[A woman in her 60s with multifactorial anaemia]. / En kvinne i 60-årene med kombinert anemi.

Anaemia may be multifactorial in origin. We present a woman with autoimmune hepatitis and secondary warm autoimmune haemolytic anaemia and most likely also concomitant anaemia of chronic disease. A relapse of autoimmune haemolysis was successfully treated with steroids and high-dose intravenous immunoglobulin. At the same time, bleeding from angiodysplasia in the coecum was masked by unauthorised perorally administrated iron. No other cause of bleeding was found. During that period, she required extensive blood transfusions, up to several times per month. Surgical or endoscopic treatment of the bleeding angiodysplasia was not possible. Alloimmunisation developed as a complication to the large number of transfusions, despite the use of steroids. Treatment with somatostatin analogue markedly reduced the need of our patient for blood transfusions for a follow-up period of more than one year, and she has not experienced any side effects. We do not know how long the haemostasis achieved will last, however, we believe that this treatment may be an alternative for other patients as bleeding from angiodysplasia is not uncommon and is often difficult to eradicate.

Familial occurrence of chronic lymphocytic leukaemia in Norway.

BACKGROUND: The only known risk factor for chronic lymphocytic leukaemia (CLL) is occurrence of the disease in close relatives. The aim of this study was to determine the frequency of familial chronic lymphocytic leukaemia. MATERIAL AND METHOD: All patients with chronic lymphocytic leukaemia notified to the Cancer Registry in the period 1.10.2007-31.12.2009 were asked to report occurrences of malignant disease in siblings, parents, grandparents and children. The information about malignant haematological disease was verified with the Cancer Registry. RESULTS: We found malignant haematological disease in close relatives of 42 of the 236 included patients (18%). CLL and lymphoma were the most common diagnoses. On average, 16 family members were identified in each family. The relative risk of developing CLL was six times higher in those who had close relatives with the disease (16 of a total of 3,776 family members) than among those who did not have close relatives who were affected (76 cases among 107,223 family members of 38,159 control subjects). The increased risk of disease was also associated with other lymphoproliferative diseases. With patrilinear, but not matrilinear inheritance, we found a birth order effect, with affection of younger men in a group of siblings, while the eldest escaped. INTERPRETATION: Malignant haematological disease is common in the family members of patients with CLL. CLL is the most common disease, but there is extensive pleiotropy.

Chronic lymphocytic leukaemia in Norway--incidence and prognostic markers at diagnosis.

BACKGROUND: The clinical courses of chronic lymphocytic leukaemia (CLL) are very heterogeneous. Biological markers that provide good prognostic information at the time of diagnosis are available. The aim of the study was to determine the prevalence of these markers in a population-based material. MATERIAL AND METHOD: Biological markers were examined using standard laboratory methods after obtaining an informed consent statement from patients diagnosed with chronic lymphocytic leukaemia in the period 1.10.2007-31.12.2009. RESULTS: There were 388 new cases of chronic lymphocytic leukaemia during the study period, and 236 patients (61%) were included in the study. Of 222 patients, 178 (80%) were in Binet's stage A, 26 (12%) in stage B and 18 (8%) in stage C. The V(H) gene was mutated in 69% and unmutated in 31% of cases. Cytogenetic aberrations were found in 68%: del(13q14) in 48%, trisomy 12 in 13%, del(11q22) in 10% and del(17p13) in 7%. CD38-positive disease was found in 28% of the patients. The V(H) gene was mutated in 67% of the patients in Binet's stage A, and in the majority of these a mutated V(H) gene was associated with non-expression of CD38 and del(13q14). INTERPRETATION: At the time of diagnosis, most patients are asymptomatic and do not need treatment. The biological markers that indicate a favourable prognosis occur most frequently in this group. Markers that indicate a poor prognosis occur more frequently in the group that has symptoms at the time of diagnosis.

Meiotic drive in chronic lymphocytic leukemia compared with other malignant blood disorders.

