The Near-infrared Visualization and Pre-emptive Ligation of the Thoracic Duct Effectively Reduce the Chyle Leak Incidence After Minimally Invasive Esophagectomy.

OBJECTIVE: The aim of the present study is to assess the effectiveness of indocyanine-green (ICG)-guided lymphography (ICG-Lg) in reducing the incidence of chyle leak (CL) after esophagectomy. BACKGROUND: Chylothorax may severely impact esophageal cancer surgery, and the pre-emptive ligation of the thoracic duct (TD) is the most widespread control of this complication. Intraoperative ICG-Lg has been recently embedded in minimally invasive esophagectomy to facilitate TD detection and pre-emptive ligation. METHODS: This retrospective analysis included consecutive patients who underwent minimally invasive Ivor Lewis esophagectomy for cancer at a tertiary referral center between January 2018 and August 2023. Patients were routinely submitted to extended lymphadenectomy with TD ligation and removal. All patients treated after January 2021 underwent ICG-Lg for TD identification and ligation (ICG group) and compared to the previous series (no-ICG group). The primary outcome was the incidence of postoperative CL, while univariate and backward stepwise multivariate logistic regression models were performed to identify associated factors. RESULTS: After including 320 patients, 151 (ICG group) were submitted to ICG-Lg before the pre-emptive TD ligation. Both groups presented similar characteristics, except for neoadjuvant therapy (P=<0.001) and preoperative comorbidities (P=0.045). Intraoperative ICG-Lg significantly reduced the incidence of postoperative CL (11.8% vs 4.6%, P=0.026) and was significantly associated with shorter median length of hospital stay (13 vs 9 days, P=0.006). However, CL after ICG-Lg was more likely to require repairing reoperation (P=0.050). CONCLUSIONS: Intraoperative ICG-Lg demonstrated significantly lower rates of CL after total minimally invasive esophagectomy and, therefore, it should be routinely embedded in the standardized surgical technique of high-volume centers for esophageal cancer.

Reconstruction Techniques and Associated Morbidity in Minimally Invasive Gastrectomy for Cancer - Insights from the GastroBenchmark and GASTRODATA databases.

OBJECTIVE/BACKGROUND: Various anastomotic and reconstruction techniques are used for minimally invasive total (miTG) and distal gastrectomy (miDG). Their effects on postoperative morbidity have not been extensively studied. METHODS: MiTG and miDG patients were selected from 9356 oncological gastrectomies performed 2017-2021 in 44 centers. Endpoints included anastomotic leakage (AL) rate and postoperative morbidity tested by multivariable analysis. RESULTS: Three major anastomotic techniques (circular stapled (CS); linear stapled (LS); hand sewn (HS)), and three major bowel reconstruction types (Roux (RX); Billroth I (BI); Billroth II (BII)) were identified in miTG (n=878) and miDG (n=3334). Postoperative complications including AL (5.2% vs. 1.1%), overall (28.7% vs. 16.3%) and major morbidity (15.7% vs. 8.2%), as well as 90-day mortality (1.6% vs. 0.5%) were higher after miTG compared with miDG. After miTG, AL rate was higher after CS (4.3%) and HS (7.9%) compared with LS (3.4%). Similarly, major complications (LS: 9.7%, CS: 16.2%, HS: 12.7%) were lowest after LS. Multivariate analysis confirmed anastomotic technique as predictive factor for AL, overall and major complications. In miDG, AL rate (BI: 1.4%, BII 0.8%, RX 1.2%), overall (BI: 14.5%, BII: 15.0%, RX: 18.7%,) and major morbidity (BI: 7.9%, BII: 9.1%, RX: 7.2%), and mortality (BI: 0%, BII: 0.1%, RY: 1.1%%) were not affected by bowel reconstruction. CONCLUSION: In oncologically suitable situations, miDG should be preferred to miTG, as postoperative morbidity is significantly lower. LS should be a preferred anastomotic technique for miTG in Western Centers. Conversely, bowel reconstruction in DG may be chosen according to surgeon's preference.

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.

Molecular Recognition in Mechanochemistry: Insights from Solid-State NMR Spectroscopy.

