The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease.

OBJECTIVE: A definitive diagnosis of gastroesophageal reflux disease (GERD) depends on endoscopic and/or pH-study criteria. However, high resolution manometry (HRM) can identify factors predicting GERD, such as ineffective esophageal motility (IEM), esophago-gastric junction contractile integral (EGJ-CI), evaluating esophagogastric junction (EGJ) type and straight leg raise (SLR) maneuver response. We aimed to build and externally validate a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD. METHODS: A population of 295 consecutive patients undergoing HRM and pH-study for persistent typical or atypical GERD symptoms was prospectively enrolled to build a model and a nomogram that provides a risk score for AET > 6%. Collected HRM data included IEM, EGJ-CI, EGJ type and SLR. A supplemental cohort of patients undergoing HRM and pH-study was also prospectively enrolled in 13 high-volume esophageal function laboratories across the world in order to validate the model. Discrimination and calibration were used to assess model's accuracy. Gastroesophageal reflux disease was defined as acid exposure time >6%. RESULTS: Out of the analyzed variables, SLR response and EGJ subtype 3 had the highest impact on the score (odd ratio 18.20 and 3.87, respectively). The external validation cohort consisted of 233 patients. In the validation model, the corrected Harrel c-index was 0.90. The model-fitting optimism adjusted calibration slope was 0.93 and the integrated calibration index was 0.07, indicating good calibration. CONCLUSIONS: A novel HRM score for GERD diagnosis has been created and validated. The MS might be a useful screening tool to stratify the risk and the severity of GERD, allowing a more comprehensive pathophysiologic assessment of the anti-reflux barrier. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT05851482).

Three-year survival and distribution of lymph node metastases in gastric cancer following neoadjuvant chemotherapy: results from a European randomized clinical trial.

BACKGROUND: Adequate lymphadenectomy is an important step in gastrectomy for cancer, with a modified D2 lymphadenectomy being recommended for advanced gastric cancers. When assessing a novel technique for the treatment of gastric cancer, lymphadenectomy should be non-inferior. The aim of this study was to assess completeness of lymphadenectomy and distribution patterns between open total gastrectomy (OTG) and minimally invasive total gastrectomy (MITG) in the era of peri-operative chemotherapy. METHODS: This is a retrospective analysis of the STOMACH trial, a randomized clinical trial in thirteen hospitals in Europe. Patients were randomized between OTG and MITG for advanced gastric cancer after neoadjuvant chemotherapy. Three-year survival, number of resected lymph nodes, completeness of lymphadenectomy, and distribution patterns were examined. RESULTS: A total of 96 patients were included in this trial and randomized between OTG (49 patients) and MITG (47 patients). No difference in 3-year survival was observed, this was 57.1% in OTG group versus 46.8% in MITG group (P = 0.186). The mean number of examined lymph nodes per patient was 44.3 ± 16.7 in the OTG group and 40.7 ± 16.3 in the MITG group (P = 0.209). D2 lymphadenectomy of 71.4% in the OTG group and 74.5% in the MITG group was performed according to the surgeons; according to the pathologist compliance to D2 lymphadenectomy was 30% in the OTG group and 36% in the MITG group. Tier 2 lymph node metastases (stations 7-12) were observed in 19.6% in the OTG group versus 43.5% in the MITG group (P = 0.024). CONCLUSION: No difference in 3-year survival was observed between open and minimally invasive gastrectomy. No differences were observed for lymph node yield and type of lymphadenectomy. Adherence to D2 lymphadenectomy reported by the pathologist was markedly low.

Comparative outcomes of Toupet fundoplication and magnetic sphincter augmentation.

