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XLSX file - 106KB, Table S5. Tabulated FGFR1, FGF2 and FGF9 mRNA expression values, FGFR1 CNV values and mutation status of TCGA lung adenocarcinomas and squamous cell carcinomas.

PDF file - 90KB, Table S2. Tabulated expression values for selected FGFs in lung cancer cell lines from the Cancer Cell Line Encyclopedia. Table S3. Tabulated FGFR1 gene copy number values determined by SISH and associated patient data for the surgical lung cancer cohort. Table S4. Tabulated FGFR1 mRNA expression values determined by ISH and associated patient data for the surgical lung cancer cohort.

PDF file - 191K, Western blotting for phosphorylated (Y1068) EGFR, total EGFR, pERK and total ERK in NSCLC cells treated with DMSO, gefitinib and/or Wnt pathway inhibitors, qPCR analyses of Axin-2 mRNA levels in cells in cells treated with canonical Wnt pathway inhibitors, western blotting for activated beta-catenin in stable cell lines, and determination of the ability of activated beta-catenin expression to mitigate the impact of gefitinib and/or XAV939 treatment in HCC4006 NSCLC cells

PDF file - 222K, Demonstration that beta-catenin or TCF-4 knockdown results in enhanced sensitivity of NSCLC cells to gefitinib treatment, that beta-catenin or TCF-4 knockdowns reduce the expression of the corresponding protein, that there is minimal correlation between the expression of canonical Wnt target genes and gefitinib sensitivity for a panel of NSCLC cell lines, that there is no significant correlation of SLuGs with gefitinib induced genes, and that SLuGs are not enriched in lung cancer specific genes

PDF file - 105K, Graphical representation of shRNA counts obtained by deep sequencing in the screen for synthetic lethality with gefitinib in H322C and HCC4006 NSCLC cells

XLS file - 683K, The table contains all screening results from the shRNA screen, including results for each of the two cell lines (H322C and HCC4006) and overlapping hits (SLuG2s). The shRNA sequences, the frequency that these sequences were detected in the different replicates, and the associated significance are provided

PDF file - 235K, Validation of shRNA-mediated knockdown of tankyrase-1 expression, demonstration of enhanced NSCLC cell killing by combined inhibition of tankyrase and EGFR in multiple NSCLC cell lines, and specificity of this synergistic cell killing for NSCLC cells with EGFR activation

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XLS file - 34K, Lists of primers and probes for real-time RT-PCR, shRNA sequences and antibodies are provided

PDF file - 240K, Demonstration that CK1alpha or CK2alpha knockdown results in enhanced sensitivity of NSCLC cells to gefitinib treatment, that these knockdowns reduce the expression of the corresponding proteins, that treatment with the CK1� activator pyrvinium pamoate acts synergistically with gefitinib to eliminate NSCLC cells, and specificity of this synergistic cell killing for NSCLC cells following EGFR inhibition

Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC. Cancer Res; 72(16); 4154–64. ©2012 AACR.

PDF file - 76K, Second xenograft experiment utilizing a different shRNA for TNKS1

2,5-Furandicarboxylic acid (FDCA) is one of the top-12 value-added chemicals from sugar. Besides the wide application in chemical industry, here we found that solid FDCA polymerized to form an atomic-scale ordered sp

Background: Cluster-randomized trials allow for the evaluation of a community-level or group-/cluster-level intervention. For studies that require a cluster-randomized trial design to evaluate cluster-level interventions aimed at controlling vector-borne diseases, it may be difficult to assess a large number of clusters while performing the additional work needed to monitor participants, vectors, and environmental factors associated with the disease. One such example of a cluster-randomized trial with few clusters was the “efficacy and risk of harms of repeated ivermectin mass drug administrations for control of malaria” trial. Although previous work has provided recommendations for analyzing trials like repeated ivermectin mass drug administrations for control of malaria, additional evaluation of the multiple approaches for analysis is needed for study designs with count outcomes. Methods: Using a simulation study, we applied three analysis frameworks to three cluster-randomized trial designs (single-year, 2-year parallel, and 2-year crossover) in the context of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria. Mixed-effects models, generalized estimating equations, and cluster-level analyses were evaluated. Additional 2-year parallel designs with different numbers of clusters and different cluster correlations were also explored. Results: Mixed-effects models with a small sample correction and unweighted cluster-level summaries yielded both high power and control of the Type I error rate. Generalized estimating equation approaches that utilized small sample corrections controlled the Type I error rate but did not confer greater power when compared to a mixed model approach with small sample correction. The crossover design generally yielded higher power relative to the parallel equivalent. Differences in power between analysis methods became less pronounced as the number of clusters increased. The strength of within-cluster correlation impacted the relative differences in power. Conclusion: Regardless of study design, cluster-level analyses as well as individual-level analyses like mixed-effects models or generalized estimating equations with small sample size corrections can both provide reliable results in small cluster settings. For 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria, we recommend a mixed-effects model with a pseudo-likelihood approximation method and Kenward–Roger correction. Similarly designed studies with small sample sizes and count outcomes should consider adjustments for small sample sizes when using a mixed-effects model or generalized estimating equation for analysis. Although the 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria is already underway as a parallel trial, applying the simulation parameters to a crossover design yielded improved power, suggesting that crossover designs may be valuable in settings where the number of available clusters is limited. Finally, the sensitivity of the analysis approach to the strength of within-cluster correlation should be carefully considered when selecting the primary analysis for a cluster-randomized trial.