Molecular-recognition events are highly relevant in biology and chemistry. In the present study, we investigated such processes in the solid state under mechanochemical conditions using the formation of racemic phases upon reacting enantiopure entities as example. As test systems, α-(trifluoromethyl)lactic acid (TFLA) and the amino acids serine and alanine were used. The effects of ball-milling and resonant acoustic mixing (RAM) on the formation of racemic phases were probed by using solid-state Nuclear Magnetic Resonance (NMR) spectroscopy. In a mixer mill, a highly efficient and fast racemic phase formation occurred for both TFLA and the two amino acids. RAM led to the racemic phase for TFLA also, and this process was facilitated upon employing pre-milled enantiopure entities. In contrast, under comparable conditions RAM did not result in the formation of racemic phases for serine and alanine.

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.

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.

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.

Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine.

In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin. This work contributes to the elucidation of a reaction mechanism that has been subjected to a number of interpretations over time and paints a clear picture of how mechanosynthesis can be applied and optimized for the preparation of added-value molecules.

ERAS guidelines-driven upper gastrointestinal contrast study after esophagectomy.

BACKGROUND: Early nasogastric tube (NGT) removal is a component of enhanced recovery after surgery (ERAS) protocol for esophagectomy. The aim of this study is to assess a protocol-driven application of UGI contrast study to facilitate early NGT removal and direct a standardized therapeutic response in patients with evidence for delayed gastric conduit emptying (DGCE). METHODS: All patients undergoing esophagectomy between January 2017 and October 2019 were prospectively enrolled. Esophageal resections were performed through different surgical approaches involving gastric conduit reconstruction. A standardized clinical protocol (SCP) was systematically applied, which targeted a UGI contrast study on POD 2-3 to allow immediate NGT removal or initiate DGCE protocols. RESULTS: This study enrolled 50 patients undergoing open Ivor Lewis (42%), left thoracoabdominal (46%), and three-field procedure (12%) with gastric conduit reconstruction and either upper thoracic (66%) or cervical (34%) anastomosis. Jejunostomy was routinely placed while pyloric procedures were not performed. Patients achieving targeted contrast study (86%) demonstrated significantly earlier NGT removal (p-value 0.010), oral protocol initiation (0.001), and decreased length of hospital stay (6 vs 10 days, 0.024). Four patients (8%) presented with radiology signs of DCGE and underwent protocoled treatment, eventually achieving discharge similar to the overall study population (7 vs 8.5 days). CONCLUSIONS: Protocol-driven UGI contrast study can effectively provide objective data facilitating early NGT removal and discharge. Patients with DGCE can successfully undergo intervention to improve conduit emptying and adhere to ERAS discharge goals.

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.

Impact of standardized clinical pathways on esophagectomy: a systematic review and meta-analysis.

Esophageal surgery is historically associated with adverse postoperative outcomes. Selected high-volume centers have previously reported the effect on clinical outcomes following the adoption of a standardized clinical pathway (SCP). This meta-analysis aims to evaluate the current literature to document the effect of SCP and enhanced recovery after surgery (ERAS) on esophagectomy outcomes. A literature search was conducted through the main search engines (PubMed, Embase, Medline, and Cochrane database) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. All eligible comparative studies (randomized control trial, prospective, retrospective, and combined) were identified and assessed based on Methodological Index for Non-Randomized Studies and Jadad quality criteria. Data concerning overall morbidity, early mortality, and length of stay (LOS) were primarily collected and compared. Secondary outcomes included anastomotic leaks, pulmonary complications, and readmission rate. Twenty-six articles (including five randomized controlled trials and six prospective trials) were included in the analysis. Overall study quality was moderate and the included studies utilized a variable approach to SCP. No statistically significant differences were found between groups in terms of overall morbidity, postoperative mortality, anastomotic leak, and readmission rates. Significant improvements included pulmonary complications (odds ratios [OR] 0.66, 95% confidence interval [CI] 0.49-0.94) and hospital LOS (OR -3.68, 95% CI -4.49 to -2.87). Previous reports of SCP within esophagectomy programs have demonstrated clinical improvements in postoperative pulmonary complications and LOS. Given the high heterogeneity historically demonstrated within SCPs, further improvement in outcomes should be expected following the adoption of standardized ERAS guidelines.

Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.

