Robert Schou Pedersen

Effect of exercise on natriuretic peptides in plasma and urine in chronic heart failure

BACKGROUND Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in chronic heart failure (CHF). ANP is known to be increased during exercise in healthy subjects and CHF, while the response in BNP during exercise is less clear and does not exist in C-type natriuretic peptide (CNP) and aquaporin-2 (AQP2) in either healthy subjects or CHF. METHODS Eleven patients with CHF and eleven healthy subjects performed a maximal aerobic exercise test. ANP and BNP in plasma were determined every 3 min and at maximum exercise by radioimmunoassay (RIA) and CNP and AQP2 in urine were determined before and after the exercise test by RIA. RESULTS The absolute increase in BNP during exercise was higher in patients with CHF (CHF: 4.1 pmol/l; healthy subjects: 1.3 pmol/l, P<0.05) and was positively correlated to BNP at rest (P<0.05), while the absolute increase in ANP during exercise was the same in the two groups (CHF: 4.2 pmol/l; healthy subjects: 6.8 pmol/l, not significant, NS). In CHF, exercise did not change either u-CNP excretion (rest: 9.8 ng/mmol creatinine; after exercise: 8.8 ng/mmol, NS) or u-AQP2 (rest: 466 ng/mmol creatinine; after exercise: 517 ng/mmol creatinine, NS) as well as in healthy subjects where u-CNP (rest: 9.7 ng/mmol creatinine; after exercise: 9.2 ng/mmol creatinine) and u-AQP2 (rest: 283 ng/mmol creatinine; after exercise: 307 ng/mmol creatinine) were the same at rest and after exercise. CONCLUSION The absolute increase in BNP during exercise is higher in patients with CHF compared to healthy subjects. It is suggested that this is a compensatory phenomenon to improve the exercise capacity in CHF, and that BNP is a more important factor in cardiovascular homeostasis during exercise in CHF than ANP.

Abnormal rhythmic oscillations of atrial natriuretic peptide and brain natriuretic peptide in heart failure.

The purpose of this study was to clarify whether the secretions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are pulsatile in patients with chronic heart failure (CHF), and whether the rhythmic oscillations for ANP and BNP are abnormal in patients with CHF. Several reports have shown that ANP and especially BNP are valuable indicators of the prognosis in CHF. Previously, a pulsatile secretion has been described for ANP and BNP in healthy humans and for ANP in CHF patients. More information about the secretion pattern of BNP in heart failure is necessary to increase the clinical usefulness of BNP in patients with CHF. Patients with left ventricular systolic dysfunction and CHF ( n =12) and controls ( n =12) were investigated. Plasma ANP and BNP levels were determined every 2 min during a 2-h period by radioimmunoassay and analysed for pulsatile behaviour by Fourier transformation. All patients and controls had significant rhythmic oscillations in plasma ANP levels, and 11 patients with CHF and 10 controls had significant rhythmic oscillations in plasma BNP levels. The amplitude of the main frequency was considerably higher in patients with CHF than in controls (ANP: CHF, 4.76 pmol/l; controls, 0.75 pmol/l; P <0.01. BNP: CHF, 3.24 pmol/l; controls, 0.23 pmol/l; P <0.001; all values are medians), but the main frequency did not differ significantly between the group with CHF and the control group for either ANP or BNP. Patients with CHF demonstrate pulsatile secretion of ANP and BNP with a much higher absolute amplitude, but with the same main frequency as healthy subjects.

Smoldering multiple myeloma risk factors for progression: a Danish population‐based cohort study

Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single‐center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population‐based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M‐protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high‐risk of transformation to MM. Using only immunoparesis and M‐protein ≥30 g/L, we created a scoring system to identify low‐, intermediate‐, and high‐risk SMM. This first population‐based study of patients with SMM confirms that an M‐protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM.

