Association between preoperative serum zinc level and prognosis in patients with advanced esophageal cancer in the neoadjuvant treatment era.

Background: Zinc (Zn), an essential trace element, has an adverse influence on the prognosis of several cancers. However, the association between the preoperative serum Zn level and outcomes in patients with advanced esophageal cancer in the current neoadjuvant treatment era remains unclear. Methods: This study involved 185 patients with esophageal cancer who underwent R0 surgery after neoadjuvant chemotherapy from August 2017 to February 2021. We retrospectively investigated the relationship between the preoperative serum Zn level and the patients' outcomes. Results: The patients were divided into a low Zn group (<64 µg/dL) and a high Zn group (≤64 µg/dL) according to the mean preoperative serum Zn level. Low Zn had significantly worse overall survival (OS) (2-year OS rate: 76.2% vs. 83.3% in low vs. high Zn; p = 0.044). A low Zn in pathological non-responders (Grade ≤ 1a) was significantly associated with a shorter 2-year recurrence-free survival (RFS) rate (39.6% vs. 64.1% in low vs. high Zn; p = 0.032). The multivariate analysis identified low BMI and Zn level among preoperative nutritional status indices as an independent risk factor for worse RFS in non-responders. Compared with responders, pathological non-responders comprised significantly more males and a performance status of ≥1, and there was no difference in Zn level according to pathological response. Conclusion: A preoperative low Zn level had a negative impact on early recurrence in esophageal cancer patients who underwent neoadjuvant chemotherapy. This suggests the need to administer Zn supplementation to patients with esophageal cancer who have preoperative Zn deficiency.

Preoperative neutrophil-to-lymphocyte ratio predicts recurrence of esophageal squamous cell carcinoma after neoadjuvant triplet chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy followed by esophagectomy is the standard treatment for resectable advanced esophageal squamous cell carcinoma (ESCC) in Japan. Triplet chemotherapy is the standard neoadjuvant regimen. Inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR) are well-known prognostic factors for esophageal cancer. However, their usefulness in patients with resectable advanced disease undergoing esophagectomy after neoadjuvant triplet chemotherapy is unknown. METHOD: We examined 144 ESCC patients who underwent neoadjuvant triplet chemotherapy followed by esophagectomy between January 2015 and December 2020 to investigate the relationship between inflammatory markers and recurrence-free survival (RFS). Optimal marker cutoff values for RFS were determined using receiver operating characteristic curve analysis. Patients were divided into high and low NLR groups (NLR cutoff, 3.0). RESULTS: NLR was high in 61 patients and low in 83. Univariate analyses demonstrated that low NLR was significantly associated with worse RFS (p = 0.049). Multivariate analyses demonstrated that high NLR was an independent predictor of RFS (odds ratio, 1.911; 95% confidence interval, 1.098-3.327; p = 0.022). RFS significantly differed between the low and high NLR groups. RFS did not significantly differ between the patients when stratified according to the other inflammatory markers. CONCLUSION: Preoperative NLR is an easily obtained and useful predictor of RFS in patients with resectable advanced ESCC treated with neoadjuvant triplet chemotherapy followed by esophagectomy.

Neoadjuvant Chemotherapy Improves Feasibility of Larynx Preservation and Prognosis in Resectable Locally Advanced Cervical Esophageal Cancer.

