Cisplatin- vs. oxaliplatin-based radiosensitizing chemotherapy for squamous cell carcinoma of the esophagus: a comparison of two preoperative radiochemotherapy regimens.

PURPOSE: To compare the outcomes of two neoadjuvant radiochemotherapy (N-RCT) regimens for squamous cell carcinoma of the esophagus (ESCC). METHODS: The standard N-RCT regimen for ESCC at our institution between 2002 and 2011 was a total dose of 45 Gy (1.8-Gy fractions) with concomitant cisplatin (20 mg/m(2), days 1-5 and 29-33) and 5-fluorouracil (5-FU; 225 mg/m(2), 24 h continuous infusion on days 1-33). During the same period, a phase I/II study comparing the standard ESCC N-RCT protocol with a regimen identical except for the replacement of cisplatin with weekly oxaliplatin (40-50 mg/m(2)) was performed at our center. The standard regimen was used to treat 40 patients; 37 received the oxaliplatin regimen. All patients subsequently underwent radical resection with reconstruction according to tumor location and two-field lymph node dissection. RESULTS: Median follow-up time from the start of N-RCT was 74 months (range 3-116 months). The two patient groups were comparable in terms of demographic and baseline tumor characteristics. R0 resection was achieved in 37/39 patients (95 %) in the cisplatin-based N-RCT group, compared to 24/37 (65 %) in the oxaliplatin-based group (p = 0.002). A pathological complete response (pCR) was seen in the resection specimens from 18/39 patients (46 %) in the cisplatin-based N-RCT group and in 8/37 (22 %) oxaliplatin-group patients. In the cisplatin group, 2- and 5-year overall survival (OS) rates were 67 ± 8 % and 60 ± 8 %, respectively (median OS 103 months), compared to 38 ± 8 % and 32 ± 8 %, respectively, for the oxaliplatin group (median OS 17 months; hazard ratio, HR 0.452; 95 % confidence interval, CI 0.244-0.839; p = 0.012). CONCLUSION: Oxaliplatin-based N-RCT resulted in poorer outcomes in ESCC patients and should not routinely replace cisplatin-based N-RCT.

Changes in adenomyosis following elagolix vs leuprolide treatment in a patient with pelvic pain and infertility: A case report.

Adenomyosis is a uterine form of endometriosis that poses unique challenges in the management of infertility. Severe pelvic pain and menorrhagia associated with these conditions are commonly managed with intramuscular injections of a gonadotropin-releasing hormone agonist (leuprolide acetate). Since receiving approval by the US Food and Drug Administration in 2018, a novel oral gonadotropin-releasing hormone antagonist, elagolix, has also been increasingly used to manage endometriosis-associated pain. However, the efficacy of elagolix in the treatment of adenomyosis and infertility remains uncertain. In this clinical case of an infertile patient with endometriosis and diminished ovarian reserve, treatment with elagolix effectively controlled her severe endometriosis-related pelvic pain but, surprisingly, failed to prevent concurrent progression of adenomyosis. Subsequently, elagolix was changed to treatment with leuprolide acetate, which led to improvement of adenomyosis in preparation for an embryo transfer during an in vitro fertilization cycle. Women's health providers should be aware that elagolix may not as effectively suppress adenomyosis as leuprolide acetate, particularly in infertility patients undergoing treatment with assisted reproductive technologies.

Prognostic factors in patients with diffuse type gastric cancer (linitis plastica) after operative treatment.

OBJECTIVE: Treatment options for patients with diffuse type gastric cancer (linitis plastica) are discussed controversial. It is sometimes discussed that these patients should be treated primarily in palliative intention conservative without resection. METHODS: In a single-center analysis, we investigated 120 patients with diffuse type gastric cancer. All patients underwent a total gastrectomy, 45 patients even a multivisceral resection because of infiltrating growth, or metastases. Serum tumor marker CEA, CA 72-4, and CA 19-9 were recorded in all patients before surgery. An immunocytochemical detection of free peritoneal tumor cells (FPTC) using Ber-EP4 antibody was correlated with tumor stage and survival. Median follow-up time was 38 months. RESULTS: Complete resection rate was 31% (n = 37). 61% (n = 73) of all patients had already distant metastases at the time of surgery, 80% of them peritoneal carcinomatosis. Median survival for the whole group was 8 months, after complete resection 17 months. Lavage cytology, distant metastases, resection rate, and CA19-9 levels had significant influence on survival. CONCLUSION: A significant survival advantage for patients with diffuse type gastric cancer can only be achived after complete resection. We could define a subset of patients with an extremely poor prognosis even after surgical resection. Meticulous preoperative staging, including a diagnostic laparoscopy to exclude peritoneal carcinomatosis and free peritoneal tumor cells before resection should be mandatory in these patients.

