Published papers

Perioperative and surgical management of gastric cancer have been changing as pivotal phase II trials and landmark phase III trials offer new insights to the existing knowledge. The results of many landmark trials have been published or presented in the past year, many of which have changed or will change current clinical practice. For example, FLOT4 has completely changed the regimen of perioperative chemotherapy in Europe. Furthermore, evidence for minimally invasive surgery for clinical Stage I was firmly established by KLASS-01 and JCOG0912 for distal gastrectomy and CLASS-02, KLASS-03, and JCOG1401 for total gastrectomy. Moreover, promising results were provided by CLASS-01 and KLASS-02 for locally advanced gastric cancer. For adjuvant chemotherapy, JACCRO GC-07 (START-2) has provided a new doublet regimen for pathological Stage III, which is often refractory to chemotherapy. Conversely, JCOG0501 poses a significant challenge for advanced tumors, such as large type 3 and scirrhous (type 4) tumors. In this review, we briefly review recent updates and discuss future perspectives of gastric cancer treatment.

Tumor stiffness is drawing attention as a novel axis that is orthogonal to existing parameters such as pathological examination. We developed a new diagnostic method that focuses on differences in stiffness between tumor and normal tissue. This study comprised a clinical application of laser resonance frequency analysis (L-RFA) for diagnosing gastric cancer. L-RFA allows for precise and contactless evaluation of tissue stiffness. We used a laser to create vibrations on a sample's surface that were then measured using a vibrometer. The data were averaged and analyzed to enhance accuracy. In the agarose phantom experiments, a clear linear correlation was observed between the Young's modulus of the phantoms (0.34–0.71 MPa) and the summation of normalized vibration peaks (Score) in the 1950–4050 Hz range (R2 = 0.93145). Higher Young's moduli also resulted in lower vibration peaks at the excitation frequency, signal-to-noise (S/N) ratios, and harmonic peaks. We also conducted L-RFA measurements on gastric cancer specimens from two patients who underwent robot-assisted distal gastrectomy. Our results revealed significant waveform differences between tumor and normal regions, similar to the findings in agarose phantoms, with tumor regions exhibiting lower vibration peaks at the excitation frequency, S/N ratios, and harmonic peaks. Statistical analysis confirmed significant differences in the score between normal and tumor regions (p = 0.00354). L-RFA was able to assess tumor stiffness and holds great promise as a noninvasive diagnostic tool for gastric cancer.

Introduction: Complexities of robotic distal gastrectomy (RDG) give reason to assess physician's surgical skill. Varying levels in surgical skill affect patient outcomes. We aim to investigate how a novel artificial intelligence (AI) model can be used to evaluate surgical skill in RDG by recognizing surgical instruments. Methods: Fifty-five consecutive robotic surgical videos of RDG for gastric cancer were analyzed. We used Deeplab, a multi-stage temporal convolutional network, and it trained on 1234 manually annotated images. The model was then tested on 149 annotated images for accuracy. Deep learning metrics such as Intersection over Union (IoU) and accuracy were assessed, and the comparison between experienced and non-experienced surgeons based on usage of instruments during infrapyloric lymph node dissection was performed. Results: We annotated 540 Cadiere forceps, 898 Fenestrated bipolars, 359 Suction tubes, 307 Maryland bipolars, 688 Harmonic scalpels, 400 Staplers, and 59 Large clips. The average IoU and accuracy were 0.82 ± 0.12 and 87.2 ± 11.9% respectively. Moreover, the percentage of each instrument's usage to overall infrapyloric lymphadenectomy duration predicted by AI were compared. The use of Stapler and Large clip were significantly shorter in the experienced group compared to the non-experienced group. Conclusions: This study is the first to report that surgical skill can be successfully and accurately determined by an AI model for RDG. Our AI gives us a way to recognize and automatically generate instance segmentation of the surgical instruments present in this procedure. Use of this technology allows unbiased, more accessible RDG surgical skill.

