Etiopathological aspects of achalasia: lessons learned with Hirschsprung's disease.

The etiology of primary esophageal achalasia is largely unknown. There is increasing evidence that genetic alterations might play an important but underestimated role. Current knowledge of the genetic base of Hirschsprung's disease in contrast is far more detailed. The two enteric neuropathies have several clinical features in common. This association may also exist on a cellular and molecular level. The aim of this review is to enlighten those etiopathogenetic concepts of Hirschsprung's disease that seem to be useful in uncovering the pathological processes causing achalasia. Three aspects are looked at: (i) the genetic base of Hirschsprung's disease, particularly its major susceptibility gene rearranged during transfection and its potential reference to achalasia; (ii) the altered motor functions in both conditions with loss of inhibitory innervation and interstitial cell pathology; and (iii) the involvement of these motility disorders in genetic syndromes.

[Achalasia and Guillain-Barré syndrome]. / Achalasie und Guillain-Barré-Syndrom.

A 47-year-old patient with a history of Guillain-Barré syndrome three years prior to evaluation and a severe persisting sensory neuronopathy, complained of dysphagia especially for solid food. He also had severe, intermittent retrosternal pain. Radiological and manometric studies showed the typical features of achalasia. Treatment with botulinum toxin injection improved the dysphagia but not the retrosternal pain. An autoimmune response triggered by an infection is discussed as one possible cause of ganglion cell degeneration within the myenteric plexus in patients with achalasia. Such a hypothesis is supported by our observation showing the simultaneous occurrence of achalasia, sensory neuronopathy, and Guillain-Barré syndrome.

Appropriateness of colonoscopy in Europe (EPAGE II). Screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for screening for colorectal cancer (CRC) in asymptomatic individuals without personal history of CRC or polyps, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding colonoscopy for screening for colorectal cancer was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy in these circumstances. RESULTS: Available evidence for CRC screening comes from small case-controlled studies, with heterogeneous results, and from indirect evidence from randomized controlled trials (RCTs) on fecal occult blood test (FOBT) screening and studies on flexible sigmoidoscopy screening. Most guidelines recommend screening colonoscopy every 10 years starting at age 50 in average-risk individuals. In individuals with a higher risk of CRC due to family history, there is a consensus that it is appropriate to offer screening colonoscopy at < 50 years. EPAGE II considered screening colonoscopy appropriate above 50 years in average-risk individuals. Panelists deemed screening colonoscopy appropriate for younger patients, with shorter surveillance intervals, where family or personal risk of colorectal cancer is higher. A positive FOBT or the discovery of adenomas at sigmoidoscopy are considered appropriate indications. CONCLUSIONS: Despite the lack of evidence based on randomized controlled trials (RCTs), colonoscopy is recommended by most published guidelines and EPAGE II criteria available online (http://www.epage.ch), as a screening option for CRC in individuals at average risk of CRC, and undisputedly as the main screening tool for CRC in individuals at moderate and high risk of CRC.

[Two-stage esophageal resection with ischemic preconditioning of the gastric tube in decompensated dolichomegaesophagus and end-stage achalasia]. / Zweizeitige Osophagusresektion mit ischämischer Präkonditionierung des Schlauchmagens bei dekompensiertem Dolichomegaösophagus im Endstadium der Achalasie.

Development of a megaesophagus with a sigmoid-shaped distal part in patients with achalasia--even in the course of successful myotomy with reduction of the resting pressure of the lower esophageal sphincter--is often the expression of an irreversible progression of the disease. Management of patients with end-stage achalasia and aperistaltic, dilated "burned-out" esophagus--with or without peptic stenosis--is a therapeutic challenge for gastroenterologists and surgeons. We report on a 37-year-old female patient with decompensated dolichomegaesophagus following multiple endoscopic and operative interventions at the lower and upper esophageal sphincters presenting with severe dysphagia and weight loss. Esophageal resection with gastric tube pull-up was indicated and performed as a two-stage procedure with ischaemic preconditioning of the esophageal substitute, with the intention of a microcirculatory improvement of the gastric fundus for the anastomosis, which was thought to be potentially compromised due to the previous interventions. The postoperative course was uneventful with dysphagia completely relieved and quality of life markedly improved. The concept of ischaemic preconditioning of the gastric tube offers, in particular, patients with esophageal resection for benign motility disorders, such as end-stage achalasia after multiple surgical procedures at the cardia and gastric fundus, a safe and practicable alternative to one-stage esophageal resection and reconstruction.

