Multicenter analysis on the value of standard (chemo)radiotherapy in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction. METHODS: This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65-92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated. RESULTS: Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%). CONCLUSIONS: In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study).

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

Perioperative immune checkpoint inhibitor therapy for gastric and gastroesophageal junction cancers: a review of current approaches and future perspectives.

Metastatic gastric and gastroesophageal junction cancers have been treated with chemotherapy, but the landscape of cancer treatment is rapidly shifting towards immune-based therapies. As established by the CheckMate 649 and ATTRACTION-4 trials, combination therapy with fluorouracil, platinum, and nivolumab, an immune checkpoint inhibitor, is now recognized as the standard first-line chemotherapy for HER2-negative gastric and gastroesophageal junction cancer. The potential of immune checkpoint inhibitors extends beyond metastatic disease. For locally advanced gastric and gastroesophageal junction cancer, perioperative chemotherapy with gastrectomy has been regarded as the standard of care, especially in Western nations. Besides, the introduction of immune checkpoint inhibitors as neoadjuvant and adjuvant treatments is currently underway, indicating a significant paradigm shift in the treatment strategies. This review summarizes the clinical developments and future perspectives of immune checkpoint inhibitor therapy with or without chemotherapy as perioperative treatment for gastric, esophageal, and gastroesophageal junction cancer.

Perioperative Modified FLOT Versus EOX in Locally Advanced Resectable Gastric and Gastro-Oesophageal Junction Adenocarcinoma: Results of a Matched-Pair Analysis.

BACKGROUND AND OBJECTIVES: There is limited real-world data on the efficacy of 2-weekly cycles of docetaxel, oxaliplatin, leucovorin, and fluorouracil (FLOT) compared to epirubicin, oxaliplatin, and capecitabine (EOX) as perioperative therapy in esophagogastric adenocarcinomas (EGAC). METHODS: The data of 611 patients with EGAC treated with perioperative chemotherapy and planned for curative resection between January 2013 and December 2019 were retrieved. Patients receiving EOX and a dose-modified version of FLOT (mFLOT) were evaluated. A 1:1 matching, using age, tumour location, signet ring histology, and Eastern Cooperative Oncology Group performance status, without replacement was performed by using nearest neighbour matching method. The primary endpoint of the study was 3-year event-free survival (EFS). RESULTS: A total of 593 patients (261 with EOX and 332 with mFLOT) were matched. One hundred and nighty-eight patients (76%) and 285 patients (86%) in the EOX and mFLOT cohorts underwent curative resection, respectively (p = 0.002). With a median follow-up of 35 and 53 months, respectively, the primary outcome of 3-year EFS was statistically superior in patients receiving mFLOT as compared to the EOX regimen (60% vs. 39%; p < 0.001). There was a greater incidence of grade 3 and grade 4 neutropenia (neoadjuvant: 18% vs. 2%; p < 0.001, adjuvant: 18% vs. 1%; p = 0.001) and febrile neutropenia (neoadjuvant: 8% vs. 1.1%; p < 0.001, adjuvant: 6% vs. 0; p = 0.001) with mFLOT. INTERPRETATION AND CONCLUSION: mFLOT is associated with improved resection rates and survival in comparison to EOX as perioperative therapy in gastric adenocarcinomas in this large real-world cohort, with manageable increase in clinically relevant toxicities such as grade 3 and grade 4 febrile neutropenia and neutropenia.

Breathing Exercises in Gastroesophageal Reflux Disease: A Systematic Review.

The pathogenesis of gastroesophageal reflux disease (GERD) is multifactorial. The severity of abnormal reflux burden corresponds to the dysfunction of the antireflux barrier and inability to clear refluxate. The crural diaphragm is one of the main components of the esophagogastric junction and plays an important role in preventing gastroesophageal reflux. The diaphragm, as a skeletal muscle, is partially under voluntary control and its dysfunction can be improved via breathing exercises. Thus, diaphragmatic breathing training (DBT) has the potential to alleviate symptoms in selected patients with GERD. High-resolution esophageal manometry (HRM) is a useful method for the assessment of antireflux barrier function and can therefore elucidate the mechanisms responsible for gastroesophageal reflux. We hypothesize that HRM can help define patient phenotypes that may benefit most from DBT, and that HRM can even help in the management of respiratory physiotherapy in patients with GERD. This systematic review aimed to evaluate the current data supporting physiotherapeutic practices in the treatment of GERD and to illustrate how HRM may guide treatment strategies focused on respiratory physiotherapy.