Background: Most estrogen receptor alpha positive (ER+) breast cancers (BCs) express androgen receptor (AR) protein, but its function is unclear. High AR relative to ER is associated with endocrine resistance. This randomized phase II trial of neoadjuvant fulvestrant (F) with or without the anti-androgen enzalutamide (E) was designed to determine if the addition of E to F in women with ≥T2 ER+/Her2- primary BC would increase the % patients (pts) with limited residual disease at time of surgery as measured by modified preoperative endocrine predictive index (PEPI). Methods: 4 months of therapy was given prior to surgery (F 500 mg IM weeks 1, 3, 5, 9, and 13) and pts were randomized to receive E 160 mg po daily for 16 weeks, stratified by node status and T-stage. Tumor biopsies were required at study entry and after 4 weeks on therapy (Wk5). PEPI score at time of surgery was the primary endpoint for efficacy. The minimax two-stage design had 80% power with type I error rate of 0.08. Reverse phase phosphoprotein array (RPPA), IHC for ER/PR/AR/GR/Ki67, and Polaris multiplex immunofluorescence (IF) panel for myeloid lineage immune cells were performed. Average signal levels were compared across arms, PEPI score (0, >0), PEPI by arm, and Ki67 ( Results: 69 pts consented; 59 evaluable. 95% completed surgery. PEPI=0 observed in 10 (17%). Of 33 pts on FE arm, 21 had T3/T4 tumors, 91% ER+/PR+, median AR expression 80%, Ki67 15%. Of 26 patients on F arm, 19% had T3/T4 tumors, 96% ER+/PR+, median AR expression 85%, Ki67 10%. PEPI=0 was achieved more frequently on the FE arm (8, 24%) than the F arm (2, 8%) (p=0.16). Toxicity was as expected with endocrine therapy. IHC of baseline vs Wk5 biopsies showed decreased ER, PR, and Ki67 levels by Wk5 that remained decreased at time of surgery. AR and GR were significantly decreased only in the FE arm at the time of surgery. RPPA revealed that baseline EGFR (Y1604 and Y992) was higher in tumors with PEPI=0 tumors, whereas the average baseline mTOR activation was higher among pts with PEPI>0. Significant changes detected by RPPA upon treatment included a significant decrease in AR. Myeloid-derived suppressor cells (MDSC) were significantly reduced by treatment only in the FE arm. Conclusions: The combination FE had manageable side effects. PEPI=0 was achieved more frequently on the FE arm (8/33) than the F arm (2/26). Activated EGFR was higher pretreatment in tumors achieving PEPI=0. mTOR pathway was elevated pretreatment in PEPI>0 tumors (also observed with resistance to FE in ER+/HER2- metastatic disease (SABCS 2021). When comparing pretreatment tumor to Wk5, total AR by RPPA was the most differentially decreased protein in PEPI=0 tumors. AR signaling is known to support immunosuppressive cells and we observed a marked decrease in MDSCs with treatment only on the FE arm. Citation Format: Anthony D. Elias, Alyse Staley, Monica Fornier, Gregory A. Vidal, Sharon Sams, Nicole Spoelstra, Peter Kabos, Jennifer R. Diamond, Elena Shagisultanova, Rosa I. Gallagher, Julia Wulfkuhle, Emanuel Petricoin, Kathryn Zolman, Stephanie Biller, Vida Alami, Tessa McSpadden, Virginia Borges, Lyndsey S. Crump, Dexiang Gao, Jennifer K. Richer. Randomized phase II trial of preoperative fulvestrant with or without enzalutamide for ER+/Her2- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT144.

In cancer-free tissues, somatic mutations accumulate in all of us over time. In most instances, these mutations are inconsequential to cellular fitness or to overall health. However, some mutations can result in a cell having a fitness advantage over its surroundings, enabling proliferation. In the blood, this proliferation - known as clonal hematopoiesis (CH) - is associated with an increased risk of hematologic malignancies, most notably leukemia, and is commonly observed in the elderly. People with Down syndrome (DS) also exhibit CH and have a markedly higher risk of leukemia (up to 400x); therefore, we investigated CH in people with DS to understand how mutations in the blood can lead to disrupted hematopoiesis and lead to varying susceptibility, onset, and severity of hematologic malignancies. To detect CH, I used a rare-mutation detection technique called DuplexSeq to analyze leukocytic genomic DNA from blood draws. This targeted-sequencing tool spans 37 genes implicated in leukemia - including leukemias seen in those with DS - and implements a double-stranded tag to incorporate mutational data from both DNA strands, enabling higher sensitivity than most sequencing methods. We characterized detected mutations using bioinformatic pipelines, various databases, and statistical methods. By comparing CH between people with and without DS, we observe an overrepresentation of protein-altering mutations in people with DS in genes important for hematopoiesis. Notably, people with DS exclusively harbor CH with JAK2 mutations, many of which have been associated with myeloid proliferative neoplasms. Mutations in NPM1 that have been previously seen in cancer are also exclusively observed in people with DS with potential to lead to differentiation block, a hallmark of leukemia. Finally, mutations with the highest variant allele frequency in TET2 are largely observed in people with DS, indicating preferential expansion in the DS context. These fledgling expansions in TET2 may be indicative of modified hematopoietic differentiation. Ongoing work is centered around understanding the consequences of these mutations and how they distinguish phenotypes among people with DS. Using a database for DS research, we are performing multi-omics analyses to understand which biological pathways may be disrupted in the same individuals with CH of interest. Additionally, we will use mouse models of DS to investigate the selective advantage of the observed mutations in the DS context, how they impact differentiation fate, and how cell intrinsic and extrinsic factors can influence clonal expansions. Overall, these studies offer a means by which risk of hematologic malignancies can be monitored by CH with elucidation of potential mechanisms. By characterizing CH, early markers of disrupted hematopoiesis can be established to determine susceptibility of leukemia and be used to monitor those who are most at risk. Citation Format: Edward J. Evans, Neetha Paul-Eduthan, Junxiao Hu, Dexiang Gao, Matthew Galbraith, Joaquin Espinosa, James DeGregori. Clonal hematopoiesis in Down syndrome and its potential impact on hematopoietic lineages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1510.

Epidermal growth factor receptor (EGFR) is often overexpressed in head and neck squamous cell carcinoma (HNSCC) and represents a top candidate for targeted HNSCC therapy. However, the clinical effectiveness of current Food and Drug Administration (FDA)‐approved drugs targeting EGFR is moderate, and the overall survival rate for HNSCC patients remains low. Therefore, more effective treatments are urgently needed. In this study, we generated a novel diphtheria toxin‐based bivalent human epidermal growth factor fusion toxin (bi‐EGF‐IT) to treat EGFR‐expressing HNSCC. Bi‐EGF‐IT was tested for in vitro binding affinity, cytotoxicity, and specificity using 14 human EGFR‐expressing HNSCC cell lines and three human EGFR‐negative cancer cell lines. Bi‐EGF‐IT had increased binding affinity for EGFR‐expressing HNSCC compared with the monovalent version (mono‐EGF‐IT), and both versions specifically depleted EGFR‐positive HNSCC, but not EGFR‐negative cell lines, in vitro. Bi‐EGF‐IT exhibited a comparable potency to that of the FDA‐approved EGFR inhibitor, erlotinib, for inhibiting HNSCC tumor growth in vivo using both subcutaneous and orthotopic HNSCC xenograft mouse models. When tested in an experimental metastasis model, survival was significantly longer in the bi‐EGF‐IT treatment group than the erlotinib treatment group, with a significantly reduced number of metastases compared with mono‐EGF‐IT. In addition, in vivo off‐target toxicities were significantly reduced in the bi‐EGF‐IT treatment group compared with the mono‐EGF‐IT group. These results demonstrate that bi‐EGF‐IT is more effective and markedly less toxic at inhibiting primary HNSCC tumor growth and metastasis than mono‐EGF‐IT and erlotinib. Thus, the novel bi‐EGF‐IT is a promising drug candidate for further development., In this study, we have developed a diphtheria toxin‐based bivalent human EGF fusion toxin for the treatment of HNSCC with significantly improved efficacy and markedly less in vivo off‐target toxicity compared with the monovalent human EGF fusion toxin. The bivalent human EGF fusion toxin is a promising novel drug candidate for the treatment of EGFR‐positive HNSCC.

