Real-world clinical characterization, healthcare resource utilization and productivity loss in chronic graft versus host patients exposed to extracorporeal photopheresis in Sweden.

BACKGROUND: Extracorporeal photopheresis (ECP) is frequently used to treat moderate-severe chronic graft versus host disease (cGVHD), however limited data exists describing ECP treatment effects on healthcare and societal costs. We aimed to characterize clinical and health economic outcomes and productivity loss in cGVHD patients exposed to ECP. METHODS: We identified 2708 patients aged ≥ 18 years with a record of allogeneic hematopoietic stem cell transplantation (HSCT) in the Swedish Patient Register between 2006 and 2020. Patients exposed to ECP from 3-months post HSCT (index) were included (n= 183). Data was linked to the Prescribed Drug Register, the Cause of Death Register, and the Longitudinal Integrated Database for Health Insurance and Labor Market Studies (LISA). RESULTS: The median patient age at index was 51 years (IQR1-3; 38-61). In the 3-month period before ECP initiation compared to 9-12 months post-ECP, the cumulative three-month dose per patient decreased prednisolone/prednisone (1,381 mg vs. 658 mg, p < 0.001) and cyclosporin (12,242 mg vs. 3,501 mg, p < 0.001). Infection incidence also decreased over the same period (79.2% vs 59.1%, p < 0.001). Time spent in healthcare decreased from 68.9% to 22.1% from the first and fifth follow-up year respectively, and corresponding annual healthcare cost reduced from €27,719 to €1,981. Among patients < 66 years of age, sickness-related workplace absence decreased from 73.2% to 31.9% between the first and fifth follow-up year, with median annual productivity loss decreasing from €20,358 to €7,211 per patient. CONCLUSIONS: ECP was associated with reduced use of corticosteroids, immunosuppressive agents, and fewer infections. Furthermore, cost and healthcare utilization decreased over time.

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease.

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. METHODS: We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. RESULTS: cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. CONCLUSION: cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT.

Cardiovascular, bone, and metabolic health in men with castrate-resistant prostate cancer treated with androgen deprivation: a matched cohort study.

BACKGROUND: Descriptive data on late effects associated with castrate-resistant prostate cancer (CRPC) are sparse. We aimed to define the timing and incidence of cardiovascular disease (CVD), fractures, and diabetes in a patient population with CRPC. METHODS: In the population-based STHLM0 cohort 1464 men with CRPC were identified and matched with three men free from prostate cancer (PC) in the Stockholm region of Sweden. Kaplan-Meier estimates of net survival were used to describe time to CVD, fracture, and diabetes. Cox regression was used to compare incidence rates (IRRs) for the respective late effects. Cumulative incidence analyses of late effects in the presence of the competing risk of death were performed to estimate absolute risks. RESULTS: The Kaplan Meier estimates demonstrated a higher net probability for CVD, fracture, and diabetes among men diagnosed with CRPC compared to the matched comparators. The IRRs were 1.94 (95% CI: 1.79-2.12) for CVD, 2.08 (95% CI: 1.70-2.53) for fracture, and 2.00 (95% CI: 1.31-3.05) for diabetes, respectively, comparing men diagnosed with CRPC to men free from PC. The cumulative incidence of CVD at 12 months of follow-up was higher in men diagnosed with CRPC compared to healthy controls regardless of age with a difference in cumulative incidence being 0.20 for men aged <65 and 0.11 for men aged >84. CONCLUSIONS: In this cohort, the incidence of CVD was significantly higher among men with CRPC compared to healthy controls. Despite having this end-stage disease this finding proves that clinicians must recognize this late effect in men diagnosed with CRPC to improve preventive actions. These men did not have a higher absolute risk of fractures and diabetes after accounting for deaths due to any cause compared to healthy controls.

Real world treatment utilization patterns in patients with castration-resistant prostate cancer.

