Proteomic Profiling of Lymph Nodes Differentiates Classic Hodgkin Lymphoma With and Without Skeletal Involvement.

Classic Hodgkin lymphoma (CHL) is a highly curable disease, even in advanced stages. Controversy remains over whether bone involvement negatively affects overall and progression-free survival in patients treated with intensive chemotherapy regimens. Whether cases that present with bone lesions harbor specific tumor microenvironmental features is unknown. We investigated protein expression in diagnostic lymph node biopsies from CHL patients with and without skeletal involvement at diagnosis to identify potential markers of skeletal disease. Protein expression patterns in diagnostic formalin-fixed paraffin-embedded lymphoma lymph node samples from CHL patients were analyzed by nano-liquid chromatography-tandem mass spectrometry. Patients were grouped according to skeletal involvement, which was defined as the presence of one or more FDG-avid lesions on a diagnostic FDG-PET/CT scan. Protein profiles identified patients with skeletal disease at diagnosis and showed disrupted cellular pathways, including immune system processes, cell adhesion, and cell growth/survival. Immunohistochemical evaluation also demonstrated differential expressions of angiotensin-converting enzyme (ACE), intercellular adhesion molecule 3 (ICAM3), integrin alpha-X (ITGAX), and calreticulin (CALR). In conclusion, proteomics identified altered protein expression profiles in lymph nodes among CHL cases presenting with disease disseminated to the skeletal system, which implies altered disease pathogenesis for these patients.

Labor market affiliation of patients with myeloproliferative neoplasms: a population-based matched cohort study.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. MATERIAL AND METHODS: We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis. RESULTS: The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. CONCLUSION: Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.

Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study.

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.

Cumulative anthracycline exposure and risk of cardiotoxicity; a Danish nationwide cohort study of 2440 lymphoma patients treated with or without anthracyclines.

Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline-containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4·6% after 3-5 cycles of R-CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate.

Metformin use and risk of myeloproliferative neoplasms: a Danish population-based case-control study.

ABSTRACT: Previous studies have suggested that metformin has beneficial effects beyond its glucose-lowering properties, particularly in terms of its potential as an antineoplastic and cancer-preventive agent. In this study, we aimed to investigate the association between metformin use and the risk of myeloproliferative neoplasms (MPN). We conducted a population-based case-control study using Danish registers. Cases with MPN diagnosed between 2010 and 2018 were identified, and metformin use before the MPN diagnosis was ascertained. We compared metformin use among cases with MPN and an age- and sex-matched control group from the Danish general population to estimate age- and sex-adjusted odds ratios (ORs) and fully adjusted ORs (aORs) for the association between metformin use and risk of MPN. The study population included 3816 cases and 19 080 controls. Overall, 7.0% of cases and 8.2% of controls were categorized as ever-users of metformin, resulting in an OR for MPN of 0.84 (95% confidence interval [CI], 0.73-0.96) and an aOR of 0.70 (95% CI, 0.61-0.81). Long-term metformin use (≥5 years) was more infrequent and comprised 1.1% of cases and 2.0% of controls, resulting in an OR of 0.57 (95% CI, 0.42-0.79) and an aOR of 0.45 (95% CI, 0.33-0.63). A dose-response relationship was observed when cumulative duration of treatment was analyzed, and this was consistent in stratified analyses of sex, age, and MPN subtypes. In conclusion, metformin use was associated with significantly lower odds of an MPN diagnosis, indicating its potential cancer-preventive effect. Given the retrospective design, causality cannot be inferred.

Use of statins and risk of myeloproliferative neoplasms: a Danish nationwide case-control study.