Causes of early death in multiple myeloma patients who are ineligible for high-dose therapy with hematopoietic stem cell support: A study based on the nationwide Danish Myeloma Database

To the Editor: Hodgkin lymphoma (HL) is a B-cell derived lymphoid malignancy that accounts for about 10% of all lymphomas. Despite most of patients being cured by modern regimens of chemotherapy and radiotherapy (RT), nearly 20% show primary refractoriness or relapse after initial remission. In these cases second-line chemotherapy followed by autologous stem cell transplantation (ASCT) consolidation leads in nearly 50% of patients to a long lasting remission. For patients with HL relapsed/refractory (R/R) to more than two lines of therapy, there is no standard approach and prognosis is generally dismal. Therapeutic options include palliative chemotherapy, radiotherapy, and transplant procedures. More recently, Brentuximab Vedotin (BV), an anti-CD30 monoclonal antibody conjugated with Auristatin, showed therapeutic activity in 75% of patients with HL R/R to ASCT, with 35% complete response (CR) and median progression-free survival (PFS) of nearly 6 months [1]. Limited data are available regarding the combination of BV with chemotherapeutic agents while, the combination of BV with RT has not been reported so far. A 45-year-old male, with no significant comorbidities, was referred at our Centre on August 2013 for onset of multiple lympho-adenopaties (size varying from 2 to 7 cm and involving bilateral the cervical area and the right axillary) associated with fever, night sweats, fatigue, mild cough, and mild skin itching. Total white blood cell count was 39 3 10/L (90% neutrophils, 4% lymphocytes), while hemoglobin and platelet count were 98 g/L and 635 3 10/L, respectively; erythrocyte sedimentation rate was 91 mm/hr. After lateral cervical lymphonode biopsy and standard staging, the patient was diagnosed to have a sclero-nodular, classic HL, stage IIIs (spleen) B. The patient was started on standard ABVD chemotherapy program (Dacarbazine, Bleomycin, Vinblastine, and Doxorubicin) with rapid resolution of systemic symptoms and lymphonodes disappearance. A CT-PET evaluation after two cycles showed a picture of response with FDG uptake lower than liver (Deauville Score 3). After the fourth planned ABVD course, the patient had evidence of supradiaphragmatic progression with recurrence of right supraclavicular, axilla, and mediastinal involvement. A lymphonode biopsy confirmed the initial diagnosis of scleronodular classic HL. The patient was treated in December 2013 and January 2014 with one course of IGEV (Vinorelbine, Ifosfamide, Metilprednisolone and Gemcitabine) and one course of DHAP chemotherapy (Dexamethasone, Cisplatin, Cytosine Arabinoside) each, with no response and further clinical and radiological evidence of rapid progression with reappearance of fever, itching, and lymphoadenopaties in all supradiaphragmatic areas with bulky right axillary involvement (12 cm 3 10 cm). Based on the disease’s status of chemoresistance, a haploidentical stem cell transplant (SCT) with the patient’s sister was considered. To induce a pre-transplant condition of response, and because of the high level of aggressiveness of the disease with rapid lymphnodes enlargement, a combination treatment with BV and extended field (EF) RT was started. From February to April 2014 the patient received four administrations of BV (1.8 mg/kg) every 21 days with concomitant classical mantle field RT at a dose of 36 Gy in 20 fractions. Hematological toxicity experienced during the therapy was mild, with Grade 2 anemia only after course 1 and 2, and no neutropenia or thrombocytopenia. There were no infective complication or any other major adverse effects to BV or RT, and, in particular, no clinical or functional signs of pulmonary toxicity. The patient showed rapid resolution of the clinical symptoms and progressive and gradual decrease of the size of’ the right axillary lymphoadenopathy. Pretransplant restaging documented a partial response status (according to Cheson 2007) due to the persistence of a residual single right axillary lymphoadenopathy of 3 cm in size. This status of improvement allowed, in May 2014, to proceed with haplo-identical SCT with no major complications. At present, 6 months after the end of BV plus EF-RT and 5 months after SCT, the patient is in good clinical conditions and in a complete response status. Patients with R/R HL have a poor prognosis and no standard treatment has been established so far. Allogeneic SCT seems to be a suitable treatment option for patients with a pre-SCT response condition, with nearly 30–40% PFS. Due to the good safety profile, BV is frequently associated with other systemic therapies. In our patient, the association of BV with EF RT allowed the patient to receive subsequent consolidation treatment with haplo-identical SCT. Further studies investigating the combination of RT with BV in HL are warranted.

