Research Spotlight

Huo, X., X. Zhang, C. Yu, E. Cheng, Q. Zhang, K. B. Dunbar, T. H. Pham, J. P. Lynch, D. H. Wang, R. S. Bresalier, S. J. Spechler and R. F. Souza (2018). “Aspirin prevents NF-kappaB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett’s oesophagus.” Gut 67(4): 606-615.

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OBJECTIVE: In previous studies using oesophageal squamous cells from patients with Barrett’s oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett’s oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. DESIGN: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IkappaB-NF-kappaB-PKAc complex activation, p65 NF-kappaB subunit function, and CDX2 expression. RESULTS: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IkappaB-NF-kappaB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IkappaB and p65 and greater NF-kappaB transcriptional activity than NES-G cells, indicating greater IkappaB-NF-kappaB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IkappaB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. CONCLUSIONS: Differences between NES-B and NES-G cells in NF-kappaB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett’s oesophagus while others do not, and why aspirin might protect against development of Barrett’s oesophagus.

Holmes, F. A., B. A. Hellerstedt, J. E. Pippen, Jr., S. J. Vukelja, R. P. Collea, D. M. Kocs, J. L. Blum, K. J. McIntyre, M. A. Barve, B. D. Brooks, C. R. Osborne, Y. Wang, L. Asmar and J. O’Shaughnessy (2018). “Five-year results of a phase II trial of preoperative 5-fluorouracil, epirubicin, cyclophosphamide followed by docetaxel with capecitabine (wTX) (with trastuzumab in HER2-positive patients) for patients with stage II or III breast cancer.” Cancer Med. Mar 26. [Epub ahead of print].

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We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5-fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2-positive disease) and to evaluate 5-year disease-free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5-fluorouracil 500 mg/m(2) , epirubicin 100 mg/m(2) , cyclophosphamide 500 mg/m(2) IV on Day 1 every 21 days) followed by 4 21-day cycles of docetaxel (35 mg/m(2) days 1 and 8) concurrently with capecitabine (825 mg/m(2) orally twice daily for 14 days followed by 7 days off) (wTX). For HER2-positive patients, treatment was modified by decreasing epirubicin to 75 mg/m(2) and adding trastuzumab (H) in standard doses (FEC75-H –>wTX-H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2-negative breast cancer and of 67% in patients with HER2-positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent-to-treat analysis, the pCR rate was 31% (37/118, 95% CI: 24-40%) in the HER2-negative patients, 24% (15/62, 95% CI: 14-37%) in ER-positive/HER2-negative patients, 39% (22/56, 95% CI: 27-53%) in the ER-negative/HER2-negative patients, and 46% (29/63, 95% CI: 34-48%) in the HER2-positive patients. The pCR rate in the 40 trastuzumab-treated patients was 53% (21/40, 95% CI: 38-67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand-foot skin reactions. One trastuzumab-treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1-2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease-free survival was 70% in the HER2-negative population (78% in ER-positive/HER2-negative and 62% in the ER-negative/HER2-negative patients) and 80% in the HER2-positive patients (87% in the trastuzumab-treated HER2-positive patients). At 5 years, overall survival was 80% in the HER2-negative population (88% in ER-positive/HER2-negative and 71% in the ER-negative/HER2-negative patients) and 86% in the HER2-positive patients (94.5% in the trastuzumab-treated HER2-positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5-year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Hernandez, M., J. Havens, S. Shafi and M. Crandall (2018). “Risk Assessment in Emergency General Surgery.” J Trauma Acute Care Surg. Mar 12. [Epub ahead of print].

