Publications by authors named "Joseph N Contessa"

42 Publications

The translocon-associated protein (TRAP) complex regulates quality control of N-linked glycosylation during ER stress.

Sci Adv 2021 Jan 15;7(3). Epub 2021 Jan 15.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Asparagine (N)-linked glycosylation is required for endoplasmic reticulum (ER) homeostasis, but how this co- and posttranslational modification is maintained during ER stress is unknown. Here, we introduce a fluorescence-based strategy to detect aberrant N-glycosylation in individual cells and identify a regulatory role for the heterotetrameric translocon-associated protein (TRAP) complex. Unexpectedly, cells with knockout of SSR3 or SSR4 subunits restore N-glycosylation over time concurrent with a diminished ER stress transcriptional signature. Activation of ER stress or silencing of the ER chaperone BiP exacerbates or rescues the glycosylation defects, respectively, indicating that SSR3 and SSR4 enable N-glycosylation during ER stress. Protein levels of the SSR3 subunit are ER stress and UBE2J1 dependent, revealing a mechanism that coordinates upstream N-glycosylation proficiency with downstream ER-associated degradation and proteostasis. The fidelity of N-glycosylation is not static in both nontransformed and tumor cells, and the TRAP complex regulates ER glycoprotein quality control under conditions of stress.
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http://dx.doi.org/10.1126/sciadv.abc6364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810369PMC
January 2021

Clinical and genomic factors associated with seizures in meningiomas.

J Neurosurg 2020 Dec 4:1-10. Epub 2020 Dec 4.

Departments of1Neurosurgery.

Objective: The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients.

Methods: Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures.

Results: Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis.

Conclusions: Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.
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http://dx.doi.org/10.3171/2020.7.JNS201042DOI Listing
December 2020

Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery.

Radiother Oncol 2020 01 13;142:168-174. Epub 2019 Sep 13.

Department of Radiation Oncology, Wake Forest School of Medicine, USA.

Introduction: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting.

Methods: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (<4 BMV), intermediate (4-13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS.

Results: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4-13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). After multivariate regression modeling, melanoma histology (β: 10.10, SE: 1.89, p < 0.0001) and number of initial brain metastases (β: 1.52, SE: 0.34, p < 0.0001) remained predictive of BMV (adjusted R = 0.06).

Conclusions: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.
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http://dx.doi.org/10.1016/j.radonc.2019.08.011DOI Listing
January 2020

Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma.

Mol Cancer Ther 2019 11 6;18(11):2124-2134. Epub 2019 Aug 6.

Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.

EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosurvival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These findings were confirmed in xenograft tumor growth experiments including an approach using growth factor-supplemented Matrigel. , the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825559PMC
November 2019

Defining an Intermediate-risk Group for Low-grade Glioma: A National Cancer Database Analysis.

Anticancer Res 2019 Jun;39(6):2911-2918

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, U.S.A.

Background: RTOG 9802 identified a cohort of patients with age less than 40 years and undergoing gross total resection as having low-risk, low-grade glioma (LR-LGG). European Organization for Research and Treatment of Cancer studies have demonstrated additional prognostic features in this group. The aim of this study was to analyze clinical factors associated with overall survival (OS), identify a potentially higher risk group within LR-LGG, and investigate patterns of care for adjuvant therapy.

Materials And Methods: Patients with LR-LGG diagnosed between 2010 to 2013 were identified in the National Cancer Database. Kaplan-Meier method was used to analyze OS. Propensity score matching and multivariate analysis were utilized to adjust for differences in cohorts.

Results: A total of 1,032 patients with LR-LGG were identified. Histological breakdown was 42.0% astrocytoma, 33.2% oligodendroglioma, and 25.8% mixed. Median follow-up was 3.9 years; median pre-operative tumor size was 4.0 cm. Overall, 834 (80.8%) underwent observation and 198 (19.2%) received adjuvant therapy. Tumor size >5 cm predicted for receipt of adjuvant therapy on regression analyses (OR=2.02, p=0.001). On multivariate analysis, tumor size >5 cm (hazard ratio=1.95) and non-oligodendroglioma histology (hazard ratio=2.50) were associated with inferior OS (both p<0.05). For patients with both poor prognostic features (a subset we consider "intermediate-risk"), 5-year OS was 78.4%, compared to 94.1% for all other low-risk patients (p<0.001). After propensity score matching, the intermediate-risk group continued to be associated with worse 5-year OS: 80.5% vs. 94.0%, p=0.004.

Conclusion: Due to inferior OS for patients with LR-LGG with >5 cm, non-oligodendroglioma tumors, we propose an 'intermediate-risk' clinical classification for this subset.
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http://dx.doi.org/10.21873/anticanres.13420DOI Listing
June 2019

Initial SRS for Patients With 5 to 15 Brain Metastases: Results of a Multi-Institutional Experience.

Int J Radiat Oncol Biol Phys 2019 08 6;104(5):1091-1098. Epub 2019 Apr 6.

Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Purpose: Several studies evaluating stereotactic radiosurgery (SRS) for patients with >4 brain metastases (BM) demonstrated similar outcomes after treatment of 1, 2 to 4, and 5 to 15 BM; others found clinically significant survival decrements in the latter group. In this review of 8 academic centers, we compared outcomes of patients undergoing initial SRS for 1, 2 to 4, and 5 to 15 BM.