The heredity of the malignant blood disorders, leukemias, lymphomas and myeloma, has so far been largely unknown. The present study comprises genealogical investigations of one hundred and twelve Scandinavian families with unrelated parents and two or more cases of malignant blood disease. For comparison, one large family with related family members and three hundred and forty-one cases of malignant blood disease from the Faroese population was included. The inheritance is non-Mendelian, a combination of genomic parental imprinting and feto-maternal microchimerism. There is significantly more segregation in maternal than in paternal lines, predominance of mother-daughter combinations in maternal lines, and father-son combinations in paternal lines. Chronic lymphocytic leukemia is the most frequent diagnosis in the family material, and chronic lymphocytic leukemia has a transgenerational segregation that is unique in that inheritance of susceptibility to chronic lymphocytic leukemia is predominant in males of paternal lines. Male offspring with chronic lymphocytic leukemia in paternal lines have a birth-order effect, which is manifest by the fact that there are significantly more male patients late in the sibling line. In addition, there is contravariation in chronic lymphocytic leukemia, i.e. lower occurrence than expected in relation to other diagnoses, interpreted in such a way that chronic lymphocytic leukemia remains isolated in the pedigree in relation to other diagnoses of malignant blood disease. Another non-Mendelian function appears in the form of anticipation, i.e. increased intensity of malignancy down through the generations and a lower age at onset of disease than otherwise seen in cases from the Cancer Registers, in acute lymphoblastic leukemia, for example. It is discussed that this non-Mendelian segregation seems to spread the susceptibility genes depending on the gender of the parents and not equally to all children in the sibling line, with some remaining unaffected by susceptibility i.e. "healthy and unaffected", due to a birth order effect. In addition, anticipation is regarded as a non-Mendelian mechanism that can amplify, «preserve¼ these vital susceptibility genes in the family. Perhaps this segregation also results in a sorting of the susceptibility, as the percentage of follicular lymphoma and diffuse large B-cell lymphoma is lower in the family material than in an unselected material. Although leukemias, lymphomas and myelomas are potentially fatal diseases, this non-Mendelian distribution and amplification hardly play any quantitative role in the survival of Homo sapiens, because these diseases mostly occur after fertile age.

Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL.

To address the proposition that familial B-cell chronic lymphocytic leukemia (CLL) may exhibit a more restricted phenotype than sporadic CLL with respect to immunoglobulin gene usage or ontogenic development, we compared immunoglobulin (Ig) heavy chain variable region (VH) gene usage and IgVH mutation status in 327 patients with CLL from 214 families with 724 patients with sporadic cases. The frequency of mutated CLL was higher in familial CLL (P < .001), and there was evidence of intrafamilial concordance in mutation status (P < .001). The repertoire and frequency of IgVH usage was, however, not significantly different between familial and sporadic CLL. Furthermore, IgVH usage was not correlated between affected members of the same family. These observations provide evidence that familial CLL is essentially indistinguishable from sporadic CLL, favoring a genetic basis to disease development in general rather than a simple environmental etiology.

Familial chronic lymphocytic leukemia in Norway and Denmark. Comments on pleiotropy and birth order.

AIM: To investigate the genetics of chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: In 56 (7%) out of 800 CLL patients with concomitant malignant hematological disease, 51 families and 141 cases were ascertained. RESULT: 106 cases (75%) of CLL, 27 cases (19%) of nonCLL and 8 cases (6%) of myeloproliferative disorders. Paternal disease was transmitted primarily to the youngest sons in the sibship while maternal disease was transmitted equally to all sibs, demonstrated by means of matrix conjugation and confirmed with Cox regression on parity and birth order (maternal-offspring combination: relative risk (RR), 95% confidence interval (CI)=1.47 (0.89 - 2.43), p=0.12, compared with paternal-offspring combination: RR=3.25, 95% CI=(1.57-6.72), p<0.001). The B-cell expression in familial and sporadic CLL was indistinguishable. CONCLUSION: Parental genomic imprinting is pointed out as one possible mechanism behind this non-Mendelian genomic output.

