Bone Metastases in Patients with Neuroendocrine Neoplasm: Frequency and Clinical, Therapeutic, and Prognostic Relevance.

BACKGROUND: The incidence and prevalence of neuroendocrine neoplasms (NEN) are rising. In view of continuously improving imaging techniques, more than half of the patients present with distant metastases at initial diagnosis. An advanced disease stage negatively correlates with the 5-year survival rate. In stage IV disease, bone metastases (BM) are frequent, yet knowledge concerning their clinical or prognostic relevance is rare. This study presents a single-center experience on the frequency and management of BM in patients with gastroenteropancreatic NEN and lung carcinoids. METHODS: Between 2000 and June 2015, 327 of 677 patients treated in the European Neuroendocrine Tumor Society (ENETS) center in Marburg (Germany) presented with distant metastases (48.3%), including 85 patients (12.6%) with BM. Data of both groups were analyzed using descriptive statistics. Overall survival was assessed by Kaplan-Meier curves and compared by log-rank test. RESULTS: Median age in the BM group was 54.9 years, the small intestine and the pancreas being the most common primaries. 83.5% of the tumors were well and moderately differentiated (G1/G2). Nearly half of the patients with BM were symptomatic and suffered either from pain (42.4%) or had fractures (11.7%). Bisphosphonates were employed in almost two-thirds of the patients, radiation therapy in 25.9%. Overall survival was significantly inferior in patients with BM than in those with other distant metastases (p = 0.01; 49.0 vs. 100.8 months). CONCLUSION: BM appear to have a significant clinical and prognostic impact. Further studies are needed to evaluate therapeutic approaches directed to the treatment of BM in particular for asymptomatic patients.

The predictability of ocriplasmin treatment effects: is there consensus among retinal experts? Results from the EXPORT study.

PURPOSE: To evaluate the agreement and predictability of ocriplasmin treatment effects among retinal experts (raters) by assessment of retinal imaging data of eyes treated for vitreomacular traction in nine different centers in Germany and Austria. METHODS: Retrospective cohort study. Combined confocal near-infrared scanning laser ophthalmoscopy and spectral-domain optical coherence tomography images (Spectralis® device, Heidelberg Engineering GmbH, Germany) from 136 eyes of 135 subjects were reviewed by 14 raters using an internet-based grading database and a standardized questionnaire. In addition to the images taken within 2 days prior to treatment, age, gender, and lens status were disclosed to the raters. Treatment success was defined as a complete cleavage of the posterior vitreous cortex at day 28±5. Main outcome was the agreement and predictability among raters for assessment of treatment success. RESULTS: Raters generally accepted starting ocriplasmin treatment (chance for treatment success ≥ 1%) in 22.4 to 69.1% (median 53.2%) of eyes (moderate intra- and interrater agreements with kappa-values of 0.6 and 0.48). The likelihood for a high potential treatment success (equal or higher than 25%) was judged by the raters in 43.4% to 86.0% (median 62.6%) of eyes (moderate intra- and fair interrater agreements with kappa-values of 0.56 and 0.22). Allocating eyes for high potential treatment success overall increased the odds by 3.07, with odds ratios of single raters up to 4.06 to 6.16. CONCLUSIONS: These results underscore the importance of training health care providers in the evaluation of retinal imaging data and also to define characteristic morphological features better in the presence of vitreoretinal interface diseases. The better results of single raters in the predictability of treatment success by the allocation of eyes in the high-potential group indicates the high relevance of the meticulous analysis of retinal images.

Bone health of the Ovahimba people of north-western Namibia in the context of urbanization and a change of the sociocultural environment.

The prevalence of osteoporosis in Sub-Saharan African (SSA) countries is low, however, as urbanization takes root, it is predicted that bone health will decrease dramatically. The bone health of the semi-nomadic Ovahimba people of Namibia was investigated in the context of urbanization and changes of the sociocultural environment. Furthermore, data on bone health in SSA countries is scarce; there exists no ethnic-specific reference group for people of black origin. Included in the study were 98 urban and rural living Ovahimba people. Quantitative ultrasound was performed, sunrise/sunset saliva cortisol concentrations was measured and a questionnaire was conducted. There was no significant difference in the QUS parameters, however, after adjustment for confounders, SOS and SI differed significantly. The saliva cortisol concentrations differed significantly. After adjustment for confounders, saliva cortisol was significantly negatively correlated to SOS (r= -0.27, p = 0.021) giving an indication for an association between cortisol concentration and QUS parameters. The urban group furthermore showed a nutritional transition. Even though the bone health of the Ovahimba is very good, first signs of the adverse effects of urbanization were detected. Beside changes of lifestyle, this may be attributed to an increased cortisol exposure of the Ovahimba people living in an urban environment due to an increased psychosocial stress.