A population-based study of prognosis in advanced stage follicular lymphoma managed by watch and wait

Watch and wait (WAW) is a common approach for asymptomatic, advanced stage follicular lymphoma (FL), but single‐agent rituximab is an alternative for these patients. In this nationwide study we describe the outcome of patients selected for WAW. A cohort of 286 out of 849 (34%) stage III‐IVA FL patients seen between 2000 and 2011, were managed expectantly and included. The 5‐year progression‐free survival (PFS) was 35% [95% confidence interval (CI) 29–42]. The 10‐year overall survival (OS) was 65% (95%CI 54–78), and the cumulative risk of dying from lymphoma within 10 years of diagnosis was 13% (95%CI 7–20). Elevated lactate dehydrogenase and > four nodal regions involved were associated with a higher risk of lymphoma treatment and death from lymphoma. The WAW patients and a matched background population had similar OS during the first 50 months after diagnosis (P = 0·7), but WAW patients had increased risk of death after 50 months (P < 0·001). The estimated loss of residual life after 10 years was 6·8 months. The 10‐year cumulative risk of histological transformation was 22% (95%CI 15–29) and the 3‐year OS after transformation was 71% (95%CI 58–87%). In conclusion, advanced stage FL managed by WAW had a favourable outcome and abandoning this strategy could lead to overtreatment in some patients.

The Danish National Multiple Myeloma Registry

Aim The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim is to support research. Patients are registered with their unique Danish personal identification number, and the combined use of DMMR, other Danish National registries, and the Danish National Cancer Biobank offers a unique platform for population-based translational research. Study population All newly diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. Main variables The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events, clinical complications, prognostics, first- and second-line treatments, treatment responses, progression free, and overall survival. Descriptive data Up to June 2015, 2,907 newly diagnosed patients with MM, 485 patients with smoldering MM, 64 patients with plasma cell leukemia, and 191 patients with solitary plasmacytomas were registered. Registration completeness of new patients is ~100%. A data validation study performed in 2013–2014 by the Danish Myeloma Study Group showed >95% data correctness. Conclusion The DMMR is a population-based data validated database eligible for clinical, epidemiological, and translational research.

A clinically based prognostic index for diffuse large B-cell lymphoma with a cut-off at 70 years of age significantly improves prognostic stratification: Population-based analysis from the Danish Lymphoma Registry

The introduction of rituximab and generally improved health among elderly patients have increased the survival of patients with diffuse large B-cell lymphoma (DLBCL). The International Prognostic Index (IPI) from 1992 is based on pre-rituximab data from clinical trials including several lymphoma subtypes. We applied IPI factors to a population-based rituximab-treated cohort of 1990 patients diagnosed 2000–2010 and explored new factors and the optimal prognostic age cut-off for DLBCL. Multivariate-analyses (MVA) confirmed the prognostic value of all IPI factors except the presence of > 1 extranodal lesion. The optimal age cut-off was 70 years. In a MVA of albumin, lymphocyte count, sex, immunoglobulin G, bulky disease, hemoglobin and B-symptoms, only albumin was prognostic. We propose: (1) a modified DLBCL prognostic index (DLBCL-PI) including: age (70 years), performance status (PS), lactate dehydrogenase (LDH), stage and albumin level, and (2) a separate age-adjusted DLBCL-PI for patients ≤ 70 years including PS, LDH, albumin level and > 1 extranodal lesion, however excluding stage.

