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Introduction: Traditional iron parameters often fail to distinguish the cause of iron-restricted anemia in patients without an obvious underlying cause. We evaluated whether an oral iron absorption test (OIAT) and hepcidin measurement could be useful diagnostic tests in these patients., Methods: We retrospectively analyzed data extracted from medical records of all patients who underwent an OIAT and hepcidin measurement, noting subsequent clinical diagnosis. Δ Iron >15 µmol/L during the OIAT and a hepcidin level below the median (or suppressed ≤0.5 nm) were considered appropriate., Results: Thirty-nine adult patients were included in the study. Sixteen patients with adequate OIAT had suppressed hepcidin levels indicative of classical iron-deficiency anemia (IDA); 59% of patients had abnormal OIAT. In this group, most patients with low hepcidin levels had anemia associated with abnormalities in the gastrointestinal tract, whereas 83.3% patients with high hepcidin levels had iron-refractory iron-deficiency anemia (IRIDA), confirmed by genetic testing. Finally, transferrin/log ferritin ratio accurately identified patients with suppressed hepcidin: AUC 0.98 [95% CI: 0.95-1.02], p < 0.001., Conclusion: OIAT differentiates between classical IDA and other types of anemia caused by abnormalities in iron absorption or systemic iron availability. Additionally, elevated hepcidin in patients with oral iron malabsorption could indicate IRIDA., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Determination of plasma vitamin B12 (B12) is a frequently requested laboratory analysis, mainly employed to establish B12 deficiency. However, an increased level of B12 is a common unexpected finding that may be related to an increased concentration of one of the B12 binding proteins, haptocorrin or transcobalamin. This paper describes the extensive laboratory evaluation of a patient with an elevated level of plasma B12 with various well-established assays. Initial studies suggested the presence of a macromolecule consisting of haptocorrin bound B12. Specific determinations of the B12-binding proteins revealed normal amounts of haptocorrin but a markedly increase in both total and B12 saturated transcobalamin (holo-TC). The results are in accord with the presence of macro-transcobalamin. These experiments reveal that determination of the nature of the B12-macromolecules is troublesome due to differences in assays applied to measure these proteins. In addition, this publication creates awareness of macro-holo-TC as a cause of an unexplained increased B12 level.

Pure red cell aplasia (PRCA) is a rare disease characterised by anaemia and low reticulocyte count, caused by absence of erythropoiesis in the bone marrow. This report describes a case of a ring-calcified thymoma that led to the development of PRCA. Moreover, we provide an overview on the classification of thymoma and the pathophysiology and treatment of PRCA.

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.

Hydroxycarbamide is used in the treatment of myeloproliferative neoplasms. Hydroxycarbamide is known for its relative lack of severe side effects. Here we present a 66-year-old man with a severe pneumonitis within three weeks after starting him on hydroxycarbamide. He developed life-threatening respiratory failure and was admitted to an intensive care unit. Extensive testing of blood and cultures from sputum and bronchoalveolar lavage fluid did not reveal a pathogenic microorganism. Discontinuation of the drug and treatment with prednisolone resulted in clinical improvement within 2 days. Radiological resolution was confirmed after one month. The clinical course suggests that the pneumonitis was induced by hydroxycarbamide. We want to alert physicians that, in spite of the common assumption that the use of hydroxycarbamide is relatively safe, patients can develop a severe pneumonitis with detrimental outcome and that hydroxycarbamide should be considered a causative agent in the differential diagnosis of pneumonitis.

