Research Spotlight

Kelly, R. J., J. Lee, Y. J. Bang, K. Almhanna, M. Blum-Murphy, D. V. T. Catenacci, H. C. Chung, Z. A. Wainberg, M. K. Gibson, K. W. Lee, J. C. Bendell, C. S. Denlinger, C. E. Chee, T. Omori, R. Leidner, H. J. Lenz, Y. Chao, M. C. Rebelatto, P. Z. Brohawn, P. He, J. McDevitt, S. Sheth, J. M. Englert and G. Y. Ku (2020). “Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma.” Clin Cancer Res 26(4): 846-854.

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PURPOSE: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. PATIENTS AND METHODS: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNgamma gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. RESULTS: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. CONCLUSIONS: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNgamma signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

Kardashian, A., S. S. Florman, B. Haydel, R. M. Ruiz, G. B. Klintmalm, D. D. Lee, C. B. Taner, F. Aucejo, A. D. Tevar, A. Humar, E. C. Verna, K. J. Halazun, W. C. Chapman, N. Vachharajani, M. Hoteit, M. H. Levine, M. H. Nguyen, M. L. Melcher, A. N. Langnas, C. A. Carney, C. Mobley, M. Ghobrial, B. Amundsen, J. F. Markmann, D. L. Sudan, C. M. Jones, J. Berumen, A. W. Hemming, J. C. Hong, J. Kim, M. A. Zimmerman, T. L. Nydam, A. Rana, M. L. Kueht, T. M. Fishbein, D. Markovic, R. W. Busuttil and V. G. Agopian (2020). “Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients with Hepatocellular Carcinoma Presenting Beyond Milan Criteria.” Hepatology Mar 2. [Epub ahead of print].

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The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are downstaged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of downstaging, and the impact of LRT in beyond-MC HCC patients from the US Multicenter HCC Transplant Consortium (20 centers, 2002-2013). Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n=3,570) and beyond MC (n=789) who were downstaged (DS, n=465), treated with LRT and not downstaged (LRT-NoDS, n=242), or untreated (NoLRT-NoDS, n=82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared to DS (64.3% and 59.5%), and lowest in NoDS (n=324; 60.2% and 53.8%; overall P<0.001). DS patients had superior RFS (60% vs 54%,P=0.043) and lower 5-year HCC-R (18% vs 32%,P<0.001) compared to NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/< 5cm and 39.1% in NoDS/>5cm,P<0.001). Multivariate predictors of downstaging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared to NoLRT-NoDS (34.1% vs 26.1%,P<0.001), even after controlling for clinicopathologic variables (HR=2.33,P<0.001) and inverse probability of treatment weighted propensity matching (HR=1.82,P<0.001). Conclusion In LT recipients with HCC presenting beyond MC, successful downstaging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden, and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared to NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

Jain, A., S. Yeramaneni, K. M. Kebaish, M. Raad, J. L. Gum, E. O. Klineberg, H. Hassanzadeh, M. P. Kelly, P. G. Passias, C. P. Ames, J. S. Smith, C. I. Shaffrey, S. Bess, V. Lafage, S. Glassman, L. Y. Carreon and R. A. Hostin (2020). “Cost-Utility Analysis of rhBMP-2 Use in Adult Spinal Deformity Surgery.” Spine (Phila Pa 1976) Feb 21. [Epub ahead of print].

