Background
Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of ...the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia.
Methods
Esophageal full‐thickness biopsies from 42 (22 females; age range: 16‐82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the “edgeR” option of R‐Bioconductor. Data were validated by real‐time RT‐PCR, western blotting and immunohistochemistry.
Key Results
Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10−3. Nine genes with a P ≤ 10−4 were further validated. CYR61, CTGF, c‐KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c‐KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho‐Akt was significantly reduced in achalasia patients vs controls.
Conclusions & Inferences
The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.
Primary achalasia is a disorder due to neuronal defects supplying the esophagus leading to altered peristalsis and lack of sphincter relaxation. Nonetheless, the molecular mechanisms involved in this condition are poorly understood.
Transcriptomic analysis of achalasic tissues identified a dysregulated expression of different genes, in particular c‐KIT (downregulated) and INPP4B (upregulated), the latter being linked to Akt pathway regulation.
Our results unravel novel signaling pathways involved in the neuronal and interstitial cells of Cajal abnormalities in primary achalasia.
SUMMARY
The prevalence of gastroesophageal (GE) mucosal prolapse in patients with gastroesophageal reflux disease (GERD) was investigated as well as the clinical profile and treatment outcome of ...these patients. Of the patients who were referred to our service between 1980 and 2008, those patients who received a complete diagnostic work‐up, and were successively treated and followed up at our center with interviews, radiology studies, endoscopy, and, when indicated, esophageal manometry and pH recording were selected. The prevalence of GE prolapse in GERD patients was 13.5% (70/516) (40 males and 30 females with a median age of 48, interquartile range 38–57). All patients had dysphagia and reflux symptoms, and 98% (69/70) had epigastric or retrosternal pain. Belching decreased the intensity or resolved the pain in 70% (49/70) of the cases, gross esophagitis was documented in 90% (63/70) of the cases, and hiatus hernias were observed in 62% (43/70) of the cases. GE prolapse in GERD patients was accompanied by more severe pain (P < 0.05) usually associated with belching, more severe esophagitis, and dysphagia (P < 0.05). A fundoplication was offered to 100% of the patients and was accepted by 56% (39/70) (median follow up 60 months, interquartile range 54–72), which included two Collis–Nissen techniques for true short esophagus. Patients who did not accept surgery were medically treated (median follow up 60 months, interquartile range 21–72). Persistent pain was reported in 98% (30/31) of medical cases, belching was reported in 45% (14/31), and GERD symptoms and esophagitis were reported in 81% (25/31). After surgery, pain was resolved in 98% (38/39) of the operative cases, and 79% (31/39) of them were free of GERD symptoms and esophagitis. GE prolapse has a relatively low prevalence in GERD patients. It is characterized by epigastric or retrosternal pain, and the need to belch to attenuate or resolve the pain. The pain is allegedly a result of the mechanical consequences of prolapse of the gastric mucosa into the esophagus.
Objectives
According to the Worldwide Oesophageal Cancer Collaboration (WECC), maximum 5-year survival is modulated by T classification: resecting a minimum of 10 nodes for pT1, 20 nodes for pT2, 30 ...nodes for pT3/4. To verify if the WECC parameters are applicable for adenocarcinoma of the oesophagus, we counted the number of lymph nodes resected/patient in a case series who received “total lymphadenectomy”.
Methods
We considered 194 consecutive patients. Visible nodes and fat tissue for each station (4L/R-3-4-7-10-8-9-15-16-17-18-19-20 TNM 7th ed. and pancreatic and pyloric nodes) were carefully resected, the number of nodes/station was counted by the pathologist. The bivariate correlation (Spearman's Rho r) between the mean number of harvested nodes and the corresponding pT parameter was calculated.
Results
Six thousand and ten lymph nodes were resected, with a median (IQR) of 30 per case (18-40). The median number of harvested nodes was 22.5 (11.7-37) for pT1, 31 (23.5-43.5) for pT2, 30 (16.5-38) for pT3 and 32 (17.5-45) for pT4a tumours. The number of nodes/patient ranged from 4 to 61. The number of nodes was: <10 in 21% (4/21) of pT1, <20 in 8% (2/27) of pT2, <30 in 44% (64/146) for pT3-4. No linear relationship between the mean number of nodes and T was calculated (rs = 0.040, P = 0.584).
