Reginald V. Lord

Telomerase reverse transcriptase expression is increased early in the Barrett’s metaplasia, dysplasia, adenocarcinoma sequence

Barrett’s esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus and csophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant diseases. To identify’ biomarkers associated with each stage of the Barrett’s process, relative mRNA expression levels of hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector (TaqMan system) in Barrett’s intestinal metaplasia (n —14), Barrett’s dysplasia (n =10), Barrett’s adenocarcinoma (n = 14), and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barren’s esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Alann-Whitney U test). hTERT expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher in histologically normal squamous esophagus tissues from cancer panents than in normal esophagus tissues from patients vrith no cancer (P = 0.013). Very high expression levels ([hTERT × 100: β-actin] >20) were found only in patients with cancer. These findings suggest that telomerase activation is an important early event in the development of Barrett’s esophagus and esophageal adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma, and that a widespread cancer ‘field’ effect is present in the esophagus of patients with Barrett’s cancer.

Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of β-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low β-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by β-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between β-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of β-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.

Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes.

Type 2 diabetes mellitus (T2D) is predicted by central obesity and circulating adipokines regulating inflammation. We hypothesized that visceral adipose tissue (VAT) in T2D expresses greater levels of proinflammatory molecules. Paired samples of subcutaneous (SAT) and VAT were excised at elective surgery (n = 16, 6 with T2D, n = 8 age‐ and gender‐ matched controls). Metabolic parameters were measured in the fasted state: body composition by dual‐energy X‐ray absorptiometry and insulin action by hyperinsulinemic–euglycemic clamp. Adipose tissue mRNA gene expression was measured by quantitative reverse transcriptase‐PCR. Subjects with T2D had higher VAT expression of molecules regulating inflammation (tumor necrosis factor‐α (TNFα), macrophage inflammatory protein (MIP), interleukin‐8 (IL‐8)). Fasting glucose related to VAT expression of TNFα, MIP, serum amyloid A (SAA), IL‐1α, IL‐1β, IL‐8, and IL‐8 receptor. Abdominal fat mass was related to VAT expression of MIP, SAA, cAMP response element–binding protein (CREBP), IL‐1β, and IL‐8. Insulin action related inversely to VAT complement C3 expression only. There were depot‐specific differences in expression of serum T2D predictors: VAT expressed higher levels of complement C3; SAT expressed higher levels of retinol‐binding protein‐4 (RBP4), adiponectin, and leptin. In summary, VAT in T2D expresses higher levels of adipokines involved in inflammation. VAT expression of these molecules is related to fasting glucose and insulin action. Increased production of these proinflammatory molecules by VAT may explain the links observed between visceral obesity, insulin resistance, and diabetes risk.

Absence of Gastroesophageal Reflux Disease in a Majority of Patients Taking Acid Suppression Medications After Nissen Fundoplication

Recent studies have shown that many patients use acid suppression medications after antireflux surgery. The aim of this study was to determine the frequency of gastroesophageal reflux disease in a cohort of surgically treated patients with postoperative symptoms and a high prevalence of acid suppression medication use. The study group consisted of 86 patients who had symptoms following Nissen fundoplication that were sufficient to merit evaluation with 24-hour distal esophageal pH monitoring. All completed a detailed symptom questionnaire. The mean postoperative follow-up period was 28 months (median 18 months). Thirty-seven patients (43%) were taking acid suppression medications after fundoplication. Only 23% (20 of 86) of all the patients and only 24% (9 of 37) of those taking acid suppression medications had abnormal esophageal acid exposure on the 24-hour pH study. Heartburn and regurgitation were the only symptoms that were significantly associated with an abnormal pH study. Endoscopic assessment of the fundoplication was the most significant factor associated with an abnormal pH study. Multivariable logistic regression analysis showed that patients with a disrupted, abnormally positioned fundoplication had a 52.6 times increased risk of abnormal esophageal acid exposure. Most patients who use acid suppression medications after antireflux surgery do not have abnormal esophageal acid exposure, and the use of these medications is thus often inappropriate. Because of the limited predictive power of symptoms, objective evidence of reflux disease should be obtained before prescribing acid suppression medication for patients who have undergone antireflux surgery.