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Patients with emergency general surgery (EGS) diseases display variable severity. The extent of disease can be amplified by comorbidity or dramatic changes in presenting physiology. Estimating the extent of disease severity in order to adequately provide prognosis, determine optimal operative or non-operative management, and plan for potential outcomes is difficult. A variety of risk factors have been studied for specific diseases but these criteria may not be universally applied. This limits the generalizability of prior work. The American Association for the Surgery of Trauma (AAST) created a grading system wherein uniform definitions could be applied to begin to measure disease severity in a granular manner. This review presents some of the initial work focused on the validation and incorporation of the AAST EGS grading system. The authors evaluate several diseases wherein the AAST EGS grade has been applied. Finally the work concludes with a review of several inclusive risk estimation tools. Taken together, the ability to measure disease severity – whether by anatomic changes, physiologic disturbance, or patient comorbidity status – will provide a better method to appraise, research, and improve patient care for several EGS conditions.

Gonzalez, S. A. and J. F. Trotter (2018). “The rise of the opioid epidemic and hepatitis C-positive organs: A new era in liver transplantation.” Hepatology 67(4): 1600-1608.

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The use of hepatitis C virus (HCV)-positive organs in liver transplantation (LT) has increased in the era of direct-acting antiviral therapy. A rising demand for organs, the increased ability to effectively treat HCV infection in the transplant setting, and an unprecedented increase in HCV-positive donors have all contributed to this trend. A recent abrupt rise in opioid use in the United States has resulted in a surge of injection drug use, transmission of HCV, and opioid-related overdose deaths. Geographical areas most affected by the opioid epidemic have experienced a rapid increase in recovery and utilization of HCV-positive donor organs, in which the proportion of deceased donor LTs in the United States from donors who are HCV positive has increased nearly 2-fold within the last 3 years. The prospect of expanding the organ donor pool with HCV-positive donors and achieving acceptable posttransplant outcomes has generated much interest in the areas of liver, kidney, and thoracic transplantation, including the potential for transplanting organs from HCV positive donors into HCV-negative recipients. Developing strategies to ensure appropriate selection of potential recipients of HCV-positive organs, initiating timely antiviral therapy, and defining associated risks will be critical in achieving optimal posttransplant outcomes in this setting.

Goldberg, D. S., C. Levy, K. Yimam, S. C. Gordon, L. Forman, E. Verna, L. Yu, R. Rahimi, K. Schwarz, B. Eksteen, D. Pratt, J. L. Boyer, D. Assis and C. Bowlus (2018). “Primary Sclerosing Cholangitis Is Not Rare Among Blacks in a Multicenter North American Consortium.” Clin Gastroenterol Hepatol 16(4): 591-593.

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In this multicenter North American consortium, we show that PSC is not rare among black patients. The proportional representation of PSC in black patients compared with each center’s MSA was variable across the 13 centers. Thus, although these data do not show that PSC is as common in black vs white patients, PSC in blacks is not as rare as what would be interpreted based on published data. This suggests that existing literature may reflect selection bias related to the demographics of the underlying population included in these studies, rather than a clinical disease largely restricted to white patients. The existing literature bias could prevent adequate evaluation and diagnosis of PSC in non-white patients by practicing clinicians. We were not able to compare the clinical characteristics of PSC in black vs white patients at each center, but have highlighted potential differences of PSC in black patients compared with published data of solely white patients: (1) 58.8% had inflammatory bowel disease, compared with 75% to 80% in white patients8; (2) 52.2% had isolated intrahepatic bile duct involvement (diagnosed using cholangiograms per American Association for the Study of Liver Diseases guidelines), compared with 20% to 30% in white patients; and (3) 51.3% were male, compared with 60% to 65% in whites. The time from diagnosis to transplant or death was similar to data from published cohort studies of white patients with PSC from tertiary care centers. We have provided evidence that PSC occurs in black patients and, in this cohort, has unique clinical features. The study had limitations because there was no direct comparator group or systematic evaluation of all included patients, thus validation of these findings is required to compare white vs black patients using detailed clinical data. This may lead to new insights into PSC in general and also particular subphenotypes. Ultimately, these results highlight the need for caution when generalizing findings in rare diseases derived from demographically homogenous groups, and the importance of conducting epidemiologic studies of diverse populations that represent the demographics of the US population. (Excerpt from text, p. 592; no abstract available.)