Machine learning­based radiomics models accurately predict Crohn's disease­related anorectal cancer.

The radiological diagnosis of Crohn's disease (CD)-related anorectal cancer is difficult; it is often found in advanced stages and has a poor prognosis because of the difficulty of curative surgery. However, there are no studies on predicting the diagnosis of CD-related cancer. The present study aimed to develop a predictive model to diagnose CD cancerous lesions more accurately in a way that can be interpreted by clinicians. Patients with CD who developed anorectal CD lesions at Hyogo Medical University (Nishinomiya, Japan) between March 2009 and June 2022 were included in the present study. T2-weighted and T1-weighted magnetic resonance (MR) images were utilized for our analysis. Images of anorectal lesions were segmented using open-source 3D Slicer software, and radiomic features were extracted using PyRadiomics. Six machine learning models were investigated and compared: i) Support vector machine; ii) naive Bayes; iii) random forest; iv) light gradient boosting machine; v) extremely randomized trees; vi) and regularized greedy forest (RGF). SHapley Additive exPlanations (SHAP) values were calculated to assess the extent to which each radiomic feature contributed to the model's predictions compared to baseline, represented as the average of the model's predictions for all test data. The T2-weighted images of 28 patients with anorectal cancer and 40 non-cancer patients were analyzed and the contrast-enhanced T1-weighted images of 22 cancer and 40 non-cancer patients. The model with the highest area under the curve (AUC) was the RGF-based model constructed using T2-weighted image features, achieving an AUC of 0.944 (accuracy, 0.862; recall, 0.830). The SHAP-based model explanation suggested a strong association between the diagnosis of CD-related anorectal cancer and features such as complex lesion texture; greater pixel separation within the same coronal cross-section; larger, randomly distributed clumps of pixels with the same signal intensity; and a more spherical lesion shape on T2-weighted images. The MRI radiomics-based RGF model demonstrated outstanding performance in predicting CD-related anorectal cancer. These results may affect the diagnosis and surveillance strategies of CD-related colorectal cancer.

Lymphatic spread patterns in young versus elderly patients with stage III colon cancer.

BACKGROUND: The anatomical pattern of lymph nodes spread differs between young (aged 45 years or younger) and elderly (aged 80 years or older) patients with stage III colon cancer and is poorly investigated. METHODS: Two groups of patients (young and elderly) with stage III colon cancer who underwent upfront extensive (D3) lymphadenectomy at eight Japanese centres between 1998 and 2018 were retrospectively analysed. The primary endpoint was the proportion of positive central lymph nodes. The lymph nodes spreading pattern and its prognostic impact on recurrence-free survival and overall survival in the two groups were also compared. RESULTS: Two hundred and ten young patients and 348 elderly patients were identified and compared. The total number of lymph nodes harvested and the total number of invaded lymph nodes were significantly higher in younger patients compared with elderly patients (median of 31.5 (3-151) versus 21 (3-116), P < 0.001 and median of 3 (1-21) versus 2 (1-25), P < 0.001 respectively). The proportion of positive central lymph nodes were higher in younger patients than in elderly patients (9.52% (95% c.i. 6.24 to 14.2%) versus 4.59% (95% c.i. 2.84 to 7.31%), P = 0.012). In multivariate models for recurrence-free survival, central lymph nodes invasion were identified as a poor prognostic factor in younger patients (HR 5.21 (95% c.i. 1.76 to 15.39)) but not in elderly patients (HR 1.73 (95% c.i. 0.80 to 3.76)). CONCLUSION: Young patients with stage III colon cancer have a higher risk of central lymph nodes invasion, suggesting a more aggressive disease biology. The presence of central lymph nodes invasion are associated with a worse outcome in young patients.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Delineation of the internal iliac vein using MRI with true FISP sequence in patients with locally recurrent rectal cancer: A pilot study using CT/MRI fusion.

PURPOSE: This study assessed the feasibility of using three-dimensional (3D) models of intrapelvic vascular patterns constructed using computed tomography (CT) and magnetic resonance imaging (MRI) fusion data for preoperative planning in patients with locally recurrent rectal cancer. METHODS: Eleven patients scheduled for pelvic exenteration were included. The 3D fusion data of the intrapelvic vessels constructed using CT and MRI with true fast imaging with steady-state precession sequence (True FISP) were evaluated preoperatively. Contrast ratios (CR) between the piriformis muscle and the intrapelvic vessels were calculated to identify a valid modality for 3D modeling and creating CT/MRI fusion-reconstructed volume-rendered images. RESULTS: The CR values of the internal and external iliac arteries were significantly higher on CT images than MR images (CT vs. MRI; 0.63 vs. 0.45, p < 0.01). However, the CR value of the internal iliac vein was significantly higher on MR than CT images (CT vs. MRI; 0.23 vs. 0.55, p < 0.01). CONCLUSIONS: MRI with True FISP yielded high signal-to-noise ratios and aided in delineating the internal iliac vein around the piriformis muscle. More precise 3D models can be constructed using this technique in the future to aid in the resection of locally recurrent rectal cancer.

