MDM2 309 polymorphism predicts outcome in platinum-treated locally advanced head and neck cancer

Chemo-radiotherapy (CRT) with cisplatin-based regimens is curative in a subset of patients with locally advanced (stage III and IV) squamous carcinomas of the head and neck (LAHNSCC), but causes considerable toxicity. To seek predictive biomarkers, we analysed single nucleotide polymorphisms (SNPs) in the p53 and MDM2 genes in LAHNSCC patients treated with cisplatin-based CRT. We analysed germ-line p53 72 Arg/Pro (R/P) and MDM2 309 SNPs and somatic p53 mutational status in 140 LAHNSCC and determined their utility as predictive biomarkers. In cases with wild-type p53, overall survival (OS) was longest in 72RR (median OS=60.8 months) and less favourable in 72PP (median OS=6.7 months, p<0.0001). OS in individuals with 72RP was intermediate between 72RR and 72PP, while in patients with missense p53 mutations, median OS did not reach statistical significance. Median OS was significantly shorter in patients with MDM2 309 SNP genotypes GG or GT, compared to TT (15 vs. 86 months; p<0.0001). The predictive effect of the G allele was maintained independent of age, gender, stage, primary site, nodal status, performance status, EGFR grade, HPV status, p53 mutation and p53 SNP (HR for death 3.241; 95% CI 1.90-5.52, p<0.001). The predictive utility of the MDM2 germ-line 309 SNP, which can be easily determined from peripheral blood, implies that it may be of value in the objective selection of patients for radical CRT. In contrast, the predictive utility of the 72 Arg/Pro SNP in p53 requires mutational analysis of p53, limiting its routine clinical use.     

External radiation therapy boost to the vaginal vault: feasibility of intracavitary dosimetry using a commercial diode system

PURPOSE: An overall check of the whole dosimetry procedure by intracavitary in vivo dosimetry, using n-type silicon diode dosimeter, was performed during 6-MV x-ray irradiation of the vaginal vault. The dose delivered to the isocenter by all treatment fields was evaluated. METHODS AND MATERIALS: The diode dosimeter was calibrated against an ion chamber and tissue maximum ratio, field size factor, SSD factor, and temperature dependence studies were performed. Diode system accuracy, linearity, and reproducibility were also tested. Patients' dose data were collected and comparision was made with respect to treatment-planning dose calculations. Ten patients with cervical cancer and endometrial cancer were treated with surgery and irradiation. During the boost to the vaginal vault, a diode was inserted by an intravaginal device and the vaginal vault was the isocenter of the four fields. The field size generally was not larger than 10 x 10 cm2. RESULTS: Diode-measured "tissue maximum ratio" agreed to within 1% with those measured with an ion chamber in field from 7 x 7 to 10 x 10 cm2. The diode also exhibited a temperature dependence of 0.1% degrees C(-1). For 10 patients treated with a 6-MV beam, the agreement with treatment-planning dose calculations was shown to be better than +/-4%. CONCLUSION: The good accuracy and reproducibility of the diode system shows that determination of the dose at isocenter, for patients treated in the pelvic region, can be performed with n-type diodes accurately. On the other hand, in the vaginal vault boost, external-beam radiotherapy is delivered accurately and in vivo dosimetry is really not indicated.     

Acquired neuromyotonia in childhood: case report and review

Recently characterized as an immune-mediated channelopaty, Isaacs' syndrome (also known as acquired neuromyotonia) was first described in 1961 in two men with persistent, generalized muscle stiffness, in addition to spontaneous, rapid discharges of motor-unit potentials on electromyography. In the peripheral nervous system, antibodies targeted to voltage-gated potassium channels induce hyperexcitability of motor axons, resulting in signs of muscle stiffness or of pseudomyotonia. A spontaneous burst of single motor-unit activity, and myokymic and neuromyotonic discharges, are the most characteristic features found in electromyography studies. This report describes Isaacs' syndrome in a child, in whom the diagnosis was made by clinical features of acquired, spontaneous muscle overactivity and typical electromyographic findings.     

Progression parameters for emphysema: a clinical investigation

In patients with airflow limitation caused by cigarette smoking, lung density measured by computed tomography is strongly correlated with quantitative pathology scores of emphysema, but the ability of lung densitometry to detect progression of emphysema is disputed. We assessed the sensitivity of lung densitometry as a parameter of disease progression of emphysema in comparison to FEV(1) and gas transfer. At study baseline and after 30 months we measured computed tomography (CT)-derived lung density, spirometry and carbon monoxide diffusion coefficient in 144 patients with chronic obstructive pulmonary disease (COPD) in five different centers. Annual change in lung density was 1.31 g/L/year (CI 95%: -2.12 to -0.50 HU, p=0.0015, 39.5 mL/year (CI 95%: -100.0-21.0 mL, p=0.2) for FEV(1) (-39.5 mL) and 24.3 micromol/min/kPa/L/year for gas transfer (CI 95%: -61.0-12.5 micromol/min/kPa/L/year, p=0.2). Signal-to-noise ratio (mean change divided by standard error of the change) for the detection of annual change was 3.2 for lung densitometry, but 1.3 for both FEV(1) and gas diffusion. We conclude that detection of progression of emphysema was found to be 2.5-fold more sensitive using lung densitometry than by using currently recommended lung function parameters. Our results support CT scan as an efficacious test for novel drugs for emphysema.     

