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Objective: In this study, we investigate the potential of large language models (LLMs) to complement biomedical knowledge graphs in the training of semantic models for the biomedical and clinical domains., Materials and Methods: Drawing on the wealth of the Unified Medical Language System knowledge graph and harnessing cutting-edge LLMs, we propose a new state-of-the-art approach for obtaining high-fidelity representations of biomedical concepts and sentences, consisting of 3 steps: an improved contrastive learning phase, a novel self-distillation phase, and a weight averaging phase., Results: Through rigorous evaluations of diverse downstream tasks, we demonstrate consistent and substantial improvements over the previous state of the art for semantic textual similarity (STS), biomedical concept representation (BCR), and clinically named entity linking, across 15+ datasets. Besides our new state-of-the-art biomedical model for English, we also distill and release a multilingual model compatible with 50+ languages and finetuned on 7 European languages., Discussion: Many clinical pipelines can benefit from our latest models. Our new multilingual model enables a range of languages to benefit from our advancements in biomedical semantic representation learning, opening a new avenue for bioinformatics researchers around the world. As a result, we hope to see BioLORD-2023 becoming a precious tool for future biomedical applications., Conclusion: In this article, we introduced BioLORD-2023, a state-of-the-art model for STS and BCR designed for the clinical domain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Chronic Fatigue Syndrome patients suffer from symptoms that cannot be explained by a single underlying biological cause. It is sometimes claimed that these symptoms are a manifestation of a disrupted autonomic nervous system. Prior works studying this claim from the complex adaptive systems perspective, have observed a lower average complexity of physical activity patterns in chronic fatigue syndrome patients compared to healthy controls. To further study the robustness of such methods, we investigate the within-patient changes in complexity of activity over time. Furthermore, we explore how these changes might be related to changes in patient functioning., Methods: We propose an extension of the allometric aggregation method, which characterises the complexity of a physiological signal by quantifying the evolution of its fractal dimension. We use it to investigate the temporal variations in within-patient complexity. To this end, physical activity patterns of 7 patients diagnosed with chronic fatigue syndrome were recorded over a period of 3 weeks. These recordings are accompanied by physicians' judgements in terms of the patients' weekly functioning., Results: We report significant within-patient variations in complexity over time. The obtained metrics are shown to depend on the range of timescales for which these are evaluated. We were unable to establish a consistent link between complexity and functioning on a week-by-week basis for the majority of the patients., Conclusions: The considerable within-patient variations of the fractal dimension across scales and time force us to question the utility of previous studies that characterise long-term activity signals using a single static complexity metric. The complexity of a Chronic Fatigue Syndrome patient's physical activity signal does not suffice to characterise their high-level functioning over time and has limited potential as an objective monitoring metric by itself., (© 2024. The Author(s).)

Information extracted from electrohysterography recordings could potentially prove to be an interesting additional source of information to estimate the risk on preterm birth. Recently, a large number of studies have reported near-perfect results to distinguish between recordings of patients that will deliver term or preterm using a public resource, called the Term/Preterm Electrohysterogram database. However, we argue that these results are overly optimistic due to a methodological flaw being made. In this work, we focus on one specific type of methodological flaw: applying over-sampling before partitioning the data into mutually exclusive training and testing sets. We show how this causes the results to be biased using two artificial datasets and reproduce results of studies in which this flaw was identified. Moreover, we evaluate the actual impact of over-sampling on predictive performance, when applied prior to data partitioning, using the same methodologies of related studies, to provide a realistic view of these methodologies' generalization capabilities. We make our research reproducible by providing all the code under an open license., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This paper contributes to the pursuit of leveraging unstructured medical notes to structured clinical decision making. In particular, we present a pipeline for clinical information extraction from medical notes related to preterm birth, and discuss the main challenges as well as its potential for clinical practice. A large collection of medical notes, created by staff during hospitalizations of patients who were at risk of delivering preterm, was gathered and analyzed. Based on an annotated collection of notes, we trained and evaluated information extraction components to discover clinical entities such as symptoms, events, anatomical sites and procedures, as well as attributes linked to these clinical entities. In a retrospective study, we show that these are highly informative for clinical decision support models that are trained to predict whether delivery is likely to occur within specific time windows, in combination with structured information from electronic health records., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diagnosis of gastroesophageal reflux disease (GORD) is delayed by the lack of uniform histopathologic criteria for diagnosis. The only practical value of pathology is the assessment of columnar lined esophagus (CLO). As a result, GORD is treated with acid suppressive drug therapy until there is a failure to control symptoms and/or advanced adenocarcinoma develops. The reasons why there is a failure of pathologic diagnosis are two false dogmas that result in two widely believed fundamental errors. These are the belief that cardiac epithelium normally lines the proximal stomach (1) and that the gastroesophageal junction (GOJ) is defined by the proximal limit of rugal folds (2). When these false dogmas are eradicated by existing powerful evidence, the pathology of GERD falls into the following stages, all defined by histology: (a) The normal state where the esophageal squamous epithelium transitions at the GOJ to gastric oxyntic epithelium with no intervening cardiac epithelium; (b) cardiac metaplasia of the squamous epithelium due to exposure to gastric juice results in cephalad movement of the squamo-columnar junction (SCJ). This creates the squamo-oxyntic gap and the dilated distal esophagus, which is distal to the endoscopic GOJ. The length of the squamo-oxyntic gap in the dilated distal esophagus is concordant with the shortening of the abdominal segment of the lower esophageal sphincter (LOS); (c) in the early stages, the gap is <5 mm and the LOS retains its competence. Reflux is uncommon and patients are asymptomatic; (d) the squamo-oxyntic gap increases in length, concordant with the amount of shortening of the LOS, which becomes increasingly incompetent. At a gap length of 5-15 mm, reflux is sufficient to cause symptoms, but in most patients, symptoms are controllable and the patients are normal at endoscopy. The gap is entirely within the dilated distal esophagus, which is mistaken by present criteria for proximal stomach. (e) The last stage of GORD is when the squamo-oxyntic gap is >15 mm. In these patients, reflux is severe with increasingly uncontrollable symptoms and columnar lined esophagus, both irreversible states.Understanding this pathophysiology of GORD by these new histologic criteria will allow diagnosis at the earliest and eminently reversible stages of the disease. This can open the door to new methods of treatment that will have the potential to prevent progression to the irreversible phase of GORD, including columnar lined esophagus. If successful, this will effectively prevent progression to adenocarcinoma.