Treatments for resectable esophageal cancer: from traditional systemic therapy to immunotherapy.

ABSTRACT: Esophageal cancer (EC) has a high incidence and poor prognosis. The two major histological types, squamous cell carcinoma and adenocarcinoma, differ in their epidemiology and treatment options. Patients with locally advanced EC benefit from multimodal therapy concepts including neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy, and perioperative chemotherapy. Currently, immunotherapy for the solid tumor is a hot spot. Treatment with adjuvant immune checkpoint inhibitors (ICIs) is the first immunotherapy for resectable EC listed in the latest National Comprehensive Cancer Network Guidelines for the Esophageal and Esophagogastric Junction Cancers. Recent clinical trials have established ICIs for three treatment models of resectable EC. Their short-term results demonstrated ideal efficacy and tolerable toxicity, though some concerns remain. This review summarizes the novel data on the ICIs for resectable EC and lists the registered related clinical trials. Hopefully, this review can provide a reference for ongoing research on the treatment options for resectable EC.

The optimal neoadjuvant chemotherapy regimen for locally advanced gastric and gastroesophageal junction adenocarcinoma: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) for locally advanced gastric and gastroesophageal junction adenocarcinoma (LAGC) has been recommended in several guidelines. However, there is no global consensus about the optimum of NAC regimens. We aimed to determine the optimal NAC regimen for LAGC. METHODS: A systematic review and Bayesian network meta-analysis was performed. The literature search was conducted from inception to June 2022. The odds ratio (OR) value and 95% confidence interval (95% CI) were used for assessment of R0 resection rate and pathological complete response rate (pCR) as primary outcomes. The hazard ratio (HR) value and 95% CI were interpreted for the assessment of overall survival (OS) and disease-free survival (DFS) as second outcomes. The risk ratio (RR) value and 95% CI were used for safety assessment. RESULTS: Twelve randomized controlled trials were identified with 3846 eligible participants. The network plots for R0 resectability, OS, and DFS constituted closed loops. The regimens of TPF (taxane and platinum plus fluoropyrimidine), ECF (epirubicin and cisplatin plus fluorouracil), and PF (platinum plus fluoropyrimidine) showed a meaningful improvement of R0 resectability, as well as OS and/or DFS, compared with surgery (including surgery-alone and surgery plus postoperative adjuvant chemotherapy). Importantly, among these regimens, TPF regimen showed significant superiority in R0 resection rate (versus ECF regimen), OS (versus ECF regimen), DFS (versus PF and ECF regimens), and pCR (versus PF regimen). CONCLUSIONS: The taxane-based triplet regimen of TPF is likely the optimal neoadjuvant chemotherapy regimen for LAGC patients.

MATTERHORN: phase III study of durvalumab plus FLOT chemotherapy in resectable gastric/gastroesophageal junction cancer.

Standard-of-care for resectable gastric/gastroesophageal junction cancer includes surgery and neoadjuvant-adjuvant 5-fluorouracil-leucovorin-oxaliplatin-docetaxel (FLOT) chemotherapy. Early-phase clinical studies support further clinical development of the immune checkpoint inhibitor (ICI); durvalumab, an anti-PD-L1 antibody, in patients with gastric/gastroesophageal junction cancer. Accumulating evidence indicates that ICIs combined with FLOT chemotherapy improve clinical outcomes in patients with advanced or metastatic cancer. We describe the rationale for and the design of MATTERHORN, a randomized, double-blind, placebo-controlled, phase III study investigating the efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy followed by adjuvant durvalumab monotherapy in patients with resectable gastric/gastroesophageal junction cancer. The planned sample size is 900 patients, the primary end point is event-free survival and safety and tolerability will be evaluated. Clinical trial registration: NCT04592913 (ClinicalTrials.gov).

Perioperative treatment in resectable gastric cancer with spartalizumab in combination with fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT): a phase II study (GASPAR).

