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Abstract Aim To evaluate the feasibility and safety of total neoadjuvant therapy with long‐course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer. Methods This prospective, multicenter, single‐arm, phase II trial was conducted at 10 centers. The eligibility criteria included age ≥20 y, locally advanced rectal cancer within 12 cm of the anal verge, and cT3‐4N0M or TanyN+M0 at diagnosis, enabling curative resection. The protocol treatment was capecitabine (1650 mg/m2/day)‐based long‐course chemoradiotherapy (50.4 Gy/28 fractions) and consolidation chemotherapy (CAPOX, four courses) followed by total mesorectal excision. Nonoperative management was allowed if a clinical complete response was achieved. The primary endpoint was the pathologic complete response rate. Results Among 28 enrolled patients (19 men, 9 women; median age, 69.5 [41–79] y), the long‐course chemoradiotherapy and consolidation chemotherapy completion rates were 100% and 96.4%, respectively. The clinical responses included clinical complete response, (35.7%, 10/28), near‐complete response (28.6%, 8/28), and incomplete response (32.1%, 9/28). Total mesorectal excision and nonoperative management were performed in 21 and six patients, respectively. The final analysis included 21 patients. Five patients (23.8% [90% confidence interval 11.8%–41.8%]) achieved pathologic complete response, while 10 of 28 patients (35.7%) achieved a pathological complete response or a sustained clinical complete response. No treatment‐related deaths occurred. Grade ≥3 adverse events included diarrhea (7.1%) and leukopenia (7.1%). Conclusion ENSEMBLE‐2 demonstrated comparable pathologic complete response rates and well‐tolerated safety of total neoadjuvant therapy with long‐course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer.

Abstract Background While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST. Methods We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status. Results In 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P

Abstract The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function.

Background: Evidence regarding the application of the multispectral camera for blood flow measurement is insufficient, and its performance has not been compared with the conventional indocyanine green (ICG) method. Therefore, we retrospectively compared the effectiveness of a new multispectral camera for non-invasive, real-time, quantitative imaging of tissue oxygen (O2) saturation and hemoglobin (Hb) levels and commercially available ICG fluorescence imaging in hemodynamic assessment of gastric tubes in esophagectomy. Methods: Thirty patients who underwent thoracoscopic esophagectomy and gastric tube reconstruction for esophageal cancer were included in this study. The multispectral camera was used to measure tissue O2 saturation and Hb levels. The ICG fluorescence imaging, with the analysis software tool Lumi view, was employed to record ICG luminance changes, with values measured at the anastomotic site. Furthermore, the usefulness of each assessment device was examined using the arterial and venous blood flow indices as cutoff lines for cases with anastomotic failure. Results: In the evaluation of arterial perfusion, anastomotic leak occurred in three of the five (60 %) patients with arterial insufficiency as assessed by the ICG imaging, while anastomotic leakage occurred in all three patients (100 %) who were assessed as having arterial insufficiency by the multispectral camera. In the evaluation of venous perfusion, anastomotic leakage occurred in three of the nine (33.3 %) patients diagnosed with venous stasis by the IC imaging and in three of the five (60 %) patients assessed by the multispectral camera. Conclusion: The multispectral camera assessed gastric tube blood flow more accurately than the ICG fluorescence method.

Abstract Aim The aim of this study was to verify the clinical feasibility of tele‐proctoring using our ultra‐low latency communication system with shared internet access. Methods Connections between two multiple remote locations at various distances were established through the TELEPRO® tele‐proctoring system. The server records the latency between the two locations for tele‐proctoring using the annotations. Questionnaires were administered to the surgeons, assistants, and medical staff. Respondents rated the quickness and quality of communication in terms of latency and disturbances in the audio, video, and usefulness of the live telestrations with annotation. Results Seven hospitals tele‐proctored with Sapporo Medical University between January 2021 and September 2022. The median latency of annotation between the two locations ranged from 24.5 to 48.5 ms. No major technological problems occurred, such as streaming interruption, loss of video or audio, poor resolution. The video encoding time was 10 ms, and its decoding time was 0.8 ms. The total latency positively correlated with the distance between two locations (R = 0.55, p

Abstract Aim Immune checkpoint inhibitors (ICIs) are less effective in mismatch repair (MMR)‐proficient (pMMR) colorectal cancers (CRCs) than in MMR‐deficient CRCs. Here, we investigated changes in the tumor microenvironment after neoadjuvant chemotherapy (NAC) without radiotherapy in locally advanced rectal cancer (LARC) and the potential of ICIs as therapeutic agents for pMMR CRCs. Methods This was an ad hoc analysis of a KSCC1301 randomized phase II trial in which patients with untreated resectable LARC were randomly assigned to receive S‐1 and oxaliplatin or folinic acid, 5‐fluorouracil, and oxaliplatin as NAC. Forty‐nine patients were studied in this ad hoc analysis. As a reference cohort, we assessed 25 rectal cancer patients who underwent surgery without NAC outside the randomized trial. Immune checkpoint molecules (ICMs; PD‐1, PD‐L1, CTLA‐4, LAG3), tumor‐infiltrating lymphocytes (TILs; CD8, FOXP3), and other related proteins were evaluated by immunohistochemistry. Next‐generation sequencing (NGS) using Oncomine™ Comprehensive Assay version 3 was conducted in 23 patients. Results The expression levels of PD‐1, CTLA‐4, and LAG3 in the NAC group were significantly higher than in reference patients (p