BACKGROUND: Studies describing treatment utilization for castration-resistant prostate cancer (CRPC) are limited. We aimed to describe the treatment utilization of a contemporary population-based CRPC cohort between 2006 and 2016. METHODS: We identified 1699 men with a PC diagnosis between 2005 and 2015, who developed CRPC between 2006 and 2015 in the Stockholm region of Sweden. Demographic information, stage and grade at PC diagnosis, stage at CRPC, prostate-specific antigen (PSA) nadir, PSA doubling time, treatment utilization rate within 1 year of CRPC diagnosis, reason for stopping therapy, treatment sequence trajectory, overall and PC specific survival was described. RESULTS: Treatment for men with de novo metastatic disease (n = 463) was 32%, treatment for men with progressive metastatic disease after PC diagnosis (n = 66) was 44%, treatment for men with nonmetastatic CRPC (n = 113) was 34% and treatment for those with an unknown stage at time of CRPC diagnosis (n = 857) was 12%. Docetaxel was used in 39%, abiraterone acetate plus prednisone in 15%, enzalutamide in 13%, cabazitaxel in 11% and radium-223 in 5% of treatments. Treatment increased from 22% in 2006-2009 for metastatic cancer to 50% in 2013-2015 (p < .001). Factors associated with treatment were an unknown stage at diagnosis (OR: 0.3, 95% CI: 0.2-0.4), age ≥75 years (OR: 0.2, 95% CI: 0.1 - 0.3), PSA doubling time >3 months (OR: 0.4, 95% CI: 0.3 - 0.6) and a diagnosis between 2013 and 2015 (OR: 3.4, 95% CI: 2.0 - 5.8). CONCLUSIONS: Despite treatment availability, in this large real-world cohort we found treatment utilization to remain low.

Healthcare resource utilisation and sickness absence in newly diagnosed multiple myeloma patients who did not undergo autologous stem cell transplantation: Trends in Sweden with the changing treatment landscape.

OBJECTIVES: The introduction of novel drugs has significantly improved outcomes for multiple myeloma (MM) patients. This study describes survival, healthcare resource utilisation and sickness absence in association with the changing MM treatment landscape over time, focussing on patients who did not undergo autologous stem cell transplantation (ASCT). METHODS: Population-based, retrospective registry study in Sweden, where 7012 non-ASCT patients diagnosed between 2001 and 2015 were stratified into diagnosis periods 2001-2005 (n = 2053), 2006-2010 (n = 2372) and 2011-2015 (n = 2587). RESULTS: Median survival increased from 2.5 to 3.4 years from 2001-2005 to 2011-2015. During the first 3 years of follow-up, patients diagnosed during 2011-2015 spent 29% and 12% less time in health care (55 days; inpatient admissions and outpatient visits) than patients diagnosed during 2001-2005 (78 days) and 2006-2010 (63 days), respectively. This was associated with less inpatient and more outpatient healthcare usage. Average 3-year sickness absence (362 days) was 31% and 12% less than for patients diagnosed during 2001-2005 (522 days) and 2006-2010 (410 days), respectively. CONCLUSIONS: These findings of improved survival, reduced healthcare needs and greater productivity in non-ASCT MM patients with access to improved treatment practices and novel drugs provide important real-world cost-benefit insights for the continued development and introduction of treatments for MM.

Real-world study of direct medical and indirect costs and time spent in healthcare in patients with chronic graft versus host disease.