Methods And Materials: A total of 2089 patients treated with initial SRS for BM were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Patient and disease characteristics were evaluated for association with OS and cumulative incidence of distant brain failure (DBF) using stepwise multivariable Cox proportional hazards and competing risk regression modeling.

Results: In this series, 989 (47%) patients had 1 metastasis, 882 (42%) had 2 to 4 metastases, and 212 (10%) had 5 to 15 metastases treated. Median OS for the 1, 2 to 4, and 5 to 15 BM groups was 14.6, 9.5, and 7.5 months, respectively (log-rank P < .01). Univariate and multivariable analyses revealed no difference in survival between 2 to 4 and 5 to 15 BM. DBF at 1 year was 30%, 41%, and 50%, respectively (Gray's P < .01). Two-year cumulative incidence of salvage SRS decreased with increasing number of BM (1: 21% vs 2-4: 19% vs 5-15: 13%; P < .01), but no difference in salvage whole brain radiation therapy was observed (1: 12% vs 2-4: 15% vs 5-15: 16%, P = .10). At the time of DBF, median brain metastasis velocity was 3.9, 6.1, and 11.7 new metastases per year in the 1, 2 to 4, and 5 to 15 BM groups, respectively (P < .01).

Conclusions: Patients treated with initial SRS for 5 to 15 BM experienced survival similar to that in patients with 2 to 4 BM. Lower rates of salvage SRS were observed in the 5 to 15 BM group, with no difference in rates of salvage whole brain radiation therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.052DOI Listing
August 2019

Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction.

FASEB J 2019 06 27;33(6):6801-6812. Epub 2019 Feb 27.

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Herpes simplex virus 1 (HSV-1) is a contagious neurotropic herpesvirus responsible for oral lesions and herpesviral encephalitis. The HSV-1 envelope contains -glycosylated proteins involved in infection and that are candidate drug targets. NGI-1 is a small-molecule inhibitor of oligosaccharyltransferase (OST) complexes STT3A-OST and STT3B-OST, which catalyze cotranslational and post-translational -glycosylation, respectively. Because host OSTs attach HSV-1 glycans, NGI-1 might have anti-HSV-1 activity. We evaluated HSV-1 function using NGI-1 and human embryonic kidney 293 knockout lines for OST isoform-specific catalytic and accessory subunits. -glycosylation of 2 representative envelope proteins (gC and gD) was primarily dependent upon STT3A-OST, but to a large extent replaceable by STT3B-OST. Knockouts impairing STT3A- or STT3B-OST activity, by themselves, did not appreciably affect HSV-1 function (plaque-forming units, normalized to viral particles measured by unglycosylated capsid protein VP5 content). However, with cells lacking STT3B-OST activity (missing the catalytic subunit STT3B or the oxidoreductase subunits magnesium transporter 1/tumor suppressor candidate 3) and thus solely dependent upon STT3A-OST for -glycosylation, NGI-1 treatment resulted in HSV-1 having cell type-dependent dysfunction (affecting infectivity with Vero cells much more than with the 293 lines). Ablation of post-translational -glycosylation can therefore make HSV-1 infectivity, and possibly masking of immunogenic peptide epitopes by glycans, highly sensitive to pharmacological inhibition of cotranslational -glycosylation.-Lu, H., Cherepanova, N. A., Gilmore, R., Contessa, J. N., Lehrman, M. A. Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction.
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http://dx.doi.org/10.1096/fj.201802044RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529348PMC
June 2019

Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors.

Cell Chem Biol 2018 10 2;25(10):1231-1241.e4. Epub 2018 Aug 2.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06511, USA; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06511, USA. Electronic address:

The oligosaccharyltransferase (OST) is a multisubunit enzyme complex that N-glycosylates proteins in the secretory pathway and is considered to be constitutive and unregulated. However, small-molecule OST inhibitors such as NGI-1 provide a pharmacological approach for regulating N-linked glycosylation. Herein we design cell models with knockout of each OST catalytic subunit (STT3A or STT3B) to screen the activity of NGI-1 and its analogs. We show that NGI-1 targets the function of both STT3A and STT3B and use structure-activity relationships to guide synthesis of catalytic subunit-specific inhibitors. Using this approach, pharmacophores that increase STT3B selectivity are characterized and an STT3B-specific inhibitor is identified. This inhibitor has discrete biological effects on endogenous STT3B target proteins such as COX2 but does not activate the cellular unfolded protein response. Together this work demonstrates that subsets of glycoproteins can be regulated through pharmacologic inhibition of N-linked glycosylation.
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http://dx.doi.org/10.1016/j.chembiol.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337728PMC
October 2018

Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors.

Cancer Res 2018 09 19;78(17):5094-5106. Epub 2018 Jul 19.

Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.