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Rationale: Outpatient treatment of pulmonary embolism (PE) may lead to improved patient satisfaction and reduced healthcare costs. However, trials to assess its safety and the optimal method for patient selection are scarce., Objectives: To validate the utility and safety of selecting patients with PE for outpatient treatment by the Hestia criteria and to compare the safety of the Hestia criteria alone with the Hestia criteria combined with N-terminal pro-brain natriuretic peptide (NT-proBNP) testing., Methods: We performed a randomized noninferiority trial in 17 Dutch hospitals. We randomized patients with PE without any of the Hestia criteria to direct discharge or additional NT-proBNP testing. We discharged the latter patients as well if NT-proBNP did not exceed 500 ng/L or admitted them if NT-proBNP was greater than 500 ng/L. The primary endpoint was 30-day adverse outcome defined as PE- or bleeding-related mortality, cardiopulmonary resuscitation, or intensive care unit admission. The noninferiority margin for the primary endpoint was 3.4%., Measurements and Main Results: We randomized 550 patients. In the NT-proBNP group, 34 of 275 (12%) had elevated NT-proBNP values and were managed as inpatients. No patient (0 of 34) with an elevated NT-proBNP level treated in hospital (0%; 95% confidence interval [CI], 0-10.2%), versus no patient (0 of 23) with a post hoc-determined elevated NT-proBNP level from the direct discharge group (0%; 95% CI, 0-14.8%), experienced the primary endpoint. In both trial cohorts, the primary endpoint occurred in none of the 275 patients (0%; 95% CI, 0-1.3%) subjected to NT-proBNP testing, versus in 3 of 275 patients (1.1%; 95% CI, 0.2-3.2%) in the direct discharge group (P = 0.25). During the 3-month follow-up, recurrent venous thromboembolism occurred in two patients (0.73%; 95% CI, 0.1-2.6%) in the NT-proBNP group versus three patients (1.1%; 95% CI, 0.2-3.2%) in the direct discharge group (P = 0.65)., Conclusions: Outpatient treatment of patients with PE selected on the basis of the Hestia criteria alone was associated with a low risk of adverse events. Given the low number of patients with elevated NT-proBNP levels, this trial was unable to draw definite conclusions regarding the incremental value of NT-proBNP testing in patients who fulfill the Hestia criteria. Clinical trial registered with www.trialregister.nl/trialreg/admin/rctview.asp?TC=2603 (NTR2603).

Hashimoto's thyroiditis is a known risk factor for the development of primary thyroid lymphoma. How the treatment of primary thyroid lymphoma influences thyroid function is however largely unknown. This case shows that treatment with R-CHOP chemotherapy can lead to a recovery of thyroid function in a patient with severe hypothyroidism, without thyroid hormone supplementation. Furthermore, this case shows that in patients with primary hypothyroidism and a rapidly enlarging, asymmetrical thyroid, fine needle aspiration should be performed to rule out primary thyroid lymphoma.

During recent years, our understanding of the pathogenesis of inherited microcytic anemias has gained from the identification of several genes and proteins involved in systemic and cellular iron metabolism and heme syntheses. Numerous case reports illustrate that the implementation of these novel molecular discoveries in clinical practice has increased our understanding of the presentation, diagnosis, and management of these diseases. Integration of these insights into daily clinical practice will reduce delays in establishing a proper diagnosis, invasive and/or costly diagnostic tests, and unnecessary or even detrimental treatments. To assist the clinician, we developed evidence-based multidisciplinary guidelines on the management of rare microcytic anemias due to genetic disorders of iron metabolism and heme synthesis. These genetic disorders may present at all ages, and therefore these guidelines are relevant for pediatricians as well as clinicians who treat adults. This article summarizes these clinical practice guidelines and includes background on pathogenesis, conclusions, and recommendations and a diagnostic flowchart to facilitate using these guidelines in the clinical setting., (© 2014 by The American Society of Hematology.)

Background: in older persons, anaemia is associated with a number of unfavourable outcomes. In approximately 30% of older persons with anaemia, the cause of the anaemia is unexplained. We assessed the clinical differences between subjects with explained and unexplained anaemia and investigated whether these subjects have different mortality patterns compared with subjects without anaemia., Design: observational prospective follow-up study., Setting: the Leiden 85-plus study., Participants: four hundred and ninety-one persons aged 86 years., Methods: the study population was divided in three groups: (i) no anaemia (reference group, n=377), (ii) explained anaemia (iron deficiency, folate deficiency, vitamin B12 deficiency, signs of myelodysplastic syndrome or renal failure, n=74) and (iii) unexplained anaemia, (n=40). Mortality risks were estimated with Cox-proportional hazard models., Results: haemoglobin levels were significantly lower in subjects with explained anaemia than in subjects with unexplained anaemia (P<0.01). An increased risk for mortality was observed in subjects with explained anaemia [HR: 1.93 (95% CI: 1.47-2.52), P<0.001], but not in subjects with unexplained anaemia [HR: 1.19 (95% CI: 0.85-1.69), P=0.31]. Adjusted analyses (sex, co-morbidity, MMSE, institutionalised and smoking) did not change the observed associations for both explained and unexplained anaemic subjects., Conclusion: older subjects with unexplained anaemia had similar survival compared with non-anaemic subjects. Increased mortality risks were observed in subjects with explained anaemia compared with non-anaemic subjects.

