Edwards Comprehensive Cancer Center

Methotrexate has been in use as an anti-cancer agent for over 60 years. Though inhibition of dihydrofolate reductase is its best known mechanisms of action, its non-dihydrofolate reductase dependent mechanisms disrupt metabolic pathways resulting in a depletion of NAD(P)H and increasing oxidative stress. These mechanisms highlight a novel dependence of cancer cells on their metabolic abnormalities to buffer oxidative stress and chemotherapeutic agents interfere with these cellular abilities. Mitochondria appear to play a significant role in maintaining cancer cell viability and alterations in metabolism seen in cancer cells aid this mitochondrial ability. Further research is needed to understand the effects of other chemotherapeutic agents on these pathways.

Advances in breast cancer research have led to declining death rates from this disease because of early detection through mammographic screening and improved therapy for breast cancer. The concept that breast cancer, in some cases, can be prevented has been explored over the last three decades. This article, part I of a two-part series, will focus on the epidemiology, the risk factors associated with breast cancer, and the available risk assessment tools, which can help define who should be considered for risk reduction strategies. Part II will focus on discussing risk reduction strategies.

Pregnancy-associated breast cancer (PABC) has been defined as breast cancer diagnosed during pregnancy or within one year of delivery. It is believed that after adjusting for age and stage, the 5-year survival rates are the same in both pregnant and nonpregnant women. We conducted a retrospective case-control study among patients treated at our institution between 1990 and 2005 to compare the 5-year survival outcomes for PABC with women treated for breast cancer who were not pregnant. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method, and log rank tests were used to assess the associations between OS, DFS and pregnancy status, HER-2 status, ER/PR status, and family history. The median age was 33 years (range 24-42) for both groups. Twenty-two (55%) patients with PABC were ER/PR receptor positive compared with 20 (50%) for the controls. Ninety percent of patients with PABC received chemotherapy compared with 87.5% in the nonpregnant group. 91.5% of patients with PABC had breast-conserving surgery and 8.5% had mastectomies compared with 86% and 14%, respectively, for the control group. The median OS was 4.9 years in the PABC group compared with 6 years for the controls (p = 0.02). The median DFS was 2.7 years for the PABC group compared with 5.1 years for the controls (p = 0.01). The most common site of relapse was bone for the PABC group (27%) and local recurrence (33%) for the controls. Univariate analysis revealed that OS and DFS were associated with pregnancy status, family history, ER/PR status, and stage. After adjusting for age and stage, PABC patients had higher risk of both death (p = 0.01) and recurrence (p = 0.02) compared with nonpregnant controls. Women with PABC had significantly shorter OS and DFS compared with nonpregnant age and stage-matched controls.

// Francesco Morra 1,2,* , Chiara Luise 1,* , Francesco Merolla 1,3 , Ina Poser 4 , Roberta Visconti 1 , Gennaro Ilardi 3 , Simona Paladino 2 , Hiroyuki Inuzuka 5 , Gianluca Guggino 6 , Roberto Monaco 7 , David Colecchia 8 , Guglielmo Monaco 6 , Aniello Cerrato 1 , Mario Chiariello 8 , Krista Denning 9 , Pier Paolo Claudio 10 , Stefania Staibano 3  and Angela Celetti 1 1 Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy 3 Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy 4 Max Plank Institute, MPI-CBG Dresden, Germany 5 Harvard Medical School, Beth Israel Deaconess Medical Center, MA, USA 6 UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy 7 UOC Anatomia Patologica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy 8 Istituto Toscano Tumori, Core Research Laboratory, Siena, Italy 9 Department of Pathology, Joan C. Edwards Cancer Center, Huntington, WV, USA 10 Department of Biochemistry and Microbiology & Dept. of Surgery, Marshall University, Joan C. Edwards Cancer Center, Huntington, WV, USA * These authors have contributed equally to this work Correspondence to: Angela Celetti, email: // Keywords : CCDC6, FBXW7, USP7, mitotic kinases, cisplatinum Received : January 20, 2015 Accepted : March 03, 2015 Published : March 30, 2015 Abstract CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet. We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response. Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.

