Citations

Abstract Lessons Learned OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models. In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed. Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma. Background OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models. Methods Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit. Results Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days). Conclusion OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.

672 Background: The optimal sequence of cytoreductive nephrectomy (CN) and targeted therapy (TT) for patients with metastatic renal cell carcinoma (mRCC) remains to be established. Herein, we compared overall survival (OS) between patients with mRCC receiving initial CN with or without subsequent TT versus initial TT with or without subsequent CN. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed between 2006-2013 with RCC that was metastatic at diagnosis who received CN, TT, or both. Those with other prior cancer history were excluded. The cumulative incidence of receiving TT after CN and CN after TT were evaluated, with death prior to second treatment as a competing risk. To account for treatment selection bias, inverse probability of treatment weighting (IPTW) was performed based on the propensity to receive initial CN or TT. OS from diagnosis was compared using Cox regression. Sensitivity analyses were performed. Results: The cohort included 15,068 patients, of whom 6,731 underwent initial CN and 8,337 underwent initial TT. At 6 months from diagnosis, the probability of receiving TT after CN was 46.2%, with 13.6% of patients having died after initial CN prior to receiving TT. Meanwhile, the probability at 6 months of undergoing CN after initial TT was 4.4%, with 38.3% of this group having died prior to undergoing CN. In the IPTW analysis, baseline characteristics were balanced (standardized difference < 0.1). Initial CN was associated with improved OS compared to initial TT (median 16.5 vs 9.2 months; HR 0.62; 95%CI 0.61-0.64; p < 0.001). Findings were similar in all sensitivity analyses (propensity score matching and adjustment; regression adjustment; 6-month landmark analysis; clear cell mRCC subset; exclusion of patients who had metastasectomy). Conclusions: Although initial CN was associated improved OS versus initial TT in this national dataset, initial CN was associated with delays in, and even death prior to, receipt of TT. As such, while the survival data here support initial CN in appropriate surgical candidates, continued efforts to develop the optimal multimodal approach to these patients are warranted.

Abstract Background Metaplastic breast cancer (MBC), characterized by a mixture of epithelial, squamous or mesenchymal elements and a usually triple-negative (TN) phenotype, accounts for &lt;1% of breast cancer diagnoses. MBC has a poor prognosis with frequent distant spread, but, paradoxically, a lower than expected rate of nodal positivity (6 to 40%). Due to its rarity there is little data on how best to evaluate and manage the axilla in women with these tumors. Thus we undertook this study to evaluate axillary management and oncologic outcomes. Methods With IRB approval, we identified adult patients diagnosed with MBC at our institution from 2001 to 2011 from our prospective surgical pathology database. Patient, pathology, imaging, treatment and outcome data were obtained from electronic medical record, tumor registry, pathology slide and imaging review. Median follow-up for surviving patients was 66 months. Statistical analyses were performed using JMP 10.0 software. Results We identified 41 MBC patients, median age 60 years (range 33-89 years), with a median tumor size of 2.7 cm; 33 (80%) were TN. 23 patients (56%) had a preoperative axillary ultrasound (AUS): 9 (39%) showed at least one suspicious axillary lymph node (LN) of whom 6 had a preoperative fine needle LN biopsy (FNA) of which 3 were positive for metastasis. 6 patients, including the 3 LN+ on FNA, had neoadjuvant chemotherapy (NAC). Operation included axillary dissection (ALND) in 14, sentinel LN biopsy (SLNB) in 23, and SLNB followed by ALND in 1, while 3 patients had no axillary surgery. 10 patients were LN+ at operation. Among 22 patients who had both an AUS and axillary surgery, AUS had a sensitivity of 100% and specificity of 78%. Patient and tumor variables in association with pathologic LN status are summarized in the table. LN positivity correlated with increasing tumor size, T stage, grade and angiolymphatic invasion. 16 patients recurred, most with distant disease (10/16, 63%), although there was a solitary axillary recurrence 8 months after a negative SLNB in one patient who did not have a preoperative AUS. Thus the accuracy of SLNB was 96% (23/24) overall, but among those without preoperative AUS, 1/7 (14%) SLNBs were falsely negative. 5-year disease-free and breast cancer-specific survival estimates were 49% and 63%. LN- N=28 (74%)LN+ N=10 (26%)p-valueSize, median (IQR), cm2.7 (1.6-4.6)6.6 (2.5-16.5)0.001T stage 0.03T19 (100%)0 (0%) T214 (78%)4 (22%) T33 (60%)2 (40%) T42 (33%)4 (67%) Grade 0.04Low6 (16%)0 (0%) Intermediate/High22 (58%)10 (26%) Estrogen Receptor 0.61Positive (&gt;1%)5 (71%)2 (29%) Negative (&lt;1%)23 (74%)8 (26%) Angiolymphatic Invasion 0.002No26 (87%)4 (13%) Yes2 (25%)6 (75%) Dominant Histology 0.65Adenosquamous2 (100%)0 (0%) Matrix producing4 (80%)1 (20%) Spindle cell14 (74%)5 (26%) Squamous*8 (67%)4 (33%) *any squamous component Conclusion Our study is the first to specifically address AUS and SLNB for patients with metaplastic breast cancer. AUS had 100% sensitivity and 78% specificity, while one patient without a preoperative AUS had a falsely negative SLNB. Further, AUS with FNA of suspicious LNs was useful for staging at the time of diagnosis and informing treatment. We recommend this approach for patients with MBC. Citation Format: Murphy BL, Fazzio RT, Hoskin TL, Glazebrook KN, Keeney MG, Habermann EB, Hieken TJ. Management of the axilla in metaplastic breast carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-01.

OBJECTIVEPatient-reported outcomes have been increasingly mandated by regulators and payers to evaluate hospital and physician performance. The purpose of this study is to delineate the differences in patient-reported experience of hospital care for cranial and spinal operations.METHODSThe authors selected all patients who underwent inpatient, elective cranial or spinal procedures and completed the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey at a single, high-volume, tertiary care institution between October 2012 and September 2015. The association of the surgical procedure and diagnosis with various HCAHPS composite measures, calculated across 9 domains using standard top-box methodology, was investigated. Multivariable logistic regression models were fitted for outcomes that were significant with procedure type and diagnosis group on univariate analysis, adjusting for age, sex, case complexity, overall health rating, and education level.RESULTSA total of 1484 patients met criteria and returned an HCAHPS survey. Overall, patients undergoing a cranial procedure gave top-box (most favorable) scores more often in pain management measure (66.3% vs 59.6%, p = 0.01) compared with those undergoing spine surgery. Furthermore, despite better discharge scores (93.1% vs 87.1%, p < 0.001), spinal patients were less likely to report excellent health (7.4% vs 12.7%). Lastly, patients with a primary diagnosis of brain or spinal tumor compared with those with degenerative spinal disease and those with other neurosurgical diagnoses provided top-box scores more often regarding communication with doctors (82.7% vs 76.4% vs 75.2%, p = 0.04), pain management (71.8% vs 60.9% vs 59.1%, p = 0.002), and global rating (90.4% vs 84.0% vs 87.3%, p = 0.02). On multivariable analysis, spinal patients had significantly lower odds of reporting top-box scores in pain management (OR 0.67, 95% CI 0.52–0.85; p = 0.001), staff responsiveness (OR 0.68, 95% CI 0.53–0.87; p = 0.002), and global rating (OR 0.59, 95% CI 0.42–0.82; p = 0.002), and significantly higher odds of top-box scoring in discharge information (OR 2.15, 95% CI 1.45–3.18; p < 0.001) than cranial patients. Similarly, brain tumor cases were associated with significantly higher odds of top-box scoring in communication with doctors (OR 1.46, 95% CI 1.01–2.12; p = 0.04), pain management (OR 1.81, 95% CI 1.29–2.55; p < 0.001), staff responsiveness (OR 1.88, 95% CI 1.33–2.66; p < 0.001), and global rating (OR 2.00, 95% CI 1.26–3.17; p = 0.003) compared with degenerative spine cases.CONCLUSIONSSignificant differences in patient-reported experience with hospital care exist across different cranial and spine surgery patient populations. Overall, spinal patients, particularly those with degenerative spine disease, rated their health and their hospital experience lower relative to cranial patients. Identifying weaker areas of hospital performance in target populations can stimulate quality initiatives that aim to increase the overall hospital score.

Importance: Media reports have questioned the safety of overlapping surgical procedures, and national scrutiny has underscored the necessity of single-center evaluations of its safety; however, sample sizes are likely small. We compared the safety profiles of overlapping and nonoverlapping pediatric procedures at a single children's hospital and discussed methodological considerations of the evaluation. Data and Design: Retrospective analysis of inpatient pediatric surgical procedures (January 2013 to September 2015) at a single pediatric referral center. Overlapping and nonoverlapping procedures were matched in an unbalanced manner (m:n) by procedure. Mixed models adjusting for Vizient-predicted risk, case-mix, and surgeon compared inpatient mortality and length of stay (LOS). Results: Among 315 overlapping procedures, 256 (81.3%) were matched to 645 nonoverlapping procedures. There were 6 deaths in all. The adjusted odds ratio for mortality did not differ significantly between nonoverlapping and overlapping procedures (adjusted odds ratio = 0.94 vs overlapping; 95% CI, 0.02–48.5; P = 0.98). Wide confidence intervals were minimally improved with Bayesian methods (95% CI, 0.07–12.5). Adjusted LOS estimates were not clinically different by overlapping status (0.6% longer for nonoverlapping; 95% CI, 9.7% shorter to 12.2% longer; P = 0.91). Among the 87 overlapping procedures with the greatest overlap (≥60 min or ≥50% of operative duration), there were no deaths. Conclusions: The safety of overlapping and nonoverlapping surgical procedures did not differ at this children's center. These findings may not extrapolate to other centers. LOS or intraoperative measures may be more appropriate than mortality for safety evaluations due to low event rates for mortality.