Gastroesophageal reflux disease (GERD) can be difficult to diagnose - symptoms alone are often not enough, and thus, objective testing is often required. GERD is a manifestation of pathologic levels of reflux into the esophagus of acidic, nonacidic, and/or bilious gastric content. However, in our current evidence-based knowledge approach, we only have reasonable outcome data in regards to acid reflux, as this particular type of refluxate predictably causes symptoms and mucosal damage, which improves with medical or surgical therapy. While there are data suggesting that nonacid reflux may be responsible for ongoing symptoms despite acid suppression in some patients, outcome data about this issue are limited. Therefore, this working group believes that it is essential to confirm the presence of acid reflux in patients with 'refractory' GERD symptoms or extraesophageal symptoms thought to be caused by gastroesophageal reflux before an escalation of antireflux therapy is considered. If patients do not have pathologic acid reflux off antisecretory therapy, they are unlikely to have clinically significant nonacid or bile reflux. Patients who do not have pathologic acid gastroesophageal reflux parameters on ambulatory pH monitoring then: (i) could attempt to discontinue antisecretory medications like proton pump inhibitors and H2-receptor antagonists (which are expensive and which carry risks - i.e. C. diff, etc.); (ii) may undergo further evaluation for other causes of their esophageal symptoms (e.g. functional heartburn or chest pain, eosinophilic esophagitis, gastroparesis, achalasia, other esophageal motor disorders); and (iii) can be referred to an ear, nose, and throat/pulmonary/allergy physician for assessment of non-GERD causes of their extraesophageal symptoms., (© 2012 Copyright the Authors. Journal compilation © 2012, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Intestinal metaplasia in the columnar-lined esophagus (CLE) has long been recognized as the most significant histologic risk indicator for esophageal adenocarcinoma. Recent concern has been expressed, however, that nonintestinalized metaplastic columnar epithelia (cardiac epithelium in the esophagus) may also indicate risk. Of 2586 consecutive patients undergoing endoscopy and biopsy in the Foregut Surgery Department, we selected (a) 214 patients with a visible CLE who had systemic 4-quadrant biopsies at 1 to 2 cm intervals, with the most proximal biopsy straddling the squamocolumnar junction, and (b) 109 patients without systematic biopsy who had dysplasia or adenocarcinoma. In the first group, 187 (87.4%) patients had intestinal metaplasia, and 27 (12.6%) had cardiac epithelium. Dysplasia or adenocarcinoma was present in 55 patients, all with intestinal metaplasia; its presence was significantly higher than in the cardiac epithelium group, none of whom had dysplasia or adenocarcinoma (P=0.01). In the second group with limited sampling, 49 had only tumor tissue in the biopsy. Of 60 patients with nontumor epithelium, only 34 (56.7%) had residual intestinal metaplasia. We conclude that systematic biopsies of CLE as described in this study separate patients into those with and without intestinal metaplasia in such a manner as to remove the possibility of false-negative diagnosis of intestinal metaplasia. When intestinal metaplasia is absent using this biopsy protocol, the patient is at no or extremely low risk for dysplasia and cancer. When biopsies have a lower level of sampling of the segment of CLE, the absence of intestinal metaplasia cannot be interpreted as a true negative for intestinal metaplasia. Inadequate sampling is a powerful reason why the near absolute association between intestinal metaplasia and adenocarcinoma is not seen in some studies.