Chronic graft versus host disease (cGVHD) is a debilitating and costly complication following haemopoietic stem cell transplantation (HSCT). This study describes the economic burden associated with cGVHD. Direct costs associated with specialised healthcare utilisation (inpatient admissions and outpatient visits), as well as indirect costs associated with sickness absence-associated productivity loss were estimated in patients who underwent allogeneic HSCT in Sweden between 2006 and 2015, linking population-based health and economic registers. To capture the period of chronic GVHD, patients were included who survived > 182 days post-HSCT (start of follow-up), and cGVHD was classified based on patient treatment records to correct for any diagnosis underreporting. Patients were classified as 'non-cGVHD' if they received no immunosuppressive treatment, 'mild cGVHD' if they received only systemic corticosteroid treatment or immunosuppressive treatment, or 'moderate-severe cGVHD' if they received extracorporeal photopheresis (ECP) only, corticosteroid treatment and immunosuppressive treatment, or systemic corticosteroid treatment and ECP treatments. Patients with moderate-severe cGVHD spent more time in healthcare, had higher healthcare resource costs and higher sickness absence-related productivity loss compared to patients with non- or mild cGVHD. The cumulative total costs during the first 3 years of follow-up were EUR 14,887,599, EUR 20,544,056, and EUR 47,811,835 for non-, mild, and moderate-severe groups, respectively. The long-term costs incurred with cGVHD following HSCT continue to be very high and significantly impacted by cGVHD severity. This study adds real-world health resource and economic insight relevant for policy-makers and healthcare providers when considering the clinical challenge of balancing immunosuppression to reduce cGVHD.

Survival in patients diagnosed with castration-resistant prostate cancer: a population-based observational study in Sweden.

Background: This study investigated prostate cancer (PC)-specific survival and overall survival (OS) in a population-based castration-resistant PC (CRPC) cohort.Methods: Data from Stockholm Prostate-Specific Antigen (PSA) and Biopsy Register patients with increasing PSA despite gonadotropin-releasing hormone treatment or surgical castration (n = 1,712) included PSA values and biopsies from 2003 to 2015 and were linked to the National Prostate Cancer Register and Prescribed Drug Register. Kaplan-Meier method estimated PC-specific survival and OS, stratified by metastasis at PC diagnosis, and Cox regression estimated hazard ratios (HRs) for Gleason score and T-stage at PC diagnosis and for age and calendar period at CRPC onset by metastasis status at diagnosis.Results: Median OS after CRPC onset was 23.2 months (95% CI = 21.0-25.9) among patients without metastases (M0) at primary diagnosis, and 13.2 months (11.3-14.5) among patients with metastases (M1). Median PC-specific survival from CRPC onset was 30.3 (27.5-34.1) months and 13.3 (12.1-15.8) months for M0 and M1 patients, respectively. Biopsy Gleason score ≥ 8 was associated with higher all-cause mortality than ≤6 (HR = 2.07 [95% CI = 1.43-3.01]) and PC-specific mortality (2.07 [1.27-3.40]) after CRPC among patients with M0 disease. Patients developing CRPC from 2012 onward had lower all-cause mortality (HR = 0.71 [95% CI = 0.60-0.85] [M0]; 0.60 [0.47-0.77] [M1]) and PC-specific mortality (0.73 [0.57-0.94] [M0]; 0.62 [0.46-0.84] [M1]) compared with those prior to 2012.Conclusions: M1 disease at PC diagnosis was associated with worse survival after CRPC onset versus M0. Higher Gleason score at diagnosis was associated with higher mortality after CRPC onset in M0 patients at diagnosis.

Survival outcomes in myelofibrosis patients treated with ruxolitinib: A population-based cohort study in Sweden and Norway.

OBJECTIVE: To estimate survival in Swedish and Norwegian myelofibrosis (MF) patients who received ruxolitinib. METHODS: Swedish and Norwegian patients with MF diagnosis in the National Cancer Registries (Sweden: 2001-2015; Norway: 2002-2016) and ≥1 record of ruxolitinib in the Prescribed Drug Registries (2013-2017) were included. Patients were followed from ruxolitinib initiation until death or end of follow-up; those who discontinued ruxolitinib were followed from ruxolitinib discontinuation. Relative survival (RS) and excess mortality rate ratios (EMRRs) were calculated vs a matched general population. Average loss in life expectancy (LEL) was predicted using flexible parametric models. RESULTS: Among patients who initiated ruxolitinib (n = 190), 1- and 4-year RS were 0.80 (95% confidence interval [CI]: 0.74, 0.86) and 0.52 (95% CI: 0.42, 0.64), respectively, and LEL was 11 years. EMRR was greater in patients aged >70 vs <60 years (3.16; 95% CI: 1.34-7.40). Among patients who discontinued ruxolitinib (n = 71), median RS was 16.0 months (95% CI: 6.3, NE), and LEL was 12 years. After ruxolitinib treatment discontinuation, Swedish patients (n = 37) received glucocorticoids, hydroxyurea, busulfan, danazol and lenalidomide. CONCLUSION: Swedish and Norwegian MF patients who discontinued ruxolitinib had dismal survival outcomes and limited subsequent treatment options, highlighting the need for improved therapies.

