Browsing by Author "Kesler, Kenneth"

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    A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study
    (Frontiers Media, 2021-09-17) Mamdani, Hirva; Schneider, Bryan; Perkins, Susan M.; Burney, Heather N.; Kasi, Pashtoon Murtaza; Abushahin, Laith I.; Birdas, Thomas; Kesler, Kenneth; Watkins, Tracy M.; Badve, Sunil S.; Radovich, Milan; Jalal, Shadia I.; Surgery, School of Medicine
    Background: Most patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients. Methods: We conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population. Results: Thirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56-84%) with median RFS of 21 months (95% CI, 14-40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05-0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15-0.93, p = 0.0351, respectively). Conclusions: Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.
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    Effect of Delirium on Physical Function in Noncardiac Thoracic Surgery Patients
    (American Association of Critical-Care Nurses, 2020-03) Khan, Sikandar H.; Xu, Chenjia; Wang, Sophia; Gao, Sujuan; Lasiter, Sue; Kesler, Kenneth; Khan, Babar A.; Medicine, School of Medicine
    Background: The effect of delirium on physical function in patients undergoing noncardiac thoracic surgery has not been well described and may differ from that in other surgical populations. Objective: To determine the effects of delirium on muscle strength and functional independence. The primary end point was change in Medical Research Council sum score (MRC-SS) by delirium status. Methods: A secondary analysis of data from a clinical trial involving English-speaking adults aged 18 years or older who were undergoing major noncardiac thoracic surgery. Exclusion criteria were history of schizophrenia, Parkinson disease, dementia, alcohol abuse, or neuroleptic malignant syndrome; haloperidol allergy; being pregnant or nursing; QT prolongation; and taking levodopa or cholinesterase inhibitors. Delirium was assessed twice daily using the Confusion Assessment Method for the Intensive Care Unit. Preoperatively and postoperatively, muscle strength was assessed using the modified MRC-SS and functional independence was assessed using the Katz scale of activities of daily living. Changes in MRC-SS and Katz score by delirium status were analyzed using the Fisher exact test. Results: Seventy-three patients were included in the analysis. Median (interquartile range) MRC-SS and Katz score before surgery did not differ significantly between patients without and with delirium (MRC-SS: 30 [30-30] vs 30 [30-30], P > .99; Katz score: 6 [6-6] vs 6 [6-6], P = .63). The percentage of patients with a change in MRC-SS was similar in patients without and with delirium (17% vs 13%, respectively; P > .99). More patients in the delirium group had a change in Katz score (13% vs 0%, P = .04). Conclusions: Postoperative delirium was not associated with change in muscle strength. Follow-up studies using other muscle measures may be needed.
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    Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors
    (Oxford, 2018-02) Albany, Costantine; Adra, Nabil; Snavely, A. C.; Cary, C.; Masterson, T. A.; Foster, R. S.; Kesler, Kenneth; Ulbright, Thomas M.; Cheng, Liang; Chovanec, Michal; Taza, Fadi; Brames, Mary J.; Hanna, Nasser H.; Einhorn, Lawrence H.; Medicine, School of Medicine
    Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant’ disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant’ cohort between 2000 and 2014, P-value <0.0001. Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant’ cohort.
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    NUT Midline Carcinoma Masquerading As a Thymic Carcinoma
    (ASCO, 2016-05) Gökmen-Polar, Yesim; Kesler, Kenneth; Loehrer, Patrick J., Sr.; Badve, Sunil; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Thymic carcinomas are rare tumors that arise from the epithelium of the thymus gland and characterized by cytologic atypia, invasiveness, and high risk of relapse and death.1–3 The current WHO schema recognizes at least 11 histologic subtypes.4–7 Undifferentiated thymic carcinoma is one of the subtypes that can be indistinguishable from other poorly differentiated carcinomas such as NUT midline carcinoma (NMC).8 Despite the aggressive nature of both diseases, a correct diagnosis is important because of the recent development of targeted therapies for NMCs. Herein we describe two cases of a particularly aggressive form of disease and discuss the differential diagnosis of these lesions.
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    Preoperative STOP-BANG Scores and Postoperative Delirium and Coma in Thoracic Surgery Patients
    (Elsevier, 2018) Wang, Sophia; Sigua, Ninotchka Liban; Manchanda, Shalini; Gradney, Steve; Khan, Sikandar H.; Perkins, Anthony; Kesler, Kenneth; Khan, Babar; Psychiatry, School of Medicine
    Background Obstructive sleep apnea (OSA) is associated with higher rates of postoperative delirium. The relationship between preoperative OSA risk and postoperative delirium and coma in thoracic surgery patients hospitalized in the intensive care unit (ICU) is not well understood. This study tests the hypothesis that thoracic surgery patients hospitalized in ICU with a higher preoperative risk for OSA are more likely to develop postoperative delirium and coma, resulting in longer hospital stays. Methods Preoperative OSA risk was measured using the STOP-BANG questionnaire. STOP-BANG scores of ≥ 3 were defined as intermediate-high risk for OSA. 128 patients who underwent major thoracic surgery completed the STOP-BANG questionnaire preoperatively. The Richmond Agitation and Sedation Scale was used to assess level of consciousness. The Confusion Assessment Method for the ICU was used to assess for delirium. Linear regression was used to assess the relationship between risk of OSA and outcome measures. Results were adjusted for age, gender, body mass index, Charlson Comorbidity Index, instrumental activities of daily living, and surgery type. Results 96 out of 128 patients (76%) were in the intermediate-high risk OSA group. Adjusted analyses showed that the intermediate-high risk OSA group had a longer duration of postoperative ICU delirium and coma compared to the low risk OSA group (1.4 days ± 1.3 vs 0.9 days ± 1.4; P = 0.04). Total number of hospital days was not significantly different. Conclusions Higher preoperative risk for OSA in thoracic surgery patients was associated with a longer duration of postoperative delirium and coma.
