ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization.

Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era.

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.5 years, 74 (61%) patients were switched to standard imatinib: 48 (65%) lost the CCyR on IFNα, and 36 (75%) are alive and in CCyR; 26 (35%) were switched to imatinib when they were still in CCyR on IFNα, and all 26 are alive and in CCyR. Forty-seven patients (39%) were never switched to imatinib: 24 (51%) continued and 23 (49%) discontinued IFNα, respectively, and 39/47 (83%) are alive and in CCyR. At last follow-up, the BCR-ABL transcripts level was available in 96/101 living patients (95%) The BCR-ABL:ABL ratio was between 0.1 and 0.01% (MR(3.0) ) in 17%, and less than 0.01% (MR(4.0) ) in 81% of patients. No patient was completely molecular negative (MR(4.5) or MR(5.0) ). The OS at 10 and 20 years is 92 and 84%, respectively. This study confirms that CCyR achieved with IFNα and maintained with or without imatinib or any other therapy significantly correlates with long term survival in CML patients who mostly have MR(4.0) . Complete molecular response (MR(4.5) or MR(5.0) ) seems to be unnecessary for such a long survival. This study further supports development of studies testing the clinical effect of the combinations of TKIs with IFNα.

CD4+ and CD8+ T-cell skewness in classic Kaposi sarcoma.

It is widely accepted that a deranged immune system plays a key role in the onset and evolution of classic Kaposi sarcoma (CKS). Nevertheless, the usage of the T-cell receptor (TCR) ß-variable (BV) chain repertoire expressed by peripheral blood lymphocytes in patients with CKS is still unknown. With the aim of providing some further insights into the complex role of the immune system in CKS pathogenesis, we performed an extensive analysis of the TCR BV repertoire in both CD4(+) and CD8(+) T cells in 30 human herpesvirus 8-positive Sardinian patients with CKS and an equal number of age-matched healthy controls. We used a panel of monoclonal antibodies covering approximately 70% of human BV subfamilies and third complementarity determining region (CDR3) spectratyping. Patients with CKS showed an increased frequency of BV expansions in both CD4(+) and CD8(+) lymphocytes, with no prevalent clones. On spectratyping analysis, most of the 720 BV CDR3 profiles obtained from both CD4(+) and CD8(+) T cells in patients with CKS were skewed. In particular, the surprising increase of BV skewing observed in CD4(+) lymphocytes mimics the pattern of progressive TCR BV narrowing described in responses to persistent viral antigen stimulations. Our findings support the hypothesis that CKS evolution is associated with inadequate activation rather than impairment of the immune system.

Asymptomatic cardiac lymphoma in a hepatitis C virus-positive thalassemic patient.

Primary cardiac non-Hodgkin lymphomas are fast-growing intracavitary and/or intramyocardial nodular masses, while secondary lymphomas most commonly infiltrate the cardiac tissue. By any definition, cardiac non-Hodgkin lymphomas usually manifest through arrhythmias, refractory heart failure, pericardial effusion, and embolic stroke. We here describe a case of a cardiac non-Hodgkin lymphoma in which the following, previously undescribed features manifest simultaneously. It occurred in a polytransfused hepatitis C virus-positive splenectomized thalassemic patient; it rapidly grew, giving rise to an enormous right atrial mass and, this notwithstanding, it was completely asymptomatic. This cardiac lymphoma was discovered during staging for a CD20+ large B-cell lymphoma of the tonsils. In particular, transesophageal echocardiography, showing that this prolapsing mass had a wide base on the atrial wall, led us to strongly suspect the lymphomatous origin of the mass itself. Notwithstanding anti-CD20 antibody therapy, urgent surgery was unavoidable and histology revealed that the mass consisted of lymphoma proliferation infiltrating even the right atrial wall and the pericardium. During the postoperative course the patient presented with a massive, fatal hemopericardium consequent to intravascular disseminated coagulation. This very unusual case, occurring in a hepatitis C virus-positive thalassemic patient, suggests that a case control study on the incidence of non-Hodgkin lymphoma in such patients may be interesting.