Laparoscopic fundoplication is the current surgical gold standard for the treatment of refractory gastroesophageal reflux disease (GERD). Magnetic sphincter augmentation (MSA) is a less invasive, standardized, and reversible option to restore competency of the lower esophageal sphincter. A comparative cohort study was conducted at a tertiary-care referral center on patients with typical GERD symptoms treated with systematic crural repair combined with Toupet fundoplication or MSA. Primary study outcome was decrease of Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQL) score. Between January 2014 and December 2021, a total of 199 patients (60.3% female, median [Q1-Q3] age: 51.0 [40.0-61.0]) underwent MSA (n = 130) or Toupet fundoplication (n = 69). Operative time and hospital stay were significantly shorter in MSA patients (P < 0.0001). At a median follow-up of 12.0 [12.0-24.0] months, there was a statistically significant decrease of GERD-HRQL score in both patient groups (P = 0.001). The mean delta values did not significantly differ between groups (P = 0.7373). The incidence of severe gas bloating symptoms was similar in the two groups (P = 0.7604), but the rate of persistent postoperative dysphagia was greater in MSA patients (P = 0.0009). Six (8.7%) patients in the Toupet group had recurrent hiatal hernia requiring revisional surgery in one (1.4%). In the MSA group, eight (7.9%) patients necessitated through-the-scope balloon dilation for relief of dysphagia, and six patients had the device removed (4.6%) because of persistent dysphagia (n = 3), device disconnection (n = 1), persistent reflux (n = 1) or need of magnetic resonance (n = 1). Toupet and MSA procedures provide similar clinical outcomes, but MSA is associated with a greater risk of reoperation. Randomized clinical trials comparing fundoplication and MSA are eagerly awaited.

Burden of Colovesical Fistula and Changing Treatment Pathways: A Systematic Literature Review.

PURPOSE: Colovesical fistula (CVF) is a rare complication of sigmoid diverticulitis causing significant morbidity and quality of life impairment. Aim of this study was to analyze contemporary literature data to appraise the current standard of care and changes of treatment algorithms over time. MATERIALS AND METHODS: A systematic review of the literature on surgical management of CVF was conducted through PUBMED, EMBASE, and COCHRANE databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement guidelines. RESULTS: Fourteen papers published between 2014 and 2020 and including 1061 patients were analyzed. One-stage colonic resection with primary anastomosis, with or without loop ileostomy, was the most common surgical procedure. A laparoscopic or robotic approach was attempted in 39.5% of patients, and conversion rate to open surgery was 7.8%. Clavien-Dindo grade ≥3 complication rate, 30-day mortality, and recurrence rate were 7.4%, 1.5%, and 0.5%, respectively. CONCLUSIONS: Minimally invasive sigmoidectomy with primary anastomosis is safe and should be the first-choice approach for CVF. Bladder repair is not necessary after a negative intraoperative leak test. A standardized perioperative care can improve clinical outcomes and reduce the length of hospital stay and the duration of Foley catheterization.

Comparison of pleural drain amylase and serum C-reactive protein for early detection of intrathoracic esophago-gastric anastomotic leaks.

INTRODUCTION: Early detection of anastomotic leaks following esophagectomy has the potential to reduce hospital length of stay and mortality. The aim of this study was to compare the predictive value of pleural drain amylase and serum C-reactive protein for the early diagnosis of leak. METHODS: A retrospective observational cohort study was conducted on 121 patients who underwent Ivor Lewis esophagectomy and intrathoracic gastric conduit reconstruction. Pleural drain amylase levels were measured daily until postoperative day (POD) 5 and compared with CRP values measured on POD 3, 5, and 7. Specificity and sensitivity for both tests, and the respective ROC curves, were calculated. RESULTS: Anastomotic leak occurred in 12 patients. There was a significant statistical association between pleural drain amylase and serum CRP levels and the presence of anastomotic leakage. Pleural drain amylase cutoff of 209 IU/L on POD 2 yielded a sensitivity of 75% and a specificity of 94% (AUC = 0.813), whereas CRP cutoff value of 22.5 mg/dL on POD 3 yielded a sensitivity of 56% and a specificity of 92% (AUC = 0.772). The negative likelihood ratio of pleural drain amylase was 0.27 and 0.12 on POD 2 and 5, respectively. There was no statistically significant difference between ROC curves of amylase and CRP on POD 3 and 5 (p = 0.79 and p = 0.14, respectively). CONCLUSIONS: Pleural drain amylase seems more efficient than serum CRP for early detection of esophago-gastric anastomotic leak. The practice of monitoring drain amylase and CRP may allow safer implementation of enhanced postoperative recovery pathway.

