Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi‐center,open‐label, 52‐week phase 3 trial

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg‐dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open‐label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand‐grip strength at week 52. This trial is registered with ClinicalTrials.gov , number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN.     

Risk management in technovigilance: construction and validation of a medical-hospital product evaluation instrument

With the continuous incorporation of health technologies, hospital risk management should be implemented to systemize the monitoring of adverse effects, performing actions to control and eliminate their damage. As part of these actions, Technovigilance is active in the procedures of acquisition, use and quality control of health products and equipment. This study aimed to construct and validate an instrument to evaluate medical-hospital products. This is a quantitative, exploratory, longitudinal and methodological development study, based on the Six Sigma quality management model, which has as its principle basis the component stages of the DMAIC Cycle. For data collection and content validation, the Delphi technique was used with professionals from the Brazilian Sentinel Hospital Network. It was concluded that the instrument developed permitted the evaluation of the product, differentiating between the results of the tested brands, in line with the initial study goal of qualifying the evaluations performed.     

MicroRNA-34b has an oncogenic role in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a common malignancy and one of the more difficult diseases to diagnose in Japan due to its poor prognosis. MicroRNAs are small non-coding RNAs of 21-23 nucleotides that regulate gene expression. MicroRNA-34b (miR-34b) has been reported to be overexpressed in various types of cancer. However, its role in ESCC has yet to be extensively studied. The present study investigated the expression of miR-34b in 88 ESCC patients. The miR-34b expression in ESCC was significantly higher than that in the corresponding normal esophageal mucosa. It was more highly expressed in tumors with more advanced stages. However, its expression did not correlate with the p53 status. Transfection of anti-miR-34b to the ESCC cells suppressed cell growth in vitro. These results suggest an oncogenic role of miR in ESCC.     

Diagnostic potential of TERT promoter and FGFR3 mutations in urinary cell‐free DNA in upper tract urothelial carcinoma

Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non‐invasive test for detecting UTUC, but its sensitivity is low. A novel non‐invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell‐free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ≤pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger‐scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non‐invasive diagnostic marker and reliable factor for tumor staging.     

Marked Respiratory Failure in an Ambulant Patient with Immune-mediated Necrotizing Myopathy and Anti-Kv1.4 and Anti-titin Antibodies

We herein report a case of seronegative immune-mediated necrotizing myopathy (IMNM) concurrent with anti-Kv1.4 and anti-titin antibodies. A 72-year-old Japanese woman presented with a 29-year history of fluctuating high serum creatine kinase (CK) levels followed by intermittent ptosis and respiratory muscle weakness. This case highlights the fact that marked respiratory muscle weakness requiring intubation can be seen in an ambulant patient with IMNM. Marked respiratory muscle weakness, rhabdomyolysis-like acute elevation of CK levels, and anti-striational muscle antibodies may be a characteristic constellation of findings in a distinct subgroup of patients with inflammatory myopathy with myasthenia gravis or similar symptoms.     

Synthesis and basic evaluation of 7α-(3-[<Superscript>18</Superscript>F]fluoropropyl)-testosterone and 7α-(3-[<Superscript>18</Superscript>F]fluoropropyl)-dihydrotestosterone

Objective

7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[¹⁸F]fluoropropyl)-testosterone ([¹⁸F]7) and 7α-(3-[¹⁸F]fluoropropyl)-dihydrotestosterone ([¹⁸F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.

Methods

We synthesized [¹⁸F]7 and [¹⁸F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-³H]-methyltrienolone ([³H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).

Results

7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC₅₀ value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [¹⁸F]7 and [¹⁸F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [¹⁸F]15 is observed in the ventral prostate. [¹⁸F]7 and [¹⁸F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.

Conclusion

[¹⁸F]15 is better than [¹⁸F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [¹⁸F]15 in prostate might be insufficient for in vivo visualization. Although [¹⁸F]7 and [¹⁸F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[¹⁸F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[¹⁸F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [¹⁸F]15, in terms of net prostate uptake and in vivo metabolic stability.

     

Impact of age and procedure on resource use for patients with ischemic heart disease

OBJECTIVES: Impact of age on healthcare expenditures should be assessed by targeting on specific diseases and controlling for procedures and severity of illness. Relationship between age and resource use in patients receiving acute care medicine for ischemic heart disease (IHD) was examined. METHODS: We analyzed 19,874 IHD patients treated in 82 academic and 92 community hospitals. Length of stay (LOS), total charges (TC), and high outliers of LOS and TC were analyzed for every age group (under 65 years, 65-74 years, 75 years or older). Independent effects of age on LOS, TC, and high outliers of LOS and TC were determined using multivariate analysis. RESULTS: 7863 (39.6%) patients were under 65 years, 7181 (36.1%) between 65 years and 74 years, and 4830 (24.3%) aged 75 years or older. Proportion of angina or non-medical treatment was significantly different among three age categories (angina 72%, 75%, 71.4%; non-medical 37.3%, 40.9%, 38.9%, respectively). Significant association with LOS or TC was identified in patients receiving coronary artery bypass graft surgery with percutaneous intracoronary intervention, who were most associated with TC high outlier. CONCLUSIONS: Age had a modest impact on resource use, as compared with procedures. Policy makers need to acknowledge the impact of procedures on healthcare spending.     

Three-dimensional CT Angiography Is Useful for Diagnosis of Postabortion Uterine Hemorrhage: 3 Case Reports and Review of the Literature

Uterine hemorrhage is a major complication associated with abortion. There are various causes of postabortion uterine hemorrhage. The objective of this article is to estimate the efficacy of three-dimensional computed tomography (3D-CT) angiography in the diagnosis of this condition. We present 3 case reports of women with massive genital bleeding after abortion. 3D-CT angiography clearly demonstrated the 3-D features of the feeding artery, the draining vein, and the surrounding normal structures. The diagnosis in patient 1 was a uterine arteriovenous malformation, in patient 2 was a placental polyp mimicking a uterine arteriovenous malformation, and in patient 3 was a placental polyp. Patients were all successfully treated with uterine artery embolization or transcervical resection of the placental polyp. We conclude that 3D-CT angiography is useful for making a differential diagnosis and for preoperative planning in patients with postabortion uterine hemorrhage.