Abstract Background Systemic sclerosis (SSc) is an autoimmune disease characterized by frequent esophageal involvement. However, there are few reports on esophagectomy for esophageal strictures associated with SSc. Herein, we present a case of successful treatment of an esophageal stricture associated with SSc through subtotal esophagectomy. Case presentation A 53-year-old female patient was diagnosed with SSc, interstitial pneumonia, and gastroesophageal reflux disease (GERD). The patient developed an esophageal ulcer and benign stricture that required a subtotal esophagectomy 10 years after the diagnosis. Histopathological findings revealed thinning of the muscle layer, a characteristic feature of SSc. The patient was free of dysphagia or regurgitation. Conclusions An esophagectomy is a valuable option for treating esophageal strictures in SSc. Therefore, surgical approaches should be established for patients with SSc.

Abstract Aim To evaluate the feasibility and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC) in Japan. Methods This prospective, multicenter, open‐label, single‐arm phase II trial was conducted at five institutions. The key eligibility criteria were age ≥ 20 years, LARC within 12 cm from the anal verge, and cT3‐4N0M0 or TanyN+M0 at the time of diagnosis that enabled curative resection. Preoperative short‐course radiation therapy (SCRT) 5 Gy × 5 days (total 25 Gy) + CAPOX (six courses) followed by total mesorectum excision (TME) was the treatment protocol. Non‐operative management (NOM) was allowed if clinical complete response (cCR) was obtained in the preoperative evaluation. The primary endpoint was the pathological complete response (pCR) rate. Results Thirty patients (male, n = 26; female, n = 4; median age, 62.5 [44–74] years; cT [T2, n = 1; T3, n = 25; T4, n = 4]; cN [N0, n = 13; N1, n = 13; N2, n = 4]) were enrolled. The final analysis included 30 patients in total. The completion rates were 100% for SCRT and 83% for CAPOX. TME and NOM were performed in 20 and seven patients, respectively. pCR was observed in six patients (30% [95% CI 14.0%–50.8%]). The primary endpoint was met. pCR+cCR was observed in 13 (43.3%) patients. There were no treatment‐related deaths. Grade ≥3 (CTCAE ver. 5.0) adverse events (≥20%), including diarrhea (23.3%) and neutropenia (23.3%). The median follow‐up period was 15.6 (10.5–22.8) months, with no recurrence or regrowth in NOM. Conclusions ENSEMBLE‐1 demonstrated satisfactory pCR and cCR, and well‐tolerated safety of TNT for patients with LARC in Japan.

Abstract Background We aimed to clarify the genomic characteristics of HER2‐positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial. Methods We collected 80 formalin‐fixed paraffin‐embedded (FFPE) samples (49 HER2+ and 31 HER2‐) from gastric cancer patients who participated in the TROX‐A1 trial (UMIN000036865). We queried a 435‐gene panel (CANCERPLEX‐JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2‐ gastric cancer patients were analyzed. Results Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2‐negative patients. The number of total mutations in HER2‐negative patients with ARID1A mutation was remarkably higher than that in HER2‐positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2‐positive cases was significantly higher than that in HER2‐negative cases. Moreover, PTEN deletion was more common in HER2‐positive cases. Finally, we found that, compared with HER2‐positive patients, HER2‐negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune‐related pathways in HER2‐negative patients. Conclusions According to the genomic profiling of HER2‐positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2‐positive gastric cancer, HER2‐negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

Abstract Background The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. Methods The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. Discussion The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. Trial registration jRCT2031220025, April. 16, 2022.

Abstract Background Because the robotic arm is located on the dorsal side of the patient, when the esophagus is pulled dorsally for the left recurrent nerve lymph node (LRLN) dissection, the robotic arm interferes with the surgical field. This made it difficult to prepare for the left recurrent lymph node dissection. We developed LRLN dissection in robotic surgery with natural space creation by physiological organ movement and evaluated the short-term results. Methods In this retrospective study, we analyzed 102 cases of robot-assisted thoracoscopic subtotal esophagectomy (RATE) among radical subtotal esophagectomies performed between December 2018 and December 2022 using medical records. LRLN dissection is preceded by a dissection of the esophagus from the trachea. Leaving the esophagus on the vertebral side and away from the trachea resulted in a physiological elevation of the esophagus, providing space between the trachea and esophagus. Results The thoracic surgery time in RATE was 181 (115–394) min. The number of LRLNs dissected was 4 (1–14). Six patients (6%) had a postoperative recurrence in the mediastinal lymph nodes. Seven patients (7%) had grade ≥ 1 left recurrent nerve palsy. Conclusions LRLN dissection with RATE using natural space creation was performed safely with a sufficient number of dissected lymph nodes and little left recurrent nerve palsy.

