Timely stereotactic body radiotherapy (SBRT) for spine metastases using a rapidly deployable automated planning algorithm.

PURPOSE/OBJECTIVES: The complex planning and quality assurance required for spine SBRT are a barrier to implementation in time-sensitive or limited resource clinical situations. We developed and validated an automated inverse planning algorithm designed to streamline planning and allow rapid delivery of conformal single fraction spine SBRT using widely available technology. MATERIALS/METHODS: The Rapid Spine (RaSp) automated script successfully generated single fraction SBRT plans for fourteen complex spinal lesions previously treated at a single high-volume institution. Automated RaSp plans were limited to 5 beams with a total of 15 segments (allowing calculation-based verification) and optimized based on RTOG 0631 objectives. Standard single fraction (16 Gy) stereotactic IMRT plans were generated for the same set of complex spinal lesions and used for comparison. A conservative 2 mm posterior isocenter shift was used to simulate minor set-up error. RESULTS: Automated plans were generated in under 5 min from target definition and had a mean dose to the PTV of 1663 cGy (SD 131.5), a dose to 90 % of PTV (D90) of 1358 cGy (SD 111.0), and a maximum point dose (Dmax) to the PTV of 2055 cGy (SD 195.2) on average. IMRT plans took longer to generate but yielded more favorable dose escalation with a mean dose to the PTV of 1891 cGy (SD 117.6), D90 of 1731 cGy (SD 126.5), and Dmax of 2218 cGy (SD 195.7). A 2 mm posterior shift resulted in a 20 % (SD 10.5 %) increase in cord dose for IMRT plans and a 10 % (SD 5.3 %) increase for RaSp plans. The 2 mm perturbation caused 3 cord dose violations for the IMRT plans and 1 violation for corresponding RaSp plans. CONCLUSION: The Rapid Spine plan method yields timely and dosimetrically reasonable SBRT plans which meet RTOG 0631 objectives and are suitable for rapid yet robust pretreatment quality assurance followed by expedited treatment delivery. RaSp plans reduce the tradeoff between rapid treatment and optimal dosimetry in urgent cases and limited resource situations.

Demographic and urodynamic factors associated with persistent OAB after anterior compartment prolapse repair.

INTRODUCTION: Overactive bladder (OAB) symptoms often accompany pelvic organ prolapse. While there seems to be a relationship between symptom resolution and anatomic repair, a subset of patients will not experience improvement in OAB symptoms. Our aim was to identify preoperative demographic and urodynamic (UD) parameters related to persistence of OAB symptoms after anterior vaginal prolapse (AVP) repair. METHODS: This retrospective cohort study examined demographic and UD data from patients undergoing AVP surgery. Pre- and post-operative Urogenital Distress Inventory (UDI-6) scores for frequency, urge urinary incontinence (UUI), and difficulty voiding were analyzed, as were correlations between scores and pre-operative UD data. RESULTS: From 2002 to 2008, 88 patients underwent AVP repair and were included in the final analysis. Surgery resulted in a reduction of frequency (33%), UUI (49%), and difficulty voiding (74%) at median 21 months follow-up. Change in symptom scores was unrelated to age, parity, BMI, or AVP grade, although older women reported greater improvement in difficulty emptying after repair. Improvement in difficulty emptying was related to a larger pre-operative post-void residual (PVR) (129 ml vs. 31 ml, P = 0.0008). Persistent UUI after repair was significantly related to a higher preoperative P(det)Q(max) (OR 1.056, 95% CI 1.003-1.11, P = 0.04). Other pre-operative UDS variables were not significantly related to the persistence of OAB symptoms. CONCLUSIONS: AVP repair reduces lower urinary tract symptoms (LUTS); however, 67% and 51% of patients will report persistent frequency and UUI, respectively, post-operatively. In this cohort, persistent OAB symptoms were not related to age, parity, BMI, or prolapse grade, but rather to pre-operative P(det)Q(max).

PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition.

The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key "executioner" caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds.