We explored the excess risk of site-specific cancer incidence and mortality among people with type 1 and type 2 diabetes, compared with the general Australian population. RESEARCH DESIGN AND METHODS: Registrants of a national diabetes registry (953,382) between 1997 and 2008 were linked to national death and cancer registries. Standardized incidence and mortality ratios (SIRs/SMRs) are reported. RESULTS: For type 1 diabetes, significant elevated SIRs were observed for pancreas, liver, esophagus, colon and rectum (females only [F]), stomach (F), thyroid (F), brain (F), lung (F), endometrium, and ovary, and decreased SIRs were observed for prostate in males. Significantly increased SMRs were observed for pancreas, liver, and kidney (males only), non-Hodgkin's lymphoma, brain (F), and endometrium. For type 2 diabetes, significant SIRs were observed for almost all site-specific cancers, with highest SIRs observed for liver and pancreas, and decreased risks for prostate and melanoma. Significant SMRs were observed for liver, pancreas, kidney, Hodgkin's lymphoma, gallbladder (F), stomach (F), and non-Hodgkin's lymphoma (F). Cancer risk was significantly elevated throughout follow-up time but was higher in the first 3 months postregistration, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: Type 1 and type 2 diabetes are associated with an excess risk of incidence and mortality for overall and a number of site-specific cancers, and this is only partially explained by bias. We suggest that screening for cancers in diabetic patients is important.

HIV, EBV and KSHV: Viral cooperation in the pathogenesis of human malignancies

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)