The VEXAS Syndrome: Uncontrolled Inflammation and Macrocytic Anaemia in a 77-Year-Old Male Patient.

The VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described X-linked autoinflammatory condition caused by a somatic mutation of the UBA1 gene and characterized by an evolving phenotype. This includes inflammatory processes such as recurrent fever, Sweet's syndrome of the skin, pulmonary fibrosis, relapsing polychondritis and venous thromboembolism. An important feature, present in almost all cases, is the development of a macrocytic anaemia with vacuolization of myeloid and erythroid precursors. Usually, these patients require high doses of steroids to control symptoms and respond poorly to disease-modifying drugs. We describe a new case of the VEXAS syndrome presenting with Sweet's syndrome which has now been followed for 6 years. LEARNING POINTS: An inflammatory syndrome with skin and pulmonary involvement in an elderly male patient with haematological abnormalities such as a macrocytic anaemia, myelodysplastic syndrome or venous thrombotic events should raise suspicion of the VEXAS syndrome.Close collaboration between rheumatologists and haematologists is important in diagnosing and managing this complex disorder.

Efficacy of rituximab and cladribine in patients with chronic lymphocytic leukemia and feasibility of stem cell mobilization: a prospective multicenter phase II trial (protocol SAKK 34/02).

This phase II trial investigated rituximab and cladribine in chronic lymphocytic leukemia. Four induction cycles, comprising cladribine (0.1 mg/kg/day days 1-5, cycles 1-4) and rituximab (375 mg/m(2) day 1, cycles 2-4), were given every 28 days. Stem cell mobilization (rituximab 375 mg/m(2) days 1 and 8; cyclophosphamide 4 g/m(2) day 2; and granulocyte colony-stimulating factor 10 microg/kg/day, from day 4) was performed in responders. Of 42 patients, nine achieved complete remission (CR), 15 very good partial remission, and two nodular partial remission (overall response rate 62%). Stem cell mobilization and harvesting (> or = 2 x 10(6) stem cells/kg body weight) were successful in 12 of 20 patients. Rituximab infusion-related adverse events were moderate. The main grade 3/4 adverse events during induction were neutropenia and lymphocytopenia. Rituximab plus cladribine was effective; however, the CR rate was modest and stem cell harvest was impaired in a large number of responding patients.

Tumor necrosis factor-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary hemochromatosis.

BACKGROUND: In vitro and animal studies suggest that tumor necrosis factor alpha (TNF-alpha) modulates intestinal iron transport. We hypothesized that the effect of TNF-alpha might be particularly relevant if iron absorption is not effectively controlled by the HFE gene. METHODS: In patients with homozygous C282Y hemochromatosis, we investigated the influence of TNF-alpha -308G>A allelic variant on total body iron overload, determined in all patients by measuring iron removed during depletion therapy, and hepatic iron index and need for phlebotomy to prevent iron reaccumulation, measured in patient subgroups. RESULTS: Of 86 patients with hereditary hemochromatosis, 16 (19%) were heterozygous carriers and 1 (1%) was a homozygous carrier of the TNF-alpha promoter -308A allele. Mean (SD) total body iron overload was increased 2-fold in TNF-alpha -308A allele carriers [10.9 (7.6) g] compared with homozygous carriers of the G allele [5.6 (5.0) g, P<0.001]. Hepatic iron index differed markedly between TNF-alpha -308A allele carriers [5.6 (3.5) micromol/g/year] and homozygous G allele carriers [3.1 (2.2) micromol/g/year, P=0.040, n=30]. After iron depletion, the need for phlebotomy to prevent iron reaccumulation (maintenance therapy) was substantially higher in TNF-alpha -308A allele carriers than in homozygous G allele carriers (P=0.014, n=73). We used multiple regression analyses to exclude possible confounding effects of sex, age, family screening, body-mass index, and meat or alcohol intake. CONCLUSION: TNF-alpha -308G>A allelic variant modulates iron accumulation in patients with hereditary (homozygous C282Y) hemochromatosis, but the effect of the TNF-alpha -308A allele on clinical manifestations of hemochromatosis was less accentuated than expected from the increased iron load associated with this allele.

Portal vein thrombosis (PVT): a study of 20 non-cirrhotic cases.

BACKGROUND: Portal and mesenteric venous thrombosis (PVT) is an uncommon disease with serious consequences if not discovered early in order to prevent complications such as variceal bleeding and intestinal ischaemia. The objective of this study was to describe the clinical presentation and outcome of patients with PVT with a view to early diagnosis and treatment of this disease. The study was restricted to patients with PVT not caused by underlying liver cirrhosis. PATIENTS AND METHODS: To analyse important clinical characteristics of this entity we performed a retrospective study of 20 non-cirrhotic patients seen in our hospital from February 1998 to March 2003. RESULTS: The main clinical symptom was abdominal pain (13 patients, 86%), sometimes in combination with diarrhoea and vomiting (5 patients, 33%), nausea and anorexia (3 patients). Laboratory signs were non-specific and diagnosis was usually by computed tomography (19 patients, 95%). Causative factors included prothrombotic states (9 patients, 45%) and/or local factors (5 patients, 25%). Complications must be expected from portal hypertension (15 patients, 75%), which was associated with variceal bleeding in 6 patients (30%). Bowel ischaemia (5 patients, 25%) and bowel infarction (2 patients) were less frequent. Treatment consisted of immediate anticoagulation in almost all cases (18 patients, 90%), while invasive approaches were followed in selected patients. The prognosis of PVT was good in patients without a severe underlying disease (median followup 21 months). CONCLUSIONS: In agreement with other studies our results suggest that early diagnosis and treatment by immediate anticoagulation are important in preventing the serious consequences of portal and mesenteric vein occlusion. The role of more invasive approaches is less well defined. Since in 18 patients (90%) of the non-cirrhotic cases in the present series causative factors were found which may have therapeutic implications, aetiological screening seems worthwhile in every case with PVT.

The PAX5 oncogene is expressed in N-type neuroblastoma cells and increases tumorigenicity of a S-type cell line.

Neuroblastoma is a neural crest-derived neoplasm of infancy with poor outcome in patients with advanced disease. The oncogenic transcription factor PAX5 is an important developmental regulator and is implicated in the pathogenesis of several malignancies. Screening of neuroblastoma cell lines revealed PAX5 expression in a malignant subset of neuroblastoma cells, so-called 'N-type' cells, but not in the more benign 'S-type' neuroblastoma cells. PAX5 expression was also detected in small cell lung cancer, an aggressive tumor of neural crest origin. Based on this observation we hypothesized that there could be a relationship between PAX5 expression and the more malignant phenotype of N-type cells. Stable PAX5 expression was established in several clones of the S-type cell line CA-2E. A noticeable difference in morphology of these transfectants was observed and there was also a significant increase in the proliferation rate. Moreover, PAX5 expressing clones gained the ability to form colonies in a soft agar assay, a marker of tumorigenicity. Down-regulation of PAX5 in several N-type cell lines and one small cell lung cancer cell line utilizing small interfering RNA resulted in a significant decrease in growth rate. Taken together we propose PAX5 as an important factor for the maintenance of the proliferative and tumorigenic phenotype of neuroblastoma. Our data, together with a recent study on the role of PAX genes in cancer suggest that PAX5 and other PAX transcription factors might be valuable targets for cancer therapy.