Multicenter study on the incidence and treatment of mediastinal leaks after esophagectomy (MuMeLe 2).

BACKGROUND: Management of mediastinal anastomotic leaks (MALs) after Ivor Lewis esophagectomy includes conservative, endoscopic, or surgical management. Endoscopic vacuum therapy (EVAC) is becoming a routine approach for MALs, although the outcomes have not been defined. This study aimed to describe the incidence, treatment, and outcomes of MALs in patients who underwent esophagectomy in 3 Italian high-volume centers that routinely use EVAC for MAL. METHODS: Patients who underwent Ivor Lewis esophagectomy between September 2018 and March 2023 were included. RESULTS: A total of 681 patients underwent Ivor Lewis esophagectomy, of whom 88 had MAL. The MAL rates for open, minimally invasive, and robotic esophagectomies were 11.5%, 13.4%, and 14.8%, respectively. Global and specific 30- and 90-day mortality rates for MAL were 0.9% and 2.1% and 6.8% and 15.9%, respectively. Nonoperative management (NOM) as the primary treatment was chosen for 62 patients. EVAC was the most common NOM (62.9%), and the most common operative management (OM) was anastomotic redo (53.8%). Diversion was the OM for 7 patients, of whom 3 patients died. Primary treatment proved successful in 40 patients. Among them, EVAC alone was successful in 35.9% of patients. Globally, endoscopic treatment, including EVAC, was successful in 79.0% of NOM and 55.7% of MALs. NOM and OM were chosen as secondary treatments for 27 and 10 patients, respectively. Secondary treatment proved successful in 21 patients. CONCLUSION: The incidence of MALs after Ivor Lewis esophagectomy is approximately 13%. Endoscopic techniques have a success rate of almost 80%, with EVAC representing a significant part of this treatment process.

Implementing protocol-based relaparoscopy for severe complications in laparoscopic colorectal surgery.

BACKGROUND: Although laparoscopy has demonstrated growing applications for either primary colorectal resections or reoperations, no standardized criteria for implementing laparoscopy in revisional surgery have been reported. This study analyzes a single-center series of major complications after laparoscopic colorectal surgery, undergoing laparoscopic (LR), or open reoperations in compliance with a hemodynamics-based institutional management. METHODS: This study retrospectively analyzes a series of consecutive patients who primarily underwent either laparoscopic left colectomy or low anterior resection in a tertiary referral center between 2016 and 2021. Major complications requiring reoperation (MCR) were managed through an interdisciplinary protocol and submitted to reoperation according to patient hemodynamics and intra-abdominal contamination. A cohort analysis primarily assessed treatment failure rates (i.e., 90-day mortality and need for further surgery), while postoperative morbidity was secondarily examined. RESULTS: Out of 1137 laparoscopic colorectal resections, 497 patients met eligibility criteria, while 45 (9.1%) developed MCRs were managed according to the standardized interdisciplinary protocol. Revisional surgery was performed through either LR (66.7%) or (33.3%). Treatment failure was 13.3% overall, including additional surgery (11.1%) and 90-day mortality (6.6%) after reoperation. In both overall and anastomotic leak-specific MCRs, relaparoscopy resulted in minimized length of hospital stay, postoperative morbidity, and intensity of care. CONCLUSIONS: Relaparoscopy for MCR preserves clinical benefits related to minimally invasive colorectal surgery. Further studies should investigate applicative determinants and impediments related to the center volume.