A systematic literature review of incidence, mortality, and relapse of patients diagnosed with chronic graft versus host disease.

INTRODUCTION: Chronic graft-versus-host disease (chronic GVHD) is a leading cause of late death and contributes significantly to morbidity following hematopoietic stem cell transplantation. This study aims to provide a systematic literature review on incidence, mortality, and relapse of chronic GVHD patients. Areas covered: The authors searched for English-language articles published between 2007 and 2017 using PubMed. Studies that applied the 2005 or 2015 NIH Consensus Criteria for the diagnosis and staging of chronic GVHD, and had a cohort size of at least 100 patients were included. Expert opinion: The authors found a wide variation of incidence rates, which can be explained by heterogeneity in the characteristics of study samples and applied transplantation protocols. Chronic GVHD was associated with higher non-relapse mortality (NRM), superior overall survival (OS) and lower risk of relapse. Studies indicated an increased risk for NRM and worse OS in the presence of more severe disease. Future therapies should focus to reach a delicate balance between controlling disease severity among patients diagnosed with chronic GVHD and preserving the graft versus tumor effect which goes along with chronic GVHD and results in improved OS and decreased relapse rate. Nonetheless, factors predicting disease severity still need to be further understood.

Humanistic burden of patients with chronic graft-versus-host disease - systematic literature review of health-related quality of life and functional status.

INTRODUCTION: Chronic graft-versus-host disease (GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to provide a systematic overview of evidence on the health-related quality of life (HRQoL) and functional capacity of HSCT patients with National Institutes of Health (NIH)-defined chronic GVHD. Areas covered: English-language articles published between 2007 and 2017 were searched using PubMed. Studies that used the 2005 or 2015 NIH consensus criteria for the diagnosis and staging of chronic GVHD and had a cohort size of at least 100 patients were included. Expert opinion: Disease severity and organ involvement were the most important predictors of HRQoL and functionality in chronic GVHD patients. Further, identified predictors of HRQoL were nutrition status and functional capacity, while functional status was also associated with disease symptoms, nutrition status, age, and survival. Data regarding the effect of symptom bother on HRQoL were limited. Our findings confirm that the management of chronic GVHD should focus on improving not only clinical outcomes but also on HRQoL and functional capacity. Therefore, to evaluate new treatment options it is recommended to include patient relevant endpoints into prospective studies. This study also highlights the importance of nonpharmacological aspects in the management of chronic GVHD.

Real-world treatment outcomes in multiple myeloma: Multicenter registry results from Finland 2009-2013.

