c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases.

The c-Met proto-oncogene encodes a receptor tyrosine kinase (TK) that promotes invasive tumor growth and metastasis. Recent studies show that the presence of c-Met gene amplification is predictive for selective c-Met TK inhibitors in gastric cancer and lung cancer. In this study, we utilized a highly quantitative PCR/ligase detection reaction technique to quantify c-Met gene copy number in primary colorectal cancer (CRC) (N=247), liver metastases (N=147), and paired normal tissues. We identified no differences in c-Met gene copy number between normal colonic mucosa and liver tissue. However, mean c-Met gene copy number was significantly elevated in CRC compared with normal mucosa (P<0.001), and in liver metastases compared with normal liver (P<0.001). Furthermore, a significant increase in c-Met was seen in liver metastases compared with primary CRC (P<0.0001). c-Met gene amplification was observed in 2% (3/177) of localized cancers, 9% (6/70) of cancers with distant metastases (P<0.02), and 18% (25/147) of liver metastases (P<0.01). Among patients treated by liver resection, there was a trend toward poorer 3-year survival in association with c-Met gene amplification (P=0.07). Slight increases in c-Met copy number can be detected in localized CRCs, but gene amplification is largely restricted to Stage IV primary cancers and liver metastases. c-Met gene amplification is linked to metastatic progression, and is a viable target for a significant subset of advanced CRC.

Esophagography predicts favorable outcomes after laparoscopic Nissen fundoplication for patients with esophageal dysmotility.

BACKGROUND: We undertook this study to determine if clearance of a food bolus at preoperative esophagography predicts acceptable outcomes after laparoscopic Nissen fundoplication for patients with manometrically abnormal esophageal motility. STUDY DESIGN: Patients with gastroesophageal reflux disease (GERD) or symptomatic hiatal hernia with evidence of esophageal dysmotility by stationary manometry underwent videoesophagography to document the ability of their esophagus to clear food boluses of varying consistencies. Sixty-six patients were identified who had manometric dysmotility yet were able to clear a food bolus at esophagography, and subsequently underwent laparoscopic Nissen fundoplication. These patients were compared with 100 randomly selected patients with normal motility who underwent laparoscopic Nissen fundoplication. Symptom reduction and satisfaction were assessed through followup. Patients with normal motility were compared with those with manometrically moderate and severe dysmotility. RESULTS: Preoperative patient demographic data, symptoms, and symptom scores were similar among patients with normal motility and moderate or severe dysmotility. After fundoplication, symptom reduction was notable for all patients regardless of preoperative motility (p < 0.01, paired Student's t-test). There was no notable difference in postoperative symptom scores (p = NS, Kruskal-Wallis ANOVA) or in patient satisfaction (p = NS, chi-square analysis) among patients stratified by esophageal motility. CONCLUSIONS: Patients with esophageal dysmotility documented by manometry who are able to clear a food bolus at contrast esophagography, have functional results after laparoscopic Nissen fundoplication similar to patients with normal motility. Preoperative esophagography predicts successful outcomes after laparoscopic Nissen fundoplication for patients with manometric esophageal dysmotility.

Obesity is not a contraindication to laparoscopic Nissen fundoplication.

Obesity has been shown to be a significant predisposing factor for gastroesophageal reflux disease (GERD). However, obesity is also thought to be a contraindication to antireflux surgery. This study was undertaken to determine if clinical outcomes after laparoscopic Nissen fundoplications are influenced by preoperative body mass index (BMI). From a prospective database of patients undergoing treatment for GERD, 257 consecutive patients undergoing laparoscopic Nissen fundoplication were studied. Patients were stratified by preoperative BMI: normal (<25), overweight (25-30), and obese (>30). Clinical outcomes were scored by patients with a Likert scale. Overweight and obese patients had more severe preoperative reflux, although symptom scores for reflux and dysphagia were similar among all weight categories. There was a trend toward longer operative times for obese patients. Mean follow-up was 26+/-23.9 months. Mean heartburn and dysphagia symptom scores improved for patients of all BMI categories (P<0.001). Postoperative symptom scores and clinical success rates did not differ among BMI categories. Most patients undergoing laparoscopic Nissen fundoplication are overweight or obese with moderate dysphagia and severe acid reflux. Clinical outcomes after laparoscopic Nissen fundoplication did not differ among patients stratified by preoperative BMI. Obesity is not a contraindication to laparoscopic Nissen fundoplication.