Preexisting Immunity Drives the Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Current treatment for patients with locally advanced esophageal adenocarcinoma (EAC) is neoadjuvant chemotherapy (nCT), alone or combined with radiotherapy, before surgery. However, fewer than 30% of treated patients show a pathologic complete response to nCT, which correlates with increased 5-year survival compared with nonresponders. Understanding the mechanisms of response to nCT is pivotal to better stratify patients and inform more efficacious therapies. Here, we investigated the immune mechanisms involved in nCT response by multidimensional profiling of pretreatment tumor biopsies and blood from 68 patients with EAC (34 prospectively and 34 retrospectively collected), comparing complete responders versus nonresponders to nCT. At the tumor level, complete response to nCT was associated with molecular signatures of immune response and proliferation, increased putative antitumor tissue-resident memory CD39+ CD103+ CD8+ T cells, and reduced immunosuppressive T regulatory cells (Treg) and M2-like macrophages. Systemically, complete responders showed higher frequencies of immunostimulatory CD14+ CD11c+ HLA-DRhigh cells, and reduced programmed cell death ligand 1-positive (PD-L1+) monocytic myeloid-derived suppressor cells, along with high plasma GM-CSF (proinflammatory) and low IL4, CXCL10, C3a, and C5a (suppressive). Plasma proinflammatory and suppressive cytokines correlated directly and inversely, respectively, with the frequency of tumor-infiltrating CD39+ CD103+ CD8+ T cells. These results suggest that preexisting immunity in baseline tumor drives the clinical activity of nCT in locally advanced EAC. Furthermore, it may be possible to stratify patients based on predictive immune signatures, enabling tailored neoadjuvant and/or adjuvant regimens. SIGNIFICANCE: Multidimensional profiling of pretreatment esophageal adenocarcinoma shows patient response to nCT is correlated with active preexisting immunity and indicates molecular pathways of resistance that may be targeted to improve clinical outcomes.

Endoscopic vacuum therapy versus self-expandable metal stent for treatment of anastomotic leaks < 30 mm following oncologic Ivor-Lewis esophagectomy: a matched case-control study.

BACKGROUND: Management of anastomotic leaks after Ivor-Lewis esophagectomy remains a challenge. Although intracavitary endoscopic vacuum therapy (EVT) has shown great efficacy for large dehiscences, the optimal management of smaller leaks has not been standardized. This study aims to compare EVT versus self-expandable metal stent (SEMS) in the treatment of leaks < 30 mm in size, due to the lack of current data on this topic. METHODS: Patients undergoing EVT (cases) or SEMS (controls) between May 2017 and July 2022 for anastomotic leaks < 3 cm following oncologic Ivor-Lewis esophagectomy were enrolled. Controls were matched in a 1:1 ratio based on age (± 3 years), BMI (± 3 kg/m2) and leak size (± 4 mm). RESULTS: Cases (n = 22) and controls (n = 22) showed no difference in baseline characteristics and leak size, as per matching at enrollment. No differences were detected between the two groups in terms of time from surgery to endoscopic treatment (p = 0.11) or total number of procedures per patient (p = 0.05). Remarkably, the two groups showed comparable results in terms of leaks resolution (90.9% vs. 72.7%, p = 0.11). The number of procedures per patient was not significant between the two cohorts (p = 0.05). The most frequent complication in the SEMS group was migration (15.3% of procedures). CONCLUSION: EVT and SEMS seem to have similar efficacy outcomes in the treatment of anastomotic defects < 30 mm after Ivor-Lewis esophagectomy. However, larger studies are needed to corroborate these findings.

Targeted therapy for intractable cancer on the basis of molecular profiles: An open-label, phase II basket trial (Long March Pathway).