Occurrence of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-) MPN) and lymphoproliferative disorders, like B cell chronic lymphocytic leukaemia (B-CLL), in the same patient is rare. JAK2(V617F) mutation was recently introduced as a powerful diagnostic tool for Ph(-) MPN. JAK2(V617F) mutation is not present in B-CLL. In 4 previously reported patients with JAK2(V617F)-positive Ph(-) MPN and B-CLL there was no definitive proof of JAK2(V617F) mutation in B-CLL cells, although this was suggested in 1 patient. We present 2 patients with JAK2(V617F)-positive polycythaemia vera who subsequently developed a monoclonal B cell disorder. The granulocytes were separated from the mononuclear cells by centrifugation on density gradient. Using an ARIA-SORP sorter, the CD20+/CD5+ B cells were separated from the CD20+/CD5- B cells, T cells, NK cells and monocytes. On each of the fractions JAK2(V617F) mutation was analysed by allele-specific competitive blocker-PCR. In both patients JAK2(V617F) mutation was present in granulocytes confirming the clinical diagnosis of polycythaemia vera. We did not detect the JAK2(V617F) mutation in the CD20+/CD5+ B cells but detected it in CD20+/CD5- B cells, T and NK cells, indicating a lymphoid subdifferentiation of the JAK2(V617F) MPN clonality. JAK2(V617F) MPN and monoclonal B cell disorder can coexist but there is no evidence that the proliferative behaviour of these B cells is mediated through the JAK2(V617F) mutation., (Copyright © 2012 S. Karger AG, Basel.)

In a patient with hypoaesthesia of the central region of the mandible, no oral cause could be found which could explain his complaint. Further examination by a neurologist and a specialist in internal medicine revealed the numb chin syndrome. The syndrome was caused by meningeal localisation of a high-grade B-cell lymphoma stade IV. After intensive chemotherapy and radiotherapy of the skull, the complaints disappeared.

Background: Plasma vitamin B12 [cobalamin (Cbl)] concentrations are usually measured as a screening marker for vitamin B12 deficiency. Siemens Healthcare Diagnostics has introduced Cbl assays for various platforms, i.e., the immulite (IML) 2000 and 2500. In our laboratories, regular validation studies for the IML 2500 were conducted and showed acceptable quality specifications. After the introduction of the IML 2500 Cbl assay, clinicians in the department of internal medicine reported an increased frequency of patients with Cbl-concentrations less than 148 pmol/L., Methods: In order to investigate this claim from the clinicians, we retrospectively analyzed the internal and external quality control (QC) of the Cbl assay. In addition, the monthly patient means for the Cbl assay were analyzed both before and after the introduction of the new Cbl assay., Results: No abnormalities were found in the internal and external QCs. However, the monthly patient means for the Cbl assay showed a statistically significant decrease in cobalamin concentrations. Siemens acknowledged the problems and formulated a new Cbl assay, which was subsequently validated in our laboratories and showed equivocal Cbl results when compared to the IML 2000 Cbl assay., Conclusions: We report a flawed validation study conducted by the manufacturer that resulted in an undetected analytical problem in the IML 2500 Cbl assay, its subsequent introduction on the market, the final recognition of the poor performance of the assay by our clinicians, and the eventual resolution by the manufacturer. Hence, it emphasizes the utmost importance for thorough comparison between assays over the entire measurement range, even when both assays are produced by the same manufacturer.

A 77-year-old man with dyspnoea was suspected to have a decompensatio cordis by the general practitioner. A diuretic was prescribed. Additional radiological and laboratory investigation (e.g. natriuretic peptides and D-dimers) showed pulmonary embolism instead of heart failure. A second patient, a woman aged 79 years, with a history of leukaemic mantle cell lymphoma, was treated with poly-chemotherapy (R-CHOP), after which remission was achieved. Four years later the lymphoma recurred and R-CHOP treatment was started. However this was without success, after which R-CHOP treatment was repeated. Subsequently the patient developed dyspnoea and pneumonia. Following additional radiological and laboratory investigation (e.g. natriuretic peptides) the patient was finally diagnosed with doxorubicin-induced heart failure. Based upon these case studies, the role of brain-natriuretic peptides in the differential diagnostic work-up of dyspnoea is highlighted. Test performance, correlation with disease, monitoring, prognostics, differential diagnostic power, reference values and pitfalls of brain natriuretic peptides are discussed.