BACKGROUND: Perioperative chemotherapy and surgery are a standard of care for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, the prognosis remains poor for this population. The FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) regimen is considered as the new standard chemotherapy regimen for perioperative strategy, despite associated with a 5-year overall survival rate (OS) amounting 45% following radical surgery. Immunotherapy with antibodies that inhibit PD-1/ PD-L1 interaction has recently emerged as a new treatment option with promising and encouraging early trial results for patients with advanced or metastatic gastric or GEJ adenocarcinoma. Currently, no trials have investigated the impact of perioperative immunotherapy in combination with chemotherapy for resectable gastric or GEJ adenocarcinoma. METHODS: GASPAR trial is a multicenter open-label, nonrandomized, phase II trial to evaluate the efficacy and safety of Spartalizumab in combination with the FLOT regimen as perioperative treatment for resectable gastric or GEJ adenocarcinoma. The main endpoint is the proportion of patients with pathological complete regression (pCR) in the primary tumour after preoperative treatment. Systemic treatment will include a pre-operative neoadjuvant and a post-operative adjuvant treatment, during which FLOT regimen will be administered every two weeks for 4 cycles and Spartalizumab every four weeks for 2 cycles. For patients with confirmed tumor resectability on imaging assessment, surgery will be realized within 4-6 weeks after the last dose of preoperative chemotherapy. Post-operative systemic treatment will then be initiated within 4-10 weeks after surgery. Using a Simon's two-stage design, up to 67 patients will be enrolled, including 23 in the first stage. DISCUSSION: Currently, no trials have investigated the impact of immunotherapy in combination with FLOT chemotherapy as perioperative treatment for resectable gastric or GEJ adenocarcinoma. Some studies have suggested a change in the tumor immune micro-environment following neoadjuvant chemotherapy in this setting, reinforcing the relevance to propose a phase II trial evaluating efficacy and safety of Spartalizumab in combination with perioperative chemotherapy, with the aim of improving treatment efficacy and survival outcomes. TRIAL REGISTRATION: NCT04736485, registered February, 3, 2021.

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma - A comparison of the FLOT and 'MAGIC' regimens.

BACKGROUND: Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. METHODS: Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas' Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. RESULTS: Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50-0.94) and disease-free survival (HR = 0.75, 95% CI 0.58-0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. CONCLUSIONS: Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

[Five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph node dissection for Siewert type â ¡ adenocarcinoma of the esophagogastric junction].

Objective: Surgical operation is the main treatment for advanced adenocarcinoma of esophagogastric junction (AEG). Due to its special anatomic location and unique lymph node reflux mode, the surgical treatment of Siewert II AEG is controversial. Lower mediastinal lymph node dissection is one of the most controversial points and a standard technique has not yet been established. This study is aim to explore the safety and feasibility of five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph node dissection for Siewert type II AEG. Methods: A descriptive case series study was conducted. The intraoperative and postoperative data of 25 patients with Siewert type II AEG who underwent five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph node dissection in Guangdong Provincial Hospital of Traditional Chinese Medicine from January 2019 to April 2021 were retrospectively analyzed. Five-step maneuver was as follows: In the first step, the subcardiac sac was exposed; the right pulmonary ligament lymph nodes and the anterior thoracic paraaortic lymph nodes were dissected cranial to inferior pericardium, left to left edge of thoracic aorta. In the second step, the left diaphragm was opened, and a 12 mm trocar was placed through the 6-7 rib in the left anterior axillary line. The supra-diaphragmatic nodes were dissected through the thoracic operation hole. In the third step, the left inferior pulmonary ligament was severed. The anterior fascia of thoracic aorta was incised to join the anterior space of thoracic aorta formed in the first step and then the lymphatic tissue was dissected upward until the exposure of left inferior pulmonary vein. In the fourth step, the posterior pericardium was denuded retrogradely from ventral side to oral side to the level of left inferior pulmonary vein, right to right pleura, and then the right pulmonary ligament lymph nodes were completely removed. In the fifth step, the esophagus was denuded, and the esophagus was transected 5 cm above the tumor using a linear stapler to complete the dissection of lower thoracic paraesophageal lymph nodes. Results: Operations were successfully completed in 25 patients without conversion, intra-operative complication and perioperative death. Total gastrectomy was performed in 19 cases and proximal gastrectomy in 6 cases. The mean operative time was (268.7±85.6) minutes, the mean estimated blood loss was (90.4±44.2) ml, the mean time of lower mediastinal lymph node dissection was (38.6±10.3) minutes, and the mean harvested number of lower mediastinal lymph node was 5.9±2.9. The length of esophageal invasion was >2 cm in 7 cases and ≤ 2 cm in 18 cases. Eight patients (33.0%) had lower mediastinal lymph node metastasis, including 3 cases with esophageal invasion >2 cm and 5 cases with esophageal invasion ≤ 2 cm. The mean time to postoperative first flatus was (5.5±3.1) days. The average time of postoperative thoracic drainage was (5.9±2.9) days. The mean hospital stay was (9.7±3.1) days. Two patients (8.0%) developed postoperative grade IIIa complications according to the Clavien-Dindo classification, including 1 case of pancreatic fistula and 1 case of pleural effusion, both of whom were cured by puncture drainage. Conclusions: Five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph nodes dissection for Siewert type II AEG is safe and feasible. Which can ensure sufficient lower mediastinal lymph node dissection to the level of left inferior pulmonary vein.