Asparagine (N)-linked glycosylation is a posttranslational modification essential for the function of complex transmembrane proteins. However, targeting glycosylation for cancer therapy has not been feasible due to generalized effects on all glycoproteins. Here, we perform sensitivity screening of 94 lung cancer cell lines using NGI-1, a small-molecule inhibitor of the oligosaccharyltransferase (OST) that partially disrupts N-linked glycosylation, and demonstrate a selective loss of tumor cell viability. This screen revealed NGI-1 sensitivity in just 11 of 94 (12%) cell lines, with a significant correlation between OST and EGFR inhibitors. In -mutant non-small cell lung cancer with EGFR tyrosine kinase inhibitor (TKI) resistance (PC9-GR, HCC827-GR, and H1975-OR), OST inhibition maintained its ability to induce cell-cycle arrest and a proliferative block. Addition of NGI-1 to EGFR TKI treatment was synthetic lethal in cells resistant to gefitinib, erlotinib, or osimertinib. OST inhibition invariably disrupted EGFR N-linked glycosylation and reduced activation of receptors either with or without the T790M TKI resistance mutation. OST inhibition also dissociated EGFR signaling from other coexpressed receptors like MET via altered receptor compartmentalization. Translation of this approach to preclinical models was accomplished through synthesis and delivery of NGI-1 nanoparticles, confirmation of activity through molecular imaging, and demonstration of significant tumor growth delay in TKI-resistant HCC827 and H1975 xenografts. This therapeutic strategy breaks from kinase-targeted approaches and validates N-linked glycosylation as an effective target in tumors driven by glycoprotein signaling.-mutant NSCLC is incurable despite the marked sensitivity of these tumors to EGFR TKIs. These findings identify N-linked glycosylation, a posttranslational modification common to EGFR and other oncogenic signaling proteins, as an effective therapeutic target that enhances tumor responses for -mutant NSCLC. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125176PMC
September 2018

Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology.

Lancet Oncol 2018 05;19(5):e240-e251

Department of Human Oncology, University of Wisconsin, Madison, WI, USA.

The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents.
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http://dx.doi.org/10.1016/S1470-2045(18)30096-2DOI Listing
May 2018

MPDU1 regulates CEACAM1 and cell adhesion in vitro and in vivo.

Glycoconj J 2018 06 18;35(3):265-274. Epub 2018 Apr 18.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, 06510, USA.

N-linked glycosylation (NLG) is a co-translational modification that is essential for the folding, stability, and trafficking of transmembrane (TM) and secretory glycoproteins. Efficient NLG requires the stepwise synthesis and en bloc transfer of a 14-sugar carbohydrate known as a lipid-linked oligosaccharide (LLO). The genetics of LLO biosynthesis have been established in yeast and Chinese hamster systems, but human models of LLO biosynthesis are lacking. In this study we report that Kato III human gastric cancer cells represent a model of deficient LLO synthesis, possessing a homozygous deletion of the LLO biosynthesis factor, MPDU1. Kato III cells lacking MPDU1 have all the hallmarks of a glycosylation-deficient cell line, including altered sensitivity to lectins and the formation of truncated LLOs. Analysis of transcription using an expression microarray and protein levels using a proteome antibody array reveal changes in the expression of several membrane proteins, including the metalloprotease ADAM-15 and the cell adhesion molecule CEACAM1. Surprisingly, the restoration of MPDU1 expression in Kato III cells demonstrated a clear phenotype of increased cell-cell adhesion, a finding that was confirmed in vivo through analysis of tumor xenografts. These experiments also confirmed that protein levels of CEACAM-1, which functions in cell adhesion, is dependent on LLO biosynthesis in vivo. Kato III cells and the MPDU1-rescued Kato IIIM cells therefore provide a novel model to examine the consequences of defective LLO biosynthesis both in vitro and in vivo.
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http://dx.doi.org/10.1007/s10719-018-9819-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013378PMC
June 2018

CDKN2A Copy Number Loss Is an Independent Prognostic Factor in HPV-Negative Head and Neck Squamous Cell Carcinoma.

Front Oncol 2018 4;8:95. Epub 2018 Apr 4.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States.

Background: HPV infection is associated with high p16 expression and good prognosis in head and neck squamous cell carcinomas (HNSCCs). Analysis of CDKN2A, the gene encoding p16, may further elucidate the association between p16 expression and prognosis. We sought to determine whether CDKN2A copy number loss was associated with poor survival in HPV-negative HNSCCs.

Methods: The Cancer Genome Atlas HNSCC clinical and genomic data were obtained and integrated. Patients <80 years old with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Stratifying by copy number loss status, CDKN2A mRNA and p16 protein expression levels were examined and overall survival (OS) and disease-free survival (DFS) were evaluated.

Results: 401 patients with HPV-negative HNSCC were identified. 146 patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group. Median OS for patients with and without CDKN2A copy number loss was 16.5 and 46.6 months, respectively ( = 0.007). Median DFS for both groups was 11.6 and 19.2 months, respectively ( = 0.03). In both univariate and multivariable analyses, stage IV designation, receipt of chemotherapy and CDKN2A copy number loss were predictive of OS.

Conclusion: CDKN2A copy number loss predicted poor survival independently of other patient and treatment factors and may be a clinically useful prognostic factor.
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http://dx.doi.org/10.3389/fonc.2018.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893829PMC
April 2018

Upfront surgery versus definitive chemoradiotherapy in patients with human Papillomavirus-associated oropharyngeal squamous cell cancer.

