John W. Harmon

Hospital Volume Can Serve as a Surrogate for Surgeon Volume for Achieving Excellent Outcomes in Colorectal Resection

OBJECTIVE To examine the association of surgeon and hospital case volumes with the short-term outcomes of in-hospital death, total hospital charges, and length of stay for resection of colorectal carcinoma. METHODS The study design was a cross-sectional analysis of all adult patients who underwent resection for colorectal cancer using Maryland state discharge data from 1992 to 1996. Cases were divided into three groups based on annual surgeon case volume--low (< or =5), medium (5 to 10), and high (>10)--and hospital volume--low (<40), medium (40 to 70), and high (> or =70). Poisson and multiple linear regression analyses were used to identify differences in outcomes among volume groups while adjusting for variations in type of resections performed, cancer stage, patient comorbidities, urgency of admission, and patient demographic variables. RESULTS During the 5-year period, 9739 resections were performed by 812 surgeons at 50 hospitals. The majority of surgeons (81%) and hospitals (58%) were in the low-volume group. The low-volume surgeons operated on 3461 of the 9739 total patients (36%) at an average rate of 1.8 cases per year. Higher surgeon volume was associated with significant improvement in all three outcomes (in-hospital death, length of stay, and cost). Medium-volume surgeons achieved results equivalent to high-volume surgeons when they operated in high- or medium-volume hospitals. CONCLUSIONS A skewed distribution of case volumes by surgeon was found in this study of patients who underwent resection for large bowel cancer in Maryland. The majority of these surgeons performed very few operations for colorectal cancer per year, whereas a minority performed >10 cases per year. Medium-volume surgeons achieved excellent outcomes similar to high-volume surgeons when operating in medium-volume or high-volume hospitals, but not in low-volume hospitals. The results of low-volume surgeons improved with increasing hospital volume but never equaled those of the high-volume surgeons.

Prospective Study of Gastrinoma Localization and Resection in Patients with Zollinger-ellison Syndrome

In 1982, a prospective study was initiated of 52 consecutive patients with proven Zollinger-Ellison syndrome (ZES), involving surgical exploration with the goal of removing the gastrinoma after an extensive protocol to localize the tumor. Each patient underwent ultrasound, computed tomography (CT) with oral/ intravenous (IV) contrast, and selective arteriography. Eighteen patients had metastatic disease identified by imaging studies and confirmed by percutaneous biopsies, and two patients had multiple endocrine neoplasia type I (MEN-I) with negative imaging studies; therefore, these 20 patients did not undergo laparotomy. Each of the remaining 32 patients (3 with MEN-I and positive imaging studies) underwent laparotomy, and gastrinomas were removed in 20 patients. Preoperative ultrasound localized tumors in 20% of patients, CT in 40%, arteriography in 60%, and any of the modalities in 70% of patients. Infusion CT and arteriography were 100% specific. In 18 patients with either negative imaging (17) or false-positive imaging (1 ultrasound), gastrinomas were found and removed in six patients (33%). Twenty-four gastrinomas were found in 20 patients at laparotomy: eight in lymph nodes around the pancreatic head, four in the pancreatic head, one in the pancreatic body, three in the pancreatic tail, three in the pyloric channel, one in the duodenal wall, two in the jejunum at the ligament of Treitz, one in the ovary, and multiple liver metastases in one patient. If one excludes patients with MEN-I or liver metastatic disease, 12/28 (43%) of patients were biochemically “cured” immediately after operation. This result decreased to 7/23 (30%) with greater than 6 months follow-up. No patients with gastrinomas resected have developed recurrent gastrinoma on follow-up imaging studies (longest follow-up: 4 years). This study indicates that 95% of metastatic gastrinoma can be diagnosed before operation and that, by a combination of careful imaging studies and thorough exploration at surgery, 30% of patients with gastrinomas may be curable.