Background: In up to 20% of patients with renal cell cancer (RCC) an inflammatory response consisting of low-grade fever, weight loss and an elevated ESR and CRP may occur with modest granulocytosis and thrombocytosis. Clinical and experimental data suggest a pathogenic role for tumour-derived cytokine production, especially interleukin-6., Case Report: A 79-year-old female with RCC presented with low-grade fever, weight loss and overt granulocytosis and thrombocytosis. Radiological examination revealed a right-sided renal tumour. During nephrectomy a gradient between the IL-6 levels in the renal artery and vein was demonstrated, providing direct evidence for in vivo production of IL-6 by the tumour affected kidney, which was confirmed by the demonstration of IL -6 in the tumour cells by immunohistochemical staining and in the supernatant of the homogenised tumour. Cytogenetic examination revealed complex abnormalities including a gain of chromosome 7. In addition we demonstrated production of IL-1alpha, IL-1beta, IL-8 and ICAM-1 in the tumour with systemic elevated levels of IL-6 and IL-8 with secondary increased serum G-CSF and TPO levels., Conclusion: We have provided direct evidence for the production of pro-inflammatory cytokines by renal cancer cells in a patient with RCC and a profound inflammatory response, with a central role of IL-6, probably due to a gain of chromosome 7. The extreme granulocytosis and thrombocytosis may have resulted from the secondary systemic production of G-CSF and TPO.

Background: Myomatous erythrocytosis syndrome is defined by the combination of erythrocytosis, myomatous uterus and persistent restoration of normal haematological values after hysterectomy. A pathogenic role of erythropoietin is suggested by clinical and experimental data., Case Report: A postmenopausal patient is described with the classical clinical signs of the myomatous erythrocytosis syndrome. During hysterectomy we demonstrated a large gradient between the erythropoietin levels in the uterine vein and artery, providing direct evidence for in vivo erythropoietin production by the myomatous uterus., Conclusion: While erythropoietin and its receptor are consecutively expressed in normal and myomatous uterine tissue, it is amazing that erythrocytosis occurs so rarely in such a frequent disorder as uterine myomatous. We strongly advocate cytogenetic examination of the myomatous tissue of subsequent patients with this entity.

A 71-year-old man with deep venous thrombosis treated with fenprocoumon presented after a trauma with a haematoma due to an INR > 8.0, and later with haemorrhagic bullae, due to venous obstruction.

A safe and effective management strategy is pivotal in excluding pulmonary embolism (PE). The combination of Wells' simplified dichotomous clinical decision rule and D-dimer test is non-invasive and could be highly efficient, though its safety has not been widely studied. We evaluated safety and efficiency of this combination in excluding PE. Wells clinical decision rule was performed in 941 consecutive patients with suspected PE and, if patients had a score

Serum cobalamin and homocysteine levels were studied in patients with chronic myelogenous leukemia (CML) and in stem cell donors treated with granulocyte-colony stimulating factor (G-CSF). Cytoreductive treatment in patients with CML resulted in a decrease of cobalamin and homocysteine levels. In stem cell donors cobalamin and homocysteine levels increased after G-CSF administration. The increase of homocysteine level was accompanied by a decrease in the serum levels of the cobalamin-binding protein transcobalamin. We hypothesize that the increased homocysteine levels in patients with CML and donors treated with G-CSF may be the result of a functional methylcobalamin deficiency due to decreased transcobalamin levels.

A woman aged 35 years presented with a haemarthros of the left elbow 6 months after her first parturition due to acquired haemophilia A. The bleeding episodes were mild and treated with recombinant activated factor VII. Because of the mild bleeding tendency and the chance of spontaneous remission it was decided to withhold immunosuppressive treatment. During the course of one year, the factor VIII level and the activated partial thromboplastin time (APTT) normalized and the autoantibodies disappeared. Four years after her first parturition, she had an uncomplicated pregnancy and the postpartum period was uneventful. Up to fourteen months postpartum, there are no signs of recurrence of the acquired haemophilia A. Acquired haemophilia A post partum usually presents in the first 3 months post partum. Frequently presenting symptoms are haemorrhages post partum, menorrhagia, soft-tissue haemorrhages and haemorrhages during surgical procedures. As a rule, the haemorrhages are slight. The titers of blocking antibodies are low in comparison with the titers in congenital haemophilia A.