[Achalasia or pseudoachalasia? Problems of diagnostic and treatment decisions in two cases]. / Achalasie oder Pseudoachalasie? Fallstricke der Diagnostik und Therapieentscheidung.

HISTORY: Patient 1 (female, aged 55 years) had for some time complained of morning nausea. She reported symptoms of reflux with regurgitation of food for two-and-a-half years and also dysphagia with retrosternal bolus obstruction for the last eighteen months. Patient 2 (male, aged 84 years) complained of restrosternal dysphagia with each intake of food for one year, weight loss of 12 kg and occasional regurgitation of food. INVESTIGATIONS: The general condition of patient 1 was only slightly impaired but that of patient 2 markedly reduced. Routine laboratory tests were unremarkable in both. Barium meal in patient 1 revealed fixed narrowing in the region of the esophageal hiatus. The inferior esophageal sphincter was closed but opened under pressure during esophagogastroscopy. At computed tomography (CT) of the thorax and abdomen an esophageal fistula was detected and bronchoscopy confirmed its opening into the esophagus. Barium meal in patient 2 (done at another hospital) demonstrated a spastic esophagus. Manometry of the esophagus revealed at rest an abnormal increase in the inferior esophageal sphincter without relaxation. DIAGNOSIS, TREATMENT AND COURSE: Patient 1 had an achalasia and an esophagogastric fistula with recurrent aspiration pneumonia, bronchial carcinoma being excluded. The fistula was closed by suture, followed by cardiomyotomy and anterior partial gastric fundectomy. In patient 2 an isolated achalasia had at first been suspected and botulinum toxin injected into the inferior esophageal sphincter. This caused a progressively worse dysphagia. CT of the thorax and abdomen established the diagnosis of a pseudoachalasia due to an adenoma of the cardia, proven by biopsy at an exploratory laparotomy. A stent was implanted in the esophagus: the postoperative course was without complication. CONCLUSION: Patient 2 with the pseudoachalasia had a relatively short history of dysphagia, marked weight loss and was elderly. This compares with the history in patient 1: shorter period of dysphagia, no weight loss and a younger age. The differential diagnosis between the two conditions may be difficult with routine methods and other imaging modalities: exploratory surgery may be necessary for a definitive diagnosis.

[Childhood achalasia: a separate entity?]. / Achalasie im Kindesalter: Eine separate Entität?

BACKGROUND: Achalasia in childhood is rare, also the etiology and the pathogenesis of the early onset ort he disease is practically unknown. Little is known about the neuropathological changes in structure of the esophageal wall in non-hereditary, sporadic achalasia in children and ist differentiation to that in adults. The aim of our study was to examine the morphological properties or high-pressure zone of the lower esophageal sphincter in children who had undergone a Heller myotomy because of achalasia as well as to compare them with the pathological findings in adults. METHODS: Muscle biopsies of the smooth musculature, a 20 x 10 mm long segment of the myenteric of the distal esophagus (lower boundary of the esophageal incision of the myotomy), were taken for histopathological and immunohistochemical studies. RESULTS: A conspicuous histomorphological finding was a marked reduction of the myenteric ganglion through to complete aganglionosis of the high-pressure zone of the lower esophageal sphincter. In contrast to achalasia in adults, neural inflammation was found only rarely. A pronounced fibrosis of the smooth muscle layers was found in all patients whereas muscular hypertrophy or visceral myopathy was not present. The interstitial Cajal cells were reduced, similar to those in adults. CONCLUSIONS: The variability of the clinical and pathological properties in cases of childhood achalasia are indicative of a complex pattern of varying etiologies and a comparison with the disease in adults does not, in principle, allow the assumption of a separate clinical entity. The present findings are compatible with the histopathological results of hereditary achalasia in children as described for Allgrove's syndrome.

[Achalasia in circumscribed scleroderma]. / Achalasie bei zirkumskripter Sklerodermie.

HISTORY: A 38-year-old man had been suffering from circumscribed scleroderma for 12 years. Dysphagia had been diagnosed 5 years ago and for the last 2 years he had retrosternal dysphagia for solid and liquid food. His symptoms had increased markedly 6 months before presenting at our hospital and the patient had lost 15 kg of weight. 2 months ago, a percutaneous endoscopic gastrostomy (PEG) had been inserted at another hospital. INVESTIGATIONS: The patient presented in a reduced general and nutritional state. The routine laboratory tests and tumor markers were within normal range. Endoscopy showed a moderately dilated esophagus with food remnants. It was not possible to pass the cardia without exerting pressure. Esophageal manometry and barium upper gastrointestinal series revealed the classical findings of achalasia. THERAPY AND COURSE: An extramucosal Heller myotomy with anterior semifundoplication (Dor's procedure) was performed. The postoperative course was uneventful and the patient was able to take solid and liquid food without any dysphagia. CONCLUSION: The association of achalasia and circumscribed scleroderma has not been described in medical publications yet. The entity could possibly be based on common autoimmune mechanisms and an analogous pathogenesis with resulting fibrosis.