Difficulties in diagnosing an intermittent mesenteroaxial gastric volvulus.

Mesenteroaxial volvulus is a form of gastric volvulus that rotates around the short axis of the stomach. Mesenteroaxial volvulus typically presents secondary to an anatomical defect with symptoms that include epigastric pain, retching, dysphagia and early satiety. Our patient presented with episodic abdominal pain, nausea and vomiting for 2 years. Previous imaging was unremarkable but an esophagogastroduodenoscopy done when the patient most recently presented with abdominal pain revealed a mesenteroaxial volvulus. He underwent a laparoscopic gastrostomy-tube gastropexy and has not had any recurrence of his symptoms to date. This case illustrates the difficulties in diagnosing an intermittent volvulus as untimely imaging of a temporarily unfolded volvulus can delay diagnosis and treatment.

HER 2/neu expression and gene amplification in colon cancer.

HER 2/neu is an important oncogene in breast cancer, but the prevalence and significance of HER 2/neu gene amplification in colon cancer have been poorly documented. We have evaluated HER 2/neu gene amplification and protein overexpression in a series of colon cancers to assess the frequency, concordance and clinical significance of these events. HER 2/neu gene copy number was measured in 154 primary colon tumors, 15 liver metastases and matched normal tissues using a quantitative PCR/ligase detection reaction (LDR) technique developed and validated in our laboratory. HER 2/neu copy number was confirmed by fluorescent in situ hybridization (FISH) in all tumors found to have gene amplification. In an independent and blinded fashion, HER 2/neu expression was assessed in paraffin sections from 139 of the tumor specimens using the HercepTest kit. HER 2/neu gene amplification was observed in 4 (2.4%) of the 169 tumor specimens and in none of the normal tissues. There was no apparent association with stage of disease, tumor grade or patient survival. Among 139 cases evaluated by immunohistochemistry (IHC), HER 2/neu overexpression was seen in 5 cases (3.6%). There was extremely high concordance (kappa = 0.852) between gene amplification and protein overexpression. The low prevalence of HER 2/neu gene amplification and protein overexpression suggests that this oncogene plays an infrequent role in the development and progression of colon cancer. These data indicate that the primary mechanism of dysregulated HER 2/neu expression in colon cancer, as in breast cancer, is gene amplification.

Evaluation of preoperative and postoperative radiotherapy on long-term functional results of straight coloanal anastomosis.

PURPOSE: Preoperative radiotherapy for rectal cancer avoids radiation to the reconstructed rectum and may circumvent the detrimental effects on bowel function associated with postoperative radiotherapy. We compared the long-term functional results of patients who received preoperative radiotherapy, postoperative radiotherapy, or no radiotherapy in conjunction with low anterior resection and coloanal anastomosis to assess the impact of pelvic radiation on anorectal function. METHODS: One hundred nine patients treated by low anterior resection and straight coloanal anastomosis for rectal cancer between 1986 and 1997 were assessed with a standardized questionnaire at two to eight years after resection. All radiotherapy was given to a total dose of 4,500 to 5,400 cGy with conventional doses and techniques. Most patients received concurrent 5-fluorouracil-based chemotherapy. RESULTS: There were 39 patients in the preoperative radiotherapy group, 11 patients in the postoperative radiotherapy group, and 59 patients in the no radiotherapy group. The postoperative radiotherapy group reported a significantly greater number of bowel movements per 24-hour period (P < 0.01) and significantly more episodes of clustered bowel movements (P < 0.02) than either the preoperative radiotherapy group or the no radiotherapy group. No significant difference in anal continence or satisfaction with bowel function was found among the three groups. CONCLUSION: In this study of straight (nonreservoir) coloanal anastomoses, postoperative pelvic radiotherapy had significant adverse effects on anorectal function, with higher rates of clustering and frequency of defecation than with preoperative radiotherapy. No differences in continence rates were demonstrated, perhaps because of the sample size of the compared groups. We attribute the adverse effects of postoperative radiotherapy to irradiation of the neorectum, which is spared when treatment is given preoperatively. The deleterious effects of adjuvant radiation on long-term anorectal function can be reduced by preoperative treatment.