Minimally invasive esophagectomy for cancer in COVID hospitals and oncological hubs: are the outcomes different?

Introduction: The outbreak of coronavirus disease 2019 (COVID-19) has caused significant delays in oncological care worldwide due to restriction of elective surgery and intensive care unit capacity. It has been hypothesized that COVID-free oncological hubs can provide safer elective cancer surgery compared to COVID hospitals. The primary aim of the present study was to analyze the outcomes of minimally invasive esophagectomy for cancer performed in both hospital settings by the same surgical staff. Methods: All esophagectomies for cancer performed during the pandemic by a single team were reviewed and data were compared with control patients operated during the preceding year. Screening for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) was performed prior to surgery, and special precautions were taken to mitigate hospital-related transmission of COVID-19 among patients and healthcare workers. Results: Compared to the prepandemic period, the esophagectomy volume decreased by 64%. Comorbidities, time from onset of symptoms to first visit, waiting time between diagnosis and surgery, operative approach and technique, and the pathological staging were similar. None of the patients tested positive for COVID-19 during in-hospital stay, and esophagectomy was associated with similar outcomes compared to control patients. Conclusion: Outcomes of minimally invasive esophagectomy for cancer performed in a COVID hospital after implementation of a COVID-free surgical pathway did not differ from those obtained in an oncological hub by the same surgical team.

Health related quality of life following open versus minimally invasive total gastrectomy for cancer: Results from a randomized clinical trial.

INTRODUCTION: Minimally invasive techniques show improved short-term and comparable long-term outcomes compared to open techniques in the treatment of gastric cancer and improved survival has been seen with the implementation of multimodality treatment. Therefore, focus of research has shifted towards optimizing treatment regimens and improving quality of life. MATERIALS AND METHODS: A randomized trial was performed in thirteen hospitals in Europe. Patients were randomized between open total gastrectomy (OTG) or minimally invasive total gastrectomy (MITG) after neoadjuvant chemotherapy. This study investigated patient reported outcome measures (PROMs) on health-related quality of life (HRQoL) following OTG or MITG, using the Euro-Qol-5D (EQ-5D) and the European Organization for Research and Treatment of Cancer (EORTC) questionnaires, modules C30 and STO22. Due to multiple testing a p-value < 0.001 was deemed statistically significant. RESULTS: Between January 2015 and June 2018, 96 patients were included in this trial. Forty-nine patients were randomized to OTG and 47 to MITG. A response compliance of 80% was achieved for all PROMs. The EQ5D overall health score one year after surgery was 85 (60-90) in the open group and 68 (50-83.8) in the minimally invasive group (P = 0.049). The median EORTC-QLQ-C30 overall health score one year postoperatively was 83,3 (66,7-83,3) in the open group and 58,3 (35,4-66,7) in the minimally invasive group (P = 0.002). This was not statistically significant. CONCLUSION: No differences were observed between open total gastrectomy and minimally invasive total gastrectomy regarding HRQoL data, collected using the EQ-5D, EORTC QLQ-C30 and EORTC-QLQ-STO22 questionnaires.

Revisional Therapy for Recurrent Symptoms After Heller Myotomy for Achalasia.