Localized colorectal cancer database integrating 4 randomized controlled trials; (JCOG2310A).

Although phase III randomized controlled trials (RCTs) represent the most robust statistical approach for answering clinical questions, they require massive expenditures in terms of time, labor, and funding. Ancillary and supplementary analyses using RCTs are sometimes conducted as alternative approaches to answering clinical questions, but the available integrated databases of RCTs are limited. In this background, the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) established a database of ancillary studies integrating four phase III RCTs (JCOG0212, JCOG0404, JCOG0910 and JCOG1006) conducted by the CCSG to investigate specific clinicopathological factors in pStage II/III colorectal cancer (JCOG2310A). This database will be updated by adding another clinical trial data and accelerating several analyses that are clinically relevant in the management of localized colorectal cancer. This study describes the details of this database and planned and ongoing analyses as an initiative of JCOG cOlorectal Young investigators (JOY).

The Impacts of Laparoscopic Restorative Proctocolectomy for Ulcerative Colitis: Systematic Review and Meta-Analysis.

Introduction: Laparoscopic surgery (LAP) is now recognized as the standard procedure for colorectal surgery. However, the standard surgery for ulcerative colitis (UC) is total proctocolectomy with ileal pouch anal anastomosis (IPAA), which may be an overly complex procedure to complete laparoscopically. We conducted this systematic review and meta-analysis to evaluate the efficacy as well as the advantages and disadvantages of LAP-IPAA in patients with UC stratified by the outcome of interest. Method: We performed a systematic literature review by searching the PubMed/MEDLINE, the Cochrane Library, and the Japan Centra Reuvo Medicina databases from inception until January 2023. Meta-analyses were performed for surgical outcomes, including morbidity and surgical course, to evaluate the efficacy of LAP-IPAA. Results: A total of 707 participants, including 341 LAP and 366 open surgery (OPEN) patients in 9 observational studies and one randomized controlled study, were included. From the results of the meta-analyses, the odds ratio (OR) of total complications in LAP was 1.12 (95% CI: 0.58-2.17, p = 0.74). The OR of mortality for LAP was 0.38 (95% CI: 0.08-1.92, p = 0.24). Although the duration of surgery was extended in LAP (mean difference (MD) 118.74 min (95% CI: 91.67-145.81), p < 0.01) and hospital stay were not shortened, the duration until oral intake after surgery was shortened in LAP (MD -2.10 days (95% CI: -3.52-0.68), p = 0.004). Conclusions: During IPAA for UC, a similar morbidity rate was seen for LAP and OPEN. Although LAP necessitates extended surgery, there may be certain advantages to this procedure, including easy visibility during the surgical procedure or a shortened time to oral intake after surgery.

Subcutaneous emphysema associated with laparoscopic or robotic abdominal surgery: a retrospective single-center study.

BACKGROUND: Subcutaneous emphysema (SCE) is a common complication in laparoscopic surgery. However, its precise incidence and impact on the clinical course are partially known. In this study, the incidence and risk factors of SCE were retrospectively analyzed. METHODS: Patients who underwent laparoscopic/robotic abdominal surgery (e.g., gastrointestinal, hepatobiliary, gynecologic, and urologic surgery) between October 2019 and September 2022 were retrospectively analyzed. The presence of SCE was confirmed by either conclusive findings obtained through chest/abdominal X-ray examination immediately after operation, or intraoperative palpation conducted by nurses. X-ray examination was performed in the operation room before extubation. RESULTS: A total of 2503 patients treated with laparoscopic/robotic abdominal surgery between October 2019 and September 2022 were identified and all of them were included in the analysis. SCE was confirmed in 23.1% of the patients (i.e., 577/2503). SCE was identified by X-ray examination in 97.6% of the patients. Extubation failure was observed in 10 patients; however, pneumothorax was not observed. Female sex (odds ratio [OR]: 2.09; 95% confidence interval [95%CI]: 1.69-2.57), age ≥ 80 years (OR 1.63; 95%CI 1.19-2.22), body mass index < 20 (OR 1.32; 95%CI 1.06-1.65), operation time > 360 min (OR 1.97; 95%CI 1.53-2.54), robotic surgery (OR 2.54; 95%CI 1.91-3.38), maximum intraabdominal pressure with CO2 > 15 mmHg (OR 1.79; 95%CI 1.02-3.16), and endo-tidal CO2 > 50 mmHg (OR 1.32; 95%CI 1.08-1.62)were identified as independent factors of SCE. Regarding the extubation failure due to SCE, age (OR 5.84; 95%CI 1.27-26.8) and maximum intraabdominal pressure with CO2 (OR 21.7; 95%CI 4.76-99.3) were identified as risk factors. CONCLUSION: Although the presence of SCE is associated with a low risk of severe complications, monitoring of the perioperative intraabdominal pressure is essential for performing safe laparoscopic/robotic surgery, particularly in elderly patients.