Oral Oncol 2018 04 8;79:64-70. Epub 2018 Mar 8.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, United States. Electronic address:

Objectives: Currently, human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-A OPC) is managed with either primary surgery or definitive chemoradiotherapy (CRT), despite the lack of supporting randomized prospective data. We therefore assessed the outcomes of each treatment strategy using the National Cancer Database (NCDB).

Methods: The NCDB was used to identify patients diagnosed with cT1 N2a-2b or cT2 N1-2b HPV-A OPC from 2010 to 2013 who underwent treatment with primary surgery or CRT. Demographic and clinicopathologic predictors of treatment were analyzed by the chi-square test and logistic regression. Overall survival (OS) was evaluated using multivariable Cox proportional hazard regression, Kaplan-Meier, log-rank test, and propensity score-matched analysis.

Results: We identified 3063 patients; 1576 (51.5%) received CRT and 1487 (48.5%) underwent primary surgery. Median follow up was 32 months. 972 (65.4%) surgical patients received adjuvant CRT. On multivariable Cox regression, 3-year OS was comparable between surgery and CRT (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.83-1.41, P = 0.58). Inferior OS was significantly associated with increasing clinical T and N stage, older age, and non-private insurance. Propensity score-matching yielded a 2526 patient cohort and redemonstrated similar OS (HR, 1.09; 95% CI 0.81-1.47; P = 0.55). Comparable outcomes persisted in a subset analysis of patients with margin-negative resection, with 3-year OS 90.8% in CRT patients vs. 93.6% in surgery patients (log-rank P = 0.27).

Conclusions: Upfront surgery and CRT yielded comparable 3-year OS outcomes in this cohort. In this national sample, 65.4% of surgical patients received trimodal therapy with adjuvant CRT, highlighting the need for improved patient selection for primary surgery.
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http://dx.doi.org/10.1016/j.oraloncology.2018.02.017DOI Listing
April 2018

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity.

Cell Rep 2017 Dec;21(11):3032-3039

Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address:

The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile, and yellow fever viruses, which pose a serious threat for global health. Recent genetic screens identified endoplasmic reticulum (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST. Viral mutants adapted to replicate in cells deficient of the OST complex showed resistance to NGI-1 treatment, reinforcing the on-target activity of NGI-1. Lastly, we show that NGI-1 also has strong antiviral activity in primary and disease-relevant cell types. This study provides an example for advancing from the identification of genetic determinants of infection to a host-directed antiviral compound with broad activity against flaviviruses.
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http://dx.doi.org/10.1016/j.celrep.2017.11.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734657PMC
December 2017

Angiotensin receptor blockade: a novel approach for symptomatic radiation necrosis after stereotactic radiosurgery.

J Neurooncol 2018 Jan 9;136(2):289-298. Epub 2017 Nov 9.

Department of Therapeutic Radiology and Smilow Cancer Center, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.

Preclinical evidence suggests angiotensin blockade therapy (ABT) decreases late radiation toxicities. This study aims to investigate the association between ABT and symptomatic radiation necrosis (SRN) following stereotactic radiosurgery (SRS). Resected brain metastases (rBM) and arteriovenous malformation (AVM) patients treated with SRS from 2002 to 2015 were identified. Patients in the ABT cohort were on therapy during SRS and at 1-month follow up. Kaplan Meier method and cumulative incidence model were used to analyze overall survival (OS) and intracranial outcomes. 228 consecutive patients were treated with SRS: 111 with rBM and 117 with AVM. Overall, 51 (22.4%) patients were in the ABT group: 32 (28.8%) in the rBM and 19 (16.2%) in AVM cohorts. Baseline characteristics were similar, except for higher Graded Prognostic Analysis (3-4) in the rBM (ABT: 25.0% vs. non-ABT: 49.0%, p = 0.033) and median age in the AVM (ABT: 51.4 vs. non-ABT: 35.4, p < 0.001) cohorts. In both populations, OS and intracranial efficacy (rBM-local control; AVM-obliteration rates) were statistically similar between the cohorts. ABT was associated with lower 1-year SRN rates in both populations: rBM, 3.1 versus 25.3% (p = 0.003); AVM, 6.7 vs. 14.6% (p = 0.063). On multivariate analysis, ABT was a significant predictive factor for rBM (HR: 0.17; 95% CI 0.03-0.88, p = 0.035), but did not reach statistical significance for AVM (HR: 0.36; 95% CI 0.09-1.52, p = 0.165). ABT use appears to be associated with a reduced risk of SRN following SRS, without detriment to OS or intracranial efficacy. A prospective trial to validate these findings is warranted.
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http://dx.doi.org/10.1007/s11060-017-2652-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784434PMC
January 2018

The prognostic value of extranodal extension in human papillomavirus-associated oropharyngeal squamous cell carcinoma.

Cancer 2017 Jul 21;123(14):2762-2772. Epub 2017 Mar 21.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.

Background: Extranodal (or extracapsular) extension (ENE) is an adverse prognostic factor in patients with head and neck cancers who undergo primary surgery. However, the significance of ENE in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is not well established, and single-institution studies have not established that ENE predicts inferior outcome. The authors investigated the prognostic value of ENE in HPV-positive patients who underwent primary surgery and whether adjuvant chemoradiation improved overall survival (OS) compared with radiation alone in ENE-positive patients.

