Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Mucosal prolapse in the pathogenesis of Peutz-Jeghers polyposis.

Germline mutations in LKB1 cause the rare cancer prone disorder Peutz-Jeghers syndrome (PJS). Gastrointestinal hamartomatous polyps constitute the major phenotypic trait in PJS. Hamartomatous polyps arising in PJS patients are generally considered to lack premalignant potential although rare neoplastic changes in these polyps and an increased gastrointestinal cancer risk in PJS are well documented. These conflicting observations are resolved in the current hypothesis by providing a unifying explanation for these contrasting features of PJS polyposis. We postulate that a genetic predisposition to epithelial prolapse underlies the formation of the polyps associated with PJS. Conventional sporadic adenomas arising in PJS patients will similarly show mucosal prolapse and carry the associated histological features.

Gastropharyngeal and gastroesophageal reflux in globus and hoarseness.

BACKGROUND: The role of gastropharyngeal reflux in patients with globus pharyngeus and hoarseness remains unclear. OBJECTIVE: To evaluate patients with complaints of globus, hoarseness, or globus and hoarseness combined for the presence of gastropharyngeal and gastroesophageal reflux. DESIGN: Prospective clinical cohort study of 3 groups of patients undergoing ambulatory 24-hour double-probe pH monitoring. In patients with pathologic gastroesophageal reflux, an upper gastrointestinal endoscopy was also performed. SETTING: Tertiary care, outpatient clinic. PATIENTS: Twenty-seven patients with globus alone, 20 patients with hoarseness alone, and 25 patients with globus and hoarseness combined. RESULTS: Patients with well-defined pathologic reflux (ie, gastroesophageal reflux with or without gastropharyngeal reflux) were present mainly in the group of patients with globus combined with hoarseness: 18 (72%) of 25 patients, compared with 7 (35%) of 20 patients with hoarseness alone and 8 (30%) of 27 with globus alone. Seven (10%) of all 72 patients had prolonged acid exposure at the laryngopharyngeal junction in the presence of a normal gastroesophageal pH registration. Abnormal findings in the esophagus were found at endoscopy in 17 (65%) of 26 patients with pathologic gastroesophageal reflux (with or without gastropharyngeal reflux). CONCLUSIONS: We found a high prevalence of pathologic reflux in patients with both globus and hoarseness. Based on these findings, we strongly advise upper gastrointestinal endoscopy for symptomatic otolaryngological patients with pathologic gastroesophageal reflux.

High incidence of laryngopharyngeal reflux in patients with head and neck cancer.

OBJECTIVES: Laryngopharyngeal reflux may play a role in the etiology of squamous cell cancer of the head and neck and contribute to complications in head and neck cancer patients after surgery or during radiotherapy. STUDY DESIGN: Prospective study. METHODS: To investigate the incidence of laryngopharyngeal and gastroesophageal reflux in patients with head and neck cancer, ambulatory 24-hour double-probe pH monitoring was performed in 24 untreated patients with laryngeal or pharyngeal squamous cell carcinoma. In addition, 10 patients who had been irradiated in the head and neck area were analyzed for reflux to study the effect of radiotherapy on reflux. RESULTS: Only 4 of the 24 head and neck cancer patients (17%) had neither pathological laryngopharyngeal nor gastroesophageal reflux. Esophageal acid exposure was abnormal in five patients and acid exposure at the level of the upper esophageal sphincter was abnormal in four patients. Eleven patients had pathological reflux in both areas. Irradiated patients did not differ from the untreated patients considering the incidence of pathological laryngopharyngeal or gastroesophageal reflux. CONCLUSIONS: The data obtained in this study indicate that reflux is a common event in head and neck cancer patients.

Bacterial contamination of ready-to-use 1-L feeding bottles and administration sets in severely compromised intensive care patients.