Creating Affirmative and Inclusive Practices When Providing Genetic and Genomic Diagnostic and Research Services to Gender-Expansive and Transgender Patients.

BACKGROUND: Gender expansive and transgender (GET) healthcare extends beyond gender-affirming therapies, reaching every medical specialty and subspecialty. As the number of GET patients seeking health services has increased, so has the need for standards of care regarding GET-affirmative practices throughout the healthcare system. As such, the number of publications surrounding GET-affirmative practices has steadily risen. However, even as such research has gained ground in other areas, one realm in which there has been a relative lag is genetics and genomics (GG). CONTENT: In this article, we track the GET patient and their laboratory sample from the clinic to the GG laboratory and back. Throughout the preanalytical, analytical, and postanalytical phases, we identify publications, recommendations, and guidelines relevant to the care of the GET community. We also identity knowledge gaps in each area and provide recommendations for affirmative and inclusive processes for addressing those gaps. SUMMARY: We have identified the practices involved in GG services that would benefit from GET-affirmative process improvement, reviewing relevant affirmative guidelines. Where guidelines could not be found, we identified those knowledge gaps and suggested potential solutions and future directions for implementing GET-affirmative practices.

Microfluidic structures for flow cytometric analysis of hydrodynamically focussed blood cells fabricated by ultraprecision micromachining.

We present three-dimensional microfluidic structures with integrated optical fibers, mirrors and electrodes for flow cytometric analysis of blood cells. Ultraprecision milling technique was used to fabricate different flow cells featuring single-stage and two-stage cascaded hydrodynamic focusing of particles by a sheath flow. Two dimensional focussing of the sample fluid was proven by fluorescence imaging in horizontal and vertical directions and found to agree satisfactorily with finite element calculations. Focussing of the sample stream down to 5 microm at a particle velocity of 3 m s(-1) is accessible while maintaining stable operation for sample flow rates of up to 20 microL min(-1). In addition to fluorescence imaging, the micro-flow cells were characterised by measurements of pulse shapes and pulse height distributions of monodisperse microspheres. We demonstrated practical use of the microstructures for cell differentiation employing light scatter to distinguish platelets and red blood cells. Furthermore, T-helper lymphocytes labelled by monoclonal antibodies were identified by measuring side scatter and fluorescence.

The Use of Whole Exome Sequencing in a Cohort of Transgender Individuals to Identify Rare Genetic Variants.

Approximately 0.5-1.4% of natal males and 0.2-0.3% of natal females meet DSM-5 criteria for gender dysphoria, with many of these individuals self-describing as transgender men or women. Despite recent improvements both in social acceptance of transgender individuals as well as access to gender affirming therapy, progress in both areas has been hampered by poor understanding of the etiology of gender dysphoria. Prior studies have suggested a genetic contribution to gender dysphoria, but previously proposed candidate genes have not yet been verified in follow-up investigation. In this study, we expand on the topic of gender identity genomics by identifying rare variants in genes associated with sexually dimorphic brain development and exploring how they could contribute to gender dysphoria. To accomplish this, we performed whole exome sequencing on the genomic DNA of 13 transgender males and 17 transgender females. Whole exome sequencing revealed 120,582 genetic variants. After filtering, 441 variants in 421 genes remained for further consideration, including 21 nonsense, 28 frameshift, 13 splice-region, and 225 missense variants. Of these, 21 variants in 19 genes were found to have associations with previously described estrogen receptor activated pathways of sexually dimorphic brain development. These variants were confirmed by Sanger Sequencing. Our findings suggest a new avenue for investigation of genes involved in estrogen signaling pathways related to sexually dimorphic brain development and their relationship to gender dysphoria.

Predictors of response and survival for neoadjuvant treated patients with esophageal adenocarcinoma.