Methods: Patients who underwent primary surgery for pathologic T1 (pT1) through pT4 tumors, pathologic N1 (pN1) through pN3 lymph node status, HPV-positive OPSCC were identified in the National Cancer Data Base from 2010 through 2012. Features associated with ENE were analyzed. Univariable and multivariable Cox regression analyses identified predictors of OS. The effect of adjuvant treatment on OS in ENE-positive cohort was also evaluated.

Results: In total, 1043 patients met inclusion criteria, among whom 43.5% were ENE-positive. Of the ENE-positive patients who had treatment details available, 72% received concurrent chemoradiotherapy, 16% received radiotherapy, and 12% received no adjuvant treatment. After a median follow-up of 28.4 months, ENE was associated with worse 3-year OS (89.3% vs 93.6%; P = .01). On multivariable analysis that included involved lymph nodes, only ENE, lymphovascular invasion, pT3/pT4 tumors, and Charlson-Deyo score were associated with worse OS. Among ENE-positive patients, there was no difference in 3-year OS between those who received adjuvant concurrent chemoradiotherapy versus radiotherapy alone (89.6% vs 89.3%, respectively; P = .55). Propensity score-matched comparison revealed similar results.

Conclusions: ENE is associated with inferior OS in patients with HPV-positive OPSCC. However, OS was not better with adjuvant chemoradiotherapy compared with radiotherapy alone in ENE-positive patients. The current findings support the need for prospective studies of adjuvant chemoradiation in HPV-positive patients with ENE. Cancer 2017;123:2762-72. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30598DOI Listing
July 2017

A multi species evaluation of the radiation dosimetry of [C]erlotinib, the radiolabeled analog of a clinically utilized tyrosine kinase inhibitor.

Nucl Med Biol 2017 Apr 2;47:56-61. Epub 2017 Jan 2.

Department of Biomedical Engineering, Yale University, New Haven, CT, United States; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, United States. Electronic address:

Introduction: Erlotinib is a tyrosine kinase inhibitor prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor mutations in the kinase domain. The objectives of this study were to (1) establish a human dosimetry profile of [C]erlotinib and (2) assess the consistency of calculated equivalent dose across species using the same dosimetry model.

Methods: Subjects examined in this multi-species study included: a stage IIIa NSCLC patient, 3 rhesus macaque monkeys, a landrace pig, and 4 athymic nude-Fox1nu mice. [C]erlotinib PET data of the whole body were acquired dynamically for up to 120min. Regions of interest (ROIs) were manually drawn to extract PET time activity curves (TACs) from identifiable organs. TACs were used to calculate time-integrated activity coefficients (residence times) in each ROI, which were then used to calculate the equivalent dose in OLINDA. Subject data were used to predict the equivalent dose to the organs of a 73.7kg human male.

Results: In three of four species, the liver was identified as the organ receiving the highest equivalent dose (critical organ). The mean equivalent doses per unit of injected activity to the liver based on human, monkey, and mouse data were 29.4μSv/MBq, 17.4±6.0μSv/MBq, and 5.27±0.25μSv/MBq, respectively. The critical organ based on the pig data was the gallbladder wall (20.4μSv/MBq) but the liver received a nearly identical equivalent dose (19.5μSv/MBq).

Conclusions: (1) When designing PET studies using [C]erlotinib, the liver should be considered the critical organ. (2) In organs receiving the greatest equivalent dose, mouse data underestimated the dose in comparison to larger species. However, the effective dose of [C]erlotinib to the whole body of a 73.7kg man was predicted with good consistency based on mice (3.14±0.05μSv/MBq) or the larger species (3.46±0.25μSv/MBq).
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http://dx.doi.org/10.1016/j.nucmedbio.2016.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360653PMC
April 2017

Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis.

J Clin Oncol 2017 Apr 23;35(10):1070-1077. Epub 2017 Jan 23.

William J. Magnuson, Nataniel H. Lester-Coll, Scott N. Gettinger, Joseph N. Contessa, James B. Yu, and Veronica L. Chiang, Yale School of Medicine, New Haven, CT; Abraham J. Wu, T. Jonathan Yang, Natalie A. Lockney, Naamit K. Gerber, and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Arya Amini, Tejas Patil, Brian D. Kavanagh, and D. Ross Camidge, University of Colorado School of Medicine, Denver, CO; Steven E. Braunstein and Lauren C. Boreta, University of California-San Francisco, San Francisco, CA; Suresh K. Balasubramanian and Manmeet S. Ahluwalia, Cleveland Clinic Foundation, Cleveland, OH; and Niteshkumar G. Rana and Albert Attia, Vanderbilt University School of Medicine, Nashville, TN.

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.
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http://dx.doi.org/10.1200/JCO.2016.69.7144DOI Listing
April 2017

Comparison of Survival Outcomes Among Human Papillomavirus-Negative cT1-2 N1-2b Patients With Oropharyngeal Squamous Cell Cancer Treated With Upfront Surgery vs Definitive Chemoradiation Therapy: An Observational Study.

JAMA Oncol 2017 Aug;3(8):1107-1111

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.