Image cytometric DNA analysis of mucosal biopsies in patients with primary achalasia.

AIM: To determine DNA aneuploidy in mucosal biopsies of achalasia patients for subsequent rapid diagnosis. METHODS: Biopsies from the middle third of the esophagus were obtained in 15 patients with achalasia. Immunohistochemical staining was carried out with monoclonal antibodies MIB-1 for Ki67 and PAb 1801 for p53, in addition to the conventional histologic examination for dysplasia. Nuclei of fresh biopsy material were enzymatically and mechanically isolated, and the DNA content was determined with image cytometry after Feulgen staining. DNA grading of malignancy was assessed according to Boecking to determine the variability of DNA values noted around the normal diploid peak. Further indices measured included the aneuploid rate, and the 5c-, 7c- and 9c-exceeding rate. RESULTS: The histological examination did not demonstrate dysplasia; while MIB-1 (basal) showed a positive reaction in 8/15 achalasia specimens, p53 was negative in all specimens. Image cytometric DNA analysis detected aneuploidy in 4/15 (26.7%) specimens. Samples from 15 patients with squamous cell carcinoma as well as specimens obtained exclusively 2 cm proximal to the tumor served as reference tests. All carcinomas (15/15) as well as 9 of the peritumoral samples (9/15) were aneuploid. The comparison of biopsies from achalasia patients with peritumoral and carcinoma specimens revealed statistically significant differences regarding the aneuploid rate (diploid: P < 0.0001; tetraploid: P = 0.001), grading of malignancy according to Boecking (P < 0.0001) and the 5c- (P < 0.0001), 7c- (P < 0.0001), and 9c- (P = 0.0001) exceeding rate with progredient DNA alterations in the respective order. CONCLUSION: The finding that DNA aneuploidy was identified by image cytometry in esophageal specimens of patients with achalasia, which may be due to specific chromosomal alterations presenting as precancerous lesions in 27% of patients, leads us to conclude that image cytometry represents a valuable screening tool.

Omega- and Omega+ production in central Pb + Pb collisions at 40 and 158A GeV.

Results are presented on Omega production in central Pb+Pb collisions at 40 and 158A GeV beam energy. For the first time in heavy ion reactions, rapidity distributions and total yields were measured for the sum Omega(-) + Omega(+) at 40A GeV and for Omega(-) and Omega(+) separately at 158A GeV. The yields are strongly underpredicted by the string-hadronic UrQMD model but agree better with predictions from hadron gas models.

[Esophageal resection for non-specific esophageal motility disorder]. / Osophagusresektion bei unspezifischer Motilitätsstörung der Speiseröhre -- Bedeutung der neuropathologischen Befunde.

A 47-year-old patient presented with a history of dysphagia for solid food for almost 10 years and weight loss of more than 50 kg. Non-resecting surgical as well as endoscopic procedures (laparoscopic cardiomyotomy with secondary antireflux operations, balloon dilation, Botulinum-toxin injection) were without success. A barium esophagogram showed a confinement of the distal esophagus with a filiform passage of the contrast medium and undigested food in the prestenotic dilated esophageal corpus. Manometry displayed a hypertensive lower esophageal sphincter with a resting pressure of 43.8 mmHg - although completely relaxing. The tubular esophagus was aperistaltic with 100 % simultaneous and repetitive contractions. As all attempts of previous therapy had failed, a transhiatal esophagectomy with gastric pull-up and cervical esophagogastrostomy ensued. Neuropathological examination of the esophagus showed that degeneration of the myenteric plexus was not severely involved, whereas inflammatory and fibrotic changes were obvious. Esophageal resection provided the only chance of a long-term benefit for our patient with relief of dysphagia.

System-size dependence of strangeness production in nucleus-nucleus collisions at squareroot[sNN]=17.3 GeV.

Emission of pi+/-, K+/-, phi, and Lambda was measured in near-central C+C and Si+Si collisions at 158 AGeV beam energy. Together with earlier data for p+p, S+S, and Pb+Pb, the system-size dependence of relative strangeness production in nucleus-nucleus collisions is obtained. Its fast rise and the saturation observed at about 60 participating nucleons can be understood as the onset of the formation of coherent systems of increasing size.