Purpose: We evaluated he effects of molecular guided-targeted therapy for intractable cancer. Also, the epidemiology of druggable gene alterations in Chinese population was investigated. Materials and methods: The Long March Pathway (ClinicalTrials.gov identifier: NCT03239015) is a non-randomized, open-label, phase II trial consisting of several basket studies examining the molecular profiles of intractable cancers in the Chinese population. The trial aimed to 1) evaluate the efficacy of targeted therapy for intractable cancer and 2) identify the molecular epidemiology of the tier II gene alterations among Chinese pan-cancer patients. Results: In the first stage, molecular profiles of 520 intractable pan-cancer patients were identified, and 115 patients were identified to have tier II gene alterations. Then, 27 of these 115 patients received targeted therapy based on molecular profiles. The overall response rate (ORR) was 29.6% (8/27), and the disease control rate (DCR) was 44.4% (12/27). The median duration of response (DOR) was 4.80 months (95% CI, 3.33-27.2), and median progression-free survival (PFS) was 4.67 months (95% CI, 2.33-9.50). In the second stage, molecular epidemiology of 17,841 Chinese pan-cancer patients demonstrated that the frequency of tier II gene alterations across cancer types is 17.7%. Bladder cancer had the most tier-II alterations (26.1%), followed by breast cancer (22.4%), and non-small cell lung cancer (NSCLC; 20.2%). Conclusion: The Long March Pathway trial demonstrated a significant clinical benefit for intractable cancer from molecular-guided targeted therapy in the Chinese population. The frequency of tier II gene alterations across cancer types supports the feasibility of molecular-guided targeted therapy under basket trials.

Endoscopic Vacuum Therapy (EVT) versus Self-Expandable Metal Stent (SEMS) for Anastomotic Leaks after Upper Gastrointestinal Surgery: Systematic Review and Meta-Analysis.

BACKGROUND: Endoscopic treatment of post-esophagectomy/gastrectomy anastomotic dehiscence includes Self-Expandable Metal Stents (SEMS), which have represented the "gold standard" for many years, and Endoscopic Vacuum Therapy (EVT), which was recently introduced, showing promising results. The aim of the study was to compare outcomes of SEMS and EVT in the treatment of post-esophagectomy/gastrectomy anastomotic leaks, focusing on oncologic surgery. METHODS: A systematic search was performed on Pubmed and Embase, identifying studies comparing EVT versus SEMS for the treatment of leaks after upper gastro-intestinal surgery for malignant or benign pathologies. The primary outcome was the rate of successful leak closure. A meta-analysis was conducted, performing an a priori-defined subgroup analysis for the oncologic surgery group. RESULTS: Eight retrospective studies with 357 patients were eligible. Overall, the EVT group showed a higher success rate (odd ratio [OR] 2.58, 95% CI 1.43-4.66), a lower number of devices (pooled mean difference [pmd] 4.90, 95% CI 3.08-6.71), shorter treatment duration (pmd -9.18, 95% CI -17.05--1.32), lower short-term complication (OR 0.35, 95% CI 0.18-0.71) and mortality rates (OR 0.47, 95% CI 0.24-0.92) compared to stenting. In the oncologic surgery subgroup analysis, no differences in the success rate were found (OR 1.59, 95% CI 0.74-3.40, I2 = 0%). CONCLUSIONS: Overall, EVT has been revealed to be more effective and less burdened by complications compared to stenting. In the oncologic surgery subgroup analysis, efficacy rates were similar between the two groups. Further prospective data need to define a unique management algorithm for anastomotic leaks.

Sarcopenia and Patient's Body Composition: New Morphometric Tools to Predict Clinical Outcome After Ivor Lewis Esophagectomy: a Multicenter Study.

BACKGROUND: The impact of preoperative body composition as independent predictor of prognosis for esophageal cancer patients after esophagectomy is still unclear. The aim of the study was to explore such a relationship. METHODS: This is a multicenter retrospective study from a prospectively maintained database. We enrolled consecutive patients who underwent Ivor-Lewis esophagectomy in four Italian high-volume centers from May 2014. Body composition parameters including total abdominal muscle area (TAMA), visceral fat area (VFA), and subcutaneous fat area (SFA) were determined based on CT images. Perioperative variables were systematically collected. RESULTS: After exclusions, 223 patients were enrolled and 24.2% had anastomotic leak (AL). Sixty-eight percent of patients were sarcopenic and were found to be more vulnerable in terms of postoperative 90-day mortality (p = 0.028). VFA/TAMA and VFA/SFA ratios demonstrated a linear correlation with the Clavien-Dindo classification (R = 0.311 and 0.239, respectively); patients with anastomotic leak (AL) had significantly higher VFA/TAMA (3.56 ± 1.86 vs. 2.75 ± 1.83, p = 0.003) and VFA/SFA (1.18 ± 0.68 vs. 0.87 ± 0.54, p = 0.002) ratios. No significant correlation was found between preoperative BMI and subsequent AL development (p = 0.159). Charlson comorbidity index correlated significantly with AL (p = 0.008): these patients had a significantly higher index (≥ 5). CONCLUSION: Analytical morphometric assessment represents a useful non-invasive tool for preoperative risk stratification. The concurrent association of sarcopenia and visceral obesity seems to be the best predictor of AL, far better than simple BMI evaluation, and potentially modifiable if targeted with prehabilitation programs.