OBJECTIVE: In intensive care patients, enteral feeding requires sterile feedings because of infectious complications and adequate supplements to meet nutritional needs. Heretofore, prepacked, large-volume formula containers were developed, but bacterial contamination occurred in 4% to 15%. Our objective was to investigate the microbial contamination rate of 1-L feeding bottles and newly designed administration sets over hanging times of 24 hrs in the intensive care unit (ICU). DESIGN AND SETTING: A prospective observational cohort study of patients admitted to the ICU of a university hospital. PATIENTS: All consecutive patients fed via a nasojejunal tube for at least 4 days. MEASUREMENTS: Cultures of feeding bottles, administration sets, and gastric and tracheobronchial aspirates at day 0, 1, 2, 4, and 7. RESULTS: A total of 4% of feeding bottles and 74% of infusion sets contained >10(2) colony forming units (CFU)/mL. Gastric and bronchial aspirates were positive in 90% and 92%, respectively. Bacterial counts of feeding bottles were 10(2)-10(5) CFU/mL, and the main bacteria isolated included Enterobacter cloacae, Klebsiella oxytoca, and enterococci. One third of all cultured bacteria in feeding bottles, administration sets, stomach, and lungs belonged to the Enterobacteriaceae family, which was held responsible for the nosocomial infections in the ICU. None of the 1-L feeding bottles with a hanging time of 19-24 hrs was contaminated. Only bottles that had to be exchanged because of need for a faster rate of infusion proved to be contaminated, apparently without clinical consequences. With time and the increasing severity of disease, the administration sets became contaminated at an increasingly faster rate and with higher bacterial counts mainly through retrograde growth of endogenous bacteria. The final step of bottle contamination might have been the bacterial transfer by nurses' hands. CONCLUSION: Despite an almost ideal design of the enteral nutrition delivery system, a 4% contamination rate of initially sterile feedings with clinically relevant bacteria and the fact that only manipulated systems showed bacterial growth are of concern.

Percutaneous endoscopic gastrostomy and gastrojejunostomy: a critical reappraisal of patient selection, tube function and the feasibility of nutritional support during extended follow-up.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a generally accepted procedure, but the appropriateness of patient selection and the justification of jejunal feeding have not been systematically investigated. Also, a critical appraisal of the applicability and tolerance of nutritional support in the immediate postinsertion period and during prolonged outpatient care is lacking. METHODS: Prospectively collected data in adult and pediatric patients during a period of 7 years were analyzed. Follow-up data were available at days 1, 7 and 28 and thereafter every 6 to 12 weeks until gastrostomy removal, death or the conclusion of the study. RESULTS: A PEG was successfully positioned in 268 of the 286 referred patients (94%). A jejunal tube through the PEG (JETPEG) was placed beyond the duodenojejunal ligament in 38 patients. Procedure-related mortality was 1%, 30-day outpatient mortality 6.7%. Total follow-up was 295 patient-years with an overall mortality of 53% (PEG 53%; JETPEG 50%). Both major (8.4%) and minor (24.0%) procedure-related complications in the first 28 days consisted merely of (infectious) wound problems. In prolonged follow-up, the complications were more tube-related. The durability of the tube in surviving patients with a PEG or JETPEG in situ was a median of 495 days (range 162 to 1732 days). Tube dysfunction because of clogging, porosity and fracture occurred after a median of 347 days (range 9 to 1123 days). Nausea, vomiting, bloating and dumping interfered with feeding during the first week and during extended follow-up. Intrajejunal feeding was associated with dumping and diarrhea. In retrospect, the anticipated need of 4 weeks of enteral nutrition was not met in 9.0%. The extension of a PEG into a JETPEG was thought inappropriate in 23.7%. In the remainder, a 91% reduction in aspiration justified its use. The tube life span was equal to or greater than that of a PEG, despite tube dysfunction in 26.8%. CONCLUSIONS: Proper selection of patients for a PEG, i.e., those with an anticipated need of greater than 4 weeks of enteral nutrition, is a challenge. Notwithstanding an increased rate of tube dysfunction, well-selected patients may benefit from a JETPEG. Follow-up is mandatory because many patients might have become malnourished or underfed while on tube feeding, mainly because of GI intolerance.

Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations.

BACKGROUND: Food in the intestine drives the enterohepatic circulation of bile components. OBJECTIVE: We investigated whether parenteral or enteral delivery of nutrients alters serum and biliary lipids in critically ill patients. DESIGN: Eight intensive care unit (ICU) patients who had received >/= 5 d of total parenteral nutrition (TPN) were compared with 8 ICU patients who had fasted for >/=5 d. Both groups were studied before and after 5 d of enteral nutrition (EN). Each patient served as his or her own control. Duodenal bile was analyzed for biliary lipid content and serum lipids were determined simultaneously. Duodenal bile samples from 18 healthy persons served as controls. RESULTS: Bile salt concentrations in all ICU patients were 17% of control values before EN (P < 0.005) and 34% of control values after 5 d of EN (P < 0.005). Phospholipid concentrations were 12% of control before EN (P < 0. 0005) but increased almost 4-fold after EN (P < 0.0005). Biliary cholesterol concentrations were 20% of control values before EN (P < 0.001) and did not improve afterward. No difference in bile composition was observed between fasted ICU patients and those who received TPN. The inverse correlation between the severity of illness and biliary lipid concentrations observed before EN disappeared with enteric stimulation. The low serum concentrations of HDL cholesterol and apolipoprotein A-I increased significantly with EN in all ICU patients. CONCLUSION: Lack of EN during critical illness was associated with profound decrements in biliary lipid concentrations that normalized partially after 5 d of EN. We hypothesize that loss of enteric stimulation in ICU patients impairs hepatic lipid metabolism.

Open versus laparoscopic adjustable silicone gastric banding: a prospective randomized trial for treatment of morbid obesity.

OBJECTIVE: To perform the first prospective trial of laparoscopic versus open adjustable silicone gastric banding (ASGB) in patients with morbid obesity. SUMMARY BACKGROUND DATA: Vertical banded gastroplasty has been used for many years to treat morbid obesity, but the size of the stoma has remained a source of failure after the procedure. ASGB has the advantages of maintaining gastric integrity and the potential for readjustment of the band, if needed. It has been suggested that laparoscopic ASGB, recently introduced to reduce postoperative complications and hospital stay, has a negative impact on outcome. METHODS: Fifty patients with morbid obesity of >5 years' duration and a body-mass index (BMI) > 40 kg/m2 were randomized to undergo laparoscopic or open ASGB. The difficulty of the procedure, surgical time, postoperative complications, and hospital stay were assessed. Stoma adjustments, long-term complications, readmissions, weight loss, and BMI were determined. RESULTS: All procedures were successfully carried out. Of 25 patients assigned to laparoscopic ASGB, 2 were converted to an open procedure. Surgical time was significantly longer for laparoscopic ASGB (150 minutes vs. 76 minutes for open ASGB). There was no difference in complications. Mean hospital stay was 5.9 days for the laparoscopic procedure versus 7.2 days for open ASGB (p < 0.05). The total number of readmissions (6 vs. 15) and overall hospital stay in the first year (7.8 vs. 11.8 days) were lower after laparoscopic ASGB (p < 0.05). Weight and BMI were reduced significantly in both groups, but there was no difference between the groups. CONCLUSION: Laparoscopic and open ASGB were equally effective in terms of early (first-year) weight loss, reduction of BMI, and postoperative complications. The laparoscopic procedure was associated with a shorter initial hospital stay and fewer readmissions during follow-up and is therefore the preferred treatment in morbidly obese patients undergoing ASGB.

High incidence of gastropharyngeal and gastroesophageal reflux after total laryngectomy.

