Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma.

OBJECTIVES/HYPOTHESIS: Gastroesophageal reflux disease and associated metaplasia of the esophagus (Barrett's esophagus [BE]) are primary risk factors for esophageal adenocarcinoma (EAC). Widespread use of acid suppression medications has failed to stem the rise of EAC, suggesting that nonacid reflux may underlie its pathophysiology. Pepsin is a tumor promoter in the larynx and has been implicated in esophageal carcinogenesis. Herein, specimens from the esophageal cancer spectrum were tested for pepsin presence. Pepsin-induced carcinogenic changes were assayed in an esophageal cell culture model. STUDY DESIGN: Laboratory analysis. METHODS: Pepsin was assayed in reflux and cancer free esophagi, BE, EAC, and esophageal cancer lacking association with reflux (squamous cell carcinoma [SCC]). Refluxed or locally synthesized pepsin was assayed by Western blot. Local synthesis of pepsin and proton pumps was assayed via reverse transcription-polymerase chain reaction. The effect of pepsin on BE and EAC markers was investigated via enzyme-linked immunosorbent assay and quantitative polymerase chain reaction in human esophageal epithelial cells treated with pepsin or control diluent. RESULTS: Pepsinogen and proton pump mRNA were observed in BE (3/5) and EAC (4/4) samples, but not in normal adjacent specimens, SCC (0/2), or reflux and cancer-free esophagi. Chronic pepsin treatment (0.1-1 mg/mL, 4 weeks) of human esophageal cells in vitro induced BE and EAC markers interleukin 8 and KRT8 and depleted normal esophageal marker KRT10 (P < .05) expression. CONCLUSIONS: Local synthesis of pepsin and proton pumps in BE and EAC is not uncommon. Absence of these molecules in normal (noncancer) esophagi, SCC, and in vitro data support a role for pepsin in reflux-attributed carcinogenic changes in the esophagus. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2687-2695, 2019.

Pre-Existing Mesh at the Hiatus in Revisional Surgery Does Not Result in Increased Morbidity: A Case-Control Evaluation.

BACKGROUND: Mesh is sometimes used to reinforce the hiatus during primary and reoperative fundoplication. This is a controversial practice as it is not clear that this leads to a decreased rate of failure of the hiatal closure, and concerns about morbidity related to the presence of mesh in this location exist. One of these concerns is that if reoperation is ever required (fundoplication herniates through the hiatus, for example), revisional surgery would be significantly more difficult and associated with a higher rate of morbidity than if mesh had not been placed at the hiatus in a previous procedure. METHODS: A retrospective review was conducted of prospectively collected data on 104 patients to undergo surgery for a failed fundoplication between 2011 and 2015. Fourteen patients (13.5%) had previous operations where mesh had been placed at the hiatus and underwent a subsequent revisional procedure. Procedures performed were reoperative fundoplication and Roux-en-Y gastric bypass as a salvage procedure for a failed fundoplication, especially in the setting of obesity. These 14 cases were matched 1:2 with randomly selected control patients from the database who underwent revisional surgery in whom mesh had not been placed at the original operation. Cases and controls were paired based on the number of previous revision attempts and operation type. Perioperative outcomes were compared. RESULTS: There was no statistically significant difference in 30-day morbidity, readmission, operative time, or length of hospital stay. CONCLUSIONS: In this retrospective case-control evaluation, mesh at the hiatus did have an impact on morbidity or operative time.

GERD and acid reduction medication use following gastric bypass and sleeve gastrectomy.

BACKGROUND: Gastroesophageal reflux disease is a common comorbid medical condition of obesity. Laparoscopic sleeve gastrectomy has been associated with de novo and worsening GERD following surgery. For this reason, patients who suffer from GERD and are considering bariatric surgery are often counseled to undergo gastric bypass. Given this practice, we sought to determine acid reduction medication (ARM) utilization in bariatric surgical patients who undergo one of these procedures prior to surgery and at 1 year following surgery. METHODS: A retrospective review of prospectively maintained data on patients to undergo gastric bypass or sleeve gastrectomy between November 2012 and December 2014 was conducted after IRB approval. ARM utilization and Gastroesophageal Reflux Disease Health-Related Quality of Life (GERD-HRQL) scores [range 0 (no symptoms)-50 (severe GERD)] were compared prior to surgery and at 1 year postoperatively. RESULTS: 334 patients underwent an eligible procedure in the study interval. 147 patients (44 %) had data on both preoperative and 1 year postoperative ARM use (93 gastric bypass and 54 sleeve gastrectomy). ARM utilization prior to surgery in gastric bypass patients did not reach statistical significance when compared to sleeve gastrectomy (40.9 vs. 26 %, p = 0.07). GERD-HRQL scores were greater prior to surgery in gastric bypass patients (GERD-HRQL 8.2 vs. 1.9; p < 0.01). At 12 months postoperatively, sleeve gastrectomy patients had a significantly higher rate of overall ARM use (48.1 vs. 16.1 %, p < 0.01), new ARM use (35 vs. 7.3 %, p < 0.01), and persistent ARM use (78.6 vs. 21.9 %, p < 0.01) when compared to gastric bypass patients. GERD-HRQL scores were similar overall at 12 months postoperatively (4.4 bypass vs. 4.8 sleeve; p = 0.72). CONCLUSION: Laparoscopic sleeve gastrectomy is associated with a significantly increased likelihood that acid reduction medications will be necessary for GERD symptom control 12 months postoperatively when compared to gastric bypass.

