The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγ^null (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies.

Purpose: Scaffold‐based autologous chondrocyte implantation is a well‐established treatment for cartilage defects in the knee joint. Hydrogel‐based autologous chondrocyte implantation using an in situ polymerizable biomaterial is a relatively new treatment option for arthroscopic cartilage defects. It is therefore important to determine if there are significant differences in the outcomes. The aim of this study is to compare the outcomes (using subjective parameters) of hydrogel‐based autologous chondrocyte implantation (NOVOCART^® Inject) with the outcomes of scaffold based autologous chondrocyte Implantation (NOVOCART^® 3D) using biphasic collagen scaffold.Methods: The data of 50 patients, which were paired with 25 patients in each treatment group, was analyzed. The main parameters used for matching were gender, number of defects and localization. Both groups were compared based on Visual Analogue Scale (VAS) and subjective IKDC scores, both of which were examined pre‐operatively and after 6, 12 and 24 months.Results: Significant benefits in both VAS and IKDC scores after 2 years of follow‐up in both groups were found. Comparing the groups, the results showed that in the hydrogel‐based autologous chondrocyte implantation group, significant changes in IKDC scores are measurable after 6 months, while it takes 12 months until they are seen in the scaffold based autologous chondrocyte group. Conclusion: Hydrogel‐based autologous chondrocyte and scaffold based autologous chondrocyte show comparable improvements and significant benefits to the patients’ subjective well‐being after a 2‐year‐follow‐up.Level of evidence: III.

Purpose: To assess the percentage of missed developmental dysplasia of the hip, which escape the German criteria for newborn hip high-risk screening, we analyzed our data gained from the general neonatal sonographic hip screening performed at our department. The aim of the study was to determine the number of potentially belatedly treated developmental dysplasia of the hip. Methods: The data from 1145 standardized newborn hip ultrasound examinations according to the Graf technique were analyzed retrospectively comparing findings for general neonatal sonographic hip screening and high-risk screening subgroups. Results: We diagnosed developmental dysplasia of the hip in 18 of the 1145 newborns via ultrasound. A total of 10 out of 18 developmental dysplasia of the hip would have been missed by high-risk screening, which corresponds to a proportion of 55.6% false-negative results. The sensitivity of high-risk screening was only 44.4% and specificity, 78.3%. The positive predictive value was 3.2%. Family history as a screening criterion yielded false-negative results in 77.8% and false-positive results in 16.8%. In all, 83.3% of the children who were born with developmental dysplasia of the hip but not from breech position as a risk factor were false negative. The clinical examination was false negative in 88.9% and false positive in 0.6%. Conclusion: High-risk screening detected less than every second developmental dysplasia of the hip, rendering the first month as the most effective treatment window unavailable for inapparent dysplastic hips, potentially resulting in the need for more invasive treatment. Due to the high sensitivity of ultrasound in the detection of developmental dysplasia of the hip, we recommend to replace the current German high-risk screening guidelines with a general newborn screening for all neonates using Graf ultrasound in the first week of life. Level of evidence: Level II.

As most chemotherapeutic drugs are ineffective in the treatment of chondrosarcoma, we studied the expression pattern and function of SOX9, the master transcription factor for chondrogenesis, in chondrosarcoma, to understand the basic molecular principles needed for engineering new targeted therapies. Our study shows an increase in SOX9 expression in chondrosarcoma compared to normal cartilage, but a decrease when the tumors are finally defined as dedifferentiated chondrosarcoma (DDCS). In DDCS, SOX9 is almost completely absent in the non-chondroid, dedifferentiated compartments. CRISPR/Cas9-mediated knockout of SOX9 in a human chondrosarcoma cell line (HTB94) results in reduced proliferation, clonogenicity and migration, accompanied by an inability to activate MMP13. In contrast, adhesion, apoptosis and polyploidy formation are favored after SOX9 deletion, probably involving BCL2 and survivin. The siRNA-mediated SOX9 knockdown partially confirmed these results, suggesting the need for a certain SOX9 threshold for particular cancer-related events. To increase the efficacy of chondrosarcoma therapies, potential therapeutic approaches were analyzed in SOX9 knockout cells. Here, we found an increased impact of doxorubicin, but a reduced sensitivity for oncolytic virus treatment. Our observations present novel insight into the role of SOX9 in chondrosarcoma biology and could thereby help to overcome the obstacle of drug resistance and limited therapy options.

Legg–Calvé–Perthes disease (LCPD) requires individualized treatment in order to regain a functional hip joint. In severe cases, in which a congruent joint cannot be achieved, other options are necessary in order to improve functionality and prevent early osteoarthritis. Therefore, we analysed the clinical and radiologic outcome of 28 patients after valgus osteotomy of the proximal femur (VOF). We examined the range of hip motion, functionality and health-related quality of life (HRQoL) via modified Harris Hip Score (mHHS) and Kidscreen-10. Radiographic analysis contained quantitative and qualitative measurements of hip morphology. In particular, we correlated the results with the change of the pelvic-femoral angle (PFA). PFA was defined as the angle between the anatomical diaphyseal line of the femur and a vertical line through the pelvis. The mean follow-up was 5.5 years. Patients showed high mHHS and good HRQoL postoperatively. An increase in ROM with an improvement of 30.5° abduction and 10.3° internal rotation was evident. PFA correlated with adduction contracture and improved significantly after surgery. In consideration of careful patient selection, VOF showed a positive effect on ROM, pain, HRQoL, radiographic congruence and outcome. We identified the age at surgery and an increasing adduction contracture—objectified by a decreased PFA—as a prognostic factor.