Takeshi Kato

Background: HER2 amplification is demonstrated to influence response to therapy and outcomes in metastatic colorectal cancer (mCRC), but its role in resectable CRC remains unclear. This study investigated the prognostic impact of WES-defined ERBB2 amplification and its association with adjuvant chemotherapy (ACT) efficacy and circulating tumor DNA (ctDNA) in resectable CRC. Methods: Data from 3607 patients with resectable CRC from the GALAXY study were analyzed. HER2 amplification was defined using ERBB2 copy number alterations based on whole exome sequencing of tumor specimens. We analyzed disease-free survival (DFS) in WES-defined ERBB2 amplified CRC, evaluating ACT benefit and the correlation between ERBB2 copy number and ctDNA status. Results: No significant difference in DFS was observed between those with and without WES-defined ERBB2 amplification in a univariate ( P = 0.0659) or a multivariate analysis ( P = 0.2300). Among patients with pathological stage III, ACT was associated with improved DFS in the non-amplified subgroup (HR 0.67, P = 0.0002), particularly in the subgroup of patients with early post-operative (2–10 weeks following surgical resection) ctDNA-positivity (HR 0.27, P < 0.0001), whereas no clear association was detected in the small amplified subgroup; however, the ACT-by- ERBB2 amplification interaction was not statistically significant. While WES-defined ERBB2 amplification correlated with higher early post-operative ctDNA positivity ( P = 0.0486), ERBB2 copy number did not associate with recurrence or levels. However, early post-operative ctDNA positivity strongly predicted poor DFS in patients with WES-defined ERBB2 amplification (HR 15.26, P < 0.0001). Conclusions: WES-defined ERBB2 amplification was not identified as a significant adverse prognostic factor in resectable CRC, unlike early post-operative ctDNA status. The limited number of amplified cases precluded a reliable assessment of whether WES-defined ERBB2 amplification modifies the association between ACT and DFS.

PURPOSE: The Shield test is a blood-based assay that uses multimodal analysis of cell-free DNA (cfDNA) to enable noninvasive colorectal cancer (CRC) detection. The aim of this study was to assess the diagnostic performance of the cfDNA test for CRC and advanced precancerous lesions (APLs) and evaluate its potential clinical utility, particularly in early-stage disease. METHODS: In this prospective, multicenter study, 451 patients with histologically confirmed CRC or APLs were enrolled across eight institutions. Blood samples collected before treatment were analyzed using the cfDNA test (Shield, Guardant Health, United States). We assessed the sensitivity of the test for different CRC stages and APLs. In addition, we examined the correlation between test positivity and clinicopathologic factors in stage I and T1 CRC. RESULTS: The test showed 87.9% sensitivity for CRC overall, with stage-specific sensitivities of 71.2% for stage I and 97.4% for stages II-IV. Sensitivity for APLs was 37.0%. In stage I CRC, test positivity was significantly associated with tumor depth (T2: 88.6% v T1: 59.7%, P < .01). Among 70 patients with T1 CRC, the test detected all to have lymph node metastasis (LNM; 100% sensitivity). Compared with guideline-based pathologic criteria, the cfDNA test achieved higher specificity for LNM prediction (38.7% v 11.3%), thereby potentially reducing the frequency of unnecessary radical surgery from 78.6% to 54.3%. CONCLUSION: This cfDNA blood-based test shows a robust diagnostic performance in CRC detection. It may improve risk stratification and support more tailored clinical decision making, particularly in the management of T1 CRC.

