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Purpose The use of anthracycline chemotherapy is associated with heart failure (HF) among survivors of non-Hodgkin lymphoma (NHL). We aimed to understand the contribution of preexisting cardiovascular risk factors to HF risk among NHL survivors. Methods Using Danish registries, we identified adults diagnosed with aggressive NHL from 2000 to 2010 and sex- and age-matched general-population controls. We assessed HF from 9 months after diagnosis through 2012. We used Cox regression analysis to assess differences in risk for HF between survivors and general population controls. Among survivors only, preexisting cardiovascular factors (hypertension, dyslipidemia, and diabetes) and preexisting cardiovascular disease were ascertained. We used multivariable Cox regression to model the association of preexisting cardiovascular conditions on subsequent HF. Results Among 2,508 survivors of NHL and 7,399 controls, there was a 42% increased risk of HF among survivors compared with general population controls (hazard ratio [HR], 1.42; 95% CI, 1.07 to 1.88). Among survivors (median age at diagnosis, 62 years; 56% male), 115 were diagnosed with HF during follow-up (median years of follow-up, 2.5). Before NHL diagnosis, 39% had ≥ 1 cardiovascular risk factor; 92% of survivors were treated with anthracycline-containing regimens. In multivariable analysis, intrinsic heart disease diagnosed before lymphoma was associated with increased risk of HF (HR, 2.71; 95% CI, 1.15 to 6.36), whereas preexisting vascular disease had no association with HF ( P > .05). Survivors with cardiovascular risk factors had an increased risk of HF compared with those with none (for 1 v 0 cardiovascular risk factors: HR, 1.63; 95% CI, 1.07 to 2.47; for ≥ 2 v 0 cardiovascular risk factors: HR, 2.86; 95% CI, 1.56 to 5.23; joint P < .01). Conclusion In a large, population-based cohort of NHL survivors, preexisting cardiovascular conditions were associated with increased risk of HF. Preventive approaches should take baseline cardiovascular health into account.

OBJECTIVE: The impact of body mass index (BMI) and body surface area (BSA) on survival in diffuse large B-cell lymphoma (DLBCL) is controversial. Recent studies show superior outcomes for overweight and obese patients.PATIENTS AND METHODS: 653 R-CHOP(-like) treated DLBCL patients were included in this retrospective cohort study. Patients, baseline clinicopathologic characteristics and treatment information were retrieved from the Danish Lymphoma Registry. Anthropometric measures were obtained from chemotherapy prescription charts.RESULTS: Underweight (BMI CONCLUSIONS: Our study demonstrates that underweight DLBCL patients have worse outcomes following R-CHOP as compared to normal as well as overweight patients. This article is protected by copyright. All rights reserved.

Treatment of diffuse large B-cell lymphoma (DLBCL) with R-CHOP(-like) regimens include large cumulative doses of prednisolone. In this retrospective study, we evaluated changes in vertebral bone density (VD) in DLBCL patients by measuring CT-ascertained Hounsfield units (HU) at the L3 level. In total, 111 patients diagnosed from 2007 to 2012 and response assessed following first line treatment were included. Post-treatment VD was significantly reduced to 86% of pretreatment VD on average (p 70 years) were significantly associated with greater post-treatment VD reduction. Two years after completing R-CHOP treatment, VD remained significantly lower than baseline VD (p

BACKGROUND: The Danish National Lymphoma Register (LYFO) prospectively includes information on all lymphoma patients newly diagnosed at hematology departments in Denmark. The validity of the clinical information in the LYFO has never been systematically assessed.AIM: To test the coverage and data quality of the LYFO.METHODS: The coverage was tested by merging data of the LYFO with the Danish Cancer Register and the Danish National Patient Register, respectively. The validity of the LYFO was assessed by crosschecking with information from medical records in subgroups of patients. A random sample of 3% (N = 364) was made from all patients in the LYFO. In addition, four subtypes of lymphomas were validated: CNS lymphomas, diffuse large B-cell lymphomas, peripheral T-cell lymphomas, and Hodgkin lymphomas. A total of 1,706 patients from the period 2000-2012 were included. The positive predictive values (PPVs) and completeness of selected variables were calculated for each subgroup and for the entire cohort of patients.RESULTS: The comparison of data from the LYFO with the Danish Cancer Register and the Danish National Patient Register revealed a high coverage. In addition, the data quality was good with high PPVs (87% to 100%), and high completeness (92% to 100%).CONCLUSION: The LYFO is a unique, nationwide clinical database characterized by high validity, good coverage and prospective data entry. It represents a valuable resource for future lymphoma research.

