The incidence of esophageal adenocarcinoma (EAC) has constantly risen in western countries over the past decades, often diagnosed at advanced stage and with a five-year survival around 20%1. In a previous study on EAC cases submitted to surgery (without neoadjuvant treatment) an algorithm (EACGSE classification)2 based on morphologic distinctions provided a significant prognostic impact. We aimed to evaluate the molecular basis underlying these differences, to improve patient management. The EAC cohort classified according to EACGSE2 was included in the study. Genomic DNA was available from formalin fixed paraffin embedded surgical specimens for 207 cases. The cases were sequenced for 26 cancer-related genes (panel #226722257; IDT) with high coverage on NextSeq500 (Illumina). Data analysis was performed using a dedicated pipeline3. 245 cases were analyzed for SMAD4 immunostaining (IHC). Loss of SMAD4 immunostaining was reported as % of negative tumor cells (at least 35% of neoplastic cells). TP53 was the most frequently altered gene (134/207 cases with at least one mutation). The presence of TP53 missense variants was associated to a poor cancer-specific survival (CSS) in the high-risk cases (glandular poorly differentiated, mucinous invasive, diffuse anaplastic, mixed) according to EACGSE2 (P=0.0005). A significant correlation was observed for TP53 truncative variants and loss of SMAD4 staining (P=0.008). Actually, SMAD4 loss was observed in 85/245 (35%) of all EAC cases analyzed via immunostaining. SMAD4 loss correlated with poor CCS (P=0.007) and disease-free survival (P=0.002) in EACGSE high-risk cases. TP53 missense mutations correlated to poor outcomes (CSS) in high-risk cases, TP53 truncative mutations were associated to SMAD4 loss. SMAD4 loss itself resulted a frequent event in EAC and correlated with lower CCS and disease-free survival in high-risk cases. Therefore, we were able to correlate EAC histological classification, clinical outcomes and molecular phenotypes. Validation in independent samples is warranted to corroborate these findings. References 1. Coleman et al. Gastroenterology2018;154:390–405. 2. Fiocca et al. Cancers 2021;13:5211. 3. Isidori et al. CTG 202011:e00202.
In 1979 our surgical group proposed the Heller-Dor operation (HD) to accomplish new concepts of surgical pathophysiology: to abolish the lower esophageal sphincter with the division of the U-and sling fibers of the lesser gastric curvature, to prevent GER with an effective but not too effective partial fundoplication which protects the myotomy surface. Aim is to report very long-term results of the treatment of esophageal achalasia with the Heller-Dor operation performed with intra operative manometry. In the period 1979-2021 HD was in first instance adopted in 202 patients (97 men; median age 45 years; IQR 31–59) in laparotomy (L-HD) and in 162 (79 men; age 48 years; IQR 35–63) in laparoscopy (V-HD). At intraoperative manometry, the complete abolition of the high-pressure zone was always obtained and the Dor length and pressure were trimmed according to reference values. Follow-up consisted of interview, endoscopy and barium swallow performed every 3 years. The overall outcome was graded from excellent to poor according to the severity of symptoms and esophagitis. Median follow-up was 14.8 years in HD, 7.5 years in V-HD (p<0.001). Esophageal diameter and residual barium column decreased substantially during the first 3 years after the operation, but not successively. In the L-HD group poor results were 22 (10.9%): due to esophagitis in 17 (8.4%) and to recurrent dysphagia in 5 (2.5%). In V-HD, 4 (2.5%) had esophagitis and 2 (1.2%) severe dysphagia. Outcome was satisfactory in 89% of L-HD and in 96% of V-HD (p<0.001). Postoperatively, according to the Kaplan Mayer curve, dysphagia, reflux symptoms and esophagitis occurred within 60-65 months after surgery. Timing of dysphagia relapse and post-myotomy reflux occurrence indicate that after five years, surgical results can be considered definitive. The 96% of satisfactory results we achieved with VL-HD, at a median follow-up time of 8 years, shows the potentiality of this surgical technique. In our experience, the learning process, not the follow-up length or the laparotomy/laparoscopy method is the cause of improved results of the laparoscopy HD.
