Incidence of myeloproliferative neoplasms - trends by subgroup and age in a population-based study in Sweden.

BACKGROUND: The reported incidence of Philadelphia-negative myeloproliferative neoplasms (MPNs) differs substantially between previous reports, likely due to true regional differences in incidence and/or variations in the quality and coverage of the cancer registers. OBJECTIVE: We therefore assessed MPN incidence in Sweden during recent years using prospectively collected information captured in Swedish health registers. METHODS: Patients with MPNs were identified through the Swedish Cancer Register and Swedish Blood Cancer Register between 2000 and 2014. Information on the Swedish population was obtained from the Human Mortality Database. Crude and age-standardized incidence rates of MPNs with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 6281 MPN cases were reported to the Swedish Cancer Register and Swedish Blood Cancer Register during 2000-2014. The age-standardized, to the Swedish population in 2000, incidence for all MPNs was 4.45 (95% confidence interval [CI] 4.34-4.56)/100 000 person-years. The age-standardized incidence for polycythemia vera was 1.48 (1.42-1.54), for essential thrombocythemia 1.60 (1.53-1.66) and for primary myelofibrosis 0.52 (0.48-0.56)/100 000 person-years, respectively. The incidence rate of MPNs was substantially higher in the older compared to the younger age groups. The incidence increased during the study period, likely to do better reporting and increasing age of the general population. CONCLUSION: The reported MPN incidences in our study, which were in the higher interval of previously published studies, are likely more accurate compared to previous reports due to the population-based setting and high level of coverage in the Swedish Cancer and Blood Cancer Registers.

Interferon γ is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells.

B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells. We proved that during combined treatment, inhibition of constitutive signal transducer and activator of transcription (STAT) 5 activation by IM allowed the specific enhancement of the STAT1 dependent, direct upregulation of BCL6 by IFNγ in CML cells. By using colony-forming assay, we found that IFNγ enhanced the ex vivo colony or cluster-forming capacity of human CML stem cells in the absence or presence of IM, respectively. Furthermore, inhibition of the transcriptional repressor function of BCL6 in the presence of IM and IFNγ almost completely blocked the cluster formation of human CML stem cells. On the other hand, by using small interfering RNA knockdown of BCL6, we demonstrated that in an IM-treated CML line the antiapoptotic effect of IFNγ was independent of BCL6 upregulation. We found that IFNγ also upregulated several antiapoptotic members of the BCL2 and BIRC gene families in CML cells, including the long isoform of MCL1, which proved to be essential for the antiapoptotic effect of IFNγ in an IM-treated CML line. Our results suggest that combination of TKIs with BCL6 and MCL1 inhibitors may potentially lead to the complete eradication of CML stem cells.

Assessing nursing students' knowledge and skills in performing venepuncture and inserting peripheral venous catheters.

Venepuncture and the insertion of peripheral venous catheters are common tasks in health care, and training in these procedures is included in nursing programmes. Evidence of nursing students' knowledge and skills in these procedures is limited. The main aim of this study was to assess nursing students' knowledge and skills when performing venepuncture and inserting peripheral venous catheters. Potential associations between level of knowledge and skills, self-training, self-efficacy, and demographic characteristics were also investigated. The assessment was performed by lecturers at a university college in Sweden using the two previously tested instruments "Assess Venepuncture" and "Assess Peripheral Venous Catheter Insertion". Between 81% and 100% of steps were carried out correctly by the students. The step with the highest rating was "Uses gloves", and lowest rating was 'Informs the patients about the possibility of obtaining local anaesthesia'. Significant correlations between degree of self-training and correct performance were found in the group of students who registered their self-training. No associations between demographic characteristics and correct performances were found. Assessing that students have achieved adequate levels of knowledge and skills in these procedures at different levels of the nursing education is of importance to prevent complications and support patient safety.

Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia.

We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

Continued improvement in survival of acute myeloid leukemia patients: an application of the loss in expectation of life.

We evaluated temporal trends in survival of Swedish acute myeloid leukemia (AML) patients diagnosed between 1973 and 2011 using relative survival ratios (RSRs) and a measure called the loss in expectation of life (LEL). RSRs increased most for patients <60 years at diagnosis during the first calendar periods, but between 1997-2005 and 2006-2011 the most pronounced increase was for those aged 61-70 years at diagnosis; RSR changed from 0.16 (95% confidence interval (CI): 0.13-0.19) to 0.28 (95% CI: 0.23-0.33), respectively. The LEL for males aged 35 years at diagnosis was 41.0 (95% CI: 40.1-41.8) years in 1975 and 19.5 (95% CI: 16.4-22.5) years in 2011. For males aged 65 years, the corresponding figures were 13.8 (95% CI: 13.7-14.0) and 12.0 (95% CI: 11.3-12.8). Conditional LEL estimates suggested that patients who survive 5 years postdiagnosis have shorter remaining lifespan than the general population. The proportion of expected life lost (PELL) suggested that male 65-year-old patients lost 75% of their life expectancy in 2005 and 66% if they were diagnosed in 2011. Survival continued to increase to 2011, with larger improvements in those aged 61-70 years at diagnosis. The LEL and PELL are intuitive measures that may be useful in communicating survival statistics to patients, clinicians and health-care providers.