Inheritance of Susceptibility to Malignant Blood Disorders.

Malignant blood disorders depend on heritable susceptibility genes and occur in familial aggregations. We suggest a model of transgenerational segregation of the susceptibility genes based on the study of malignant blood disorders in Norwegian and Danish families with unrelated parents, and in the inbred Faroese population with related parents. This model, consisting of parental genomic imprinting and mother-son microchimerism, can explain the male predominance in most of the diseases, the predominance of affected parent-offspring when parents are not related, and the different modes of segregation in males and females. The model displays a specific pattern in the distribution of affected relatives for each diagnosis, viz. a characteristic distribution in the pedigrees of family members with malignant blood disorder related to the proband. Three such patterns, each reflecting a specific transgenerational passage, were identified: (1) alterations in the number of affected relatives in paternal lines alone, e.g. in patterns for probands with multiple myeloma; (2) alterations in the number of affected relatives in both paternal and maternal lines for probands with chronic lymphocytic leukemia; and (3) no alterations in the numbers of male and female affected relatives in the parental lines, e.g. for probands with some types of malignant lymphoma.

Birth order pattern in the inheritance of chronic lymphocytic leukaemia and related lymphoproliferative disease.

Rank order of affected offspring in a sibship can inform on epigenetic factors in disease susceptibility. Here we report an analysis of birth order in 32 families segregating chronic lymphocytic leukaemia (CLL) and other B-cell lymphoproliferative disorders. A paternal-offspring, but not a maternal-offspring birth rank order was observed. Cox regression analysis provided relative risks (RR) for paternal and maternal transmission of 3.60 (CI 95%: 1.54 - 8.42; P = 0.0005) and 1.64 (CI 95%: 0.90 - 3.01; P = 0.096), respectively. The significance of paternal and maternal transmission of CLL-CLL pairs employing Haldane and Smith's test were 0.006 and 0.63, respectively. There was no evidence of a relationship between parental age and birth order. The genetic mechanism behind the birth order effect observed is discussed in the light of non-Mendelian imprinting and pregnancy related microchimerism.

The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia.

Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) catalyze the first step in the intracellular cascade of fludarabine (2-fluoroadenine-beta-D-arabinofuranoside) and cladribine (2-chlorodeoxyadenosine) phosphorylation, which leads to activation of these prodrugs, commonly used for treatment of chronic lymphocytic leukemia (CLL). Thus, resistance to nucleoside analogues may primarily be due to low levels of deoxynucleoside kinase activity. The purpose of this study was to investigate the activity profiles of dCK and dGK and characterize the possible relationship between the levels of dCK enzymatic activities and mRNA levels in B-CLL cells from untreated patient samples in an attempt to determine the best approach for predicting sensitivity to nucleoside analogues and thereby optimizing treatment of CLL. For this purpose, dCK and dGK analyses were done in blood cells from 59 untreated symptomatic patients with CLL. The dGK activity towards 2-chlorodeoxyadenosine was significantly lower than of dCK (median 73 pmol/mg protein/min (85-121, 95% CI) versus 353 pmol/mg protein/min (331-421)). The median dCK mRNA level was 0.107 (0.096-0.120, 95% CI). There was a lack of correlation between the activities of dCK and dGK, which indicates that these proteins are regulated independently. We also found that the dCK and dGK activity measurement towards their endogenous substrates were comparable to the nucleoside analogues tested. Such variations in enzyme activities and mRNA levels may well explain differences in clinical responses to treatment. There was no correlation between the levels of dCK mRNAs and enzymatic activities using a quantitative real-time PCR procedure. Sequencing of dCK mRNA did not reveal alternate splicing or mutations in the coding region. The relation between activity and mRNA levels was studied by short interfering RNA (siRNA) method, which showed that in the siRNA treated cells the down-regulation of dCK expression, and activity followed each other. However, in control cells the mRNA levels remained stable but the protein activity markedly decreased. These data demonstrate that the dCK activity is not reflected by dCK mRNA expression that indicates a post-translational mechanism(s).

