Citations

Abstract Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3′ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31–12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704–15. ©2017 AACR.

AbstractBackgroundThe Choosing Wisely campaign has called for better engagement of palliative and hospice care services for patients in the emergency department (ED). PREDICT is a clinical prediction tool that was derived in an Australian ED cohort. It assesses a patient's risk of mortality at 1 year to select those who would benefit from advanced care planning. Such goals‐of‐care discussion can improve patients’ ability to communicate what they want out of their healthcare and, in cases of end of life, potentially reduce the number of futile interventions. Using a cutoff of 13 points, PREDICT had a reported 95.3% specificity and 53.9% sensitivity for 1‐year mortality. We externally validated PREDICT and derived a simpler modified PREDICT tool to systematically identify high‐risk patients eligible for goals‐of‐care discussions and palliative care consultation in the ED.MethodsThis was an observational cohort study of a random sample of 927 patients aged 55+ seen in the ED in 2014. We identified advance healthcare directives (AHDs) on file. We summarized diagnostic accuracy of the clinical tool to predict 1‐year mortality using sensitivity, specificity, and area under the curve (AUC). We refined PREDICT using multivariable modeling. We followed reporting guidelines including STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) for cohort studies and Standards for Reporting of Diagnostic Accuracy (STARD).ResultsA total of 927 patients were included: 55.0% were male, 63 (7.0%) were nursing home residents, 389 (42.0%) patients had an AHD in their medical record at the time of ED visit, and 245 (26.4%) were deceased at 1 year. Of the 780 patients with PREDICT scores < 13, a total of 164 (21.0%; 95% confidence interval [CI] = 18.3–24.1) were deceased at 1 year, and of the 147 patients with PREDICT scores ≥ 13, a total of 81 (55.1%; 95% CI = 46.7–63.2) were deceased at 1 year. The AUC of the PREDICT score was 0.717 (95% CI = 0.680–0.754), sensitivity was 33.1% (95% CI = 27.3–39.4), and specificity was 90.3% (95% CI = 87.8–92.4) to predict 1‐year mortality. The modified PREDICT tool resulted in an AUC of 0.709 (95% CI = 0.671–0.747). We decided to select this model as the preferred model, as the variable of intensive care unit (ICU) admission with multiorgan failure can be difficult to assess in the ED and may delay advanced care planning. Reweighting the score did not improve fit or the AUC, so points assigned to each variable were not adjusted.ConclusionPREDICT is an easy tool to administer to be able to identify patients who are at high risk of 1‐year mortality and who could benefit from AHDs, goals‐of‐care discussion, and when appropriate in the context of an end‐of‐life setting, palliative medicine consultation. External validation of PREDICT was successful in our population. We simplified PREDICT and derived a new tool, the modified PREDICT minus ICU tool, without significantly altering the sensitivity, specificity, and AUC for death at 1 year. The next steps include external validation of the newly derived rule and prospective implementation.

Abstract BACKGROUND The goal of microsurgical removal of a vestibular schwannoma is to completely remove the tumor, to provide long-term durable cure. In many cases, less than gross total resection (GTR) is performed to preserve neurological, and especially facial nerve function. OBJECTIVE To analyze long-term quality of life (QoL) in a cohort of patients who received either GTR or less than GTR. METHODS Patients operated for vestibular schwannoma less than 3.0 cm in posterior fossa diameter at 1 of 2 international tertiary care centers were surveyed using generic and disease-specific QoL instruments. RESULTS A total of 143 patients were analyzed. GTR was performed in 122, and 21 underwent less than GTR. QoL was assessed at a mean of 7.7 yr after surgery (interquartile range: 5.7-9.6). Patients who underwent GTR had smaller tumors; otherwise, there were no baseline differences between groups. Patients who underwent GTR, after multivariable adjustment for baseline features and facial nerve and hearing outcomes, reported statistically significantly better Short Form Health Survey-36 (SF-36) physical and mental scores, Patient-Reported Outcomes Measurement Information System (PROMIS-10) physical and mental scores, and Penn Acoustic Neuroma Quality of Life (PANQOL) facial, energy, general health, and total scores compared to patients receiving less than GTR. CONCLUSION GTR is associated with better QoL using the general QoL measures SF-36 and PROMIS-10 and the disease-specific PANQOL, even after controlling for baseline and outcome differences. This is especially significant in the assessment of mental health, indicating there may indeed be a psychological advantage to the patient that translates to overall well-being to have the entire tumor removed if microsurgical resection is undertaken.

ObjectiveTo describe management and oncologic outcomes for patients who develop locoregional recurrence (LRR) or distant metastasis (DM) following transoral robotic surgery for human papilloma virus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC).Study DesignCase series with chart review.SettingTertiary care referral center.Subjects and MethodsA total of 286 patients with HPV‐positive OPSCC who underwent transoral robotic surgery–based treatment from May 2007 to May 2015.ResultsOf 286 patients (12.2%), 35 met inclusion criteria. Of these, 19 experienced an LRR and 16 developed a DM; 2 patients with LRR subsequently developed DM. In those patients with an LRR, 79% had T1/T2 tumors, and 47% had N0/N1 nodal disease, compared with 75% and 6% in the DM group, respectively. The median time to LRR or DM was 0.6 years (interquartile range [IQR], 0.4‐1.0) and 1.8 years (IQR, 1.0‐2.1), respectively. Salvage treatment with intent to cure was attempted in 23 patients (16 LRR, 7 DM). The median time from LRR or DM to last follow‐up for the 18 patients who were still alive after salvage was 1.9 years (IQR, 0.4‐3.8; range, 7 days–6.2 years). Estimated cancer‐specific survival rates at 3 years following intent‐to‐cure treatment were 63% (95% CI, 39‐100; number still at risk, 5) in the LRR group and 100% (95% CI, 100‐100; number still at risk, 2) in the DM group.ConclusionOverall, LRR and DM for HPV‐positive OPSCC following transoral robotic surgery–based therapy are infrequent. In our subset of patients who underwent intent‐to‐cure treatment, cancer‐specific survival rates were favorable. Therefore, aggressive salvage treatment for LRR and DM for HPV‐positive OPSCC should be recommended for appropriate candidates.

432 Background: In clinical trials and clinical practice, tumor response assessment with computed tomography (CT) defines critical end points in patients with metastatic disease treated with systemic agents. Methods to reduce errors and improve efficiency in tumor response assessment could improve patient care. Methods: Eleven readers from 10 different institutions independently categorized tumor response according to three different therapeutic response criteria using paired baseline and initial post-therapy CT studies from 20 randomly selected patients with metastatic renal cell carcinoma treated with sunitinib as part of a completed phase III multi-institutional study. Images were evaluated with a manual tumor response evaluation method (standard-of-care) and with computer-assisted response evaluation (CARE) that included stepwise guidance, interactive error-identification and correction methods, automated tumor metric extraction, calculations, response categorization, and data/image archival. A cross-over design, patient randomization, and two-week washout period were used to reduce recall bias. Comparative effectiveness metrics included error rate and mean patient evaluation time. Results: The standard-of-care method was on average associated with one or more errors in 30.5% (6.1/20) of patients while CARE had a 0.0% (0.0/20) error rate (p<0.001). The most common errors were related to data transfer and arithmetic calculation. In patients with errors, the median number of error types was 1 (range 1-3). Mean patient evaluation time with CARE was twice as fast as the standard-of-care method (6.4 vs. 13.1 minutes, p<0.001). Conclusions: Computer-assisted tumor response evaluation reduced errors and time of evaluation, indicating better overall effectiveness than manual tumor response evaluation methods that are the current standard-of-care.