Background: We previously reported that endoscopic response evaluation can preoperatively predict the prognosis and distribution of residual tumors after neoadjuvant chemotherapy (NAC). In this study, we developed artificial intelligence (AI)-guided endoscopic response evaluation using a deep neural network to discriminate endoscopic responders (ERs) in patients with esophageal squamous cell carcinoma (ESCC) after NAC. Method: Surgically resectable ESCC patients who underwent esophagectomy following NAC were retrospectively analyzed in this study. Endoscopic images of the tumors were analyzed using a deep neural network. The model was validated with a test data set using 10 newly collected ERs and 10 newly collected non-ER images. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the endoscopic response evaluation by AI and endoscopists were calculated and compared. Results: Of 193 patients, 40 (21%) were diagnosed as ERs. The median sensitivity, specificity, PPV, and NPV values for ER detection in 10 models were 60%, 100%, 100%, and 71%, respectively. Similarly, the median values by the endoscopist were 80%, 80%, 81%, and 81%, respectively. Conclusion: This proof-of-concept study using a deep learning algorithm demonstrated that the constructed AI-guided endoscopic response evaluation after NAC could identify ER with high specificity and PPV. It would appropriately guide an individualized treatment strategy that includes an organ preservation approach in ESCC patients.

This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.

Background: We previously reported that postoperative recurrence in responders occurred in the regional field mostly as a solitary lesion without distant failure. However, further validation is necessary due to the low percentage of pathological responders, especially those with pCR. This study aimed to validate the prognostic impact of pathological response and the distribution of residual tumors in pathological responders using a nationwide database from 85 Japanese esophageal centers. Methods: We retrospectively reviewed patients with esophageal squamous cell carcinoma (ESCC) who underwent subtotal esophagectomy at 85 authorized institutes for esophageal cancer between 2010 and 2015. The recurrence free survival (RFS), overall survival (OS), and recurrent tumor patterns were compared among the pathological responses. Results: Of 4781 patients initially enrolled, 3840 were selected for subsequent analysis, including 237 patients with pathological complete response (pCR, 6%). The RFS and OS were significantly correlated with pathological response. When the recurrence pattern was classified into regional or distant recurrence, the incidence of distant failure was significantly lower in patients with pCR in cT1/2. Three percent of all patients with pCR in cT1/2 encountered postoperative recurrence in distant organs. Conclusion: The prognostic impact of pathological response was reproduced in the nationwide data. pCR in ESCC patients with cT1/2 provides a favorable prognosis with less incidence of distant failure. This finding may contribute to selecting appropriate candidates for an organ preservation approach based on the response to induction therapy.

The 11th edition of the "Japanese Classification of Esophageal Cancer"by the Japan Esophageal Society (JES) and the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) "Cancer Staging Manual"are two separate classification systems both widely used for the clinical and pathological staging of esophageal cancer. Furthermore, the lymph node stations from these classification systems are combined for research purposes in the multinational TIGER study, which investigates the distribution pattern of lymph node metastases. The existing classification systems greatly differ with regard to number, location and anatomical boundaries of locoregional lymph node stations. The differences in these classifications cause significant heterogeneity in studies on lymph node metastases in esophageal cancer. This makes data interpretation difficult and comparison of studies challenging. In this article, we propose a match for these two commonly used classification systems and additionally for the TIGER study classification, in order to be able to compare results of studies and exchange knowledge and to make steps towards one global uniform classification system for all patients with esophageal cancer.

