WNT5B drives osteosarcoma stemness, chemoresistance and metastasis.

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. RESULTS: In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. CONCLUSIONS: Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. KEY POINTS: WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Ureteropelvic junction obstruction caused by metastatic cholangiocarcinoma.

We describe the rare case of a 61-year-old female with right ureteropelvic junction (UPJ) obstruction caused by metastatic cholangiocarcinoma. Her past medical history was notable for cholangiocarcinoma treated with neoadjuvant chemoradiation and two orthotopic liver transplants six years earlier. Urology was consulted when she presented with flank pain and urinary tract infection. Diagnostic workup demonstrated right UPJ obstruction. She was managed acutely with percutaneous nephrostomy. She subsequently underwent robotic pyeloplasty and intrinsic obstruction of the UPJ was discovered. Histological examination revealed adenocarcinoma, consistent with systemic recurrence of the patient's known cholangiocarcinoma.

Ureteropelvic junction obstruction caused by metastatic cholangiocarcinoma

ABSTRACT We describe the rare case of a 61-year-old female with right ureteropelvic junction (UPJ) obstruction caused by metastatic cholangiocarcinoma. Her past medical history was notable for cholangiocarcinoma treated with neoadjuvant chemoradiation and two orthotopic liver transplants six years earlier. Urology was consulted when she presented with flank pain and urinary tract infection. Diagnostic workup demonstrated right UPJ obstruction. She was managed acutely with percutaneous nephrostomy. She subsequently underwent robotic pyeloplasty and intrinsic obstruction of the UPJ was discovered. Histological examination revealed adenocarcinoma, consistent with systemic recurrence of the patient's known cholangiocarcinoma.

Retroperitoneal access for robotic renal surgery.

INTRODUCTION AND OBJECTIVE: Retroperitoneal access for robotic renal surgery is an effective alternative to the commonly used transperitoneal approach. We describe our contemporary experience and technique for attaining retroperitoneal access. MATERIALS AND METHODS: We outline our institutional approach to retroperitoneal access for the instruction of urologists at the beginning of the learning curve. The patient is placed in the lateral decubitus position. The first incision is made just inferior to the tip of the twelfth rib as described by Hsu, et al. After the lumbodorsal fascia is traversed, the retroperitoneal space is dilated with a round 10 millimeter AutoSutureTM (Covidien, Mansfield, MA) balloon access device. The following trocars are used: A 130 millimeter KiiR balloon trocar (Applied Medical, Rancho Santa Margarita, CA), three robotic, and one assistant. Key landmarks for the access and dissection are detailed. RESULTS: 177 patients underwent a retroperitoneal robotic procedure from 2007 to 2015. Procedures performed include 158 partial nephrectomies, 16 pyeloplasties, and three radical nephrectomies. The robotic fourth arm was utilized in all cases. When compared with the transperitoneal approach, the retroperitoneal approach was associated with shorter operative times and decreased length of stay (1). Selection bias and surgeon preference accounted for the higher proportion of patients who underwent partial nephrectomy off-camp via the retroperitoneal approach. CONCLUSIONS: Retroperitoneal robotic surgery may confer several advantages. In patients with previous abdominal surgery or intra-abdominal conditions, the retroperitoneum can be safely accessed while avoiding intraperitoneal injuries. The retroperitoneum also provides a confined space that may minimize the sequelae of potential complications including urine leak. Moreover, at our institution, retroperitoneal robotic surgery is associated with shorter operative times and a decreased length of stay when compared with the transperitoneal approach (2). In selected patients, the retroperitoneal approach is a viable alternative to the transperitoneal approach for a variety of renal procedures.

Patient and nonradiographic tumor characteristics predicting lipid-poor angiomyolipoma in small renal masses: Introducing the BEARS index.

PURPOSE: To create a simple model using clinical variables for predicting lipid-poor angiomyolipoma (AML) in patients with small renal masses presumed to be renal cell carcinoma (RCC) from preoperative imaging. MATERIALS AND METHODS: A series of patients undergoing partial nephrectomy (PN) for renal masses ≤4 cm was identified using a prospectively maintained database. Patients were excluded if standard preoperative imaging was not consistent with RCC. Chi square and Mann-Whitney U analyses were used to evaluate differences in characteristics between patients with AML and other types of pathology. A logistic regression model was constructed for multivariable analysis of predictors of lipid-poor AML. RESULTS: A total of 730 patients were identified that underwent PN for renal masses ≤4 cm between 2007-2015, including 35 with lipid-poor AML and 620 with RCC. In multivariable analysis, the following features predicted AML: female sex (odds ratio, 6.89; 95% confidence interval, 2.35-20.92; p<0.001), age <56 years (2.84; 1.21-6.66; p=0.02), and tumor size <2 cm (5.87; 2.70-12.77; p<0.001). Sex, age, and tumor size were used to construct the BEnign Angiomyolipoma Renal Susceptibility (BEARS) index with the following point values for each particular risk factor: female sex (2 points), age <56 years (1 point), and tumor size <2 cm (2 points). Within the study population, the BEARS index distinguished AML from malignant lesions with an area under the curve of 0.84. CONCLUSIONS: Young female patients with small tumors are at risk for having lipid-poor AML despite preoperative imaging consistent with RCC. Identification of these patients may reduce the incidence of unnecessary PN for benign renal lesions.

Partial Nephrectomy for Presumed Renal-Cell Carcinoma: Incidence, Predictors, and Perioperative Outcomes of Benign Lesions.

BACKGROUND: The aim of this study was to investigate the incidence of benign histology after partial nephrectomy (PN) in patients with presumed malignancy from preoperative imaging. Furthermore, preoperative predictors of benign lesions and perioperative outcomes were also assessed. METHODS: A series of patients undergoing PN for renal masses was identified using a prospectively maintained database. Patients were excluded for known genetic conditions, if more than one renal mass was resected, or if standard preoperative imaging was not suspicious for renal-cell carcinoma (RCC). Differences in characteristics between patients with benign and malignant pathology were assessed. RESULTS: A total of 916 patients were identified who underwent PN between 2007 and 2015, including 129 (14.1%) patients with a final diagnosis of benign disease. The most common types of benign pathology were oncocytoma (n = 66, 51.2%), angiomyolipoma (n = 37, 28.7%), and complex cysts (n = 10, 7.8%). Low body mass index (BMI) [0.96 (0.92-0.99) p = 0.02], low R.E.N.A.L. score [0.86 (0.76-0.96) p = 0.007], and low preoperative creatinine [0.37 (0.14-0.91) p = 0.04] predicted benign histology in multivariate analysis. Tumor size was a significant predictor in additional modeling [0.81 (0.69-0.94) p = 0.008]. Patients with benign histology had significantly shorter operative times (p < 0.001) and less estimated blood loss (p < 0.001), and there was no difference in complication (p = 0.93) or blood transfusion (0.24) rates. CONCLUSIONS: In this study, the rate of benign pathology after PN for presumed RCC is 14.1%. BMI, R.E.N.A.L. score, and preoperative creatinine are predictive of benign histology, but the ability of different variables to predict benign lesions may be influenced by the distribution of benign tumor subtypes, reflecting potential unidentified selection bias.