Brain tumors in patients with myotonic dystrophy: a population-based study.

BACKGROUND AND PURPOSE: Patients with myotonic dystrophy (DM) are at high risk of brain cancer. This study describes the spectrum of brain neoplasms in DM patients. METHODS: Data from 1119 DM patients identified from the National Swedish Patient Register between 1987 and 2007 were linked to the National Cancer and the Cause of Death Registers. Standardized incidence ratios (SIRs) and cumulative incidence to quantify the relative and absolute risks of brain neoplasms were calculated and the Kaplan-Meier estimator was used for survival analysis. Patient follow-up started at birth or the age at the start of Swedish cancer registration (1 January 1958) and ended at the age of brain neoplasm diagnosis, death or on 31 December 2007. RESULTS: Twenty patients developed brain neoplasm during follow-up {median age 53, range 2-76 years, accounting for a five-fold excess risk of brain tumors during the patient lifetime [SIR = 5.4, 95% confidence interval (CI) 3.4-8.1, P = 1 × 10(-5) ]}. Astrocytoma was the most common histological subtype (n = 16, 80%), and almost all cases (n = 19) developed after age 20. No statistically significant differences in gender-specific risks (SIR in men 6.3 and in women 3.8, P-heterogeneity 0.46) were observed. After accounting for competing mortality related to DM, the cumulative incidence of brain neoplasms reached 2.9% (95% CI 1.8%-4.7%) by age 70. Five-year survival after brain tumor diagnosis was 52% (95%CI 29%-75%) overall (number at risk 8) and 34% (95% CI 26%-47%) for malignant neoplasms (number at risk 5). CONCLUSION: Despite the high relative risk of DM-related brain tumors, the absolute risk is modest. Nonetheless, careful evaluation of DM patients with new central nervous system symptoms is warranted.

Dendritic cells in bone marrow at diagnosis and after chemotherapy in adult patients with acute myeloid leukaemia.

Dendritic cells (DCs) develop in the bone marrow from haematopoietic progenitor cells. Two subsets, plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), have been identified. Little is known regarding DC levels in bone marrow of patients with acute myeloid leukaemia (AML) before and after chemotherapy. We investigated relative pDC and mDC levels in bone marrow from 37 hospital controls and 60 patients with AML [at diagnosis, complete remission (CR) and follow-up] using four-colour flow cytometry. The pDC immunophenotype was characterized as lin-/HLA-DR+/CD123 +  and mDC as lin-/HLA-DR+/CD11c+. In 69% of patients with AML, no DCs were detected at diagnosis. At CR, mDC levels were the same in patients with AML and hospital controls while pDC levels were slightly lower. There was no association between minimal residual disease or survival rates and DC levels. Patients with low mDC levels at CR were more likely to suffer from complicated infections, although the difference was not statistically significant. Altogether, there was a profound decrease in DC levels in patients with AML at diagnosis. DC levels increased at CR and were higher than in hospital controls after post-remission therapy, suggesting that DCs recover after repeated chemotherapy. There may be an association between mDC levels and infectious complications.

Elevated risk of venous but not arterial thrombosis in Waldenström macroglobulinemia/lymphoplasmacytic lymphoma.

BACKGROUND: Many malignancies, including multiple myeloma and its precursor, monoclonal gammopathy of unknown significant, are associated with an elevated risk of thromboembolism. There is limited information on the risk of thrombosis in patients with Waldenström macroglobulinemia (WM) and lymphoplasmacytic lymphoma (LPL). OBJECTIVES: To assess the risk of venous and arterial thrombosis in WM/LPL patients in a large population-based cohort study in Sweden. PATIENTS/METHODS: A total of 2190 patients with WM/LPL and 8086 matched controls were identified through Swedish registers between 1987 and 2005. Information on occurrence of venous and arterial thrombosis after the diagnosis of WM/LPL was obtained through the centralized Swedish Patient Register, with follow-up to 2006. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Patients with WM/LPL had a significantly increased risk of venous thrombosis and the highest risk was observed during the first year following diagnosis (HR = 4.0, 95% CI 2.5-6.4). The risk was significantly elevated 5 (HR = 2.3, 95% CI 1.7-3.0) and 10 years after diagnosis (HR = 2.0, 95% CI 1.6-2.5). There was no increased risk of arterial thrombosis during any period of follow-up time (10-year HR = 1.0, 95% CI 0.9-1.1). CONCLUSIONS: Venous thrombosis is a significant cause of morbidity in patients with WM/LPL. The potential role of thromboprophylaxis in WM/LPL, especially during the first year after diagnosis and in patients treated with thrombogenic agents, needs to be assessed to further improve outcome in WM/LPL patients.