PURPOSE: Symptom recurrence after initial surgical management of esophageal achalasia occurs in 10-25% of patients. The aim of this study was to analyze safety and efficacy of revisional therapy after failed Heller myotomy (HM). METHODS: A retrospective review of a prospective database was performed searching for patients with recurrent symptoms after primary surgical therapy for achalasia. Patients with previously failed HM were considered for the final analysis. The Foregut questionnaire, and the Atkinson and Eckardt scales were used to assess severity of symptoms. Objective investigations routinely included upper gastrointestinal endoscopy and barium swallow study. Redo treatments consisted of endoscopic pneumatic dilation (PD), laparoscopic HM, hybrid Ivor Lewis esophagectomy, or stapled cardioplasty. A yearly clinical and endoscopic follow-up was scheduled in all patients. RESULTS: Over a 20-year period, 26 patients with a median age of 66 years (IQR 19.5) underwent revisional therapy after failed HM for achalasia at a tertiary-care university hospital. The median time after index procedure was 10 years (IQR 21). Revisional therapy consisted of endoscopic pneumatic dilation (n=13), laparoscopic HM and fundoplication (n=10), esophagectomy (n=2), and stapled cardioplasty and fundoplication (n=1). Nine (34.6%) of these patients required further endoscopic or surgical treatments. There was no mortality, and the overall complication rate was 7.7%. At a median follow-up of 42 months (range 10-149), a significant decrease of dysphagia, regurgitation, chest pain, respiratory symptoms, and median Eckardt score (p<0.05) was noted. CONCLUSION: In specialized and multidisciplinary centers, revisional therapy for achalasia is feasible, safe, and effective.

Delayed presentation of inflammatory breast carcinoma during the COVID-19 pandemic.

Background: Breast cancer may present with distinct cutaneous manifestations that may be paraneoplastic or secondary to direct skin infiltration, distant skin metastases, or dermal lymphatic tumor embolization (inflammatory breast carcinoma). Case report: A 51-year-old Asian woman visited the emergency care department during the outbreak of COVID-19 in Northern Italy. About 6 months before, she had noted the onset of right breast swelling accompanied by skin redness and itching. She never consulted a physician, and, over time, the local skin condition progressed to a large scaly plaque covering the entire breast surface including the nipple. At presentation, abduction of the right upper limb was impaired due to severe shoulder pain. CT scan showed the presence of bilateral breast masses with necrotic and colliquative features, and multiple skeletal, nodal, pulmonary, and brain images suggestive of metastases. An ultrasound-guided core biopsy of the contralateral breast showed grade 2 non-special type infiltrating carcinoma. The patient was referred to the breast oncology unit and is currently being treated with aromatase inhibitors and chemotherapy. Conclusion: The COVID-19 pandemic has disrupted the entire spectrum of oncological care including breast cancer. Hopefully, telemedicine will contribute to increase patients' confidence and will provide earlier diagnosis and treatment while minimizing the risk of contagion.

Dysphagia aortica.

Background: Dysphagia aortica is an umbrella term to describe swallowing obstruction from external aortic compression secondary to a dilated, tortuous, or aneurysmal aorta. We performed a systematic literature review to clarify clinical features and outcomes of patients with dysphagia aortica. Materials and methods: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library. The terms "aortic dysphagia," "dysphagia aortica," "dysphagia AND aortic aneurysm" were matched. We also queried the prospectively updated database of our esophageal center to identify patients with aortic dysphagia referred for diagnosis and treatment over the past two decades. Results: A total of 57 studies including 69 patients diagnosed with dysphagia aortica were identified, and one patient from our center was added to the database. The mean age was 72 years (range 22-98), and the male to female ratio 1.1:1. Of these 70 patients, the majority (n = 63, 90%) had an aortic aneurysm, pseudoaneurysm, or dissection. Overall, 37 (53%) patients received an operative treatment (81.1% a vascular procedure, 13.5% a digestive tract procedure, 5.4% both procedures). Thoracic endovascular aortic repair (TEVAR) accounted for 60% of all vascular procedures. The postoperative mortality rate was 21.2% (n = 7/33). The mortality rate among patients treated conservatively was 55% (n = 11/20). Twenty-six (45.6%) studies were deemed at a high risk of bias. Conclusion: Dysphagia aortica is a rare clinical entity with high morbidity and mortality rates and no standardized management. Early recognition of dysphagia and a high suspicion of aortoesophageal fistula may be lifesaving in this patient population.