Outcomes for patients with multiple myeloma (MM) have improved with the advent of novel therapies, however, real-world evidence of outcomes in clinical practice is scarce. We conducted a multi-center registry study to build a reliable picture of treatment and patient outcomes in Finland. The aim of this study was also to understand any methodological challenges in assessing treatment outcomes using disease registry data. METHODS: We carried out a retrospective, observational study using data from the national Finnish Hematology Registry (FHR) to provide real-world evidence of outcomes for all adult patients diagnosed with and treated for MM between 2009-2013 at one of the six regional hospitals, with at least six months of recorded follow-up. Patients were identified within the FHR by applying eligibility criteria of a diagnosis of MM and verifiable records of medical treatment and lines of treatment during the study period. Patients receiving allogenic stem cell transplantation were excluded from the cohort, as were individuals who only had monoclonal gammopathy of undetermined significance diagnosis and patients who had not initiated treatment during this period. Kaplan Meier curves were used to calculate overall survival and time to next treatment. Stratification was carried out by drug status (conventional/novel) and by autologous stem cell transplant (ASCT) status. RESULTS: A total of 321 patients met the inclusion criteria and were included in this study. Overall survival (OS) was longest in patients who received first-line novel therapy and ASCT (median not reached during 60-month follow-up) versus 46.2 months for novel first-line therapy without ASCT and 25.6 months for first-line conventional therapy without ASCT. Similarly, median time to next treatment were 33.9 months, 12.6 months and 7.8 months, respectively. CONCLUSIONS: The adoption of novel treatments in MM in Finland has had substantial impact on patient outcomes. Given the reality of complex treatment combinations for MM and relatively low patient numbers, assessing individual treatment effectiveness will require substantial cohort sizes and advanced, collaborative analytics on an international scale.

Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.

Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnström, Å., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjöberg, J., Xu, D., Westerberg, L. S., Björkholm, M., Claesson, H.-E. Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation.

Epigenetic and transcriptional control of the 15-lipoxygenase-1 gene in a Hodgkin lymphoma cell line.

Lipoxygenases oxidatively metabolize polyunsaturated fatty acids to a rich spectrum of biologically active metabolites. The present study aimed at delineating the transcriptional and epigenetic mechanisms leading to 15-lipoxygenase-1 (15-LOX-1) expression in the Hodgkin lymphoma (HL) cell line L1236. Examination of the 15-LOX-1 5' promoter region demonstrated three putative binding sites for signal transducer and activator of transcription (STAT6) within the proximal 1200 base pairs relative to the start codon. Analysis by serial promoter deletions and STAT6 binding site mutations indicated that all three STAT6 binding sites are required for full activation of the 15-LOX-1 promoter. Chromatin immunoprecipitation assay demonstrated that these regions were occupied by STAT6 in L1236 (15-LOX-1 positive) but not in L428 (15-LOX-1 negative) cultured HL cells. Furthermore, DNA hypomethylation and histone hyperacetylation were detectable within the core promoter region of 15-LOX-1 only in L1236 cells but not L428 cells. Taken together, our data indicate that STAT6 activation and chromatin remodeling by DNA demethylation and histone acetylation are crucial for transcriptional activation of 15-LOX-1 in cultured HL cells. These prerequisites are fulfilled in the L1236 cell line, but not in the L428 cell line.

Transcriptional regulation of 15-lipoxygenase expression by histone h3 lysine 4 methylation/demethylation.

15-Lipoxygenase-1 (15-LOX-1) oxidizes polyunsaturated fatty acids to a rich spectrum of biologically active metabolites and is implicated in physiological membrane remodelling, inflammation and apoptosis. Its deregulation is involved in the pathogenesis of diverse cancer and immune diseases. Recent experimental evidence reveals that dynamic histone methylation/demethylation mediated by histone methyltransferases and demethylases plays a critical role in regulation of chromatin remodelling and gene expression. In the present study, we compared the histone 3 lysine 4 (H3-K4) methylation status of the 15-LOX-1 promoter region of the two Hodgkin lymphoma (HL) cell lines L1236 and L428 with abundant and undetectable 15-LOX-1 expression, respectively. We identified a potential role of H3-K4 methylation in positive regulation of 15-LOX-1 transcription. Furthermore, we found that histone methyltransferase SMYD3 inhibition reduced 15-LOX-1 expression by decreasing promoter activity in L1236 cells. SMYD3 knock down in these cells abolished di-/trimethylation of H3-K4, attenuated the occupancy by the transactivator STAT6, and led to diminished histone H3 acetylation at the 15-LOX-1 promoter. In contrast, inhibition of SMCX, a JmjC-domain-containing H3-K4 tri-demethylase, upregulated 15-LOX-1 expression through induction of H3-K4 trimethylation, histone acetylation and STAT6 recruitment at the 15-LOX-1 promoter in L428 cells. In addition, we observed strong SMYD3 expression in the prostate cancer cell line LNCaP and its inhibition led to decreased 15-LOX-1 expression. Taken together, our data suggest that regulation of histone methylation/demethylation at the 15-LOX-1 promoter is important in 15-LOX-1 expression.