Previous studies have indicated a possible cancer-protective effect of statins in solid cancers; however, this has never been investigated in myeloproliferative neoplasms (MPNs). We aimed to investigate the association between statin use and the risk of MPNs in a nested nationwide case-control study, using Danish national population registries. Information on statin use was obtained from the Danish National Prescription Registry, and patients diagnosed with MPNs between 2010 and 2018 were identified from the Danish National Chronic Myeloid Neoplasia Registry. The association between statin use and MPNs was estimated using age- and sex-adjusted odds ratios (ORs) and fully adjusted ORs (aORs), adjusting for prespecified confounders. The study population included 3816 cases with MPNs and 19 080 population controls (5:1) matched for age and sex using incidence density sampling. Overall, 34.9% of the cases and 33.5% of the controls ever used statins, resulting in an OR for MPN of 1.07 (95% confidence interval [CI], 0.99-1.16) and an aOR of 0.87 (95% CI, 0.80-0.96), respectively. 17.2% were categorized as long-term users (≥5 years) among the cases compared with 19.0% among controls, yielding an OR for MPN of 0.90 (95% CI, 0.81-1.00) and an aOR of 0.72 (95% CI, 0.64-0.81). Analysis of the effect of the cumulative duration of statin use revealed a dose-dependent response, and the association was consistent for sex, age, and MPN subgroups and across different statin types. Statin users were associated with significantly lower odds of being diagnosed with an MPN, indicating a possible cancer-preventive effect of statins. The retrospective of this study precludes causal inferences.

[Elevated blood cell counts and vascular disease with the myeloproliferative neoplasms as model diseases].

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.

Protein-enriched diet increases water absorption via the aquaporin-2 water channels in healthy humans.

BACKGROUND: According to animal experiments, a protein-enriched diet increased renal absorption of sodium and water. We wanted to test the hypothesis that a protein-enriched diet would increase the expression of the aquaporin-2 water channels and the epithelial sodium channels in the distal part of the nephron using biomarkers for the activity of the two channels. METHODS: We performed a randomized, placebo controlled crossover study in 13 healthy humans to examine the effect of a protein-enriched diet on renal handling of water and sodium during baseline condition and during hypertonic saline infusion. We measured the effect of the protein-enriched diet on urinary excretions of aquaporin-2 (u-AQP2), the beta-fraction of the epithelial sodium channels (u-ENaC(beta)), free water clearance (C(H2O)), fractional excretion of sodium and vasoactive hormones. RESULTS: During baseline conditions, u-AQP2 increased, and C(H2O) decreased during the protein-enriched diet, whereas u-ENaC(beta) was unchanged, although the urinary sodium excretion increased. During hypertonic saline infusion, the response in the effect variables did not deviate between protein-enriched and normal diet. Plasma concentrations of angiotensin II and aldosterone increased as well as pulse rate. Vasopressin in plasma was unchanged, and prostaglandin E(2) fell during the protein-enriched diet. CONCLUSIONS: The protein-enriched diet increased water absorption via an increased transport via the aquaporin-2 water channels. The increased u-AQP2 might be due to a reduced prostaglandin level. The increase in renal sodium excretion seems to be mediated in another part of the nephron than the epithelial sodium channels.

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels.

BACKGROUND: Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels. METHODS: The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2), the beta-fraction of the epithelial sodium channel (u-ENaCbeta), cyclic-AMP (u-cAMP), prostaglandin E2 (u-PGE2). Free water clearance (CH2O), fractional excretion of sodium (FENa), and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide. RESULTS: Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher. CONCLUSION: During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system TRIAL REGISTRATION: Clinical Trials Identifier: NCT00281762.

Increased risk of osteoporosis following commonly used first-line treatments for lymphoma: a Danish Nationwide Cohort Study.

High-dose prednisolone is used in first-line treatment for lymphoma, but the potential adverse impact on bone health is unclear. Danish patients with diffuse large B-cell lymphoma or follicular lymphoma diagnosed between 2000 and 2012 were matched to the background population. Osteoporotic events (osteoporosis treatment or low-energy fracture) were identified using the Danish National Patient Registry and Prescription Registry. In total, 2589 patients and 12,945 controls were included. Lymphoma patients had increased risk of osteoporotic events compared to the matched population (hazard ratio 1.61 [95% confidence interval 1.40;1.84]). The 5- and 10-year cumulative risks of osteoporotic events for lymphoma patients were 10.0% [8.6;11.4] and 16.3% [13.8;18.7], whereas corresponding risks in the background population were 6.8% [6.3;7.3] and 13.5% [12.4;14.6]. Patients without osteoporotic event in the first two years after treatment were not at higher risk of osteoporotic events in subsequent years. Risk factors for osteoporotic events were female sex and age >70 years.

