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Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less ( Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.

BackgroundImmune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting.MethodsWe retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS).Results and conclusionICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.

Agonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.

ObjectivesTo validate the adherence of urologists to chemotherapy recommendations given in the EAU guidelines on PeCa. The European Association of Urology (EAU) guidelines on penile cancer (PeCa) are predominantly based on retrospective studies with low level of evidence.Materials and methodsA 14-item-survey addressing general issues of PeCa treatment was developed and sent to 45 European hospitals. 557 urologists participated in the survey of which 43.5%, 19.3%, and 37.2% were in-training, certified, and in leading positions, respectively. Median response rate among participating departments was 85.7% (IQR 75–94%). Three of 14 questions addressed clinical decisions on neoadjuvant, adjuvant, and palliative chemotherapy. Survey results were analyzed by bootstrap-adjusted multivariate logistic-regression-analysis to identify predictors for chemotherapy recommendations consistent with the guidelines.ResultsNeoadjuvant, adjuvant, and palliative chemotherapy was recommended according to EAU guidelines in 21%, 26%, and 48%, respectively. For neoadjuvant chemotherapy, urologists holding leading positions or performing chemotherapy were more likely to recommend guideline-consistent treatment (OR 1.85 and 1.92 with p(bootstrap) = 0.007 and 0.003, respectively). Supporting resources (i.e., guidelines, textbooks) were used by 23% of survey participants and significantly improved consistency between treatment recommendations and Guideline recommendations in all chemotherapy settings (p(bootstrap) = 0.010–0.001). Department size and university center status were no significant predictors for all three endpoints.ConclusionsIn this study, we found a very low rate of adherence to the EAU guidelines on systemic treatment for PeCa. Further investigations are needed to clarify whether this missing adherence is a consequence of limited individual knowledge level or of the low grade of guideline recommendations.

With the aging of the population, the medical and social costs of skeletal fragility leading to fractures will cause an immense burden on society unless effective prophylactic and therapeutic regimens can be developed. Exercise is suggested as a possible regimen against involutional bone loss. The purpose of the present meta-analysis is to address a quantitative review of the randomized controlled trials (RCTs) and nonrandomized controlled trials (CTs) on the effects of exercise training programs on bone mass, measured as bone mineral density (BMD) or bone mineral content (BMC), of the lumbar spine (LS) and the femoral neck (FN) in pre- and postmenopausal women. The literature from 1966 through December 1996 was searched for published RCTs and CTs. Study treatment effect is defined as the difference between percentage change in bone mass per year in the training group and the control group. Overall treatment effects (OTs) with the 95% confidence intervals of these study treatment effects were calculated using inverse-variance weighting. Of the 62 articles identified, 25 met the inclusion criteria and were maintained for further analyses. The weighted OTs for the RCTs showed very consistently that the exercise training programs prevented or reversed almost 1% of bone loss per year in both LS and FN for both pre- and postmenopausal women. The two OTs that could be calculated for strength training programs did not reach significance. The OTs for the CTs were almost twice as high as those for the RCTs, which gives an indication of the confounding introduced by the nonrandom allocation of the subjects to groups.

Acute ischaemic stroke is a devastating postoperative complication that significantly impacts upon a patient’s quality of life. Endovascular retrieval of thromboembolic material from proximal cerebral arteries by mechanical thrombectomy is the new standard of care for patients presenting with a proximal artery occlusion. We report the case of a patient developing an acute ischaemic stroke following pulmonary lobectomy, who was transferred to the regional neurosciences unit, despite the absence of an established referral pathway, to undergo mechanical thrombectomy, with significant prognostic neurological benefit. We would advocate all cardiothoracic centres identify their regional neurosciences unit and initiate discussion to establish a referral pathway.

