Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients

BACKGROUND: Mixed cryoglobulinemia (MC) is a systemic vasculitis secondary to circulating immune complex deposition in the small vessels. In the overwhelming majority of patients, hepatitis C virus (HCV) infection represents the triggering factor of the disease. MC is characterized by multiple organ involvement, mainly skin, liver, renal, peripheral nerves, and less frequently by widespread vasculitis and cancer. OBJECTIVES: To investigate the demographic, clinical, serologic features, and survival in a large series of MC patients. METHODS: The study included 231 MC patients recruited between 1972 and 2001 at the Rheumatology Unit of the University of Pisa. All patients underwent wide clinicoserologic and virologic assessment. Cumulative survival rates were computed by the Kaplan-Meier method; moreover, the prognostic relevance of the main variables was investigated by Cox model analysis. RESULTS: In 92% of cases, the presence of HCV infection was demonstrated (anti-HCV antibody, 92%; HCV RNA, 90%), whereas hepatitis B virus (HBV) represented the possible causative agent in only 1.8% of patients (HBV DNA). Clinically, the MC syndrome followed a relatively benign clinical course in over 50% of cases, whereas a moderate-severe clinical course was observed in one third of patients whose prognosis was severely affected by renal and/or liver failure. In a limited, but significant, percentage (15%) of individuals, the disease was complicated by a malignancy, ie, B-cell lymphoma, and less frequently by hepatocellular carcinoma, or thyroid cancer. The survival study by the Kaplan-Meier method revealed a significantly lower cumulative 10th-year survival, calculated from time of diagnosis, in MC patients compared with expected death in the age- and sex-matched general population. Moreover, significantly lower survival rates were observed in males and in subjects with renal involvement. The multivariate analysis by the Cox proportional hazard regression model further supported the above findings: an increased mortality risk of 98% was observed for male gender (male/female hazard ratio, 1.978) and of 197% in patients with, compared with those without, renal involvement (hazard ratio, 2.967). At the end of the follow-up, 97 patients were deceased, and in 79 of 97 patients, the causes of death were ascertained: nephropathy (33%), malignancies (23%), liver involvement (13%), and diffuse vasculitis (13%) were the most frequent causes of death. CONCLUSIONS: Careful patient monitoring is recommended for a timely diagnosis of life-threatening MC complications, mainly nephropathy, widespread vasculitis, and B-cell lymphoma or other malignancies.     

Cerebral amyloid load determination in a clinical setting: interpretation of amyloid biomarker discordances aided by tau and neurodegeneration measurements

Neurological Sciences - Alzheimer’s disease (AD) diagnosis can be hindered by amyloid biomarkers discordances. We aim to interpret discordances between amyloid positron emission tomography...     

Vascularised fibular grafts as a salvage procedure in failed intercalary reconstructions after bone tumour resection of the femur

Vascularised fibular grafts (VFGs) are widely used for primary reconstruction of long bones after bone tumour resections. The biological properties of VFGs are such that they can be a useful option even in failed intercalary reconstructions. The purpose of the current study was to investigate the results and the morbidity of VFGs as a salvage procedure in failed previous reconstructions after intercalary bone tumour resection of the femur. Our series included 12 patients, treated from April 1989 to March 2005, with an average age of 23 years (range 10–43 years) at presentation. The initial diagnosis was osteosarcoma in 10 cases and Ewing's sarcoma in two cases. All patients received chemotherapy and none received radiation therapy. Seven patients received VFG as biologic augmentation in intercalary allograft non-union and in the other five patients, a combination of allograft and VFG was used to replace a cement spacer with hardware failure (four patients) and a failed intercalary prosthesis (one patient). Three patients died during follow-up, in all cases because of metastatic disease. At an average follow-up of 147 months (range 11–260 months), the remaining nine patients were continuously disease-free. Complete healing of the osteotomy of both allograft and VFG was observed in 10 patients at final follow-up. Two major complications were observed that required surgical revision, eventually healing in one case and leading to a poor functional outcome in one case. Significant hypertrophy of the VFG was detected in seven of nine evaluable patients. At final follow-up the mean Musculoskeletal Tumour Society (MSTS)’93 functional score of the nine evaluable patients was 90% (range 66–100%). These results indicate that VFG is a valid salvage procedure in failed intercalary reconstructions of the femur after bone resection.     