Background: On the basis of JCOG1109, neoadjuvant chemotherapy (NAC) with Docetaxel, Cisplatin, and 5-FU (DCF) has become one of the standard treatments for locally advanced esophageal squamous cell carcinoma (LAESCC). Although the efficacy of adjuvant therapy with nivolumab after preoperative chemoradiotherapy for LAESCC has been proven by CheckMate 577, the survival benefits of adjuvant therapy after NAC remain controversial. Additionally, a single-arm phase II trial of adjuvant S-1 for LAESCC who received NAC demonstrated favorable survival outcomes and safety. Methods: Eligibility criteria include the followings: thoracic esophageal squamous cell carcinoma, adenosquamous carcinoma, or basaloid squamous cell carcinoma, reception of NAC (at most three courses of DCF or two courses of Cisplatin plus 5-FU) and a diagnosis of clinical stage I (except for T1N0), II, III, IVA (except for T4), or IVB (only supraclavicular lymph node metastasis except for T4), right thoracoabdominal esophagectomy with D2 or higher lymph node dissection, R0 resection was performed, residual pathological disease in the resected specimens [ypStage T0-4aN1-3M0, T1-4aN0M0, T0-4aNanyM1 (only supraclavicular lymph node metastasis)], aged 18-80 years, ECOG performance status 0 or 1, and adequate organ function. The primary endpoint is relapse-free survival (RFS), and the secondary endpoints are disease-free survival, overall survival, adverse events, and incremental cost-effectiveness ratio. After the confirmation of patient eligibility including pathological diagnosis, patients will be randomized (1:1:1) to either the observation alone arm, adjuvant nivolumab arm (240 mg/body every two weeks or 480 mg/bodies every four weeks for one year), or adjuvant S-1 arm (four courses of twice-daily oral S-1 for four weeks followed by two weeks of rest for 6 month, three dose levels of S-1 are set according to the patient’s body surface area (BSA), as follows: BSA, 1.25 m2, 40 mg; BSA 1.25–1.50 m2, 50 mg; BSA. 1.50 m2, 60 mg, twice a day). We assumed a three-year RFS of 60% in the observation alone arm and expected an 11% increase for the nivolumab arm and the S-1 arm (HR = 0.67). The total required sample size was calculated as 435 (145 per arm) to achieve the desired power of 70% for each pair comparison (observation alone arm vs. the nivolumab arm and observation alone arm vs. S-1 arm) with an overall one-sided alpha of 5%, an accrual period of 5.5 years, and a follow-up period of three years. The planned sample size was set at 450 patients (150 patients per arm). This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230219. This trial was initiated in July 2023, and the first patient was enrolled in September 2023. Clinical trial information: jRCTs031230219. Research Sponsor: None.

Background: Thoracoscopic esophagectomy (TE) as minimally invasive esophagectomy for thoracic esophageal cancer has become widely prevalent around the world over the past decade. However, results from a large-scale, multicenter randomized controlled trial that compared long-term survival as the primary endpoint between TE and conventional open transthoracic esophagectomy (OE) have not yet been demonstrated. We conducted a multicenter randomized phase III study (JCOG1409) to confirm the non-inferiority of TE to OE in terms of overall survival (OS) for thoracic esophageal cancer (UMIN000017628). Methods: Eligible patients with clinical stage I-III, excluding T4, thoracic esophageal squamous cell carcinoma were randomized to undergo either OE or TE. The primary endpoint was OS, with secondary endpoints including relapse-free survival (RFS), the proportion of patients achieving R0 resection, the proportion of patients needing conversion from TE to OE, adverse events, the proportion of patients requiring re-operation, changes in postoperative respiratory dysfunction, and postoperative quality-of-life score. Non-inferiority would be confirmed if the upper limit of the confidence interval (CI) for the hazard ratio (HR) does not exceed 1.44, the predefined non-inferiority margin. Results: We randomized 300 patients, assigning 150 to the TE group and 150 to the OE group between May 2015 and June 2022. The second planned interim analysis with 64 OS events was conducted in June 2023. Median follow-up (interquartile range) was 2.6 (1.4-4.9) years. Three-year OS was 82.0% (95% CI, 73.8%-87.8%) in the TE group, and 70.9% (61.6%-78.4%) in the OE group. The Data and Safety Monitoring Committee recommended terminating the trial and publishing the results because the non-inferiority of TE to OE in terms of OS was demonstrated after adjusting for multiplicity (HR 0.64; 98.8% CI, 0.34-1.21 [<1.44], one-sided p-value for non-inferiority = 0.000726 < 0.00616). Three-year RFS in the TE group was markedly better than that in the OE group (72.9% vs. 61.9%) with HR of 0.68 (95% CI, 0.46-1.01). R0 resection proportions were 95.3% in the TE group and 90.0% in the OE group. One patient in the TE group needed conversion from TE to OE intraoperatively. The postoperative overall morbidity was similar between the two groups, but the proportion of re-operation was 2.0% in the TE group and 4.1% in the OE group. Respiratory dysfunction proportion at 3 months after surgery were significantly lower in the TE group than in the OE group. Conclusions: TE was shown to be a standard treatment for patients with clinical stage I-III thoracic esophageal cancer. Clinical trial information: UMIN000017628.