Present management algorithms for patients with gastroesophageal reflux disease (GERD) limit endoscopy to patients with advanced disease. When endoscopy is performed, biopsy is limited to patients who have a visible columnar-lined esophagus. Biopsy is not recommended for patients whose endoscopy is normal. This algorithm results in the failure to evaluate patients with early stages of GERD at a pathologic level. We report 714 patients with normal endoscopic findings irrespective of symptoms who had adequate biopsies taken from the squamocolumnar junction and the area 1-cm distal to this from mucosa that had rugal folds. Concurrent biopsies were also taken from the gastric body and/or antrum. All patients had a gap between their esophageal squamous epithelium and gastric oxyntic mucosa in the junctional region composed of oxyntocardiac ± cardiac ± intestinal epithelia. A total of 643 (90.1%) patients had no significant pathology in the gastric antrum and/or body, indicating that the squamooxyntic gap was an isolated abnormality in this region in all but 71 (9.9%) patients. The gap contained only oxyntocardiac epithelium in 71 (9.9%) patients, cardiac mucosa without intestinal metaplasia in 482 (67.5%) patients, and intestinal metaplasia in 161 (22.6%) patients. The pathologic interpretation of biopsies taken from the gastroesophageal junction is confusing and has significant interobserver variation. This results from lack of agreement as to whether these biopsies originate in the proximal stomach ("gastric cardia") or in the esophagus. We provide evidence that the presence of oxyntocardiac ± cardiac ± intestinal epithelia in biopsies from patients who are endoscopically normal is diagnostic of a dilated GERD-damaged distal esophagus. The dilated distal esophagus is the pathologic manifestation of destruction of the abdominal segment of the lower esophageal sphincter. Its presence is the pathologic basis of early GERD, which is missed if patients who are endoscopically normal are not biopsied, as is the present recommendation. Its recognition allows for accurate and evidence-based interpretation of biopsies from this region and removes the present confusion and permits the development of a reproducible pathologic diagnostic method.

Objectives: One- and 2-year evaluation of a feasibility trial (clinicaltrials.gov registration numbers NCT01057992, NCT01058070, and 01058564) to assess the safety and efficacy of a laparoscopically implanted sphincter augmentation device for the treatment of gastroesophageal reflux disease (GERD)., Methods: A sphincter augmentation device (LINX Reflux Management System; Torax Medical, Shoreview, MN), designed to prevent reflux due to abnormal opening of the lower esophageal sphincter (LES), was laparoscopically implanted at the gastroesophageal junction in 44 patients. At baseline, all patients had abnormal esophageal acid exposure on 24-hour pH monitoring and improved, but persistent, typical GERD symptoms while on acid suppression therapy with proton pump inhibitors (PPIs). The device comprises a miniature string of interlinked titanium beads, with magnetic cores, placed around the gastroesophageal junction. The magnetic bond between adjacent beads augments sphincter competence. The beads temporarily separate to accommodate a swallowed bolus, allow belching or vomiting, and reapproximate to augment the LES in the closed position. Patients were evaluated after surgery by GERD Health-Related Quality of Life symptom score, PPI usage, endoscopy, esophageal manometry, and 24-hour esophageal pH monitoring., Results: The total mean GERD Health-Related Quality of Life symptom scores improved from a mean baseline value of 25.7 to 3.8 and 2.4 at 1- and 2-year follow-up, representing an 85% and 90% reduction, respectively (P < 0.0001). Complete cessation of PPI use was reported by 90% of patients at 1 year and by 86% of patients at 2 years. Early dysphagia occurred in 43% of the patients and self-resolved by 90 days. One device was laparoscopically explanted for persistent dysphagia without disruption of the anatomy or function of the cardia. There were no device migrations, erosions, or induced mucosal injuries. At 1 and 2 years, 77% and 90% of patients had a normal esophageal acid exposure. The mean percentage time pH was less than 4 decreased from a baseline of 11.9% to 3.1% (P < 0.0001) at 1 year and to 2.4% (P < 0.0001) at 2 years. Patient satisfaction was 87% at 1 year and 86% at 2 years., Conclusions: The new laparoscopically implanted sphincter augmentation device eliminates GERD symptoms without creating undue side effects and is effective at 1 and 2 years of follow-up.