Mainly patients with advanced esophageal adenocarcinoma who respond to neoadjuvant chemotherapy show a significant survival benefit after resection. Therefore, prediction of response before treatment is desirable. The aim of this study was to assess genetic predictors of response and survival for patients with esophageal adenocarcinoma prior to neoadjuvant therapy. Thirty-two patients with advanced esophageal adenocarcinoma who underwent neoadjuvant therapy with resection of their tumor were analyzed for thymidylate synthase (TS), excision repair cross complementing (ERCC1) and Gluthatione S-transferase (GSTP-1) mRNA levels prior to the treatment. These results were analyzed in regards of response and survival. In total, 18 patients responded to this protocol. Seventeen of those did show a gene expression level at or below the respective median of at least one gene. This had a profound impact on survival, demonstrating an increase in survival for patients who have TS, ERCC1, or GSTP-1 mRNA level at or below the median. These results demonstrate a potential predictive value of a gene expression profile available prior to therapy. These data have to be confirmed by a larger prospective trial.

Expression of prostaglandin E synthase in Barrett's cancer.

Expression of prostaglandin E synthase (PGES) - an enzyme of the prostaglandin biosynthetic pathway with suspected impact on carcinogenesis--was studied in Barrett's cancer to determine its pathogenetic role and prognostic impact in this entity. Expression analysis of PGES was performed on mRNA level (quantitative reverse transcription polymerase chain rection [RT-PCR]) in a large surgical series of 123 primary resected adenocarcinomas of the distal esophagus (Barrett's cancer). Gene expression results were correlated with clinical parameters, overall survival and expression levels of previously analyzed target genes of the cyclooxygenase (COX) pathway (COX-1, COX-2) and mediators of angiogenesis (vascular endothelial growth factor [VEGF]-A) and lymphangiogenesis [VEGF-C]. Expression of PGES was demonstrated in all 123 tumors (100%) on mRNA level (quantitative RT-PCR). Relative mRNA expression levels were highly variable between different cases. Gene expression showed a strong positive correlation with both COX isoforms (COX-1: r = 0.502, P < 0.001; COX-2: r = 0.679, P < 0.001), with the angiogenetic VEGF-A (r = 0.583, P < 0.001) and with the lymphangiogentic VEGF-C (r = 0.465, P < 0.001). PGES mRNA expression showed no significant correlation with clinicopathologic parameters (i.e. pTNM categories, UICC stage, survival). Variable overexpression of PGES seems to be potentially implicated in Barrett's carcinogenesis. Gene expression of PGES is strongly correlated with other mediators of the prostaglandin biosynthetic pathway, that is both COX isoforms (COX-1 and COX-2). However, no impact on patients' outcome in relation to PGES expression was found.

Management of early esophageal cancer.

In early esophageal cancer, squamous cell cancer and early adenocarcinoma must be managed differently because they have different origins, pathogenesis. and clinical characteristics. The current treatment options vary widely, from extended resection with lymphadenectomy to endoscopic mucosectomy or ablation. None of these treatment options can be recommended universally. Instead, an individualized strategy should be based on the depth of tumor infiltration into the mucosa or submucosa, the presence or absence of lymph node metastases, the multicentricity of tumor growth, the length of the segment of intestinal metaplasia, and comorbidities of the patient. Endoscopic mucosectomy may be sufficient in a subset of patients who have m1 or m2 squamous cell carcinoma and in patients who have isolated foci of high-grade intraepithelial neoplasia or mucosal cancer. Surgical resection is the treatment of choice for carcinomas invading the submucosal and multicentric tumors. Limited resection with jejunal interposition provides an effective treatment option for patients who have early esophageal adenocarcinoma. The onset of lymph node involvement is later in patients who have early adenocarcinoma than in patients who have squamous cell cancer, probably because chronic injury and repair mechanisms obliterate the otherwise abundant lymph vessels.

Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

BACKGROUND: Barrett's metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett's mucosa for the development of esophageal adenocarcinoma. METHODS: The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. RESULTS: Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). CONCLUSIONS: The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett's mucosa seems to be the most vulnerable location for the development of invasive cancer.

COX2 expression, angiogenesis, proliferation and survival in Barrett's cancer.