BACKGROUND: The optimal strategy for cervical advanced esophageal cancer remains controversial in terms of oncologic outcome as well as vocal and swallowing function. Recently, in East Asian countries, neoadjuvant chemotherapy (NAC) has been a standard strategy for advanced esophageal cancer. METHODS: This study included 37 patients who underwent NAC, and 33 patients who underwent definitive chemoradiation therapy (dCRT) as larynx-preserving treatment for locally advanced cervical esophageal cancer from 2016 to 2021. This study retrospectively investigated outcomes, with comparison between NAC and dCRT for locally advanced cervical esophageal cancer. RESULTS: Larynx preservation was successful for all the patients with NAC and dCRT. After NAC, the rate of complete or partial response was 78.4%, and 30 patients underwent larynx-preserving surgery. On the other hand, after dCRT, the complete response rate was 71.9%, and 4 patients underwent larynx-preserving salvage surgery. Overall survival (OS) and progression free survival were similar between the two groups. However, for the patients with resectable cervical esophageal cancer (cT1/2/3), the 2-year OS rate was significantly higher with NAC (79.9%) than with dCRT (56.8%) (P = 0.022), and the multivariate analyses identified only NAC and cN0, one of the two as a significantly independent factor associated with a better OS (NAC: P = 0.041; cN0, 1: P = 0.036). CONCLUSION: The study showed that NAC as larynx-preserving surgery for resectable cervical esophageal cancer preserved function and had a better prognosis than dCRT. The authors suggest that NAC may be standard strategy for larynx preservation in patients with resectable cervical esophageal cancer.

Technical feasibility and oncological outcomes of robotic esophagectomy compared with conventional thoracoscopic esophagectomy for clinical T3 or T4 locally advanced esophageal cancer: a propensity-matched analysis.

BACKGROUND: Minimally invasive esophagectomy is the first-line approach for esophageal cancer; however, there has recently been a paradigm shift toward robotic esophagectomy (RE). We investigated the clinical outcomes of patients who underwent RE compared with those of patients who underwent conventional minimally invasive thoracoscopic esophagectomy (TE) for locally advanced cT3 or cT4 esophageal cancer using a propensity-matched analysis. METHODS: Overall, 342 patients with locally advanced cT3 or cT4 esophageal cancer underwent transthoracic esophagectomy with total mediastinal lymph node dissection between 2018 and 2022. The propensity-matched analysis was performed to assign the patients to either RE or TE by covariates of histological type, tumor location, and clinical N factor. RESULTS: Overall, 87 patients were recruited in each of the RE and TE groups according to the propensity-matched analysis. The total complication rate and the rates of the three major complications (recurrent laryngeal nerve paralysis, anastomotic leakage, and pneumonia) were not significantly different between the RE and TE groups. However, the peak C-reactive protein concentration on postoperative day 3, rate of surgical site infection, and intensive care unit length of stay after surgery were significantly shorter in the RE group than in the TE group. No significant differences were observed in the harvested total and mediastinal lymph nodes. The total operation time was significantly longer in the RE group, while the thoracic operation time was shorter in the RE group than in the TE group. There was no significant difference between the two groups in the recurrence rate of oncological outcomes after surgery. CONCLUSION: RE may facilitate early recovery after esophagectomy with total mediastinal lymph node dissection and has the same technical feasibility and oncological outcomes as TE.

A new scope warmer/cleaner for laparoscopic surgery: a disposable hot pack.

BACKGROUND: Fogging and staining of a laparoscope lens negatively impact surgical visualization. We hypothesized that the disposable hot pack could not only warm but also clean laparoscopes. Hence, this study verified and developed the disposable hot pack with anti-fogging and cleaning function. MATERIAL AND METHODS: The laparoscope was inserted into a swine abdominal cavity for five minutes. Then, the laparoscopic tip was heated with 65 °C saline or the folded disposable hot pack with nonwoven fabric coated surfactant for ten seconds (n = 15). Also, a laparoscopic tip with dirt was wiped with the prototype or conventional gauze for 10 s (n = 10). The dirt, fogging, and temperature of the laparoscopic tip were respectively evaluated after the laparoscope was inserted into the abdominal cavity. RESULTS: The laparoscopic tip temperature five minutes after insertion into the abdominal cavity was similar (31.1 °C vs 31.2 °C, p = 0.748) and there was no fogging in both methods. The conventional gauze had significantly less temperature of the laparoscopic tip after cleaning and higher fogging occurrence than the prototype (29.5 °C vs 34.0 °C, p < 0.001, 30% vs 0%, p = 0.030, respectively), although there was no dirt left after both methods. CONCLUSION: The disposable hot pack has a strong potential as an anti-fogging and cleaning device for use during laparoscopic surgery.