Disentangling the Effect of Pressure and Mixing on a Mechanochemical Bromination Reaction by Solid-State NMR Spectroscopy.

Mechanical forces, including compressive stresses, have a significant impact on chemical reactions. Besides the preparative opportunities, mechanochemical conditions benefit from the absence of any organic solvent, the possibility of a significant synthetic acceleration and unique reaction pathways. Together with an accurate characterization of ball-milling products, the development of a deeper mechanistic understanding of the occurring transformations at a molecular level is critical for fully grasping the potential of organic mechanosynthesis. We herein studied a bromination of a cyclic sulfoximine in a mixer mill and used solid-state nuclear magnetic resonance (NMR) spectroscopy for structural characterization of the reaction products. Magic-angle spinning (MAS) was applied for elucidating the product mixtures taken from the milling jar without introducing any further post-processing on the sample. Ex situ 13 C-detected NMR spectra of ball-milling products showed the formation of a crystalline solid phase with the regioselective bromination of the S-aryl group of the heterocycle in position 4. Completion is reached in less than 30 minutes as deduced from the NMR spectra. The bromination can also be achieved by magnetic stirring, but then, a longer reaction time is required. Mixing the solid educts in the NMR rotor allows to get in situ insights into the reaction and enables the detection of a reaction intermediate. The pressure alone induced in the rotor by MAS is not sufficient to lead to full conversion and the reaction occurs on slower time scales than in the ball mill, which is crucial for analysing mixtures taken from the milling jar by solid-state NMR. Our data suggest that on top of centrifugal forces, an efficient mixing of the starting materials is required for reaching a complete reaction.

Relaparoscopy in the management of post-operative complications after minimally invasive gastrectomy for gastric cancer.

Laparoscopy has already been validated for treatment of early gastric cancer. Despite that, no data have been published about the possibility of a minimally invasive approach to surgical complications after primary laparoscopic surgery. In this multicentre study, we describe our experience in the management of complications following laparoscopic gastrectomy for gastric cancer. A chart review has been performed over data from 781 patients who underwent elective gastrectomy for gastric cancer between January 1996 and July 2020 in two high referral department of gastric surgery. A fully descriptive analysis was performed, considering all the demographic characteristics of patients, the type of primary procedure and the type of complication which required reoperation. Moreover, a logistic regression was designed to investigate if either the patients or the primary surgery characteristics could affect conversion rate during relaparoscopy. Fifty-one patients underwent reintervention after elective laparoscopic gastric surgery. Among patients who received a laparoscopic reintervention, 11 patients (34.3%) required a conversion to open surgery. Recovery outcomes were significantly better in patients who completed the reoperation through laparoscopy. Relaparoscopy is safe and effective for management of complications following laparoscopic gastric surgery and represent a useful tool both for re-exploration and treatment, in expert and skilled hands.

Post-esophagectomy tracheobronchoesophageal fistula: management and results of a tertiary referral center.