Background: Almost all ER+ breast cancers express androgen receptor (AR), but its function is uncertain. AR expression is associated with more indolent tumors, however high AR expression relative to ER is associated with endocrine resistance, and in the absence of estradiol or if ER function is blocked, preclinical data would suggest that AR can take over to signal cell survival and proliferation. This non-blinded randomized phase II trial of neoadjuvant fulvestrant with or without enzalutamide was performed in women with T2 or greater ER+/Her2- primary breast cancer. Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- primary breast cancer cT2 or greater. A total of 4 months of therapy was given (fulvestrant 500 mg IM weeks 1, 3, 5, 9, and 13). Patients were randomized to receive enzalutamide 160 mg po daily on a continual basis for 16 weeks. Stratification factors were clinical node status (N0 vs N1/2) and T-stage (T2 vs T3/4). Surgery was planned for week 17. Fresh tumor biopsies were required at study entry and at ~4 weeks on therapy. Tissue, both fresh frozen and FFPE, was also obtained at time of surgery. The PEPI score at time of surgery was the primary endpoint for efficacy. The statistical design were parallel phase II trials with the experimental arm designed as a Simon 2-stage. The expectation for the control arm was a PEPI score of 0 in 16% and 32% for the combination arm. Additional enrollment of 12 patients would ensue if 4 or more achieved a PEPI score of 0 within the first 22 patients enrolled onto the combination arm. 27 patients would be enrolled into the fulvestrant alone arm. Results: The Simon 2-stage criteria were met and the trial continues to accrue up to 11 more evaluable patients. Thus far, 58 patients were consented of whom 50 were treated. Median age was 61.5 years (45-83); PS 0 (0-2). Among the 46 patients with information on AEs, there are 25 patients with Grade 2 AEs, including 5 with fatigue, 3 with headache, and 2 with hot flashes. There are 5 patients with grade 3 AEs including abdominal pain, gallbladder obstruction, ALT elevation, hyperglycemia, and hypertension. We also have 2 patients with grade 4 AEs , chest pain-cardiac and cardiac disorder-other. There is no grade 5 event. Paired samples at baseline and at 4 weeks are collected so far from 49 patients. 42 patients have completed surgery, while two patients have not undergone surgery. Conclusions: The combination of fulvestrant plus enzalutamide had manageable side effects. The trial is now in its extended stage since PEPI score = 0 was achieved in at least 4 of the first 22 patients on the combination arm. Extensive molecular studies of paired fresh biopsies from pretreatment and at 4 weeks are underway. These analyses and correlations with clinical outcome will be described. Citation Format: Anthony D Elias, Monica Fournier, Gregory A Vidal, Sharon Sams, Nicole Spoelsta, Peter Kabos, Jennifer R Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Julia Wulfkuhle, Emanuel Petricoin, Lisa Carter, Kathryn Zolman, Stephanie Armstead, Alyse Winchester, Tessa McSpadden, Gloria Crawford, Virginia Borges, Dexiang Gao, Jennifer Richer. Phase II randomized trial of fulvestrant with or without enzalutamide in ER+/Her2- primary breast cancer (BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-06.

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood–derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM, and NOD/SCID/IL2rg−/− (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non–HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFNγ)–related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.

Background 16–25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer. Aim Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps. Methods We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range. Results A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance. Conclusions 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes.

Significance The diamond nanothread is predicted to have comparable or larger strength and stiffness than the carbon nanotube but severely suffers from intrathread bonding disorder in practice. Here, we synthesized a bulk crystalline diamond nanothread material C 3 N 3 H 3 with a C/N-ordered tube (3,0) structure via high-pressure topochemical polymerization of s -triazine. The π-stacked s -triazine experienced a selective concerted bonding of three neighbored C···N pairs, completely different from the classical Diels–Alder reactions of aromatics under high pressure. This study obtained the structure-specific diamond nanothread with an unambiguous elemental reaction, which is the basis to realize the expected excellent properties of diamond nanothreads. Following the identified reaction selectivity under high pressure, more structure-specific carbon materials can be designed.

Carbon nanothread (CNTh) is a “one-dimensional diamond polymer” that combines high tensile strength and flexibility, but it severely suffers from intrathread disorder. Here, by modifying the reactivity and the stacking ordering of the aromatic precursor, crystalline C3N3H3 CNTh with perfect hexagonal orientation and stacking was synthesized at 10.2 GPa and 573 K from s-triazine. By Rietveld refinement of X-ray diffraction data, gas chromatography mass spectrometry investigation, and theoretical calculation, we found that synthesized CNTh has a tube (3,0) structure, with the repeating s-triazine residue connected solely by C–N bonds along the thread. A “peri-cage” reaction, the concerted bonding between six C and N atoms, instead of [4 + 2] or [1,4] addition reactions, was concluded for the formation of CNThs, and the critical bonding distance between the nearest intermolecular C and N was ∼2.9 Å. The formation of a “structure-specific” crystalline CNTh with C and N orderly distributed highlighted the importance of reaction selectivity and stacking order of reactant molecules, which have great significance for understanding the polymerization of aromatic molecules under high pressure and developing new crystalline CNThs.