Significance of Surgery for Resectable M1 Lymph Node Metastases Without Organ Metastasis in Esophageal Carcinoma in the Era of Neoadjuvant Treatment.

BACKGROUND: M1 esophageal carcinoma goes beyond localized disease and requires treatment with systemic therapy. M1 status is primarily divided into two categories: M1 lymph node metastasis and distant organ metastasis. Oligometastasis is defined as a state of limited metastatic disease, and surgery for oligometastasis of distant organs is reported to be beneficial in limited conditions. The aim of this study was to investigate resected cases of M1 lymph node metastases as the only metastatic site in stage IVB esophageal carcinoma. PATIENTS AND METHODS: This study was a single-center retrospective cohort study. Patients with esophageal carcinoma who underwent esophagectomy with curative intent between April 2017 and December 2021 were examined. Neoadjuvant chemotherapy was our standard therapy and administered in almost all cases. We hypothesized that four sites of metastatic M1LN (supraclavicular (no. 104), pretracheal (no. 106pre), posterior thoracic para-aortic (no. 112aoP), and abdominal para-aortic (no. 16a2lat) LNs) were potentially resectable M1LN (rM1LN) metastases with curative intent and compared the prognosis of patients with and without rM1LN metastasis. RESULTS: Six hundred eight-two patients were included in the study. Among these patients, 80 had rM1LN metastasis and received surgery for curative intent. Short-term safety outcomes were equivalent between patients with and without rM1LN metastases. After propensity score matching, there were no significant differences in overall survival between patients with and without rM1LN metastasis. Multivariate analyses revealed that the only independent prognostic factor was ypN status. CONCLUSION: The present study suggests the feasibility and favorable OS in the patients with resection of rM1LN metastasis.

Nonadditivities of the Particle Sizes Hidden in Model Pair Potentials and Their Effects on Physical Adsorptions.

It is important to understand the mechanism of colloidal particle assembly near a substrate for development of drug delivery systems, micro-/nanorobots, batteries, heterogeneous catalysts, paints, and cosmetics. Understanding the mechanism is also important for crystallization of the colloidal particles and proteins. In this study, we calculated the physical adsorption of colloidal particles on a flat wall mainly using the integral equation theory, wherein small and large colloidal particles were employed. In the calculation system, like-charged electric double-layer potentials were used as pair potentials. In some cases, it was found that the small particles are more easily adsorbed. This result is unusual from the viewpoint of the Asakura-Oosawa theory, and we call it a "reversal phenomenon". Theoretical analysis revealed that the reversal phenomenon originates from the nonadditivities of the particle sizes. Using the knowledge obtained from this study, we invented a method to analyze the size nonadditivity hidden in model pair potentials. The method will be useful for confirmation of various simulation results regarding the adsorption and development of force fields for colloidal particles, proteins, and solutes.

Randomized controlled trial of new hemostatic material "sodium calcium alginate" in a preclinical model.

