Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 g/kg body wt; maintenance dose: 5 g/kg body wt, once weekly) and TCDD-75 (initial dose: 75 g/kg body wt; maintenance dose: 15 g/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.     

Kluger's “Fixateur interne” for spinal instability

Kluger's Fixateur Interne proved to be an excellent tool not only in spinal trauma for repositioning of impacted fractures and transpedicular stabilization of the dorsal column but also in other forms of thoracic or lumbar instability.After spinal tumor excision from a dorsal approach and vertebral replacement with methylmethacrylate additional stability through dorsal fixation was achieved with this device.Spondylodiscitis, symptomatic spondylolisthesis, spinal instability from degenerative disc disease as well as nonunion following previous surgery could be cured using Kluger's internal fixation. Rare complications, i.e. from broken screws or rods (5%) caused no problems, but some patients required a second operation for readjustment of malpositioned screws which were causing pain or neurological deficit.     

HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin.

PURPOSE: For the first time a large number (563) of non-small cell lung cancer (NSCLC) samples was used to compare three different technologies for the assessment of HER2 status. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were used for tumor tissue samples, and ELISA for serum samples. The results were compared with other tumor entities, mainly breast. EXPERIMENTAL DESIGN: Samples (563) from patients suffering from primary advanced or metastatic NSCLC were evaluated. RESULTS: HER2 overexpression was demonstrated using IHC in 20% (83 of 410) of the specimens, whereas 2% (7 of 378) were positive by FISH and 6% (31 of 511) showed elevated serum HER2 levels (>15 ng/ml) by ELISA. Sixty-six specimens were positive by IHC only and 13 by ELISA only, whereas none of the specimens was positive only by FISH. Concordance between all of the techniques was seen for only 3 specimens. Of 7 IHC 3+ specimens, 4 showed gene amplification by FISH, and 3 were positive by ELISA (>15 ng/ml), whereas of 76 IHC 2+ cases only 2 were amplified by FISH, and 4 were positive by ELISA. HER2 positivity by at least one of the three techniques was most common in adenocarcinomas, at 29% (42 of 143). CONCLUSION: Gene amplification and HER2 protein overexpression at the 3+ level appear to be uncommon in NSCLC. The concordance between FISH and IHC 3+ disease was good in this study, in addition, ELISA would have detected several patients without IHC/FISH-positive disease.     

The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer.

The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression.     

Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer.

PURPOSE: Cancer-testis genes mapping to the X chromosome have common expression patterns and show similar responses to modulators of epigenetic mechanisms. We asked whether cancer-testis gene expression occurred coordinately, and whether it correlated with variables of disease and clinical outcome of non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Tumors from 523 NSCLC patients undergoing surgery were evaluated for the expression of nine cancer-testis genes (NY-ESO-1, LAGE-1, MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, CT7/MAGE-C1, SSX2, and SSX4) by semiquantitative PCR. Clinical data available for 447 patients were used to correlate cancer-testis expression to variables of disease and clinical outcome. RESULTS: At least one cancer-testis gene was expressed by 90% of squamous carcinoma, 62% of bronchioloalveolar cancer, and 67% of adenocarcinoma samples. Statistically significant coexpression was observed for 34 of the 36 possible cancer-testis combinations. Cancer-testis gene expression, either cumulatively or individually, showed significant associations with male sex, smoking history, advanced tumor, nodal and pathologic stages, pleural invasion, and the absence of ground glass opacity. Cox regression analysis revealed the expression of NY-ESO-1 and MAGE-A3 as markers of poor prognosis, independent of confounding variables for adenocarcinoma of the lung. CONCLUSIONS: Cancer-testis genes are coordinately expressed in NSCLC, and their expression is associated with advanced disease and poor outcome.     

Complex regional pain syndrome and dysautonomia in a 14‐year‐old girl responsive to therapeutic plasma exchange

Reflex sympathetic dystrophy, also known as complex regional pain syndrome (CRPS), has recently been shown to be associated with autoantibodies against β2‐adrenergic and muscarinic M2 receptors. In addition to pain and sudomotor/vasomotor symptoms, dysautonomia is also observed in a subset of CRPS patients. Despite its severity, there are few effective therapies for CRPS described to date. We report a case of a 14‐year‐old girl with CRPS of her right leg and dysautonomia (gastroparesis, postural tachycardia) refractory to multiple therapies, successfully treated with therapeutic plasma exchange (TPE) with albumin replacement. The patient, who has serum anti β2‐adrenergic and muscarinic M2 receptor autoantibodies in addition to nicotinic acetylcholine receptor ganglionic autoantibodies, underwent an initial course of five TPEs over a 2‐week period. She demonstrated a clinical response to TPE as manifested by a rapid improvement in her fatigue and gastroparesis, with a gradual yet significant improvement in her leg pain and sudomotor/vasomotor flares. Following the loading procedures, the patient was treated with rituximab. She continues to require periodic TPE to maintain a remission, with additional immunosuppression being considered long term. Although further studies are needed, TPE (in combination with immunosuppression) may be an appropriate therapy for CRPS patients with detectable autoantibodies, as it is for better characterized diseases with autoantibodies against neuronal surface receptors such as myasthenia gravis or Lambert Eaton myasthenic syndrome. J. Clin. Apheresis 31:368–374, 2016. © 2015 Wiley Periodicals, Inc.     

Disability,coping and quality of life in individuals with muscular dystrophy: a prospective study over five years

Purpose : The present study investigates progressive muscular dystrophy over a five year period. The purpose is twofold: to describe changes over time and to investigate relations between disability, coping and quality of life. Method : The study group comprised 45 adults (16 men and 29 women), with an average age of 44 years. All were assessed in 1991 and 1996, with the following instruments: the ADL staircase, the Self-report ADL, the Mental Adjustment to Cancer scale, the Sickness Impact Profile and the Psychosocial well-being questionnaire (Kaasa). Results : Increasing disability was accompanied by an increase in dependence on others and a significant deterioration of health-related quality of life and with regard to 'Satisfaction'. The predominant type of coping was 'Fighting spirit', whilst 'Fatalism' showed the greatest decline over time. 'Ambulation' and the ADL staircase correlated with 'Physical index' on the SIP. Correlations between disability, coping and quality of life were moderate. The results can serve as a basis for planning and evaluation of recurring rehabilitation for persons with MD.     

Disability and quality of life in individuals with postpolio syndrome

Purpose : The purpose of the study is to investigate disability and quality of life in individuals with the characteristic symptoms of postpolio syndrome. Method : Disability is assessed by means of the self-report activities of daily living instrument, and quality of life by means of Kaasa's questionnaire and the quality of life profile. Results : The 39 subjects have on average lived with polio sequelae for 52 years. Their main difficulties are with moving, lifting and carrying. This means restricted mobility, sedentary activities and a need to prioritize. Half of them feel that polio has lessened their possibilities in life, and a quarter have still not accepted the limitations polio has involved. Nevertheless the majority report a high level of psychosocial well-being, and almost a quarter say that living with polio has meant personal development and strength. We found a significant correlation between on the one hand disability with regard to ambulation, arm strength and finger strength on the self-report ADL, and on the other hand the number of negative problems on the quality of life profile (0.33-0.45). Conclusion : The latter instrument needs further testing before its validity can be determined with certainty.