Purpose Because the prognostic impact of the clinical and pathological features on cancer-specific survival (CSS) and overall survival (OS) in patients with papillary renal cell carcinoma (papRCC) is still controversial, we want to assess the impact of clinicopathological features, including Fuhrman grade and age, on survival in surgically treated papRCC patients in a large multi-institutional series. Methods We established a comprehensive multi-institutional database of surgically treated papRCC patients. Histopathological data collected from 2189 patients with papRCC after radical nephrectomy or nephron-sparing surgery were pooled from 18 centres in Europe and North America. OS and CSS probabilities were estimated using the Kaplan–Meier method. Multivariable competing risks analyses were used to assess the impact of Fuhrman grade (FG1-FG4) and age groups (<50 years, 50–75 years, >75 years) on cancer-specific mortality (CSM). Results CSS and OS rates for patients were 89 and 81% at 3 years, 86 and 75% at 5 years and 78 and 41% at 10 years after surgery, respectively. CSM differed significantly between FG 3 (hazard ratio [HR] 4.22, 95% confidence interval [CI] 2.17–8.22; p  < 0.001) and FG 4 (HR 8.93, 95% CI 4.25–18.79; p  < 0.001) in comparison to FG 1. CSM was significantly worse in patients aged >75 (HR 2.85, 95% CI 2.06–3.95; p  < 0.001) compared to <50 years. Conclusions FG is a strong prognostic factor for CSS in papRCC patients. In addition, patients older than 75 have worse CSM than patients younger than 50 years. These findings should be considered for clinical decision making.

Within the BUSTER trial, we analyzed the surgeon’s amount of experience and other parameters associated with URS procedures regarding the stone-free rate, complication rate, and operative time. Patient characteristics and surgical details on 307 URS procedures were prospectively documented according to a standardized study protocol at 14 German centers 01–04/2015. Surgeon’s experience was correlated to clinical characteristics, and its impact on the stone-free rate, complication rate, and operative time subjected to multivariate analysis. 76 (25%), 66 (21%) and 165 (54%) of 307 URS procedures were carried out by residents, young specialists, and experienced specialists (> 5 years after board certification), respectively. Median stone size was 6 mm, median operative time 35 min. A ureteral stent was placed at the end of 82% of procedures. Stone-free rate and stone-free rate including minimal residual stone fragments (adequate for spontaneous clearance) following URS were 69 and 91%, respectively. No complications were documented during the hospital stays of 89% of patients (Clavien–Dindo grade 0). According to multivariate analysis, experienced specialists achieved a 2.2-fold higher stone-free rate compared to residents (p = 0.038), but used post-URS stenting 2.6-fold more frequently (p = 0.023). Surgeon’s experience had no significant impact on the complication rate. We observed no differences in this study’s main endpoints, namely the stone-free and complication rates, between residents and young specialists, but experienced specialists’ stone-free rate was significantly higher. During this cross-sectional study, 75% of URS procedures were performed by specialists. The experienced specialists’ more than two-fold higher stone-free rate compared to residents’ justifies ongoing efforts to establish structured URS training programs.

Purpose Optical coherence tomography (OCT) is an imaging technology based on low-coherence interferometry, which provides non-invasive, high-resolution cross-sectional images of biological tissues. A potential clinical application is the intraoperative examination of resection margins, as a real-time adjunct to histological examination. In this ex vivo study, we investigated the ability of OCT to differentiate colorectal liver metastases (CRLM) from healthy liver parenchyma, when combined with convolutional neural networks (CNN). Methods Between June and August 2020, consecutive adult patients undergoing elective liver resections for CRLM were included in this study. Fresh resection specimens were scanned ex vivo, before fixation in formalin, using a table-top OCT device at 1310 nm wavelength. Scanned areas were marked and histologically examined. A pre-trained CNN (Xception) was used to match OCT scans to their corresponding histological diagnoses. To validate the results, a stratified k-fold cross-validation (CV) was carried out. Results A total of 26 scans (containing approx. 26,500 images in total) were obtained from 15 patients. Of these, 13 were of normal liver parenchyma and 13 of CRLM. The CNN distinguished CRLM from healthy liver parenchyma with an F1-score of 0.93 (0.03), and a sensitivity and specificity of 0.94 (0.04) and 0.93 (0.04), respectively. Conclusion Optical coherence tomography combined with CNN can distinguish between healthy liver and CRLM with great accuracy ex vivo. Further studies are needed to improve upon these results and develop in vivo diagnostic technologies, such as intraoperative scanning of resection margins.