Preclinical Quantification of Prostate Cancer-Associated Vascular Alterations in the Bone Microenvironment in vivo.

INTRODUCTION: Prostate cancer has a special predilection to form bone metastases. Despite the known impact of the microvascular network on tumour growth and its dependence on the organ-specific microenvironment, the characteristics of the tumour vasculature in bone remain unknown. METHODS: The cell lines LNCaP, DU145, and PC3 were implanted into the femurs of NSG mice to examine the microvascular properties of prostate cancer in bone. Tumour growth and the functional and morphological alterations of the microvasculature were analysed for 21 days in vivo using a transparent bone chamber and fluorescence microscopy. RESULTS: Vascular density was significantly lower in tumour-bearing bone than in non-tumour-bearing bone, with a marked loss of small vessels. Accelerated blood flow velocity led to increased volumetric blood flow per vessel, but overall perfusion was not affected. All of the prostate cancer cell lines had similar vascular patterns, with more pronounced alterations in rapidly growing tumours. Despite minor differences between the prostate cancer cell lines associated with individual growth behaviours, the same overall pattern was observed and showed strong similarity to that of tumours growing in soft tissue. DISCUSSION: The increase in blood flow velocity could be a specific characteristic of prostate cancer or the bone microenvironment.

Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III).

BACKGROUND: Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) comprises a group of rare, lysosomal storage diseases caused by the deficiency of one of four enzymes involved in the degradation of heparan sulfate. The clinical hallmark of the disease is severe neurological deterioration leading to dementia and death in the second decade of life. Adult MPS patients are generally of short stature. To date there is no clear description of the physical development of MPS III patients. The aim of this study was to document growth reference data for MPS III patients. We collected growth data of 182 German MPS III patients and were able to develop growth charts for this cohort. Growth curves for height, weight, head circumference, and body mass index were calculated and compared to German reference charts. RESULTS: Birth height, weight and head circumference were within the physiological ranges. Both genders were significantly taller than healthy children at 2 years of age, while only male patients were taller at the age of four. Growth velocity decelerated after the ages of 4.5 and 5 years for female and male patients, respectively. Both genders were significantly shorter than the reference group at the age of 17.5 years. Head circumference was larger compared to healthy matched controls within the first 2 years of life and remained enlarged until physical maturity. CONCLUSION: MPS III is a not yet treatable severe neuro-degenerative disease, developing new therapeutic strategies might change the course of the disease significantly. The present charts contribute to the understanding of the natural history of MPS III. Specific growth charts represent an important tool for families and physicians as the expected height at physical maturity can be estimated and therapeutic effects can be monitored.

The bone microenvironment promotes tumor growth and tissue perfusion compared with striated muscle in a preclinical model of prostate cancer in vivo.

BACKGROUND: Prostate cancer-related morbidity is associated with its preferential spread to the bone. Although the molecular interactions between the bone microenvironment and cancer cells have been researched extensively, the relevance of the microvascular properties of prostate cancer bone metastases remains largely unknown. Most preclinical studies focusing on microvascular analyses are based on heterotopic tumor implantation, whereas the impact of the microenvironment on site-specific growth behavior and angiogenesis is rarely addressed. METHODS: The microvascular changes associated with tumor growth in bone and soft tissue were characterized by implanting single cell suspensions of LnCap, Du145, and Pc3 cells into the femur (femur window) or striated muscle (dorsal skinfold chamber) of NSG mice. Tumor growth and the local microvasculature were analyzed for 21 days using intravital fluorescence microscopy. RESULTS: The results showed a higher engraftment of tumor cells in bone than in striated muscle associated with accelerated growth of LnCap cells and Pc3 cells. Permeability, blood flow, and tissue perfusion rates were greater in bone than in striated muscle. Du145 cells showed similar growth behavior in both tissues with similar vascular properties. The bone microenvironment facilitated tumor engraftment and growth. Increased microvascular density in striated muscle led to a higher tumor burden during early growth, whereas the increased perfusion promoted later prostate cancer growth in bone. CONCLUSIONS: Monitoring prostate cancer microcirculation in bone and soft tissue may be useful to evaluate the organ-specific efficacy of new treatments.