Importance: Human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) has shown resistance to conventional concurrent chemoradiation (CRT) therapy and carries a relatively poor prognosis in comparison with HPV-positive disease, with decreased locoregional control and overall survival (OS). In the present analysis, we examine whether upfront surgical resection improves overall survival in a large national sample.

Objective: To compare survival outcomes among patients with newly diagnosed cT1-2 N1-2b HPV-negative OPSCC when treated with primary surgical resection vs CRT.

Design, Setting, And Participants: This was an observational study of factors associated with primary treatment modality were identified using multivariable logistic regression. Overall survival was compared using Kaplan-Meier analysis with log-rank tests, multivariable Cox regression, and propensity score matching. Statistical tests were 2-sided. Patients newly diagnosed as having cT1-2 N1-2b pathologically confirmed HPV-negative OPSCC in 2010 to 2012 were identified using the National Cancer Data Base, which includes more than 70% of patients newly diagnosed as having cancer in the United States.

Exposures: Primary surgical resection vs definitive CRT.

Main Outcomes And Measures: Overall survival.

Results: We identified 1044 patients, among whom 460 (44.1%) received upfront surgery and 584 (55.9%) received CRT. Median age was 59 years (range, 25-90 years); 812 patients were male (77.8%), 232 were female (22.2%). Median follow-up was 30 months. Approximately 59% of surgical patients received adjuvant CRT. On multivariable Cox regression, upfront surgery was not associated with increased OS when compared with CRT (adjusted hazard ratio [HR], 1.01; 95% CI, 0.74-1.39; P = .93). Propensity score-matching identified a cohort of 822 patients and redemonstrated equivalent OS (HR, 1.14; 95% CI, 0.81-1.62; P = .46). Lack of OS benefit with upfront surgery persisted in a subset analysis of patients with margin-negative resection (HR, 0.97; 95% CI, 0.66-1.45; P = .88).

Conclusions And Relevance: In this observational study, OS was similar for patients with HPV-negative OPSCC when treated with primary surgery vs CRT. Most surgical patients received trimodal therapy with adjuvant CRT. Our data may have implications for future research focusing on optimal patient selection for surgery.
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http://dx.doi.org/10.1001/jamaoncol.2016.5769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824218PMC
August 2017

Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells.

Nat Chem Biol 2016 Dec 3;12(12):1023-1030. Epub 2016 Oct 3.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, USA.

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.
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http://dx.doi.org/10.1038/nchembio.2194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393272PMC
December 2016

Reply to M.S. Copur et al and to M.C. Chamberlain.

J Clin Oncol 2016 07 25;34(19):2316-7. Epub 2016 Apr 25.

Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1200/JCO.2016.67.2816DOI Listing
July 2016

Demonstration of differential radiosensitivity based upon mutation profile in metastatic melanoma treated with stereotactic radiosurgery.

J Radiosurg SBRT 2016 ;4(2):97-106

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA.

Background: Metastatic melanoma often involves the brain. Radiotherapy is an important treatment of melanoma brain metastases, although melanoma radiosensitivity is considered heterogeneous. Thus, identifying subsets with differential radiosensitivity is essential.

Materials And Methods: Patients with metastatic melanoma were identified in a prospective stereotactic radiosurgery (SRS) database. Tumor were tested for alterations in B-RAF, N-RAS, and c-KIT. Standardized imaging following SRS was reviewed for recurrence. Differences in local and distant failure were determined using modified Cox proportional hazards models.

Results: 102 patients and 1,028 brain metastases were included. N-RAS mutated patients were significantly less likely to develop local recurrence after SRS than wild type patients (HR 0.17, 95% CI 0.04-0.72, p=0.017). B-RAF and c-KIT mutations were not associated with altered rates of local recurrence. Lower local recurrence rates for N-RAS mutated tumors persisted on multivariate analysis (HR 0.18, 95% CI 0.04-0.84p=0.029).

Conclusions: N-RAS mutation is associated with improved local control following SRS. Local recurrence is more common in wild type patients and those with B-RAF or c-KIT mutations. Further research is needed to validate these findings and integrate into practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658871PMC
January 2016

A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases - An initial report.

J Radiosurg SBRT 2016 ;4(1):43-52

Department of Therapeutic Radiology, Yale-New Haven Hospital and Yale University School of Medicine, New Haven, CT 06520, USA.

Summary: Indications and treatment goals for SRS have changed since the publication of RTOG 90-05. We present initial retrospective outcomes from a new dose selection algorithm in use at our institution felt to be more contemporary with doses being used in the radiosurgery community today and report our local control and toxicity outcomes. This dose selection algorithm will be subject to a forthcoming prospective phase 2 trial.

Introduction: To evaluate safety and efficacy of an institutional dose selection algorithm in the treatment of brain metastases (BM) with single fraction radio-surgery (SRS).

Methods And Materials: The medical records of 65 patients with ≤10 BM treated with GK at our institution between April 2012 and October 2012 were reviewed retrospectively. The prescription doses used in this study ranged from 16-22Gy and were based upon RTOG 90-05 guideline doses subsequently modified at our institution depending on lesion number, lesion volume, institutional experience and prior history of whole brain radiation therapy (WBRT). Primary endpoint was local recurrence (LR) with additional outcomes measured including distant intracranial recurrence (DIR), death without local recurrence (DWLR) and alive and disease free (ADF). Fine Gray competing risk analysis was used to examine factors affecting local recurrence.