Cardiotoxic manifestation associated with breast cancer treatment by anthracycline regimen increases patients' susceptibility to myocardial injury, reduction in left ventricular ejection fraction and complications associated with heart failure. There is currently no standardized, minimally invasive, cost effective and clinically verified procedure to monitor cardiotoxicity post-anthracycline therapy initiation, and to detect early onset of irreversible cardiovascular complications. This study aims to create a panel of novel biomarkers and circulating miRNAs associated with cardiotoxicity, further assessing their correlation with cardiac injury specific markers, troponin I and T, and demonstrate the development of cardiac dysfunction in breast cancer patients. Blood obtained from West Virginian females clinically diagnosed with breast cancer and receiving anthracyclines showed upregulated level of biomarkers and circulating miRNAs after 3 and 6 months of chemotherapy initiation with increased levels of cardiac troponin I and T. These biomarkers and miRNAs significantly correlated with elevated troponins. Following 6 months of anthracycline-regimens, 23% of the patient population showed cardiotoxicity with reduced left ventricular ejection fraction. Our results support the clinical application of plasma biomarkers and circulating miRNAs to develop a panel for early diagnosis of chemotherapy related cardiac dysfunction which will enable early detection of disease progression and management of irreversible cardiac damage.

Diarrheal diseases (DD) are leading causes of disease burden, death, and disability, especially in children in low-income settings. DD can also impact a child's potential livelihood through stunted physical growth, cognitive impairment, and other sequelae. As part of the Global Burden of Disease Study, we estimated DD burden, and the burden attributable to specific risk factors and particular etiologies, in the Eastern Mediterranean Region (EMR) between 1990 and 2013. For both sexes and all ages, we calculated disability-adjusted life years (DALYs), which are the sum of years of life lost and years lived with disability. We estimate that over 125,000 deaths (3.6% of total deaths) were due to DD in the EMR in 2013, with a greater burden of DD in low- and middle-income countries. Diarrhea deaths per 100,000 children under 5 years of age ranged from one (95% uncertainty interval [UI] = 0-1) in Bahrain and Oman to 471 (95% UI = 245-763) in Somalia. The pattern for diarrhea DALYs among those under 5 years of age closely followed that for diarrheal deaths. DALYs per 100,000 ranged from 739 (95% UI = 520-989) in Syria to 40,869 (95% UI = 21,540-65,823) in Somalia. Our results highlighted a highly inequitable burden of DD in EMR, mainly driven by the lack of access to proper resources such as water and sanitation. Our findings will guide preventive and treatment interventions which are based on evidence and which follow the ultimate goal of reducing the DD burden.

BACKGROUND: Results from increasing numbers of in vitro and in vivo studies have demonstrated that omega 3 fatty acids incorporated in cell culture media or in the diet of the animals can suppress the growth of cancers. When human clinical trials are initiated to determine the ability of omega 3 fatty acids to alter growth or response to chemotherapeutic interventions of cancers, it will be essential to determine the omega 3 intake of individuals in the trial to determine compliance with consumption of the supplement and to correlate with endpoints of efficacy. We wondered if the fatty acid composition of RBCs might accurately indicate incorporation of omega 3 fatty acids in the WBCs. In this report we determine and compare the changes in fatty acid compositions of red blood cells and white blood cells in response to consumption of three doses of an omega 3 fatty acid supplement. RESULTS: We found that the fraction of omega 3 fatty acids in both red blood cells and white blood cells increased following consumption of the supplement. There was a linear, dose responsive increase in the fraction of omega 3 fatty acids in red blood cells but the increase in omega 3 in white blood cells was not linear. The magnitude of increase in omega 3 fatty acids was different between the two cell types. CONCLUSIONS: Fatty acid analysis of red blood cells is a good measure of compliance with supplement consumption. However, fatty acid analysis of white blood cells is needed to correlate changes in fatty acid composition of white blood cells with other biochemical changes in the white blood cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT00899353.

