Ines Gockel

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.

Heller Myotomy for Failed Pneumatic Dilation in Achalasia: How Effective Is It?

Objectives:This long-term prospective study describes the effect of myotomy in patients who fail to respond to repeated pneumatic dilations and compares their clinical course with that of patients responding to dilation therapy. Methods:Nineteen consecutive patients who had never reached a clinical remission after repeated pneumatic dilation underwent myotomy. Their clinical course was compared with that of patients who had reached a clinical remission after a single (n = 34) or multiple (n = 14) pneumatic dilation(s). Symptoms were graded with a previously described symptom score ranging from 0 to 12. Remission was defined as a score of 3 or less persisting for at least 6 months. Duration of remission was summarized using Kaplan Meier survival curves. Association between baseline factors and the need for surgery was evaluated using logistic regression. Results:Complete follow-up was obtained for 98.5% of the patients. The median duration of follow-up was similar in patients treated by myotomy (10.0 years), in patients reaching a clinical remission after a single dilation (10.6 years), but differed in patients undergoing repeated dilations (6.9 years). The 10-year remission rate was 77% (95% CI 53–100%) in patients undergoing myotomy, 72% (95% CI: 56–87%) in patients “successfully” treated with a single pneumatic dilation and 45% (95% CI: 16–73%) in patients undergoing several dilations. Among all baseline factors investigated, young age was associated with an increased need of surgery. Conclusions:Myotomy is an effective treatment modality in patients with achalasia who have failed to respond to pneumatic dilation. Young patients may benefit from primary surgical therapy.

Pseudoachalasia: a case series and analysis of the literature.

Objective Pseudoachalasia frequently cannot be distinguished from idiopathic achalasia by manometry, radiologic examination or endoscopy. Mechanisms proposed to explain the clinical features of pseudoachalasia include a circumferential mechanical obstruction of the distal esophagus or a malignant infiltration of inhibitory neurons within the myenteric plexus. Material and methods Between January 1980 and December 2002, the clinical features of 5 patients with pseudoachalasia and 174 patients with primary achalasia, diagnosed in a single center, were compared. A literature analysis of the etiology of pseudoachalasia for the time period 1968 to December 2002 was performed. The search concentrated on the databases and online catalogues PubMed, Web of Science, Cochrane Library and Current Contents Connect. Results In our case series, patients with pseudoachalasia reported a shorter duration of symptoms and tended to be older than patients with primary achalasia. Conventional manometry, endoscopy and radiologic examination of the esophagus proved to be of little value in distinguishing between the diseases. In the majority of cases only surgical exploration revealed the underlying cause. A coincidence of primary achalasia and disorders of the gastroesophageal junction was excluded by showing return of peristalsis following treatment. The analysis of the literature showed a total of 264 cases of pseudoachalasia in 122 publications. Most cases of were due to malignant disease (53.9% primary and 14.9% secondary malignancy), followed by benign lesions (12.6%) and sequelae of surgical procedures at the distal esophagus or proximal stomach (11.9%). In rare instances, the disease was an expression of a paraneoplastic process due to distant neuronal involvement rather than to local invasion with destruction of the myenteric plexus (2.6%). Conclusions The diagnosis of pseudoachalasia is difficult to establish by conventional diagnostic measures. The main distinguishing feature of secondary versus primary achalasia is the complete reversal of pathologic motor phenomena following successful therapy of the underlying disorder.

Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis and meta-regression of outcomes.

To examine the impact of steroid withdrawal from the immunosuppression protocols in liver transplantation. The electronic databases Medline, Embase, Pubmed and the Cochrane Library were searched. Meta‐analysis pooled the effects of outcomes of a total of 2590 patients enrolled into 21 randomized controlled trials (RCTs), using classic and modern meta‐analytic methods. Meta‐analysis of RCTs addressing patients transplanted for any indication showed no differences between corticosteroid‐free immunosuppression and steroid‐based protocols in most of the analyzed outcomes. More importantly, steroid‐free cohorts appeared to benefit in terms of de novo diabetes mellitus development [R.R = 1.86 (1.43, 2.41)], Cytomegalovirus (CMV) infection [R.R = 1.47 (0.99, 2.17)], cholesterol levels [WMD = 19.71 (13.7, 25.7)], the number of patients that received the allocated treatment [O.R = 1.55 (1.17, 2.05)], severe acute rejection [R.R = 1.71 (1.14, 2.54)] and overall acute rejection [R.R = 1.31 (1.09, 1.58)] (when steroids were replaced in the steroid‐free arm). Taking RCTs into account independently when steroids were not replaced, overall acute rejection was favoring the steroid‐based arm [R.R = 0.75 (0.58, 0.98)]. Studies addressing exclusively transplanted HCV patients demonstrated a significant advantage of steroid‐free protocols considering HCV recurrence [R.R = 1.15 (1.01, 1.13)], acute graft hepatitis [O.R = 3.15 (1.18, 8.40)], and treatment failure [O.R = 1.87 (1.33, 2.63)]. No unfavorable effects were observed after steroid withdrawal during short‐term follow‐up. On the contrary, significant advantages were documented.