Oncological and surgical outcome of total laryngectomy in combination with neck dissection in the elderly.

There are controversial data on oncological and surgical outcome after major head and neck cancer surgery in the elderly. The aim of this study was to evaluate the outcome of elderly cancer patients after total laryngectomy in combination with neck dissection. A total of 58 patients separated into two age groups (28 < 65 vs. 30 ≥ 65 years) with hypopharyngeal and laryngeal cancer who underwent total laryngectomy and neck dissection were enrolled. Comorbidities of both age groups using the Charlson comorbidity index, hospitalization days as well as surgical complications evaluated by the Clavien-Dindo classification were examined. Overall and disease-free survivals of all patients were analyzed. The average follow-up was 2.9 years. Surgical complication rate was significantly increased in elderly (p = 0.04). However, complications could be treated without surgical intervention in most cases without significant extension of hospitalization. Locoregional and distant control did not significantly differ in both age groups. Disease-free and overall survival showed no significant differences for the two age groups by the Kaplan-Meier analysis (p = 0.66 and 0.08, respectively). Total laryngectomy in combination with neck dissection can be considered in elderly patients with satisfactory oncological and surgical outcome.

Biomarker driven population enrichment for adaptive oncology trials with time to event endpoints.

The development of molecularly targeted therapies for certain types of cancers has led to the consideration of population enrichment designs that explicitly factor in the possibility that the experimental compound might differentially benefit different biomarker subgroups. In such designs, enrollment would initially be open to a broad patient population with the option to restrict future enrollment, following an interim analysis, to only those biomarker subgroups that appeared to be benefiting from the experimental therapy. While this strategy could greatly improve the chances of success for the trial, it poses several statistical and logistical design challenges. Because late-stage oncology trials are typically event driven, one faces a complex trade-off between power, sample size, number of events, and study duration. This trade-off is further compounded by the importance of maintaining statistical independence of the data before and after the interim analysis and of optimizing the timing of the interim analysis. This paper presents statistical methodology that ensures strong control of type 1 error for such population enrichment designs, based on generalizations of the conditional error rate approach. The special difficulties encountered with time-to-event endpoints are addressed by our methods. The crucial role of simulation for guiding the choice of design parameters is emphasized. Although motivated by oncology, the methods are applicable as well to population enrichment designs in other therapeutic areas.

Expression of Estrogen Receptor Alpha and Evaluation of Histological Degeneration Scores in Fibroblasts of Hypertrophied Ligamentum Flavum: A Qualitative Study.

The most common spinal disorder in elderly is lumbar spinal stenosis (LSS), resulting partly from ligamentum flavum (LF) hypertrophy. Its pathophysiology is not completely understood. The present study wants to elucidate the role of estrogen receptor α (ER α) in fibroblasts of hypertrophied LF. LF samples of 38 patients with LSS were obtained during spinal decompression. Twelve LF samples from patients with disk herniation served as controls. Hematoxylin & Eosin (H&E) and Elastica stains and immunohistochemistry for ER α were performed. The proportions of fibrosis, loss and/or degeneration of elastic fibers and proliferation of collagen fibers were assessed according to the scores of Sairyo and Okuda. Group differences in the ER α and Sairyo and Okuda scores between patients and controls, male and female sex and absence and presence of additional orthopedic diagnoses were assessed with the Mann-Whitney U test. There was a tendency towards higher expression of ER α in LF fibroblasts in the hypertrophy group (p = 0.065). The Sairyo and Okuda scores were more severe for the hypertrophy group but, in general, not statistically relevant. There was no statistically relevant correlation between the expression of ER α and sex (p = 0.326). ER α expression was higher in patients with osteochondrosis but not statistically significant (p = 0.113). In patients with scoliosis, ER α expression was significantly lower (p = 0.044). LF hypertrophy may be accompanied by a higher expression of ER α in fibroblasts. No difference in ER α expression was observed regarding sex. Further studies are needed to clarify the biological and clinical significance of these findings.

Evaluation of Organisational Structures of Self-help Groups in the Field of Paediatric Orthopaedics. / Evaluation der Organisationsstrukturen von Selbsthilfegruppen auf dem Gebiet der Kinderorthopädie.