Summary Leukotoxin (LtxA) is a virulence factor secreted by the bacterium Aggregatibacter actinomycetemcomitans, which can cause localized aggressive periodontitis and endocarditis. LtxA belongs to the repeat-in-toxin (RTX) family of exotoxins of which other members inflict lysis by formation of membrane pores. Recently, we documented that the haemolytic process induced by another RTX toxin [α-haemolysin (HlyA) from Escherichia coli] requires P2X receptor activation and consists of sequential cell shrinkage and swelling. In contrast, the cellular and molecular mechanisms of LtxA-mediated haemolysis are not fully understood. Here, we investigate the effect of LtxA on erythrocyte volume and whether P2 receptors also play a part in LtxA-mediated haemolysis. We observed that LtxA initially decreases the cell size, followed by a gradual rise in volume until the cell finally lyses. Moreover, LtxA triggers phosphatidylserine (PS) exposure in the erythrocyte membrane and both the shrinkage and the PS-exposure is preceded by increments in the intracellular Ca2+ concentration ([Ca2+]i). Interestingly, LtxA-mediated haemolysis is significantly potentiated by ATP release and P2X receptor activation in human erythrocytes. Furthermore, the LtxA-induced [Ca2+]i increase and following volume changes partially depend on P2 receptor activation. Theseobservations imply that intervention against local P2-mediated auto- and paracrine signalling may prevent LtxA-mediated cell damage.

10082 Background: Increased risk of myocardial infarction (MI) and cerebrovascular accident (CVA) among NHL survivors is commonly attributed to NHL treatment. The extent to which pre-existing CV risk factors also contribute to increased risk is unknown. We investigated this association among an entire national population of NHL survivors who have a full range of important CV risk factors. Methods: Using Danish population-based registries, we identified all adults diagnosed with primary aggressive NHL from 2000-2010 and followed them for MI and CVA from 9 months after diagnosis through 2012. MI and CVA diagnoses were ascertained from the nationwide Hospital Discharge Register and Cause of Death Register. CV risk factors (hypertension, dyslipidemia, and diabetes), vascular disease, and intrinsic heart disease prevalent at NHL diagnosis were ascertained algorithmically using the National Prescription Register and the Hospital Discharge Register. Cumulative anthracycline dose was coded continuously. Receipt of radiation was coded dichotomously for both chest and neck. Controlling for age, sex, treatment, and CV diseases, we used Cox multivariate regression to test the association between pre-existing CV risk factors and subsequent CVA or MI. Results: Among 2604 patients with NHL, median age was 62, and median follow-up time was 2.4 years. Overall, 131 patients were diagnosed with MI or CVA. Before NHL diagnosis, 40% of patients had at ≥1 CV risk factor, 13% had vascular disease, and 6% had intrinsic heart disease. 90% of the patients were treated with anthracyclines, 9% had received chest radiation, and 15% had received neck radiation. Patients with ≥1 CV risk factor had an increased risk of MI or CVA compared to patients with none (HR = 1.5 [95% CI = 1.1-2.2). Prevalent vascular disease, prevalent intrinsic heart disease, and NHL treatment were not associated with MI or CVA (p’s > 0.05). Conclusions: In a large, well-characterized, and nationally representative cohort of NHL survivors, prevalent CV risk factors were associated with later CVA and MI. To prevent MI and CVA among survivors, decisions about post-treatment monitoring should take into account prevalent CV risk.

Leukotoxin (LtxA) from Aggregatibacter actinomycetemcomitans is known to target and lyse β 2 -integrin-expressing cells such as polymorphonuclear leukocytes and macrophages. LtxA is an important virulence factor that facilitates chronic inflammation and is strongly associated with a fast-progressing form of periodontitis caused by the JP2 clone of the bacterium. Here, we show that sialic acid residues are important for LtxA-induced cell lysis, regardless of whether the cell express β 2 -integrin or not. Clearly, removal of sialic acid groups significantly reduces a β 2 -integrin-specific LtxA-induced lysis. Moreover, sialic acid presented on alternative proteins, such as, for instance, on erythrocytes that do not express β 2 -integrin, also makes the cells more sensitive to LtxA. The data also illustrate the importance of the negative charge in order for the sialic acid to associate LtxA with the membrane. Removal of sialic acid is in itself sufficient to significantly reduce the negative charge on the erythrocytes. Moreover, we found that on human erythrocytes there is a positive association between the sensitivity to LtxA and the amount of negative charge caused by sialic acid. Interestingly, these features are not shared by all RTX toxins, since α-hemolysin from Escherichia coli induced cell lysis of both β 2 -integrin-expressing and nonexpressing cells and this lysis is independent of the presence of sialic acid residues. In conclusion, LtxA not only is cytotoxic to β 2 -integrin-expressing cells but can potentially initiate cell lysis in all cells that present a sufficient density of sialic acid groups on their plasma membrane.