BACKGROUND: Gastroesophageal reflux (GER) appears to be related to laryngeal carcinoma. Little is known about GER and gastropharyngeal reflux (GPR) in the laryngectomized patient. Therefore, GER and GPR were studied in laryngectomized patients. METHODS: In 11 patients, 24-hour double-probe pH monitoring was performed in an ambulant setting. An optic fiberscope was used for the accurate positioning of the proximal probe in the upper esophageal sphincter. RESULTS: In 9 of 11 patients pathologic GPR was found. Four of these 9 patients had reflux in upright and supine position, 5 patients had reflux only in upright position. CONCLUSIONS: A high incidence of GPR in laryngectomized patients was found. These results raise the question whether all laryngectomized patients should be investigated for reflux and in the presence of pathologic reflux findings should be treated with reflux prophylaxis.

Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis are not only at high risk of developing adenomas in the colorectum but a substantial number of patients also develop polyps in the duodenum. Because treatment of duodenal polyps is extremely difficult and it is unknown how many patients ultimately develop duodenal cancer, the value of surveillance of the upper digestive tract is uncertain. AIMS: (1) To assess the cumulative risk of duodenal cancer in a large series of polyposis patients. (2) To develop a decision model to establish whether surveillance would lead to increased life expectancy. METHODS: Risk analysis was performed in 155 Dutch polyposis families including 601 polyposis patients, and 142 Danish families including 376 patients. Observation time was from birth until date of last contact, death, diagnosis of duodenal cancer, or closing date of the study. RESULTS: Seven Dutch and five Danish patients developed duodenal cancer. The lifetime risk of developing this cancer by the age of 70 was 4% (95% confidence interval 1-7%) in the Dutch series and 3% (95% confidence interval 0-6%) in the Danish series. Decision analysis showed that surveillance led to an increase in life expectancy by seven months. CONCLUSIONS: Surveillance of the upper digestive tract led to a moderate gain in life expectancy. Future studies should evaluate whether this increase in life expectancy outweighs the morbidity of endoscopic examination and proximal pancreaticoduodenectomy.

Twenty-four-hour pH measurements in morbid obesity: effects of massive overweight, weight loss and gastric distension.

OBJECTIVE: To investigate the influence of untreated (super)morbid obesity and the effects of massive weight loss and chronic gastric distension on gastro-oesophageal reflux. PATIENTS AND METHODS: Seventeen young morbidly obese patients (32 years old; body weight 166.5 kg; body mass index 55 kg/m2) underwent 24-h ambulatory oesophageal pH monitoring before weight reduction and 4 months after treatment with energy-restricted diet, physical exercise and intragastric balloon or sham placement in a randomized, double-blind design. To minimize bias, both 24-h pH measurements were performed under similar conditions and dietary intake, and patients were matched for age, sex, body weight and body mass index. RESULTS: At the start, group median data for the fraction of total time, time upright and time supine with pH less than 4 were within normal limits. After a major median weight loss of 38.8 kg in 4 months these parameters did not change. On an individual basis, five out of 17 patients had pathological acid reflux prior to weight loss. This reversed to normal in three subjects, but remained abnormal in two and became abnormal in one patient. The weight loss (58.4 kg) of those remaining or becoming acid refluxers was significantly different (P < 0.01) from those with normal or normalizing pH measurements (36.9 kg). A 4-month period of gastric distension by a 500 ml balloon did not influence acid reflux parameters. CONCLUSION: The influence of untreated (super)morbid obesity on acid reflux was less pronounced than expected. There was also no major adverse effect of chronic gastric distension. Only excessive weight loss (i.e. 58 kg) appeared to have an untoward effect on acid reflux.

Extreme obesity: sociodemographic, familial and behavioural correlates in The Netherlands.