[Epiphrenic diverticulum: possible causes and surgical therapy]. / Epiphrenisches Divertikel. Mögliche Ursachen und chirurgische Therapie.

INTRODUCTION: In the majority of patients suffering from epiphrenic diverticula, functional disorders of the esophagus are evident. The significance of surgical therapy is unclear, especially in case of nonspecific esophageal motility disorders. Besides "triple therapy" with diverticulectomy, myotomy, and semifundoplication, myotomy alone is also applied. Based on our own long-term results, we intended to prove if a treatment concept modeled on the motility disorder is justified. PATIENTS AND METHODS: Between July 1989 and December 2002, 12 patients with symptomatic epiphrenic diverticula underwent surgery at our clinic. Myotomy was carried out with diverticulectomy (and semifundoplication) only if achalasia had been proven, and an antireflux procedure was done only in case of gastroesophageal reflux. Surgery was performed openly in ten patients, and laparoscopically in two. RESULTS: After a median follow-up of 46 months (range 9-169), all patients regarded the operative results as good to very good (11 follow-up investigations). CONCLUSION: To alleviate symptoms in patients with epiphrenic diverticula, myotomy is only rarely indicated. As with diverticulectomy, it is only necessary, if achalasia has been proven. Our long-term results do not suggest performing myotomy as a rule for underlying unspecific motility disorders of the esophagus.

[Long-term results for Heller-myotomy with anterior semifundoplication in achalasia]. / Langzeitergebnisse nach Heller-Myotomie mit anteriorer Semifundoplikatio bei Achalasie.

INTRODUCTION: The positive success rate of cardiomyotomy in the treatment of achalasia has recently - especially in young patients - resulted in a primary operative treatment concept. Few studies of long-term effects of myotomy concerning the removal of dysphagia and the development of gastroesophageal reflux have been submitted. PATIENTS AND METHODS: In the period between September 1985 and March 2003, an open, transabdominal Heller-myotomy combined with a Dor-semifundoplication was carried out in 93 patients with achalasia. 77 patients were followed for more than 6 months postoperatively (median follow-up: 70 months). The procedure was prospectively observed, and patients were questioned concerning their clinical symptoms by means of structured interviews. X-ray examinations of the esophagus were pre- and postoperatively available of 47 patients, manometrical findings before and after myotomy of 26 patients. RESULTS: The pre-operatively existing symptoms dysphagia, regurgitation, retrosternal pain and weight-loss could be improved by myotomy in 97 % of the patients with good to excellent long-term results. Post-operatively, a significant reduction of the median maximum diameter of the esophagus of 50 mm to 30 mm was evident (p < 0.001), whereas the diameter of the cardia increased from 3 mm to 10 mm (p < 0.001). The pre-operative resting pressure of the lower esophageal sphincter (LES) of 29.3 mmHg was reduced to 7.9 mmHg (p < 0.001). Patients suffering from reflux esophagitis showed a significant lower resting pressure of the LES (4 mmHg) in comparison with patients without reflux esophagitis (8.5 mmHg) after myotomy (p=0.045). The clinical long-term results of patients with preceding pneumatic dilation did not differ significantly from those with primary myotomy. CONCLUSION: Conventional Heller-myotomy with anterior semifundoplication can in the long run remove the symptoms existent in achalasia with high efficiency. If the decrease of the post-operative resting pressure of the LES is too intense (< 5 mmHg), a possible gastroesophageal reflux has to be taken into account. The results of open cardiomyotomy have to be regarded as standard for assessing the minimal-invasive procedure.

Transabdominal ultrasonography in achalasia.

BACKGROUND: The aim of this study was to investigate whether transabdominal ultrasonography can differentiate between achalasia and neoplasms involving the oesophagogastric junction. METHODS: Ultrasonography was performed in 28 patients with achalasia, 28 sex- and age-matched controls and 13 patients with neoplasms. All studies were done with a 3.5 MHz real time curved array scanner and using an electronic caliper to measure oesophageal wall thickness and the maximum oesophageal diameter. Specificity and sensitivity in making a diagnosis of achalasia and tumours were determined by having unmarked images interpreted by a blinded observer. RESULTS: Patients with achalasia were identified by recognition of a dilated oesophagus without the presence of a neoplastic lesion (maximum oesophageal diameter (median)=achalasia: 20.0 (14; 25)mm; controls 10.1 (9; 11) mm; P < 0.001). Oesophageal wall thickness was similar in the two groups (achalasia: 3.2 (2.5; 3.4) mm; controls: 2.9 (2.5; 3.4)). In patients with neoplasms, a hypoechoic lesion was identified at the level of the gastric cardia. The sensitivity of making a tumour diagnosis was 100% and the specificity 82%. CONCLUSION: Transabdominal ultrasonography is a useful, non-invasive diagnostic aid in differentiating patients with primary achalasia from those with neoplastic lesions at the gastric cardia.