Patients with metastatic breast cancer (MBC) refractory to standard of care therapies have a poor prognosis. The purpose of this study was to assess patient characteristics and clinical outcomes for patients with MBC treated on phase I clinical trials. We performed a retrospective review of all patients with MBC who were enrolled in phase I clinical trials at the University of Colorado Cancer Center from January 2012 to June 2018. A total of 208 patients were identified. Patients had a mean age of 57 years and received on average 2.1 (range 0‐10) prior lines of chemotherapy. The majority of patients had hormone receptor‐positive/HER2‐negative breast cancer (58.6%) and 30.3% had triple‐negative breast cancer. The median progression free survival (PFS) was 2.8 months (95% CI, 2.3‐3.9) and median overall survival (OS) was 11.5 months (95% CI, 9.6‐13.2). Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer‐selective trial or cohort (p = 0.016), age >50 years (p = 0.002), and ≤2 prior lines of chemotherapy in the metastatic setting (p = 0.025). Phase I clinical trials remain a valuable option for select patients with MBC and enrollment should be encouraged when available., We performed a retrospective review of all patients with metastatic breast cancer (MBC) who were enrolled in phase I clinical trials at the University of Colorado Cancer Center. Independent factors associated with longer PFS in multivariable analysis were treatment in a breast cancer‐selective trial or cohort, age >50 years, and ≤2 prior lines of chemotherapy in the metastatic setting. Phase I clinical trials remain a valuable option for selecting patients with MBC and enrollment should be encouraged when available.

Purpose Pediatric, adolescent and young adult (PAYA) patients with renal cell carcinoma (RCC) have a high rate of LN involvement, yet data to guide surgical lymph node (LN) management in this group is limited. The objective is to describe a LN yield threshold to quantify the chance of missing occult LN involvement at ≤ 10% in PAYAs with RCC. Materials & methods The National Cancer Database was queried for patients aged ≤ 30 y with unilateral, non-metastaticRCC from 2004 to 2013. The probability of a false negative LN sampling was determined on the cohort of patients who had at least one positive LNand ≥ 2 LNs examined. For a given LN yield, the probability that a positive LN exists but none were found was estimated using a beta-binomial model. Results We identified 112 patients meeting study criteria. Median age was 24 y and median tumor size was 9.5 cm (IQR 5.8–14). The median number of LNs sampled was 7 (IQR 4–12) and the median number of LNs positive was 4 (IQR 2–7). To achieve ≤ 10% probability of a false-negativeLN sampling, the beta-binomial model estimated that 5 LNs (95% CI4–7) must be sampled. Conclusions The desired LN yield to reduce the risk of a false-negativeLN sampling in PAYAs with RCC to ≤ 10% is 5. This is in keeping with prior studies identifying a LN yield of 6–10 to achieve the same. These data may be used to standardize surgical guidelines when treating PAYAs with renal tumors. Level of Evidence II.

Introduction Phase I and II trials provide the initial human safety and tolerability data for new drugs. Nevertheless, the methods for presenting toxicity data are not standardized. Clinicians often first encounter these data at professional conferences. We sought to characterize how the burden of adverse events (AEs) is reported at the largest professional conference in clinical oncology. Methods We collected toxicity data from all lung cancer-associated phase I and II trial presentations and posters at the American Society for Clinical Oncology annual meetings from 2017 to 2019. We captured the various AE features, including the minimum incidence used for reporting; whether AEs found were treatment emergent or treatment related, grouped by organ system or separated by individual descriptors; whether combined or separated across dose levels when a dose-escalation component was included; and whether dose-limiting toxicities, serious AE, dose-reduction rules, and denominators for laboratory tests were described. Results A total of 209 trials were analyzed. There was wide variability in toxicity reporting practices. Six different thresholds for reporting AEs of any grade were used. Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. Toxicities were as likely to be reported across dose levels as by dose level. Terms such as dose-limiting toxicity and serious AE were rarely defined. Dose-reduction rules and denominators for laboratory tests were never defined. Conclusions Standardization of methods for reporting toxicities could improve the quality and ease of comparability of data on adverse effects in early phase therapeutic trials. A minimal AE data disclosure template is proposed.

There is an urgent need of having a rapid, high throughput, yet accurate SARS-COV-2 PCR testing to control the COVID19 pandemic. However, the RNA extraction step in conventional PCR creates a major bottle neck in the diagnostic process. In this paper we modified the CDC COVID-19 assay and developed an RNA-extraction free RT-qPCR assay for SARS-CoV-2, i.e. COVIDFast™. Depending on sample types, the assay is further divided into SwabFAST™, which uses anterior nares nasal swab, and SalivaFAST™, which uses saliva. By utilizing the proprietary buffer for either swab or saliva samples, the performance of SwabFAST or SalivaFAST is equivalent to RNA-extraction SARS-CoV-2 RT-qPCR in both contrived and clinical samples. The limit of detection of either assay is 4 copies/μL. We further developed a semi-automatic system, which is easy to adapt by clinical lab for implementation of a high-throughput SARS-CoV-2 test. Working together with the COVIDCheck Colorado, we have tested over 400,000 samples using COVIDFast (83.62% SwabFAST and 16.38% SalivaFAST) in less than a year, resulting in significant clinical contribution in the battle against COVID-19 during the pandemic.

Cold snare polypectomy (CSP) is the preferred resection technique for small (6-9 mm) polyps due to lower rate of incomplete resection compared to cold forceps polypectomy (CFP) and improved safety profile over hot snare polypectomy (HSP).To describe resection techniques for small (6-9 mm) polyps and determine factors associated with sub-optimal technique.This was retrospective cohort study of colonoscopies performed by gastroenterological and surgical endoscopists from 2012 to 2019 where at least one 6-9 mm polyp was removed. Patient, provider, and procedure characteristics were collected. Univariate and multivariate regression analyses were performed to determine factors associated with sub-optimal technique.In total, 773 colonoscopies where 1,360 6-9 mm polyps removed by 21 endoscopists were included. CSP was used for 1,122 (82.5%), CFP for 61 (4.5%), and HSP for 177 (13.0%). Surgeon specialty was associated with CFP use (aOR 7.81; 95% CI 3.02-20.16). Polyp location in left colon (aOR 1.65; 95% CI 1.17-2.33) and pedunculated morphology (aOR 12.76; 95% CI 7.24-22.50) were associated with HSP. There was a significant increase in overall CSP use from 30.4% in 2012 to 96.8% in 2019.82.5% of all 6-9 mm polyps removed from 2012 to 2019 were removed using a cold snare with significant increase in CSP from 2012 to 2019. Differences in how optimal technique was adopted over time based on specialty highlight the need for standardized practice guidelines and quality monitoring.