Scoliosis and chest cage deformity measures predicting impairments in pulmonary function: a cross-sectional study of 492 patients with scoliosis to improve the early identification of patients at risk.

STUDY DESIGN: This study examines the correlations between pulmonary function tests (PFTs) and radiographical measures of spinal deformities in patients with scoliosis. OBJECTIVE: To define the parameters that enable more accurate predictions of restricted pulmonary function (PF) in patients with scoliosis. SUMMARY OF BACKGROUND DATA: The early identification of patients with scoliosis who are at risk of developing severe curve progression and restricted PF is critical to improving patient care. METHODS: A total of 492 patients with a thoracic/thoracolumbar curve (TC) and preoperative PFTs as well as radiographical analysis of the TC and thoracic kyphosis (TK) were assessed. The forced vital capacity (FVC) was expressed as a percentage of the predicted value (FVC%). According to guidelines for the severity of pulmonary impairments, classifications were used: no impairment (FVC > 80%), mild (65 < FVC ≤ 80%), moderate (50 < FVC ≤ 65), and severe impairment (FVC ≤ 50%). Main radiographical parameters were included and statistical analyses were used to identify radiographical predictors and to develop prediction models. RESULTS: The average age was 17 years, 94% of the patients had adolescent idiopathic scoliosis, 20% had lordoscoliosis (TK <10°). The average FVC% was 75% ± 17%, their average TC was 57° ± 21°, and TK was 26° ± 25°. A total of 38% had no impairment, 37% exhibited mild impairment, 15% had moderate impairments, and 10% were severely impaired. Spinal deformities identified by radiographical analysis (TC, TC-flexibility, apical vertebral rotation, TK, and rib hump) significantly influenced FVC% (P < 0.01). TK logistic regression analysis revealed that 2 factors are predictive for an FVC 50% or less: increased scoliosis with a low TK less than 0° (odds ratio = 7.3) or a high TK more than 60° (odds ratio = 20). A model for predicting FVC values more than 50% was established and shown to achieve a correct classification rate of 94%. CONCLUSION: Patients with increasing coronal and sagittal plane deformities with a high thoracic scoliosis apex are at the highest risk for reduced FVC%. The models developed provided improved estimations of actual PF based on the magnitude of the radiographical deformity.

Radiological dorsal tilt analysis of AO type A, B, and C fractures of the distal radius treated conservatively or with extra-focal K-wire plus external fixateur.

OBJECTIVE: Fractures of the distal radius are amongst the most common injury patterns. The dorsal tilt represents an important co-factor determining functional outcome. The purpose of this study was to analyze the radiological dorsal tilt and identify critical time frames in conservative and operative treatment of distal radius fractures. MATERIALS AND METHODS: Eighty-seven conservatively treated (hematoma block assisted reduction and splinting) and 37 operatively treated (reduction, extra-focal K-wire fixation, bridging external fixateur) AO type A, B, and C fractures of the distal radius in 124 females were retrospectively analyzed. The dorsal tilt at the initial, post-reduction, and 2 weeks post-reduction stages was correlated with the final radiographic outcome at 6 weeks. RESULTS: Mean initial dorsal tilt was 16.53° in the conservatively treated group and 26.76° in the operatively treated group. Mean dorsal tilt after 6 weeks showed significant differences from the mean initial dorsal tilt at time of presentation within both groups (both groups p < 0.000). No significant differences between the two groups were found after 6 weeks of treatment (p = 0.194) regardless of the underlying AO fracture type. Conservatively treated radius fractures showed a significantly higher slip rate within the first 2 weeks (primary slip rate), whereas the operative group presented a significantly higher slip rate between the 2-week and 6-week radiographic checks (secondary slip rate). CONCLUSION: In terms of dorsal tilt, conservative (cast immobilization) and operative (K-wire fixation plus external fixateur) treatment demonstrated no significant differences at the final radiographic examination (6 weeks) regardless of the underlying AO fracture type. Both treatment groups showed treatment-associated different primary and secondary slip rates, indicating a need for more frequent radiographic checks within these critical time frames.