[Safety and feasibility of laparoscopic double-flap technique in digestive tract reconstruction after proximal gastrectomy for esophagogastric junction tumors larger than 5 cm].

Objective: To investigate the safety and feasibility of laparoscopic double-flap technique (Kamikawa) in digestive tract reconstruction after proximal gastrectomy for esophagogastric junction (EGJ) leiomyoma and gastrointestinal stromal tumor (GIST) with the maximum diameter >5 cm. Methods: A descriptive case-series study was used to retrospectively analyze the data of patients with EGJ leiomyoma and GIST undergoing laparoscopic-assisted proximal gastrectomy and double-flap technique (Kamikawa) at the Department of Gastrointestinal Surgery, Guangdong Hospital of Traditional Chinese Medicine from September 2017 to March 2019. All the tumors invaded the cardia dentate line, and the maximum diameter was >5 cm. After the exclusion of patients requiring emergency surgery and complicating with severe cardiopulmonary diseases, a total of 4 patients, including 3 males and 1 female with age of 29-49 years, were included in this study. After laparoscopic-assisted proximal gastrectomy, the residual stomach was pulled out of the abdominal cavity and marked with methylene blue at the proximal end 3~4 cm from the anterior wall of the residual stomach in the shape of "H". The gastric wall plasma muscular layer was cut along the "H" shape, and the space between the submucosa and the muscular layer was separated to both sides along the longitudinal incision line to make the seromuscular flap. The residual stomach was put back into the abdominal cavity. Under laparoscopy, 4 stitches were intermittently sutured at the upside of "H" shape and 4-5 cm from the posterior wall of the esophageal stump. The stump of the esophagus was cut open, and the submucosa and mucosa were cut under the "H" shape to enter the gastric cavity. The posterior wall of the esophageal stump was sutured continuously with the gastric stump mucosa and submucosa under laparoscopy. The anterior wall of the esophageal stump was sutured continuously with the whole layer of the residual stomach. The anterior wall of the stomach was sutured to cover the esophagus. The anterior gastric muscle flap was sutured and embedded in the esophagus to complete the reconstruction of digestive tract. The morbidity of intraoperative complications and postoperative reflux esophagitis and anastomosis-related complications were observed. Results: All the 4 patients completed the operation successfully, and there was no conversion to laparotomy. The median operative time was 239 (192-261) minutes, the median Kamikawa anastomosis time was 149 (102-163) minutes, and the median intraoperative blood loss was 35 (20-200) ml. The abdominal drainage tube and gastric tube were removed, and the fluid diet was resumed on the first day after surgery in all the 4 patients. The median postoperative hospitalization time was 6 (6-8) days. Postoperative pathology revealed 3 leiomyomas and 1 GIST. There were no postoperative complications such as anastomotic leakage or stenosis, and no reflux symptoms were observed. The median follow-up time was 22 (11-29) months after the operation, and no reflux esophagitis occurred in any of the 4 patients by gastroscopy. Conclusion: For >5 cm EGJ leiomyoma or GIST, double-flap technique (Kamikawa) used for digestive tract reconstruction after proximal gastrectomy is safe and feasible.

p-MEK expression predicts prognosis of patients with adenocarcinoma of esophagogastric junction (AEG) and plays a role in anti-AEG efficacy of Huaier.