Kidney outcomes using a sustained ≥40% decline in eGFR: A meta‐analysis of SGLT2 inhibitor trials

BackgroundA recent meta‐analysis of sodium–glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials.HypothesisThe apparent heterogeneity of the meta‐analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials.MethodsWe performed a meta‐analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV ({"type":"clinical-trial","attrs":{"text":"NCT01986881","term_id":"NCT01986881"}}NCT01986881), CANVAS Program ({"type":"clinical-trial","attrs":{"text":"NCT01032629","term_id":"NCT01032629"}}NCT01032629 and {"type":"clinical-trial","attrs":{"text":"NCT01989754","term_id":"NCT01989754"}}NCT01989754), DECLARE‐TIMI 58 ({"type":"clinical-trial","attrs":{"text":"NCT01730534","term_id":"NCT01730534"}}NCT01730534), and EMPA‐REG OUTCOME ({"type":"clinical-trial","attrs":{"text":"NCT01131676","term_id":"NCT01131676"}}NCT01131676).ResultsData from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51–0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I ² = 0.0%).ConclusionsOur meta‐analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors.     

Tularemia presenting as a unilateral pleural effusion in a metropolitan city

We report a young patient who went on a camping trip to a local park in a metropolitan area complaining of chest pain. On further investigations, he was found to have left sided pleural effusion. Thoracentesis revealed alkaline PH and the fluid was an exudate. The culture grew Francisella tularensis. The patient was treated with streptomycin with marked clinical improvement.     

Two years' outcome of lung volume reduction surgery in different morphologic emphysema types

BACKGROUND: Lung volume reduction surgery (LVRS) improves dyspnea, pulmonary function, and quality of life in selected patients with severe emphysema. We investigated the role of emphysema morphology in 37 patients as an outcome predictor for up to 2 years after operation. METHODS: Patients selected for bilateral thoracoscopic LVRS were divided, according to a simplified emphysema morphology classification, into three groups (homogeneous, moderately heterogeneous, and markedly heterogeneous) based on a preoperative chest computed tomogram. Pulmonary function, walking distance, and dyspnea were assessed. RESULTS: Functional improvement after LVRS was best in markedly heterogeneous emphysema with an increase from preoperative forced expiratory volume in 1 second of 31% +/- 2% (mean +/- standard error of the mean) to 52% +/- 4% of predicted postoperatively. It was significantly higher than in homogeneous emphysema (from 26% +/- 1% to 38% +/- 2% predicted) and in intermediately heterogeneous emphysema (from 29% +/- 2% to 44% +/- 45% predicted). At 24 months postoperatively, forced expiratory volume in 1 second and dyspnea score continued to be significantly better than preoperative levels in all three morphologic groups. The survival rate was highest in patients with markedly heterogeneous emphysema. CONCLUSIONS: Functional and subjective improvements were maintained after LVRS for at least 24 months in patients with heterogeneous or homogeneous emphysema type.     

Peripheral database module for clinical management and research in sleep medicine.

Hospital-wide information systems may provide economical solutions for communication processes or for documentation by means of centralized digital medical records. Within a large university hospital, however, there may be too many diverse subspecialties and too many special medical procedures to be supported comprehensively by a single database information system. A peripheral modular system has been tailored to the specific needs of a sleep disorder clinic as an adjunct to the main clinical information system. The client server application allows for automatic data acquisition by on-line devices and by a graphical user interface. It supports administrative tasks for patient management, specific encounter interactions and data retrieval for research. Performance and acceptance of the system was assessed during clinical use, revealing positive response by the users, also with respect to significant time savings. Our experience suggests that the concept of peripheral database modules as "satellites" to a main clinical system provides flexibility in design and implementation of the specialized databases while providing access to data of more general relevance via the main database.     

Alpha 1-antiproteinase deficiency

The dysbalance between proteolytic neutrophil elastase and its endogeneous inhibitor seems to be a pathogenetic key mechanism in the origin of pulmonary emphysema (elastase-antielastase hypothesis). This hypothesis is supported by the observation, that low serum levels of alpha 1-antitrypsin can be observed in smokers with premature pulmonary emphysema. alpha 1-proteinase inhibitor is an acute phase protein with known structural and moleculargenetic aspects, which is synthesized by the liver and reaches the lung by the circulation. Its role is the inactivation of excessive neutrophil elastase in the pulmonary parenchyma, which is liberated during inflammation and destroys elastin and other components of extra-cellular connective tissue matrix. This is an overview on epidemiology, clinical aspects, genetics and molecular biology of this particular disease which was described in 1963.