OBJECTIVES: To examine COX2 expression and its relation to angiogenesis, Ki67 and Bcl2 expression in Barrett's cancer. METHODS: Specimens from 48 R0-resected Barrett's adenocarcinoma were immunostained for cyclooxygenase 2 (COX2), CD 31 and alpha-sm actin to discriminate between mature and immature vessels, Mib-1 and Bcl2. COX2 staining, angiogenesis, Ki67 expression and Bcl2 expression were also measured. RESULTS: COX2 expression was increased in 25 of 48 cases. There was no significant correlation between COX2 expression and age, sex and tumor differentiation. A significant association was found between lymph node positive cases and elevated COX2 expression (p=0.008). The percentage of Ki67 positive cancer cells was 43.8% (range 15.4-67.5%) in the low COX2 group and 57.8% (range 12.0-84.6%) in the high COX2 group. The difference was statistically significant (p=0.046). The median neovascularisation coefficient in the low COX2 group was 11.68 (range 8.22-43.64) and 25.47 (range 8-38.3) in the high COX2 group. The difference was statistically significant (p=0.012). A significant difference in survival was observed between patients in the COX2 low category when compared with the COX2 high category (log-rank test p=0.013). CONCLUSIONS: Elevated COX2 expression is associated with lymph-node metastases and reduced survival in Barrett's cancer. This appears to be related to the induction of angiogenesis and proliferation.

The extent of Barrett's esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure.

OBJECTIVE: The purpose of this study was to assess whether the extent of intestinal metaplasia is related to the severity of the gastroesophageal reflux disease. METHODS: A total of 556 consecutive patients with symptoms suggestive of foregut disease had upper gastrointestinal endoscopy with extensive biopsies from the gastroesophageal junction and the esophagus. All patients had esophageal motility and 24-hour pH monitoring. In 411 patients, cardiac-type mucosa was identified; in 147 patients, the cardiac-type mucosa showed intestinal metaplasia. They were divided into 3 groups based on the extent of intestinal metaplasia commonly seen clinically: long segments (>3 cm), short segments (<3 cm), and limited to the gastroesophageal junction. The duration of symptoms, the status of the lower esophageal sphincter, the degree of esophageal acid exposure, and the time to clear a reflux episode were assessed in each group. RESULTS: The presence of intestinal metaplasia in cardiac-type mucosa was associated with the hallmarks of gastroesophageal reflux disease. The extent of intestinal metaplasia correlated strongly with the degree of esophageal acid exposure (r = 0.711; P <.001) and inversely with the lower esophageal sphincter pressure (r = 0.351; P <.001) and length (r = 0. 259; P =.002). Patients with a long segment of intestinal metaplasia (>3 cm) had longer duration of symptoms (16 years) than those patients with a segment of intestinal metaplasia less than 3 cm (10 years; P =.048) or those patients with intestinal metaplasia limited to the gastroesophageal junction (10 years; P =.01). CONCLUSION: The extent of intestinal metaplasia, that is, Barrett's esophagus, is related to the status of the lower esophageal sphincter and the degree of esophageal acid exposure.

Prevalence and location of nodal metastases in distal esophageal adenocarcinoma confined to the wall: implications for therapy.

OBJECTIVE: The purpose of this study was to characterize the prevalence and location of regional lymph node metastases in adenocarcinoma confined to the esophagal wall, to determine the extent of dissection required, and to investigate the applicability of nonoperative therapy. METHODS: Histologic evaluation of the resected specimens after en bloc esophagogastrectomy with mediastinal and abdominal lymphadenectomy was performed on 37 patients with adenocarcinoma confined to the esophageal wall. Follow-up was complete in all patients (median 24 months). RESULTS: Fifteen patients (41%) had intramucosal tumors. Twelve (32%) had submucosal tumors and 10 (27%) had muscular invasion. The prevalence of regional lymph node metastases (15/37 patients, 41%) increased progressively with depth of tumor invasion, with involved nodes identified in 80% of patients with muscular invasion. Lymph node metastases were also more common at distant node stations in intramuscular tumors (5/10, 50%). Actuarial survival for the entire group was 63% at 5 years. Recurrence was identified in 6 of the 37 patients (16%), with the risk of recurrence correlating with tumor depth. CONCLUSIONS: Tumor depth is a strong predictor of the probabilities of regional lymph node metastases, the likelihood of involvement of distant node groups, and the risk of recurrence. Patients with invasion of the muscular wall are at particularly high risk. En bloc esophagectomy with mediastinal and abdominal lymphadenectomy has the highest likelihood of achieving an R0 resection. The long-term survival and low recurrence rate achieved with an en bloc esophagectomy emphasizes the importance of an aggressive lymph node dissection to remove all potentially involved nodes.

Short esophagus: analysis of predictors and clinical implications.