Resection of the mesopancreas (RMP): a new surgical classification of a known anatomical space

BackgroundPrognosis after surgical therapy for pancreatic cancer is poor and has been attributed to early lymph node involvement as well as to a strong tendency of cancer cells to infiltrate into the retropancreatic tissue and to spread along the peripancreatic neural plexuses. The objective of our study was to classify the anatomical-surgical layer of the mesopancreas and to describe the surgical principles relevant for resection of the mesopancreas (RMP). Immunohistochemical investigation of the mesopancreatic-perineural lymphogenic structures was carried out with the purpose of identifying possible routes of metastatic spread.MethodsResection of the mesopancreas (RMP) was performed in fresh corpses. Pancreas and mesopancreas were separated from each other and the mesopancreas was immunohistochemically investigated.ResultsThe mesopancreas strains itself dorsally of the mesenteric vessels as a whitish-firm, fatty tissue-like layer. Macroscopically, in the dissected en-bloc specimens of pancreas and mesopancreas nerve plexuses were found running from the dorsal site of the pancreatic head to the mesopancreas to establish a perineural plane. Immunohistochemical examinations revealed the lymphatic vessels localized in direct vicinity of the neuronal plexuses between pancreas and mesopancreas.ConclusionThe mesopancreas as a perineural lymphatic layer located dorsally to the pancreas and reaching beyond the mesenteric vessels has not been classified in the anatomical or surgical literature before. The aim to ensure the greatest possible distance from the retropancreatic lymphatic tissue which drains the carcinomatous focus can be achieved in patients with pancreatic cancer only by complete resection of the mesopancreas (RMP).

Reduction of interstitial cells of Cajal (ICC) associated with neuronal nitric oxide synthase (n-NOS) in patients with achalasia.

BACKGROUND:The etiology of achalasia is still unknown. The current theories of chronic inflammation leading to autoimmune response with destruction and loss of the inhibitory myenteric ganglion cells enlighten its pathogenesis in a limited way only. Interstitial cells of Cajal (ICC) have been shown to be involved in nitrergic neurotransmission of the lower esophageal sphincter (LES).AIM:To investigate the significance of ICC and neuronal nitric oxide synthase (n-NOS) in esophageal wall tissue of patients undergoing surgery for achalasia.METHODS:In 53 patients with a median age of 45 (6–78) yr undergoing surgery for achalasia, the immunoreactivity of ICC (CD117/c-kit) and n-NOS was assessed. In 42 patients, biopsies were taken from the LES high-pressure zone during Heller myotomy, whereas in 11 patients with end-stage achalasia and a decompensated megaesophagus, the complete esophagus was resected. A semiquantitative analysis was carried out and ICC and n-NOS impairments were classified into four grades. Staining intensity was correlated with preoperative clinical, radiologic, and manometric findings and with long-term postoperative Eckardt score.RESULTS:Grade III/IV ICC reduction (severe reduction to complete loss) was seen in 59.5% of all biopsy specimens of the LES high-pressure zone. Patients with grade III/IV ICC reduction had a significantly longer duration of achalasia symptoms (3 [0–43] yr) than patients with minor to marked (grade I/II) impairment (1 [0–16] yr, P = 0.028). A majority (72.5%) of tissue samples revealed severe reduction to complete loss of n-NOS immunoreactivity. The preoperative Eckardt score was statistically significantly different between patients with grade I/II and those with grade III/IV n-NOS reductions (P = 0.031). CD117 (c-kit) positivity was statistically significantly correlated with n-NOS staining intensity (correlation coefficient r = 0.781, P < 0.0001).CONCLUSION:The present results suggest that in the pathogenesis of achalasia, especially in the development of the LES high-pressure zone, depletion of ICC networks and potential changes in the electrical activity of smooth muscle cells may play a crucial role. The reduction in CD117-positive ICC in a few patients also seemed to be of relevance, even if the cells of Auerbachs plexus were unscathed. The associated reduced NOS release might underlie the profound ICC impairment and could possibly be responsible for the lack of LES relaxation, because of missing inhibitory neurotransmission. It is unclear, however, whether the ICC loss is primarily caused by the accelerated attrition of mature cells or their impaired regeneration.

Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygotes two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10−12; T1D, P = 2.4 × 10−10; psoriasis, P = 5.9 × 10−6; celiac disease, P = 1.2 × 10−87). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10−3; T1D, P = 8.6 × 10−27; celiac disease, P = 6.0 × 10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.

Risk of lymph node metastasis in submucosal esophageal cancer: a review of surgically resected patients.

Objectives: Endoscopic local procedures are increasingly applied in patients with superficial esophageal cancer as an alternative to radical oncologic resection. The objective of this article is to determine the risk of nodal metastases in submucosal (sm) esophageal cancer, comparing the two predominating histologic tumor types, squamous cell cancer (SCC) and adenocarcinoma (ADC). Methods: A query of PubMed, MEDLINE, Embase and Cochrane Library (1980–2009) using predetermined search terms revealed 675 abstracts, of which 485 full-text articles were reviewed. A total of 105 articles met the selection criteria. A review of article references and consultation with experts revealed additional articles for inclusion. Studies that enrolled patients with submucosal esophageal cancer and provided adequate extractable data were included. Results: The pooled outcomes of 7645 patients with esophageal cancer involving the sm level of infiltration were included in the analysis. Overall, the percentage of lymph node metastasis in submucosal cancer was 37%. Lymph node (N), lymphatic (L) and vascular (V) invasion in sm1 esophageal cancers was 27, 46 and 22%, respectively. Within sm2 lesions, N, L and V invasion were involved in 38, 63 and 38% of patients, respectively. Finally, N, L and V involvement in patients with sm3 lesions was 54, 69 and 47%, respectively. The rates of lymph node metastasis for sm1 and sm2 were higher in SCC compared with ADC, whereas the lymph node metastasis for sm3 was comparable, with >50% involvement in both histologic subtypes. SCC revealed an overall more aggressive behavior compared with ADC (N+: 45 vs 26%; L+: 57 vs 37%; V+: 40 vs 18%). Discussion: While endoscopic therapy may be adequate in selected patients with ‘low-risk’ sm1 ADC, submucosal SCC necessitates esophageal resection and systematic lymphadenectomy because of its aggressive nature and tendency for early metastasis.

Achalasia: will genetic studies provide insights?

Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.

Morbidity and mortality after esophagectomy for esophageal carcinoma: A risk analysis

BackgroundThe study was aimed to identify pre- and intraoperative risk factors that potentially influence morbidity and mortality after esophagectomy for esophageal carcinoma with particular emphasis on the predominant tumor types.Patients and methodsBetween September 1985 and March 2004, 424 patients underwent esophagectomy for esophageal carcinoma. Of these, 186 (43.9%) patients had a transhiatal, and 231 (54.5%) patients underwent a transthoracic procedure with two-field lymphadenectomy. Pre-, intraoperative risk factors and tumor characteristics were included in the risk analysis to assess their influence on postoperative morbidity and mortality.ResultsMultivariate analysis (logistic regression model) identified the surgical procedure as the most important risk factor for postoperative morbidity and mortality with the transthoracic technique associated with a significant higher risk. The comparison of the risk profile between the different histological tumor types, a significantly higher nutritional risk, poorer preoperative lung function and a higher prevalence of hepatopathy was observed in patients with squamous cell carcinoma (n = 229) compared to adenocarcinoma (n = 150) (p < 0.05). Although there was no significant difference in surgical complications between the two groups, the rate of general complications, length of postoperative intensive care unit-stay and mortality rate was significantly higher in patients with squamous cell carcinoma (p < 0.05).ConclusionThe present risk analysis shows that the selection and the type of the surgical procedure are crucial factors for both the incidence of postoperative complications and the mortality rate. The higher risk of the transthoracic procedure is justified with a view to a better long term prognosis.