Proinflammatory Interleukin-33 Induces Dichotomic Effects on Cell Proliferation in Normal Gastric Epithelium and Gastric Cancer.

Interleukin (IL)-33 is a member of the interleukin (IL)-1 family of cytokines linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has a direct effect on human gastric epithelial cells (GES-1), the human gastric adenocarcinoma cell line (AGS), and the gastric carcinoma cell line (NCI-N87) by assessing its role in the regulation of cell proliferation, migration, cell cycle, and apoptosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assays, migration by wound healing assay, and apoptosis by caspase 3/7 activity assay and annexin V assay. Cell cycle was analyzed by means of propidium iodine assay, and gene expression regulation was assessed by RT-PCR profiling. We found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell lines, and it can stimulate proliferation and reduce apoptosis in normal epithelial cell lines. These effects were also confirmed by the analysis of cell cycle gene expression, which showed a reduced expression of pro-proliferative genes in cancer cells, particularly in genes involved in G0/G1 and G2/M checkpoints. These results were confirmed by gene expression analysis on bioptic and surgical specimens. The aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell-type-dependent manner.

Falciform Ligament Flap as Crural Buttress in Laparoscopic Hiatal Hernia Repair.

Background: Crural repair is an essential technical component in laparoscopic hiatal hernia surgery, but there is no consensus regarding the optimal method to prevent postoperative hernia recurrence. Mesh augmentation, especially with permanent materials, is associated with dysphagia and complications. The rotational falciform ligament flap (FLF) has been reported to be effective in reinforcing standard suture closure of the hiatus. Materials and Methods: Patients with primary or secondary hiatal hernia in whom FLF was used to buttress the hiatus repair were included. The FLF was dissected from the anterior abdominal wall, detached from the umbilical area, and transposed below the left lateral liver segment to buttress the cruroplasty. Indocyanine green fluorescence was used to assess vascularization of the flap before and after mobilization. Results: Eighteen consecutive patients underwent laparoscopic FLF cruroplasty reinforcement between October 2019 and January 2021. Indications were primary hiatal hernia (n = 9), recurrent hiatal hernia (n = 4), postsleeve gastrectomy hernia (n = 1), prophylactic hiatal repair during esophagectomy and gastric conduit reconstruction (n = 2), and postesophagectomy hernia (n = 2). All flaps were well vascularized and covered the entire hiatal area. There was no morbidity. At a median follow-up of 8 months (range 3-15), the symptomatic and quality of life scores significantly improved compared with baseline (P < .001), and no anatomic hernia recurrences were detected. Conclusions: FLF is safe for crural buttress and is a viable alternative to mesh in laparoscopic hiatal hernia surgery.

The semirecumbent position for high-resolution esophageal manometry. Results of a feasibility study.

OBJECTIVE: Normative values for high-resolution manometry (HRM) have been obtained with the patient lying supine. The aim of the study was to compare supine, semirecumbent and sitting positions during HRM in terms of variation in normative metrics, diagnostic yield, and patient's comfort. METHODS: A prospective, single-center feasibility study was planned in consecutive patients referred to the esophageal function laboratory. In each of the three positions, 10 consecutive 5 ml water swallows and three 10 ml multiple rapid swallows were administered. Validated reflux questionnaires were administered prior to the test, and a visual analogue scale (VAS) assessing the patient's comfort after the test. RESULTS: Twenty patients presenting with gastroesophageal reflux symptoms completed the study protocol. The intra-abdominal segment of the lower esophageal sphincter was significantly longer in the sitting position (P = 0.013), and the multiple rapid swallow distal contractile integral was lowest in the supine position (P = 0.012). The VAS comfort score did not significantly differ in the three body positions (P = 0.295). The concordance in the final diagnosis was 80% for semirecumbent vs. sitting (kappa = 0.15; P = 0.001), 70% for supine vs. sitting and 65.0% for semirecumbent vs. supine. CONCLUSION: Compared to the supine position, both the semirecumbent and sitting position seems to provide similar advantages. HRM metrics and the final manometric diagnosis may be affected by body position, but complementary maneuvers, such are the rapid drink challenge, can resolve diagnostic discrepancies and improve the overall accuracy of the test.

