Systemic PPARγ Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents.

Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPARγ) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

High stroma-derived WNT5A is an indicator for low-risk prostate cancer.

Prostate cancer (PCa) is a major cause of cancer-related death in men. Tumor-derived protein derived from Wnt5A gene (WNT5A) plays an important role in primary and metastatic PCa. Surrounding stroma cells also produce WNT5A, which may modulate the biology of PCa. Here, we assessed the role of stroma-derived WNT5A (stWNT5A) in primary PCa. A tissue microarray of samples obtained from 400 patients who underwent radical prostatectomy and control samples from 41 patients with benign prostate hyperplasia (BPH) was immunohistochemically assessed for expression of stWNT5A. The cores were scored for staining intensity: 0 (no staining), 1 (weak), 2 (moderate), or 3 (strong) and the stained stromal surface area: 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%). Gleason Score (GS) and TNM-stage were assessed by stratifying the cohort into high-risk (≥ pT3, pN1, GS ≥ 8) and non-high-risk patients. Ki67 and TUNEL assays were performed to assess proliferation and apoptosis. Expression of stWNT5A in BPH and tumor-free control samples was 1.2-fold higher compared to tumor samples (P < 0.001). Non-high-risk patients had a higher stWNT5A score than high-risk patients (P < 0.05). stWNT5A expression was not correlated with overall and cancer-specific survival. Proliferation (r2  = 0.038, P < 0.001) and apoptosis (r2  = 0.277, P < 0.001) negatively correlated with stWNT5A expression. In summary, we show that expression of stWNT5A is higher in benign tissue and non-high-risk PCa. Stroma-derived Wnt signaling and tumor-derived Wnt may differentially impact on tumor behavior. Future studies are warranted to dissect the Wnt profile in tumor vs. surrounding stroma tissues.

Radiographic scoliosis angle estimation: spline-based measurement reveals superior reliability compared to traditional COBB method.

INTRODUCTION AND OBJECTIVE: Although being standard for scoliosis curve size estimation, COBB angle measurement is well known to be inaccurate, due to a high interobserver variance in end vertebra selection and end plate contour delineation. We propose a stepwise improvement by using a spline constructed from vertebra centroids to resemble spinal curve characteristics more closely. To enhance precision even further, a neural net was trained to detect the centroids automatically. MATERIALS & METHODS: Vertebra centroids in AP spinal X-ray images of varying quality from 551 scoliosis patients were manually labeled by 4 investigators. With these inputs, splines were generated and the computed curve sizes were compared to the manually measured COBB angles and to the curve estimation obtained from the neural net. RESULTS: Splines achieved a higher interobserver correlation of 0.92-0.95 compared to manual COBB measurements (0.83-0.92) and showed 1.5-2 times less variance, depending on the anatomic region. This translates into an average of 1° of interobserver measurement deviation for spline-based curve estimation compared to 3°-8° for COBB measurements. The neural net was even more precise and achieved mean deviations below 0.5°. CONCLUSION: In conclusion, our data suggest an advantage of spline-based automated measuring systems, so further investigations are warranted to abandon manual COBB measurements.

Impact of Different Exercise Programs on Severe Fatigue in Patients Undergoing Anticancer Treatment-A Randomized Controlled Trial.

CONTEXT: Physical exercise can alleviate cancer-related fatigue. Randomized controlled trials in patients with advanced cancer are scarce. OBJECTIVES: We test the impact of a structured, individual sports program on fatigue in patients with advanced cancer. METHODS: Seventy-seven patients were invited to participate in this randomized controlled trial exploring the effects of physical exercises on fatigue 12 and 24 weeks after baseline. Patients were randomized into three groups. Group A received treatment as usual, Group B was taught a structured, individual sports program, and Group C received additional ambulatory physiotherapeutical supervision. Primary outcome was general fatigue, secondary outcomes included rate of severe general fatigue, further dimensions of the Multidimensional Fatigue Inventory (MFI), as well as walking distance. RESULTS: Mean score of general fatigue as well as other MFI subdimensions differed nonsignificantly between all groups at 12 weeks. However, the mental fatigue score demonstrated a statistically significant difference between the three groups. The rate of severe general fatigue was significantly reduced within Intervention Group C. Significant longitudinal change of MFI-dimension mental fatigue was found and reached the threshold for minimal clinically important difference, while all MFI-dimensions increased in Group A. CONCLUSION: Our results imply that tumor-patients' severe general fatigue can be reduced when patients conduct appropriate physical exercise. This study amends previous knowledge, as it describes the impact of outpatient physical exercise on fatigue in a heterogeneous patient cohort with various advanced cancer entities. Furthermore, this trial differentiates between patients with only a self-directed exercise program versus those receiving additional partially professional supervision.