The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome).

Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is caused by mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene and the resulting defective lysosomal degradation of the glycosaminoglycan heparan sulfate. The onset and progression of the disease are highly variable. Seventy-five mutations distributed over the SGSH gene have been described. We here report on the analysis of the natural course of the disease in 54 MPS IIIA patients through the use of a detailed questionnaire and four-point scoring system and an examination of the underlying mutations. By assessing the degree of developmental regression over time a group of seven patients with a slowly progressive course of the disease were identified. In these seven patients and in 3 other mildly affected patients the missense mutation c.892T>C (p.Ser298Pro) was found on one allele. These patients showed a lower frequency and later onset of the typical symptoms of the disease. The onset of regression in speech abilities and cognitive functions were delayed by 0.7 and 0.8 years, respectively, and the onset of regression of motor functions occurred 6.1 years later than in all other MPS IIIA patients. Severe regression in speech, cognitive and motor functions were delayed by 5, 5.9, and 11.2 years, respectively. These data suggest that in MPS IIIA patients carrying the mutation p.Ser298Pro a slowly progressive phenotype can be predicted and this may have an important impact on parental counselling and therapeutic interventions.

Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A).

OBJECTIVE: Mucopolysaccharidosis types IIIA through IIID (Sanfilippo syndrome) are caused by deficiencies of enzymes involved in the degradation of heparan sulfate. The onset and severity of the disease are highly variable. The purpose of this study was to describe the natural course of mucopolysaccharidosis type IIIA in a large cohort of patients. PATIENTS AND METHODS: The natural course of mucopolysaccharidosis type IIIA was assessed in 71 patients by using a detailed questionnaire and a 4-point scoring system and compared with the course of the disease in 14 patients with mucopolysaccharidosis type IIIB and 4 patients with mucopolysaccharidosis type IIIC. RESULTS: In the cohort of patients with mucopolysaccharidosis type IIIA, first symptoms of disease were observed, on average, at 7 months of age. Speech and motor development were delayed in 66.2% and 33.9% of patients, respectively. The median age at diagnosis was 4.5 years. The onset of regression in speech, motor, and cognitive function was observed at an average age of 3.3 years. The loss of all 3 of the assessed abilities was observed at an average age of 12.5 years. Speech was lost before motor and cognitive functions. In a small group of patients who were >12.5 years of age (9.9%), speech, motor, and cognitive skills were partially preserved up to a maximum age of 23.8 years. CONCLUSIONS: To our knowledge, this is the first systematic and comprehensive study on the natural course of mucopolysaccharidosis type IIIA. The 4-point scoring system may be used to classify patients into groups with a rapid or slower course of the disease. This may have an important impact on parental counseling as well as therapeutic interventions.

The German system of medical in-patient rehabilitation in children and adolescents.

The prevalence of chronic health conditions in young people is constantly increasing. A very important question is in which setting (in-patient or out-patient) these patients should ideally be treated. In Germany, in-patient rehabilitation of children and adolescents with chronic health conditions has a long history. So far, however, no systematic data concerning structure, process or outcome quality have been assessed across facilities. Therefore, as a first step, a conjoint project of the statutory pension and health insurance institutes was initiated to assess and to describe the structure quality of in-patient medical rehabilitation clinics for children and adolescents in Germany. A questionnaire was filled out by the clinic directors which covered general information and the characteristics of structure quality, as well as structure-affiliated process characteristics of the clinics. The survey was planned as a cross-sectional study. A total of 177 clinic addresses were available. The return rate was 83.3%. Eventually, 79 clinics were included in the analysis. In sum, the results underline the heterogeneity of services in the field of child and adolescent rehabilitation. In conclusion, in-patient rehabilitation plays a major role for the treatment of children and adolescents with chronic health conditions in Germany. The results allow an analysis of the current clinic structures.