Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk: 0.05; HR no high-risk: 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N ¼ 1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P ¼ 0.014, OR ¼ 6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

Purpose Non-melanoma skin cancers of the face are at high-risk for local recurrence and metastatic spread. While surgical interventions such as Mohs microsurgery are considered the standard of care, this modality has the potential for high rates of toxicity in sensitive areas of the face. Catheter flap high-dose-rate (HDR) brachytherapy has shown promising results, with high rates of local control and acceptable cosmetic outcomes. Material and methods Patients with non-melanoma skin cancers (NMSC) located on the face were treated with 40 Gy in 8 fractions, given twice weekly via catheter flap HDR brachytherapy. Clinical target volume (CTV) included the visible tumor plus a margin of 5 mm in all directions, with no additional planning target volume (PTV) margin. Results Fifty patients with 53 lesions on the face were included, with a median follow-up of 15 months. All were considered high-risk based on NCCN guidelines. Median tumor size and thickness were 18 mm and 5 mm, respectively. Median PTV volume and D 90 were 1.7 cc and 92%, respectively. Estimated rate of local control at twelve months was 92%. Three patients (5%) experienced acute grade 2 toxicity. Two patients (4%) continued to suffer from chronic grade 1 skin toxicity at 12 months post-radiotherapy (RT), with an additional two patients (4%) experiencing chronic grade 2 skin toxicity. Forty-nine lesions (92%) were found to have a good or excellent cosmetic outcome with complete tumor remission. Conclusions CT-based flap applicator brachytherapy is a valid treatment option for patients with NMSC of the face. This modality offers high rates of local control with acceptable cosmetic outcomes and low rates of toxicity.

BackgroundUrinary symptoms and sexual dysfunction are the two most common complaints following prostate radiotherapy. The impact of hypofractionated treatment on sexual function, irritative symptoms, and voiding symptoms has not been determined within the same patient population. Here we present our institutional data on sexual function, voiding function, irritative symptoms, and treatment response following SBRT.MethodsThis retrospective analysis includes 102 non-metastatic patients treated with SBRT at a single institution between May 2008 and September 2014. The course of radiotherapy consisted of 36.25 Gy (range 35–40) over five daily fractions. International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM), and PSA were recorded at baseline, 1, 3, 6, 9, 12, 18, 24, and 36 months after treatment.ResultsMedian patient age was 72 years old with a median follow-up of 4.3 years. Pretreatment IPSS-I score was 5.21, increasing to 6.97 (p < .001) after 1 month. The mean IPSS-I score returned close to baseline after 3 months to 5.86 and decreased to below baseline after 2 years to 5.09. At 3 months, 9 months, and 2 years, 47.5, 76.2, and 91.1 % of patients had reached IPSS-I resolution. The mean IPSS-O score prior to treatment was 5.31 and there was an increase in the score to 6.45 (p = 0.344) at 1 month. The score remained close to baseline and decreased to 4.00 at 2 years and significantly decreased to 3.74 (p = 0.035) at 3 years. 64.4, 82.1, and 96.0 % of patients had IPSS-O resolution by 3 months, 9 months, and 2 years. The mean SHIM score prior to treatment was 13.52 and continually decreased to below baseline a year after treatment to 10.56 (p < .001). SHIM score began to improve at 18 months, but was still significantly less than baseline at 12.12 (p = .01).ConclusionsWhile an increase in AUA/IPSS score initially occurred, all patients resume normal activities immediately following treatment and the AUA/IPSS symptoms improved from baseline. Irittative symptoms take longer to resolve when compared to obstructive voiding symptoms in patients treated with SBRT. Three year PSA response, reported toxicity, erectile function preservation, and urinary function improvement, shows favorable results.

Purpose: To present a retrospective analysis of the efficacy, toxicity, and quality of life (QoL) of patients treated with OARExtreme-sparing stereotactic body radiotherapy (SBRT) in previously-irradiated head and neck cancer.Materials/Methods: From 11/2012 to 7/2015, 60 patients with in-field recurrence of head and neck cancer underwent re-irradiation with SBRT. Retreatment sites included the aerodigestive tract (43%), lateral neck (22%), and skull base (35%). The median prior RT dose was 63.6 Gy with a median time from prior irradiation of 16.5 months. The median volume treated was 61.0 cc. Patients were treated with 40 Gy in the definitive setting or 35 Gy in the post-operative setting in five fractions. Dose constraints to the OARExtreme were calculated with a BED calculator using an alpha/beta ratio of 3 to reduce the risk of late toxicities. QoL data was collected from patients at the time of consultation and at subsequent follow up appointments using the MD Anderson Dysphagia Inventory (MDADI) and Symptom Inventory (MDASI).Results: The 1- and 2- year rates of local, regional, and distant control and overall survival were 79/79, 74/70, 74/71, and 59/45%, respectively. Late grade 3 toxicities were seen in 3% in the group treated to the aerodigestive tract and 1% in the group treated to the skull base. No grade 4 or 5 toxicities were observed. Patients with skull base re-irradiation maintained a stable QoL score after radiation treatment, while patients treated to the aerodigestive tract demonstrated a slight impairment associated with worsening dysphagia, compared to their pretreatment baseline. All groups experienced an increase in xerostomia.Conclusions: OARExtreme-sparing SBRT is able to achieve excellent tumor coverage while protecting the organs at highest risk of re-irradiation-related complications. The potential for lower toxicities and maintained QoL with this treatment makes it a promising option for salvage of recurrent head and neck cancer.SummaryLocal control and overall survival rates for recurrent head and neck cancer remain poor, despite the use of local therapy. In addition, re-irradiation with conventional radiation therapy confers a high rate of grade 3 and higher late toxicities. SBRT appears to improve the therapeutic ratio in this patient population, and treatment planning with a focus on sparing OARExtreme may further decrease the rates of morbidity in these patients.