EORTC 1409 GITCG/ESSO 01 - A prospective colorectal liver metastasis database for borderline or initially unresectable diseases (CLIMB): Lessons learnt from real life. From paradigm to unmet need.

AIM: Multidisciplinary management of metastatic colorectal liver metastases (CRLM) is still challenging. To assess postoperative complications in initially unresectable or borderline resectable CRLM, the prospective EORTC-1409 ESSO 01-CLIMB trial capturing 'real-life data' of European centres specialized in liver surgery was initiated. MATERIAL AND METHODS: A total of 219 patients were registered between May 2015 and January 2019 from 15 centres in nine countries. Eligible patients had borderline or initially unresectable CRLM assessed by pre-operative multidisciplinary team discussion (MDT). Primary endpoints were postoperative complications, 30-day and 90-days mortality post-surgery, and quality indicators. We report the final results of the 151 eligible patients that underwent at least one liver surgery. RESULTS: Perioperative chemotherapy with or without targeted treatment were administered in 100 patients (69.4%). One stage resection (OSR) was performed in 119 patients (78.8%). Two stage resections (TSR, incl. Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS)) were completed in 24 out of 32 patients (75%). Postoperative complications were reported in 55.5% (95% CI: 46.1-64.6%), 64.0% (95% CI: 42.5-82%), and 100% (95% CI: 59-100%) of the patients in OSR, TSR and ALPPS, respectively. Post-hepatectomy liver failure occurred in 6.7%, 20.0%, and 28.6% in OSR, TSR, and ALPPS, respectively. In total, four patients (2.6%) died after surgery. CONCLUSION: Across nine countries, OSR was more often performed than TSR and tended to result in less postoperative complications. Despite many efforts to register patients across Europe, it is still challenging to set up a prospective CRLM database.

[Questionnaire Survey on the Timing of Comprehensive Genomic Profiling for Advanced Recurrent Colorectal Cancer and Its Impact on Patients].

BACKGROUNDS: Comprehensive genomic profiling(CGP)has been covered by health insurance since June 2019. However, the clinical impact of CGP on patients with metastatic colorectal cancer(mCRC)remains unclear. To date, there are very limited reports regarding patient-oriented outcomes of CGP in mCRC. PATIENTS: A questionnaire was completed by patients with mCRC who had already received their CGP results after April 2021. Eight questions were posed, covering the degree of satisfaction and timing when CGP was conducted. RESULTS: Of the 51 patients with mCRC who had received their CGP test results by August 2021 in our department, 21 patients responded to our questionnaire. In total 66.7% patients with mCRC answered "(very)satisfied"with the CGP testing. 28.6% of the patients already knew about CGP testing before their local doctors informed them. Except for 3 patients who did not answer, 47.6% and 9.5% of patients with mCRC"agreed"and "moderately agreed"with the timing of the CGP test. CONCLUSION: Although most patients with mCRC failed to access promising new treatment via CGP, approximately half of the patients answered that they were satisfied with the CGP testing. Conversely, a few patients already knew about CGP testing before it was proposed by their doctors. Thus, the provision of information at an early stage is necessary.

Clinical features and surgical selection in colitis-associated colorectal cancer with ulcerative colitis.