Elevated levels of serum cobalamin may be a sign of a serious, even life-threatening, disease. Hematologic disorders like chronic myelogeneous leukemia, promyelocytic leukemia, polycythemia vera and also the hypereosinophilic syndrome can result in elevated levels of cobalamin. Not surprisingly, a rise of the cobalamin concentration in serum is one of the diagnostic criteria for the latter two diseases. The increase in circulating cobalamin levels is predominantly caused by enhanced production of haptocorrin. Several liver diseases like acute hepatitis, cirrhosis, hepatocellular carcinoma and metastatic liver disease can also be accompanied by an increase in circulating cobalamin. This phenomenon is predominantly caused by cobalamin release during hepatic cytolysis and/or decreased cobalamin clearance by the affected liver. Altogether it can be concluded that an observed elevation of cobalamin in blood merits the a full diagnostic work up to assess the presence of disease.

Background: In patients with multiple myeloma a variety of metabolic events may occur. One of these are changes in the serum cobalamin (vitamin B12) concentration. Elevated as well as decreased serum cobalamin levels have been reported. The prevalence and clinical consequences of low cobalamin levels are largely unknown., Objective: To investigate the prevalence of low serum cobalamin levels in patients with multiple myeloma and to describe the clinical features, haematological parameters and outcome in patients with multiple myeloma with low and normal serum cobalamin levels., Methods: A retrospective study was conducted in the Deaconess Hospital in Eindhoven. Thirty-two patients were identified who fulfilled the diagnostic criteria for multiple myeloma and had at least one serum cobalamin level tested during the diagnostic or treatment period. A number of clinical characteristics, haematological parameters and outcome were scored., Results: Twenty-one (66%) patients had a normal serum cobalamin level, nine (28%) patients had a low one and two (6%) patients had an elevated serum cobalamin level. Between the group with a normal and a low serum cobalamin level there were no differences in patients characteristics such as sex and age, tumour characteristics such as the type of paraprotein, tumour load or tumour stage nor in haematological parameters such as haemoglobin level, mean corpuscular volume and megaloblastic changes in the bone marrow. The median survival was not statistically different between both groups.

In a 64-year-old white male with abdominal pain, fever, diarrhoea and weight loss there were radiological signs of mesenteric panniculitis: thickening of the small bowel loops, an infiltrate above the bladder and in the lower right abdomen an ileum loop with a spiculated border, and streaky strands emanating from the mesenteric fat in the lower abdomen. The clinical signs resolved spontaneously with conservative treatment in 3 weeks and after 3 months the radiological abnormalities had disappeared completely. The pathogenesis of mesenteric panniculitis is unknown. The prognosis is favourable. In advanced cases of the disease, anti-inflammatory or immunosuppressive medication may be beneficial.

Elevated levels of serum cobalamin may be a sign of a serious, even life-threatening, disease. Diseases such as chronic myeloid leukaemia, promyelocytic leukaemia, polycythaemia vera and hypereosinophilic syndrome are often accompanied by markedly elevated levels of cobalamin in the blood. A rise in the serum cobalamin concentration is one of the diagnostic criteria for polycythaemia vera and hypereosinophilic syndrome. In haematological disorders, the increase in circulating cobalamin levels is predominantly caused by enhanced production of haptocorrin. Several liver diseases such as acute hepatitis, cirrhosis of the liver, hepatocellular carcinoma and metastatic liver disease can also be accompanied by an increase in circulating cobalamin. In liver diseases, the increase in cobalamin is predominantly caused by cobalamin release during hepatic cytolysis and/or through decreased clearance of circulating cobalamin by the affected liver. Liver disorders are not an indication for determining the serum cobalamin concentration. However, a coincidentally observed elevated serum cobalamin concentration is reason for further investigation.

The pathogenesis of the hyaline vascular variant of Castleman's disease is currently unknown; however, vascular and dendritic cell proliferations are common in this disorder. We report a clonal karyotypic abnormality (46,XX,t(1;16) (p11;p11), del(7)(q21q22),del(8)(q12q22)) in 15 of 20 cells obtained after short-term stromal cultures of a typical case of hyaline vascular Castleman's disease (HVCD). There was no histologic, immunohistochemical, or genotypic evidence of a clonal lymphoid or plasma cell proliferation supporting origin of this aberration from the stromal component, possibly dendritic cells. We re-examined 15 previous cases of HVCD and identified a spectrum of dysplastic changes in the follicular dendritic cells (FDC) of atrophic lymphoid follicles, with some cases showing expansions of FDC networks by CD21 immunostaining. We propose that localized clonal proliferations of stromal elements, particularly follicular dendritic cells, occur in typical HVCD and likely explain the increased incidence of FDC sarcomas in these patients.