The Duodenal Switch Operation for the Treatment of Morbid Obesity

Objective: To determine the safety and efficacy of the duodenal switch procedure as surgical treatment of morbid obesity. Summary Background Data: The longitudinal gastrectomy and duodenal switch procedure as performed for morbid obesity involves a 75% subtotal greater curvature gastrectomy and long limb suprapapillary Roux-en-Y duodenoenterostomy. This results in a restricted caloric intake and diversion of bile and pancreatic secretions to induce fat malabsorption. Broad acceptance of this procedure has been impeded because of concerns that the malabsorptive component may produce serious nutritional complications. Methods: Review of data collected prospectively from all patients who underwent duodenal switch as the primary surgical treatment of morbid obesity at a single institution during the 10-year period beginning September 1992. Operative morbidity and mortality, weight loss, volume of food intake, and bowel function were recorded. Sequential measurements of serum albumin, hemoglobin, and calcium levels were obtained to assess metabolic function and nutrient absorption. Results: Duodenal switch was performed as the primary operation in 701 (81%) of a total 863 patients undergoing bariatric surgery during the period of study. The average body mass index (BMI) was 52.8 (range, 34–95). Perioperative mortality was 1.4%, and morbidity (including leaks, wound dehiscence, splenectomy, and postoperative hemorrhage) occurred in 21 patients (2.9%). Weight loss averaged 127 pounds at 1 year, 131 at 3 years, and 118 at 5 or more years (% EBWL of 69%, 73%, and 66%, respectively). The mean number of bowel movements was fewer than 3 per day. Patients reported and maintained a mean restriction of 63% of their preoperative intake (approximately 1600 calories), with no specific food intolerance, at 3 or more years follow-up. At 3 years, serum albumin remained at normal levels in 98% of patients, hemoglobin in 52%, and calcium in 71%. No patients reported dumping, and marginal ulcers were not seen. Conclusions: The longitudinal gastrectomy with duodenal switch is a safe and effective primary procedure for the treatment of morbid obesity. It has the advantage of allowing acceptable alimentation with a minimum of side effects while producing and maintaining significant weight loss. These results are achieved without developing significant dietary restrictions or clinical metabolic or nutritional complications.

Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival

Methylation of 5′ CpG islands in promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of this study was to determine whether hypermethylation of the adenomatous polyposis coli (APC) gene promoter occurs in primary non-small cell lung cancer (NSCLC), and whether hypermethylated APC has any relationship with survival. APC promoter 1A methylation was determined in normal and corresponding tumor tissue from 91 NSCLC patients and in a control group of 10 patients without cancer, using a quantitative fluorogenic real-time PCR (Taqman®) system. APC promoter methylation was detectable in 86 (95%) of 91 tumor samples, but also in 80 (88%) of 91 normal samples of NSCLC patients, and in only two (20%) of 10 normal lung tissues of the control group. The median level of APC promoter methylation was 4.75 in tumor compared to 1.57 in normal lung tissue (P<0.001). Patients with low methylation status showed significantly longer survival than did patients with high methylation status (P=0.041). In a multivariate analysis of prognostic factors, APC methylation was a significant independent prognostic factor (P=0.044), as were pT (P=0.050) and pN (P<0.001) classifications. This investigation shows that APC gene promoter methylation occurs in the majority of primary NSCLCs. High APC promoter methylation is significantly associated with inferior survival, showing promise as a biomarker of biologically aggressive disease in NSCLC.

Physiologic Basis for the Treatment of Epiphrenic Diverticulum

ObjectiveTo quantitate and characterize the motility abnormalities present in patients with epiphrenic diverticula and to assess the outcome of surgical treatment undertaken according to these abnormalities. Summary Background DataThe concept that epiphrenic diverticula are complications of esophageal motility disorders rather than primary anatomic abnormalities is gradually becoming accepted. The inconsistency in identifying motility abnormalities in patients with epiphrenic diverticula is a major obstacle to the general acceptance of this concept. MethodsThe study population consisted of 21 consecutive patients with epiphrenic diverticula. All patients underwent videoesophagography, upper gastrointestinal endoscopy, and esophageal motility studies. The diverticula ranged in size from 3 to 10 cm and were predominantly right-sided. Seventeen patients underwent transthoracic diverticulectomy or diverticulopexy with esophageal myotomy and an antireflux procedure. The length of the myotomy was determined by the extent of the motility abnormality. Transhiatal esophagectomy was performed in one patient with multiple diverticula. Two patients declined surgical treatment and another patient died of aspiration before surgery. Symptomatic outcome was assessed via a questionnaire at a median of 24 months after surgery. ResultsThe primary symptoms were dysphagia in 5 (24%) patients, dysphagia and regurgitation in 11 (52%) patients, and pulmonary symptoms in 5 (24%) patients. The median duration of the primary symptoms was 10 years. Esophageal motility abnormalities were identified in all patients. An esophageal motor disorder was diagnosed only by 24-hour ambulatory motility testing in one patient, and 24-hour ambulatory motility testing clarified the motility diagnosis in five other patients. The most common underlying disorder was achalasia, which was detected in nine (43%) patients. A hypertensive lower esophageal sphincter was diagnosed in three patients, diffuse esophageal spasm in five, “nutcracker” esophagus in two, and a nonspecific motor disorder in two patients. One patient had an intraoperative myocardial infarction and died. Two patients had persistent mild dysphagia after surgery. The remaining patients had complete relief of their primary symptoms. ConclusionsThere is a high prevalence of named motility disorders in patients with epiphrenic diverticula, and this condition is associated with the potential for lethal aspiration. Twenty-four-hour ambulatory motility testing can be helpful if the results of the stationary examination are normal or indefinite. Resection of the diverticula and a surgical myotomy of the manometrically defined abnormal segment results in relief of symptoms and protection from aspiration.