Breast cancer is the most common non-skin cancer and the second leading cause of cancer death in North American women. Mammography is the only screening test shown to reduce breast cancer-related mortality. There is general agreement that screening should be offered at least biennially to women 50 to 74 years of age. For women 40 to 49 years of age, the risks and benefits of screening should be discussed, and the decision to perform screening should take into consideration the individual patient risk, values, and comfort level of the patient and physician. Information is lacking about the effectiveness of screening in women 75 years and older. The decision to screen women in this age group should be individualized, keeping the patient's life expectancy, functional status, and goals of care in mind. For women with an estimated lifetime breast cancer risk of more than 20 percent or who have a BRCA mutation, screening should begin at 25 years of age or at the age that is five to 10 years younger than the earliest age that breast cancer was diagnosed in the family. Screening with magnetic resonance imaging may be considered in high-risk women, but its impact on breast cancer mortality is uncertain. Clinical breast examination plus mammography seems to be no more effective than mammography alone at reducing breast cancer mortality. Teaching breast self-examination does not improve mortality and is not recommended; however, women should be aware of any changes in their breasts and report them promptly.

BACKGROUND: The combination of paclitaxel and carboplatin is widely used in the treatment of patients with advanced nonsmall cell lung carcinoma. In this Phase I/II study the authors evaluated the feasibility, toxicity, and efficacy of adding a third active antineoplastic agent, gemcitabine, to the paclitaxel/carboplatin combination for the treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Patients with advanced (AJCC Stage IIIB or IV) nonsmall cell lung carcinoma previously untreated with chemotherapy were eligible for this trial. The maximum tolerated doses, determined in the Phase I trial and subsequently used in the Phase II trial, were: paclitaxel, 200 mg/m2, as a 1-hour infusion on Day 1; carboplatin, at area under the curve dose of 5.0 intravenously (i.v.), on Day 1; and gemcitabine, 1000 mg/m2 i.v., on Days 1 and 8. Treatment courses were repeated every 21 days. The Phase II study was conducted in 13 community-based practices in the Minnie Pearl Cancer Research Network; 77 patients were treated between December 1996 and September 1997. RESULTS: Thirty-four of 77 patients (44%) in the Phase II trial had major responses (partial responses, 32 patients and complete responses, 2 patients). An additional 25 patients (33%) had stable disease or minor response; only 23% of patients progressed or were removed from study at or prior to first reevaluation. The median survival was 9.4 months, with a 45% actuarial 1-year survival rate. Myelosuppression was the most common toxicity, with Grade 3/4 NCI Common Toxicity Criteria leukopenia and thrombocytopenia in 49% and 45% of patients, respectively. However, only 11 patients (14%) required hospitalization for neutropenia/ fever, and none had bleeding complications. Grade 3/4 nonhematologic toxicities included fatigue (41%), arthralgias/myalgias (26%), peripheral neuropathy (8%), nausea/emesis (6%), and hypersensitivity reactions (4%). There was one treatment-related death due to sepsis. CONCLUSIONS: This three-drug regimen is active and has acceptable toxicity in patients with advanced nonsmall cell lung carcinoma. Myelosuppression, particularly thrombocytopenia, is increased in comparison to the paclitaxel/carboplatin regimen. Fatigue also may be increased, but other nonhematologic toxicities are not altered substantially by adding gemcitabine. Although the response rate and median survival are improved modestly compared with our previous experience with paclitaxel/carboplatin, definitive conclusions regarding the efficacy of this regimen await the completion of randomized trials.

Consumption of walnuts has slowed breast cancer growth and/or reduced the risk of mammary cancer in mice. The benefit against cancer was associated with altered expression of genes for cancer growth and survival. We hypothesized that walnut consumption would alter gene expression in pathologically confirmed breast cancers of women in a direction that would be expected to decrease breast cancer growth and survival, as was seen in mice. The study was a nonplacebo, 2-arm, clinical trial. Women with breast lumps large enough for research and pathology biopsies were recruited and randomized to walnut consuming or control groups. Immediately after biopsy collection, women in the walnut group began to consume 2 oz of walnuts per day until follow-up surgery. Pathological studies confirmed that lumps were breast cancer in all women who remained in the trial. At surgery, about 2 weeks after biopsy, additional specimens were taken from the breast cancers. Changes in gene expression in the surgical specimen compared to baseline were determined in each individual woman in walnut-consuming (n = 5) and control (n = 5) groups. RNA sequencing expression profiling revealed that expression of 456 identified genes was significantly changed in the tumor due to walnut consumption. Ingenuity Pathway Analysis showed activation of pathways that promote apoptosis and cell adhesion, and inhibition of pathways that promote cell proliferation and migration. These results support the hypothesis that, in humans, walnut consumption could suppress growth and survival of breast cancers.