Conclusions
For adenocarcinoma of the oesophagus, it is evident that in a high number of cases total lymphadenectomy is necessary to provide a number of nodes/T ratio close to the WECC indications which nevertheless are not applicable in all patients (in over 40% of T3/4) to estimate survival. In order to avoid the risk of undervaluing the quality of surgical resection because of the lack of resectable nodes, we suggest to adopt “total lymphadenectomy” rather than to refer to a theoretical nodes/T ratio.
Disclosure
All authors have declared no conflicts of interest.
Abstract
Background and aim
Recently it has been recommended not to perform the Heller myotomy in Achalasia type III (Chicago classification) because of the persistence of chest pain after surgery; ...alternatively, POEM was proposed. This position is based on short term follow up studies. In the last 40 years our group performed the Heller-Dor operation (HD) in achalasia diagnosed according to Vantrappen and Castell PMDE classification also in the presence of chest pain (vigorous achalasia included, diffuse spasm and nutcracker esophagus excluded). In cases operated upon of HD, we investigated in the long term chest pain, inside the global surgery evaluation.
Methods
Between 1978 and 2020, 390 achalasia patients underwent the Heller-Dor operation. Among them, 79 preoperatively complained of chest pain (group A), 311 did not (group B). Patients were preoperatively classified and postoperatively followed up according to a timed protocol based on clinical assessment of intensity and frequency of dysphagia (D0 absent—D3 daily), GERD symptoms (RS0 absent-RS3 daily); chest pain was quantified according to the Eckardt’s scale (0 none—3 each meal). Barium swallow and endoscopy (E0: normal, E1: mild esophagitis, E2–3: erosive/ulcerative esophagitis) were performed at each planned control. A and B groups were compared.
Results
Groups were homogeneous according to sex (P = 0.42) and age (P = 0.51). After HD median follow-up was 10 years (IQR 4.7–12.6 years) for A, 14 years (IQR 5.6–20 years) for B (P = 0.166); at barium swallow the percentage of decrease in esophageal diameter and barium column was similar (P = 0.59 and P = 0.85, respectively) as well as the frequency of GERD symptoms and esophagitis (P = 0.27). Chest pain progressively attenuated; median Eckard score preoperatively was 3, at follow-up it was 1 (P < 0.001). The clinical evaluation at the last control was significantly more favorable for A (satisfactory D0–2, RS0–2, and E1 in 95%) versus B (satisfactory in 89%) (P = 0.02).
Conclusion
In the long term HD achieves very satisfactory results with the decrease/disappearance of chest pain possibly present in regular achalasia. The clinical-radiological-manometric patterns of type 3 achalasia should be revised, to eliminate eventual misunderstandings.
Nowadays the subjective assessment of Health-Related Quality of Life after surgery for achalasia is often associated with the instrumental methods in order to evaluate long-term results of therapy.
...To assess the long-term objective and subjective results of the surgical treatment of achalasia and to study the correlation between clinical–instrumental methods and those based on the patient's self-assessment and on Health-Related Quality of Life questionnaires.
One hundred and twenty-four patients consecutively submitted to trans-abdominal Heller–Dor operation were periodically followed up with clinical examination, endoscopy, barium swallow and manometry. The Health-Related Quality of Life was assessed using the 36 item short form (SF-36) and the Psychological General Well-Being Index questionnaire. The statistical comparison between the results of the self-assessment questionnaires and the long-term clinical–instrumental result was calculated by means of linear regression analysis.
Over the years, 123 patients underwent at least one complete clinical–instrumental check-up and filled the self-assessment questionnaires. Mean follow-up was 105 months (range 12–288) with a median of 82.5 months. The result of the surgery was considered satisfactory in 93.5% of the patients, while the reflux oesophagitis observed in 6.5% of the cases was the main cause of failure. Clinical scores for dysphagia and for gastro-oesophageal reflux symptoms were significantly reduced after surgery. The results of the SF-36 and Psychological General Well-Being Index questionnaires were in our population very high and clinical correlation (
p
<
0.05) emerged in physical function, in role physical, in mental health and in vitality domains of SF-36 questionnaire, and in self-control and general health scales of Psychological General Well-Being Index questionnaire.
Health-Related Quality of Life questionnaires can be considered valid aids in evaluating surgical results, but the clinical–instrumental evaluation remains the cardinal point of every long-term assessment in order to diagnose complications, the disease-related conditions of the patient and to acquire reliable data on which scientific discussion can be based.
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