Substituted polyacetylene is expected to improve the chemical stability, physical properties, and combine new functions to the polyacetylene backbones, but its diversity is very limited. Here, by applying external pressure on solid acetylenedicarboxylic acid, we report the first crystalline poly-dicarboxylacetylene with every carbon on the

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) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

Background While immune checkpoint inhibitors (ICI) were approved for head and neck squamous cell carcinomas (HNSCCs), the response rate remains relatively low. Mechanisms underlying ICI unresponsiveness versus sensitivity are not fully understood. Method To better delineate differential responses to ICI treatment, we employed mouse SCC models, termed KPPA tumors that were caused by deleting p53 and hyperactivating PIK3CA, two most frequently mutated genes in human HNSCCs. We transplanted two KPPA tumor lines (TAb2 versus TCh3) into C57BL/6 recipients and examined the immune tumor microenvironment using flow cytometry. Furthermore, we employed single-cell RNA sequencing to identify the difference in tumor infiltrating lymphocytes (TILs). Results We found that different KPPA tumors exhibited heterogeneous immune profiles pre-existing treatment that dictated their sensitivity or unresponsiveness to anti-PD-L1. Unresponsive TAb2 tumors were highly enriched with functional tumor-associated macrophages (TAMs), especially M2-TAMs. In contrast, sensitive TCh3 tumors contained more CD8 TILs with better effector functions. TAb2 tumor cells drastically expanded F4/80+ TAMs from bone marrow precursors, requiring CSF1 and VEGF. Consistently, a higher combined expression of VEGF-C and CSF1 predicts worse survival in PIK3CAAmp/TP53Mutated HNSCC patients. Unresponsive TAb2 tumors upregulated distinct signaling pathways that correlate with aggressive tumor phenotypes. While anti-PD-L1 did not affect the TME of TAb2 tumors, it significantly increased the number of CD8 TILs in TCh3 tumors. Conclusions We uncovered tumor-intrinsic differences that may underlie the differential responses to ICI by establishing and employing two SCC tumor lines, TAb2 vs. TCh3, both of which harbor TP53 deletion and PIK3CA hyperactivation. Our study indicates the limitation of stratifying cancers according to their genetic alterations and suggests that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses. Our experimental models may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy.

Up to 91% of ER+ breast cancers express androgen receptor (AR), but its function is uncertain. Although AR expression is associated with more indolent tumors, high AR expression relative to ER is associated with endocrine resistance, and in the absence of estradiol or if ER function is blocked, preclinical studies suggest that AR can take over to signal cell survival and proliferation. Following extensive preclinical studies and a brief phase I to demonstrate a lack of significant PK interaction, this phase II trial of fulvestrant plus enzalutamide in ER+/Her2- metastatic breast cancer was conducted. Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- measurable or evaluable metastatic breast cancer without CNS disease. Prior fulvestrant was allowed, if clinically indicated as per treating physician. Fulvestrant was administered in standard dosing at 500 mg IM days 1, 15, 29 and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily on a continual basis. Fresh tumor biopsies were required at study entry and at about 4 weeks on therapy. The primary efficacy endpoint of the trial was clinical benefit rate at 24 weeks (CBR24). Assuming the undesirable rate of 10% and desirable rate of 30%, a sample size of 24 provided 89% power to detect this 25% rate difference using an exact binomial test with a one-sided alpha of 0.085. Due to the exploratory nature of biomarker analysis, the type I error rate was not adjusted for exploring multiple biomarkers. Results: A total of 38 patients were consented, of whom 32 were eligible. 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. Twelve patients had prior fulvestrant, and 90% had visceral disease. TEAEs >20% included fatigue, nausea/vomiting, constipation, headache, anorexia, although most were low grade. There were no G4 or G5 toxicities. Median PFS was 2.0 months (0.5-12). CBR24 was 25% (7/28 evaluable).Conclusions: In a heavily pretreated population of women with metastatic ER+/Her2- BC, the combination of fulvestrant plus enzalutamide had manageable side effects, and modest activity. About 25% reached the primary endpoint of clinical benefit of more than 6 months on therapy. Extensive molecular studies of paired fresh biopsies from pretreatment and at 4 weeks are underway. These analyses and correlations with clinical outcome will be described. Citation Format: Anthony D Elias, Nicole Spoelsta, Gregory A Vidal, Sharon Sams, Peter Kabos, Jennifer R Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadden, Gloria Crawford, Lisa Carter, Kathryn Zolman, Stephanie Armstead, Alyse Winchester, Virginia Borges, Julia Wulfkuhle, Emanuel Petricoin, Dexiang Gao, Jennifer Richer. Phase II trial of fulvestrant plus enzalutamide in ER+/Her2- advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-14.

The pressure-induced phase transition and polymerization of nitrogen-rich molecules are widely focused on due to their extreme importance for the development of green high-energy-density materials. Here, we present a study of the phase-transition behaviour and chemical reaction of 1H-tetrazole up to 100 GPa using in situ Raman, IR, X-ray diffraction, neutron diffraction techniques and theoretical calculations. A phase transition above 2.6 GPa was identified and the high-pressure structure was determined with one molecule in a unit cell instead of two molecules as reported before. The 1H-tetrazole polymerized reversibly below 100 GPa, probably through carbon–nitrogen bonding instead of nitrogen–nitrogen bonding. Our studies update the structure model of the high-pressure phase of 1H-tetrazole, and present the possible intermolecular bonding route for the first time, which gives new insights to understand the phase transition and chemical reaction of nitrogen-rich compounds, and is of benefit for designing new high-energy-density materials.

INTRODUCTION AND OBJECTIVE:Two chemotherapeutic agents used widely in pediatric oncology are vincristine (VCR) and doxorubicin (DOX), which cause neuropathy and myopathy, respectively. The study hy...

Real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) remains the foundation of SARS-CoV-2 testing due to its accessibility, scalability, and superior assay performance. Variability in specimens and methods prevent standardization of RT-qPCR assays and reliable quantitative reporting to assess viral load. We developed an extraction-free RT-qPCR assay for detection of SARS-CoV-2 in saliva and monitored viral load until convalescence in COVID-19 patients. Comparison of 231 matched anterior nares swab and saliva specimens demonstrated that extraction-free testing of saliva has equivalent analytical and clinical assay performance compared to testing of RNA extracts from either anterior nares or saliva specimens. Analysis of specimen pairs revealed higher viral loads in the nasal cavity compared to the oral cavity, although this difference did not impact clinical sensitivity for COVID-19. Extraction-free testing of a combination specimen consisting of both nasal swab and saliva is also demonstrated. Assessment of viral load by RT-qPCR and parallel digital droplet PCR (ddPCR) revealed that cycle threshold (Ct) values less than approximately 30 correlated well with viral load, whereas Ct values greater than 30 correspond to low viral loads 10 copies/µL. This technology can facilitate high-throughput laboratory testing for SARS-CoV-2, monitor viral load in individual patients, and assess efficacy of therapies for COVID-19.