The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia.

To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person-years of follow-up. Autoimmune manifestations were analyzed in 194 women with known obstetric history and known number of long-term sexual partners, and in the 389 male CLL patients for comparison. One hundred and fifty-nine of the CLL patients exhibited autoimmune manifestations, 38% in females and 21% in men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer with parietal cell autoantibodies and idiopathic thrombocytopenic purpura were equally common in women and men, whereas autoimmune thyroiditis, Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus were seen in higher rates in women than in men. The spectrum of autoimmunity suggests that pregnancy-related alloimmunization may be involved in the development of autoimmunity in CLL.

99mTc-aprotinin scintigraphy in amyloidosis.

UNLABELLED: Changes in the amount and distribution of amyloid lesions have been difficult to monitor because they can usually be demonstrated only by evident symptoms or from a biopsy. The recent progress in the treatment of amyloidosis stresses the need for an early diagnosis and the need for noninvasive monitoring during the course of treatment. To validate (99m)Tc-aprotinin scintigraphy, we studied 23 consecutive patients with known or suspected amyloidosis. METHODS: (99m)Tc-Aprotinin (500-700 MBq) was injected intravenously and whole-body scans, regional images, and SPECT tomograms were obtained 90 min after tracer injection. RESULTS: Focal accumulations of (99m)Tc-aprotinin were seen in different organs of 22 patients with a total of 90 lesions, of which 20 were confirmed by biopsy or autopsy. Scintigraphy revealed "silent" amyloid deposits in at least 5 patients who later developed clinical symptoms. Physiologic uptake or excretion in liver and kidneys could not be differentiated from pathologic lesions in those organs. CONCLUSION: (99m)Tc-Aprotinin scintigraphy appears to be a fairly sensitive and specific diagnostic modality in patients with suspected amyloidosis. The technique is noninvasive, and it entails a minimal stress to the patient and is useful for detection of a wide range of lesions.

CD56+ lymphoma with skin involvement: clinicopathologic features and classification.

BACKGROUND: Extranodal lymphomas expressing CD56 (neuronal cell adhesion molecule) are characterized by a high incidence of cutaneous involvement and a very aggressive clinical course. Knowledge about the prognosis and clinicopathologic features of CD56(+) lymphomas with skin involvement is very limited. OBJECTIVES: To determine survival and prognostic factors for extranodal CD56(+) lymphomas with skin involvement and to describe their clinicopathologic features. DESIGN: Retrospective literature survey and case studies. PATIENTS: A total of 181 patients with CD56(+) lymphoma involving the skin: 177 cases from the literature and 4 new cases. MAIN OUTCOME MEASURE: Survival and its dependence on the following putative prognostic factors: staging, histopathologic findings, lymphocyte markers, T-cell receptor gene rearrangement, Epstein-Barr virus infection, treatment modality. RESULTS: Three major subtypes of CD56(+) lymphoma in the skin were distinguished: blastic lymphoma, nasal-type natural killer-cell/T-cell lymphoma, and subcutaneous panniculitislike lymphoma. The disease disseminated readily, mainly to lymph nodes, bone marrow, the central nervous system, and the liver, but 45% of patients had a purely cutaneous disease at presentation. All subtypes had a very aggressive course with a median survival of 14 months. The main risk factors were age older than 55 years (hazard ratio [HR], 2.5; 95% confidence interval [CI], 1.8-3.2), systemic dissemination at presentation (HR, 2.0; 95% CI, 1.5-3.3), and lack of CD30 (HR, 3.8; 95% CI, 1.4-4.9) or CD4 expression (HR, 1.56; 95% CI, 1.06-2.57). The different treatment modalities did not improve survival. CONCLUSIONS: CD56(+) lymphomas involving the skin are rare and extremely aggressive regardless of their histologic presentation and the extent of skin involvement. No effective treatment is available. The risk of death is particularly increased in older patients with CD30(-)CD4(-) lymphomas.