Objective: To evaluate 5-year survival of patients with locally advanced esophageal cancer (LAEC) who have undergone multimodality treatment with complete histopathologic response., Background: Patients with LAEC may obtain excellent local-regional response to multimodality therapy. The overall benefit of a complete histopathologic response, when no viable tumor is present in the surgical specimen, is incompletely understood and existing data are limited to single-center studies with relatively few patients. The aim of this multicenter study was to define the outcome of patients with complete histopathologic response after multimodality therapy for LAEC., Methods: The study population included 299 patients (229 male, 70 female; median age: 60 years) with LAEC (cT2N1M0, T3-4N0-1M0; 181 adenocarcinomas, 118 squamous carcinomas) who underwent either neoadjuvant radiochemotherapy (n = 284) or chemotherapy (n = 15) followed by esophagectomy at 6 specialized centers: Europe (3) and United States (3). All patients in the study had stage ypT0N0M0R0 after resection., Results: Esophagectomy with thoracotomy (n = 255) was more frequent than with a transhiatal approach (n = 44). The median number of analyzed lymph nodes in the surgical specimens was 20 (minimum-maximum: 1-77). Thirty-day mortality rate was 2.4% and 90-day mortality rate was 5.7%. Overall 5-year survival rate was 55%. The disease-specific 5-year survival rate was 68%, with a recurrence rate of 23.4% (n = 70; local vs distant recurrence: 3.3% vs 20.1%). Cox regression analysis identified age as the only independent predictor of survival, whereas gender, histology, type of esophagectomy, type of neoadjuvant therapy, and the number of resected lymph nodes had no prognostic impact., Conclusion: Patients with histopathologic complete response at the time of resection of LAEC achieve excellent survival.

Controversy exists as to whether adenocarcinomas occurring in the gastroesophageal junctional region and gastric cardia originate in the esophagus or the stomach. Esophageal adenocarcinoma is known to be strongly associated with gastroesophageal reflux disease; gastric adenocarcinoma with Helicobacter pylori gastritis, and gastric intestinal metaplasia. This study evaluates the association of these tumors with pathologic findings in the biopsies of the gastric body and the antrum. It is hypothesized that if these malignancies are esophageal, they should have little or no significant association with gastric pathology; if they are gastric, these patients should have a high prevalence of gastric pathology. Between 2004 and 2008, 234 patients were diagnosed with high-grade dysplasia (HGD) and/or adenocarcinoma; 107 were distal esophageal, 79 straddled the distal end of the tubular esophagus, and 48 were in the "gastric cardia." Simultaneous biopsies of the distal body and antrum were present in 185 patients; 49 had biopsy of either antrum or body. Gastric biopsies were assessed for inflammation, H. pylori infection, and intestinal metaplasia. During this period, 2146 patients had nonmalignant columnar epithelia in the esophagus with similar assessment of the stomach; these acted as a control group. The gastric biopsy was normal in 201/234 (85.9%) patients and showed significant inflammation, H. pylori infection, and/or gastric intestinal metaplasia in 33/234 (14.1%) patients. There was no gastritis, H. pylori infection, or intestinal metaplasia in 88/107 (82.2%) of the patients with distal esophageal HGD and/or adenocarcinoma, 70/79 (88.6%) with junctional HGD and/or adenocarcinoma, and 43/48 (85.9%) with "gastric cardiac" HGD and/or adenocarcinoma. The incidence of gastritis was significantly higher in the patients with HGD and/or adenocarcinoma (33/234 or 14.1%) than in the control population (146/2146 or 9.0%; P=0.01). This difference was largely the result of a higher incidence of gastritis in patients with HGD and/or adenocarcinoma in the distal third of the esophagus (19/107 or 17.8%) versus the control population (146/2146 or 9.0%; P=0.01). The incidence of H. pylori positivity was also significantly higher in the patients with HGD and/or adenocarcinoma in the distal third of the esophagus (13/107 or 12.2%) than in the control population (117/2146 or 5.5%; P=0.01). There was no significant difference between the control group and the patients with junctional and gastric cardiac HGD and/or adenocarcinoma for gastritis, H. pylori infection, or the gastric intestinal metaplasia. The absence of gastritis, H. pylori, and the gastric intestinal metaplasia in 85.9% of the patients with HGD and/or adenocarcinoma of the gastroesophageal junctional region strongly suggest that most of these originate in the esophagus. In the small minority of patients whose HGD and/or adenocarcinoma were associated with gastric pathology, the incidence of gastritis and H. pylori infection was significantly higher in patients with HGD and/or adenocarcinoma in the distal third of the esophagus and not in the junctional and "gastric cardiac" tumors. This suggests that the reflux of the gastric juice whose composition has been altered by gastritis and H. pylori infection may be associated with an increased tendency to HGD and/or adenocarcinoma in the distal third of the esophagus.