Staging esophageal cancer: low EUS accuracy in t2n0 patients.

Background and study aims Esophageal cancer (EC) is one of the most lethal malignancies worldwide. Staging of EC is performed with computed tomography (CT), positron-emission tomography (PET), and endoscopic ultrasonography (EUS). Patient management mostly depends on lymph node status. Compared to histopathology, the accuracy of EUS for T and N parameters is about 85 % and 75 %, respectively. Errors in staging may change prognosis. The aim of this study was to assess the role of EUS in T2-N0 EC considering the experience of two high-volume digestive endoscopic centers. Methods Two prospectively collected databases were queried to identify all patients with EC, staged as cT2N0 by EUS, with no distant metastases at CT/PET scan and who underwent transthoracic esophagectomy. Preoperative EUS staging (cTNM) was compared to histopathology of the surgical specimen (pTNM) to evaluate accuracy. Results Of 729 consecutive patients with EC between January 2011 and September 2018, 72 (49 men) had cT2N0 disease. CT and PET scans confirmed the absence of distant metastasis. In 43 of 72 patients (60 %), the evaluation was correct, 23 of 72 (31,7 %) were understaged, and six of 72 patients (8,3 %) were overstaged. Among the understaged patients, eight were understaged by tumor depth (35 %), seven by nodal involvement (30 %), and eight by both (35 %). All six patients who were overstaged had T1b-N0 disease. EUS accuracy was 77 % in staging for tumor depth and 82 % in staging for nodal metastases. The positive predictive value (PPV) for cT2N0 EC was 60 % (43 pT2N0 /72 cT2N). Conclusions The accuracy of EUS staging of T2N0 EC is low, with only 60 % of patients undergoing appropriate therapy based on histopathology.

The Effect of Postoperative Complications After Minimally Invasive Esophagectomy on Long-term Survival: An International Multicenter Cohort Study.

BACKGROUND: Esophagectomy is a technically challenging procedure, associated with significant morbidity. The introduction of minimally invasive esophagectomy (MIE) has reduced postoperative morbidity. OBJECTIVE: Although the short-term effect on complications is increasingly being recognized, the impact on long-term survival remains unclear. This study aims to investigate the association between postoperative complications following MIE and long-term survival. METHODS: Data were collected from the EsoBenchmark Collaborative composed by 13 high-volume, expert centers routinely performing MIE. Patients operated between June 1, 2011 and May 31, 2016 were included. Complications were graded using the Clavien-Dindo (CD) classification. To correct for short-term effects of postoperative complications on mortality, patients who died within 90 days postoperative were excluded. Primary endpoint was 5-year overall survival. RESULTS: A total of 915 patients were included with a mean follow-up time of 30.8 months (standard deviation 17.9). Complications occurred in 542 patients (59.2%) of which 50.2% had a CD grade ≥III complication [ie, (re)intervention, organ dysfunction, or death]. The incidence of anastomotic leakage (AL) was 135 of 915 patients (14.8%) of which 84 patients were classified as a CD grade ≥III. Multivariable analysis showed a significantly deteriorated long-term survival in all patients with AL [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.25-2.24]. This inverse relation was most distinct when AL was scored as a CD grade ≥III (HR 1.83, 95% CI 1.30-2.58). For all other complications, no significant association with long-term survival was found. CONCLUSION: The occurrence and severity of AL, but not overall complications, after MIE negatively affect long-term survival of esophageal cancer patients.