Effects of simulated microgravity on colorectal cancer organoids growth and drug response.

Cellular and molecular dynamics of human cells are constantly affected by gravity. Alteration of the gravitational force disturbs the cellular equilibrium, which might modify physiological and molecular characteristics. Nevertheless, biological responses of cancer cells to reduced gravitational force remains obscure. Here, we aimed to comprehend not only transcriptomic patterns but drug responses of colorectal cancer (CRC) under simulated microgravity. We established four organoids directly from CRC patients, and organoids cultured in 3D clinostat were subjected to genome wide expression profiling and drug library screening. Our observations revealed changes in cell morphology and an increase in cell viability under simulated microgravity compared to their static controls. Transcriptomic analysis highlighted a significant dysregulation in the TBC1D3 family of genes. The upregulation of cell proliferation observed under simulated microgravity conditions was further supported by enriched cell cycle processes, as evidenced by the functional clustering of mRNA expressions using cancer hallmark and gene ontology terms. Our drug screening results indicated an enhanced response rate to 5-FU under conditions of simulated microgravity, suggesting potential implications for cancer treatment strategies in simulated microgravity.

Tumor Deposits as an Adverse Prognostic Indicator in Stage III Colon Cancer: A Multicenter Database Study.

Objective: We explored the oncological impact of tumor deposits (TDs) on colon cancer and proposed optimal modifications to the current staging system. Background: In the existing American Joint Committee on Cancer colon cancer staging system, TDs are incorporated into the N category as N1c. When lymph node metastases (LNMs) are present, their number is considered to determine nodal stages, such as N1a/b or N2a/b, regardless of TDs. Methods: 4212 patients with primary colon cancer who underwent surgical resection in the Seoul Colorectal Group (2010-2020) and 93,057 patients from the Surveillance, Epidemiology, and End Results*Stat database (2000-2017) were included in this study. Patients were classified according to the number of metastatic lymph nodes (LNs) (0/1-3/≥4) and the presence of TDs. Results: TDs were significantly associated with left colon cancer, a higher T category, and vascular/perineural invasion. Patients with TDs had higher recurrence rates (23.1 vs 7.5%, P < 0.001). The TD-positive patients had notably worse overall survival (OS) and recurrence-free survival rates. The survival outcomes of TD-positive patients without LNM were inferior to those of TD-negative patients with LN1-3 (5-year OS: 78.9 vs 87.8%, P = 0.04). The survival outcomes of TD-positive patients with LN1-3 were similar to those of TD-negative patients with LN ≥4 (5-year OS: 87.0 vs 77.1%, P = 0.11). Survival outcomes obtained using the Surveillance, Epidemiology, and End Results *Stat database yielded consistent results. Conclusions: TDs were associated with poor prognostic factors and had a significant impact on survival outcomes. The incorporation of tumor deposits into nodal classifications beyond the current N1c criteria may improve the staging system and more accurately reflect the recurrence and survival rates among patients with colon cancer. TD-positive in N1a or N1b could be categorized as N2.

Are sporadic colorectal cancers in young patients distinct from those in elderly patients?

AIM: The aim of this study was to compare the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) between young and elderly patients without any genetic mutations that cause hereditary CRC. METHOD: In this cross-sectional, retrospective study conducted at three tertiary referral hospitals, we enrolled 1599 patients with CRC who underwent surgery between January 2010 and December 2017, including 157 young patients (age ≤ 40 years; yCRC) and 1442 elderly patients (age ≥ 70 years; eCRC). The clinicopathological and oncological outcomes were compared between the two groups. RESULTS: The median age at diagnosis was 37 years in the yCRC group (range 33.0-39.2 years) and 76 years in the eCRC group (range 72.0-79.0 years). The yCRC group did not present with advanced stages at diagnosis compared with the eCRC group, and the distribution of tumour stages was similar between the two groups. Microsatellite instability (MSI) testing revealed no difference in the frequency of tumours with high MSI (7.8% in yCRC, 5.8% in eCRC), and the frequency of mutations in the KRAS, NRAS and BRAF genes was also similar. The 3-year overall survival was better in the yCRC group than in the eCRC group (97.4% vs. 83.5%, p < 0.001); however, no such difference was observed in cancer-specific survival. CONCLUSION: Genetically proven sporadic CRCs did not differ significantly between young and elderly patients in terms of tumour stage, tumour location and various molecular features. CLINICAL TRIAL REGISTRATION NUMBER: The study was retrospectively registered with Clinical Trials.gov (no. NCT05601609).

Surgical quality assessment for the prospective study of oncologic outcomes after laparoscopic modified complete mesocolic excision for nonmetastatic right colon cancer (PIONEER study).