BACKGROUND: The demand for nonbiological hemostatic materials has increased in surgical practice; however, few have sufficient hemostatic efficacy. This study investigated whether optimizing the composition of sodium calcium alginate, which forms a stable gel, improves hemostatic efficacy. METHODS: The sodium calcium alginate was changed for each composition, including powder size, calcium substitution rate, molecular weight, and mannuronic/guluronic acid ratio. The hemostasis in liver punch-out injury and bleeding was evaluated using swine. For the study, sodium calcium alginate with different compositions was randomly applied to bleeding sites. Previous hemostatic materials, including cellulose and sodium alginate, were used as a control. We investigated hemostasis at 2 and 5 minutes after application. RESULTS: Each powder size (53-150 µm, 150-250 µm, 53-250 µm) had a similar hemostatic effect. However, the hemostatic rate was significantly higher in sodium calcium alginate than in previous hemostatic materials (P value < .01). A 74.1% calcium substitution rate had the highest hemostasis at 2 and 5 minutes after application (2 minutes: 100%, 5 minutes: 95.2%). Regarding molecular weight, the hemostatic rate was significantly higher in 333,000 than in 50,000 (2 minutes: 95% vs 70%, 5 minutes: 95% vs 70%, P = .038). Moreover, a 1.9 mannuronic/guluronic acid ratio had the highest hemostasis compared with the 0.4 mannuronic/guluronic acid ratio (2 minutes: 58.8% vs 11.8%, 5 minutes: 58.8% vs 0%, P = .033) CONCLUSION: The composition of sodium calcium alginate with a high hemostatic effect was optimized. This new hemostatic material demonstrated potential usefulness for bleeding during surgery.

Three-Course Neoadjuvant Chemotherapy Associated with Unfavorable Survival of Non-responders to the First Two Courses for Locally Advanced Esophageal Cancer.

BACKGROUND: Three-course neoadjuvant chemotherapy (NAC) followed by surgery has become a standard of care for locally advanced esophageal cancer (EC). However, some patients occasionally experience a poor tumor response to the third course and have a poor clinical outcome. METHODS: An exploratory analysis of data from the authors' recent multicenter randomized phase 2 trial compared patients with locally advanced EC who received two courses (n = 78) and those who received three courses (n = 68) of NAC. The association between tumor response and clinico-pathologic factors, including survival, was evaluated to identify risk factors in the three-course group. RESULTS: Of 68 patients who received three courses of NAC, 28 (41.2%) had a tumor reduction rate lower than 10% during the third course. This rate was associated with unfavorable overall survival (OS) and progression-free survival (PFS) compared with a tumor reduction rate of 10% or higher (2-year OS rate: 63.5% vs. 89.3%, P = 0.007; 2-year PFS rate: 52.6% vs. 79.7%, P = 0.020). The independent prognostic factors for OS were tumor reduction rate lower than 10% during the third course (hazard ratio [HR], 2.735; 95% confidence interval [CI] 1.041-7.188; P = 0.041) and age of 65 years or older (HR, 9.557, 95% CI 1.240-73.63; P = 0.030). Receiver operating characteristic curve and multivariable logistic regression analyses identified a tumor reduction rate lower than 50% after the first two courses as an independent predictor of a tumor reduction rate lower than 10% during the third course of NAC (HR, 4.315; 95% CI 1.329-14.02; P = 0.015). CONCLUSION: Continuing NAC through a third course may worsen survival for patients who do not experience a response to the first two courses in locally advanced EC.

Mechanism underlying lens fogging and its countermeasure in laparoscopic surgery.

BACKGROUND: During laparoscopic surgery, visualization is fogged due to the influence of temperature. Fogging on the laparoscopic lens heightens the difficulty of the procedure. Therefore, the aim of this study was to analyse thermodynamics in laparoscopy. MATERIAL AND METHODS: A temperature sensor was attached to the laparoscopic tip and the abdominal cavity of five swine under general anaesthesia. The laparoscope was inserted into the abdominal cavity for five minutes after heating its tip with 65 °C saline for 10-300 s. The defogged laparoscope was wiped at room temperature for 10-300 s. Then, the laparoscope was inserted into the abdominal cavity for five minutes. RESULTS: The temperature five minutes after insertion was similar for the 10-300 s heating durations (approximately 32.0 °C). There was no fogging when the laparoscope was wiped for 10-30 s. Two fogging events occurred when it was wiped for 60 s (temperature difference: -3.5 °C, -4.6 °C). Five fogging events were observed immediately after insertion when it was wiped for 300 s. CONCLUSION: This study showed that the heating time was more than ten seconds to prevent fogging. We found that fogging occurred when the laparoscopic tip temperature was 3.5 °C lower than the abdominal cavity temperature.