Background: We occasionally experience incomplete resection of esophageal cancer due to the surrounding organ invasion. The efficacy of additional treatment in these cases is unknown. Methods: We studied 445 patients with esophageal squamous cell carcinoma who were unable to undergo curative esophagectomy due to cancer invasion to the surrounding organs at 45 esophageal centers in Japan. Survival outcomes were compared based on the additional treatment modalities. Results: Postoperatively, 175 (40.0%) received no additional treatment, while 59 (13.5%), 153 (35.0%), and 50 (11.4%) received additional chemotherapy, chemoradiotherapy, or radiotherapy, respectively. The three-year disease progression and overall survival rates were 90.6% (95% confidence interval 87.2–93.1%) and 15.4% (95% confidence interval 12.2–19.3%), respectively. Multivariable analysis revealed that chemotherapy, chemoradiotherapy, and radiotherapy were all independently associated with reduced disease progression (hazard ratios [95% confidence intervals]: 0.57 [0.40–0.81], 0.52 [0.39–0.69], and 0.48 [0.33–0.72], respectively). Meanwhile, additional treatment with chemotherapeutic agents (chemotherapy and chemoradiotherapy) was independently associated with better overall survival (hazard ratios [95% confidence intervals]: 0.51 [0.35–0.73] and 0.59 [0.44–0.79], respectively); however, radiotherapy alone had a limited impact (hazard ratio [95% confidence interval]: 0.74 [0.50–1.10]). Conclusions: Any additional treatment could suppress disease progression after incomplete resection, but radiotherapy alone has a limited effect. Additional systemic chemotherapeutics may increase patient survival.

Aim: The National Clinical Database (NCD) of Japan is the largest nationwide registry, covering over 95% of surgeries in the country. This 2022 annual report summarizes the short-term outcomes of gastroenterological surgeries and discusses trends and insights over the past decade. Methods: We analyzed the NCD data for gastroenterological surgeries performed between 2013 and 2022. The number of surgeries, patient demographics, surgical approaches, postoperative outcomes, and the involvement of board-certified surgeons and anesthesiologists were examined. Results: A total of 591 221 surgeries were recorded in 2022. Compared to 2021, the overall surgical volume remained stable, with a continued increase in minimally invasive procedures. Patient aging continued across all organ categories, with a rise in the proportion of patients aged ≥ 80 years. Board-certified surgeon participation remained high in complex procedures, while emergency surgeries were associated with higher morbidity and mortality. Operative mortality continued to decrease, particularly in pancreatic and hepatic surgeries. Conclusion: The 2022 NCD data provide a comprehensive overview of the current status and evolving trends in gastroenterological surgery in Japan. Continued efforts toward data-driven quality improvement and surgical education remain essential.