INTRODUCTION: Achieving margin-negative complete resection in locally recurrent rectal cancer often requires en bloc resection involving adjacent structures such as the sacrum. However, sacrectomy is technically demanding and poses a high risk of significant intraoperative bleeding and postoperative pelvic sepsis due to the dead space created after resection. We developed a minimally invasive surgical technique to address these challenges. TECHNIQUE: We employed a laparoscopic approach to sacrectomy as part of en bloc resection for posterior locally recurrent rectal cancer. In this technique, the anterior and lateral dissection of the sacrum was performed laparoscopically, whereas the final sacral transection was carried out under direct vision in the prone position. Preoperative imaging was used to identify the planned sacral transection line, which was reproduced intraoperatively using a premeasured vascular tape. Anterior and lateral dissection of the sacrum was performed laparoscopically to allow secure vascular control. Final sacral transection was performed under direct vision in the prone position. A pedicled omental flap and a dead-space filling non-functional anastomosis were used to fill the pelvic cavity and prevent postoperative sepsis. A double-barreled stoma was created to facilitate fecal diversion. RESULTS: Laparoscopic sacrectomy was successfully performed in 43 patients with locally recurrent rectal cancer. The margin-negative complete resection rate was 86%, which is notably high for this challenging population. The 5-year overall survival rate was approximately 59%. No cases of major intraoperative bleeding or early complications related to the dead-space filling non-functional anastomosis were observed. CONCLUSIONS: This laparoscopic technique offers a safe and feasible option for selected patients with posterior locally recurrent rectal cancer. Combined dead-space management may further help reduce postoperative complications while preserving oncological validity.

Objective: To evaluate the prognostic utility of postoperative circulating tumor DNA (ctDNA) for recurrence and treatment response in patients with rectal cancer undergoing upfront surgery. Background: ctDNA-based molecular residual disease (MRD) testing shows promise in colorectal cancer, but its role in patients with rectal cancer not receiving neoadjuvant therapy is unclear. This study evaluates whether postoperative ctDNA predicts disease-free survival (DFS) and guides adjuvant chemotherapy (ACT) decisions. Methods: We analyzed ctDNA from patients with stage II to III rectal cancer (N=250) enrolled in the GALAXY study, a multicenter registry in Japan. A clinically validated, personalized, tumor-informed 16-plex PCR next-generation sequencing assay (Signatera) was used to detect and quantify ctDNA. The primary outcome was DFS, defined as the time from landmark to recurrence, death, or the latest radiologic assessment. Results: In the MRD window (2–10 wk postsurgery, before ACT), 14.2% (35/246) of patients were ctDNA-positive and had significantly shorter DFS (HR: 9.96, 95% CI: 5.76–17.2, P P =0.031), whereas no benefit was seen in ctDNA-negative patients (HR: 0.59, 95% CI: 0.26–1.35, P =0.211). When analyzing ctDNA dynamics from the MRD window to 6 months postsurgery, recurrence risk was higher in patients who converted from ctDNA-negative to positive (HR: 8.22, 95% CI: 1.86–36.32, P =0.0055) and who remained ctDNA-positive (HR: 45.48, 95% CI: 14.31–144.57, P <0.0001) compared with serially ctDNA-negative patients. Conclusions: Postoperative ctDNA status is a robust biomarker predicting recurrence risk and ACT benefit in patients with rectal cancer undergoing upfront surgery.

Association of ICI efficacy with ASV based on treatment.

The ALDEx2 analysis of flora according to PFS of ICI treatment.

α diversity of gut microbiome according to clinical features and cancer types. A, Diagram depicting the selection of the MONSTAR-SCREEN cohorts. ECOG, Eastern Cooperative Oncology Group; PS, performance status. B, Definition of oral bacteria. A total of 10 genera were defined as oral bacteria in this study from the data of the article by Atarashi and colleagues. C, Violin plot of α diversity based on ASV counts in feces according to concomitant medication use. A two-sided P value was calculated with the Welch t test. D, Violin plot of α diversity by ASV count in feces according to lifestyle habit. A two-sided P value was calculated with the Welch t test. For the number of defecations per day, the Kruskal–Wallis test was applied. LABB, lactic acid bacteria beverage.

Patient characteristics of PPI user and non-user in Cohort 1.

The association with cancer types and alpha diversity with Shannon and Simpson index.

Association of ICI efficacy with ASV based on treatment.