This study seeks to define long-term variation in body composition in patients undergoing esophagectomy for cancer and to associate those changes with survival. Assessment of skeletal muscle, visceral (VAT) and subcutaneous adipose tissue (SAT) was performed using computed tomography (CT) images routinely acquired: at diagnosis; after neoadjuvant therapy, and; >6 months after esophagectomy. In cases where multiple CT scans were performed >6 months after surgery, all available images were assessed. Ninty-seven patients met inclusion criteria with a median of 2 (range 1-10) postoperative CT images acquired between 0.5 and 9.7 years after surgery. Following surgical treatment of esophageal cancer, patients lost on average 13.3% of their skeletal muscle, 64.5% of their VAT and 44.2% of their SAT. Sarcopenia at diagnosis was not associated with worse overall survival (66.3% vs. 68.5%; P = 0.331). Sarcopenia 1 year after esophagectomy was however associated with lower 5-year overall survival (53.8% vs. 87.5%; P = 0.019). Survival was lower in those patients who had >10% decrease in skeletal muscle index (SMI; 33.3% vs. 72.1%; P = 0.003) and >40% decrease in SAT 1 year after surgery (40.4% vs. 67.4%; P = 0.015). On multivariate analysis, a decline in SMI 1 year after surgery was predictive of worse survival (HR 0.38, 95%CI 0.20-0.73; P = 0.004). This study provides new insight relating to long-term variation in body composition in patients undergoing esophagectomy for cancer. Findings provide further evidence of the importance of body composition, in particular depletion of skeletal muscle, in predicting survival following esophagectomy.

Early Red Flags Associated with Delayed Discharge in Patients Undergoing Gastrectomy: Analysis of Perioperative Variables and ERAS Protocol Items.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) perioperative pathways are safe and effective for patients undergoing gastrectomy. However, adherence to these protocols varies and is generally underreported. This retrospective study aimed to assess whether perioperative variables or deviation from ERAS items is associated with delayed discharge after gastrectomy. METHODS: All patients undergoing gastrectomy at our institution were managed with a standardised perioperative pathway according to ERAS principles. The target length of stay was set as the ninth post-operative day (POD). All significant variables were derived from a bivariate analysis and were entered into a logistic regression to confirm their statistical value. RESULTS: The study included 180 patients. Multivariate regression analysis revealed that incomplete immunonutrition, failure to extubate the patient at the end of surgery, intraoperative crystalloids >2150 ml and blood transfusion >268 ml, surgery duration >195 min, and failure to mobilise patients within 24 h from surgery were associated with delayed discharge. The logistic regression model was statistically significant (p < 0.001) and correctly classified 73.6% of cases. Sensitivity and specificity were 74.1% and 73.2%, respectively. CONCLUSIONS: These results seem clinically significant and consistent with those of previous studies. The reported perioperative variables showed a strong relationship with the length of hospital stay.

Enhanced Recovery After Surgery (ERAS) Pathway in Esophagectomy: Is a Reasonable Prediction of Hospital Stay Possible?

OBJECTIVE: To assess whether perioperative variables or deviation from enhanced recovery after surgery (ERAS) items could be associated with delayed discharge after esophagectomy, and to convert them into a scoring system to predict it. SUMMARY BACKGROUND DATA: ERAS perioperative pathways have been recently applied to esophageal resections. However, low adherence to ERAS items and high rates of protocol deviations are often reported. METHODS: All patients who underwent esophagectomy between April 2012 and March 2017 were managed with a standardized perioperative pathway according to ERAS principles. The target length of stay was set at eighth postoperative day (POD). All significant variables at bivariate analysis were entered into a logistic regression to produce a predictive score. An initial validation of the score accuracy was carried out on a separate patient sample. RESULTS: Two hundred eighty-six patients were included in the study. Multivariate regression analysis showed that American Society of Anesthesiology score ≥ 3, surgery duration > 255 min, "nonhybrid" esophagectomy, and failure to mobilize patients within 24 h from surgery were associated with delayed discharge. The logistic regression model was statistically significant (P < 0.001) and correctly classified 81.9% of cases. The sensitivity was 96.6%, and the specificity was 17.6%. The prediction score applied to 23 patients correctly identified 100% of those discharged after eighth POD. CONCLUSIONS: The results of this study seem to be clinically meaningful and in line with those from other studies. The initial validation revealed good predictive properties.

Mechanochemical Activation of Iron Cyano Complexes: A Prebiotic Impact Scenario for the Synthesis of α-Amino Acid Derivatives.

Mechanochemical activation of iron cyano complexes by ball milling results in the formation of HCN, which can be trapped and incorporated into α-aminonitriles. This prebiotic impact scenario can be extended by mechanochemically transforming the resulting α-aminonitriles into α-amino amides using a chemical route related to early Earth conditions.