Effects of acid and bile salts on the rabbit esophageal mucosa

We used the rabbit esophagus as a model to study clinically significant variables which may be important in the pathophysiology of reflux esophagitis in man.* Increased permeability to hydrogen ion, as indicated by a net acid flux (NAF) out of the lumen, was our index of injury. NAF was measured with an in-line pH stat autoburette in rabbits lightly anesthetized with Innovar. We found minimal NAF at pH 5 and 2, but NAF was 70±11 μEq/10 min at pH 1. At pH 2, the addition of bile salts resulted in the appearance of a significant increase in NAF. When we varied the concentration of bile salts from 0 to 5 mM, we found that NAF (μEq/10 min) varied directly and significantly with the bile salt concentration (B, mM) according to this relationship: NAF=12.7 (B)−0.8 (r=0.96,P<0.01). When we varied the duration of time (t, min) for which the mucosa was exposed to bile salts, we found NAF varied directly and significantly with time from 1 to 60 min according to the following relationship: NAF=1.25t+10.8 (r=0.93,P<0.05). In other experiments, we demonstrated that the taurine-conjugated bile salts taurodeoxycholate and taurocholate increased NAF at pH 2, while the unconjugated forms did not. The unconjugated forms did increase NAF at pH 7. This difference is attributable to the lower pKa of the taurine-conjugated bile salts. Deoxycholate increased NAF more than cholate. In none of our experiments did we see evidence that the esophageal mucosa could recover from bile salt-induced injury.We used the rabbit esophagus as a model to study clinically significant variables which may be important in the pathophysiology of reflux esophagitis in man.* Increased permeability to hydrogen ion, as indicated by a net acid flux (NAF) out of the lumen, was our index of injury. NAF was measured with an in-line pH stat autoburette in rabbits lightly anesthetized with Innovar. We found minimal NAF at pH 5 and 2, but NAF was 70±11 μEq/10 min at pH 1. At pH 2, the addition of bile salts resulted in the appearance of a significant increase in NAF. When we varied the concentration of bile salts from 0 to 5 mM, we found that NAF (μEq/10 min) varied directly and significantly with the bile salt concentration (B, mM) according to this relationship: NAF=12.7 (B)−0.8 (r=0.96,P<0.01). When we varied the duration of time (t, min) for which the mucosa was exposed to bile salts, we found NAF varied directly and significantly with time from 1 to 60 min according to the following relationship: NAF=1.25t+10.8 (r=0.93,P<0.05). In other experiments, we demonstrated that the taurine-conjugated bile salts taurodeoxycholate and taurocholate increased NAF at pH 2, while the unconjugated forms did not. The unconjugated forms did increase NAF at pH 7. This difference is attributable to the lower pKa of the taurine-conjugated bile salts. Deoxycholate increased NAF more than cholate. In none of our experiments did we see evidence that the esophageal mucosa could recover from bile salt-induced injury.

Aberrant Epithelial–Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia

BACKGROUND & AIMS The molecular mechanism underlying epithelial metaplasia in Barretts esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barretts esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. METHODS Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. RESULTS Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barretts epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barretts epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barretts epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins. CONCLUSIONS Epithelial Hedgehog ligand expression may contribute to the initiation of Barretts esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

The role of magnetic resonance cholangiography in the management of patients with Gallstone pancreatitis

Objective:To examine the utility of magnetic resonance cholangiography (MRC) in the preoperative evaluation of patients with gallstone pancreatitis. Summary Background Data:Gallstone pancreatitis is often associated with the presence of common bile duct (CBD) stones that may require endoscopic removal prior to planned laparoscopic cholecystectomy. No reliable clinical criteria exist, however, that can accurately predict CBD stones and the need for preoperative endoscopic retrograde cholangiopancreatography (ERCP). Methods:Sixty-four patients were identified with gallstone pancreatitis based on clinical presentation and imaging studies over a three-and-a-half-year period. All patients underwent MRC, and the images were evaluated for gallstones, CBD stones, cholecystitis, and pancreatitis Results:Seventeen of the 64 patients (27%) with gallstone pancreatitis were found to have CBD stones confirmed by ERCP. MRC correctly predicted CBD stones in 16 of the 17 patients (sensitivity = 94%). In 1 additional patient, MRC demonstrated CBD stones not seen at ERCP, consistent with probable passage. By comparison, the sensitivities of other criteria for predicting CBD stones were (1) elevated bilirubin ≥2.0 mg/dL = 65%; (2) dilated duct on ultrasound = 55%; and (3) CBD stones on ultrasound = 27%. MRC was able to visualize gallbladder stones in 57 of 62 patients (94%) and correctly predicted acute cholecystitis in 6 of 8 patients. MRC also detected peripancreatic edema and inflammatory changes consistent with acute pancreatitis in 45 of 64 patients (70%). Conclusions:These results demonstrate that MRC can accurately identify CBD stones preoperatively in patients with gallstone pancreatitis and provide valuable information with respect to other biliary pathology, including cholelithiasis, acute cholecystitis, and pancreatitis. MRC is an effective noninvasive screening tool for CBD stones, appropriately selecting candidates for preoperative ERCP and sparing others the need for an endoscopic procedure with its associated complications.

Experimental esophagitis in a rabbit model: Clinical relevance

Esophagitis occurs in patients with excessive acid and/or alkaline gastroesophageal reflux. This observation prompted us to develop a continuously perfused in vivo rabbit esophageal model to examine the potential for different endogenous injurious agents to cause H+ back diffusion and morphologic evidence of esophagitis. We found that HCl at physiologic pH values did not break the mucosal barrier to H+ back diffusion or cause esophagitis. Bile salts at physiologic concentrations in both an acid or alkaline perfusate broke the mucosal barrier and caused H+ back diffusion, but failed to cause a morphologic injury consistent with clinical reflux esophagitis. Instead, proteolytic enzymes, such as pepsin in an acid environment and trypsin in an alkaline environment, caused a severe hemorrhagic erosive esophagitis consistent with that seen clinically. We feel new therapeutic strategies for the treatment of reflux esophagitis should be directed at proteolytic enzymes rather than only HCl or bile salts. Finally, we showed sucralfate to be a mucosal protectant against the acid-pepsin injury.

Hypermethylation of the GATA gene family in esophageal cancer.