DNA repair and cisplatin resistance in non-small-cell lung cancer

The results of cisplatin-based chemotherapy seem to have reached a plateau, and empirical approaches are targeting the inclusion of novel biological agents with different mechanisms of action, but their clinical benefit is still unknown. In preparing this review of cisplatin resistance, we posed two questions: Who are we writing for and why? We believe that medical oncologists should be involved in the reality of the growing list of genetic mechanisms of cancer and chemoresistance. Only by becoming familiar with these mechanisms will we be able to circumvent them. In this review, we provide some insight into DNA repair defects involved in non-small-cell lung cancer (NSCLC) and cisplatin effect. Some DNA repair genes, like ERCC1, have been shown to be crucial in predicting cisplatin resistance and can be used for tailoring cisplatin-based chemotherapy.

Risk factors and the prevalence of trocar site herniation after laparoscopic fundoplication

Background: Although there have been case reports describing trocar site herniation after laparoscopic fundoplication, its overall prevalence and the risk factors for its development are unclear. Methods: The records of 320 patients undergoing primary laparoscopic fundoplication as treatment for gastroesophageal reflex disease (GERD) or hiatal hernia between 1991 and 1999 were reviewed retrospectively. Placement of the initial supraumbilical trocar was by the open Hassan technique in all patients. Results: Nine patients (five male) with a mean age 54 years (range, 37-75) developed trocar site herniation, for an overall prevalence of 3%. The mean interval between surgery and diagnosis was 12 months (range, 4-21). In all patients, the hernia occurred at the supraumbilical camera port site. Patients with trocar hernias tended to have a higher body mass index (BMI) than those without hernias (mean BMI, 29.4 kg/m2 vs 27.2 kg/m2, p = 0.13). None of the patients developed intestinal obstruction as a consequence of herniation. To date, all but one of the hernias have been repaired. Six of them required the insertion of a prosthetic mesh. Conclusions: The prevalence of trocar site herniation after laparoscopic fundoplication was minimal at 3%. All hernias occurred at the midline supraumbilical port, the only site where open trocar insertion was employed. As a consequence of these observations, we have developed a new method of open trocar placement. This method utilizes a paramedian skin incision and separate fascial incisions through anterior and posterior rectus sheathes, with retraction of the rectus abdominis muscle laterally.

Prognostic significance of cyclooxygenase 2 mRNA expression in non-small cell lung cancer.

ObjectiveTo investigate cyclooxygenase-2 (COX-2) mRNA expression in curatively resected non-small cell lung cancer (NSCLC) and to determine its association with prognosis. Summary Background DataLung cancer is one of the most common malignancies in the world. Despite improvements in the diagnosis and treatment of NSCLC, the 5-year survival rate remains less than 15%. Identification of prognostic predictors based on molecular alterations could lead to additional diagnostic tools and eventually to more effective therapeutic options. Overexpression of COX-2 has been reported in several human malignancies, including lung cancer, but the prognostic importance of this overexpression has not been elucidated. MethodsCOX-2 mRNA expression was analyzed using a quantitative real-time polymerase chain reaction (Taqman) method in surgically resected tumor specimens from 89 patients with curatively resected NSCLC. ResultsCOX-2 mRNA was detectable in all 89 (100%) tumor tissues. High COX-2 expression in tumors was significantly associated with inferior survival. Multivariate analysis showed that high COX-2 expression is an independent predictor of worse survival in patients with NSCLC. ConclusionsHigh COX-2 mRNA expression is an important biomarker for biologically aggressive disease in NSCLC and might be helpful in identifying patients who would benefit from additional therapies for controlling their disease.