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

High affinity diethylnitrosamine-deethylase in liver microsomes from acetone-induced rats

The effects of acetone treatment on microsomal cytochrome P-450-dependent mono-oxygenases of the rat liver have been investigated to elucidate the role of this system in the metabolism of diethylnitrosamine (DEN). Acetone markedly enhanced the hepatic P-450 content and the activities of p-nitrophenol hydroxylase, acetone hydroxylase, ethoxycoumarin deethylase and DEN deethylase (DENd), whereas activities of pentoxy-resorufin O-deethylase and ethoxy-resorufin O-deethylase were not affected. Two distinct apparent Km values (0.43 and 9.1 mM), dependent on the substrate concentration, were observed for the DENd of acetone-induced microsomes. Only one Km value (8.4 mM) was observed for the DENd of control microsomes. In control microsomes at a DEN concentration of 1 mM, the N-deethylation of DEN was undetectable whereas in acetone-induced microsomes the N-deethylation rate was approximately 2.3 nmol/mg protein per min. The results suggest that acetone-induced microsomes of rat liver contain a high affinity form of DEN-deethylase which should be the P-450j isozyme (known to catalyze the oxidation of dimethylnitrosamine at low Km). P-450j is strongly enhanced by acetone treatment as indicated by the increase of the specific acetone hydroxylase. The treatment also enhanced the metabolism of DEN at substrate concentrations higher than 1 mM, suggesting that other P-450(s) catalyse DEN-deethylation although with lower substrate affinity. The low Km form of DENd is a P-450-dependent mono-oxygenase. It requires NADPH and O2, is inhibited by CO, but not by mannitol, superoxide dismutase, catalase or desferrioxamine. Its action therefore appears not to be mediated by oxygen radical species. Many solvents such as dimethylsulfoxide, dioxolane, chloroform and butanol when present at 10 mM in the incubation mixture inhibited the low Km form of DENd. However, pyrazole and piperonylbutoxide were found to be the strongest inhibitors. These results establish that acetone affects the metabolism of DEN, particularly at low concentrations, in a fashion somewhat similar to dimethylnitrosamine.     

Latent Subclinical Medullary Thyroid Carcinoma: Diagnosis and Treatment

n = 11), palpable metastatic lymph node ( n = 6), distant metastases ( n = 4). In nine cases the diagnosis was made by both fine-needle aspiration cytology and serum CT measurement. In the four other cases the initial cytology was incorrect, but the diagnosis was revised on the basis of elevated basal CT values. In 11 patients (group 2) presenting with nodular thyroid disease, SMTC was not clinically detectable. SMTC was preoperatively suspected by elevated CT levels: basal CT > 10 pg/ml and pentagastrin-stimulated CT peak > 100 pg/ml. One patient in group 1 with distant metastases was not operated on. All of the other 12 patients underwent total thyroidectomy and extensive lymph node dissection. The mean size of the tumors was 27 mm. Lymph node involvement was found in nine patients. After surgery, CT levels returned to normal in five patients but remained elevated in five others; the two remaining patients died of distant metastases. All 11 patients in group 2 underwent total thyroidectomy and central neck dissection. None of the 11 patients had nodal extension. All 11 patients are biochemically cured. It was concluded that routine measurement of basal serum CT in those with nodular thyroid disease allows early, preoperative diagnosis of subclinical SMTC and improves the results of surgery.     

Outbreak of extended spectrum beta-lactamase-producing Klebsiella pneumoniae infection in a neonatal intensive care unit related to onychomycosis in a health care worker

Four cases of infection by extended spectrum beta-lactamase-producing Klebsiella pneumoniae occurred in the neonatal intensive care unit. Isolation, empiric therapy change and education produced no effect. Newborn weekly colonization rates were 0-18.7%. One health care worker with onychomycosis was positive for extended spectrum beta-lactamase-producing K. pneumoniae. Isolates were identical by molecular typing. Outbreak was controlled when the health care worker was excluded from the neonatal intensive care unit.