PURPOSE: Biological contamination of insulin pens in a hospital setting was studied. METHODS: This prospective study, conducted at two hospitals within a multihospital system, examined 125 insulin pens that had been returned to the inpatient pharmacies after patient discharge and were refrigerated for up to 48 hours before laboratory testing. Insulin was removed from the 125 pens and examined microscopically for the presence of nucleated cells and red blood cells (RBCs). Positive samples were examined by a pathologist to determine the cell types present. An immunochromatographic assay was used to determine the presence of free hemoglobin in the insulin. The 10 control samples were negative on microscopic examination. RESULTS: Out of 125 insulin pens, 7 (5.6%) tested positive for cells or hemoglobin. Microscopic examination revealed six positive samples containing a total of nine cells, including macrophages, squamous cells, and an RBC. The sample containing the RBC was not the same sample that tested positive for hemoglobin. Based on findings of intact cells and hemoglobin in insulin pens after administration, the potential exists for transmission of infectious agents from patient to patient if a single pen cartridge is used to administer insulin to multiple patients, even if a new needle is used for each individual. CONCLUSION: Examination of 125 insulin pens used in hospitals revealed hemoglobin in 1 pen and at least one cell in another 6 pens. The nine detected cells consisted of four squamous epithelial cells, four macrophages, and one RBC.

OBJECTIVES: Non-small-cell lung cancer (NSCLC) patient survival depends on a number of factors, including early diagnosis and initiation of treatment. Standard treatment options for patients with NSCLC include surgery, radiation therapy, and chemotherapy. The objective of this study was to evaluate the impact that the initiation of timely treatment has on patient survival among a cohort of privately insured patients with NSCLC in South Carolina. METHODS: Data for the study were retrospectively obtained from the South Carolina Central Cancer Registry and the state health plan Blue Cross and Blue Shield claims. Patients were diagnosed as having NSCLC between January 1, 2005 and December 31, 2010, were aged 18 years or older, and were covered under the state health plan for at least 1 year before diagnosis. The final study sample included 746 patients. Kaplan-Meier curves and Cox proportional hazard modeling were conducted to examine factors associated with survival, stratified by stage at diagnosis. RESULTS: The majority in the study cohort (80%) received timely (≤6 weeks) rather than untimely (>6 weeks) care (20%). The mean survival time for patients receiving timely treatment by stage was 36.9, 27.1, and 12.4 months for localized, regional, and distant metastasis, respectively. The mean survival time for patients receiving untimely care by stage was 39.4, 33.8, and 25.2 months for localized, regional, and distant metastasis, respectively. Among patients with NSCLC in the distant metastasis stage, those receiving timely treatment experienced significantly decreased survival (hazard ratio 2.2) in comparison to those receiving untimely care. CONCLUSIONS: Initiation of treatment within 6 weeks is not associated with greater survival time across all stages of cancer (localized, regional, and distant metastasis). Additional research is needed to examine the impact of other treatment quality metrics on the survival of patients with NSCLC, different time thresholds for treatment initiation that may be more meaningful to survival among patients with NSCLC, and timely care among patients with NSCLC in other geographic areas and populations.

Introduction: Ovarian cancer is one of the leading causes of death for women with cancer worldwide. Energy requirements for tumor growth in epithelial high-grade serous ovarian cancer (HGSOC) are fulfilled by a combination of aerobic glycolysis and oxidative phosphorylation (OXPHOS). Although reduced OXPHOS activity has emerged as one of the significant contributors to tumor aggressiveness and chemoresistance, up-regulation of mitochondrial antioxidant capacity is required for matrix detachment and colonization into the peritoneal cavity to form malignant ascites in HGSOC patients. However, limited information is available about the mitochondrial biogenesis regulating OXPHOS capacity and generation of mitochondrial reactive oxygen species (mtROS) in HGSOC. Methods: To evaluate the modulation of OXPHOS in HGSOC tumor samples and ovarian cancer cell lines, we performed proteomic analyses of proteins involved in mitochondrial energy metabolism and biogenesis and formation of mtROS by immunoblotting and flow cytometry, respectively. Results and discussion: We determined that the increased steady-state expression levels of mitochondrial- and nuclear-encoded OXPHOS subunits were associated with increased mitochondrial biogenesis in HGSOC tumors and ovarian cancer cell lines. The more prominent increase in MT-COII expression was in agreement with significant increase in mitochondrial translation factors, TUFM and DARS2. On the other hand, the ovarian cancer cell lines with reduced OXPHOS subunit expression and mitochondrial translation generated the highest levels of mtROS and significantly reduced SOD2 expression. Evaluation of mitochondrial biogenesis suggested that therapies directed against mitochondrial targets, such as those involved in transcription and translation machineries, should be considered in addition to the conventional chemotherapies in HGSOC treatment.