STUDY OBJECTIVE: To investigate the relationship between sociodemographic, behavioural, and family characteristics and the body mass index (BMI) (weight (kg)/height (m2)) of extremely obese people. DESIGN: Self reported sociodemographic, behavioural, and familial characteristics and weight and height were obtained by postal questionnaire. PARTICIPANTS AND SETTING: Adult, obese Dutch people who, on their own initiative, contacted our hospital for information on obesity treatment were sent a questionnaire. A total of 244 of 690 subjects had returned the questionnaire within the stated period of 80 days. Due to missing data 19 subjects could not be included in this analysis, leaving 191 women and 34 men. MAIN RESULTS: In women the BMI seemed to be significantly inversely associated with the level of education of the partner, the number of cups of coffee consumed, and number of cigarettes smoked a day. In addition, the BMI of women was positively related to BMI of their mothers. Together these variables explained 18.0% of the total variation in BMI. In men none of the selected variables was associated with their BMI. CONCLUSION: As the selected variables explained almost one fifth of the total variation in BMI, the impact of sociodemographic, familial, and behavioural factors should have more recognition in strategies aimed at reducing obesity.

Percutaneous endoscopic gastrostomy in patients with amyotrophic lateral sclerosis and impaired pulmonary function.

Amyotrophic lateral sclerosis is a rapidly progressive disease of unknown etiology resulting in tetraparalysis, dysarthria, dysphagia, and ultimately death from respiratory insufficiency. In the course of the disease, recurrent episodes of aspiration, pneumonia, dehydration, and malnutrition may necessitate nasoenteral tube placement, an inconvenient and unattractive arrangement in patients with dribbling and impaired swallowing. A percutaneous endoscopic gastrostomy seemed a better, though potentially hazardous, alternative in view of the often severely restricted pulmonary function of these patients. Therefore, we prospectively investigated the use of percutaneous endoscopic gastrostomy in 68 consecutive patients with amyotrophic lateral sclerosis. Minimum required pulmonary function was defined as forced vital capacity (FVC) of 1 L or more and CO2 gas exchange capability as pCO2 of 45 mm Hg or less. The methodology of insertion was adapted to facilitate the early removal of gastric air. Fifty-five patients (median FVC, 1.7 L; pCO2, 40 mm Hg) were eligible for the gastrostomy procedure, and 13 patients (median FVC, 0.8 L; pCO2, 47 mm Hg) were not. Despite the fact that modification of the method of insertion rendered the procedure more difficult, the success rate was 89% (49/55); it was 96% (49/51) when failures related to distorted anatomy were excluded. The procedure-related mortality rate was 1.8% and the 24-hour in-hospital mortality rate was 3.6%, mainly related to respiratory insufficiency. The 30-day out-of-hospital mortality rate was 11.5%. Major complications (3.6%) consisted of a spontaneously draining cutaneous abscess in 2 cases. Peristomal redness was present in 6 cases, and 5 patients required analgesics for wound pain.(ABSTRACT TRUNCATED AT 250 WORDS)

Colorectal adenomas: inflammatory changes that simulate malignancy after laser coagulation--evaluation with transrectal US.

To evaluate the assumption that inflammatory changes in the rectal wall after treatment of colorectal adenoma with photocoagulation may simulate malignant infiltration, the findings were reviewed in 23 follow-up examinations performed with transrectal ultrasound (TRUS) in 17 patients with benign adenoma. Special attention was given to the appearance of the wall layers underneath the adenoma. After partial coagulation, changes in the colorectal wall were usually seen on TRUS scans obtained early in follow-up; sometimes the thickened muscle layer had an irregular outer margin. In three of the 13 early examinations, lesions mimicked malignancy. To correlate these findings with histologic proof, an experimental study was performed: Colorectal specimens from pigs were examined with ultrasound (US) and microscopy. The abnormal sonographic appearance of specimens on US scans was caused by an inflammatory reaction in the deep wall layers; concomitant serositis appeared to be responsible for the malignancy-mimicking irregular outer margin. In screening for malignancy in colorectal adenoma, TRUS may cause overstaging during the first 6 weeks after polypectomy or after a session of laser treatment and should be avoided.