Aim: The National Clinical Database (NCD) of Japan is a nationwide data entry system for surgery, and it marked its 10th anniversary in 2020. The aim was to present the 2020 annual report of gastroenterological surgery of the NCD. Methods: The data of the surgical procedures stipulated by the training curriculum for board-certified surgeons of the Japanese Society of Gastroenterological Surgery in the NCD from 2011 to 2020 were summarized. Results: In total, 5 622 845 cases, including 593 088 cases in 2020, were extracted from the NCD. The total number of gastroenterological surgeries increased gradually in these 10 years, except for the year 2020 due to the COVID-19 pandemic. The annual number of surgeries of each organ, except the pancreas and liver, decreased by 0.4%–13.1% in 2020 compared to 2019. The surgical patients were consistently aging, with more than 20% of all gastroenterological surgeries in 2020 involving patients aged 80 years or older. The participation of board-certified surgeons increased for each organ (75.9%–95.7% in 2020). The rates of endoscopic surgery also increased constantly. Although the incidences of postoperative complications of each organ increased by 0.7%–7.9% in these 10 years, postoperative mortality rates decreased by 0.2%–1.5%. Conclusions: We present here the short-term outcomes of each gastroenterological operative procedure in 2020. This review of the 10-years of NCD data of gastroenterological surgery revealed a consistent increase of the number of surgeries (except for in 2020), especially endoscopic procedures, and aging of the Japanese population. The good safety of Japanese gastroenterological surgeries was also indicated.

Aim: The Japanese National Clinical Database, which covers more than 95% of the surgeries performed in Japan, is the largest nationwide database. This is the 2021 annual report of the Gastroenterological Section of the National Clinical Database, which aims to present the short-term outcomes of cases registered in 2021 and discuss significant changes and insights into gastroenterological surgeries observed over the decade. Methods: We reviewed the data of patients registered in the National Clinical Database between 2012 and 2021. Results: In total, 5 788 093 cases, including 597 780 cases in 2021, were extracted from the National Clinical Database. The number of surgeries resumed its original trend after a uniform decrease due to the coronavirus disease 2019 pandemic. The patient population continues to age, and the proportion of female patients is steadily increasing. The trend of surgeries being conducted in certified institutions with the involvement of board-certified surgeons is consistently rising. Moreover, the increasing trend of endoscopic surgery rate is still maintained. Although operative mortality is declining, the trend of increasing postoperative complications continues. Surgery on the esophagus, liver, and pancreas has shown substantial improvements in operative mortality, with a high participation rate of board-certified surgeons. Surgical procedures with a high incidence of emergency surgeries are characterized by low participation rates of board-certified surgeons, increased morbidity rates, and worse mortality outcomes. Conclusion: This overview of surgical patients in Japan, obtained using data extracted from the National Clinical Database, may serve as a critical cornerstone for the future development of gastroenterological surgery.

Objective: To assess the effect of antimicrobial prophylaxis with ampicillin-sulbactam (ABPC/SBT) compared with cefazolin (CEZ) on the short-term outcomes after esophagectomy. Background: CEZ is widely used for antimicrobial prophylaxis in esophagectomy without procedure-specific evidence, whereas ABPC/SBT is preferred in some hospitals to target both aerobic and anaerobic oral bacteria. Methods: Data of patients who underwent esophagectomy for cancer between July 2010 and March 2019 were extracted from a nationwide Japanese inpatient database. Overlap propensity score weighting was conducted to compare the short-term outcomes [including surgical site infection (SSI), anastomotic leakage, and respiratory failure] between antimicrobial prophylaxis with CEZ and ABPC/SBT after adjusting for potential confounders. Sensitivity analyses were also performed using propensity score matching and instrumental variable analyses. Results: Among 17,772 eligible patients, 16,077 (90.5%) and 1695 (9.5%) patients were administered CEZ and ABPC/SBT, respectively. SSI, anastomotic leakage, and respiratory failure occurred in 2971 (16.7%), 2604 (14.7%), and 2754 patients (15.5%), respectively. After overlap weighting, ABPC/SBT was significantly associated with a reduction in SSI [odds ratio 0.51 (95% CI: 0.43–0.60)], anastomotic leakage [0.51 (0.43–0.61)], and respiratory failure [0.66 (0.57–0.77)]. ABPC/SBT was also associated with reduced respiratory complications, postoperative length of stay, and total hospitalization costs. The proportion of Clostridioides difficile colitis and noninfectious complications did not differ between the groups. Propensity score matching and instrumental variable analyses demonstrated equivalent results. Conclusions: The administration of ABPC/SBT as antimicrobial prophylaxis for esophagectomy was associated with better short-term postoperative outcomes compared with CEZ.