The pharmacokinetic characteristics of granulocyte colony-stimulating factor (G-CSF) appears to be related to the neutrophil count. We report the case of an 81-year-old male with acquired antibody induced neutropenia treated with G-CSF. This produced a rapid increase in the neutrophil count which appeared to be associated with diminished trough plasma G-CSF levels. Our data appears to indicate that mature neutrophils may play a part in the clearance of G-CSF from plasma.

We describe a patient with an atypical chronic lymphocytic leukemia (CLL) of the mixed cell type with a hypercalcemia due to parathyroid hormone-related protein production by the malignant B cells. On regard of the elevated serum calcium level without overt lytic bone lesions we found elevated serum levels of PTH-rP and demonstrated the presence of PTH-rP on the malignant lymphocytes. PTH-rP-related hypercalcemia in CLL is very rare. The role in PTH-rP in humoral hypercalcemia of malignancy is discussed.

Gastro-intestinal stromal tumour (GIST) is increasingly recognized as a distinct entity within the group of soft tissue tumours. Mostly, GIST arises from the muscular components of the stromal layer, but the tumour may also originate from the autonomic nerve system, recently designated as gastro-intestinal autonomic nerve tumour (GANT). The majority of GIST is located in the stomach and small intestine; only 4% of GIST is found in the duodenum. Clinical and pathological criteria to differentiate benign from malignant GIST are not well established. Tumour size and mitotic activity are commonly considered as important features, predicting biological behaviour and outcome. It has been suggested that the clinical course of the GANT-type tumours may be more aggressive. We present a case of a radically resected duodenal stromal tumour with benign features, in a young woman, with metastases to the liver and peritoneum occurring 8 years after the initial diagnosis.

A patient with a stage II seminoma of the testis was treated with a routine orchidectomy and irradiation. One and a half years later enlarged mediastinal lymph nodes were noted. Additional staging showed no other abnormalities and a mediastinoscopy was performed. The initial histologic examination confirmed the clinically suspected diagnosis of sarcoidosis. However, additional immunohistochemical analysis unexpectedly demonstrated that there was also a microscopic relapse of the testis tumor. The literature concerning the co-incidence of non-caseating granulomas and testis tumors is reviewed. It is not clear, whether the granulomas indicate the presence of genuine idiopathic sarcoidosis or whether they reflect a sarcoid-like reaction against tumor antigens. The immunopathogenesis of sarcoid formation and its possible biologic significance in obtaining a spontaneous tumor remission is discussed.

We report a patient with congenital homozygous factor V deficiency in whom a large pseudotumour in the right upper leg was successfully surgically excised under continuous substitution with fresh-frozen plasma.

A 65-year-old woman developed haemorrhagic diathesis due to a profound thrombocytopenia (thrombocyte count: 1 x 10(9)/l) within one week after a 10-day course of norfloxacin (2 x 400 mg/day), prescribed for cystitis. On account of increased megakaryopoiesis in the bone marrow and absence of other causes of thrombocytopenia norfloxacin-induced immune thrombocytopenia was diagnosed. No norfloxacin-dependent antibodies against platelets were detected. Treatment with prednisone (1.5 mg/kg/day) resulted in the normalization of the platelet count within 5 days.

We present a case of an 81-year-old man with secondary autoimmune granulocytopenia in association with autoimmune thrombocytopenia. Treatment with granulocyte colony-stimulating factor (G-CSF) (5 micrograms/ kg/day s.c.) resulted in a rapid increase in the number of circulating granulocytes with a pronounced left shift. These changes were accompanied by up-regulation of the surface expression of Fc gamma RI (CD64) and Fc gamma RII (CD32) on the granulocytes. In addition, we noted a strong up-regulation of the Fc gamma RIII (CD16) and the activation markers CD11b and CD66b on the granulocytes. The increase in the number of circulating granulocytes was followed by a dramatic decrease in the level of cell-bound as well as circulating anti-granulocyte antibodies. It is hypothezised that the decrease in the level of cell-bound as well as circulating anti-granulocyte antibodies may be the result of an increased adsorption of the antibodies by the granulocytes.