PURPOSE: The aim of this study was to compare the clinical characteristics of ulcerative colitis (UC) patients who underwent surgery for cancer/dysplasia with those who underwent surgery for refractory disease and to discuss the preoperative preparation for successful hand-sewn IPAA. METHODS: Patients who underwent surgery for UC between January 2014 and December 2021 at Hyogo Medical University were included in the study. A total of 443 UC surgical cases were included in the study, which comprised 188 cancer/dysplasia patients and 255 refractory patients. Clinical records were compared retrospectively. RESULTS: The proportion of surgical UC cases with cancer/dysplasia has been on the rise, accounting for approximately 40% in recent years. The duration of disease (months) was 186 (2-590) in the cancer/dysplasia group and 48 (1-580) in the refractory group (p = 0.02). UC severity (mild/moderate/severe) was 119/69/0 in the cancer/dysplasia group and 18/157/80 in the refractory group (p < 0.01). The four nutrition factors of weight (55.2 (32.7-99.6) kg: 49.9 (20.3-85.2) kg), body mass index (21.0 (13.9-32.5) kg/m2: 18.3 (11.4-34.1)kg/m2), serum albumin level (4.3 (2.7-5.0)g/dl: 3.4 (1.4-5.2)g/dl) and prognostic nutrition index (49.2 (33.2-61.2): 40.9 (17.4-61.1)) were significantly higher in the cancer/dysplasia group (p < 0.01). The degree of obesity was also significantly higher in the cancer/dysplasia group (p < 0.01). CONCLUSION: UC patients with cancer/dysplasia were more likely than refractory patients to have mild inflammation; they also had a longer duration of UC disease and better nutritional status.

Anatomical Validation of Internal Iliac Vessels Assessed by Three-dimensional Angiographic Analysis.

Objectives: Anatomical understanding of the internal iliac vessels is important with the increasing frequency of minimally-invasive pelvic surgery. We aimed to investigate the branch patterns of internal iliac vessels, especially the veins. Methods: This study included 30 patients with 60 half-pelvises who underwent minimally-invasive pelvic surgery. Branch patterns were assessed on surgical videos with a multi-detector computed tomography-based three-dimensional simulation. Branch patterns of the superior gluteal artery and vein (SGA and SGV), inferior gluteal artery and vein (IGA and IGV), internal pudendal artery and vein (IPA and IPV), and obturator artery and vein (ObA and ObV) were investigated. Results: In the most frequent internal iliac vein (IIV) branch pattern, 67% of SGV branched from the IIV, 95% of the IGV branched from the IPV and 82% of the ObV branched from the IPV. According to Adachi's classification, 62% of IIVs were Type I and 33% Type IV. Although IIV branch patterns are heterogeneous, in individual patients with the most frequent branch patterns, good correlation (75-100%) of the branch patterns was observed between the internal iliac artery (IIA) and IIV, and between the right and left IIVs. Conclusions: This study clarified the branch patterns of IIV. In patients with the most frequent branch patterns, good correlation of the branch patterns was observed between the IIA and IIV, and between right and left IIV. We believe this helps secure the safety and standardization of minimally-invasive pelvic surgery.

Transanal Minimally Invasive Surgical Approach to Total Pelvic Exenteration.

BACKGROUND: Total pelvic exenteration, a surgical procedure for patients with highly advanced primary and recurrent rectal cancer, is technically demanding. IMPACT OF INNOVATION: We report the utility of a transanal minimally invasive surgical approach to total pelvic exenteration. TECHNOLOGY MATERIALS AND METHODS: A 2-team approach with a laparoscopic transabdominal approach and transanal minimally invasive surgery was adopted. During the transabdominal approach in the pelvis, dissection was performed to remove the pelvic organs and visceral branches of the internal iliac vessels. The dissection goal via the transabdominal approach is the levator ani. During the transperineal approach, dissection is performed along the levator ani, and the tendinous arch of the levator ani is penetrated at the lateral side to achieve rendezvous between the 2 approaches. The levator ani is then dissected circumferentially, with identification of the internal pudendal vessels passing through the levator ani at the 4 o'clock and 8 o'clock positions, known as Alcock's canal. The anterior wall of Alcock's canal is formed by the coccygeus muscle and sacrospinous ligament, which are dissected by the transperineal approach to open Alcock's canal, thus obtaining a clear view of the internal pudendal vessels. On the anterior side, the urethra is divided with a laparoscopic linear stapler via the transperineal approach. PRELIMINARY RESULTS: Eight patients with rectal cancer underwent this procedure. The median (range) blood loss was 200 (120-1520) mL and operating time was 467 (321-833) minutes. Reoperation was performed in 1 internal hernia case; however, there were no mortalities, and there were no cases with severe complications or conversion to open surgery. CONCLUSIONS AND FUTURE DIRECTIONS: When performing total pelvic exenteration, transanal minimally invasive surgery offers direct visualization behind the tumor from the anal side and shows the deep pelvic structures, including the retroperitoneal space of the pelvic sidewall.

Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases.

BACKGROUND: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.

[Educational Project of Self-Removal of the Intravenous Central Venous Access Port Guided by Patients with Advanced Colorectal Cancer Instructed by a Nurse in the University Hospital].

