Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra‐abdominally, and are defined by EWSR1‐WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion‐positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6–25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma‐like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1‐WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1‐WT1 fusion provides a definitive diagnosis of DSRCT. Genome‐wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.     

Myxoid glioneuronal tumor,PDGFRA p.K385‐mutant: clinical,radiologic, and histopathologic features

“Myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow‐up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports “myxoid glioneuronal tumor, PDGFRA p.K385‐mutant” as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.     

Electrical impedance tomographic imaging of a single cell electroporation

A living cell placed in a high strength electric field, can undergo a process known as electroporation. It is believed that during electroporation nano-scale defects (pores) occur in the membrane of the cell, causing dramatic changes to the permeability of its membrane. Electroporation is an important technique in biotechnology and medicine and numerous methods are being developed to improve the understanding and use of the technology. We propose to extend the toolbox available for studying electroporation by generating impedance distribution images of the cell as it undergoes electroporation using Electrical Impedance Tomography (EIT). To investigate the feasibility of this concept, we develop a mathematical model of the process of electroporation in a single cell and of EIT of the process and show simulation results of a computer-based finite element model (FEM). Our work is an attempt to develop a new imaging tool for visualizing electroporation in a single cell, offering a different temporal and spatial resolution compared to the state of the art, which includes bulk measurements of electrical properties during single cell electroporation, patch clamp and voltage clamp measurement in single cells and optical imaging with colorimetric dyes during single cell electroporation. This paper is a preliminary theoretic feasibility study.     

Antibiotic Susceptibility of Periodontal Streptococcus constellatus and Streptococcus intermedius Clinical Isolates

Background: Streptococcus constellatus and Streptococcus intermedius in subgingival dental plaque biofilms may contribute to forms of periodontitis that resist treatment with conventional mechanical root debridement/surgical procedures and may additionally participate in some extraoral infections. Because systemic antibiotics are often used in these clinical situations, and little is known of the antibiotic susceptibility of subgingival isolates of these two bacterial species, this study determined the in vitro susceptibility to six antibiotics of fresh S. constellatus and S. intermedius clinical isolates from human periodontitis lesions. Methods: A total of 33 S. constellatus and 17 S. intermedius subgingival strains, each recovered from separate patients with severe chronic periodontitis (n = 50) before treatment, were subjected to antibiotic gradient strip susceptibility testing with amoxicillin, azithromycin, clindamycin, ciprofloxacin, and doxycycline on blood‐supplemented Mueller‐Hinton agar and to the inhibitory effects of metronidazole at 16 mg/L in an enriched Brucella blood agar dilution assay. Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing interpretative standards were used to assess the results. Results: Clindamycin was the most active antibiotic against S. constellatus (minimum inhibitory concentration at 90% [MIC₉₀] 0.25 mg/L), and amoxicillin was most active against S. intermedius (MIC₉₀ 0.125 mg/L). A total of 30% of the S. constellatus and S. intermedius clinical isolates were resistant in vitro to doxycycline, 98% were only intermediate in susceptibility to ciprofloxacin, and 90% were resistant to metronidazole at 16 mg/L. Conclusion: Subgingival S. constellatus and S. intermedius exhibited variable antibiotic susceptibility profiles, potentially complicating empirical selection of periodontitis antibiotic therapy in patients who are species positive.     

Influence of Diabetes Mellitus and Glycaemic Control on the Characteristics and Outcome of Common Infections

The aim of the present study was to elucidate the effect of diabetes and metabolic control on the presentation, sources, pathogens and outcome of common infections. Of 515 patients admitted to three departments of internal medicine because of a suspected acute infection, 132 (26 %) had diabetes mellitus. Osteomyelitis was diagnosed in 3 % of the diabetic patients and in 1 % of patients without diabetes, and infection of the extremities in 7 % and 0 %, respectively (p = 0.003). Klebsiella sp. caused 24 % of urinary tract infections in diabetic patients, versus 13 % in patients without diabetes (p = 0.1). The percentage of Staphylococcus aureus infections in diabetic patients was 10 % versus 5 % in non-diabetic patients (p = 0.06). The gross mortality rate in the diabetic patients was 10 %, and in patients without diabetes, 12 %. In patients without fatal underlying disorders, mortality in the diabetic patients was 10 % (2 % in patients with glycosylated haemoglobin (GHb) lower than median, and 17 % in patients with GHb higher than median) and in the non-diabetic patients 4 % (p = 0.04). Five factors were independently and significantly related to mortality in diabetic patients: acute respiratory distress (very large odds-ratio [OR]), coma (OR 3.8, 95 % confidence interval [CI] 1.0–14.3), GHb above the median (OR 3.3, 95 % CI 1.8–6.2), the interaction between GHb and absence of a severe underlying disorder (OR 12.0, 95 % CI 2.9–50.7) and duration of diabetes (OR of 1.072 for 1-year increment, and 1.42 for a 5-year increment). Choice of empiric antibiotic treatment in diabetic patients with suspected bacterial infection should take into account the preponderance of Klebsiella sp. and Staphylococcus aureus infections. The present results favour an association between poor glycaemic control and a fatal outcome of infectious diseases in diabetic patients.     

COLCHICINE TREATMENT OF AA AMYLOIDOSIS OF FAMILIAL MEDITERRANEAN FEVER

Objective. To elucidate factors possibly influencing the outcome of colchicine therapy in patients with amyloidosis of familial Mediterranean fever (FMF). Methods. Retrospective analysis of data abstracted from the charts of all 68 FMF patients with amyloidosis who presented during the study period (1974–1992) with proteinuria (≥0.5 gm/24 hours) and creatinine values ≤2.5 mg/dl, received colchicine, and were followed up for ≥5 years. Results. At the end of the study period, kidney disease had worsened in 31 patients and remained stable in 22. Proteinuria had regressed in 15 patients. Deterioration was related to initial serum creatinine values ≥1.5 mg/dl (P ≤ 0.01) and to mean colchicine dosage ≤1.5 mg/day (P ≤ 0.001). The 3 groups were comparable in terms of initial urinary protein levels, duration of proteinuria, presence of hypertension, occurrence of febrile attacks, sex distribution, and proportion of non-compliant patients. Conclusion. The therapeutic dosage of colchicine for amyloidosis of FMF is >1.5 mg/day. This dosage is effective only in patients with initial serum creatinine levels <1.5 mg/dl.     

Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.     

Derangements of intravascular remodeling of lipoproteins in type 2 diabetes mellitus: Consequences for atherosclerosis development

In type 2 diabetes mellitus, elevated fasting and postprandial plasma triglycerides, small dense low-density lipoprotein particles, low high-density lipoprotein (HDL) cholesterol levels, and increased action of lipid transfer proteins may enhance peripheral lipid accumulation and increase cardiovascular risk. Despite low HDL cholesterol, plasma’s ability to stimulate cellular cholesterol efflux, reflecting an early step in the reverse cholesterol transport pathway, appears to be maintained, perhaps implicating a compensatory mechanism.