Background Two chemotherapeutic agents used widely in pediatric oncology are vincristine (VCR) and doxorubicin (DOX), which may cause neuropathy and myopathy, respectively. The study hypothesis is that neurotoxic effects of VCR and/or myotoxic effects of DOX affect bladder physiology and manifest clinically as lower urinary tract dysfunction (LUTD). Procedure Based on a priori power analysis, 161 children divided evenly by gender were recruited. Children aged 5-10 years completed the dysfunctional voiding scoring system (DVSS) survey. The study cohort comprised cancer survivors treated with VCR and/or DOX. Healthy controls were recruited from well-child clinic visits. Exclusion criteria included pelvic-based malignancy, pelvic irradiation, pre-existing LUTD, neurologic abnormalities, and treatment with cyclophosphamide/ifosfamide. DVSS scores and presence of LUTD, defined as DVSS scores above gender-specific thresholds (males ≥9, females ≥6), were compared across cohorts. Results Median DVSS scores were higher in the study cohort (6 vs. 4, p = .003). Moreover, children in the study cohort were more likely to exceed threshold scores for LUTD (38.8% vs. 21%, p = .014; OR 1.8). Subanalysis by gender revealed female cancer survivors are more likely to report LUTD than controls (57.5% vs. 30%, p = .013, OR 1.9). This did not hold true for males (20% vs. 12.2%, p = .339). Conclusions Childhood cancer survivors who received VCR and/or DOX reported higher rates of LUTD than controls. Female cancer survivors appear more likely to suffer from LUTD than males. Further study with a positive control cohort of cancer survivors who received non-VCR, non-DOX chemotherapy is underway to elucidate the contribution of a cancer diagnosis to LUTD.

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.

Purpose Current investigational priorities in the treatment of favorable histology Wilms tumor (FHWT) center on accurate staging and risk-stratification. The extent of lymph node (LN) sampling has not been clearly defined; its importance cannot be overstated as it guides adjuvant therapy. The identification of a minimum LN yield to minimize the risk of harboring occult metastatic disease could help development of surgical guidelines. This study focuses on using the beta-binomial distribution to estimate the risk of occult metastatic disease in patients with FHWT. Materials & methods The National Cancer Database was queried for patients with unilateral FHWT from 2004 to 2013. Data were used to characterize nodal positivity for patients who underwent surgery and had ≥ 1 positive LN and ≥ 2 LNs examined. The probability of missing a positive LN (i.e., false negative) for a given LN yield was calculated using an empirical estimation and the beta-binomial model. Patients were then stratified by tumor size. Results 422 patients met study criteria. To limit the chance of missing a positive LN to ≤ 10%, the empirical estimation and beta-binomial model estimated that 6 and 10 LNs needed to be sampled, respectively. Tumor size did not influence the result. Internal validation showed little variation to maintain a false negative rate ≤ 10%. Conclusions Using mathematical modeling, it appears that the desired LN yield in FHWT to reduce the risk of false-negative LN sampling to ≤ 10% is between 6 and 10. The current analysis represents an objective attempt to determine the desired surgical approach to LN sampling to accurately stage patients with FHWT. Level of evidence II

Immune suppression is one of the 10 hallmarks of cancer. Interleukin-37 (IL-37), a member of the IL-1 family, inhibits both innate and adaptive immunity, and has been shown to modulate immune responses in various disease conditions. Yet, IL-37 has rarely been investigated in cancer patients, and its biological role in cancer remains to be elucidated. In this study, we investigated the gene expression of IL-37 in age- and sex-matched blood samples of healthy individuals and melanoma patients, and demonstrated upregulation of IL-37 messenger RNA (mRNA) in the blood samples of melanoma patients. By further analyzing immune cell subsets responsible for the upregulated IL-37 expression, we discovered that IL-37 mRNA was highly expressed in T cells and granulocytes, with the highest expression in regulatory T (Treg ) cells in healthy individuals, and that IL-37 mRNA was upregulated in lymphocytes (T, B, and natural killer cells) in melanoma patient blood. Among all cell subsets, Treg cells from melanoma patients exhibited the highest IL-37 gene expression levels. We provided evidence that melanoma-conditioned media induces IL-37 mRNA and protein expression in multiple lymphocyte populations, particularly in Treg cells. We further confirmed that the IL-1-mediated secretome from human melanoma cells, specifically transforming growth factor-β, induces IL-37 mRNA expression in human Treg cells. Our results suggest a potential immunosuppressive role for IL-1 and IL-37 in melanoma tumorigenesis. Highly elevated IL-37 in specific lymphocyte populations could serve as a biomarker for tumor-induced immunosuppression.

To assess the current practice patterns of pediatric otolaryngologists in managing obstructive sleep-disordered breathing 6 years following the 2011 publication of the clinical practice guideline "Polysomnography for Sleep-Disordered Breathing prior to Tonsillectomy in Children."Cross-sectional survey.American Society of Pediatric Otolaryngology (ASPO) members.An electronic survey to assess ASPO members' adherence to polysomnography guidelines prior to tonsillectomy.Forty percent (170 of 427) of ASPO members completed the survey, with 73% in academic practice and 27% in private practice. Snoring represented, on average, 48% of the respondents' practices. The percentage of respondents who requested a polysomnogram prior to tonsillectomy ≥90% of the time was 55% (n = 94) for Down syndrome, 41% (n = 69) for a child2 years old, and 29% (n = 49) for obese children. A total of 109 (73%) and 112 (75%) respondents admit at least 90% of the time for a child with Down syndrome and for a child3 years of age, respectively, but only 52 (35%) have a similar practice for an obese child. Only 37% adhere to the inpatient admission recommendation for children with documented obstructive sleep apnea on polysomnogram.The current polysomnogram practice patterns for responding pediatric otolaryngologists are not aligned with the clinical practice guideline of the American Academy of Otolaryngology-Head and Neck Surgery Foundation. The threshold for overnight observation when a preoperative polysomnogram has not been performed may be too low. A campaign is necessary to educate clinicians who take care of children with obstructive sleep-disordered breathing and to obtain more evidence to further define best practice.