A tracheobronchoesophageal fistula (TBEF) is a rare but life-threatening complication after esophagectomy. The existing literature on TBEF management is limited and many previous recommendations are contradictory. We aimed to describe our series of TBEF after esophagectomy and compare it with other reported series. Patients who developed a TBEF after esophagectomy were identified retrospectively. Baseline and intraoperative characteristics, postoperative and TBEF details, treatments for TBEF, and main outcomes are described. A univariate analysis was performed to compare some of the analyzed variables with the overall sample. Finally, our results are compared with the previously described series. Altogether, 16 patients with TBEF (3.11%) were analyzed from 514 patients who received esophagectomies between January 2014 and February 2020. As a first treatment attempt, 14 (87.5%) were treated with surgery, one was treated conservatively, and one was treated endoscopically. Surgery both at a first or second treatment attempt achieved a survival rate of 62.5% and oral intake at discharge of 43.75%. Six patients died during their hospital stay (37.5%). The presence of an anastomotic leak showed a strong association with TBEF development (100% vs. 19.7%; OR 1.163, 95% CI 1.080-1.253, p = 0.000). In our experience, surgical treatment as the first approach for TBEF associated with anastomotic leak after esophagectomy obtained good results. However, there is an urgent need to elaborate treatment guidelines based on international consensus.

Application of ERAS protocols in esophagogastric emergency surgery: is it feasible and does it make sense?

Management and treatment of esophagogastric diseases have been evolving in terms of multimodal approach and quality of care. The recent introduction of standardized perioperative protocols has represented the opportunity to homogenize the multiple factors enhancing patients' recovery after surgery worldwide. A further optimization would lead to the extension of the ERAS program to upper GI emergencies. This review provides a comprehensive collection of scientific basis, current supporting evidence, and potential applicative limitations.

Analysis of Compliance with Enhanced Recovery After Surgery (ERAS) Protocol for Esophagectomy.

BACKGROUND: ERAS guidelines have provided an effective recovery approach for esophagectomy. This study aimed to identify the relationship between the length of hospital stay (LOS) and compliance with clinical benchmarks of an established institutional ERAS program. METHODS: A single-center prospective database of esophageal cancer patients was retrospectively analyzed between January 2016 and January 2020. All patients underwent surgery within a standardized ERAS pathway for esophagectomy. Compliance with individual ERAS benchmarks and postoperative outcomes were evaluated according to patient's LOS; accelerated (≤ 6 days, AR), targeted (7-8 days, TR), and delayed recovery (≥ 9 days, DR). RESULTS: The study included 100 consecutive patients undergoing esophagectomy with a median LOS of 7 (3.8-40.8) days, and a 30-day readmission rate of 12.6%. LOS was not affected by comorbidities, tumor type or stage, neoadjuvant therapy, operative approach or anastomotic leak. Postoperative complications were 49.5%, and 90-day mortality was 3.8%. AR, TR, and DL were achieved by 45%, 31%, and 24% of patients, respectively. Postoperative morbidity differed significantly among groups, impacting LOS (p < 0.001). Overall compliance with ERAS protocol was 82.7% and adherence to specific benchmarks was initially (< 48 h) high, but significantly affected by postoperative complications afterwards. CONCLUSIONS: Adherence to recovery benchmarks in patients undergoing esophagectomy is most commonly impacted by postoperative complications. In esophageal cancer surgery, the adherence to ERAS benchmarks after esophagectomy should be regularly audited. Modification to ERAS protocols to increase application in patients with complications should be considered.

Does immunotherapy change the treatment paradigm in metastatic gastric cancer?

Gastric cancer represents one of the leading causes of cancer-related death worldwide. Even if the last decade has witnessed an improvement in surgical and systemic treatments, with an increase of overall life expectancy, survival rates still remain unsatisfactory, especially for patients with metastatic disease. Systemic therapies represent the gold standard in the management of stage IV gastric cancer. In this scenario, the availability of effective second and third lines has represented for a long time the only hope to offer an overall survival improvement to these patients. Recently, the advent of immune checkpoint inhibitors has involved also gastric cancer with encouraging efficacy data in the metastatic setting, becoming integral part of the management of selected patients.