Mazabraud's syndrome is a rare disorder characterized by the association of single or multiple intramuscular myxomas with fibrous dysplasia. Here, we present the first case of Mazabraud's syndrome visualized on 18F-FDG PET/CT with histopathological confirmation of the myxoma. Our case demonstrates a slightly increased FDG uptake (SUVmax 2.1) within the myxomas and a moderately to highly increased tracer uptake (SUVmax 7.0) within the fibrous dysplastic lesions. The typical histological appearance of the intramuscular myxoma confirmed the radiological diagnosis. Further, we discuss the imaging findings and the histopathological features of this rare case with a review of the related literature.

Leukotoxin (LtxA) is a virulence factor secreted by the bacterium Aggregatibacter actinomycetemcomitans, which can cause localized aggressive periodontitis and endocarditis. LtxA belongs to the repeat-in-toxin (RTX) family of exotoxins of which other members inflict lysis by formation of membrane pores. Recently, we documented that the haemolytic process induced by another RTX toxin [α-haemolysin (HlyA) from Escherichia coli] requires P2X receptor activation and consists of sequential cell shrinkage and swelling. In contrast, the cellular and molecular mechanisms of LtxA-mediated haemolysis are not fully understood. Here, we investigate the effect of LtxA on erythrocyte volume and whether P2 receptors also play a part in LtxA-mediated haemolysis. We observed that LtxA initially decreases the cell size, followed by a gradual rise in volume until the cell finally lyses. Moreover, LtxA triggers phosphatidylserine (PS) exposure in the erythrocyte membrane and both the shrinkage and the PS-exposure is preceded by increments in the intracellular Ca(2+) concentration ([Ca(2+)](i)). Interestingly, LtxA-mediated haemolysis is significantly potentiated by ATP release and P2X receptor activation in human erythrocytes. Furthermore, the LtxA-induced [Ca(2+)](i) increase and following volume changes partially depend on P2 receptor activation. Theseobservations imply that intervention against local P2-mediated auto- and paracrine signalling may prevent LtxA-mediated cell damage.

Objective This article represents a review of histologic and genetic findings in endometriosis and describes the mechanisms whereby genetic and non-genetic factors potentially contribute to the neoplastic progression of endometriosis. Methods Literature review of the English language literature based on searching in the MEDLINE (PubMed) database and additional collection of reports by systematically reviewing all references from retrieved papers. Results Atypical endometriosis seems to represent a transition from benign endometriosis to carcinoma. Endometriosis is characterized by genetic instability: like neoplasms endometriosis seems to be monoclonal in origin, several studies have documented loss of heterozygosity (LOH) in endometriosis, data suggest that mutation of the tumor suppressor gene PTEN play a part in the malignant transformation of endometriosis, some studies have revealed TP53 mutations in endometriotic lesions, and mutation of ARID1A seems to be an important early event in the malignant transformation of endometriosis to endometrioid and clear cell carcinomas. Heme and iron induced oxidative stress, inflammation, and hyperestrogenism are possible links between endometriosis and cancer. Conclusions The histological and genetic alterations in endometriosis seem to explain why endometriosis can be a precursor of some ovarian cancers, especially clear cell and endometrioid carcinomas. However, the exact molecular mechanisms that may lead to this malignant transformation of endometriosis are not completely understood. More and larger studies are needed to clarify how exactly endometriotic tissue undergoes malignant transformation.

article i nfo Objective. This article critically reviews the literature on the association between endometriosis and gynecological cancers and breast cancer, based on epidemiologic data. Methods. Literature review of the English language literature based on searching in the MEDLINE (PubMed) database and additional collection of reports by systematically reviewing all references from retrieved papers. Results. Data from large cohort and case-control studies indicate that endometriosis patients only have an increased risk of ovarian cancer among the gynecological malignancies and breast cancer, although most of the observed associations are modest. Data on the association between endometriosis and breast cancer are inconsistent. Endometriosis patients have a reduced risk of cervical cancer, and there is no association between endometriosis and endometrial cancer. Endometriosis-associated ovarian cancer seems to be a distinct clinical entity; patients are younger, diagnosed in earlier stages, have lower grade lesions and a better survival. Further, endometriosis-associated ovarian cancers are predominantly clear cell and endometrioid histologic subtypes. Conclusions. Endometriosis seems to be a precursor of epithelial ovarian cancer, especially clear cell and endometrioid adenocarcinomas. However, current evidence is insufficient to draw any definitive conclusions whether this association represents causality or the sharing of similar risk factors and/or antecedent mechanisms.