Alpha-1-antitrypsin deficiency-associated cervical artery dissection: report of three cases

The pathogenesis of cervical artery dissection is poorly understood. Deficiency of the elastase inhibitor alpha-1-antitrypsin may represent a predisposing condition. Biochemical and genetic analyses in a series of 12 consecutive patients with spontaneous dissection of the neck vessels showed 3 cases associated to alpha-1-antitrypsin deficiency, in combination with transient precipitating factors. A disequilibrium between proteolytic enzymes and protease inhibitors may contribute to the pathogenesis of cervical artery dissection leading to structural abnormalities of the extracellular matrix and increasing the susceptibility of the vessel wall to additional short-lived trigger mechanisms.     

Abnormal accumulation of tTGase products in muscle and erythrocytes of chorea-acanthocytosis patients

Chorea-Acanthocytosis (CHAC) is an autosomal recessive disease characterized by neurodegeneration and acanthocytosis. Enhanced creatine kinase concentration is a constant feature of the condition. The mechanism underlying CHAC is unknown. However, acanthocytosis and enhanced creatine kinase suggest a protein defect that deranges the membrane-cytoskeleton interface in erythrocytes and muscle, thereby resulting in neurodegeneration. Acanthocytes have been correlated with structural and functional changes in membrane protein band 3--a ubiquitous anion transporter. Residue Gln-30 of band 3 serves as a membrane substrate for tissue transglutaminase (tTGase), which belongs to a class of intra- and extra-cellular Ca2+-dependent cross-linking enzymes found in most vertebrate tissues. In an attempt to cast light on the pathophysiology of CHAC, we used reverse-phase HPLC and immunohistochemistry to evaluate the role of tTGase in this disorder. We found increased amounts of tTGase-derived N(epsilon)-(-gamma-glutamyl)lysine isopeptide cross-links in erythrocytes and muscle from CHAC patients. Furthermore, immunohistochemistry demonstrated abnormal accumulation of tTGase products as well as proteinaceous bodies in CHAC muscles. These findings could explain the mechanisms underlying the increased blood levels of creatine kinase and acanthocytosis, which are the most consistent features of this neurodegenerative disease.     

Chronic eosinophilic ascites in a very young child

A case of chronic eosinophilic ascites with onset in early infancy is described. An intensive diagnostic work-up ruled out other known causes of ascites in childhood. The final diagnosis was made at 2 years of age when a large number of eosinophils was detected in the ascitic fluid. The outcome was complicated by an ex vacuo intraperitoneal haemorrhage. Steroids were able to control the disease only after complete aspiration (1600 ml) of the ascitic fluid. On discontinuation of treatment, peritoneal inflammation recurred indicating steroid-dependency. Conclusion: eosinophilic ascites, a very rare disorder in children, should be considered in the differential diagnosis of even very young children presenting with ascites.     

Escalating doses of paclitaxel and epirubicin in combination with cisplatin in advanced ovarian epithelial carcinoma: a phase I-II study

Our objective was to identify a new active three-drug combination regimen consisting of paclitaxel (PTX), epirubicin (EPI) and cisplatin as first-line line chemotherapy for advanced ovarian carcinoma. A phase I study was carried out to evaluate the dose-limiting toxicity (DLT) and the maximally tolerated dose (MTD) of PXT and EPI in combination with a fixed dose of cisplatin every 4 weeks. Side-effects were recorded according to the NCI Common Toxicity Criteria. Patients were treated in cohorts of three with fixed-dose cisplatin 80 mg/m2 and EPI 80-->100 mg/m2 and PXT 100-->160 mg/m2 until DLT was reached. Once MTD was identified, a single-step phase II study was therefore carried out to test the clinical activity and panel of toxicity of such regimen. Objective responses were recorded according to the WHO criteria. Time to progression and overall survival (OS) were secondary endpoints. The DLT was myelosuppression and, in more detail, febrile neutropenia, which occurred at the fifth dose level (PTX 140 mg/m2, EPI 100 mg/m2 and cisplatin 80 mg/m2) in two out of three patients. Other side-effects were grade 3 mucositis in two out of three patients and grade 3 anemia in one case. The combination of cisplatin 80 mg/m2 plus EPI 80 mg/m2 and PCT 140 mg/m2 every 4 weeks was considered as the MTD. In the phase II study a complete response was observed in six patients (33%) and a partial response in nine cases (50%) for an overall response rate of 83% [95% confidence limits (CL) 59-96%]. Median time to progression of patients with measurable disease was 16.4 months. Median OS was not reached after a follow-up of 42 months. This study demonstrated that PTX and EPI can be safely administered in combination with cisplatin to fit patients with advanced epithelial ovarian carcinoma. The three-drug regimen of cisplatin 80 mg/m2, EPI 80 mg/m2 and PTX 140 mg/m2 every 4 weeks is very active, at least in terms of objective response rate. This level of activity overlaps with the 95% CL of the activity of cisplatin alone; however, it does encourage future trials of the combination.     

Complete remission in advanced blastic NK-cell lymphoma/leukemia in elderly patients using the hyper-CVAD regimen

Although its cell of origin is still controversial, the blastic NK-cell leukemia/lymphoma clearly represents a distinct type of hematopoietic neoplasm that is particularly clinically aggressive when it occurs in elderly patients as a disseminated, multi-organ disease. Consistently effective treatments have not been developed for this malignancy. The present report describes two elderly patients with widespread blastic NK-cell leukemia/lymphoma involving the skin, bone marrow, peripheral blood, lymph nodes, and viscera. In both cases the malignant cells were CD56+, CD2+, and terminal deoxynucleotidyl transferase (TdT) positive with no detectable T-cell receptor (TCR) gamma chain gene rearrangement. The cells also exhibited a low CD45 expression and strong CD99 (mic-2) expression, as seen in immature lymphoid malignancies. The above findings support the precursor NK-cell, rather than mature NK- or non-NK-cell, origin of the malignant cells. It is noteworthy that the two patients achieved complete responses to treatment with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate/cytarabine, a regimen currently utilized in acute lymphoblastic leukemia and high-grade lymphoma. The complete remission (CR) was sustained for 24 months in one patient who received four cycles (eight courses) of the treatment. It lasted 9 months in the second patient, who received only two cycles (four courses). If similar results are obtained with future patients, a randomized study comparing the hyper-CVAD regimen to other therapeutic strategies may be warranted.