A 5-item frailty index based on NSQIP data correlates with outcomes following paraesophageal hernia repair.

BACKGROUND: Frailty is a measure of physiologic reserve associated with increased vulnerability to adverse outcomes following surgery in older adults. The 'accumulating deficits' model of frailty has been applied to the NSQIP database, and an 11-item modified frailty index (mFI) has been validated. We developed a condensed 5-item frailty index and used this to assess the relationship between frailty and outcomes in patients undergoing paraesophageal hernia (PEH) repair. METHODS: The NSQIP database was queried for ICD-9 and CPT codes associated with PEH repair. Subjects ≥60 years who underwent PEH repair between 2011 and 2013 were included. Five of the 11 mFI items present in the NSQIP data on the most consistent basis were selected for the condensed index. Univariate and multivariate logistic regressions were used to determine the validity of the 5-item mFI as a predictor of postoperative mortality, complications, readmission, and non-routine discharge. RESULTS: A total of 3711 patients had data for all variables in the 5-item index, while 885 patients had complete data to calculate the 11-item mFI. After controlling for competing risk factors, including age, ASA score, wound classification, surgical approach, and procedure timing (emergent vs non-emergent), we found the 5-item mFI remained predictive of 30-day mortality and patients being discharged to a location other than home (p < 0.05). A weighted Kappa was calculated to assess agreement between the 5-item and 11-item mFI and was found to be 0.8709 (p < 0.001). CONCLUSIONS: Frailty, as assessed by the 5-item mFI, is a reasonable alternative to the 11-item mFI in patients undergoing PEH repair. Utilization of the 5-item mFI allows for a significantly increased sample size compared to the 11-item mFI. Further study is necessary to determine whether the condensed 5-item mFI is a valid measure to assess frailty for other types of surgery.

Cost analysis of robotic versus laparoscopic general surgery procedures.

BACKGROUND: Robotic surgical systems have been used at a rapidly increasing rate in general surgery. Many of these procedures have been performed laparoscopically for years. In a surgical encounter, a significant portion of the total costs is associated with consumable supplies. Our hospital system has invested in a software program that can track the costs of consumable surgical supplies. We sought to determine the differences in cost of consumables with elective laparoscopic and robotic procedures for our health care organization. METHODS: De-identified procedural cost and equipment utilization data were collected from the Surgical Profitability Compass Procedure Cost Manager System (The Advisory Board Company, Washington, DC) for our health care system for laparoscopic and robotic cholecystectomy, fundoplication, and inguinal hernia between the years 2013 and 2015. Outcomes were length of stay, case duration, and supply cost. Statistical analysis was performed using a t-test for continuous variables, and statistical significance was defined as p < 0.05. RESULTS: The total cost of consumable surgical supplies was significantly greater for all robotic procedures. Length of stay did not differ for fundoplication or cholecystectomy. Length of stay was greater for robotic inguinal hernia repair. Case duration was similar for cholecystectomy (84.3 robotic and 75.5 min laparoscopic, p = 0.08), but significantly longer for robotic fundoplication (197.2 robotic and 162.1 min laparoscopic, p = 0.01) and inguinal hernia repair (124.0 robotic and 84.4 min laparoscopic, p = â‰ª0.01). CONCLUSIONS: We found a significantly increased cost of general surgery procedures for our health care system when cases commonly performed laparoscopically are instead performed robotically. Our analysis is limited by the fact that we only included costs associated with consumable surgical supplies. The initial acquisition cost (over $1 million for robotic surgical system), depreciation, and service contract for the robotic and laparoscopic systems were not included in this analysis.

The impact of frailty on outcomes of paraesophageal hernia repair.