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    Preventing Postoperative Delirium After Major Noncardiac Thoracic Surgery—A Randomized Clinical Trial
    (Wiley, 2018) Khan, Babar A.; Perkins, Anthony J.; Campbell, Noll L.; Gao, Sujuan; Khan, Sikandar H.; Wang, Sophia; Fuchita, Mikita; Weber, Daniel J.; Zarzaur, Ben L.; Boustani, Malaz A.; Kesler, Kenneth; Medicine, School of Medicine
    Objectives: To assess the efficacy of haloperidol in reducing postoperative delirium in individuals undergoing thoracic surgery. Design: Randomized double-blind placebo-controlled trial. Setting: Surgical intensive care unit (ICU) of tertiary care center. Participants: Individuals undergoing thoracic surgery (N=135). Intervention: Low-dose intravenous haloperidol (0.5 mg three times daily for a total of 11 doses) administered postoperatively. Measurements: The primary outcome was delirium incidence during hospitalization. Secondary outcomes were time to delirium, delirium duration, delirium severity, and ICU and hospital length of stay. Delirium was assessed using the Confusion Assessment Method for the ICU and delirium severity using the Delirium Rating Scale-Revised. Results: Sixty-eight participants were randomized to receive haloperidol and 67 placebo. No significant differences were observed between those receiving haloperidol and those receiving placebo in incident delirium (n=15 (22.1%) vs n=19 (28.4%); p = .43), time to delirium (p = .43), delirium duration (median 1 day, interquartile range (IQR) 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, ICU length of stay (median 2.2 days, IQR 1-3.3 days vs median 2.3 days, IQR 1-4 days; p = .29), or hospital length of stay (median 10 days, IQR 8-11.5 days vs median 10 days, IQR 8-12 days; p = .41). In the esophagectomy subgroup (n = 84), the haloperidol group was less likely to experience incident delirium (n=10 (23.8%) vs n=17 (40.5%); p = .16). There were no differences in time to delirium (p = .14), delirium duration (median 1 day, IQR 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, or hospital length of stay (median 11 days, IQR 10-12 days vs median days 11, IQR 10-15 days; p = .26). ICU length of stay was significantly shorter in the haloperidol group (median 2.8 days, IQR 1.1-3.8 days vs median 3.1 days, IQR 2.1-5.1 days; p = .03). Safety events were comparable between the groups. Conclusion: Low-dose postoperative haloperidol did not reduce delirium in individuals undergoing thoracic surgery but may be efficacious in those undergoing esophagectomy.
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    Serum Biomarkers in Postoperative Delirium after Esophagectomy
    (Elsevier, 2022) Khan, Sikandar H.; Lindroth, Heidi; Jawed, Yameena; Wang, Sophia; Nasser, Jason; Seyffert, Sarah; Naqvi, Kiran; Perkins, Anthony J.; Gao, Sujuan; Kesler, Kenneth; Khan, Babar; Medicine, School of Medicine
    Background: Esophagectomy is associated with postoperative delirium, but its pathophysiology is not well defined. We conducted this study to measure the relationship among serum biomarkers of inflammation and neuronal injury and delirium incidence and severity in a cohort of esophagectomy patients. Methods: Blood samples were obtained from patients preoperatively and on postoperative days 1 and 3 and were analyzed for S100 calcium-binding protein B, C-reactive protein (CRP), interleukin (IL) 8 and IL-10, tumor necrosis factor-α, and insulin-like growth factor 1. Delirium was assessed twice daily using the Richmond Agitation Sedation Scale and Confusion Assessment Method for Intensive Care Unit. Delirium severity was assessed once daily with the Delirium Rating Scale-Revised-98. Results: Samples from 71 patients were included. Preoperative biomarker concentrations were not associated with postoperative delirium. Significant differences in change in concentrations from preoperatively to postoperative day 1 were seen in IL-8 (delirium, 38.6; interquartile range [IQR], 29.3-69.8; no delirium, 24.8; IQR, 16.0-41.7, P = .022), and IL-10 (delirium, 26.1; IQR, 13.9-36.7; no delirium, 12.4; IQR, 7.7-25.7; P = .025). Greater postoperative increase in S100 calcium-binding protein B (Spearman r = 0.289, P = .020) and lower levels of insulin-like growth factor 1 were correlated with greater delirium severity (Spearman r = -0.27, P = .040). Greater CRP change quartiles were associated with higher delirium incidence adjusting for severity of illness (odds ratio, 1.68; 95% confidence interval, 1.03-2.75; P = .037) or comorbidities (odds ratio, 1.70; 95% confidence interval, 1.05-2.76, P = .030). Conclusions: Differences in change in serum CRP, IL-8, and IL-10 concentrations were associated with postoperative delirium, suggesting biomarker measurement early in the postoperative course is associated with delirium.