Low mitochondrial DNA copy number induces chemotherapy resistance via epithelial-mesenchymal transition by DNA methylation in esophageal squamous cancer cells.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most severe cancers and is characterized by chemotherapy resistance and poor prognosis associated with epithelial-mesenchymal transition (EMT). In a previous study, a low mitochondrial DNA (mtDNA) copy number was associated with poorer prognosis and induced EMT in ESCC. However, the detailed mechanism related to mtDNA copy number and EMT is unclear. The aim of this study was to clarify the mechanism by which a change in mtDNA copy number contributes to EMT and to examine treatment of chemotherapy resistance in ESCC. METHODS: The association between low mtDNA copy number and chemotherapy resistance was investigated using specimens from 88 patients who underwent surgery after neoadjuvant chemotherapy. Then, the mtDNA content of human ESCC cell lines, TE8 and TE11, was depleted by knockdown of mitochondrial transcription factor A expression. The present study focused on modulation of mitochondrial membrane potential (MMP) and DNA methylation as the mechanisms by which mtDNA copy number affects EMT. mRNA and protein expression, chemotherapy sensitivity, proliferation, MMP and DNA methylation were evaluated, and in vitro and in vivo assays were conducted to clarify these mechanisms. RESULTS: ESCC patients with decreased mtDNA copy number who underwent R0 resection after neoadjuvant chemotherapy had significantly worse pathological response and recurrence-free survival. Additionally, low mtDNA copy number was associated with resistance to chemotherapy in vitro and in vivo. mtDNA controlled MMP, and MMP depolarization induced EMT. Depletion of mtDNA and low MMP induced DNA methylation via a DNA methylation transcription factor (DNMT), and a DNMT inhibitor suppressed EMT and improved chemotherapy sensitivity in mtDNA-depleted ESCC cells, as shown by in vitro and in vivo assays. CONCLUSION: This study showed that decreased mtDNA copy number induced EMT via modulation of MMP and DNA methylation in ESCC. Therapeutic strategies increasing mtDNA copy number and DNMT inhibitors may be effective in preventing EMT and chemosensitivity resistance.

The Impact of Perioperative Fluid Balance on Postoperative Complications after Esophagectomy for Esophageal Cancer.

BACKGROUND: Perioperative fluid balance is an important indicator in the management of esophageal cancer patients who undergo esophagectomy. However, the association between perioperative fluid balance and postoperative complications after minimally invasive esophagectomy (MIE) remains unclear. METHODS: This study included 115 patients with thoracic esophageal squamous cell cancer who underwent MIE between January 2018 and January 2020. We retrospectively evaluated the association between perioperative fluid balance from during surgery to postoperative day (POD) 2, and postoperative complications. RESULTS: The patients were divided into lower group and higher group based on the median fluid balance during surgery and at POD 1 and POD 2. We found that the higher group at POD 1 (≥3000 mL) was the most important indicator of postoperative complications, such as acute pneumonia within 7 days after surgery, and anastomotic leakage (p = 0.029, p = 0.024, respectively). Moreover, the higher group at POD 1 was a significant independent factor for acute postoperative pneumonia by multivariate analysis (OR: 3.270, 95% CI: 1.077-9.929, p = 0.037). CONCLUSION: This study showed that fluid overload at POD 1 had a negative influence on postoperative complications in patients with esophageal cancer. The fluid balance must be strictly controlled during the early postoperative management of patients undergoing esophageal cancer surgery.

The stability of a novel synthetic peptide-type hemostatic material under digestive enzyme.

