Initial in vivo testing of a multitarget kinase inhibitor, regorafenib, by the Pediatric Preclinical Testing Consortium.

BACKGROUND: Regorafenib is a small molecule multikinase inhibitor that inhibits multiple kinases including BRAF, KIT, PDGFRB, RAF, RET, and VEGFR1-3. PROCEDURES: The in vivo anticancer effects of regorafenib were assessed in a panel of six osteosarcoma models, three rhabdomyosarcoma models, and one Ewing sarcoma model. RESULTS: Regorafenib induced modest inhibition of tumor growth in the models evaluated. CONCLUSION: The overall pattern of response to regorafenib appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models, limited to the period of agent administration, being the primary treatment effect.

Operative experience of urological trainees in the UK.

What's known on the subject? And what does the study add? One of the main components of surgical training is the development of operative skills which, in part, is related to the extent of the practical operative experience. The operative experience of urological trainees in the UK has not being previously published. We examine trainees' current operative experience and analyse the changes over recent years. With a notable decrease in experience of certain procedures, we highlight the possible reasons and discuss the implications for future training. We have examined the operative experience of urological trainees in the UK over a 6-year period. Between 2004 and 2009, urological trainees submitting their operative logbooks to the Specialist Advisory Committee for the award of Certificate of Completion of Training were analysed. We recorded trainees' experience in eight operative procedures; transurethral resection of the prostate (TURP, including bipolar TURP), transurethral resection of bladder tumour (TURBT), radical nephrectomy (RN, open and laparoscopic), radical cystectomy (RC), radical prostatectomy (RP), percutaneous nephrolithotomy (PCNL) and ureteroscopy (flexible and rigid). In all, 251 logbooks were identified over the 6-year period. In 2008/2009, the mean (range) number of cases 'performed' and 'supervised' were as follows; TURP 189 (41-516), TURBT 190 (50-432), open RN 21 (2-78), RC 10 (0-70), RP 13 (0-80), PCNL 19 (0-125), ureteroscopy 131 (14-465), laparoscopic RN 11 (0-97). Latterly there has been a significant reduction in the numbers of TURP, open RNs and RCs. There has been an increase in the use of trainees as assistants for RC, RP and open RN. There was a large variation in numbers of procedures performed between trainees. In summary there has been a recent decline in the numbers of TURP, open RNs and RCs performed. For all procedures, significant variability exists between trainees.

Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma.

Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable development of effective therapeutics in this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP-targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma.

Current and future therapeutic approaches for osteosarcoma.

INTRODUCTION: Current treatment of osteosarcoma includes surgical resection of all gross disease in conjunction with systemic chemotherapy to control micro-metastatic disease. This yields a 5-year event free survival (EFS) of approximately 70% for patients with localized osteosarcoma while patients with metastatic or recurrent disease fare poorly with overall survival rates of less than 20%. Areas covered: This review outlines the current and future approach towards the treatment of osteosarcoma. A literature search was performed utilizing PubMed. Several recent clinical trials are reviewed in detail, as is innovative research evaluating novel agents and surgical techniques which hold promise. Expert commentary: The outcome for patients with osteosarcoma has not changed in several decades. This plateau in survival rates highlights the need for a novel approach towards research. There remains a great deal of interest in utilizing the very high risk population of recurrent osteosarcoma patients to rapidly and sequentially evaluate novel agents to determine if any of these agents hold promise. Several phase II studies are ongoing or in development that offer hope based on intriguing preclinical data. Furthermore, initiatives in obtaining specimens to further explore the genetic and immunological profile behind osteosarcoma will be essential towards identifying novel pathways and targets to exploit.

Yolk sac tumor of the seminal vesicles: A rare malignant cause of hematospermia.

Extra-gonadal yolk sac tumors (YSTs) are rare and generally associated with poor outcomes. Involvement of the seminal vesicles is extremely rare with only one previously described case. We report a case of a primary YST of the seminal vesicles and discuss the management strategy.

Orthotopic neobladder perforation: an unusual presentation of small bowel obstruction.

Orthotopic bladder reconstruction is becoming increasingly popular in patients who have undergone radical cystectomy. One of the rare complications is spontaneous rupture, which presents with various symptoms, but in particular, abdominal pain. We report a case of orthotopic bladder perforation in a patient who presented with the symptoms and signs of small bowel obstruction.