The Danish National Acute Leukemia Registry

Aim of database The main aim of the Danish National Acute Leukemia Registry (DNLR) was to obtain information about the epidemiology of the hematologic cancers acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Study population The registry was established in January 2000 by the Danish Acute Leukemia Group and has been expanded over the years. It includes adult AML patients diagnosed in Denmark since 2000, ALL patients diagnosed since 2005, and MDS patients diagnosed since 2010. The coverage of leukemia patients exceeds 99%, and the coverage of MDS patients is currently 90%. Main variables and descriptive data Approximately, 250 AML patients, 25 ALL patients, and 230 MDS patients are registered in the DNLR every year. In January 2015, the registry included detailed patient characteristics, disease characteristics, treatment characteristics, and outcome data on more than 3,500 AML, 300 ALL, and 1,100 MDS patients. Many of the included prognostic variables have been found to be of high quality including positive predictive values and completeness exceeding 90%. These variables have been used in prognostic observational studies in the last few years. To ensure this high coverage, completeness, and quality of data, linkage to the Danish Civil Registration System and the Danish National Registry of Patients, and several programmed data entry checks are used. Conclusion The completeness and positive predictive values of the leukemia data have been found to be high. In recent years, the DNLR has shown to be an important high-quality resource for clinical prognostic research.

Danish National Lymphoma Registry.

Aim of database The Danish National Lymphoma Registry (LYFO) was established in order to monitor and improve the diagnostic evaluation and the quality of treatment of all lymphoma patients in Denmark. Study population The LYFO database was established in 1982 as a seminational database including all lymphoma patients referred to the departments of hematology. The database became nationwide on January 1, 2000. Main variables The main variables include both clinical and paraclinical variables as well as details of treatment and treatment evaluation. Up to four forms are completed for each patient: a primary registration form, a treatment form, a relapse form, and a follow-up form. Variables are used to calculate six result quality indicators (mortality 30 and 180 days after diagnosis, response to first-line treatment, and survival estimates 1, 3, and 5 years after the time of diagnosis), and three process quality indicators (time from diagnosis until the start of treatment, the presence of relevant diagnostic markers, and inclusion rate in clinical protocols). Descriptive data Approximately 23,000 patients were registered in the period 1982–2014 with a median age of 65 years (range: 16–100 years) and a male/female ratio of 1.23:1. Patients can be registered with any of 42 different subtypes according to the World Health Organization classifications. Conclusion LYFO is a nationwide database for all lymphoma patients in Denmark and includes detailed information. This information is used for both epidemiological research and clinical follow-up as well as for administrative purposes.

The Danish National Chronic Lymphocytic Leukemia Registry

Aim In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes. Study population All patients diagnosed with CLL in Denmark from 2008 onward are included in the registry. Patients are followed in one of nine hematology centers. All centers participate in the registry and are all obliged to collect data. Main variables Predefined data are collected at the time of diagnosis, and follow-up at the time of significant events: treatment, progression, transplantation, and death. Parameters included in the International Workshop on Chronic Lymphocytic Leukaemia criteria for diagnosis, and for decision on treatment initiation as well as characteristics included in the CLL International Prognostic Index are collected. Descriptive data To ensure full coverage of Danish CLL patients in the registry, both continuous queries in case of missing data, and cross-referencing with the Danish National Patient Registry are performed. Data from the registry are published in an annual report summarizing the collected data, the overall survival for yearly cohorts, and the degree of data coverage. Per year approximately 450 new patients with CLL are registered in the registry, cumulative as of July 1, 2015, 3,082 patients have been registered. Conclusion The Danish National CLL Registry is based within the Danish National Hematology Database. The registry covers a cohort of all patients diagnosed with CLL in Denmark since 2008. It forms the basis for quality assessment of CLL treatment in Denmark and offers a unique opportunity for population-based research.