Introduction This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. Methods Venous and arterial TEEs within ±365 days of diagnosis of ROS1+, ALK+, EGFR+, or KRAS+ advanced NSCLC at five academic centers in the United States and China were captured (October 2002–April 2018). The primary endpoint was incidence of TEE in ROS1+ compared to anaplastic lymphoma kinase (ALK)+, EGFR+, and KRAS+ NSCLC within ±90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers. Results Eligible data from 95 ROS1+, 193 ALK+, 300 EGFR+, and 152 KRAS+ NSCLC patients were analyzed. The incidence rate of TEE was 34.7% (n = 33), 22.3% (n = 43), 13.7% (n = 41), and 18.4% (n = 28), respectively. In univariate analysis, the odds of a TEE in ROS1+ NSCLC were higher than ALK+, EGFR+, and KRAS+ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1+ compared to EGFR+ and KRAS+ cohorts, the odds ratio (OR) was 2.44, with a 95% confidence interval of 1.31–4.57 (p = 0.005), and OR: 2.62, with a 95% confidence interval of 1.26–5.46 (p = 0.01), respectively. Although numerically superior, the odds for a TEE with ROS1+ compared to ALK+ was not statistically significant (OR: 1.45, p = 0.229). Overall survival was not significantly different in patients with or without TEE within ±90 days of diagnosis in the overall study cohort or within each molecular group. Conclusions The risk of peridiagnostic TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC.

Introduction Preclinically, high epidermal growth factor receptor 1 (FGFR1) messenger RNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to fibroblast growth factor receptor inhibitors in non–small-cell lung cancer and small-cell lung cancer cell lines. KRAS mutations did not preclude sensitivity. Patients and Methods Metastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Patients with positive findings were offered ponatinib, a multi–kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed by the log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed by Fisher exact test and Kruskal-Wallis rank sum test. Results A total of 171 cases were prescreened: 9 (7.3%) of 123 SISH+; 53 (42.1%) of 126 ISH+; and 6 cases concordantly positive for SISH and ISH. SISH+ cases had fewer coincident KRAS mutations (P = .03) than SISH− cases, and ISH+ cases had worse OS (P = .020) than ISH− cases. Data distributions suggested a distinct higher positivity cut point for FGFR1 ISH (≥ 20%), occurring in 29 (23%) of 126 cases, was associated with small-cell lung cancer histology (P = .022), soft tissue metastases (P = .050) and shorter OS (P = .031). Four patients received ponatinib on study: All ISH+ by the initial cut point, 2 of 4 by higher cut point, 1 of 4 SISH+. Tolerability was poor. The best response for the 2 higher ISH cases was stable disease and progressive disease for the 2 lower ISH cases. Conclusion Elevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib's poor tolerance suggests further fibroblast growth factor receptor exploration in ISH+ cases should utilize more selective FGFR1 inhibitors.

Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) is one of the most important energetic materials. Investigations on its phase transitions and chemical reactions under extreme conditions are very important to understand the explosion process and design new energetic materials. By using a diamond anvil cell combined with in situ Raman, IR and X-ray diffraction techniques up to a pressure of ∼40 GPa, we found that β-HMX undergoes four reversible phase transitions without any chemical reaction under external pressure at room temperature. Isostructural phase transitions emerge around 5 GPa (ζ-HMX) and 10–13 GPa (e-HMX), and another two phases emerge at 16 GPa (η-HMX) and 27 GPa (ϕ-HMX). The unit cells of ζ-HMX and e-HMX were determined as a = 6.215 A, b = 10.417 A, c = 8.272 A, β = 124.88°, P21/c at 6.2 GPa and a = 6.130 A, b = 9.846 A, c = 8.258 A, β = 125.06°, P21/c at 12.6 GPa, respectively. The crystal structures of β, ζ, and e-HMX were obtained by Rietveld refinement, based on which the rotations of NO2 groups were found to be related to the phase transition at 5 GPa. Additionally, HMX decomposes at 8.7 GPa and 300 °C. Carbon dioxide, hydroxyl, imino and hydroxyimino groups were detected in the IR spectrum, which indicates that the reaction contains a hydrogen transfer process. Our investigation uncovers the structural variation of β-HMX under external pressure and identifies the decomposition products under extreme conditions, which provides new insight to understand the detonation process of energetic materials.

Pressure is an effective method to modulate the optical properties of organic solid-state light-emitting materials through enhancing intermolecular interactions and/or generating new polymorphs. Herein, we find that the organic molecular crystal of diphenylfluorenone (DPFO) undergoes a large-scale and continuous redshift of the UV-vis absorption and photoluminescence (PL) spectra under high pressure, across the entire visible light region. Remarkably, a redshift of about 300 nm was observed for its PL peak at 13.32 GPa, from greenish-yellow to the near-infrared (NIR) region. The in situ high-pressure IR spectra and synchrotron X-ray diffraction (XRD) analyses suggest a phase transition from the α- to the γ-phase (newly identified) at around 3 GPa, accompanied by the phenyl unit in DPFO converting from perpendicular to parallel packing. Theoretical calculations show that the enhanced π⋯π interactions and the overlap of the molecular orbitals in the γ-phase are responsible for such a tremendous redshift in the PL spectra. Our work highlights the large redshift phenomenon in the DPFO system under high pressure, which may have potential photonic device applications. Furthermore, this work reveals the clear structure-property relation, providing deep insight into the tailoring of the optical characteristics of molecular materials.

Standardized simulation training geared towards interstitial brachytherapy (IS BT) for gynecologic malignancies is lacking in radiation oncology resident education. We developed and implemented a curriculum for IS BT training with (1) lecture on equipment, workflow, and guidelines, (2) hands-on ultrasound-guided IS BT workshop, and (3) treatment planning workshop.The cost in materials of each phantom was approximately $66. After a lecture, two alternating workshops were performed. The first session consisted of a hands-on ultrasound-guided IS BT workshop with one resident imaging the phantom with a transabdominal ultrasound probe and the other resident implanting the phantom with needles. A second session consisted of a hands-on treatment planning workshop using BrachyVision and an l-Q spreadsheet with the following objectives: coverage goal, meeting D2cc constraints, and minimizing V200. The primary outcome was improvement in knowledge assessed with Likert-style questions and objective knowledge-based questions (KBQs).Four of the seven medical residents that participated in this curriculum had prior IS BT experience. Residents reported significantly improved knowledge regarding gynecologic IS BT equipment and procedure, evaluating gynecologic anatomy using ultrasound, CT simulation, contouring, and plan review (overall median pre-session subjective score 2 (1)Residents participating in phantom training with an ultrasound curriculum and a treatment planning session is effective for improving knowledge and skills in IS BT for radiation oncology residents.