Applicative Limitations of Indocyanine Green Fluorescence Assistance to Laparoscopic Lymph Node Dissection in Total Gastrectomy for Cancer.

BACKGROUND: Indocyanine green (ICG) fluorescence has been recently introduced as a novel imaging technique improving the accuracy of lymph node (LN) dissection in gastric cancer (GC) surgery, although procedure standardization and achievements have not been clearly defined. This study analyzed the feasibility and effectiveness of ICG-guidance for laparoscopic D2-lymphadenectomy during total gastrectomy for cancer. METHODS: This study retrospectively analyzed a single-center series of patients who underwent laparoscopic total gastrectomy for cancer between April 2015 and August 2021. All patients underwent surgery with standard D2 LN dissection. Intraoperative ICG-fluorescence was institutionally implemented in April 2018 and was performed routinely afterward. Primary outcomes were LN harvest and ratio. Secondary endpoints included operative time and subgroup analysis to assess variables potentially affecting LN retrieval. RESULTS: The study population included 102 patients, and ICG-fluorescence was applied in 38 (37.3%). ICG and no-ICG groups presented similar median age, gender proportions, ASA score and comorbidities (age-adjusted Charlson Comorbidity Index), body mass index, and advanced pathological stage. The median of LNs retrieved was significantly higher after the intraoperative ICG-guidance (44 vs. 32; p = 0.004), although this association was not significant after neoadjuvant therapy or among patients with positive LNs. Lymph node ratio and operative time were not significantly impacted by ICG fluorescence. Multivariate analysis identified the ICG-assistance as the only independent determinant for LN harvest (p = 0.029). CONCLUSIONS: ICG-guidance contributes to a significantly wider LN retrieval after laparoscopic D2-lymphadenectomy during total gastrectomy for cancer. However, neoadjuvant therapy and positive LN stage appeared to limit the procedural effectiveness to ICG-assisted LN identification.

Impact of Early Jejunostomy Tube Feeding on Clinical Outcome and Parameters of Body Composition in Esophageal Cancer Patients Receiving Multimodal Therapy.

BACKGROUND: Malnutrition commonly affects patients with esophageal cancer and has the potential to negatively influence treatment outcomes. The aim of this study was to investigate the impact of early (preoperative) jejunostomy tube feeding (JTF) in nutritionally 'high risk' patients receiving multimodal therapy for esophageal cancer. METHODS: Patients were selected to undergo early JTF during neoadjuvant chemoradiotherapy (nCRT) in accordance with European Society for Clinical Nutrition and Metabolism (ESPEN) and Enhanced Recovery after Surgery (ERAS®) Society guidelines. Clinical outcomes were compared with patients who received routine JTF from the time of esophagectomy. Body composition was determined from computed tomography (CT) images acquired at diagnosis, after nCRT, and ≥ 3 months after surgery. RESULTS: In total, 81 patients received early JTF and 91 patients received routine JTF. Patients who received early JTF had lower body mass index (BMI; 26.1 ± 4.6 vs. 28.4 ± 4.9; p = 0.002), greater weight loss, and worse performance status at diagnosis. Groups were otherwise well-matched for baseline characteristics. Rate of re-intubation (8.8% vs. 1.1%; p = 0.027), pulmonary embolism (5.0% vs. 0.0%; p = 0.046), and 90-day mortality (10.0% vs. 1.1%; p = 0.010) were worse in the early JTF group; however, overall survival was equivalent for both the early and routine JTF groups (p = 0.053). Wide variation in the degree of preoperative muscle loss and total adipose tissue loss was observed across the entire study cohort. Relative preoperative muscle and adipose tissue loss in patients with early and routine JTF was equivalent. CONCLUSIONS: In patients determined to be at 'high risk' of malnutrition, early JTF may prevent excess morbidity after esophagectomy with an associated relative preservation of parameters of body composition.