Chronic lymphocytic leukemia, the most common adult leukemia worldwide, is considered an indolent but incurable non-Hodgkin lymphoma. Leukemia cutis is an uncommon manifestation of chronic lymphocytic leukemia. We present a case of an adult patient who presented with skin lesion of bilateral ears, which led to the diagnosis of chronic lymphocytic leukemia. We also reviewed the cases of auricular involvement in chronic lymphocytic leukemia patients reported in the literature. Local treatment is indicated in case of leukemia cutis; however, systemic treatment is recommended when there are systemic signs and symptoms. Better awareness of disease evolution and prompt diagnosis of this leukemia cutis of chronic lymphocytic leukemia will improve the effectiveness and outcome of its management.

Dietary walnut altered gene expressions related to tumor growth, survival, and metastasis in breast cancer patients: a pilot clinical trial' [1] Hardman et al., 2019. Included are tables for all mapped genes and all unmapped loci identifications that were significantly changed in breast cancers by consumption of walnut for about 2 weeks. All gene networks that were identified by Ingenuity Pathway Analyses as modified are shown in table 3. Files containing the raw reads, along with a shell script describing the complete data analysis pipeline, were deposited to the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) and can be obtained via accession number GSE111073. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE111073.

In Brief BACKGROUND: An intracranial subdural hematoma is a rare and potentially fatal complication of spinal anesthesia. CASE: A gravida 2, para 1 underwent a repeat cesarean for transverse fetal lie. Four hours postoperatively she developed a severe headache with acute nausea and vomiting. Computed tomography scan revealed a 6-mm right subdural hematoma and midline shift of ventricles. She underwent a right frontal craniotomy with evacuation of the hematoma and eventually had a complete recovery. CONCLUSION: Headache and atypical neurologic signs presenting after spinal anesthesia should prompt rapid evaluation for intracranial hemorrhage. Intracranial subdural hematoma may follow spinal or epidural anesthesia administered to parturients, who may present with severe headache and altered mental status.

OBJECTIVE: Using an online decision aid developed to support parental decision making about newborn genomic sequencing, we tested whether adding a values clarification exercise to educational content would improve decision making outcomes and influence intention to pursue genomic sequencing. We also examined whether the effect of values clarification varied depending on one's health literacy level. METHOD: In an online experiment, women and men aged 18 to 44 who were either pregnant or had a pregnant partner, were currently trying to get pregnant, or were preparing for a pregnancy within the next 2 years were randomly assigned to complete either a decision aid with educational information about newborn genomic sequencing or a decision aid with the same educational information and a values clarification exercise. RESULTS: = .018. There was not a significant moderation effect of health literacy and decision aid condition on decision regret. CONCLUSIONS: Adding a values clarification exercise to decision aids for parents making decisions about genomic sequencing may improve the decision-making experience and provide some benefit to individuals with lower health literacy. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

