Discordant repeat size and phenotype in Kennedy syndrome

Previous reports in the literature have described correlation of increasing repeat length with severity of the phenotype, in Kennedy syndrome. We describe male siblings with different repeat lengths, with lack of expression of the phenotype in the sibling with the longer repeat length. The phenotype was identical to motor neurone disease. There is variability of expression in Kennedy syndrome and repeat length even in siblings cannot be taken as a conclusive indicator of severity. CAG repeat length cannot be used to predict the natural history of Kennedy disease. The diagnosis of Kennedy syndrome should be considered in male patients presenting with atypical motor neurone disease.     

Imaging spectrum in disseminated histoplasmosis: Case report and brief review

The clinical manifestations of chronic disseminated histoplasmosis are non-specific and resemble those of other chronic infections and malignancies. We report the radiographic, sonographic and contrast-enhanced CT appearances of histoplasmosis in an adult male with non-insulin dependent diabetes mellitus, who was HIV negative and presented with weight loss and pyrexia. Imaging studies simulated tuberculosis with mediastinal lymphadenopathy, bilateral fibrotic lung lesions, hepatomegaly and bilateral hypoattenuating adrenal enlargement, without clinical or laboratory evidence of hypoadrenalism. Computed tomography-guided fine-needle aspiration biopsy of adrenal glands revealed Histoplasma capsulatum. We report our experience to increase awareness of the imaging spectrum of disseminated histoplasmosis and its similarity to tuberculosis as, with increasing incidence of AIDS, the chances of these infections are likely to increase. Moreover, awareness of this entity is important because it is known that untreated disseminated histoplasmosis is fatal.     

Automated quantitation of cell-mediated HIV type 1 infection of human syncytiotrophoblast cells by fluorescence in situ hybridization and laser scanning cytometry

Infection of human placental syncytiotrophoblast cells with HIV requires direct contact with infected leukocytes. In vitro investigations into mechanisms regulating placental HIV transmission and into the development of therapeutic interventions have been hampered by difficulties inherent in quantitating HIV levels in cocultures of infected lymphocytes and adherent multinucleated syncytiotrophoblast cells. Here, we have used fluorescence in situ hybridization (FISH) for the direct detection of HIV-1 RNA within syncytiotrophoblast cells combined with laser scanning cytometry (LSC) to quantitate HIV levels exclusively in the syncytiotrophoblast cells. HIV-1-infected lymphocytic MOLT-4 cells were cocultured with primary human syncytiotrophoblast cells. Lymphocytic cells were identified with an anti-vimentin antibody and Cy5. HIV RNA was localized by in situ hybridization, using a digoxigenin-labeled riboprobe detected by Oregon Green, and nuclei were stained with 7-aminoactinomycin D. The three-color cocultures were analyzed by LSC to remove unwanted cell populations and quantitate HIV expression levels. The total HIV RNA level (green fluorescence integral) in each colony was normalized for cell size by dividing by the total DNA content (red fluorescence integral). The nuclear-normalized fluorescence integral was 2.3 times higher in infected cocultures than in uninfected cultures. When cocultures were incubated with 10 microM AZT, the green/red fluorescence integral value was significantly lower than that of cocultures incubated in the absence of AZT, corresponding to a 78% reduction in fluorescence. Laser scanning cytometry can be used to quantitate cell-mediated HIV infection in syncytiotrophoblast cells and should allow drug assessment studies and studies aimed at understanding the mechanism of virus entry into trophoblast cells to be carried out.     

EHR-based cohort assessment for multicenter RCTs: a fast and flexible model for identifying potential study sites

ObjectiveThe Recruitment Innovation Center (RIC), partnering with the Trial Innovation Network and institutions in the National Institutes of Health-sponsored Clinical and Translational Science Awards (CTSA) Program, aimed to develop a service line to retrieve study population estimates from electronic health record (EHR) systems for use in selecting enrollment sites for multicenter clinical trials. Our goal was to create and field-test a low burden, low tech, and high-yield method.Materials and MethodsIn building this service line, the RIC strove to complement, rather than replace, CTSA hubs’ existing cohort assessment tools. For each new EHR cohort request, we work with the investigator to develop a computable phenotype algorithm that targets the desired population. CTSA hubs run the phenotype query and return results using a standardized survey. We provide a comprehensive report to the investigator to assist in study site selection.ResultsFrom 2017 to 2020, the RIC developed and socialized 36 phenotype-dependent cohort requests on behalf of investigators. The average response rate to these requests was 73%.DiscussionAchieving enrollment goals in a multicenter clinical trial requires that researchers identify study sites that will provide sufficient enrollment. The fast and flexible method the RIC has developed, with CTSA feedback, allows hubs to query their EHR using a generalizable, vetted phenotype algorithm to produce reliable counts of potentially eligible study participants.ConclusionThe RIC’s EHR cohort assessment process for evaluating sites for multicenter trials has been shown to be efficient and helpful. The model may be replicated for use by other programs.     

Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma?

BACKGROUND: Muscle-invasive urothelial carcinoma of the bladder is a highly lethal malignancy, particularly in the setting of locally advanced or metastatic disease. Prior reports of HER2/neu (c-erbB-2 or HER2) expression in bladder carcinoma have been mixed; therefore, its value in predicting metastasis or response to therapy has not been established in this tumor type. Thus, the authors evaluated a possible correlation between HER2 expression in patients with high-grade, muscle-invasive urothelial carcinoma of the bladder and outcome in patients who received paclitaxel-based chemotherapy. METHODS: Archival tumor tissues from patients with advanced urothelial carcinoma who were enrolled on two clinical trials of paclitaxel-based chemotherapy regimens were analyzed for HER2/neu expression by immunohistochemistry (IHC). The authors correlated HER2 expression by IHC with clinical outcomes, such as response rate, progression free survival, and overall survival, using univariate analysis. RESULTS: Thirty-nine tumor specimens were assessed for HER2 expression, most of which (70%) were collected from patients with metastatic disease. All were high-grade urothelial carcinomas (transitional cell carcinomas, Grade 3). Strong HER2 expression (2+/3+) was seen in 28 patients (71%). Patients with responding disease had an HER2 expression rate of 78%, similar to the rate seen in patients with stable disease (75%). In contrast, patients with progressive disease had an HER2 expression rate of 50%, although this difference did not reach statistical significance. However, univariate analysis showed that increased HER2 expression predicted an improvement in progression free and overall survival. When HER2 status was used as a dichotomous variable, tumors with positive HER2 expression did not have any association with response or with progression free survival; however, positive HER2 status was associated significantly with a decreased risk of death (P = 0.03). CONCLUSIONS: This study of HER2 expression in bladder carcinoma focused on patients who were treated prospectively in a standardized fashion, unlike prior studies that have evaluated banked, archival specimens. The authors confirmed the findings of others that high-grade, muscle-invasive urothelial carcinoma of the bladder has a significant rate of HER2 expression (71%). However, contrary to other reports, the current study found that HER2 expression in the context of paclitaxel-based chemotherapy decreased the risk of death significantly. Further research is warranted on the possible association of HER2 expression with chemosensitivitiy in urothelial carcinoma as well as the efficacy of HER2-targeted therapies (such as trastuzumab) for patients with high-grade, muscle-invasive urothelial carcinoma of the bladder.     

Factors affecting patency of femoropopliteal bypass grafts

A 16 year review of femoropopliteal bypass grafts identified five factors with significant influence on long term patency. Most important was the nature of the graft itself, with vein grafts having superior long term performance as compared to a variety of prosthetic grafts. Arteriographic runoff, indications for operation, site of the distal anastomosis and prior femoropopliteal operation had a major influence on long term patency of prosthetic grafts but rather minimal effects on the patency of autogenous vein grafts. The influence of several variables proved cumulative, leading to a favorable subset of patients in whom prosthetic grafts may approach long term performance of vein grafts. Differences in such key variables is a major contribution to the widely differing patency rates of previous studies and must be carefully controlled in any future prospective studies.     

Single-pill therapy in the treatment of concomitant hypertension and dyslipidemia (the amlodipine/atorvastatin gemini study)

The Gemini Study was a 14-week, open-label, non-comparative, office-based, multicenter trial to evaluate single-pill therapy in the treatment of concomitant hypertension and dyslipidemia. In addition to recommending lifestyle modifications, eight dosage strengths of amlodipine/atorvastatin single pill (5/10, 5/20, 5/40, 5/80, 10/10, 10/20, 10/40, and 10/80 mg) were electively titrated to improve blood pressure and lipid control. A total of 1220 patients with uncontrolled hypertension at baseline received study medication. At baseline, mean blood pressure was 146.6/87.9 mm Hg and mean low-density lipoprotein cholesterol concentration was 152.9 mg/dL. At study end, 57.7% of patients had achieved both their blood pressure and low-density lipoprotein cholesterol goals (51.9% of patients with uncontrolled low-density lipoprotein cholesterol at baseline). The mean dose of study medication at end point was amlodipine component 7.1 mg and atorvastatin component 26.2 mg. Fifty-eight patients (4.8%) discontinued therapy due to adverse events. Single-pill therapy is effective in reducing both blood pressure and lipid levels and in helping patients achieve goals for both hypertension and dyslipidemia.