Background & Aims Incidence and mortality associated with early-age onset colorectal cancer (EAO-CRC) is increasing, prompting professional society recommendations to lower the screening age in average-risk individuals. The yield of screening individuals younger than 50 years is not known. Methods A systematic review of 3 databases from inception through July 2020 was performed in all languages that reported colonoscopy findings in average-risk individuals younger than 50 years. The primary outcomes were EAO colorectal neoplasia (CRN) and advanced colorectal neoplasia (aCRN) prevalence. Subgroup analyses were performed based on sex, geographic location, time period, and age, including comparison with those aged 50–59 years. Generalized linear mixed model with random intercept logistic regression and fixed subgroup effects were performed. Results Of 10,123 unique articles, 17 studies published between 2002 and 2020, including 51,811 average-risk individuals from 4 continents, were included. The pooled rate of EAO-CRN was 13.7% (95% confidence interval [CI], 0.112%–0.168%) and EAO-aCRN was 2.2% (95% CI, 0.016%–0.031%). Prevalence of CRC was 0.05% (95% CI, 0.00029%–0.0008%). Rates of EAO-CRN were higher in men compared with women (relative risk, 1.71%; 95% CI, 1.49%–1.98%), and highest in the United States (15.6%; 95% CI, 12.2%–19.7%) compared with Europe (14.9%; 95% CI, 6.9%–29.3%), East Asia (13.4%; 95% CI, 10.3%–17.2%), and the Middle East (9.8%; 95% CI, 7.8%–12.2%) (P = .04) The rate of EAO-CRN in age groups 45–49 years and 50–59 years was 17.8% (95% CI, 14.5%–21.6%) and 24.8% (95% CI, 19.5%–30.8%), respectively (P = .04). The rate of EAO-aCRN in age group 45–49 years was 3.6% (95% CI, 1.9%–6.7%) and 4.2% (95% CI, 3.2%–5.7%), respectively (P = .69). Conclusions The rate of aCRN in individuals aged 45–49 years was similar to the rate observed in individual aged 50–59 years, suggesting that expanding screening to this population could yield a similar impact on colorectal cancer risk reduction.

OBJECTIVE: To evaluate the role of curative intent concurrent chemoradiation (CCRT) vs radiation (RT) alone for T1-T3N0 HPV-positive and HPV-negative oropharyngeal squamous cell cancer (OPSCC). METHODS: The NCDB was queried for patients diagnosed between 2010 and 2017 with CT1-3N0M0 OPSCC treated with definitive RT or CCRT. Univariable analysis (UVA) and multivariable analysis (MVA) Cox regression analysis was performed with OS as the endpoint. Propensity score matching (PSM) 1:1 was performed. Interaction test to assess heterogeneity of treatment effect. RESULTS: A total of 2830 patients were queried. On MVA, CCRT was associated with improved OS for T3N0 tumors (HR 0.49; 95% CI 0.39–0.63) but not for T1N0 (HR 1.43; 95% CI 0.99–2.07) and T2N0 (HR 0.92; 95% CI 0.75–1.13). For T3 patients, CCRT improved OS for HPV-negative (HR 0.43; 95% CI 0.31–0.59) and HPV-positive tumors (HR 0.39; 95% CI 0.25–0.61). After PSM, CCRT was not statistically different to RT for patients with T1-2N0 HPV-negative tumors (HR 1.10; 95% CI 0.85–1.43; p = 0.48) and T1-2N0 HPV-positive tumors (HR 1.15; 95% CI 0.79–1.68; p = 0.45). After PSM, CCRT improved OS compared to RT alone for patients with T3N0 HPV-negative (HR 0.43; 95% CI 0.31–0.59; p < 0.01) and HPV-positive tumors (HR 0.39; 95 %CI 0.25–0.61; p < 0.01). CONCLUSIONS: CCRT is associated with improved OS in HPV-positive and HPV-negative T3N0 OPSCC. RT alone vs. CCRT demonstrated similar OS for T1-T2N0 OPSCC for both HPV negative and HPV positive tumors.

BackgroundImmuno-oncology (IO) agents have demonstrated efficacy across many tumor types and have led to change in standard of care. In breast cancer, atezolizumab and pembrolizumab were recently FDA-approved in combination with chemotherapy specifically for patients with PD-L1-positive metastatic triple-negative breast cancer (TNBC). However, the single agent PD-1/PD-L1 inhibitors demonstrate only modest single agent efficacy in breast cancer. The purpose of this study was to investigate the efficacy of novel IO agents in patients with metastatic breast cancer (MBC), beyond TNBC, treated in phase I clinical trials at the University of Colorado.MethodsWe performed a retrospective analysis using a database of patients with MBC who received treatment with IO agents in phase I/Ib clinical trials at the University of Colorado Hospital from January 1, 2012 to July 1, 2018. Patient demographics, treatments and clinical outcomes were obtained.ResultsWe identified 43 patients treated with an IO agent either as a single agent or in combination. The average age was 53 years; 55.8% had hormone receptor-positive/HER2-negative breast cancer, 39.5% TNBC and 4.7% HER2-positive. Patients received an average of 2 prior lines of chemotherapy (range 0-7) in the metastatic setting. Most patients (72.1%) received IO alone and 27.9% received IO plus chemotherapy. Median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 12.1 months. Patients remaining on study ≥ 6 months (20.9%) were more likely to be treated with chemotherapy plus IO compared to patients with a PFS < 6 months (77.8% v. 14.7%). No differences in number of metastatic sites, prior lines of chemotherapy, breast cancer subtype, absolute lymphocyte count, or LDH were identified between patients with a PFS ≥ 6 months vs. < 6 months.ConclusionsOur phase I experience demonstrates benefit from IO therapy that was not limited to patients with TNBC and confirms improved efficacy from IO agents in combination with chemotherapy. A subset of patients with MBC treated in phase I clinical trials with an IO agent derived prolonged clinical benefit. Predictors of response to immunotherapy in breast cancer remain uncharacterized and further research is needed to identify these factors.