Lambda and lambda production in central Pb-Pb collisions at 40, 80, and 158A GeV.

Production of Lambda and Antilambda hyperons was measured in central Pb-Pb collisions at 40, 80, and 158A GeV beam energy on a fixed target. Transverse mass spectra and rapidity distributions are given for all three energies. The Lambda/pi ratio at midrapidity and in full phase space shows a pronounced maximum between the highest BNL Alternating Gradient Synchrotron and 40A GeV CERN Super Proton Synchrotron energies, whereas the Lambda/pi ratio exhibits a monotonic increase.

Pneumatic dilation for achalasia: late results of a prospective follow up investigation.

BACKGROUND: and aims: In this prospective study, we determined the long term clinical course of patients with achalasia who were treated by pneumatic dilation using the Browne-McHardy dilator, and determined whether previously described predictors of outcome remain significant after prolonged follow up. METHODS: Between 1981 and 1991, 54 consecutive patients were treated by pneumatic dilation and followed up at regular intervals for a median of 13.8 years. Remission was determined with the use of a structured interview and a previously described symptom score. Duration of remission was evaluated by Kaplan-Meier estimates of time to recurrence. Predictors of outcome were determined using the log rank test. RESULTS: Complete follow up until 2002 was obtained in 98% of all patients. Seven patients had died and were censored. A single pneumatic dilation resulted in a five year remission rate of 40% and a 10 year remission rate of 36%. Repeated dilations only mildly improved the clinical response. Patients who were older than 40 years had a significantly better outcome than younger patients (log rank test, p = 0.0014). However, the most significant predictive factor for a favourable long term outcome was a post-dilation lower oesophageal sphincter pressure of less than 10 mm Hg (log rank test, p = 0.0001). CONCLUSIONS: Long term results of pneumatic dilation are less favourable than previously thought. Young patients and those not responding to a single pneumatic dilation should be offered alternative therapy. Patients who remain in remission for five years are likely to benefit from the longlasting treatment effect of pneumatic dilation.

Evidence for an exotic S= -2, Q= -2 baryon resonance in proton-proton collisions at the CERN SPS.

Results of resonance searches in the Xi(-)pi(-), Xi(-)pi(+), Xi;(+)pi(-), and Xi;(+)pi(+) invariant mass spectra in proton-proton collisions at sqrt[s]=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi(-)pi(-) baryon resonance with mass of 1.862+/-0.002 GeV/c(2) and width below the detector resolution of about 0.018 GeV/c(2). The significance is estimated to be above 4.2sigma. This state is a candidate for the hypothetical exotic Xi(--)(3/2) baryon with S=-2, I=3 / 2, and a quark content of (dsdsu). At the same mass, a peak is observed in the Xi(-)pi(+) spectrum which is a candidate for the Xi(0)(3/2) member of this isospin quartet with a quark content of (dsus[-]d). The corresponding antibaryon spectra also show enhancements at the same invariant mass.

[Dolichomegaesophagus in achalasia. Therapy by esophogectomy in an aged patient]. / Dolichomegaösophagus bei Achalasie. Therapie durch Osophagusresektion bei einer alten Patientin.

HISTORY AND CLINICAL FINDINGS: A 78-year-old woman suffered from achalasia since 63 years with a progressive decompensation over the last year. 53 years ago, treatment with the Stark Dilator and 24 years ago, pneumatic dilation had been carried out. Currently, the patient presented with dysphagia for liquid and solid food, with permanent retrosternal pain and regurgitation for every meal, leading to a weight loss of 10 kg. INVESTIGATIONS: The barium esophagogram showed a marked dilation of the esophagus with retinated secretions and food. The cardia had a maximum width of 15 mm. On endoscopy, reflux esophagitis and an insufficient lower esophageal sphincter were evident. TREATMENT AND COURSE: Transhiatal esophageal resection with gastric pull-up and cervical esophagogastrostomy was performed. The postoperative course was without complications and normal alimentation could be restored with a marked improvement of preoperative symptoms. CONCLUSION: Esophageal resection and gastric pull up is the more favourable treatment option in elderly patients with decompensated achalasia and dolichomegaesophagus compared to a gastric tube for alimentation--adjusted to the individual surgical risk.