Results: Median follow up was 8.9 months (range 1.0-29.6months) and 12 month overall survival was 37% (95% CI 24.9-49.1%). Overall local recurrence rate was 7.7%. On competing risks regression analysis, no variable was significantly associated with local recurrence, including previous whole brain radiotherapy (WBRT), (SHR 1.21 [95%CI 0.13-11.5], p=0.87 and radioresistant versus radiosensitive histology (SHR 0.51 [95% CI 0.06-7.73], p=0.55). No patient developed grade 3 or higher neurotoxicity at 12 months following GK.

Conclusions: Initial local control and toxicity results from our institutional dose selection algorithm are reported here. Comparison of our results with RTOG 90-05 is difficult due to significant differences in the patient population and their treatments. The applicability of this algorithm merits further investigation across multiple centers for the purpose of treatment and clinical trial standardization in single fraction SRS and will be the subject of a forthcoming phase 2 prospective study within our own institution.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658834PMC
January 2016

Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis.

J Clin Oncol 2016 Jan 5;34(2):123-9. Epub 2015 Oct 5.

Kimberly L. Johung, Sarah Goldberg, James B. Yu, Veronica L. Chiang, and Joseph N. Contessa, Yale University School of Medicine, New Haven, CT; Norman Yeh, Brian D. Kavanagh, and D. Ross Cambidge, University of Colorado Comprehensive Cancer Center, Aurora, CO; Neil B. Desai and Kathryn Beal, Memorial Sloan Kettering Cancer Center, New York, NY; Terence M. Williams and Tim Lautenschlaeger, Ohio State University, Columbus, OH; Nils D. Arvold, Dana-Farber/Brigham and Women's Hospital, Boston, MA; and Matthew S. Ning, Albert Attia, and Christine M. Lovly, Vanderbilt University School of Medicine, Nashville, TN.

Purpose: We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis.

Patients And Methods: A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.

Results: Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).

Conclusion: Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.
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http://dx.doi.org/10.1200/JCO.2015.62.0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070549PMC
January 2016

Lung Cancer Brain Metastases.

Cancer J 2015 Sep-Oct;21(5):398-403

From Yale School of Medicine, New Haven, CT.

Brain metastases are common among patients with lung cancer and have been associated with significant morbidity and limited survival. However, the treatment of brain metastases has evolved as the field has advanced in terms of central nervous system imaging, surgical technique, and radiotherapy technology. This has allowed patients to receive improved treatment with less toxicity and more durable benefit. In addition, there have been significant advances in systemic therapy for lung cancer in recent years, and several treatments including chemotherapy, targeted therapy, and immunotherapy exhibit activity in the central nervous system. Utilizing systemic therapy for treating brain metastases can avoid or delay local therapy and often allows patients to receive effective treatment for both intracranial and extracranial disease. Determining the appropriate treatment for patients with lung cancer brain metastases therefore requires a clear understanding of intracranial disease burden, tumor histology, molecular characteristics, and overall cancer prognosis. This review provides updates on the current state of surgery and radiotherapy for the treatment of brain metastases, as well as an overview of systemic therapy options that may be effective in select patients with intracranial metastases from lung cancer.
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http://dx.doi.org/10.1097/PPO.0000000000000146DOI Listing
June 2016

Mannose phosphate isomerase regulates fibroblast growth factor receptor family signaling and glioma radiosensitivity.

PLoS One 2014 14;9(10):e110345. Epub 2014 Oct 14.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, United States of America.

Asparagine-linked glycosylation is an endoplasmic reticulum co- and post-translational modification that enables the transit and function of receptor tyrosine kinase (RTK) glycoproteins. To gain insight into the regulatory role of glycosylation enzymes on RTK function, we investigated shRNA and siRNA knockdown of mannose phosphate isomerase (MPI), an enzyme required for mature glycan precursor biosynthesis. Loss of MPI activity reduced phosphorylation of FGFR family receptors in U-251 and SKMG-3 malignant glioma cell lines and also resulted in significant decreases in FRS2, Akt, and MAPK signaling. However, MPI knockdown did not affect ligand-induced activation or signaling of EGFR or MET RTKs, suggesting that FGFRs are more susceptible to MPI inhibition. The reductions in FGFR signaling were not caused by loss of FGF ligands or receptors, but instead were caused by interference with receptor dimerization. Investigations into the cellular consequences of MPI knockdown showed that cellular programs driven by FGFR signaling, and integral to the clinical progression of malignant glioma, were impaired. In addition to a blockade of cellular migration, MPI knockdown also significantly reduced glioma cell clonogenic survival following ionizing radiation. Therefore our results suggest that targeted inhibition of enzymes required for cell surface receptor glycosylation can be manipulated to produce discrete and limited consequences for critical client glycoproteins expressed by tumor cells. Furthermore, this work identifies MPI as a potential enzymatic target for disrupting cell surface receptor-dependent survival signaling and as a novel approach for therapeutic radiosensitization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196966PMC
December 2015

Quantitative analysis of [11C]-erlotinib PET demonstrates specific binding for activating mutations of the EGFR kinase domain.