Interleukin-13 stimulation of the mediastinal B-cell lymphoma cell line Karpas-1106P induces a phenotype resembling the Hodgkin lymphoma cell line L1236.

OBJECTIVE: Primary mediastinal B-cell lymphoma (PMBCL) and Hodgkin lymphoma (HL) share many biological and clinical characteristics supporting a common pathogenetic pathway. Interleukin (IL)-13 has an important pathophysiological role in HL. In this study, we asked the question of whether IL-13 is a major contributor to the observed difference in features of inflammation between HL and PMBCL. MATERIALS AND METHODS: Expression of IL-13 and IL-4 receptors was studied by flow cytometry, expression of a functional cysteinyl leukotriene receptor type 1 (CysLT1R) was investigated by calcium flux measurement, expression and activity of 15-lipoxygenase type 1 (15-LO-1) was determined by Western blot and reversed-phase high-performance liquid chromatography, respectively, and cytokines were quantified by Bioplex detection. RESULTS: Stimulation of the PMBCL cell line Karpas-1106P with IL-13 or IL-4 induced a proinflammatory phenotype similar to that of the HL cell line L1236. Upon interleukin stimulation of the PMBCL cell line, the cellular size increased and cells became multinucleated. Cells also expressed CysLT1R and 15-LO-1, and produced the proinflammatory eoxins. The IL-13 or IL-4 treated PMBCL cell line and the HL cell line secreted a similar set of cytokines such as IL-6, tumor necrosis factor-alpha, interferon-inducible protein-10, interferon-gamma, and RANTES. CONCLUSIONS: IL-13 or IL-4 stimulation of the PMBCL cell line Karpas-1106P induced an inflammatory phenotype that resembles that of the HL cell line. Our results suggest that the autocrine release of IL-13 in HL is one critical factor that can at least partly explain the difference in phenotype between these two lymphoma entities.

15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells.

15-Lipoxygenase-1 (15-LOX-1) has been proposed to be involved in various physiological and pathophysiological activities such as inflammation, atherosclerosis, cell maturation, and tumorigenesis. Asthma and chronic obstructive pulmonary disease are associated with increased expression of 15-LOX-1 in bronchial epithelial cells, but the potential functions of 15-LOX-1 in airway epithelial cells have not been well clarified. To study the function of 15-LOX-1 in bronchial epithelial cells, we ectopically expressed 15-LOX-1 in the human lung epithelial cell line A549. We found that overexpression of 15-LOX-1 in A549 cells leads to increased release of the chemokines MIP-1alpha, RANTES, and IP-10, and thereby to increased recruitment of immature dendritic cells, mast cells, and activated T cells. These results suggest that an increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders.

Differential expression of cysteinyl leukotriene receptor 1 and 15-lipoxygenase-1 in non-Hodgkin lymphomas.