The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) is increasing worldwide with poor prognosis and unclear pathogenesis. Trametes robiniophila Murr. (Huaier), a traditional Chinese medicine has been used in the clinical treatment of a variety of solid tumors, including AEG. However, its anticancer components and molecular mechanisms are still unclear. In our previous studies, we have found that Huaier n-butanol extract (HBE) shows the most potent anticancer activity among different extracts. In the present study, we aimed to investigate the clinical relevance of p-MEK expression in AEG patients and the role of the MEK/ERK signaling pathway in the anti-AEG efficacy of HBE in vitro and in vivo. We herein demonstrate that p-MEK expression in AEG tissues was significantly higher than that in paracancerous tissues and correlated with a poor prognosis in AEG patients. We further found that HBE inhibited the colony formation, migration, and invasion in AEG cell lines in a concentration-dependent manner in vitro. HBE also suppressed the growth of AEG xenograft tumors without causing any host toxicity in vivo. Mechanistically, HBE caused the inactivation of the MEK/ERK signaling pathway by dephosphorylating MEK1 at S298, ERK1 at T202, and ERK2 at T185 and modulating the expression of EMT-related proteins. In summary, our results demonstrate that the high expression of p-MEK may be an independent factor of poor prognosis in patients with AEG. The clinically used anticancer drug Huaier may exert its anti-AEG efficacy by inhibiting the MEK/ERK signaling pathway.

Novel minimally invasive approach to lymph node dissection around the left renal vein in patients with esophagogastric junction cancer.

The left renal vein lymph node (LRVLN) may be the extended locoregional node in esophagogastric junction cancer; however, only open-surgical methods of dissection have been reported. We therefore developed a novel minimally invasive laparoscopic method for LRVLN dissection. Following esophagectomy, the stomach was mobilized and LRVLN dissection was started by taping the pancreatic body using two silicone drains. The transverse mesocolon was then retracted through the superior duodenal fossa to expose the horizontal duodenum and permit LRVLN dissection. We carried out the procedure successfully in 17 patients with advanced esophagogastric cancer. The median total and laparoscopic operative times were 415 and 161 min, respectively. Postoperative esophagectomy-related complications occurred in six patients. The median estimated blood loss was 120 ml and hospital stay was 15 days. This minimally invasive laparoscopic LRVLN dissection method was safe and effective, and may support faster recovery and earlier postoperative adjuvant therapy in patients with esophagogastric junction cancer.

Five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph node dissection for Siewert type Ⅱ adenocarcinoma of the esophagogastric junction / 中华胃肠外科杂志

Objective: Surgical operation is the main treatment for advanced adenocarcinoma of esophagogastric junction (AEG). Due to its special anatomic location and unique lymph node reflux mode, the surgical treatment of Siewert II AEG is controversial. Lower mediastinal lymph node dissection is one of the most controversial points and a standard technique has not yet been established. This study is aim to explore the safety and feasibility of five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph node dissection for Siewert type II AEG. Methods: A descriptive case series study was conducted. The intraoperative and postoperative data of 25 patients with Siewert type II AEG who underwent five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph node dissection in Guangdong Provincial Hospital of Traditional Chinese Medicine from January 2019 to April 2021 were retrospectively analyzed. Five-step maneuver was as follows: In the first step, the subcardiac sac was exposed; the right pulmonary ligament lymph nodes and the anterior thoracic paraaortic lymph nodes were dissected cranial to inferior pericardium, left to left edge of thoracic aorta. In the second step, the left diaphragm was opened, and a 12 mm trocar was placed through the 6-7 rib in the left anterior axillary line. The supra-diaphragmatic nodes were dissected through the thoracic operation hole. In the third step, the left inferior pulmonary ligament was severed. The anterior fascia of thoracic aorta was incised to join the anterior space of thoracic aorta formed in the first step and then the lymphatic tissue was dissected upward until the exposure of left inferior pulmonary vein. In the fourth step, the posterior pericardium was denuded retrogradely from ventral side to oral side to the level of left inferior pulmonary vein, right to right pleura, and then the right pulmonary ligament lymph nodes were completely removed. In the fifth step, the esophagus was denuded, and the esophagus was transected 5 cm above the tumor using a linear stapler to complete the dissection of lower thoracic paraesophageal lymph nodes. Results: Operations were successfully completed in 25 patients without conversion, intra-operative complication and perioperative death. Total gastrectomy was performed in 19 cases and proximal gastrectomy in 6 cases. The mean operative time was (268.7±85.6) minutes, the mean estimated blood loss was (90.4±44.2) ml, the mean time of lower mediastinal lymph node dissection was (38.6±10.3) minutes, and the mean harvested number of lower mediastinal lymph node was 5.9±2.9. The length of esophageal invasion was >2 cm in 7 cases and ≤ 2 cm in 18 cases. Eight patients (33.0%) had lower mediastinal lymph node metastasis, including 3 cases with esophageal invasion >2 cm and 5 cases with esophageal invasion ≤ 2 cm. The mean time to postoperative first flatus was (5.5±3.1) days. The average time of postoperative thoracic drainage was (5.9±2.9) days. The mean hospital stay was (9.7±3.1) days. Two patients (8.0%) developed postoperative grade IIIa complications according to the Clavien-Dindo classification, including 1 case of pancreatic fistula and 1 case of pleural effusion, both of whom were cured by puncture drainage. Conclusions: Five-step maneuver of transthoracic single-port assisted laparoscopic lower mediastinal lymph nodes dissection for Siewert type II AEG is safe and feasible. Which can ensure sufficient lower mediastinal lymph node dissection to the level of left inferior pulmonary vein.

