Tony Frisk

Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids.

Carcinoid tumors are rare neuroendocrine tumors occurring in the lung or in the digestive tract where they are further subclassified as foregut, midgut, or hindgut carcinoids. To gain a better understanding of the genetic basis of the different types of carcinoid tumors, we have characterized numerical imbalances in a series of midgut carcinoids, and compared the results to previous findings in carcinoids from the lung. Numerical imbalances were revealed in 16 of the 18 tumors, and the most commonly detected aberrations were losses of 18q22-qter (67%), 11q22-q23 (33%), and 16q21-qter (22%), and gain of 4p14-qter (22%). The total number of alterations found in the metastases was significantly higher than in the primary tumors, indicating the accumulation of acquired genetic changes in the tumor progression. Losses of 18q and 11q were present both in primary tumors and metastases, whereas loss of 16q and gain of 4 were only detected in metastases. Furthermore, the pattern of comparative genomic hybridization alterations varied depending on the total number of detected alterations. Taken together, the findings would suggest a progression of numerical imbalances, in which loss of 18q and 11q represent early events, and loss of 16q and gain of 4p are late events in the tumor progression of midgut carcinoids. When compared to previously published comparative genomic hybridization abnormalities in lung carcinoids, loss of 11q was found to occur in both tumor types, whereas loss of 18q and 16q and gain of 4 were not revealed in lung carcinoids. The results indicate that inactivation of a putative tumor suppressor gene in 18q22-qter represents a frequent and early event that is specific for the development of midgut carcinoids.

Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer

Germline mutations in the tumor‐suppressor gene PTEN (MMAC1, TEP1) are found in Cowden syndrome, which predisposes to hamartomas, breast cancer, trichilemmomas, and thyroid tumors of follicular epithelium. PTEN has also been found to be somatically deleted, mutated, and/or silenced in various sporadically occurring cancers such as glioblastoma, breast cancer, kidney cancer, malignant melanoma, and endometrial cancer. Loss or reduction of PTEN protein expression as well as inappropriate subcellular compartmentalization is seen in non‐medullary thyroid cancers. However, although allelic loss of the PTEN locus in 10q23.3 is frequently seen, this is not coupled with mutations in the PTEN gene. To approach further the frequency and mechanism behind PTEN silencing, we screened a panel of 87 sporadic thyroid tumors for PTEN mRNA expression, including 14 anaplastic carcinomas, 37 follicular carcinomas, 21 atypical adenomas, and 15 ordinary adenomas. Complete loss of PTEN mRNA expression was evident in six of the tumors, including four anaplastic carcinomas, one widely invasive carcinoma, and one ordinary adenoma. The transcriptional silencing of PTEN was significantly associated with the anaplastic subtype, suggesting that PTEN is involved in the carcinogenesis of highly malignant or late‐stage thyroid cancers, whereas this particular mechanism appears to be of minor importance in differentiated follicular thyroid tumors. No association was observed between the expression, loss of heterozygosity, and mutation status in the 33 cases in which these parameters were compared. This indicates that PTEN silencing is a result of a wide variety of epigenetic and/or structural silencing mechanisms rather than a consequence of structural biallelic inactivation of the classical type. Furthermore, the high rate of alterations in the 10q23 region might indicate the presence of an as‐yet unknown tumor‐suppressor gene with an important role in the development of thyroid tumors.

Low frequency of numerical chromosomal aberrations in follicular thyroid tumors detected by comparative genomic hybridization

Follicular thyroid tumors vary from adenomas to widely invasive carcinomas, and a stepwise progression from normal thyrocyte to malignant tumor has been suggested to be due to an accumulation of genetic alterations. We have used comparative genomic hybridization to screen 21 follicular thyroid tumors (8 adenomas and 13 carcinomas) for gains and losses of DNA sequence copy numbers. In general, the tumors showed few alterations involving several different chromosomal regions. The frequency of alterations was similar in the benign (mean, 1.9) and malignant (mean, 1.5) tumors, as well as in minimally (mean, 1.5) and widely invasive carcinomas (mean, 1.6). However, specific loss of 9q13–q21.3 was detected in three tumors, which were all carcinomas showing oxyphilic changes (Hürthle cell carcinomas; P = 0.003). The fact that DNA copy number alterations were found with a similarly low frequency in both benign and malignant follicular thyroid tumors does not support the hypothesis of a multistep tumor progression in these tumors. Genes Chromosomes Cancer 25:349–353, 1999.

Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.

Management of rivaroxaban or apixaban associated major bleeding with prothrombin complex concentrates: a cohort study

There is uncertainty regarding the effectiveness and occurrence of thromboembolic events in patients treated with prothrombin complex concentrates (PCCs) for the management of major bleeding events (MBEs) on rivaroxaban or apixaban. We investigated the effectiveness of PCCs given for the management of MBEs in patients on rivaroxaban or apixaban. Between 1 January 2014 and 1 October 2016, we prospectively included patients on rivaroxaban or apixaban treated with PCCs for the management of MBEs. The effectiveness of PCCs was assessed by using the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria for the assessment of the effectiveness of major bleeding management. The safety outcomes were thromboembolic events and all-cause mortality within 30 days after treatment with PCCs. A total of 84 patients received PCCs for the reversal of rivaroxaban or apixaban due to a MBE. PCCs were given at a median (interquartile range) dose of 2000 IU (1500-2000 IU). Intracranial hemorrhage (ICH) was the most common site of bleeding requiring reversal (n = 59; 70.2%), followed by gastrointestinal bleeding in 13 (15.5%) patients. Management with PCCs was assessed as effective in 58 (69.1%) patients and ineffective in 26 (30.9%) patients. Most patients with ineffective hemostasis with PCCs had ICH (n = 16; 61.5%). Two patients developed an ischemic stroke, occurring 5 and 10 days after treatment with PCC. Twenty-seven (32%) patients died within 30 days after a MBE. The administration of PCCs for the management of MBEs associated with rivaroxaban or apixaban is effective in most cases and is associated with a low risk of thromboembolism. Our findings are limited by the absence of a control group in the study.

Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) have several risk factors for deep venous thromboses (DVTs) such as central venous catheters and asparaginase (ASP), related antithrombin (AT) deficiency. After introduction of a new standard and intermediate-risk ALL treatment protocol with prolonged continuous ASP treatment, two symptomatic DVTs in 10 patients were observed at the Childrens Hospital, Helsinki, Finland. To prevent further thrombotic complications yet ensuring continuous exposure to ASP, an AT substitution strategy was adopted in Helsinki. The same ALL treatment protocol is used without AT substitution in the other Nordic countries. In this retrospective study, we describe the effect of prolonged ASP treatment on AT and fibrinogen levels in children without AT substitution in Stockholm, Sweden (n = 39) and the AT substitution in children with AT activity below 0.55 kIU/l in Helsinki (n = 36, intervention group). The intervention group is compared with children treated similarly earlier in Helsinki without AT substitution (n = 10). The median lowest AT activity during the ASP treatment without AT substitution was 0.55 kIU/l. Fibrinogen level of 1.0 g/l or less was found in 14% of all routine samples during the ASP treatment. In the intervention group, 23 (64%) received AT concentrate. Two (20%) children had symptomatic DVT before initiation of the AT substitution and two (6%) thereafter. We conclude that most children are exposed to low AT activity during ASP treatment predisposing to thrombosis. The effect of prophylactic AT substitution remains unclear.

Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study

Essentials Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15–17 years. A TE‐associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment.

Malignant Fibrous Histiocytoma, Aggressive Fibromatosis and Benign Fibrous Tumors Express mRNA for the Metalloproteinase Inducer EMMPRIN and the Metalloproteinases MMP-2 and MT1-MMP.

Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to stimulate fibroblasts to production of matrix metalloproteinases (MMPs). MMPs comprise a family of proteolytic enzymes implicated in the degradation of extracellular matrix which has been proposed to be one of the essential steps in tumor invasion and metastases. In the present study we investigated the expression and location of mRNAs for EMMPRIN, matrix metalloproteinase-2 (MMP-2), and membrane-type 1 matrix metalloproteinase (MT1-MMP) in mesenchymal tumors with different tendencies to recur or metastasize. Subjects: Eight malignant fibrous histiocytomas (MFH), seven aggressive fibromatosis (AF), and six benign fibrous tumors (BF). Method: The mRNA-expression of EMMPRIN, MMP-2 and MT1-MMP were studied using mRNA in situ hybridization technique. Results: The mRNA-expression of EMMPRIN, MMP-2 and MT1-MMP respectively were found at varying frequency and level in all tumor types. The mRNAs corresponding to EMMPRIN and MMP-2 were seen in neoplastic cells as well as in endothelial cells both inside and outside the tumor pseudo-capsule, whereas MT1-MMP was seen only within the tumors. The estimated mRNA levels of EMMPRIN and MMP-2 covariated significantly. Overall, the highest expression was found in the MFH tumors and the lowest levels in the BF tumors. Discussion: These findings suggest that the MMP-inducer EMMPRIN and the extracellular matrix degrading system involving the metalloproteinases MMP-2 and MT1-MMP is frequently activated in mesenchymal tumors. The covariation between EMMPRIN and MMP-2 support previous findings that EMMPRIN may be an inducer of MMP-2. The high levels of MMP-2 mRNA in MFH indicate a relationship between the proteolytic activity of MMP-2 and the tumor aggressiveness.

Perioperative haemostasis in children with haemophilia and inhibitors during central venous catheter surgery: The Karolinska model

national tender process with higher prices per unit for standard FVIII and FIX concentrates, the absence of difference in price per unit for standard FVIII and EHLFVIII concentrates, the only recent introduction of a network of certified haemophilia treatment centres, and the absence of a national registry (and associated collection of patient data, as performed for decades within the UK health system by the UKHCDO) all influence how EHLs will be integrated into clinical practice in Belgium, and their potential impact on patient management. UKHCDO guidance provides a robust framework to agree an approach to the use of EHL CFCs in routine clinical practice. This framework should be reviewed in the context of each country ’ s unique healthcare system and adapted accordingly.

Venous thrombosis in children and adolescents with Hodgkin lymphoma in Sweden

INTRODUCTION Pediatric patients with Hodgkin lymphoma (HL) have several risk factors for venous thromboembolism (VTE). Although these patients are occasionally treated with thromboprophylaxis, no guidelines are implemented in Sweden. Scarce data from adult patients indicate an increased risk of VTE, but pediatric data is largely missing. Given the favorable overall survival of HL, there should reasonably be more focus on preventing complications. MATERIALS AND METHODS We conducted a retrospective cohort study, including all patients registered in the Childhood Cancer Registry under the age of 18years diagnosed with HL between January 2005 and December 2015 in Sweden. RESULTS Data was retrieved from the medical records of all 163 patients (100%) at six Swedish pediatric cancer centers. The incidence of VTE was 7.7% (symptomatic VTE 3.9%). The median follow-up was 3.4years (range 0.3-10.5). Only five patients (3.1%) were treated with thromboprophylaxis. All VTE events occurred in the older age category (11-17years) and all but one (92.7%) had a mediastinal mass. While the VTE did not significantly affect the treatment of HL, it caused increased morbidity and 2/12 developed a post-thrombotic syndrome. No significant risk factors for VTE were identified. CONCLUSIONS VTE is a relatively common complication of HL and its treatment, causing increased acute and long-term morbidity. However, due to limited number of events we could not demonstrate risk-factors for VTE that would identify patients who might benefit from thromboprophylaxis.