BACKGROUND: Arachidonic acid metabolites have been suggested to play an important role in carcinogenesis. We have recently reported that the cysteinyl leukotriene receptor 1 (CysLT1) and 15-lipoxygenase-1 (15-LO-1) are expressed by the malignant Hodgkin Reed-Sternberg cells of Hodgkin lymphoma and certain Hodgkin lymphoma cell lines, and that these cells convert arachidonic acid to the novel proinflammatory eoxins. MATERIALS AND METHODS: The expression of the CysLT1 receptor and 15-LO-1 was investigated in a broad range of non-Hodgkin lymphomas (NHLs) by immunohistochemistry. The functionality of the CysLT1 receptor in primary mediastinal B-cell lymphoma (PMBCL) cell lines was studied by calcium mobilization assays. RESULTS: Primary mediastinal B-cell lymphoma was the only NHL entity showing tumor cells positive for the CysLT1 receptor (9 of 10 tumors), and the PMBCL cell line Med-B1 expressed functional CysLT1 receptors, responding with a robust calcium signal upon cysteinyl leukotriene challenge. Furthermore, the tumor cells in 1 of 4 T-cell-derived anaplastic large-cell lymphomas, in contrast to all other studied NHLs, strongly expressed 15-LO-1. CONCLUSION: Among the NHL entities included in this study, the CysLT1 receptor was exclusively expressed by the tumor cells of PMBCL. Thus, this further corroborates the pathologic overlap between PMBCL and classical Hodgkin lymphoma.

Evidence for a pathophysiological role of cysteinyl leukotrienes in classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is characterized histologically by a minority of malignant Hodgkin Reed-Sternberg cells surrounded by abundant inflammatory cells, generally believed to be of major importance in the pathophysiology of the disease. Here, we present data that link inflammatory cell-derived arachidonic acid metabolites, the cysteinyl leukotrienes (CysLT), to the pathogenesis of cHL. Two HL cell lines, L1236 and KMH2, were shown to express functional CysLT(1) receptors, responding with a robust calcium signal upon leukotriene (LT) D(4) challenge. LTD(4) stimulated protein release of tumor necrosis factor-alpha, interleukin-6 and -8 by L1236 cells and interleukin-8 by KMH2 cells. Importantly, all these LTD(4)-induced effects were blocked by the CysLT(1) receptor-specific antagonist zafirlukast. Immunohistochemical studies of cHL biopsies and microarray analysis of microdissected cells revealed that the CysLT(1) receptor is expressed also by primary Hodgkin Reed-Sternberg cells. As these cells are surrounded by CysLT-producing eosinophils, macrophages and mast cells, our results suggest the CysLTs as mediators in the pathogenesis of cHL, contributing to the aberrant cytokine network of this lymphoma.

Hodgkin Reed-Sternberg cells express 15-lipoxygenase-1 and are putative producers of eoxins in vivo: novel insight into the inflammatory features of classical Hodgkin lymphoma.

Classical Hodgkin lymphoma has unique clinical and pathological features and tumour tissue is characterized by a minority of malignant Hodgkin Reed-Sternberg cells surrounded by inflammatory cells. In the present study, we report that the Hodgkin lymphoma-derived cell line L1236 has high expression of 15-lipoxygenase-1 and that these cells readily convert arachidonic acid to eoxin C(4), eoxin D(4) and eoxin E(4). These mediators were only recently discovered in human eosinophils and mast cells and found to be potent proinflammatory mediators. Western blot and immunocytochemistry analyses of L1236 cells demonstrated that 15-lipoxygenase-1 was present mainly in the cytosol and that the enzyme translocated to the membrane upon calcium challenge. By immunohistochemistry of Hodgkin lymphoma tumour tissue, 15-lipoxygenase-1 was found to be expressed in primary Hodgkin Reed-Sternberg cells in 17 of 20 (85%) investigated biopsies. The enzyme 15-lipoxygenase-1, however, was not expressed in any of 10 biopsies representing nine different subtypes of non-Hodgkin lymphoma. In essence, the expression of 15-lipoxygenase-1 and the putative formation of eoxins by Hodgkin Reed-Sternberg cells in vivo are likely to contribute to the inflammatory features of Hodgkin lymphoma. These findings may have important diagnostic and therapeutic implications in Hodgkin lymphoma. Furthermore, the discovery of the high 15-lipoxygenase-1 activity in L1236 cells demonstrates that this cell line comprises a useful model system to study the chemical and biological roles of 15-lipoxygenase-1.