BACKGROUND AND OBJECTIVE: Studies are limited regarding the impact of obesity on early erectile functional outcomes after robotic radical prostatectomy. Our goal was to determine this impact using patient-reported validated questionnaires. METHODS: International Index of Erectile Function (IIEF-6) scores were prospectively collected with institutional review board approval, for patients who underwent robotic radical prostatectomy with bilateral nerve sparing from February 2007 to October 2009. The data were categorized into nonobese and obese groups and subsequently into 2 subgroups based on risk for postprostatectomy erectile dysfunction. Low risk is preoperative IIEF-6 ≥19 and high risk is IIEF-6 <19. The groups and subgroups were compared using chi-square analysis. RESULTS: Of 190 consecutive patients, 67 were excluded for preoperative severe erectile dysfunction (IIEF-6<7), or lack of IIEF-6 scores, or both. There were 69 nonobese patients of which 88% were potent preoperatively and 20% regained potency at 12 months postoperatively. Of 54 obese patients, 85% were potent preoperatively and 25% at 12 months. There was no difference in erectile function recovery rates between the groups (P=0.755). In both groups, patients with low risk of postoperative erectile dysfunction had statistically similar postoperative mean IIEF-6 scores at 6 and 12 months (P=0.580 and P=0.389, respectively), and no difference in erectile function recovery rates existed at 12 months (P=0.735). CONCLUSION: Obesity has no major contribution to the rate of early erectile function recovery after robotic radical prostatectomy. Preoperative erectile function remains the determining factor in postradical prostatectomy erectile dysfunction.

There are significant challenges in developing in vitro human tissue and tumor models that can be used to support new drug development and evaluate personalized therapeutics. The challenges include: (1) working with primary cells which are often difficult to maintain ex vivo, (2) mimicking native microenvironments from which primary cells are harvested, and (3) the lack of culture devices that can support these microenvironments to evaluate drug responses in a high-throughput manner. Here we report a versatile well plate-based perfusion culture device that was designed, fabricated and used to: (1) ascertain the role of perfusion in facilitating the expansion of human multiple myeloma cells and evaluate drug response of the cells, (2) preserve the physiological phenotype of primary murine osteocytes by reconstructing the 3D cellular network of osteocytes, and (3) circulate primary murine T cells through a layer of primary murine intestine epithelial cells to recapitulate the interaction of the immune cells with the epithelial cells. Through these diverse case studies, we demonstrate the device's design features to support: (1) the convenient and spatiotemporal placement of cells and biomaterials into the culture wells of the device; (2) the replication of tissues and tumor microenvironments using perfusion, stromal cells, and/or biomaterials; (3) the circulation of non-adherent cells through the culture chambers; and (4) conventional tissue and cell characterization by plate reading, histology, and flow cytometry. Future challenges are identified and discussed from the perspective of manufacturing the device and making its operation for routine and wide use.

TPS8584 Background: Platinum-based concurrent chemoradiation(CRT) followed by one year of the human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, durvalumab, which blocks the interaction of PD-L1 with its receptors PD-1 and CD80, is the standard of care for locally advanced, unresectable non-small cell lung cancer (NSCLC). Early studies have noted the feasibility of concomitant administration of radiotherapy and immune checkpoint inhibition in NSCLC. EA5181 will evaluate the use of concomitant durvalumab with chemo-radiotherapy for locally advanced NSCLC. Methods: EA5181 is a randomized, multi-center, phase III study for patients with unresectable Stage III NSCLC comparing the efficacy of CRT with concomitant durvalumab to CRT, followed by one year of durvalumab. Eligibility criteria include: an ECOG PS of 0-1, adequate pulmonary function (FEV1 and DLCO both &gt; 40%), no history of auto-immune disease and no past chemotherapy or RT for this lung cancer. Stratification factors include age, sex, stage, and planned concurrent chemotherapy type. Eligible patients with be randomized 1:1 to receive 60Gy RT (2Gy fractions) CRT and durvalumab (Arm A) or 60Gy CRT (Arm B). Investigators will be allowed to choose from three different chemotherapy options: cisplatin/etoposide q 28 days, Pemetrexed/cisplatin q 21 days, and weekly paclitaxel/Carboplatin. Arm A will use 750mg fixed of durvalumab (considered equivalent to 10mg/kg) on days 1, 11, and 21 of RT. Assuming no disease progression, patients in both arms will be followed by monthly (q28 days) fixed dose of 1500mg durvalumab for one year which will be given optimally within 14 days of radiation or when (non)hematologic toxicity is &lt; Grade 2. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, incidence of local/distant progression and toxicity. The target sample size is 660 patients, anticipated to recruit over 55 months, with follow up for an additional 42 months. This provides approximately 82% power if the true hazard ratio for overall survival was 0.75 or less, with 2-sided alpha of 0.05, and assuming a median survival of 42.5 months in the control arm. The study was activated on 04/09/20 and has currently accrued 90 patients on 02/03/21. Clinical trial information: NCT04092283.