Literature supporting the adoption of POEM in place of the standard Heller myotomy in the presence of significant chest pain associated with typical symptoms like in case of Achalasia Type III according to the Chicago classification, generally reports on outcome data collected after short follow up periods. We aimed to assess behaviors of chest pain in the long term in a case series of patients submitted to the Heller-Dor operation. Between 1978 and 2021,394 achalasia patients underwent the Heller-Dor operation. Chest pain was evaluated according to its frequency (0: absent; 1: occasional; 2: weekly; 3: daily): 81 preoperatively complained of chest pain (score 2-3) (CP group), 313 did not (score 0-1) (NCP group). Patients were followed up according to a timed protocol based on clinical assessment of dysphagia (D0 absent – D3 each meal), GERD symptoms (RS0 absent-RS3 each meal). Barium swallow and endoscopy (E0: normal, E1: mild esophagitis, E2-3: erosive/ulcerative esophagitis) were performed at each planned control. CP and NCP were compared. CP group had shorter duration of dysphagia (p=0.03), smaller esophageal diameter and lower barium column (p<0.05). At a median follow-up of 10 years for CP and 11 years for NCP (p=0.166), the frequency of dysphagia (p=0.05), GERD symptoms (p=0.3) and esophagitis (p=0.27) was similar in the two groups. Chest pain progressively attenuated in intensity and frequency.; median chest pain score preoperatively was 3, at follow-up it was 0 (p<0.01). Clinical results obtained in CP patients (satisfactory D0–2, RS0–2, and E1 in 95%) were not inferior to those obtained in NCP patients (satisfactory in 93%) (p=0.05). According to our single center case series, in the long term chest pain does not influence negatively HD outcome which is absolutely competitive with that generally reported for POEM and pneumatic dilation. Results presented in this study must be verified: as new randomized prospective studies would require a too long lag time, valid retrospective multi center studies should be performed.
Since the adoption of the Heller myotomy, surgeons have modified the original technique to balance the cure of dysphagia and the consequent cardial incontinence. Surprisingly, today post POEM 30-50% erosive-ulcerative esophagitis rates are by some put inside normality. Our group had the opportunity to follow up methodically patients submitted to Heller myotomy since 1955. Aim is to provide information on long-term outcomes of Heller myotomy for esophageal achalasia with or without an antireflux fundoplication. In first instance 83 patients underwent a long abdominal myotomy (AM 1955-72), 30 patients a transthoracic myotomy according to Ellis (TM 1973-78), 364 patients the Heller-Dor operation with intraoperative manometry to calibrate myotomy, length and pressure of the Dor fundoplication (HD 1979-2021). Starting on 1973 these patients underwent a prospective follow-up program of timed lifelong clinical, radiological, endoscopic evaluations. Since 1973 an endoscopic-radiologic-clinical timed follow up has been established. GERD symptoms/esophagitis were evaluated. AM, TM and HD groups were followed up for a median period of 25, 27, 14 years respectively. GERD symptoms-esophagitis occurred in AM 29.5%-28.1%, TM 30%-30%, HD 6.6%-5.8%. Timing of esophagitis after HD revealed: early onset (6-24 months) in 8 (2.2%), late onset (25 months-14 years) in 13 (3.6%). PPIs controlled reflux symptoms (71%vs14%, p<0.0001) but not esophagitis (43%vs46%, p= 0.075). Among 50 patients with erosive/ulcerative reflux esophagitis, Barrett’s esophagus was diagnosed in 21 (42%) at a median period of 112 months since myotomy. In this group low-grade dysplasia occurred in 12 (24%) and high grade dysplasia/adenocarcinoma in 5 (10%). After surgical Heller myotomy not associated with an efficient antireflux procedure, GERD occurred in 30% which decreased to 6% after HD. A Heller-Dor operation is a competitive option for the cure of esophageal achalasia if this operation is performed according to the rules of surgical physiology learned by means of intraoperative manometry. The adoption of POEM in alternative to HD for the treatment of achalasia should be questioned.
The outcome of achalasia treatment in patients with sigmoid esophagus is worse than that achieved for fusiform achalasia. We compared two groups of sigmoid achalasia patients, in which we performed the standard Heller-Dor procedure (HD) and the Heller-Dor plus a technique aimed to restore the vertical axis of the intraabdominal portion of the esophagus pull-down Heller-Dor (PD-HD). Long-term results were evaluated. We considered 48 patients affected by primitive esophageal sigmoid achalasia operated upon consecutively (1979-2021) in first instance. After 1987, we routinely isolated 360° of the gastro-esophageal junction and the lower esophagus and applied U stitches at the right side of the lower esophagus to pull down and rotate the gastro-esophageal junction toward the right. Twenty-five patients underwent the standard HD and 23 patients underwent the PD-HD technique. Postoperative follow-up included barium swallow, clinical interview investigating dysphagia and reflux symptoms and endoscopy. The overall outcome was graded from excellent to poor according to the severity of symptoms and esophagitis. The median follow-up period was 11 years (IQR 6-22) for HD group and 9 (IQR 6-14) for PD-HD (p=0.22). At postoperative barium swallow, patients in the PD-DH group had smaller esophageal diameter [4 cm (IQR 4-4.7) vs 4.7 cm (IQR 4-5), p=0.04] and lower residual barium column [10 cm (IQR 6-13) vs 6 cm (IQR 0-8), p=0.001] than those in the HD group. Postoperative moderate-severe (D2-D3) dysphagia rates were 40% for HD and 13% for PD-HD group (p=0.003). The outcome of treatment revealed satisfactory (excellent, good, fair) results in 68% and 91.4% of HD and PD-HD group patients, respectively. The Heller-Dor operation is effective in the presence of sigmoid achalasia. The clinical and instrumental evaluations showed better results with the PD-HD technique. This technique may be the first choice for end-stage achalasia with null or low risk for cancer.
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