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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.

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.

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.

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.

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 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.

Seven patients with low-grade non-Hodgkin's lymphoma were treated with a combination of a murine monoclonal antibody directed against the B-cell-specific antigen CD19 (CLB-CD19), given twice weekly, and continuous infusion of low-dose recombinant interleukin-2 (rIL-2). We demonstrated stable serum CLB-CD19 levels throughout the 12 weeks of treatment, and homing of the antibody into the tumour sites. A variable degree of antigenic modulation was noted. Prolonged treatment resulted in a sustained increase in the number of natural killer cells in the circulation with enhanced cytotoxic capacity, including antibody-dependent cellular cytotoxicity. During the first weeks of treatment, T cell activation occurred in the majority of patients. Toxicity was related to the rIL-2 treatment and consisted of transient constitutional symptoms and a flu-like syndrome without organ dysfunction. A partial remission occurred in one patient, and in another patient who was primarily leukaemic a greater than 50% reduction of circulating B cells was noted. An antitumour effect occurred early during treatment and could not be related to rIL-2-induced modulation of natural killer cell or T lymphocyte activation.

Background: Previously we described the immunological and clinical effects of prolonged continuous infusion of low dose rIL-2. In this phase II study we explored the therapeutic efficacy of intermittent continuous infusion of low dose rIL-2., Patients and Methods: We selected 15 patients with advanced melanoma and 8 patients with renal cell cancer in good clinical condition, with low tumour burden and no previous systemic treatment. A treatment cycle consisted of infusion of 1.8 x 10(6) IU/m2/24 hrs rIL-2 for 3 weeks on an out-patient basis followed by a 3-week rest. A maximum of four cycles were given., Results: A total of 35 cycles were given. Treatment was well tolerated. Transient hyperthyroidism occurred in 8 patients. No objective responses were noted. We noted a high incidence of central nervous system involvement occurring shortly after treatment., Conclusions: Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.

Objective: Major thromboses can occur in the venous system in association with central venous catheters. This usually necessitates removal of the catheter., Methods: The effectiveness of low dose recombinant tissue type plasminogen activator (rt-PA) in combination with heparin was assessed in patients with central venous catheter associated thrombosis., Results: In five patients, all suffering from cancer, a 5-7 day continuous infusion resulted in complete lysis of the thrombus without complications in three. In the other two patients moderately severe haemorrhage was observed with only partial lysis, of the thrombus., Conclusions: The infusion of heparin and rt-PA is potentially effective in thrombosis related to use of central venous catheters, but the risk of haemorrhage is not inconsiderable.

A patient with renal cell cancer developed acute renal failure due to biopsy-proven acute tubulo-interstitial nephritis (AIN) in the 6th week of continuous infusion of 9 x 10(6) IU m-2 day-1 recombinant interleukin-2 (rIL-2). We investigated whether the AIN was the result of a cellular cytotoxic reaction induced by the rIL-2 treatment. The cytolytic activity of cryopreserved peripheral blood lymphocytes (PBL), isolated before and at the end of the rIL-2 treatment (at the time of AIN), was studied after 5 days of culture with or without rIL-2 or anti-CD28 and immobilized anti-CD3 antibodies. The PBL isolated before and at the end of the rIL-2 treatment showed cytolytic activity towards a number of allogeneic targets. However, only the PBL isolated at the end of the rIL-2 treatment showed, when stimulated with rIL-2 in vitro, significant cytolytic activity against an autologous renal cell line cultured from the AIN biopsy specimen and against an allogeneic renal cell cancer cell line. These PBL displayed no enhanced killing capacity towards autologous PBL and the melanoma cell line M14. These observations suggest that the AIN may be the result of a cytotoxic lymphocyte-mediated reaction induced by the rIL-2 treatment.

Sixteen patients received a high-dose chemotherapy regimen consisting of carboplatin (1600 mg/m2) and cyclophosphamide (6000 mg/m2) as daily two-hour infusions over four days (CC). All but two of them also received thiotepa (480 mg/m2) in eight 30-minute infusions given every 12 hours (CTC). Bone marrow and/or peripheral stem cell (PSC) reinfusions took place 72 hours after the last course of chemotherapy. The major toxicity was bone marrow suppression, the duration of which was markedly reduced in the patients receiving PSC reinfusions. Non-hematological toxicity was relatively mild and consisted of nausea and vomiting, minor mucositis and skin rashes. All but one patient had mild and completely reversible elevations of serum ALAT and/or LDH levels. One patient, who had received full-dose chemotherapy despite a creatinine clearance of 56 ml/min, developed significant toxicity consisting of transient cyclophosphamide-associated pancarditis, reversible neurotoxicity and partially reversible hearing loss and renal function impairment. There were no toxic deaths. In view of the high carboplatin dose, the CTC regimen may be particularly suitable for use in the salvage treatment of germ cell cancer. Since CTC causes no serious organ toxicity, further studies to determine its suitability for double or even triple transplantation programs are warranted.

Eleven patients with testicular cancer, either relapsing after or refractory to cisplatin-based chemotherapy, underwent salvage chemotherapy with high-dose carboplatin (800 mg/m2 on day 1) and high-dose etoposide (500 mg/m2 on days 1, 3 and 5). A total of 21 courses were administered. The major toxicity consisted of profound myelosuppression. There were two toxic deaths, both caused by infection during neutropenia. Bone marrow recovery was usually complete around day 26 (range 19-129). Other toxicities included mild mucositis, nausea and vomiting, and alopecia. No significant neurotoxicity or hearing loss were observed and only one patient had a moderate decrease in renal function. Nine of ten evaluable patients responded, with one complete remission, 6 partial remissions with normalization of tumor markers, and two partial remissions with over one log decrease of tumor markers. The duration of these remissions was not evaluable, since only three evaluable and responding patients did not receive additional therapy after HD-CE. All three relapsed after discontinuing chemotherapy. HD-CE has activity in relapsing or refractory testicular cancer and can be administered without bone marrow support. The regimen may thus be suitable to be used as a remission induction regimen prior to consolidation with intensive chemotherapy and autologous bone marrow transplantation.

A 47 year old woman presented with invasive pulmonary aspergillosis complicated by subclavian artery occlusion and rib fracture due to fungal osteomyelitis. This followed persistent pancytopenia resulting from autologous bone marrow transplantation for metastatic breast cancer.

A retrospective clinical study was performed to determine the clinical impact of neutropenic enterocolitis (NE) in adult patients with acute leukemia and non-Hodgkin's lymphoma treated with cytosine arabinoside (Ara-C)-containing regimens. The diagnosis of NE was restricted to conditions with clinical signs of peritonitis, ileus, or intestinal hemorrhage. Forty episodes of NE were noted during 461 Ara-C-containing courses (8.6%) in 36 of 211 patients (17%) over a 6-year period. Clinically, 18 cases of ileus, 16 cases of peritonitis, and 6 cases of intestinal hemorrhage were recognized as the most important presentation of NE. NE started about 2 weeks after the initiation of the chemotherapy and lasted for an average of 1 week. All patients had a profound neutropenia. The incidence of septicemia was higher during courses complicated by NE (p less than 0.001). All cases of NE were treated with conservative measures. The mortality was 22.5% and represented one third of all therapy-related deaths during the pancytopenic period. The incidence of NE was significantly higher in courses consisting of high-dose Ara-C for 6 consecutive days when the drug was combined with amsacrine for 3 consecutive days (p less than 0.0001).