Characterization of hyperlipidemia in two patients with analbuminemia

The results of plasma lipid and lipoprotein analysis in two related patients, brother (R.U.) and sister (R.R.) with analbuminemia, and three first-degree relatives (parents and sister) are reported. Both patients showed a remarkable increase in cholesterol and phospholipid levels, and there was a corresponding increase in serum apo B and apo A-I. This hyperlipidemia is due to a selective increase in LDL and HDL concentrations. R.U. showed an increase in both HDL2- and HDL3-cholesterol, R.R. only in HDL3-cholesterol. VLDL concentration was reduced in R.U. and normal in R.R. The plasma lipoprotein electrophoretic pattern did not correspond to any of the phenotypes in Fredrickson's classification. Composition of the different lipoprotein fractions was normal in the patients and family members. Serum FFA level in R.R. was very low. An increase in the plasma protein fractions, particularly the transport fractions, was confirmed in both patients. The possible pathophysiology of the hypercholesterolemia in these patients is discussed. Unlike other reported cases, clinical signs of atherosclerotic complications were absent.     

Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non‐Hodgkin lymphoma: dose‐limiting myelosuppression without evidence of DNA hypomethylation

Targeting aberrant DNA hypermethylation in chronic lymphocytic leukaemia (CLL) and non‐Hodgkin lymphoma (NHL) with decitabine may reverse epigenetic silencing in B‐cell malignancies. Twenty patients were enrolled in two phase I trials to determine the minimum effective pharmacological dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL (n = 4). Patients received 1–3 cycles of decitabine. Dose‐limiting toxicity (DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving decitabine at 15 mg/m² per d days 1–10, consisting of grade 3–4 thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received decitabine at 10 mg/m² per d days 1–10 without DLT; however, re‐expression of methylated genes or changes in global DNA methylation were not observed. Therefore, a 5‐day decitabine schedule was examined. With 15 mg/m² per d decitabine days 1–5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients, consisting of grade 3–4 neutropenia, thrombocytopenia, and febrile neutropenia. Eight patients had stable disease. In 17 patients, there were no significant changes in genome‐wide methylation or in target gene re‐expression. In conclusion, dose‐limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re‐expression in CLL and NHL.     

Mass spectrometry analysis of IgA1 hinge region in patients with IgA nephropathy

BACKGROUND: Physicochemical alterations of the IgA molecule are supposed to play a pathogenetic role in IgA nephropathy (IgAN). The present study was carried out to analyze the structural variety of O-glycans on the IgA1 hinge region in IgAN. Sera from 9 IgAN patients and 9 healthy controls were individually examined to evaluate the IgA1 content and binding lectins (jacalin and Helix aspersa), using enzyme-linked immunosorbent assay (ELISA) techniques. The IgA1 from pooled sera were separated by affinity chromatography (jacalin), and the fragment containing the hinge region was prepared by pyridylethylation and trypsin treatment. The IgA fragments containing the hinge glycopeptide (33-mer hinge peptide core (HP) + O-glycans) were separated by jacalin affinity chromatography. Because we used jacalin, we only analyzed the Gal-3GalNAc residue containing IgA. The molecular weight (MW) of the IgA1 fragments was estimated using an ion trap mass spectrometer equipped with an electrospray ion source (ESI/MS). RESULTS: IgA1 concentration in pathological sera was higher than in the control serum (p<0.01). Compared with controls, serum IgA1 from IgAN patients showed significantly greater binding to the 2 lectins, jacalin (p<0.01) and Helix aspersa (HA, p<0.001), which are specific for O-linked Gal-beta1,3-GalNAc and GalNAc, respectively. Analyses of pooled sera showed that the number of O-glycosidic chains was comparable in IgAN and normal sera. With regards to the individual residues, we found that IgAN sera contained less sugar and galactose and sialic acid moieties than sera from control subjects, was reduced in IgAN sera, while terminal N-acetylgalactosamine levels were higher when compared with normal serum.CONCLUSIONS: Abnormalities of hinge region O-linked glycans were confirmed using advanced spectrometry technology. The pathogenetic implications for aggregation and defective removal of IgA1 are discussed.     

Mitomycin C and 5-fluorouracil salvage chemotherapy in platinum-resistant ovarian carcinoma.

Twenty-four patients with progressing or recurrent ovarian carcinoma, all pretreated with cisplatin, were evaluated for response and toxicity to mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy. Eligible patients had histologically proven intra-abdominal disease (67% clinically measurable; 33% nonmeasurable), and 67% of them had progressed on prior platinum-based chemotherapy. WHO response criteria were adopted in patients with measurable disease while those with nonmeasurable lesions were considered as responding in case of nonevident disease and CA-125 values less than 35 U/dl for at least 6 months. All patients received at least 2 treatment courses (median 6, range 2-10), and 5 patients (21%) could be considered as responding: 4/8 (50%) with nonmeasurable and 1/16 (6%) with measurable disease. The overall median survival was 12 months, range 7-30+ (median follow-up: 29.5 months, range 28-30). Progression-free survival was significantly different in responders (15 months) versus nonresponders (3 months) (p = 0.0001). Toxicity was mainly represented by myelosuppression (grade I 29%; II 8% and III 4%). MMC and 5-FU did not show significant activity against large tumor burden, while a relatively good activity was detected in patients with minimal disease. The limited toxicity and possible schedule modifications have to be taken into account for further investigation on selected patients.     

Does previous surgery influence the asymmetric distribution of endometriotic lesions?

Our objective was to investigate the role of previous abdominal-pelvic surgery in the asymmetric distribution of pelvic endometriosic lesions. This was a retrospective study carried out at the Clinic of Obstetrics and Gynecology, University of Ancona, Italy, and included 238 patients with histological confirmation of endometriosis. The interventions were surgical treatment, at laparoscopy or laparotomy, for pelvic pain and endometriosis. The main outcome measure(s) were endometriotic lesions and adhesions in the pelvis found during surgery and the dinical records of the patients. We found unilateral lesions in 149 patients (62.6%): the right side of the pelvis affected in 55 patients (36.9%) and the left side in 94 patients (63.1%) (p < 0.01). In the group of patients who had undergone previous abdominal surgery, we found lesions on the right side in 26 cases (32.5%), and on the left in 54 cases (67.5%) (p < 0.01). We found that the patients who had undergone previous abdominal surgery had significantly more adhesions than those with no previous surgery (80/116 vs. 73/122, p = 0. 002). As a new finding, we have demonstrated that the left side of asymmetric distribution of intrapelvic macroscopic lesions is preserved and more evident in patients with previous abdominal surgery, including previous appendectomy. These data seem to be in agreement with our previous supposition of a possible interaction between previous abdominal surgery and the mechanisms of endometriosis development.     

Personalized therapeutic strategies in HER2-driven gastric cancer

Gastric Cancer - Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them...