Safety and feasibility of laparoscopic double-flap technique in digestive tract reconstruction after proximal gastrectomy for esophagogastric junction tumors larger than 5 cm / 中华胃肠外科杂志

Objective: To investigate the safety and feasibility of laparoscopic double-flap technique (Kamikawa) in digestive tract reconstruction after proximal gastrectomy for esophagogastric junction (EGJ) leiomyoma and gastrointestinal stromal tumor (GIST) with the maximum diameter >5 cm. Methods: A descriptive case-series study was used to retrospectively analyze the data of patients with EGJ leiomyoma and GIST undergoing laparoscopic-assisted proximal gastrectomy and double-flap technique (Kamikawa) at the Department of Gastrointestinal Surgery, Guangdong Hospital of Traditional Chinese Medicine from September 2017 to March 2019. All the tumors invaded the cardia dentate line, and the maximum diameter was >5 cm. After the exclusion of patients requiring emergency surgery and complicating with severe cardiopulmonary diseases, a total of 4 patients, including 3 males and 1 female with age of 29-49 years, were included in this study. After laparoscopic-assisted proximal gastrectomy, the residual stomach was pulled out of the abdominal cavity and marked with methylene blue at the proximal end 3~4 cm from the anterior wall of the residual stomach in the shape of "H". The gastric wall plasma muscular layer was cut along the "H" shape, and the space between the submucosa and the muscular layer was separated to both sides along the longitudinal incision line to make the seromuscular flap. The residual stomach was put back into the abdominal cavity. Under laparoscopy, 4 stitches were intermittently sutured at the upside of "H" shape and 4-5 cm from the posterior wall of the esophageal stump. The stump of the esophagus was cut open, and the submucosa and mucosa were cut under the "H" shape to enter the gastric cavity. The posterior wall of the esophageal stump was sutured continuously with the gastric stump mucosa and submucosa under laparoscopy. The anterior wall of the esophageal stump was sutured continuously with the whole layer of the residual stomach. The anterior wall of the stomach was sutured to cover the esophagus. The anterior gastric muscle flap was sutured and embedded in the esophagus to complete the reconstruction of digestive tract. The morbidity of intraoperative complications and postoperative reflux esophagitis and anastomosis-related complications were observed. Results: All the 4 patients completed the operation successfully, and there was no conversion to laparotomy. The median operative time was 239 (192-261) minutes, the median Kamikawa anastomosis time was 149 (102-163) minutes, and the median intraoperative blood loss was 35 (20-200) ml. The abdominal drainage tube and gastric tube were removed, and the fluid diet was resumed on the first day after surgery in all the 4 patients. The median postoperative hospitalization time was 6 (6-8) days. Postoperative pathology revealed 3 leiomyomas and 1 GIST. There were no postoperative complications such as anastomotic leakage or stenosis, and no reflux symptoms were observed. The median follow-up time was 22 (11-29) months after the operation, and no reflux esophagitis occurred in any of the 4 patients by gastroscopy. Conclusion: For >5 cm EGJ leiomyoma or GIST, double-flap technique (Kamikawa) used for digestive tract reconstruction after proximal gastrectomy is safe and feasible.