BACKGROUND: A synthetic peptide 'TDM-623' is a promising hemostatic material for endoscopic surgery in the gastrointestinal tract. However, its stability under gastric/pancreatic secretion has yet to be shown. Hence, this study verified the stability of TDM-623 under digestive enzyme. MATERIAL AND METHODS: TDM-623 (1 mL) was applied to a dish and left at 37 °C for gel formation. Artificial gastric/pancreatic juice and saline were applied to each dish (n = 10). The stability of TDM-623 was evaluated at 0 min-48 h. The evaluation methods were the peptide amount dissolved in the solvent measured by high-performance liquid chromatography and morphological changes revealed by photography and eosin staining, as well as physical changes found by weight. RESULTS: The amount of dissolved peptides originating from the TDM-623 gel after gastric juice exposure was negligible compared to its original amount: a maximum of 10.3% dissolved after 48 h. No significant amounts of dissolved peptides were seen at any timepoint of exposure to pancreatic juice. Also, there were neither morphological nor physical changes after exposure to digestive enzymes for 48 h. CONCLUSION: This study suggests that TDM-623 is sufficiently stable under digestive enzyme. TDM-623 is thus expected to be a durable hemostatic material that protect wound left by endoscopic surgery.

Endoscopic application of novel, infection-free, advanced hemostatic material: Its usefulness to upper gastrointestinal oozing.

Background: Self-assembling peptides (TDMs) comprise synthetic amphipathic peptides that immediately react to changes in pH and/or inorganic salts to transform into a gelatinous state. The first generation of these peptides (TDM-621) is currently used as a hemostatic agent in Europe. However, TDM-621 exhibits slow gel-formation and low retention capabilities on tissue surfaces. The second generation (TDM-623) was therefore developed to encourage faster gel-formation and better tissue-sealing capabilities. Aim: The aim of this study was to verify the efficacy of TDM-623 in terms of its hemostatic effect in endoscopic surgery. Materials and methods: Evaluation of the hemostatic effect in endoscopic surgery (animal study) was performed using eight porcine in spine position. Following systemic heparinization, we established a "bleeding model" by endoscopic grasping forceps on the anterior walls of the stomach and duodenum. In the hemostasis method, an endoscope with a distal hood was brought into contact with the bleeding point, and 1 ml TDM-623 was applied to the wound. After TDM-623 gelation, the endoscope was removed, and the acute hemostatic effect (after 2 min) was confirmed. Result: In the endoscopic bleeding model, 17 of the 23 cases (74%) showed complete hemostatic effects on the anterior wall of the stomach, and 18 of the 20 cases (80%) on the anterior wall of the duodenum, respectively. None of the applied gels were displaced from the anterior walls of the stomach and duodenum. Conclusion: The new self-assembling peptide (TDM-623) showed high hemostatic effects. TDM-623 had potential usefulness for upper gastrointestinal endoscopic surgery.

Heparinized swine models for better surgical/endoscopic training.

Introduction: Animal experiments with large living animals are essential for the development of medical devices and the training of surgical procedures. Swine are frequently used in animal experiments due to their similar size and anatomy compared to humans. However, it is well known that swine has less local bleeding than humans. The aim of the study was to verify whether animal models with appropriate local bleeding capability could be established. Methods: The activated clotting time (ACT) was measured for eight swine (piglet, 35 kg) under general anesthesia. The flexible endoscope was advanced orally, and the gastric mucosa was intentionally traumatized to bleed by biopsy forceps, and the time until spontaneous hemostasis was obtained (mucosal bleeding time). Then, heparin (50 U/kg) was administered intravenously. After 10 min, the ACT was remeasured, and the gastric mucosa was again damaged to bleed by biopsy forceps. The mucosal bleeding time was remeasured. The above measurements were repeated until the ACT exceeded 200 s. Results: The median ACT values (seconds) were 83 (no heparin), 155 (50 U/kg heparin), and 204 (100 U/kg heparin), which were significantly increased. The median mucosal bleeding times (seconds) were 152 (no heparin), 283 (50 U/kg), and 423 (100 U/kg), which were significantly extended. Conclusion: A bleeding animal model for surgical and endoscopic training was successfully established by bolus heparin administration.