HYPOTHESIS: Preoperative assessment can identify the predictors of esophageal shortening in patients with gastroesophageal reflux disease. DESIGN AND SETTING: Patient comparison study in a university-based tertiary care center. PATIENTS: A total of 236 patients with gastroesophageal reflux disease underwent primary antireflux procedures. Sixty-five patients were suspected of having a short esophagus and underwent a transthoracic approach. In 37 patients, a lengthening procedure was necessary to avoid tension on the repair. The remaining 28 patients were thought-after complete esophageal mobilization-to have sufficient length for a repair without needing a gastroplasty. An abdominal approach (laparoscopic Nissen fundoplication) was performed on 171 patients judged to have normal esophageal length. MAIN OUTCOME MEASURES: Univariate and multivariate analyses of preoperative variables were performed to identify predictors of a short esophagus. RESULTS: On univariate analysis, manometric esophageal length below the fifth percentile of normal was associated with esophageal shortening. On multivariate analysis, only the presence of an esophageal stricture predicted the need for a Collis gastroplasty (odds ratio, 7.5). The presence of Barrett's esophagus of 3 cm or greater identified patients in whom the transthoracic esophageal mobilization alone was sufficient (odds ratio, 3.4). CONCLUSIONS: The presence of a stricture was associated with esophageal shortening sufficient to require a gastroplasty. Transthoracic esophageal mobilization alone was usually sufficient to perform a safe repair without tension in patients with a Barrett's esophagus of 3 cm or greater.

Helicobacter pylori is not associated with the manifestations of gastroesophageal reflux disease.

HYPOTHESIS: Helicobacter pylori is not associated with gastroesophageal reflux disease and its complications, including adenocarcinoma of the esophagus and the gastroesophageal junction (GEJ). DESIGN: Retrospective analysis. SETTING: University tertiary referral center. PATIENTS: Two hundred twenty-nine patients with symptoms suggestive of foregut disease underwent esophageal manometry, 24-hour pH monitoring, and upper gastrointestinal tract endoscopy, with biopsy specimens obtained from the gastric antrum, the GEJ, and the distal esophagus. In these and in an additional 114 patients with adenocarcinoma of the esophagus and the GEJ, the presence of H. pylori was determined by Giemsa stain. The presence of gastroesophageal reflux disease, defined by abnormal esophageal acid exposure, and its manifestations (carditis, erosive esophagitis, intestinal metaplasia limited to the GEJ, Barrett esophagus, and adenocarcinoma of the esophagus and GEJ) were correlated with the presence of H. pylori. RESULTS: Helicobacter pylori was found on the biopsy specimens of the gastric antrum in 14.0% (32/229) of the patients with benign disease. It was not related to the features of gastroesophageal reflux disease, including abnormal esophageal acid exposure, erosive esophagitis, or Barrett esophagus. The presence of inflamed cardiac mucosa at the GEJ or carditis was inversely related to H. pylori infection and strongly associated with increased esophageal acid exposure. There was no association between the presence of intestinal metaplasia and H. pylori infection. Helicobacter pylori was found in 22 (19.3%) of the 114 patients with esophageal adenocarcinoma, which was not different from the prevalence of H. pylori in patients with benign disease. CONCLUSION: Helicobacter pylori plays no role in the pathogenesis of gastroesophageal reflux disease or its complications.

Laparoscopic repair of large type III hiatal hernia: objective followup reveals high recurrence rate.

BACKGROUND: Recent studies based on symptomatic outcomes analyses have shown that laparoscopic repair of large type III hiatal hernias is safe, successful, and equivalent to open repair. These outcomes analyses were based on a relatively short followup period and lack objective confirmation that the hernia has not recurred. The aim of this study was to compare the outcomes of laparoscopic and open repair of large type III hiatal hernia using both symptomatic evaluation and barium study to assess the integrity of the repair. STUDY DESIGN: Fifty-four patients underwent repair of a large type III hiatal hernia between 1985 and 1998. The surgical approach was laparotomy in 13, thoracotomy in 14, and laparoscopy in 27. An antireflux procedure was included in all patients. Symptomatic outcomes were assessed using a structured questionnaire at a median of 24 months and was complete in 51 of 54 patients (94%). A single radiologist, without knowledge of the operative procedure, assessed the integrity of the repair using video esophagram. Videos were performed at a median of 27 months (35 months open and 17 laparoscopic) and were completed in 41 of 54 patients (75%). RESULTS: Symptomatic outcomes were similar in both groups with excellent or good outcomes in 76% of the patients after laparoscopic repair and 88% after an open repair. Reherniation was present in 12 patients and was asymptomatic in 7. A recurrent hernia was present in 12 of the 41 patients (29%) who returned for a followup video esophagram. Forty-two percent (9 of 21) of the laparoscopic group had a recurrent hernia compared with 15% (3 of 20) of the open group (p < 0.001 log-rank value on recurrence-free followup). CONCLUSIONS: Laparoscopic repair of type III hiatal hernias is associated with a disturbingly high (42%) prevalence of recurrent hernia. More than half such recurrences have few, if any, symptoms.

Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids.

The aim of this study was to test the hypothesis that gastric bacterial overgrowth is a side effect of acid suppression therapy in patients with gastroesophageal reflux disease (GERD) and that the bacteria-contaminated gastric milieu is responsible for an increased amount of deconjugated bile acids. Thirty patients with GERD who were treated with 40 mg of omeprazole for at least 3 months and 10 patients with GERD who were off medication for at least 2 weeks were studied. At the time of upper endoscopy, 10 ml of gastric fluid was aspirated and analyzed for bacterial growth and bile acids. Bacterial overgrowth was defined by the presence of more than 1000 bacteria/ml. Bile acids were quantified via high-performance liquid chromatography. Eleven of the 30 patients taking omeprazole had bacterial overgrowth compared to one of the 10 control patients. The median pH in the bacteria-positive patients was 5.3 compared to 2.6 in those who were free of bacteria and 3.5 in the control patients who were off medication. Bacterial overgrowth only occurred when the pH was >3.8. The ratio of conjugated to unconjugated bile acids changed from 4:1 in the patients without bacterial overgrowth to 1:3 in those with bacterial growth greater than 1000/ml. Proton pump inhibitor therapy in patients with GERD results in a high prevalence of gastric bacterial overgrowth. The presence of bacterial overgrowth markedly increases the concentration of unconjugated bile acids. These findings may have implications in the pathophysiology of gastroesophageal mucosal injury.

The 'angiogenic switch' in the progression from Barrett's metaplasia to esophageal adenocarcinoma.

AIMS: We investigated VEGF expression and neovascularisation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus and 47 shades of adenocarcinoma. METHOD: Slides of 27 cases of Barrett's metaplasia and high grade dysplasia were immunostained for VEGF, CD 31 and alpha-sm actin to discriminate between mature and immature vessels. VEGF stained slides were quantitatively evaluated measuring optical density with a computer based program. The neovascularisation coefficient was estimated with an interactive analytic computer program. RESULTS: The median VEGF expression increased from metaplasia to advanced carcinoma. VEGF expression and the neovascularisation coefficient reached statistical significance between Barrett's metaplasia and high grade dysplasia (p<0.001), but were not statistically different between high grade dysplasia and microinvasive carcinoma (p=0.421; p=0.146). Comparing microinvasive to advanced carcinoma the difference was significant for both parameters (p<0.001). CONCLUSIONS: Based on a quantitative computer based evaluation program, the present study suggests, that an angiogenic switch might exist and that it is an early event in the metaplasia-dysplasia-carcinoma sequence of Barrett's carcinoma. The neovascularisation phase in Barrett's carcinoma may precede tumour growth.

Learned preference for the limiting amino acid in rats fed a threonine-deficient diet.

Preference for an odor associated with protein is only seen in protein-deprived rats. We hypothesized that rats depleted of the amino acid threonine (THR) would prefer a flavored solution paired with a THR replete diet. Rats were given a flavored drink paired with THR-deficient (DEV) diet followed by a second flavor paired with a corrected (COR) diet. In choice testing, the animals clearly selected the COR-paired flavor, while control rats preferred the other flavor. This did not, however, differentiate between aversion to the DEV-paired flavor and learned preference for the COR-paired flavor. In subsequent tests, an unpaired flavor was given rather than the DEV-paired flavor. The COR-paired flavor was included in the test as before. In the second and third trials, using either DEV or a less profoundly deficient diet, animals depleted of THR selected the COR-paired flavor to a greater extent than control rats. We conclude that animals deficient in the essential amino acid, THR, show a learned preference for the flavor paired with repletion.

Pneumatosis cystoides intestinalis coli.

The rare case of a 63-year-old male diagnosed with pneumatosis cystoides intestinalis coli is presented and discussed. The patient was found to have an unsymptomatic pneumoperitoneum on plain chest x-ray. The results of a contrast enema, computed tomography scan, and laparoscopy are presented. The patient had an uneventful hospital course without any specific therapy. Causes and possible therapeutic options are discussed.