BACKGROUND: There have been few publications on the organisational structures of self-help groups that handle orthopaedic disorders in children. MATERIAL AND METHODS: A standardised questionnaire was sent by post to the corresponding support groups. The aim was to evaluate the self-help group's structure, use of social media and financial background. RESULTS: Support groups for dwarfism, infantile cerebral palsy and Down syndrome responded and sent the questionnaire back to our department. Most self-help groups were incorporated societies and belonged to an umbrella organisation. The founding year was predominantly in the decade 1990 - 2000 (n = 15). The founders were predominantly parents (n = 28; 77.8%), concerned individuals (n = 11; 30.6%) and - in two cases - physicians (5.6%). 29 support groups (80.6%) received donations for financial support. The aims, activities, and manner of contact were presented in the home page (n = 35; 97.2%). Most self-help group focussing on paediatric orthopaedic disorders cooperate with physicians in different specialisations to obtain information and recommendations. CONCLUSIONS: The study presents the first information on self-help groups and documents the multidisciplinarity of paediatric orthopaedics. Close collaboration between paediatric orthopaedic surgeons and regional support groups might contribute to the reduction of uncertainty and fears and improve of medical provision.

The prognostic value of sST2 and galectin-3 considering different aetiologies in non-ischaemic heart failure.

Objective: Several studies indicate a prognostic value of sST2 and galectin-3 in heart failure (HF). While previous studies focused on ischaemic cause of HF, we investigated the role of sST2 and galectin-3 in patients with non-ischaemic dilated cardiomyopathy (DCM). Methods: sST2 and galectin-3 serum concentrations were measured in 262 subjects with DCM. Survival rates were determined for all-cause mortality (ACM) and cardiac mortality (CM). Results: In a univariate model, sST2 as a continuous variable was a predictor of ACM (HR 1.05; 95% CI 1.03 to 1.07, P<0.001) and CM (HR 1.03; 95% CI 1.00 to 1.06, P=0.040). In the subgroup of patients with inflammatory and/or viral DCM (DCMi⋎viral), the endpoints ACM (HR 1.10; 95% CI 1.05 to 1.17, P<0.001) and CM (HR 1.10; 95% CI 1.02 to 1.18, P=0.013) were significant. In the subgroup of patients with idiopathic DCM, the endpoint ACM (HR 1.04; 95% CI 1.01 to 1.07, P=0.019) was significant. In a multivariate model, the prognostic value of the sST2 main group remained intact for ACM (HR 1.04; 95% CI 1.02 to 1.07, P=0.003).Univariate and multivariate analysis of galectin-3 as continuous variable did not show any significant result. However, in a quartile model, intermediate values of galectin-3 were significantly associated with a lower event rate of ACM and CM. Conclusion: The study revealed that sST2 predicts ACM and CM in patients with non-ischaemic HF and could be useful especially in patients with inflammatory background. Our findings that intermediate levels of galectin-3 allow for better prognosis were new and different to other investigations. Trial registration number: NCT03090425; Results.

Continuous positive air pressure improves orthonasal olfactory function of patients with obstructive sleep apnea.

OBJECTIVE: Recent studies have suggested that patients with obstructive sleep apnea (OSA) might be affected by olfactory impairment. However, more evidence is needed on the effect that OSA has on the chemical senses (olfaction and gustatory) of these patients, and whether continuous positive airway pressure (CPAP) treatment might help to reverse possible impairment. METHODS: A prospective study was conducted with 44 OSA patients (17 female and 27 male, mean age 54 ± 9.9 years) who were diagnosed via polysomnography and eligible for CPAP treatment. Orthonasal olfactory and gustatory function was measured with the extended Sniffin' Sticks test battery and "taste strips," respectively, before and after CPAP treatment. RESULTS: Baseline olfaction was decreased in OSA patients and after CPAP therapy olfactory scores (odor threshold-discrimination-identification score [TDI]: baseline 29.4 ± 4.11 after CPAP 32.3 ± 4.82; p = 0.001; odor threshold [THR]: baseline 5.28 ± 1.69 after CPAP 6.78 ± 2.61; p = 0.000; odor identification [ID]: baseline 12.9 ± 1.95 after CPAP 13.6 ± 1.33; p = 0.013) improved significantly. In contrast, neither baseline taste function in OSA patients nor gustatory function after treatment seemed to be affected. CONCLUSION: Orthonasal olfactory function in patients with OSA improves under CPAP therapy; however, gustatory function is not impaired in OSA patients.