Background: The high prevalence of gastroesophageal reflux disease continues to encourage the development of treatment modalities to fill the gap between acid-suppression therapy and the laparoscopic Nissen fundoplication. The Magnetic Sphincter Augmentation device has been designed to augment the lower esophageal sphincter barrier using magnetic force. A multi-center feasibility trial was done to evaluate safety and efficacy., Methods: Patients with typical heartburn (at least partially responding to proton-pump inhibitors), abnormal esophageal acid exposure, and normal esophageal peristalsis were enrolled. Patients with hiatal hernia >3 cm were excluded from the study. The device was implanted laparoscopically around the distal esophagus., Results: Over a 1-year period, 38 out of 41 enrolled patients underwent this procedure in 3 hospitals. No operative complications were recorded. A free diet was allowed since post-operative day one, and 97% of patients were discharged within 48 h. The mean follow-up was 209 days (range 12-434 days). The GERD-HRQL score decreased from 26.0 to 1.0 (p < 0.005). At 3 months post-operatively, 89% of patients were off anti-reflux medications, and 79% of patients had a normal 24-h pH test. All patients preserved the ability to belch. Mild dysphagia occurred in 45% of patients. No migrations or erosions of the device occurred., Conclusions: Laparoscopic implant of the MSA device is safe and well tolerated. It requires minimal surgical dissection and a short learning curve compared to the conventional Nissen fundoplication.

Background: Adenocarcinoma of the distal esophagus and gastric cardia are defined by the relationship of its epicenter to the gastro-esophageal junction, which is presently defined as the end of the tubular esophagus. We have recently suggested that the true gastro-esophageal junction is best defined by the proximal limit of gastric oxyntic mucosa., Aim: To reclassify adenocarcinomas of this region by the relationship of the tumor to the proximal limit of gastric oxyntic mucosa., Methods: Seventy-four patients who had esophago-gastrectomy for adenocarcinomas in this region were classified as adenocarcinoma of distal esophagus (38 patients) and gastric cardia (36 patients) by present criteria. The epithelial type at the epicenter and distal edge of these tumors was assessed., Results: The epicenter of the tumor in 64 patients with noncircumferential tumors had squamous (5 cases), cardiac (21 cases), oxynto-cardiac (4 cases), and intestinal (Barrett-type) (34 cases) epithelia. None had gastric oxyntic mucosa. Of the 10 patients with circumferential tumors, 7 had cardiac or oxynto-cardiac epithelium at the distal tumor edge., Conclusions: If the gastro-esophageal junction is defined histologically as the proximal limit of oxyntic mucosa, 71/74 patients would be classified as adenocarcinoma of the distal esophagus. The other 3 patients were questionable as to gastric or esophageal origin. We suggest that this reclassification based on the proposed new definition of the gastro-esophageal junction provides an explanation for the epidemiologic relationship that exists between adenocarcinoma of the "gastric cardia" and gastro-esophageal reflux disease.

Careful scrutiny of pH recordings and symptom diaries in patients having 24-hour pH-metry reveals that most reflux episodes are asymptomatic. Although this observation is well known and long recognized, the explanation for why one reflux episode leads to symptoms and others do not is incompletely understood. Forty-four patients with chronic typical gastroesophageal reflux disease (GERD) symptoms referred for ambulatory pH testing were studied. Antisecretory medication was stopped 2 weeks prior to the study. Two meals were taken during the study; one standardized (hamburger, fries, milk-shake) and one at the patient's discretion. A system onset marker noted the type, beginning and end of symptoms (heartburn, regurgitation, chest pain). Age, sex, upright/supine position, nadir pH, time pH < 4, and relationship to meals were compared for symptomatic/asymptomatic reflux episodes. An acid reflux event was defined as a drop in pH < 4 lasting > 5 seconds. The pH catheter detected 1464 reflux episodes. Only 93 (6.3%) were symptomatic. Forty-six of the 93 (49.4%) were associated with heartburn, 38 (40.9%) with regurgitation, and nine (9.7%) with chest pain. Nadir pH was significantly lower in symptomatic episodes. Nearly 50% of symptomatic reflux episodes occurred after meals, especially after non-standardized compared to standardized meal. Symptomatic episodes tended to be longer in duration and to occur in the supine position, while age/sex made no difference. Six percent of the reflux episodes were temporally associated with typical GERD symptoms. This association seems to be influenced by the acidity of the refluxate. Nearly half of the symptomatic reflux episodes occurred after eating.