Abstract It is important to ensure the redundancy of communication during remote surgery. The purpose of this study is to construct a communication system that does not affect the operation in the event of a communication failure during telesurgery. The hospitals were connected by two commercial lines, a main line and a backup line, with redundant encoder interfaces. The fiber optic network was constructed using both guaranteed and best-effort lines. The surgical robot used was from Riverfield Inc. During the observation, a random shutdown and restoration process of either line was conducted repeatedly. First, the effects of communication interruption were investigated. Next, we performed a surgical task using an artificial organ model. Finally, 12 experienced surgeons performed operations on actual pigs. Most of the surgeons did not feel the effects of the line interruption and restoration on still and moving images, in artificial organ tasks, and in pig surgery. During all 16 surgeries, a total of 175-line switches were performed, and 15 abnormalities were detected by the surgeons. However, there were no abnormalities that coincided with the line switching. It was possible to construct a system in which communication interruptions would not affect the surgery.

Abstract Background Intramural metastasis (IM) of esophageal cancer is classified as distant metastasis according to the Japanese Classification of Esophageal Cancer, and it is well-known to be associated with a poor prognosis. We herein report a case of perforated gastric IM of esophageal cancer that was successfully controlled with nonradical surgery and subsequent immune checkpoint inhibitor (ICI) treatment. Case presentation A 72-year-old woman was referred to our department for the treatment of esophageal cancer and perforated gastric ulcer. A histological examination of the main tumor and gastric ulcer lesion revealed squamous cell carcinoma. Since the gastric wall tumor had invaded the celiac artery, complete resection was considered impossible. Chemotherapy was administered but led to severe adverse events, so palliative resection was performed. Two months after surgery, computed tomography revealed enlargement of the residual tumor around the celiac artery. However, after nivolumab monotherapy was started, the tumor diminished remarkably, and the quality of life of the patient dramatically improved. Nine months after nonradical surgery, she is surviving without any disease concern. Conclusions With the increased availability of ICIs, multidisciplinary treatment with surgery and ICIs can potentially lead to long-term survival, even in cases expected to have a poor prognosis.

Objective:. To clarify the surgical outcomes of esophagectomy in Japan and comprehensively evaluate trends over time. It is important to analyze data from a large number of consecutive patients from a single institution. Methods:. We evaluated the treatment outcomes, complications, and prognosis of 1500 consecutive patients who underwent esophagectomy during 5 periods: group A (n = 284), 1964–1984; group B (n = 345), 1985–1993; group C (n = 253), 1994–2002; group D (n = 297), 2003–2012; and group E (n = 321), 2013–March 2020. Results:. The incidences of squamous cell carcinoma and adenocarcinoma were 93.8% and 3.3%, respectively. The proportion of adenocarcinoma cases has gradually increased over time. The in-hospital mortality rates for groups A, B, C, D, and E were 12%, 4.6%, 1.2%, 2.9%, and 1.5%, respectively. Group A had a significantly higher mortality rate than the other groups (P

Abstract Aim Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. Methods Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura–Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C‐1 and C‐2), grade 2 (C‐3 and O‐1), and grade 3 (O‐2 and O‐3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. Results miR‐196b‐3p was significantly upregulated, and miR‐92a‐2‐5p was downregulated (P

Abstract Aim Communication and video transmission delays negatively affect telerobotic surgery. Since latency varies by communication environment and robot, to realize remote surgery, both must perform well. This study aims to examine the feasibility of telerobotic surgery by validating the communication environment and local/remote robot operation, using secure commercial lines and newly developed robots. Methods Hirosaki University and Mutsu General Hospital, 150 km apart, were connected via a Medicaroid surgical robot. Ten surgeons performed a simple task remotely using information encoding and decoding. The required bandwidth, delay time, task completion time, number of errors, and image quality were evaluated. Next, 11 surgeons performed a complex task using gallbladder and intestinal models in local/remote environments; round trip time (RTT), packet loss, time to completion, operator fatigue, operability, and image were observed locally and remotely. Results Image quality was not so degraded as to affect remote robot operation. Median RTT was 4 msec (2‐12), and added delay was 29 msec. There was no significant difference in accuracy or number of errors for cholecystectomy, intestinal suturing, completion time, surgeon fatigue, or image evaluation. Conclusion The fact that remote surgery succeeded equally to local surgery showed that this system has the necessary elemental technology for widespread social implementation.