Neoplasia 2013 Dec;15(12):1347-53

Department of Therapeutic Radiology, Yale University, New Haven, CT.

Activating mutations of the epidermal growth factor receptor (EGFR) occur in multiple tumor types, including non-small cell lung cancer (NSCLC) and malignant glioma, and have become targets for therapeutic intervention. The determination of EGFR mutation status using a noninvasive, molecular imaging approach has the potential for clinical utility. In this study, we investigated [(11)C]-erlotinib positron emission tomography (PET) imaging as a tool to identify activating mutations of EGFR in both glioma and NSCLC xenografts. Radiotracer specific binding was determined for high and low specific activity (SA) [(11)C]-erlotinib PET scans in mice bearing synchronous human cancer xenografts with different EGFR expression profiles (PC9, HCC827, U87, U87 ΔEGFR, and SW620). Although xenograft immunohistochemistry demonstrated constitutive EGFR phosphorylation, PET scan analysis using the Simplified Reference Tissue Model showed that only kinase domain mutant NSCLC (HCC827 and PC9) had significantly greater binding potentials in high versus low SA scans. Xenografts with undetectable EGFR expression (SW620), possessing wild-type EGFR (U87), and expressing an activating extracellular domain mutation (U87 ΔEGFR) were indistinguishable under both high and low SA scan conditions. The results suggest that [(11)C]-erlotinib is a promising radiotracer that could provide a novel clinical methodology for assessing EGFR and erlotinib interactions in patients with tumors that harbor EGFR-activating kinase domain mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884525PMC
http://dx.doi.org/10.1593/neo.131666DOI Listing
December 2013

A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer.

Clin Cancer Res 2013 Oct 29;19(19):5523-32. Epub 2013 Jul 29.

Authors' Affiliations: Departments of Therapeutic Radiology, Medical Oncology, Neurosurgery, Yale University School of Medicine; and Yale Center for Analytic Sciences, Yale University School of Public Health, New Haven, Connecticut.

Purpose: Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.

Experimental Design: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.

Results: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.

Conclusions: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0836DOI Listing
October 2013

High-throughput screening identifies aclacinomycin as a radiosensitizer of EGFR-mutant non-small cell lung cancer.

Transl Oncol 2013 Jun 1;6(3):382-91. Epub 2013 Jun 1.

Department of Therapeutic Radiology, Yale University, New Haven, CT.

The endoplasmic reticulum (ER) provides a specialized environment for the folding and modification of trans-membrane proteins, including receptor tyrosine kinases (RTKs), which are vital for the growth and survival of malignancies. To identify compounds which disrupt the function of the ER and thus could potentially impair cancer cell survival signaling, we adapted a set of glycosylation-sensitive luciferase reporters for the development and optimization of a cell-based high-throughput screen (HTS). Secondary screens for false-positive luciferase activation and tertiary lectin-based and biochemical analyses were also devised for compound triage. Through a pilot screen of 2802 compounds from the National Cancer Institute (NCI) chemical libraries, we identified aclacinomycin (Acm) as a compound that preferentially affects ER function. We report that Acm reduces plasma membrane expression of glycoproteins including epidermal growth factor receptor (EGFR) and Met but does not inhibit N-linked glycosylation or generalized protein translation. Fluorescence microscopy co-localization experiments were also performed and demonstrated Acm accumulation in the ER in further support of the overall HTS design. The consequences of Acm treatment on cell survival were analyzed through clonogenic survival analysis. Consistent with the reduction of EGFR levels, pretreatment with Acm sensitizes the EGFR-mutant non-small cell lung cancer (NSCLC) cell lines HCC827 and HCC2935 to ionizing radiation and did not affect the sensitivity of the RTK-independent and KRAS-mutant A549 NSCLC cell line. Thus, Acm and similar compounds targeting the ER may represent a novel approach for radiosensitizing tumor cells dependent on RTK function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660808PMC
http://dx.doi.org/10.1593/tlo.13232DOI Listing
June 2013

Role of excision repair cross-complementation 1 expression as a prognostic marker for response to radiotherapy in early-stage laryngeal cancer.

Head Neck 2013 Jun 28;35(6):852-7. Epub 2012 Jun 28.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: High expression of excision repair cross-complementation 1 (ERCC1) predicts for resistance to platinum-based chemotherapy or chemoradiotherapy. We evaluated the prognostic value of ERCC1 expression in a cohort of laryngeal cancer treated with radiotherapy alone.

Methods: ERCC1 expression was examined by immunohistochemical analysis of tissue microarrays constructed from 123 patients with stages I-II laryngeal squamous cell carcinoma treated with standard radiotherapy.

Results: ERCC1 expression did not correlate with clinicopathologic risk factors, local control, or overall survival. At 5 years, local control was 75% versus 71% (p = .78) and overall survival was 68% versus 54% (p = .65), for nonexpressors and expressors of ERCC1, respectively. On multivariate analysis, T classification predicted for local control, and T classification and age predicted for overall survival.

Conclusions: ERCC1 expression did not predict for radiotherapy resistance or worse survival. Therefore, radiotherapy remains an effective treatment in tumors with high ERCC1 expression.
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http://dx.doi.org/10.1002/hed.23041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723082PMC
June 2013