BACKGROUND: Frailty is a measure of physiological reserve that has been used to predict outcomes after surgical procedures in the elderly. We hypothesized that frailty would be associated with outcomes after paraesophageal hernia (PEH) repair. METHODS: The National Surgical Quality Improvement Program database (2011-2013) was queried for International Classification of Diseases, Version 9 and Current Procedural Terminology codes associated with PEH repair in patients aged ≥ 60 y. A previously described modified frailty index (mFI), based on 11 clinical variables in National Surgical Quality Improvement Program was used to quantify frailty. Multivariate logistic regression was used to determine the relationship between frailty, complications, and mortality. RESULTS: Of the 4434 PEH repairs that met inclusion criteria, 885 records were included in the final analysis (20%). Excluded patients were missing one or more variables in the mFI. The rate of complications that were Clavien-Dindo Grade ≥ 3 was 6.1%. Mortality was 0.9%. The readmission rate was 8.2%, and 10.9% of patients were discharged to a facility other than home. Relative to mFI scores of 0, 1, 2, and ≥3, the respective occurrence percentages were as follows; Grade ≥3 complication: 3.2%, 4.7%, 9.8%, and 23.3% (P < 0.0001; odds ratio [OR] 3.51; confidence interval [CI] 1.46-8.46); mortality: 0.0%, 0.9%, 1.8%, and 2.3% (P = 0.0974); discharge to facility other than home: 4.4%, 10.9%, 15.7%, and 31.7% (P < 0.0001; OR 4.07; CI 1.29-12.82); and readmission: 8.9%, 6.8%, 8.5%, and 16.3% (P = 0.1703; OR 1.01; CI 0.36-2.84). Complications and discharge destination were significantly correlated with the mFI. CONCLUSIONS: Frailty, as assessed by the mFI, is correlated with postoperative complications and discharge to a facility other than home after PEH repair.

Local Synthesis of Pepsin in Barrett's Esophagus and the Role of Pepsin in Esophageal Adenocarcinoma.

OBJECTIVE: Despite widespread use of proton pump inhibitors (PPIs), the incidence of esophageal adenocarcinoma (EAC) continues to rise. PPIs reduce reflux acidity, but only transiently inactivate gastric enzymes. Nonacid reflux, specifically nonacid pepsin, contributes to carcinogenesis in the larynx. Given the carcinogenic potential of pepsin and inefficacy of PPIs to prevent EAC, the presence and effect of pepsin in the esophagus should be investigated. METHODS: Normal and Barrett's biopsies from 8 Barrett's esophagus patients were collected for pepsin analysis via Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR). Human esophageal cells cultured from healthy patients were treated with pepsin (0.01-1 mg/mL; 1-20 hours), acid (pH 4)±pepsin (5 minutes); real-time RT-PCR, ELISA, and cell migration were assayed. RESULTS: Pepsin was detected in all 8 Barrett's and 4 of 8 adjacent normal specimens. Pepsinogen mRNA was observed in 22 Barrett's, but not in normal adjacent samples. Pepsin induced PTSG2 (COX-2) and IL-1ß expression and cell migration in vitro. CONCLUSIONS: Pepsin is synthesized by metaplastic, Barrett's esophageal mucosa. Nonacid pepsin increases metrics of tumorigenicity in esophageal epithelial cells in vitro. These findings implicate refluxed and locally synthesized pepsin in development and progression of EAC and, in part, explain the inefficacy of PPIs in the prevention of EAC.

Medically refractory gastroesophageal reflux disease in the obese: what is the best surgical approach?

BACKGROUND: Obesity is a recognized risk factor for gastroesophageal reflux disease (GERD). Traditional antireflux surgery (fundoplication) may not be appropriate in the morbidly obese, especially when other effective alternatives exist (bariatric surgery). METHODS: A 13-item survey was designed to elicit professional opinions regarding the treatment of medically refractory GERD in obese patients. Members of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) were randomly selected and emailed a link to an online survey. RESULTS: A total of 550 surgeons were contacted via email, and 92 (17 %) completed the survey. Of the respondents, 88 % perform laparoscopic antireflux surgery, 63 % perform bariatric surgery, and 59 % perform both. Overall, 77 % completed a minimally invasive surgery fellowship. In response to the question "Would you perform a laparoscopic fundoplication in a patient with medically refractory GERD and a BMI of 'X'?" surgeons were less likely to offer fundoplication at a higher body mass index (BMI). The majority of respondents felt that laparoscopic Roux-en-Y gastric bypass was the best option (91 %), followed by laparoscopic sleeve gastrectomy (6 %). Many had a morbidly obese patient with a primary surgical indication of GERD denied a bariatric procedure by their insurance company (57 %), and 35 % of those surgeons chose to do nothing rather than subject the patient to a fundoplication. Respondents uniformly felt that bariatric surgery should be recognized as a standard surgical option for treating GERD in the obese (96 %). CONCLUSION: When surgical treatment of GERD is indicated in an obese patient, bariatric surgery is the optimal approach, in the opinion of surgeons responding to our survey. Unfortunately, third-party payers often decline to provide benefits for a bariatric procedure for this indication. Additional data is necessary to confirm our belief that the opinions elicited through this survey are consistent with the standard of care as defined by the medical community.