BACKGROUND: Fluorouracil infusion for 46±5h from the central venous(CV)port is required for mFOLFOX6, FOLFIRI, and FOLFOXIRI in patients with advanced colorectal cancer(CRC), followed by self-removal of the needle by patients. At our hospital, outpatients were instructed for self-removal of the needle, but the results were unsatisfactory. Therefore, instructions for self-removal of the needle from the CV port have been initiated at the patient ward since April 2019, making use of a hospital stay of 3 days. PATIENTS: We retrospectively enrolled patients with chemotherapy-introduced advanced CRC from the CV port who received instructions for self-removal of the needle in the outpatient department and ward between January 2018 and December 2021. RESULTS: Of all patients with advanced CRC, 21 received instructions at the outpatient department(OP)while 67 at patient ward(PW). Incidences of successful self-removal of the needle without the aid of others were similar: 47% in OP and 52% in PW(p=0.80). However, after several additional instructions involving their families, it was higher in PW than in OP(97.0 vs 76.1%, p=0.005). Incidences of successful self-removal of the needle without the aid of others in those aged≥75/<75, and≥65/<65 years were 0%/61.1%, and 35.4%/67.5%, respectively. OP was as a risk factor for failed self-removal of the needle in the logistic regression analysis(odds ratio: 11.19, 95%CI: 1.86- 67.30). CONCLUSION: Repeated instructions involving patients' families during the hospital stay improved the incidence of successful self-removal of the needle. Involvement of patients' families from the beginning may effectively improve self- removal of the needle, particularly in the elderly patients with advanced CRC.

Risk factors for the postoperative recurrence of ulcerative colitis-associated colorectal cancer.

PURPOSE: Although ulcerative colitis-associated colorectal cancer (UC-CRC) has been described, there are few reports regarding recurrent cases of UC-CRC. In this study, we investigated the risk factors for UC-CRC recurrence. METHODS: Recurrence-free survival (RFS) was determined for 144 stage I to III cancer patients among 210 UC-CRC patients from August 2002 to August 2019. The Kaplan‒Meier method was used to obtain the cumulative RFS rate, and the Cox proportional hazard model was used to extract recurrence risk factors. The interaction term between cancer stage and prognostic factors specific to UC-CRC was evaluated using the Cox model. The Kaplan‒Meier method was applied by cancer stage to the UC-CRC-specific prognostic factors for which interaction effects were indicated. RESULTS: There were 18 cases of recurrence involving patients with stage I to III cancer, and the recurrence rate was 12.5%. The cumulative 5-year RFS rate was 87.5%. Multivariable analysis showed that age at surgery (hazard ratio (HR): 0.95, 95% CI: 0.91-0.99, p = 0.02), undifferentiated carcinoma (HR: 4.42, 95% CI: 1.13-17.24, p = 0.03), lymph node metastasis (HR: 4.11, 95% CI: 1.08-15.69, p = 0.03), and vascular invasion (HR: 8.01, 95% CI: 1.54-41.65, p = 0.01) were significant risk factors for recurrence. Patients with stage III CRC in the young adult (age < 50 years) group had a significantly worse prognosis than those in the adult (age ≥ 50 years) group (p < 0.01). CONCLUSION: Age at surgery was identified as a risk factor for UC-CRC recurrence. Young adult patients with stage III cancer may have a poor prognosis.

Erratum forTotal Neoadjuvant Chemotherapy in Rectal Cancer: Current Facts and Future Strategies.

[This corrects the article DOI: 10.23922/jarc.2022-060.].

Total Neoadjuvant Chemotherapy in Rectal Cancer: Current Facts and Future Strategies.

Despite preoperative chemoradiotherapy (CRT) and total mesorectal excision improving the local control for locally advanced rectal cancer (LARC), oncologic outcomes and survival were not significantly improved because the main prognostic factor is distant metastasis. Thus, total neoadjuvant chemotherapy (TNT) as a novel approach has been proposed to improve chemotolerance. Since the first randomized phase II trial of TNT versus standard CRT demonstrated in 2012, many prospective and retrospective studies have been published. The initial consensus from TNT studies was that pathological complete response, pathological response of the main tumor, and local control are more favorable at TNT than at CRT. Furthermore, recent studies such as the PAPIDO trial and PRODIGE 23 trial made a major breakthrough of the treatment of TNT, showing that TNT improves the disease-free survival compared to standard treatment with long-course CRT. In addition, several innovative findings of TNT were clarified by prospective phase II trial. In this review, we summarize the most recent advances in TNT based on the findings of pivotal clinical trials for patients with LARC.

Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer.

Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II-IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49-24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT.