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There exist several viable first-line treatment options for metastatic renal cell carcinoma, making the choice of initial therapy difficult. Metrics other than patient factors, such as cost, may assist in selecting the most appropriate therapy. Using data from CheckMate 214, KEYNOTE 426, and JAVELIN Renal 101 and including costs of medication administration, monitoring, and adverse events, a cost-effectiveness analysis revealed that nivolumab + ipilimumab is more cost-effective than both pembrolizumab + axitinib and avelumab + axitinib. BACKGROUND: There now exist several viable first-line treatment options for metastatic renal cell carcinoma, making the choice of initial therapy difficult. Considering metrics other than patient factors may be necessary to select the most appropriate therapy. We aimed to assess the cost-effectiveness of the three combination therapies currently approved in treatment-naïve advanced or metastatic renal cell carcinoma—nivolumab + ipilimumab (NI), pembrolizumab + axitinib (PA), and avelumab + axitinib (AA)—from a US payer perspective. PATIENTS AND METHODS: Our analysis was performed based on previously obtained data derived from progression-free survival and overall survival curves from CheckMate 214, KEYNOTE 426, and JAVELIN Renal 101. RESULTS: The total costs of each treatment were found to be $437,556.12 for NI, $450,597.15 for PA, and $542,882.34 for AA, with quality-adjusted life-year (QALY) values of 4.04, 3.77, and 2.95 for each combination, respectively. The incremental cost-effectiveness ratio (ICER) of NI versus PA was ($47,504.73/QALY); for NI versus AA, it was ($96,533.11/QALY); for PA versus AA, it was ($113,015.87/QALY). Net health benefit scaled against a willingness-to-pay threshold of $150,000 per QALY was positive for NI versus PA at 0.36 and versus AA at 1.79, and this index was also positive for PA versus AA at 1.43, indicating that the additional value of these therapies versus their alternatives is greater than the extra cost. CONCLUSION: NI was found to be the most cost-effective treatment option compared with the other considered therapies. PA was found to be cost effective compared to AA. When patient factors such as social issues and pre-existing conditions do not dictate their first-line therapy, clinicians may use this additional information to make financially conscious choices.

Background: Metastatic triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking hormone receptor expression and HER2 over-expression. Metastatic TNBC has been difficult to treat due to a general lack of targeted therapies, however, immunotherapy has shown substantial activity in a subset of patients. In metastatic TNBC patients with PD-L1-positive (combined positive score (CPS) ≥ 10) disease, KEYNOTE-355 demonstrated that addition of pembrolizumab (PD-1 inhibitor) to chemotherapy (nab-paclitaxel, paclitaxel, or carboplatin/gemcitabine) prolonged median progression free survival (PFS) compared to chemotherapy alone (9.7 months vs 5.6 months). Median 1-year PFS was also increased from 12.0% to 39.1% in these patients treated with pembrolizumab. These data led to the FDA approval of pembrolizumab with chemotherapy in PD-L1-positive metastatic TNBC patients. Despite these encouraging results, the majority of patients do not have long-term disease control. Radiotherapy (RT) in combination with immunotherapy and chemotherapy represents a promising avenue to prolong long-term response. RT can stimulate cellular damage and cause the release of tumor antigens, promoting a local T cell response. In addition, localized RT can result in the shrinkage of distant sites of metastasis via the abscopal effect when used with immunotherapy. The purpose of this study is to investigate the benefit of combining RT with pembrolizumab and chemotherapy in patients with metastatic PD-L1-positive TNBC. Methods: This two-stage, single-arm phase II study will assess the efficacy of RT in combination with nab-paclitaxel/paclitaxel plus pembrolizumab in PD-L1-positive unresectable or metastatic TNBC patients aged ≥18 years. To be included, patients must have only received < 1 prior line of systemic therapy in the metastatic setting or adjuvant/neoadjuvant setting if metastatic recurrence was within 12 months of treatment. The primary endpoint of the study is the 1-year PFS rate and a total of 29 subjects will be enrolled. Patients will be treated first with RT followed by the initiation of systemic therapy within seven days. Ablative RT will be directed at 1-4 sites of metastatic disease in 3 fractions of 8 Gy each. Nab-paclitaxel or paclitaxel will be given weekly day 1, day 8 every 3 weeks and pembrolizumab will be given every 3 weeks. Imaging will be repeated every 9 weeks to assess response based on RECIST 1.1. Systemic treatment will be continued until disease progression or intolerable toxicity. Treatment beyond progression will be allowed in certain patients who had initial response followed by progression. In these patients, repeat RT to new sites of disease can be administered with continuation of pembrolizumab to investigate the potential of re-sensitizing patients to immunotherapy. Blood will be collected before and after treatment for immune profiling. The sample size was determined using a null hypothesis for the 1-year PFS rate of 39% and an alternate hypothesis of 60%. The sample size of 29 yields a power of 80% to detect this difference with an alpha of 0.1 (1-sided). An interim analysis will be performed after enrollment of seventeen subjects in stage one. Citation Format: Anna R. Schreiber, Jodi Kagihara, Andrew Nicklawsky, Dexiang Gao, Anosheh Afghahi, Anthony Elias, Peter Kabos, Elena Shagisultanova, Todd Pitts, Julie Lang, Sana Karam, Virginia Borges, Christine Fisher, Jennifer R. Diamond. Phase II study of radiotherapy in combination with chemotherapy and immunotherapy in patients with PD-L1-positive metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT120.

Breast cancer is a global health threat and cases diagnosed in women during the years after childbirth, or postpartum breast cancers (PPBCs), have high risk for metastasis. In preclinical murine models, semaphorin 7a (SEMA7A) drives the metastatic potential of postpartum mammary tumors. Thus, we hypothesize that SEMA7A may drive metastasis of PPBC in women. We report that SEMA7A protein expression is increased in PPBCs compared to their nulliparous counterparts in our University of Colorado cohort. Additionally, tumors from PPBC patients with involved lymph nodes and lymphovascular invasion were higher on average suggesting a potential role for SEMA7A as a prognostic biomarker. Consistent with this hypothesis we identify a level of SEMA7A expression in tumors that can predict for recurrence. We propose SEMA7A as a potential biomarker and therapeutic target for PPBC patients, who currently lack strong predictors of outcome and unique targeted therapy options.

Solid-state topochemical polymerization (SSTP) is a promising method to construct functional crystalline polymeric materials, but in contrast to various reactions that happen in solution, only very limited types of SSTP reactions are reported. Diels-Alder (DA) and dehydro-DA (DDA) reactions are textbook reactions for preparing six-membered rings in solution but are scarcely seen in solid-state synthesis. Here, using multiple cutting-edge techniques, we demonstrate that the solid 1,4-diphenylbutadiyne (DPB) undergoes a DDA reaction under 10-20 GPa with the phenyl as the dienophile. The crystal structure at the critical pressure shows that this reaction is "distance-selected". The distance of 3.2 A between the phenyl and the phenylethynyl facilitates the DDA reaction, while the distances for other DDA and 1,4-addition reactions are too large to allow the bonding. The obtained products are crystalline armchair graphitic nanoribbons, and hence our studies open a new route to construct the crystalline carbon materials with atomic-scale control.

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

IMPORTANCE: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. OBJECTIVE: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. DESIGN, SETTING, AND PARTICIPANTS: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. INTERVENTIONS: SRS and WBRT for small cell lung cancer brain metastases. MAIN OUTCOMES AND MEASURES: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score–matched analyses. RESULTS: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score–matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P

Importance Central Nervous System (CNS) metastasis from prostate cancer (PCA) is a rare event, but one with significant prognostic impact for those affected. There are limited data on its impact in contemporary cohorts treated with modern agents. Design A retrospective institutional review was performed to characterize the occurrence/outcome of PCA CNS metastasis on all cases of PCA from 2011-2017. A manual chart review was performed to confirm PCA CNS metastases in all cases identified through a diagnostic code screening of the health data. Results 6,596 cases of PCA were identified, with 29 (20 dural and 9 intraparenchymal) confirmed cases of CNS metastases from prostate cancer. The median survival from the time of diagnosis of CNS metastasis was 2.6 (95%CI: 2.04 – 10.78) months and 5.41 (95% CI: 3.03 – not reached) months for dural and parenchymal metastases respectively. Among those who developed CNS metastases, approximately 79% of patients had prior exposure to abiraterone and/or enzalutamide, of whom 50% had ≥6 months of exposure. Four of the 5841 (0.07%) patients developed CNS metastases prior to the initiation of therapy or on androgen deprivation therapy (ADT) alone. In contrast, 24 of the 279 (8.6%) patients with 2 or more lines of medical therapy developed CNS metastases. Conclusions and Relevance: Our analysis highlights the continued poor prognosis of parenchymal and dural CNS metastases from PCA. CNS metastases in prostate cancer remain a rare event with a 0.4% incidence in this series, but this incidence is considerably increased in patients who receive medical therapy beyond first line ADT.

Squamous cell lung cancer arises from premalignant dysplasias characterized by squamous replacement of the normal mucociliary airway epithelium. Individuals with persistent, compared to regressive, dysplasias are at increased risk for lung cancer. Most studies have focused on genomic changes accrued in dysplasia, but the failure of normal epithelial repair has not been addressed. We hypothesized that basal progenitor cells, responsible for normal repair, are impaired in dysplasia. Functional analysis of basal progenitors from dysplastic bronchial biopsies showed decreased self-renewal and multipotentiality compared to non-dysplastic biopsies. The stable prostacyclin analog iloprost, the only drug to have improved dysplasia in a clinical trial, also rescued progenitor function and reversed dysplasia in a subset of lesions. In a series of 32 dysplastic lesions followed in 19 subjects who underwent serial bronchoscopic biopsies, baseline progenitor function predicted dysplasia persistence or regression. Epithelial repair dysfunction is an early and potentially manipulable event in bronchial premalignancy.

Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from RD Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r=-0.162, p = 0.352).HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co-relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients.

Chronic abdominal pain (CAP) is a common and challenging problem in pediatric primary and specialty care. We developed a diagnostic algorithm to organize workup for gastrointestinal causes of CAP and improve identification of patients who are low suspicion (LS) or high suspicion (HS) to have significant intestinal pathology identified with endoscopy. We retrospectively used this algorithm to categorize 150 outpatients with CAP as LS (n = 99) or HS (n = 51) and examined subsequent endoscopic findings for all patients. There were 6% significant diagnoses in the LS group compared with 34% in the HS group ( P < .0001). The LS group had no patients with celiac or inflammatory bowel disease. These results can be used to help a clinician approach CAP, and discuss with families the likelihood of endoscopy finding a cause for CAP based on LS or HS designation.

Objectives To determine the risk of healthy children undergoing tympanostomy tubes of an additional surgery prior to age three and associated risk factors. Methods A retrospective chart review of pediatric patients at a tertiary metropolitan children's hospital who underwent tympanostomy tube insertion procedure before age of three from January 2010 through March 2015. We determined patient demographics, indication for tympanostomy tube insertion, as well as information about additional procedures requiring general anesthesia before the age of three years. A prospective telephone interview was also performed on a portion of the study population to assess if there were additional surgeries before the age of three that did not occur at our institution. Results In our institution there was a 13% risk of getting an additional surgery after tympanostomy tubes in children who are otherwise healthy. The most common second procedure was an otolaryngologic procedure in 77.8% of the cases. Children with a diagnosis of recurrent acute otitis media had a threefold greater chance of getting an additional surgery than those with a diagnosis of chronic otitis media with effusion. Patients that identified as Black or African American were 3.2 times more likely to have additional surgery. With every year increase at age of surgery, the odds of an additional surgery decreased by 77%. Conclusions In healthy children undergoing tympanostomy tube insertion at our institution, the incidence of additional procedures under general anesthesia (GA) is low at 13%. Although there is evidence of possible deleterious effects of anesthesia on the developing brain, it is generally accepted that one short (≤1 h) anesthetic exposure under the age of three has not been associated with adverse neurodevelopmental outcomes. As a specialty that regularly performs procedures on young children, we need to be aware of the possible effects of anesthetic agents on our patients. However, this study shows that the exposure risk is low and should help reassure patient's families.

Germanium selenide is a promising material for electronic, photovoltaic, and thermoelectric applications; however, structural phase transitions of GeSe under pressure are controversial. Combining evolutionary algorithms, density functional theory, tight-binding method, and laser-heated diamond anvil cell experiments, pressure-induced phase transitions of GeSe are thoroughly investigated. Two novel intermediate phases are predicted to exist in between the well-known α-GeSe and the recently discovered β-GeSe under high pressure. α-GeSe is found to transform into a rhombohedral crystal structure with a space group of R3m at a low hydrostatic pressure. The R3m phase of GeSe exhibits robust ferroelectricity analogous to GeTe. By further increasing the pressure to approximately 6 GPa, the R3m phase is predicted to transform into a rock-salt structure, becoming a 3D topological crystalline insulator with an inverted band structure. The newly discovered GeSe high-pressure phases greatly enrich our knowledge of IV–VI compounds. The atoms in germanium selenide can adopt more configurations than previously thought according to a study by researchers in China. A phase change, the rearrangement of atoms in a solid from one crystal structure to another, can radically alter a material’s properties. Such a change in phase can be induced by exposing matter to high pressure. Kuo Li from the Center for High Pressure Science and Technology Advanced Research in Beijing, Yue Chen from The University of Hong Kong, and their co-workers have combined multiple computational and experimental techniques to identify the phases of germanium selenide, a material useful for energy conversion. Recently a high-pressure phase called β-GeSe was discovered in addition to the common low-pressure α-GeSe phase. The researchers predict two further phases at intermediate pressure, each with its own distinctive electrical properties. Pressure-induced phase transitions in GeSe are investigated from theory and experiment. Two new phases are predicted to exist in-between the well-known α-GeSe and the recently discovered β-GeSe under pressures. It is predicted that α-GeSe transforms into a rhombohedral structure with a space group of R3m and exhibits robust ferroelectricity at a low hydrostatic pressure. Laser-heated DAC experiments have been conducted to provide further evidence on the existence of the R3m phase. By increasing the hydrostatic pressure to approximately 6 GPa, the R3m phase is predicted to transform into a rock-salt crystal structure ( $$Fm\bar 3m$$ ) and become a topological crystalline insulator.

Objectives Small cell lung cancer (SCLC) patients of all stages are treated with etoposide and cisplatin or carboplatin with or without surgery or chest radiotherapy. Initial response rates are ≥70% however the majority of patients relapse and are resistant to additional therapies due to pan-resistance to these salvage therapies. Therefore, new treatments are urgently needed. The non-taxane microtubule inhibitor eribulin has produced responses in heavily pretreated breast cancer patients. We evaluated the efficacy of eribulin alone and in combination with radiation in a panel of SCLC cell lines established from patients prior to or after receiving chemotherapy and or radiation. Material and methods Growth inhibition by eribulin alone, radiation alone and the combination was assessed by MTS assay and clonogenic survival. Eribulin induced cell cycle arrest was evaluated by FACS. Apoptosis was evaluated by using the Caspase-GLO 3/7 luminescent plate assay and by the Vybrant apoptosis assay with analysis by FACS. Results Eribulin mesylate inhibited the growth of all 17-SCLC lines at concentrations of ≤10 nM which is a clinically achievable dose. Growth inhibition was not significantly different between cell lines established prior to or after chemotherapy (p = .5). Concurrent eribulin + radiation induced a greater G2-M arrest, an increase in apoptotic cells and increased growth inhibition over radiation alone. Conclusions Eribulin was highly active alone and in combination with radiation in treatment naive SCLC lines and lines established from previously treated patients. In vivo pre-clinical studies of eribulin alone and in combination with radiation should be considered in SCLC cell lines.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype defined by the lack of expression of the estrogen and progesterone receptors and lack of HER2 over-expression. ENMD-2076 is an orally bioavailable small molecule inhibitor of Aurora and angiogenic kinases with pro-apoptotic and antiproliferative activity in preclinical models of TNBC. Methods: This two institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC refractory to 1-3 prior lines of chemotherapy in the advanced setting. Patients had ECOG PS ≤ 1, measureable disease by RECIST 1.1 and no evidence of brain metastasis. Patients were treated with ENMD-2076 250 mg PO daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary end point was 6-month clinical benefit rate (6-CBR) and secondary endpoints included time to progression (TTP), PK profile, safety and biologic correlatives in archival and fresh serial tumor biopsies in a subset of patients. Results: Between July 2012 and October 2016, 41 patients were enrolled (median age 54; range 30-73; female 40; male 1). Patients received a mean 1.7 prior lines of chemotherapy for locally advanced unresectable or metastatic disease and 80.5% received prior neoadjuvant or adjuvant chemotherapy (N=33). Thirty-six patients were evaluable per protocol for the primary efficacy analysis. Five patients (12.2%) were not included in the efficacy analysis due to: adverse events (AE) leading to discontinuation prior to objective efficacy assessment (N=3), not meeting eligibility criteria on day 1 (N=1) and withdraw of consent in cycle 1 (N=1). The study proceeded to the second stage of enrollment based on observing three 6-CBR events in Stage 1 (N=18 patients). The 6-CBR in the overall trial was 16.7% (95% exact CI: 6%-32.8%; 2 patients with PR and 4 patients with SD > 6 mos). The median duration of response or clinical benefit in these patients was 32 weeks (8 cycles). 4-CBR was 27.8% (95% exact CI: 14%-45.2%). Dose reduction occurred in 8 patients (20%) for fatigue, hypertension and proteinuria. The most common grade 3 treatment-related adverse events were hypertension (37.5%) and fatigue (10%). One patient experienced grade 4 hypertension. Analysis of serial tumor biopsies prior to and following 2 weeks of ENMD-2076 (N=8 patients), demonstrated a treatment-induced decrease in cellular proliferation (Ki-67) and microvessel density (CD34) as assessed by IHC. Immunofluorescence performed on a subset of samples demonstrated an increase in p53-family member expression following treatment, consistent with changes observed in preclinical TNBC patient-derived tumor xenograft models. Conclusions: ENMD-2076 has durable clinical activity in a subset of patients with pretreated, advanced or metastatic triple-negative breast cancer. Predictive biomarker development using archival and fresh tumor tissue is underway. Exploration of lower doses of ENMD-2076 in future clinical trials may improve tolerability. Citation Format: Diamond JR, Eckhardt SG, Pitts TM, van Bokhoven A, Aisner D, Gustafson DL, Capasso A, Elias AD, Storniolo AM, Schneider BP, Gao D, Tentler JJ, Borges VF, Miller KD. Clinical safety and efficacy of the aurora and angiogenic kinase inhibitor ENMD-2076 in previously treated, locally advanced or metastatic triple-negative breast cancer [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 PD3-16.

Background: The clinical implications of the androgen receptor (AR), particularly in the context of aromatase inhibitor (AI) refractory metastatic breast cancer (MBC) are unclear. While AR is associated with more indolent primary tumors, high AR relative to ER in primary breast cancer is associated with endocrine resistance, and in the absence of estradiol or low or blocked ER, AR can exert a pro-survival signal. In a phase II trial of fulvestrant plus enzalutamide in ER+/Her2- MBC we analyzed serial biopsies pre- and post-treatment Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- MBC. Fulvestrant 500 mg IM days 1, 15, 29 and every 4 weeks thereafter and Enzalutamide at 160 mg po daily on a continual basis were administered. Biopsies were required at study entry and at ~4 weeks on therapy. The clinical benefit rate at 24 weeks (CBR24) was the primary endpoint for efficacy. We performed mutational analysis to detect mutations including ESR1 exon 8 mutations.We examined estrogen, progesterone, androgen and glucocorticoid receptors, multiplex analysis of immune cells and PD-L1, and performed reverse phase protein array (RPPA) based protein pathway activation analysis of over 150 proteins/phosphoprotein drug targets from LCM-enriched tumor epithelium in baseline and post-treatment metastatic biopsies. Comparisons of PFS Responders (PFS longer than or equal to 24 weeks) and PFS Non-Responders (PFS shorter than or equal to 5 weeks) were performed using moderated t-tests on log2 transformed data. Results: 32 were eligible and median age was 61 years (46-87); PS 1 (0-1); a median of 2 prior chemotherapy and 2 prior hormonal therapies for metastatic disease (including 7 with prior Fulvestrant) and 90% had visceral disease. ESR1 mutant metastases had higher levels of ER and PR than those with wild type ESR1 (p Conclusions: Clinical benefit lasting 6-12 months was observed in 23% of patients. Our studies show important differences in hormone receptor expression and immune infiltrates in ESR1 mutated disease. RPPA based pathway activation mapping showed that mTOR pathway activation was associated with shorter PFS (p Citation Format: Jennifer K. Richer, Nicole S. Spoelstra, Alyse Winchester, Julia Wulfkuhle, Sharon B. Sams, Gregory Vidal, Peter Kabos, Jennifer Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadden, Gloria Crawford, Virginia Borges, Dexiang Gao, Emanuel Petricoin, Anthony D. Elias. Laboratory analyses of metastatic ER+/Her2- breast cancer treated with fulvestrant plus enzalutamide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2867.

Objectives/Hypothesis To define the clinical features and natural history of pediatric tinnitus from a practicing otolaryngologist's perspective and formulate hypotheses therein. Study Design Retrospective chart review. Methods A retrospective chart review of the electronic medical record was undertaken. Only relevant records with a prior otolaryngology clinic visit and audiologic testing were included. Patients seen during the last 2 years of the study period were contacted and completed a questionnaire to assess change in tinnitus and quantify potential alterations in quality of life, associated symptoms, and natural history. Results One hundred eighty subjects with mean/median age of 11.5/11.5 years were identified. Hearing loss was identified in 40 subjects (22.2%). Etiology of tinnitus was identified in 95 subjects (52.8 %). Tinnitus-specific and/or nonspecific therapies were given to 80 subjects (44.4%). Of the 54 available subjects, 28 (51.9%) participated in the telephone questionnaire. Tinnitus complaints shifted favorably to the improvement or resolution categories (P = .001) between the initial clinic visit and the telephone interview. Shorter duration of tinnitus was associated with a higher probability of having improved tinnitus (P = .046). Conclusions This study distinguishes pediatric tinnitus from adult tinnitus in terms of lower association with underlying hearing loss, lower likelihood of reported anxiety, and higher likelihood of improvement and resolution. There are opportunities for tinnitus prevention in the areas of reducing head injury and noise-induced hearing loss. Level of Evidence 4 Laryngoscope, 2017

Objective To assess long-term complication rate and parental satisfaction of osseointegrated bone conduction hearing implants (OBCHIs). Study Design Retrospective chart review of children undergoing OBCHIs. Methods A retrospective chart review of children undergoing OBCHIs for the treatment of conductive, mixed, and single-sided sensorineural hearing loss in children. Results Forty-five subjects were identified with 0.3 to 10.4 years of follow-up. The mean/median age and age range at implant were 9.0/7.8 and 1.7 to 19.1 years. The underlying hearing loss for the cohort included conductive (N = 30), sensorineural (N = 7), and mixed (N = 8) hearing loss. Conductive hearing loss, caused by aural atresia (62.9), was the most common indication for implantation. Fifty-eight complications occurred in 29 subjects, most related to skin infection or overgrowth. Seventeen events required revision surgery, and 18 required oral antibiotics and/or office-based cauterization. Children under the age of 5 years were more likely to have failure of osseointegration or require revision surgery. Parents of 33 subjects underwent a phone interview; 76% rated the overall satisfaction as satisfied or very satisfied. Conclusion A large percentage of children undergoing OBCHI develop postoperative complications, and up to 44% require revision surgery—a figure higher than generally reported and higher than in adults. No factors were found to adequately explain the higher complication rates in children compared to adults. Despite the occurrence of complications, parents viewed this device as satisfactory from many perspectives. Level of Evidence 4. Laryngoscope, 2017

Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC.PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only.The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody.A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.

To estimate how many boys with UDT must undergo orchiopexy to prevent one case of TC, one death from TC and one exposure to TC treatment beyond radical orchiectomy as compared to being treated at an older age.This retrospective study utilized data from a 2007 Swedish study of males who underwent orchiopexy for UDT (Pettersson et al.). TC incidence for boys undergoing orchiopexy for UDT was assessed based on the age at orchiopexy (0-6 years, 7-9 years, 10-12 years, 13-15 years). The incidence of TC in each age cohort was calculated and used to determine the number needed to treat (NNT) for each age group using assumptions based on published TC outcomes.For an index patient ≤ 6 years, 372 boys need to undergo orchiopexy to prevent a single case of TC, 1488 boys to prevent exposure to TC therapy beyond radical orchiectomy, and 5315 boys to prevent a single TC-related death compared to treatment at an older age.While there is evidence supporting benefits of early orchiopexy, the NNT to affect TC outcomes is very high. Even those with delayed orchiopexies have low risk for TC poor outcomes. This information can be used when counseling patients and families faced with UDT about the risks related to TC, especially with comorbidities.

Objective:To determine whether nonsupine sleep improves obstructive sleep apnea (OSA) in infants with cleft palate undergoing polysomnography (PSG).Design:Retrospective chart review.Setting:Tertiary care pediatric hospital.Patients:Twenty-seven infants (1 month to 1 year) with cleft palate with or without cleft lip (CP ± L) undergoing PSG testing for suspected OSA were included.Main Outcome Measures:Polysomnography measures included obstructive apnea–hypopnea index (OAHI), central apnea–hypopnea index (CAHI), oxygen saturation (SpO2) nadir, SpO2, and end-tidal carbon dioxide (ETCO2).Results:Twenty-three PSGs with at least 20 minutes of sleep in both the supine and the nonsupine positions were analyzed. The supine OAHI (mean: 16.8 events/hour; standard deviation [SD]: 18.5) and nonsupine OAHI (mean: 12.6 events/hour; SD: 12.6) did not differ significantly ( P = .10). The supine CAHI (mean: 1.9 events/hour; SD: 2.7) and nonsupine CAHI (mean: 3.1 events/hour; SD: 3.7; P = .15), the supine SpO2nadir (mean: 81.2%; SD: 6.3) and nonsupine SpO2nadir (mean: 81.8%; SD: 5.3; P = .70), the supine mean SpO2(mean: 95.5%; SD: 1.9) and nonsupine mean SpO2saturation (mean: 95.3%; SD: 2.4; P = .34), and the supine ETCO2(mean: 45.4 mm Hg; SD: 5.3) and nonsupine ETCO2(mean: 42.5 mm Hg; SD: 10.1; P = .24) were also similar.Conclusions:There were no significant improvements in OSA metrics during nonsupine sleep in infants with CP ± L. Prior to recommending nonsupine positioning which increases infant’s exposure to sudden infant death syndrome risk, we advocate obtaining a PSG to verify an objective improvement in OSA.

Platinum-based doublets were the recommended systemic therapy for newly diagnosed patients with stage IV non-small cell lung cancer (NSCLC) for decades. Median overall survival (OS) for patients whose first treatment was these chemotherapy regimens was 8–12 months and 5-year OS was estimated at 2% (1-3).

9536 Background: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) reduces MDSC frequency. This analysis seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in advanced melanoma patients. Methods: This single arm, single institution, phase I/II study (NCT03200847) enrolled 24 patients diagnosed with stage IV melanoma. Eligible patients were over the age of 18 and had not been previously treated anti-PD-1 therapy. Treatment consisted of 200mg Q3W pembrolizumab plus the supplemental treatment of 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions of pembrolizumab, with patients continuing pembrolizumab for up to two years until confirmed disease progression or unacceptable toxicity. The primary endpoints were safety and reduction in circulating MDSCs. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) according to RECIST v1.1. Results: At data cut off (Feb, 2021) 22 patients were evaluable for tumor response. Median follow-up was 1.0 years (0.3-2 years). In general, the combination of pembrolizumab and ATRA was well tolerated. The most common treatment-related adverse events (AEs) were grade 1 or 2, including headache (22 pts, 92%), fatigue (18 pts, 75%), rash (16 pts, 66%), and nausea (8 pts, 33%), most of which corresponded with the 3-day course of ATRA treatment. Ten patients had grade 3 or higher AEs with most being common ICI-related AEs. The ORR was 60% and DCR was 83%. Six-month PFS rate was 62%. Excluding patients diagnosed with uveal melanoma (n = 2) the ORR was 72%, DCR was 86%, and the six-month PFS rate was 68%. Paired analysis showed sustained decreases in absolute numbers ( p = 0.002) and percentage ( p = 0.007) of circulating MDSCs (CD3-CD19-CD56-CD11b+CD33+HLA-DR-/low) 4-6 weeks after stopping ATRA. The study is ongoing and further data will be presented in the future. Conclusions: This study demonstrates that the combination of ATRA and pembrolizumab is well tolerated and suggests that reducing MDSCs with ATRA may enhance the efficacy of pembrolizumab. This strategy of targeting MDSCs in combination with pembrolizumab warrants further development. Research Funding: Merck. Clinical trial information: NCT03200847.

10531 Background: Genomic assays, such as RS, are used to determine chemotherapy benefit in early-stage, estrogen receptor (ER)- and/or progesterone receptor (PR)-positive, HER2 negative BC patients (pts). Currently, guidelines to use pts’ germline genetic testing results to guide adjuvant therapy are lacking. Several reports have indicated worse outcomes for BC pts with g CHEK2 pathogenic variants (PV). We investigated whether PV in CHEK2 were associated with increased RS. Methods: Patient-level clinical data and RS were derived from electronic medical records of seven medical centers between years 2013-17. Confirmation of RS using the Genomic Health provider portal was performed. 38 pts with germline PV in CHEK2 (15 pts/39.5% with c.1100delC mutation) and RS score (cases) were matched with BC pts whose genetic testing did not identify PV (controls) using a 1:2 matching schema. Pts were matched based on age at diagnosis and lymph node (LN) status. LN negative pts were further matched based on T-stage. A multivariate random intercept linear mixed model of CHEK2 mutation status on RS was performed, adjusting for PR. A secondary ordinal univariate analysis was conducted that categorized RS into low, intermediate and high risk ( < 18, 18-30, and > 30, respectively). P-values were reported based on a null hypothesis of no effect against a two-sided alternative. Results: The median RS for cases was 19.5 (interquartile range [IQR]: 15 to 25) and the median RS for controls was 18 (IQR: 12 to 22). A greater proportion of cases were categorized as high risk (10.5%) compared to controls (5.6%), and a smaller proportion of cases were categorized as low risk (36.8%) compared to controls (49.3%). Cases had higher grade and increased proportion of PR-negative BC as compared with controls (grade 1: 12.1% of cases versus 32.4% of controls; PR-negative: 7.9% of cases versus 5.6% of controls). The variables used to match cases and controls (age, lymph node status, and T-stage) had similar summary statistics. The RS was 1.97-point higher in pts with g CHEK2 PV compared to controls, after adjusting for PR (95% confidence interval [CI]: 1.02-point lower to 4.96-point higher; p = 0.194). The secondary analysis of CHEK2 mutation status on an ordinal RS risk group yielded comparable results; on average, the odds of being high risk compared to the combined intermediate/low risk groups was 1.72 times higher in cases compared to controls (95% CI: 0.77 to 3.80; p = 0.181), but these differences were not significant. Conclusions: Our case-control study did not show a statistically higher RS for BC that develops in pts with g CHEK2 PV. Further studies are warranted to evaluate the association between type of CHEK2 PV (frameshift versus missense) and other modifying genetic variables and RS.

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

Excessive or persistent programmed death 1 (PD-1) expression on virus- or tumor-specific T cells during chronic viral infection or malignancy has been associated with impaired immune control. To assess the role of the PD-1 pathway in allogeneic stem cell transplantation (SCT), we examined PD-1 expression and maturation phenotype on T cells from 42 patients early (day 55 to 85) after cord blood (CB), matched unrelated donor, and matched related donor transplantation. Expression of PD-1 on CD4+ T cells was significantly elevated in all transplantation types, with the highest level observed in CB subjects. Elevated PD-1 expression on CD4+ T cells early after transplantation was observed in nonsurvivors (median, 40.2%; range, 15.1 to 86.1) compared with survivors (median, 23.6%; range, 8.4 to 55.2; P = .001), indicating its association with increased risk for mortality, especially with CB transplantations, where PD-1 was increased in nonsurvivors (median, 64.6%; range, 36.5 to 86.1) compared with survivors (median, 34.1%; range, 15.9 to 55.2; P = .01). Furthermore, T cell subset analysis revealed that PD-1 expression was further elevated on CD4+ T central memory in nonsurvivors (median, 49.8%; range, 15.1 to 83.4) compared with survivors (median, 24.8%; range, 8.9 to 71.3; P = .002) and on T effector memory cells in nonsurvivors (median, 69.1%; range, 24.7 to 92.6) compared with survivors (median, 43.7%; range, 13.9 to 96.5; P = .0003). Our findings suggest that elevation of PD-1 expression on CD4+ T cells is associated with mortality in CB and possibly all SCT recipients.

Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib, with IC50 values of 75% growth inhibition at 100 nmol/L. Growth inhibition correlated with cMYC amplification (P = 0.018) and cMYC gene expression (P = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (P = 0.042). In vivo, barasertib inhibited the growth of xenografts established from an SCLC line that had high cMYC gene expression, no cMYC amplification, and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated. Mol Cancer Ther; 15(10); 2314–22. ©2016 AACR.

Adult umbilical cord blood transplantation (CBT) has emerged as an important option for patients lacking matched related (MRD) and matched unrelated donors (MUD). We compared chronic GVHD (cGVHD) incidence, immunosuppression burden and late infections and hospitalizations in consecutive patients undergoing CBT (n=51) versus peripheral blood MUD transplant (n=57) at our center between June 2009 and April 2014. At 3 years post transplantation, the cumulative incidence (CI) of moderate to severe cGVHD was 44% following MUD versus 8% following CBT (P=0.0006) and CI of any cGVHD was 68% following MUD versus 32% following CBT (P=0.0017). Median time to being off immunosuppression among CB patients was 268 days versus not reached among MUD patients (P

// Kevin S. Quackenbush 1 , Stacey Bagby 1 , Wai Meng Tai 1, 2 , Wells A. Messersmith 1 , Anna Schreiber 1 , Justin Greene 1 , Jihye Kim 1 , Guoliang Wang 1 , Alicia Purkey 1 , Todd M. Pitts 1 , Anna Nguyen 1 , Dexiang Gao 1 , Patrick Blatchford 1 , Anna Capasso 1 , Alwin G. Schuller 3 , S. Gail Eckhardt 1 , John J. Arcaroli 1 1 Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, CO, USA 2 Division of Medical Oncology, National Cancer Centre Singapore, Singapore 3 AstraZeneca R & D Boston, Massachusetts, Waltham, Massachusetts, MA, USA Correspondence to: John J. Arcaroli, email: john.arcaroli@ucdenver.edu Keywords: CRC, WNT, IRN, NuMA, PDTX Received: December 30, 2015 Accepted: February 28, 2016 Published: April 07, 2016 ABSTRACT Background: Dysregulation of the canonical Wnt signaling pathway has been implicated in colorectal cancer (CRC) development as well as incipient stages of malignant transformation. In this study, we investigated the antitumor effects of AZ1366 (a novel tankyrase inhibitor) as a single agent and in combination with irinotecan in our patient derived CRC explant xenograft models. Results: Six out of 18 CRC explants displayed a significant growth reduction to AZ1366. There was one CRC explant (CRC040) that reached the threshold of sensitivity (TGII ≤ 20%) in this study. In addition, the combination of AZ1366 + irinotecan demonstrated efficacy in 4 out of 18 CRC explants. Treatment effects on the WNT pathway revealed that tankyrase inhibition was ineffective at reducing WNT dependent signaling. However, the anti-tumor effects observed in this study were likely a result of alternative tankyrase effects whereby tankyrase inhibition reduced NuMA levels. Materials and Methods: Eighteen CRC explants were treated with AZ1366 single agent or in combination for 28 days and treatment responses were assessed. Pharmacokinetic (AZ1366 drug concentrations) and pharmacodynamic effects (Axin2 levels) were investigated over 48 hours. Immunohistochemistry of nuclear β-catenin levels as well as western blot was employed to examine the treatment effects on the WNT pathway as well as NuMA. Conclusions: Combination AZ1366 and irinotecan achieved greater anti-tumor effects compared to monotherapy. Activity was limited to CRC explants that displayed irinotecan resistance and increased protein levels of tankyrase and NuMA.

Prostate cancer patients (pts) with non-metastatic prostate specific antigen (PSA) progression after local therapy and a long PSA doubling time (PSADT) usually have a period of PSA observation prior to starting on androgen deprivation therapy (ADT). We report results of an investigator-initiated, IRB-approved Phase II clinical trial (CT.gov-NCT03087903) investigating grape seed extract (GSE) in pts with PSA-only recurrence after maximum local therapy for prostate cancer. Pts with baseline PSA ≥ 0.2 ng/mL and rising PSA on 2 separate occasions and no evidence of metastases were eligible. Pts with baseline PSADT < 4 weeks (if absolute PSA > 2 ng/mL) were excluded. Pts were given 150mg of GSE orally twice daily for 12 months. GSE was administered as a formulation Leucoselect Phytosome-Indena S.p.A. (~100% proanthocyanidins, enriched in lower procyanidin oligomers complexed with soy phospholipids, about 1:2.6 w/w), with increased bioavailability. Study endpoints included PSA response (defined as an increase in PSADT by 30%) and change in PSA velocity. PSA was checked at baseline, 6 weeks and 3, 6, 9, and 12 months after starting GSE. Pts were removed from the trial with clinical/radiographic progression or if PSADT was less than 3 months. Pts completed dietary surveys and provided biologic specimens for tissue banking. The association of time and PSA level was assessed using a mixed effect modeling approach with the intention of calculating the doubling time. The natural log of PSA was taken to satisfy the linearity assumption of this method. Notably, pts on observation with a rising PSA after treatment for prostate cancer could be accrued rapidly to clinical trials; 27 pts were screened for this clinical trial at two sites (between January 2018 - August 2018) with 20 pts registered and started on treatment. Median (range) age and baseline PSA of pts enrolled were 71 (60 - 83) and 2.65 (0.44 - 17.44), respectively. Mean pretreatment PSADT was 5.4 months. GSE was well tolerated without serious adverse effects. 8 patients were withdrawn early due to PSADT progression of Citation Format: Paul Maroni, Elizabeth R. Kessler, Rodrigo Rodrigues-Pessoa, Andrew Nicklawsky, Thomas Flaig, Elaine Lam, Brandon Bernard, James Moore, Kyra Anderson, Dexiang Gao, Komal Raina, Rajesh Agarwal. A phase II trial using grape seed extract for prostate cancer patients with non-metastatic PSA progression after local therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT207.

Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive cancer in which high rates of recurrence (local, locoregional, or distant) contribute significantly to poor patient survival. One of the primary goals for current clinical practice of HNSCC surveillance is to detect recurrence at an early stage. However, current methods are either subjective, invasive, hard to access, not able to detect recurrence in a timely manner, or expensive. Saliva, given its directly adjacence to the anatomic location of HNSCC, may represent an opportunity to monitor HNSCC progression in a completely noninvasive, easy-to-access, and cost-effective method for HNSCC surveillance in a timely manner. We have developed a panel of seven biomarkers through screening of methylated microRNA loci (i.e., 9-1, 124-1, 124-2, 124-3, 129-2, 137, and 148) for HNSCC, and hereafter referred to as HNKlear. HNKlear demonstrated 92.1% sensitivity and 97.8% specificity in 189 HNSCC and 92 control tissue samples and 84.9% sensitivity and 95.4% in 86 pretreatment HNSCC and 108 control saliva samples. HNKlear is able to detect 93.5% T1 tumor and 91.2% stage I tumor in tissue, and 85.0% or 80.0% of HNSCC saliva when tumor is at T1 or stage I, respectively. In our prospective study, the value of HNKlear in patients’ saliva correlates with the tumor burden in 42 patients’ saliva before and after surgery within 3 months. HNKlear value is associated with progression-free survival in 57 primary tumor tissues and 38 treatment-naïve saliva. More importantly, HNKlear in saliva was shown to detect recurrence ranging from 90-337 days ahead of clinical detection of recurrence in the longitudinal follow-up of 43 HNSCC patients. Although these findings need to be validated in a large clinical trial, they suggest that analysis of certain methylated mciroRNA in saliva could have clinical significance for surveillance of HNSCC patients. Citation Format: Ling Lv, Steve Quattlebaum, Dexiang Gao, Yu Cao, Ben Milam, Francis Hall, Derek Smith, Elyse Handley, Sophia Bornstein, Neil Gross, John Song, Shi-Long Lu. Potential clinical value of methylated microRNAs in saliva-liquid biopsy for surveillance of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B07.

Background: Immuno-oncology (IO) agents have demonstrated exceptional clinical benefit in patients with many tumor types, including melanoma and lung cancer. The PD-L1 inhibitor, atezolizumab, was recently FDA approved in combination with nab-paclitaxel for patients with PD-L1 positive triple-negative breast cancer (TNBC); however, single-agent PD-1/PD-L1 inhibitors demonstrate modest efficacy in breast cancer. The purpose of this study was to investigate the efficacy of IO agents in patients with metastatic breast cancer treated in phase I clinical trials. Methods: We performed a retrospective analysis using a database of patients with metastatic breast cancer who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Anschutz Medical Campus from January 1, 2012 to July 1, 2018. Abstracted data included patient demographics, baseline characteristics, and clinical outcomes. Results: 208 patients with metastatic breast cancer were treated in phase I/Ib clinical trials; 43 were treated with an IO agent. The average age was 53 years old and 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC, and 4.6% HER2-positive disease. On average, patients received two prior lines of chemotherapy (range 0-7) in the metastatic setting. 31/43 patients (72.1%) received single agent or combination IO, and 12/43 (27.9%) received IO + chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months in all patients. 9/43 (21%) of patients remained on study > 6 months and had a median PFS of 8.6 months. Patients remaining on study > 6 months were more likely to be treated with IO + chemotherapy compared to patients with a PFS < 6 months (77.8% v. 14.7%, p=0.0007). There was no difference in sites of metastasis, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH between patients with a PFS > 6 months compared to < 6 months. Conclusions: A subset of patients with metastatic breast cancer treated in phase I clinical trials at our center with an IO agent had derived prolonged clinical benefit. The benefit was not limited to patients with TNBC and was associated with receipt of chemotherapy in combination with IO. Predictors of response to immunotherapy in breast cancer beyond PD-L1 expression remain uncharacterized, and further research is needed to identify these factors. Citation Format: Jodi A. Kagihara, Jennifer A. Weiss, Andrew Nicklawsky, Dexiang Gao, Virginia F. Borges, Peter Kabos, Antonio Jimeno, Jennifer R. Diamond. Efficacy of immunotherapy agents in patients with metastatic breast cancer treated in phase I clinical trials [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A76.

OBJECTIVES: To examine weight changes relative to surgical success in children with Down syndrome and obstructive sleep apnea (OSA). STUDY DESIGN: Retrospective chart review of children with Down syndrome undergoing tonsillectomy from 2005 to 2016 for OSA at a tertiary care children’s hospital. Only patients with pre-and postoperative polysomnogram within 6 months of tonsillectomy were included. Demographics, weight, height, and polysomnogram data were collected. Body mass index (BMI), expressed as a percentage of the 95th percentile (%BMI(p95)), was calculated for 24 months prior to and following surgery. Pre-and postoperative OSA severity were also recorded. The postoperative obstructive/hypopnea index identified subjects with resolution of obstruction (obstructive/hypopnea index

Mutations in oncogenes and tumor suppressor genes engender unique metabolic phenotypes crucial to the survival of tumor cells. EGFR signaling has been linked to the rewiring of tumor metabolism in non–small cell lung cancer (NSCLC). We have integrated the use of a functional genomics screen and metabolomics to identify metabolic vulnerabilities induced by EGFR inhibition. These studies reveal that following EGFR inhibition, EGFR-driven NSCLC cells become dependent on the urea cycle and, in particular, the urea cycle enzyme CPS1. Combining knockdown of CPS1 with EGFR inhibition further reduces cell proliferation and impedes cell-cycle progression. Profiling of the metabolome demonstrates that suppression of CPS1 potentiates the effects of EGFR inhibition on central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism, coinciding with reduced glycolysis and mitochondrial respiration. We show that EGFR inhibition and CPS1 knockdown lead to a decrease in arginine levels and pyrimidine derivatives, and the addition of exogenous pyrimidines partially rescues the impairment in cell growth. Finally, we show that high expression of CPS1 in lung adenocarcinomas correlated with worse patient prognosis in publicly available databases. These data collectively reveal that NSCLC cells have a greater dependency on the urea cycle to sustain central carbon metabolism, pyrimidine biosynthesis, and arginine metabolism to meet cellular energetics upon inhibition of EGFR. Implications: Our results reveal that the urea cycle may be a novel metabolic vulnerability in the context of EGFR inhibition, providing an opportunity to develop rational combination therapies with EGFR inhibitors for the treatment of EGFR-driven NSCLC.

In this report, we describe in detail the evolving procedures to optimize humanized mouse cohort generation, including optimal conditioning, choice of lineage for engraftment, threshold for successful engraftment, HNSCC tumor implantation, and immune and stroma cell analyses. We developed a dual infusion protocol of human hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem cells (MSCs), leading to incremental human bone marrow engraftment, and exponential increase in mature peripheral human immune cells, and intratumor homing that includes a more complete lineage reconstitution. Additionally, we have identified practical rules to predict successful HSPC/MSC expansion, and a peripheral human cell threshold associated with bone marrow engraftment, both of which will optimize cohort generation and management. The tremendous advances in immune therapy in cancer have made the need for appropriate and standardized models more acute than ever, and therefore, we anticipate that this manuscript will have an immediate impact in cancer-related research. The need for more representative tools to investigate the human tumor microenvironment (TME) has led to the development of humanized mouse models. However, the difficulty of immune system engraftment and minimal human immune cell infiltration into implanted xenografts are major challenges. We have developed an improved method for generating mismatched humanized mice (mHM), using a dual infusion of human HSPCs and MSCs, isolated from cord blood and expanded in vitro. Engraftment with both HSPCs and MSCs produces mice with almost twice the percentage of human immune cells in their bone marrow, compared to mice engrafted with HSPCs alone, and yields 9- to 38-fold higher levels of mature peripheral human immune cells. We identified a peripheral mHM blood human B cell threshold that predicts an optimal degree of mouse bone marrow humanization. When head and neck squamous cell carcinoma (HNSCC) tumors are implanted on the flanks of HSPC-MSC engrafted mice, human T cells, B cells, and macrophages infiltrate the stroma of these tumors at 2- to 8-fold higher ratios. In dually HSPC-MSC engrafted mice we also more frequently observed additional types of immune cells, including regulatory T cells, cytotoxic T cells, and MDSCs. Higher humanization was associated with in vivo response to immune-directed therapy. The complex immune environment arising in tumors from dually HSPC-MSC engrafted mice better resembles that of the originating patient's tumor, suggesting an enhanced capability to accurately recapitulate a human TME.

Importance Many treatments for clogged tympanostomy tubes (TTs) have been proposed, but none have met scientific rigor for safety and efficacy, including the popular empirical use of ototopical antibiotic drops. Dornase alfa, a recombinant molecule with the unique property of cleaving DNA, may be ideal in treating clogged TTs because both middle-ear effusion and the plug are abundant with DNA. Objective To investigate the ototoxic effects of dornase alfa in a chinchilla model and its efficacy in a clinical trial in children with clogged TTs. Design, Setting, and Participants The safety profiles of dornase alfa (full-strength and 1:10 strength) were evaluated in chinchilla middle ears using serial auditory brainstem response. The efficacy of ototopical dornase alfa (full-strength) was evaluated in children with clogged TTs in a prospective, single-blind randomized clinical trial. The animal study included 21 chinchillas and was conducted at Loma Linda University, Loma Linda, California, and the clinical trial was conducted at Children’s Hospital Colorado, Aurora. A total of 40 children (50 ears with tubes) were enrolled. Interventions In the animal study, chinchillas were assigned to 3 groups: controls (saline), full-strength dornase alfa, or 1:10 dornase alfa dilution. Children were randomly assigned to receive either topical dornase alfa or ofloxacin for clogged TT, 5 drops each ear twice a day for 7 days. Main Outcomes and Measures Animal study: Auditory brainstem responses. Randomized trial of children participants: The primary outcome was patency of TT at day 14 assessed by otoscopy and tympanometry. Results The chinchilla study showed similar auditory brainstem response degradation during a 6-hour period between the control (n = 5) and treatment groups (n = 21). In the clinical trial, a total of 40 clogged TTs (in 33 children, including 25 boys [76%]; mean age, 4.3 years; median [range] age, 3.4 [1.0-14.3] years) were analyzed. The number of unclogged TTs was higher in the dornase alfa group (13 [59%]) compared with the ofloxacin group (8 [44%]), with a difference of 15% (odds ratio, 1.8; 95% CI, 0.54-6.72). Conclusions and Relevance The chinchilla model suggests that dornase alfa is likely nonototoxic. The pilot clinical trial failed to show efficacy of dornase alfa to unclog TTs. With the difference seen between the treatment groups, a sample size estimate could be calculated for a future large-scale trial. Trial Registration ClinicalTrials.gov identifier:NCT00419380

Background Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC. Methods This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients. Results Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6–32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14–45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations. Conclusions Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies. Trial registration ClinicalTrials.gov, NCT01639248. Registered on July 12, 2012.

Introduction Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase gene rearrangement positive (ALK-positive) NSCLC and their relationship with long-term overall survival (OS) have not previously been described in detail. Methods Patients with stage IV NSCLC treated with an ALK inhibitor at the University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were constructed by using Kaplan-Meier methods. Multivariate Cox proportional hazard analysis was used to determine the relationship of variables with OS. Results Of the 110 patients with ALK-positive NSCLC who were identified, 105 received crizotinib as their initial ALK inhibitor. With a median follow-up time of 47 months, the median OS time from diagnosis of stage IV disease was 81 months (6.8 years). Brain metastases at diagnosis of stage IV disease (hazard ratio = 1.01, p = 0.971) and year of stage IV presentation (p = 0.887) did not influence OS. More organs with tumor at diagnosis of stage IV disease was associated with worse OS (HR = 1.49 for each additional organ with disease, including the CNS [p = 0.002]). Each additional month of pemetrexed-based therapy was associated with a 7% relative decrease in risk of death. Conclusion Patients with stage IV ALK-positive NSCLC can have prolonged OS. Brain metastases at diagnosis of stage IV disease does not influence OS. Having more organs involved with tumor at stage IV presentation is associated with worse outcomes. Prolonged benefit from pemetrexed is associated with better outcomes.