Prognostic value of level IV metastases from head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of level IV metastases in head and neck squamous cell carcinoma (HNSCC). METHODS: The clinical and histopathological data of 111 patients with HNSCC with pN+ neck who underwent a primary tumor resection with unilateral or bilateral neck dissection were analyzed. RESULTS: Level IV metastases were histopathologically proven in 33 patients (29.7%). Pulmonary metastases were observed in 12 of 33 patients (36.4%) with level IV metastases, and in 13 of 78 patients (16.7%) without level IV metastases (p = .04). Multivariate analyzes revealed a significant association between level IV metastases and pulmonary metastases (p = .038). However, an influence on overall (p = .65) or disease-free survival (p = .66) was not observed. CONCLUSION: Level IV metastases seem to be a predictive factor for pulmonary metastases but not for overall and disease-free survival in patients with HNSCC.

Alterations of cortisol homeostasis may link changes of the sociocultural environment to an increased diabetes and metabolic risk in developing countries: a prospective diagnostic study performed in cooperation with the Ovahimba people of the Kunene region/northwestern Namibia.

CONTEXT: Diabetes mellitus is increasingly affecting Africa. OBJECTIVE: Urbanization of the Ovahimba people in Namibia is associated with an increased prevalence of disorders of glucose metabolism, and may thus be attributed to changes of cortisol homeostasis. DESIGN: A prospective, cross-sectional, diagnostic study was applied. SETTING: The study was conducted in the field. Location of the Diabetes Epidemic: Africa and Namibia. PARTICIPANTS: Ovahimba people: group 1 "urban" n = 60, 42 females, 46.3 ± 11.3 years (town); group 2 "rural" n = 63, 44 females, 51.1 ± 12.0 years (seminomadic). INTERVENTIONS: oGTT, sunrise and sunset saliva cortisol, metabolic parameters, questionnaire. MAIN OUTCOME MEASURE: The prevalence of disorders of glucose metabolism (DM, IGT, IFT). RESULTS: The prevalence of disorders of glucose metabolism differed significantly: urban group n = 17(28.3%) vs rural group n = 8(12.7%) (P = 0.04). The saliva cortisol concentrations also differed significantly: sunrise 0.34 ± 0.18 vs 0.12 ± 0.15 µg/dL, sunset 0.18 ± 0.20 vs 0.07 ± 0.09 µg/dL, area under the curve 6.16 ± 3.48 vs 2.28 ± 2.56 µg/dL * 24 h (all P < 0.001). Further metabolic parameters were unfavorably changed in the urban group: hip circumference (P < 0.001), waist circumference (P < 0.001), body mass index (P = 0.014), systolic BP at rest (P < 0.001), diastolic BP at rest (P = 0.002), systolic BP after exercise (P < 0.001), heart rate after exercise (P = 0.007), fasting glucose (P < 0.001), 2-h-glucose by OGTT (P = 0.002), triglycerides (P = 0.04), HDL-cholesterol (P = 0.014), prevalence of the metabolic syndrome (P < 0.001). Physical activity was higher in the rural group, and intake of fast food and sweets were higher in the urban group. CONCLUSIONS: Urbanization of the Ovahimba people is associated with an increasing prevalence of disorders of glucose metabolism and other unfavorable metabolic parameters. Besides changes of lifestyle, this may be attributed to an increased cortisol exposure of the Ovahimba people living in an urban environment.

Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification.

BACKGROUND AND AIM: Chemotherapy with streptozocin (STZ) in combination with 5-FU or doxorubicin (Dox) represents a standard of care for patients with metastatic pancreatic neuroendocrine neoplasms (pNEN). However, predictive markers for patient selection are still missing. The aim of this study was a retrospective evaluation of the clinicopathological characteristics of pNEN patients receiving STZ-based chemotherapies and to identify predictive and prognostic markers. PATIENTS AND METHODS: We retrospectively analyzed 77 patients treated at our center between 1995 and 2013. The median overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and Cox regression methods, respectively. Uni- and multivariate analyses were performed. RESULTS: The median PFS (mPFS) in patients receiving STZ/5-FU/Dox was 16 months with a median OS (mOS) of 28 months. Objective response rate (ORR) and disease control rate (DCR) were 34% and 72%, respectively. Biochemical response and positive octreotide scintigraphy predicted objective response. Univariate analysis revealed Ki-67 > 10% and the absence of biochemical or objective response by imaging as independent risk factors for shorter PFS. Additionally, performance status (PS) and resection of the primary tumor were observed to influence mOS. Treatment was well tolerated with less than 10% grade 3 and 4 toxicities. CONCLUSIONS: STZ-based chemotherapy is an effective and well-tolerated treatment option in patients with well differentiated neuroendocrine neoplasms. Positive octreotide scintigraphy and biochemical response predict objective response.