Telomerase reverse transcriptase inhibition stimulates cyclooxygenase 2 expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects.

BACKGROUND: Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials. Targeting telomerase or hTERT is a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and cyclooxygenase 2 (COX2) and evaluated synergistic anti-cancer effects of targeting both hTERT and COX2. METHODS: hTERT was depleted in gastric and cervical cancer cells using small interfering RNA (siRNA) and analysed for COX2 expression using quantitative PCR and immunoblotting. Viable cells and apoptotic cells in gastric cancer cells treated with hTERT siRNA or/and the COX2 inhibitor celecoxib were measured using Trypen blue exclusion and flow cytometry. The in vivo anti-cancer effect of hTERT depletion or/and celecoxib was evaluated using mouse xenograft models. RESULTS: Knocking down hTERT expression in cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cells. hTERT depletion led to the activation of p38 mitogen-activated protein kinase responsible for the stimulation of COX2 gene transcription. hTERT depletion or celecoxib alone did not affect cancer cell survival, whereas their combination synergistically killed them both in vitro and in vivo. CONCLUSION: hTERT induces COX2 expression and simultaneously targeting hTERT and COX2 synergistically kills cancer cells.

Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study.

BACKGROUND: Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events. PATIENTS AND METHODS: Inclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2-3 and WHO performance score 0-3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years. RESULTS: A total of 156 eligible patients with a median age of 54 years (range 20-64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months. CONCLUSIONS: The results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis. CinicalTrials.gov. identifier NCT01502982.

Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells.

Telomerase activation through induction of telomerase reverse transcriptase (hTERT) contributes to malignant transformation by stabilizing telomeres. Clinical studies demonstrate that higher hTERT expression is associated with cancer progression and poor outcomes, but the underlying mechanism is unclear. Because epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are key factors in cancer metastasis and relapse, and hTERT has been shown to exhibit multiple biological activities independently of its telomere-lengthening function, we address a potential role of hTERT in EMT and CSCs using gastric cancer (GC) as a model. hTERT overexpression promotes, whereas its inhibition suppresses, EMT and stemness of GC cells, respectively. Transforming growth factor (TGF)-ß1 and ß-catenin-mediated EMT was abolished by small interfering RNA depletion of hTERT expression. hTERT interacts with ß-catenin, enhances its nuclear localization and transcriptional activity, and occupies the ß-catenin target vimentin promoter. All these hTERT effects were independent of its telomere-lengthening function or telomerase activity. hTERT and EMT marker expression correlates positively in GC samples. Mouse experiments demonstrate the in vivo stimulation of hTERT on cancer cell colonization. Collectively, hTERT stimulates EMT and induces stemness of cancer cells, thereby promoting cancer metastasis and recurrence. Thus, targeting hTERT may prevent cancer progression by inhibiting EMT and CSCs.

Long-term treatment of invasive sinus, tracheobroncheal, pulmonary and intracerebral aspergillosis in acute lymphoblastic leukaemia.

A 59-year-old male with acute lymphoblastic leukemia developed sinus, tracheobroncheal, pulmonary, and intracerebral aspergillosis. All lesions except the intracerebral aspergillosis healed after combination antifungal treatment. Long-term voriconazole--but not posaconazole--therapy induced partial regression of the cerebral manifestations. At the time of writing, 3.5 years after the initial diagnosis, the patient is working half-time and suffers from a possible voriconazole-induced polyneuropathy.

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma.

BACKGROUND: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. METHODS: We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. RESULTS: In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qalpha, C1Qbeta and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. CONCLUSIONS AND INTERPRETATIONS: We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment.

Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma.

This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965-1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or >or=2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme.

Quality of life before and one year following stem cell transplantation using an individualized and a standardized instrument.

OBJECTIVE: The aim was to prospectively measure quality of life in patients with malignant blood disorders following stem cell transplantation (SCT) using an individualized and a standardized measure. METHODS: Twenty-two consecutive patients were assessed before and one year following SCT, using a generic and disease-related version of the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW) and the EORTC QLQ-C30. Results of the QLQ-C30 were compared with Swedish norm values. RESULTS: A majority of the patients reported concerns related to health before as well as one year after SCT, recorded by both instruments. Mean scores produced by the SEIQoL-DW, and four scales of the EORTC QLQ-C30, showed a change over time, indicating improved quality of life one year after SCT. In comparison with Swedish norm values for the EORTC QLQ-C30, SCT recipients reported a worse functioning. CONCLUSIONS: In addition to well-known disease and treatment-related problems, areas not typically included in standardized instruments were nominated in the disease-related SEIQoL-DW. Such areas included positive aspects, e.g. a changed view of life and oneself. The results support the use of the generic and disease-related SEIQoL-DW to achieve a comprehensive picture of patient's clinical situation under treatment or when recovering from illness.