To test whether a microRNA (miRNA) panel may serve as an alternative biomarker of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor sensitivity in lung cancer.Histologically diverse lung cancer cell lines were submitted to assays for ponatinib and AZD4547 sensitivity. miRNAs, FGFR1 messenger RNA, gene copy number, and protein expression were detected by real-time quantitative PCR, fluorescence in-situ hybridization, and immunoblotting in 34 lung cancer cell lines.Among 34 cell lines, 14 exhibited ponatinib sensitivity and 20 exhibited AZD4547 sensitivity (drug concentration causing 50% inhibition values 100 nmol/L). A total of 39 of the 377-miRNA set were initially identified from the 4 paired ponatinib-sensitive or -insensitive cell lines to have at least an 8-fold differential expression and then were detected in all the 34 cell lines. A predictive panel of 3 miRNAs (let-7c, miRNA155, and miRNA218) was developed that had an area under the curve (AUC) of 0.886 with a sensitivity of 71.4% and specificity of 77.3% to predict response to ponatinib. The miRNA panel performed similar to FGFR1 protein expression (AUC = 0.864) and messenger RNA expression (AUC = 0.939), and better than FGFR1 amplification (AUC = 0.696). Furthermore, we validated this panel using data for sensitivity to AZD4547 in the cell line cohort with an AUC of 0.931 and a sensitivity of 73.3% and specificity of 76.2%, respectively.The developed miRNA panel (let-7c, miRNA155, and miRNA218) may be useful in predicting response to FGFR tyrosine kinase inhibitors, either ponatinib or AZD4547 in lung cancer cell lines, and warrants further validation in the clinical setting.

Background To identify aberrant promoter methylation of genomic loci encoding microRNA (mgmiR) in head and neck squamous cell carcinoma (HNSCC) and to evaluate a biomarker panel of mgmiRs to improve the diagnostic accuracy of HNSCC in tissues and saliva. Methods Methylation of promoter regions of mgmiR candidates was initially screened using HNSCC and control cell lines and further selected using HNSCC and control tissues by quantitative methylation-specific PCR (qMS-PCR). We then examined a panel of seven mgmiRs for validation in an expanded cohort including 189 HNSCC and 92 non-HNSCC controls. Saliva from 86 pre-treatment HNSCC patients and 108 non-HNSCC controls was also examined using this panel of seven mgmiRs to assess the potentials of clinical utilization. Results Among the 315 screened mgmiRs, 12 mgmiRs were significantly increased in HNSCC cell lines compared to control cell lines. Seven out of the 12 mgmiRs, i.e., mgmiR9-1, mgmiR124-1, mgmiR124-2, mgmiR124-3, mgmiR129-2, mgmiR137, and mgmiR148a, were further found to significantly increase in HNSCC tumor tissues compared to control tissues. Using multivariable logistic regression with dichotomized variables, a combination of the seven mgmiRs had sensitivity and specificity of 92.6 and 92.4% in tissues and 76.7 and 86.1% in saliva, respectively. Area under the receiver operating curve for this panel was 0.97 in tissue and 0.93 in saliva. This model was validated by independent bootstrap validation and random forest analysis. Conclusions mgmiR biomarkers represent a novel and promising screening tool, and the seven-mgmiR panel is able to robustly detect HNSCC in both patient tissue and saliva. Electronic supplementary material The online version of this article (10.1186/s13148-018-0470-7) contains supplementary material, which is available to authorized users.

Supplementary_Table for Obstructive Sleep Apnea and Sleep Position: Does It Matter for Infants With a Cleft Palate? by Christopher J. Greenlee, Melissa A. Scholes, Dexiang Gao, and Norman R. Friedman in The Cleft Palate-Craniofacial Journal

Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes.

OBJECTIVES/HYPOTHESIS: There is limited data linking demographic determinants to clinical outcomes in facial trauma, particularly when comparing regional to national datasets; these are the aims of the present study. STUDY DESIGN: Retrospective chart review. METHODS: A 10-year, retrospective single-institutional chart review was undertaken at Children's Hospital Colorado (CHC) to characterize a pediatric population with facial fractures. A comparative analysis between the CHC and National Trauma Data Bank (NTDB) datasets was also conducted. RESULTS: In the CHC dataset, increased hospital stay was positively predicted by bilateral mandible fracture, skull, intracranial, spine, thoracic, abdominal, and limb injuries. Predictors of increased intensive-care unit (ICU) stay included skull, spine, and limb injuries. The CHC cohort had younger subjects, more females, fewer African Americans, and more Hispanics than the NTDB dataset. They were more likely to be injured by nonviolent activities than by altercations. Divergent facial and associated injuries between the datasets were found. Multivariate models showed longer length of hospital stay for the CHC group (P = .0085), but the NTDB group had higher ICU admission (P = .04) and longer lengths of ICU stay (P = .007). CONCLUSION: The demographic disparities (age, ethnicity, mechanism of injury, and injury type) resulted in divergent injury patterns and likely influenced clinical outcomes. LEVEL OF EVIDENCE: 4. Laryngoscope, 2015. Language: en

PURPOSE: Functional imaging has been proposed that uses 4DCT images to calculate 4DCT-based lung ventilation (4DCT-ventilation). We have started a 2-institution, phase 2 prospective trial evaluating the feasibility, safety, and preliminary efficacy of 4DCT-ventilation functional avoidance. The trial hypothesis is that the rate of grade ≥2 radiation pneumonitis could be reduced to 12% with functional avoidance, compared with a 25% rate of pneumonitis with a historical control. The trial employed a Simon 2-stage design with a planned futility analysis after 17 evaluable patients. The purpose of this work is to present the trial design and implementation, dosimetric data, and clinical results for the planned futility analysis. METHODS AND MATERIALS: Eligible patients were patients with lung cancer who were prescribed doses of 45 to 75 Gy. For each patient, the 4DCT data were used to generate a 4DCT-ventilation image using the Hounsfield unit technique along with a compressible flow-based image registration algorithm. Two intensity modulated radiation therapy treatment plans were generated: (1) a standard lung plan and (2) a functional avoidance treatment plan that aimed to reduce dose to functional lung while meeting target and normal tissue constraints. Patients were treated with the functional avoidance plan and evaluated for thoracic toxicity (presented as rate and 95% confidence intervals [CI]) with a 1-year follow-up. RESULTS: The V20 to functional lung was 21.6% ± 9.5% (mean ± standard deviation) with functional avoidance, representing a decrease of 3.2% (P < .01) relative to standard, nonfunctional treatment plans. The rates of grade ≥2 and grade ≥3 radiation pneumonitis were 17.6% (95% CI, 3.8%−43.4%) and 5.9% (95% CI, 0.1%−28.7%), respectively. CONCLUSIONS: Dosimetrically, functional avoidance achieved reduction in doses to functional lung while meeting target and organ at risk constraints. On the basis of Simon’s 2-stage design and the 17.6% grade ≥2 pneumonitis rate, the trial met its futility criteria and has continued accrual.

Objective In 2011, the American Academy of Pediatrics published a guideline for children with Down syndrome (DS), recommending a polysomnogram (PSG) by age 4 years regardless of symptoms. Their rationale was based on 2 publications with small cohorts, where at least 50% of the children had no obstructive sleep apnea (OSA) symptoms but their PSG results were abnormal. The American Academy of Otolaryngology-Head and Neck Surgery Foundation published a clinical practice guideline recommending PSG prior to adenotonsillectomy for these children. This study aimed to assess parents' accuracy of their children's breathing patterns as compared with PSGs in a larger cohort of children with DS. Study Design Case series with chart review. Setting Tertiary care academic pediatric hospital. Subjects and Methods Sleep intake forms assessing frequency of parent-observed apnea, snoring, and restless sleep were analyzed. None of the children had a previous tonsillectomy. Two groups were analyzed according to symptoms: infrequent (