The GATA family of transcription factors promotes the normal development of the gastrointestinal tract during embryogenesis and determines tissue differentiation in adult gut epithelium. Loss of GATA‐4 and GATA‐5 has been reported in human gastric and colon cancer. We examined GATA‐4,‐5 and ‐6 gene expression in established esophageal squamous cancer cell lines and the relationship to DNA methylation in the promoter region of these genes. GATA‐4 and GATA‐5 expression was absent in most esophageal cancer cell lines, but was restored upon treatment with the demethylating agent 5‐aza‐2′‐deoxycytidine. For each of the cell lines without detectable GATA gene expression, aberrant methylation of the promoter region CpG‐island was detected by methylation specific PCR. We confirmed these results with genomic bisulfite sequencing. GATA‐6 expression was found in each of the cell lines. GATA‐4/‐5 promoter methylation was not detected in normal esophageal mucosa, but GATA‐4 methylation was present in 27 of 44 (61%) squamous carcinomas and 31 of 44 (71%) adenocarcinoma of the esophagus, while GATA‐5 methylation was present in 14 of 44 (32%) squamous carcinomas and 24 of 44 (55%) adenocarcinoma of the esophagus. Our studies demonstrate frequent silencing of GATA‐4 and GATA‐5, but not GATA‐6, in human esophageal neoplasia associated with gene promoter hypermethylation.

Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF-β signaling

Chronic systemic hypertension causes cardiac pressure overload leading to increased myocardial O2 consumption. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of O2 homeostasis. Mouse embryos lacking expression of the O2-regulated HIF-1α subunit die at midgestation with severe cardiac malformations and vascular regression. Here we report that Hif1af/f;Tie2-Cre conditional knockout mice, which lack HIF-1α expression only in Tie2+ lineage cells, develop normally, but when subjected to pressure overload induced by transaortic constriction (TAC), they manifest rapid cardiac decompensation, which is accompanied by excess cardiac fibrosis and myocardial hypertrophy, decreased myocardial capillary density, increased myocardial hypoxia and apoptosis, and increased TGF-β signaling through both canonical and noncanonical pathways that activate SMAD2/3 and ERK1/2, respectively, within endothelial cells of cardiac blood vessels. TAC also induces dilatation of the proximal aorta through enhanced TGF-β signaling in Hif1af/f;Tie2-Cre mice. Inhibition of TGF-β signaling by treatment with neutralizing antibody or pharmacologic inhibition of MEK–ERK signaling prevented TAC-induced contractile dysfunction and pathological remodeling. Thus, HIF-1 plays a critical protective role in the adaptation of the heart and aorta to pressure overload by negatively regulating TGF-β signaling in endothelial cells. Treatment of wild-type mice with digoxin, which inhibits HIF-1α synthesis, resulted in rapid cardiac failure after TAC. Although digoxin has been used for decades as an inotropic agent to treat heart failure, it does not improve survival, suggesting that the countertherapeutic effects of digoxin observed in the TAC mouse model may have clinical relevance.

Bile acid accumulation by rabbit esophageal mucosa

Bile acids are one of the noxious components of the gastroduodenal contents which may injure the esophageal mucosa in clinical reflux esophagitis. Animal models of esophagitis have shown that exposure to low luminal bile acid concentrations can cause increased mucosal permeability to a variety of ions and molecules without causing dramatic gross morphologic damage. In order to explore the mechanism by which bile acids alter mucosal permeability, we measured the esophageal mucosal concentration of taurocholic acid and chenodeoxycholic acid after exposure to these bile acids in anesthetized New Zealand white rabbits. We found that bile acids can accumulate in the esophageal mucosa to levels as high as seven times the initial luminal concentration. Thin-layer chromatography showed that this accumulation was not due to bile acid degradation in the mucosa. Since butyric acid also showed some mucosal accumulation, and is a weak acid like taurocholic acid, intracellular ionization may account for some of the accumulation. Mucosal accumulation of these molecules is not a nonspecific phenomenon, since the four-carbon polyol erythritol did not accumulate at all. Bile acid accumulation occurred under the same conditions and in a parallel temporal relationship to the bile-induced permeability changes. It is hypothesized, therefore, that the presence of high concentrations of bile acids in the esophageal mucosa may be pathophysiologically related to the alterations in mucosal permeability which occur after exposure to bile acids.

Somatostatin analogue treatment inhibits post-resectional adaptation of the small bowel in rats

Post-resectional hyperplasia is the phenomenon in which residual small bowel increases in size and absorptive capacity after segmental enterectomy. This experiment studied the effect of somatostatin analogue therapy on the development of two structural parameters of post-resectional hyperplasia in rats subjected to 40% proximal small bowel resection. Octreotide acetate-treated rats failed to develop increased villus height (902 +/- 50 microns) relative to saline-treated rats (1,103 +/- 98 microns). Augmentation of residual intestinal weight was also significantly impaired in analogue-treated rats (92 +/- 3 versus 118 +/- 5 mg/cm). We conclude that somatostatin analogue treatment during the early postoperative period does impair the growth of residual bowel in rats. These findings raise concern regarding the use of this drug for postoperative patients who have undergone massive small bowel resection in whom the process of post-resectional adaptation may be critical to allow sustenance with enteral nutrition.