Medical students' experience in practical skills is far from stakeholders' expectations.

This study compares medical graduates' experience in practical skills with a range of stakeholders' expectations. A questionnaire listing 58 practical skills was sent out to a group of graduating medical students. The medical students were asked to indicate their experience in each skill during medical school. A similar questionnaire was sent out to five groups of stakeholders asking for their expectations regarding graduates' experience. The stakeholders were: faculty members; consultants at clinical departments with interns in training; general practitioners; nurses; recently graduated junior doctors. A total of 472 questionnaires were sent out and 315 (67%) were returned. Medical graduates showed substantial variation in level of experience, and their experience was substantially lower than the expectations of the stakeholders. Nurses and junior doctors tended to have higher expectations compared with faculty members and consultants. Differences between our results and reports in the literature from elsewhere emphasize the importance of performing local needs assessments, and in this process stakeholders apart from faculty members should be involved.

[Forty four pregnancies with idiopathic thrombocytopenic purpura]. / Fireogfyrre svangerskaber med idiopatisk trombocytopenisk purpura.

INTRODUCTION: The aim of this project was to describe the course of pregnancy with idiopathic thrombocytopenic purpura (ITP) and to estimate risk factors and indications for treatment. MATERIAL AND METHODS: Birth, haematological, and neonatal files were examined retrospectively. RESULTS: Forty-eight ITP women with 55 pregnancies gave birth to 61 children, 59 live-born. The first singleton pregnancy in the observation period (the index pregnancy) was used for statistics, namely 44 index pregnancies. A maternal platelet fall from the first trimester to delivery was seen, as was a platelet rise three days after delivery (p < 0.0001), even in splenectomised women. Thirty-six per cent of the women had bleeding manifestations, none of which were fatal; 33% of the newborn infants had thrombocytopenia in cord blood. The following risk factors for perinatal thrombocytopenia were found: a sibling with thrombocytopenia, severe maternal thrombocytopenia, male gender. The nadir platelet count in the newborn infants was seen up to seven days after delivery. The presence of an older sibling with neonatal ITP is a risk factor for neonatal ITP in subsequent pregnancies. A significant association was found between the maternal platelet count in the second trimester and the platelet count in cord blood. DISCUSSION: The diagnosis and treatment of ITP in pregnancy are controversial. Vaginal delivery is generally recommended. The platelet kinetics in pregnancy with ITP is comparable with the platelet kinetics of the spleen.

[Pregnancy-related thrombocytosis]. / Svangerskabsrelateret trombocytose.

Pregnancy-related thrombocythaemia comprises myeloproliferative and inflammatory reactive subsets. In pregnant women treated for myeloproliferative disorders, especially polycythaemia vera and primary thrombocytosis, only 50-70 per cent are delivered successfully of a normal healthy baby. The maternal complications are cerebral, cardiac, and abdominal arterial thrombosis, and with deep venous thrombosis of the legs, whereas bleedings are mainly seen in the case of extreme thrombocythaemia, owing to absorption of factors by the platelets. The foetal complication are dominated by abruptio placentae, pre-eclampsia, placental insufficiency, and death. Reactive thrombocythaemia includes the physiological rise in platelets postpartum, believed to be part of the normal maternal haemostasis, which almost never causes thromboembolic complications, as far as is known today. In contrast, the inflammatory reactive thrombocythaemia, related to severe foetal and/or maternal necrosis, is generally related only to a moderate rise in the platelet count. As the blood-platelet count does not appear to be routine at general pregnancy check-ups, it is necessary to be aware of risk groups, consisting of women with otherwise unexplained abortions or stillbirths, unexplained foetal and placental malformations, and pre-eclampsia, even if the woman has never had any thromboembolic complications.

Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia.

We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.