Effects of statins on renal sodium and water handling: acute and short-term effects of atorvastatin on renal haemodynamics, tubular function, vasoactive hormones, blood pressure and pulse rate in healthy, normocholesterolemic humans.

BACKGROUND: Statins have a beneficial effect on cardiovascular morbidity and mortality due to a reduction in plasma cholesterol. However, statins seem to have effects beyond the lowering of plasma cholesterol. We hypothesize that these effects are caused by an effect on renal function. METHODS: We measured the effects of atorvastatin (AS) on renal function in two randomized, placebo-controlled, double-blinded and crossover studies in healthy man. In an acute trial (Study 1), 19 subjects received either 80 mg AS as a single dose or placebo. In a short-term trial (Study 2), 20 subjects received either 80 mg AS or placebo daily for 4 weeks. In both studies glomerular filtration rate (GFR), renal plasma flow (RPF), plasma concentrations of angiotensin II (Ang II), renin (PRC), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), aldosterone (Aldo), vasopressin (AVP) and blood pressure (BP) were determined. RESULTS: In Study 1 AS decreased fractional excretion of sodium (FE(Na)) significantly (P = 0.035), but very modestly, and reduced diastolic BP (P = 0.024). Apart from this, we found no significant differences in GFR, RPF, tubular function and vasoactive hormones in either Study 1 or 2. CONCLUSIONS: An acute dose of AS decreased FE(Na) and DBP in healthy humans. The reduction in fractional urinary sodium excretion was very modest and transitory, and most likely secondary to the fall in diastolic blood pressure (DBP). However, renal haemodynamics, tubular function, vasoactive hormones and blood pressure were unchanged during short-term statin treatment in healthy man.

[Status and perspectives on chronic myeloproliferative neoplasm treatment]. / Status og perspektiver for behandling af de kroniske myeloproliferative neoplasier.

Polycythaemia vera, essential thrombocytosis and primary myelofibrosis are closely related, clonal myeloproliferative neoplasms. Our knowledge of the underlying molecular mechanisms driving these diseases has increased dramatically during the latest ten years. Traditionally, treatment of these malignancies has focused on lowering their inherent thromboembolic risk but with the discovery of the JAK2-V617F mutation and most recently the calreticulin mutations new therapeutic options such as interferon-alpha, JAK2-inhibitors and statins are being contemplated. This article reviews these new treatment options.

Down-regulation of urinary AQP2 and unaffected response to hypertonic saline after 24 hours of fasting in humans.

BACKGROUND: In rats, 24 hours of fasting impairs urinary concentrating ability by down-regulation of aquaporin-2 (AQP2). We tested the hypothesis that 24 hours of fasting in humans reduces the capability to form AQP2 and impairs the antidiuretic response to hypertonic saline infusion. METHODS: In a crossover study of 14 healthy subjects, the effect of 24 hours of fasting was compared to a nonfasting control experiment on urinary excretion of AQP2 (u-AQP2), free water clearance (C(H(2)O)), plasma arginine vasopressin (AVP), urinary cyclic AMP (u-cAMP), and natriuretic peptides. The following response to 3% sodium infusion was measured using the same effect variables. U-AQP2, AVP, and u-cAMP were determined by radioimmunoassays. RESULTS: Fasting during 24 hours reduced u-AQP2 (14%), increased AVP (30%) despite a reduction in serum osmolality (P < 0.05), and depleted volume. C(H(2)O) and urine volume were not reduced, thus relatively increased after fasting. u-cAMP was not significantly different between the two procedures. Three percent saline resulted in the same relative increases in AVP, serum osmolality, u-AQP2, and u-cAMP and decreases in C(H(2)O) and urine volume independently of fasting. The reduced u-AQP2 and increased AVP after fasting were maintained during and after saline infusion. CONCLUSION: Twenty-four hours of fasting decreased u-AQP2 and reduced urine osmolality likely as a result of decreased sensitivity of collecting duct cells to AVP. Fasting-related insensitivity of collecting duct cells to AVP was restored by 3% saline infusion. Finally, after saline infusion, other factors such as the increased plasma atrial natriuretic peptide (p-ANP) levels could contribute to the u-AQP2 regulation.