Esophagus and Gastrointestinal Junction Tumors.

Esophageal squamous cell carcinoma and adenocarcinoma account for 95% of all esophageal malignancies. The rates of esophageal adenocarcinoma have increased in Western countries, making it the predominant type of esophageal cancer. Treatment of both types of cancer has transformed to a more minimally invasive approach, with endoscopic methods being used for superficial cancers and more frequent use of video-assisted and laparoscopic modalities for locally advanced tumors. The current National Comprehensive Cancer Network guidelines advocate a trimodal approach to treatment, with neoadjuvant chemoradiation and surgery for locally advanced cancers.

[Preliminary efficacy analysis of Cheng's Giraffe reconstruction after proximal gastrectomy in adenocarcinoma of esophagogastric junction].

Objective: To investigate the safety and feasibility of proximal partial gastrectomy with Cheng's Giraffe esophagogastric reconstruction for the treatment of early Siewert II adenocarcinoma of esophagogastric junction (AEG). Methods: Indication of Cheng's Giraffe esophagogastric reconstruction: (1) Siewert II AEG or Siewert III AEG with diameter < 4 cm; (2) preoperative staging as cT1-2N0M0. A descriptive case series study was carried out. Clinical data of 34 patients with Siewert II AEG undergoing proximal partial gastrectomy and Cheng's Giraffe esophagogastric reconstruction at Department of Abdominal Surgery of Zhejiang Cancer Hospital and Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from February to July 2018 were retrospectively collected and analyzed, including 14 cases in IA stage, 11 cases in IIA stage and 8 cases in IIB stage. Brief procedure of Cheng's Giraffe esophagogastric reconstruction was as follows: Firstly, 12 cm long tubular stomach was formed by longitudinal incision 4 cm away from the great curvature of the stomach. Secondly, the gastric fundus and His angle were formed. Finally, the distance from His angle to esophagal-tubular gastric anastomosis should be more than 5 cm. The reflux disease questionare (RDQ) scores, radionuclide gastric emptying scintigraphy, and 24-hour multichannel intraluminal (MII)-pH monitoring technology were used to evaluate postoperative gastric emptying and gastroesophageal reflux. Result: All 34 patients successfully completed proximal partial gastrectomy with Cheng's Giraffe esophagogastric reconstruction, including 13 cases by open surgery and 21 cases by laparoscopic surgery. The operation time was (144.6±39.8) minutes, the blood loss during operation was (35.4±17.2) ml. No laparoscopic case was converted to open surgery and no postoperative complication was observed. The postoperative hospital stay was (8.4±2.5) days. The postoperative RDQ score was 4.4±3.1 one month after operation, and 3.3±2.5 six months after operation. Gastric-half emptying time was (67.0±21.5) minutes, and the residual ratio was (52.2±7.7)% in 1 hour, (36.4±3.1)% in 2 hours and (28.8±3.6)% in 3 hours at postoperative 1-month. The 24-hour MII-pH monitoring at postoperative 2-month revealed the frequency of acid reflux was (12.6±7.9) times, frequency of non-acid reflux was (19.6±9.7) times, DeMeester score was 5.8±2.9. Conclusion: Cheng's Giraffe esophagogastric reconstruction is safe and feasible in the treatment of Siewert type II AEG, and has good dynamic and anti-reflux effects.

Diagnostic tests for preoperative staging of esophagogastric junction tumors: performance and evidence-based recomendations. / Pruebas diagnósticas empleadas en la estadificación preoperatoria del cáncer de la unión esofagogástrica: rendimiento y recomendaciones basadas en la evidencia.

Preoperative clinical staging is critical to select those patients whose disease is localized and may benefit from surgery with curative intent. Ideally, such staging should predict tumor invasion, lymphatic involvement and distant metastases. With the cTNM, we are able to select patients who could benefit from endoscopic resection, radical surgery or less radical treatment in patients with distant metastasis. The initial diagnosis of adenocarcinomas of the esophagogastric junction requires endoscopy with biopsies. For clinical staging, thoracoabdominal-pelvic CT scan, endoscopic ultrasound and PET or PET/CT are used. Other useful explorations are: barium swallow, endoscopic mucosal resection or endoscopic submucosal dissection (for assessment in initial stages) and staging laparoscopy. Once the resectability of the tumor has been established, the operability of the tumor should be assessed according to the patient's condition.