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STUDY DESIGN: Economic modeling of data from a multicenter, prospective registry. OBJECTIVE: To analyze the cost utility of recombinant human bone morphogenetic protein-2 (BMP) in adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: ASD surgery is expensive and presents risk of major complications. BMP is frequently used off-label to reduce the risk of pseudarthrosis. METHODS: Of 522 ASD patients with fusion of 5 or more spinal levels, 367 (70%) had at least 2-year follow-up. Total direct cost was calculated by adding direct costs of the index surgery and any subsequent reoperations or readmissions. Cumulative quality-adjusted life years (QALYs) gained were calculated from the change in preoperative to final follow-up SF-6D health utility score. A decision-analysis model comparing BMP vs. no-BMP was developed with pseudarthrosis as the primary outcome. Costs and benefits were discounted at 3%. Probabilistic sensitivity analysis was performed using mixed first-order and second-order Monte Carlo simulations. One-way sensitivity analyses were performed by varying cost, probability, and QALY estimates. Alpha = 0.05. RESULTS: BMP was used in the index surgery for 267 patients (73%). The mean (+/- standard deviation) direct cost of BMP for the index surgery was $14,000 +/- $6,400. Forty patients (11%) underwent revision surgery for symptomatic pseudarthrosis (BMP group, 8.6%; no-BMP group, 17%; P = 0.022). The mean 2-year direct cost was significantly higher for patients with pseudarthrosis ($138,000 +/- $17,000) than for patients without pseudarthrosis ($61,000 +/- $25,000) (P < 0.001). Simulation analysis revealed that BMP was associated with positive incremental utility in 67% of patients and considered favorable at a willingness-to-pay threshold of $150,000/QALY in >52% of patients. CONCLUSIONS: BMP use was associated with reduction in revisions for symptomatic pseudarthrosis in ASD surgery. Cost-utility analysis suggests that BMP use may be favored in ASD surgery; however, this determination requires further research. LEVEL OF EVIDENCE: 2.

Jackson, D. N., M. Panopoulos, W. L. Neumann, K. Turner, B. L. Cantarel, L. Thompson-Snipes, T. Dassopoulos, L. A. Feagins, R. F. Souza, J. C. Mills, R. S. Blumberg, K. Venuprasad, W. E. Thompson and A. L. Theiss (2020). “Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis.” Gut Feb 28. [Epub ahead of print].

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OBJECTIVE: Although perturbations in mitochondrial function and structure have been described in the intestinal epithelium of Crohn’s disease and ulcerative colitis patients, the role of epithelial mitochondrial stress in the pathophysiology of inflammatory bowel diseases (IBD) is not well elucidated. Prohibitin 1 (PHB1), a major component protein of the inner mitochondrial membrane crucial for optimal respiratory chain assembly and function, is decreased during IBD. DESIGN: Male and female mice with inducible intestinal epithelial cell deletion of Phb1 (Phb1(i) (DeltaIEC) ) or Paneth cell-specific deletion of Phb1 (Phb1(DeltaPC) ) and Phb1(fl/fl) control mice were housed up to 20 weeks to characterise the impact of PHB1 deletion on intestinal homeostasis. To suppress mitochondrial reactive oxygen species, a mitochondrial-targeted antioxidant, Mito-Tempo, was administered. To examine epithelial cell-intrinsic responses, intestinal enteroids were generated from crypts of Phb1(i) (DeltaIEC) or Phb1(DeltaPC) mice. RESULTS: Phb1(i) (DeltaIEC) mice exhibited spontaneous ileal inflammation that was preceded by mitochondrial dysfunction in all IECs and early abnormalities in Paneth cells. Mito-Tempo ameliorated mitochondrial dysfunction, Paneth cell abnormalities and ileitis in Phb1(i) (DeltaIEC) ileum. Deletion of Phb1 specifically in Paneth cells (Phb1(DeltaPC) ) was sufficient to cause ileitis. Intestinal enteroids generated from crypts of Phb1(i) (DeltaIEC) or Phb1(DeltaPC) mice exhibited decreased viability and Paneth cell defects that were improved by Mito-Tempo. CONCLUSION: Our results identify Paneth cells as highly susceptible to mitochondrial dysfunction and central to the pathogenesis of ileitis, with translational implications for the subset of Crohn’s disease patients exhibiting Paneth cell defects.

Huo, X., K. B. Dunbar, X. Zhang, Q. Zhang, S. J. Spechler and R. F. Souza (2020). “In Barrett’s epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38.” Am J Physiol Gastrointest Liver Physiol 318(3): G464-g478.

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The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Because p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus.NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett’s metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett’s metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett’s esophagus.