Adenocarcinoma of the distal esophagus and gastroesophageal junction are believed to arise in Barrett's esophagus with intestinal metaplasia. Whether adenocarcinoma can arise in columnar lined esophagus without intestinal metaplasia is in doubt. Whether adenocarcinoma of the gastric cardia arises in intestinal metaplasia of the gastric cardia is also in doubt. We aim to evaluate the relationship of size and stage of adenocarcinoma of the distal esophagus, gastroesophageal junction and gastric cardia to intestinal metaplasia and other types of columnar epithelium. Seventy-four patients who had esophagogastrectomy for adenocarcinomas in this region were examined histologically to assess the frequency of residual intestinal metaplasia in the surrounding epithelium. Tumors without residual intestinal metaplasia were evaluated for the presence of other columnar epithelia and correlated with tumor size and stage. Cardiac mucosa was present around all tumors. Residual intestinal metaplasia was present in 48 (65%) tumors, including 33/38 (87%) distal esophageal, 10/25 (45%) junctional and 5/11 (45%) gastric cardia tumors. The prevalence of intestinal metaplasia was 100% in all tumors that were less than 1 cm in maximum diameter and all intramucosal tumors. The prevalence of residual intestinal metaplasia decreased with increasing tumor size and stage. These data strongly support the contention that adenocarcinomas of this region, including those in the gastric cardia, arise in intestinal metaplastic epithelium. The absence of residual intestinal metaplasia in larger tumors is the result of tumor overgrowing the intestinal metaplasia from which it arose.

A positive association between body mass index (BMI) and risk of esophageal adenocarcinoma has been reported. Barrett esophagus (BE) is a precursor lesion for esophageal adenocarcinoma. Cardiac mucosa (CM) and BE are both reflux-induced metaplastic columnar epithelia in the esophagus. We investigated the association between BMI and BE/CM in a case-control study. A total of 174 BE patients, 333 CM patients, and 274 controls were included in this study. Multivariate logistic regression methods were used to estimate odds ratios (OR) for BE or CM associated with BMI. Linear regression analysis was employed to examine the relationship between length of columnar lined esophagus (CLE) and BMI. A dose-dependent relationship was found between BMI and BE (P=.0004). The multivariate-adjusted OR for BE was 3.3 (95% confidence interval [CI], 1.6-6.7) when obese individuals (BMI >or=30 kg/m(2)) were compared to lean individuals (BMI < 22 kg/m(2)). Similarly, a dose-dependent relationship was found between BMI and CM (P=.03). The multivariate-adjusted OR for CM comparing obese to lean persons was 1.8 (95% CI, 1.04-3.10). The length of CLE was positively related to BMI (P=.04). In conclusion, BMI is associated with BE and CM and appears to act early in the sequence of events leading from gastroesophageal reflux disease to metaplasia (CM and BE) to dysplasia and finally to adenocarcinoma.

Present definitions of the gastroesophageal junction (GEJ) are the point of flaring of the tubular esophagus and the proximal limit of the gastric rugal folds. Neither of these has been validated as the true GEJ. This study aims to validate the location of the true GEJ using the criterion of esophageal submucosal glands. Ten esophagogastrectomy specimens, in which there was a well-defined point of flaring of the tubular esophagus that coincided with the proximal limit of gastric rugal folds, were examined by complete histological mapping to evaluate the distribution of esophageal submucosal glands and surface epithelial types. Oxyntocardiac and cardiac mucosa with or without intestinal metaplasia were present under rugal folds distal to the end of tubular esophagus in all patients to a length of 0.31 to 2.05 cm. Submucosal glands were present in the tubular esophagus and in the proximal pouch distal to the tubular esophagus in a distribution that closely coincided with squamous epithelium, oxyntocardiac, cardiac, and intestinal epithelia. Submucosal glands were never found under oxyntic mucosa. We conclude that a variable part of the saccular region distal to the tubular esophagus contains esophageal submucosal glands, therefore representing reflux-damaged distal esophagus. This results in an error, where up to 2.05 cm of distal reflux-damaged dilated esophagus can be mistaken as proximal stomach when presently accepted definitions for the GEJ are used. The true GEJ is the proximal limit of gastric oxyntic mucosa defined by histology.

