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Among premature infants, the incidence of inguinal hernias is reported to be as high as 30%. Despite being one of the most commonly performed procedures, the optimal setting of inguinal hernia repair (IHR) that is inpatient versus outpatient remains debatable. We sought to compare the 30-day outcomes of each approach by querying the National Surgical Quality Improvement Program-Pediatric database.A retrospective cohort study comparing inpatient versus outpatient IHR using the National Surgical Quality Improvement Program-Pediatric database from 2013 to 2019 was performed. Demographic and clinical data were initially compared using univariate analysis. Continuous variables are presented as median and interquartile range and categorical variables are presented as n (%). Subsequently, cohorts were propensity matched using clinically and statistically significant patient characteristics.928 patients underwent IHR, 634 (68.3%) while inpatient, 294 (31.7%) following hospital discharge. Inpatient IHR was associated with lower age at the time of surgery (120 versus 147 d; P 0.0001), younger gestational age (27 versus 33 wk; P 0.0001), decreased probability of repair in elective setting (87.2% versus 97.3%; P 0.0001), and increased preoperative supplemental oxygen need (42% versus 4.4%; P 0.0001). Comparison of propensity matched cohorts revealed that inpatient IHR was associated with increased procedure time (82 versus 51 min; P 0.0001) and anesthetic duration (146 versus 102 min; P 0.0001), wound infection rates (3.8% versus 0%; P = 0.007), blood transfusions (4.2% versus 0.5%; P = 0.036), unplanned intubations (2.8% versus 0%; P = 0.03), ventilator days (0 versus 0; range [0,30 versus 0,2]; P = 0.002), reoperation rate (5.6% versus 0%; P 0.001), postoperative hospital length of stay (4 versus 1 d; P 0.0001), and unplanned readmissions (8.9% versus 0.9%; P = 0.002).Inpatient IHR in premature neonates were associated with different postoperative outcomes than outpatient IHR. At least in the elective setting among premature infants, outpatient IHR can be considered safe in select patients while we await higher quality prospective data.

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Purpose:Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis.Experimental Design:We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival.Results:cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level 0 and number of prior therapies >4 were independent predictors of worse OS.Conclusions:Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

Background MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. Methods Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. Results ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. Conclusion The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Purpose: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. Experimental Design: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. Results: cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level 0 and number of prior therapies >4 were independent predictors of worse OS. Conclusions: Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

Most tumors with activating MAPK (mitogen-activated protein kinase) pathway alterations respond poorly to MEK inhibitors alone. Here, we evaluated combination therapy with MEK inhibitor selumetinib and MDM2 inhibitor KRT-232 in TP53 wild-type and MAPK altered colon and thyroid cancer models. In vitro, we showed synergy between selumetinib and KRT-232 on cell proliferation and colony formation assays. Immunoblotting confirmed p53 upregulation and MEK pathway inhibition. The combination was tested in vivo in seven patient-derived xenograft (PDX) models (five colorectal carcinoma and two papillary thyroid carcinoma models) with different KRAS, BRAF, and NRAS mutations. Combination therapy significantly prolonged event-free survival compared with monotherapy in six of seven models tested. Reverse-phase protein arrays and immunohistochemistry, respectively, demonstrated upregulation of the p53 pathway and in two models cleaved caspase 3 with combination therapy. In summary, combined inhibition of MEK and MDM2 upregulated p53 expression, inhibited MAPK signaling and demonstrated greater antitumor efficacy than single drug therapy in both in vitro and in vivo settings. These findings support further clinical testing of the MEK/MDM2 inhibitor combination in tumors of epithelial origin with MAPK pathway alterations.

Background: MDMX and MDM2 are endogenous inhibitors of the p53 tumor suppressor protein. MDMX levels are frequently elevated in luminal breast cancer, which generally expresses wild-type p53. ALRN-6924, an α-helical stapled peptide, is the first and only dual inhibitor of MDMX and MDM2 currently in clinical trials for solid tumors and hematological malignancies. We sought to determine the antitumor efficacy of the combination of ALRN-6924 with taxanes in models of human breast cancer. Methods: Sulforhodamine B colorimetric assay was used to assess the cytotoxicity of the combination of ALRN-6924 with taxanes in vitro. Athymic nude mice were implanted with MCF-7 tumors and treated for four weeks with ALRN-6924 alone and in combination with paclitaxel in cremaphor (Taxol®, study #1) or a nanoparticle-albumin-bound (nab) formulation (Abraxane®, study #2). In study #1, ALRN-6924 (5, 10 mg/kg) was dosed twice weekly and paclitaxel (10, 15 mg/kg) was dosed weekly, with paclitaxel administered 6 h prior to ALRN-6924. In study #2, ALRN-6924 alone (5 mg/kg) was dosed twice weekly while nab-paclitaxel (15 mg/kg) was administered weekly in combination at -24h, -6h, 0h, +6h, or +24h relative to ALRN-6924 administration. Results: ALRN-6924 was found to have synergistic activity with paclitaxel in both MCF-7 and ZR-75-1 cell lines in vitro (Combination index: 0.874 and 0.323 respectively). In in vivo study #1, the combination of ALRN-6924 and paclitaxel significantly inhibited MCF-7 tumor growth compared to either agent alone (p In study #2, the combination of nab-paclitaxel with ALRN-6924 administered -6h to +24h relative to nab-paclitaxel resulted in improved efficacy over either single agent and a significant increase in the number of tumor regressions (up to 6/10 with 3 consecutive measurements In both studies, drug treatments were well tolerated with no significant weight loss in mice. Conclusion: The significant increase in efficacy observed with ALRN-6924 in combination with paclitaxel supports further evaluation in patients with breast cancer. Citation Format: Pairawan SS, Yuca E, Evans K, Annis A, Narasimhan N, Sutton D, Carvajal LA, Ren J-G, Santiago S, Guerlavais V, Akcakanat A, Tapia C, Illeana Dumbrava EE, Aivado M, Meric-Bernstam F. The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-11.

12022Background: Prognostication has been a challenging subject in patients with metastatic disease. Physicians are expected to assess prognosis of patients with advanced disease both for determini...