SUMMARY. There is controversy as to whether oxynto-cardiac mucosa (OCM), cardiac mucosa (CM) and intestinal metaplasia (IM) found in the gastroesophageal-junction region line the anatomic stomach, esophagus or both. A total of 785 retroflex biopsies taken at the endoscopic gastroesophageal junction in 244 patients were evaluated for the presence of gland ducts and multilayered epithelium which are two recognized markers of esophageal mucosa. Oxyntic mucosa was found in 287 biopsies, OCM in 283, CM in 158, IM in 30 and squamous epithelium in 53 (some biopsies had more than one epithelial type). Esophageal gland ducts and multilayered epithelium were absent in all biopsies with oxyntic mucosa. Sixty-four (13.6%) of 471 biopsies with OCM, CM and IM contained esophageal gland ducts, and 68 of 471 (14.4%) contained multilayered epithelium. Ninety-eight of 471 (20.8%) biopsies contained either gland ducts or multilayered epithelium. This study shows that 20.8% of biopsies at the gastroesophageal junction with OCM, CM and IM can be definitively characterized as lining the anatomic esophagus by the finding of gland ducts and multilayered epithelium. The absence of these markers in oxyntic mucosa confirms this epithelium as gastric. The presence of gland ducts and multilayered epithelium can be used by pathologists to objectively ascribe an esophageal or gastric location to a biopsy from the gastroesophageal junction.

This study consists of 959 consecutive patients in whom endoscopic biopsies were taken according to a protocol that permitted mapping and measurement of epithelial types in the gastroesophageal region. The epithelial types were classified as normal (oxyntic and squamous) and questionably abnormal (oxyntocardiac, cardiac, intestinal) by strict histologic criteria. Patients were classified into four groups based on the length of histologically defined abnormal glandular epithelium in the measured biopsies. A total of 811 (84.6%) patients had 0 to 0.9 cm of questionably abnormal columnar epithelium between normal oxyntic mucosa and squamous epithelium. Of these, 161 (19.9%) patients had no abnormal epithelium, 158 (19.4%) patients had oxyntocardiac mucosa, 372 (45.9%) patients had cardiac mucosa, and 120 (14.8%) patients had intestinal metaplasia. A total of 148 (15.4%) patients had >or=1 cm of abnormal columnar epithelium. All but one patient in this group had cardiac or intestinal epithelia. The prevalence of intestinal epithelium increased progressively with increasing length of abnormal columnar epithelium, being present in 70.4% in the 1- to 2-cm group, 89.5% in the 3- to 4-cm group, and 100% with in the >or=5 cm group. We propose a histologic grading system of biopsies based on these findings.

An abnormal columnar-lined esophagus (CLE) is characterized by the presence of cardiac mucosa (CM) oxynto-cardiac mucosa (OCM), and intestinal metaplastic epithelium (IM) between gastric oxyntic mucosa and esophageal squamous epithelium. Thirty-two patients with CLE measuring 2-16 cm long had 5-37 biopsies per patient that showed CM, OCM, or IM for a total of 424 biopsies. Detailed mapping of the distribution of epithelial types within the CLE showed a distinct zonation of epithelial types; CM was present throughout the CLE, whereas OCM and IM tended to occur in the distal and proximal part of the CLE, respectively. All 32 patients (64 of 68 biopsies) showed IM at the most proximal level, compared with 22 of 32 patients (40 of 102 biopsies) in the most distal level biopsies. The density of goblet cells was highest in the most proximal level. The differences in prevalence and density of goblet cells between most proximal and most distal level biopsies were highly significant. These data suggest that for a given number of biopsies within the CLE, the likelihood of finding IM is greatest when the biopsies are concentrated in the most proximal area of the CLE. We suggest that glandular transformation of squamous epithelium results in CM. which evolves into OCM and IM by development of specialized parietal cells and goblet cells, respectively. The severity and nature of reflux cause these epithelial transformations in a constant and predictable manner. Recognition of these changes permits the development of morphologic definitions of reflux disease and the characterization of the sequence of epithelial changes that represent the reflux-adenocarcinoma sequence.

This series consists of 141 patients in whom cardiac mucosa (CM) was present in biopsy samples from the gastroesophageal junctional region. Inflammation of CM, irrespective of its exact anatomic location, was defined as carditis and classified as acute or chronic based on the number of inflammatory cells present. In all cases, CM showed significant chronic inflammation. One hundred and eleven (79%) of the 141 patients with carditis showed no evidence of gastritis in biopsy samples from the gastric antrum and body. Helicobacter pylori was present in 20 of 141 (14%) patients; of these, 17 had evidence of a pangastritis, with 15 of these patients also showing H. pylori in CM. Patients with severe chronic inflammation in CM had a significantly higher acid exposure of the lower esophagus as quantitated by a 24-hour pH test than those with mild chronic inflammation in CM. Acute inflammation was uncommon in CM; it was present in only 26 of 141 (18.4%) patients. There was no significant difference in acid exposure of the lower esophagus between patients with and without acute inflammation in CM. The presence of acute inflammation in CM was significantly associated with distal gastritis and H. pylori infection. Men with carditis had quantitatively higher acid exposure of the lower esophagus than did women with this disorder. This difference was greatest in men with severe inflammation in CM who had no evidence of distal gastritis. These findings provide evidence that chronic inflammation in CM is strongly associated with acid reflux and that H. pylori is not a significant etiologic factor in carditis. They also show that in patients with CM in whom H. pylori gastritis develops, the infection frequently spreads to involve CM, resulting in acute inflammation with neutrophils that is superimposed on the chronic inflammation already present.

The Angelchik prosthesis appears to be effective in preventing gastroesophageal reflux, although its precise mechanism of action remains controversial. In a unique in vitro model, 10 freshly harvested canine esophagogastric specimens were tested for their ability to remain competent against challenges of intragastric pressure under controlled conditions of intra-abdominal pressure, longitudinal esophageal tension, lower esophageal sphincter pressure and overall length and circumference of the cardia (measure of gastric dilatation). Competency of the specimen was assessed by stepwise variation in the overall length of the sphincter, while keeping constant intraabdominal pressure (20 cm H2O), intragastric pressure (20 cm H2O), esophageal tension (physiologic), lower esophageal sphincter pressure (15 cm H2O) and degree of gastric dilatation (3 cm). With each specimen serving as its own control, the effect produced by the application of an Angelchik prosthesis was evaluated. Results consistently demonstrated that at any lower esophageal sphincter length the percent of competency was increased when the prosthesis was applied (P < 0.01). The findings indicate that the Angelchik prosthesis controls reflux by preventing unfolding of the lower esophageal sphincter when challenged by intragastric pressure.

A case of endobronchial adenoid cystic carcinoma of the lung is presented. This is probably the first report of endobronchial brachytherapy being applied for recurrent adenoid cystic carcinoma of the lung with a good response. We found that endobronchial implantation therapy is very useful in the control of endobronchial adenoid cystic carcinoma. In addition, a clinical history and options for treatment are briefly discussed.

In our report, the presence or absence of angina pectoris did not predict the presence of coronary artery disease. A significant number of patients with aortic stenosis and angina pectoris have coronary artery disease but coronary artery disease also exists in asymptomatic form in a significant number of patients with severe aortic stenosis that could not be detected clinically and therefore suggests that the routine use of selective coronary arteriography is indicated in patients over 40 years undergoing cardiac catheterization because of aortic stenosis. This is very important in the preoperative evaluation and in planning the technique of operation to employ during extracorporeal circulation and in determining the necessity of combining aortic valve replacement and myocardial revascularization.

Thirty-nine patients with stage IIIMO non-cell bronchogenic carcinoma (NOBC) were treated with combined modality therapy: radiation therapy and chemotherapy with cyclophosphamide, adriamycin, methotrexate, and procarbazine. The median survival for all patients treated was 9.6 months compared to 6.4 months for historical controls (P = 0.015). Patients who responded to the treatment program had a significantly longer survival (median, 15.2 months) compared to nonresponders and historical controls (P less than 0.005). It is concluded that combined modality therapy is moderately effective therapy in stage IIIMO NOBC.

Fifty-four patients with metastatic non-oat-cell bronchogenic carcinoma were treated with cyclophosphamide, doxorubicin hydrochloride (Adriamycin), methotrexate, and procarbazine hydrochloride (CAMP). Eighteen of 51 of these patients with measurable disease showed an objective response to CAMP chemotherapy, with a median survival of 12.6 months. Eight of the 18 patients are still alive, and two have been in continuous remission for 20 and 26 months. Survival for patients with stable disease was 12 months, similar to that for patients demonstrating objective regression in response to CAMP treatment. Weight loss, performance status, and dominant site of metastases proved to be important prognostic factors. The CAMP regimen was well tolerated; there were only two drug-related deaths, both secondary to infectious complications.

Between 1975 and 1980, 101 patients with inoperable Stage IIIMO non-small cell lung carcinoma were entered into combined radiotherapy and chemotherapy trials at Michael Reese Hospital and University of Chicago Hospital. Sixty-four percent of the patients responded. Median survival for all patients was 8.8 months. Responders survived 13.7 months and nonresponders 4.6 months (P = 0.002). Patients treated with 4200 rad had a higher response rate than those treated with 3000 rad (74% versus 54%, P = 0.04) but there was no difference in survival. Although all patients with squamous cell carcinoma died by 30 months, 18% of patients with adenocarcinoma and 20% of patients with large cell carcinoma are long-term survivors. Brain metastases occurred more frequently in patients with large cell or adenocarcinoma than in patients with squamous cell carcinoma (P = 0.02). The prognostic effect of age, initial performance status, sex, histology, and tumor extent are examined. Toxicity was substantial with a 13% treatment-related mortality. Combined modality therapy may benefit selected patients with non-squamous cell types, but more effective chemotherapeutic agents are needed. Prophylactic cranial irradiation in patients with large cell carcinoma or adenocarcinoma may decrease the incidence of subsequent brain metastases.