BACKGROUND: The modified complete mesocolic excision (mCME) procedure for right-sided colon cancer is a tailored approach based on the original complete mesocolic excision (CME) methodology. Limited studies evaluated the safety and feasibility of laparoscopic mCME using objective surgical quality assessments in patients with right colon cancer. The objectives of the PIONEER study were to evaluate oncologic outcomes after laparoscopic mCME and to identify optimal clinically relevant endpoints and values for standardizing laparoscopic right colon cancer surgery based on short-term outcomes of procedures performed by expert laparoscopic surgeons. MATERIALS AND METHODS: This is an ongoing prospective, multi-institutional, single-arm study conducted at five tertiary colorectal cancer centers in South Korea. Study registrants included 250 patients scheduled for laparoscopic mCME with right-sided colon adenocarcinoma (from the appendix to the proximal half of the transverse colon). The primary endpoint was 3-year disease-free survival. Secondary outcomes included 3-year overall survival, incidence of morbidity in the first 4 weeks postoperatively, completeness of mCME, central radicality, and distribution of metastatic lymph nodes. Survival data will be available after the final follow-up date (June 2024). RESULTS: The postoperative complication rate was 12.9%, with a major complication rate of 2.7%. In 87% of patients, central radicality was achieved with dissection at or beyond the level of complete exposure of the superior mesenteric vein. Mesocolic plane resection with an intact mesocolon was achieved in 75.9% of patients, as assessed through photographs. Metastatic lymph node distribution varied by tumor location and extent. Seven optimal clinically relevant endpoints and values were identified based on the analysis of complications in low-risk patients. CONCLUSIONS: Laparoscopic mCME for right-sided colon cancer produced favorable short-term postoperative outcomes. The identified optimal clinically relevant endpoints and values can serve as a reference for evaluating surgical performance of this procedure.

Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis.

BACKGROUND: Clinical diabetic traits have been reported to be associated with increased colorectal cancer (CRC) risk in observational studies. Using the Mendelian randomization (MR) analysis method, we examined the causal association between glycemic traits, such as fasting glucose (FG), fasting insulin (FI), and glycosylated hemoglobin A1c (HbA1c), and survival in a cohort of CRC patients. METHODS: We conducted a two-sample MR analysis among a cohort of patients with locally advanced CRC at Seoul National University Hospital. Single-nucleotide polymorphisms robustly associated (p < 5 × 10-8 ) with the three glycemic traits were obtained from the Meta-Analyses of Glucose and Insulin-related traits Consortium, Asian Genetic Epidemiology Network, and Korea Biobank Array. Three-year and 5-year overall survival (OS) and progression-free survival (PFS) were used as outcomes. Survival analysis was conducted using subgroup analysis by cancer stage and subsite in a multivariate Cox proportional hazards model adjusted for age and sex to examine whether glycemic traits affected survival. RESULTS: A total of 509 patients were included in our final analysis. MR analysis showed that HbA1c levels were associated with poor 3-year OS (ß = 4.20, p = 0.02). Sensitivity analyses did not show evidence of any violations of the MR assumptions. In the cancer subgroup analysis of the Cox proportional hazards model, pooled hazard ratios for FG were significantly associated with poor 3-year OS and PFS regardless of cancer stage. FI was not significantly associated with any 3-year survival endpoints. Among Stage III patients, three glycemic traits were significantly associated with both 5-year OS and PFS. Location-specific subgroup analysis showed a significant association between three glycemic traits and 5-year PFS in patients with left-sided colon cancer. FG was associated with poor 3-year survival for colon cancer but not rectal cancer. CONCLUSIONS: Our results suggest that FG and HbA1c could be used to predict prognosis in CRC patients. Lifestyle and/or pharmacological interventions targeting glycemic traits could help improve survival for CRC patients.

Risk Factor Analysis of Lymph Node Metastasis for Rectal Neuroendocrine Tumors: Who Needs a Radical Resection in Rectal Neuroendocrine Tumors Sized 1-2 cm?

BACKGROUND: Rectal neuroendocrine tumors (NETs) have malignant potential, and lymph node (LN) or distant metastases can occur; however, treatment of NETs 1-2 cm in size is controversial. OBJECTIVE: This study aimed to identify predictive factors for LN metastasis and prognostic factors for recurrence of rectal NETs, especially tumors 1‒2 cm in size. METHODS: Between October 2004 and November 2020, 453 patients underwent endoscopic or surgical treatment for rectal NETs in Seoul National University Hospital. The data on these patients were prospectively collected in our database and reviewed retrospectively. In cases of local excision, we evaluated LN metastasis with radiologic imaging, including computed tomography or magnetic resonance imaging before treatment and during the follow-up periods. RESULTS: LN metastasis was observed in 40 patients (8.8%). A higher rate of LN metastasis was observed in larger-sized tumors, advanced T stage, lymphovascular invasion (LVI), perineural invasion (PNI), and high tumor grade. In multivariable analysis, the significant risk factors for LN metastasis were tumor size (1 ≤ size < 2 cm: hazard ratio [HR] 64.07; size ≥2 cm: HR 102.37, p < 0.001) and tumor grade (G2: HR 3.63, p = 0.034; G3: HR 5.09, p = 0.044). In multivariable analysis for tumors 1-2 cm in size, the risk factor for LN metastasis was tumor grade (G2: HR 6.34, p = 0.013). CONCLUSIONS: Tumor grade and size are important predictive factors for LN metastasis. In NETs 2 cm in size, tumor grade is also important for LN metastasis, and radical resection should be considered.

Three-dimensional body composition parameters using automatic volumetric segmentation allow accurate prediction of colorectal cancer outcomes.

BACKGROUND: Parameters obtained from two-dimensional (2D) cross-sectional images have been used to determine body composition. However, data from three-dimensional (3D) volumetric body images reflect real body composition more accurately and may be better predictors of patient outcomes in cancer. This study aimed to assess the 3D parameters and determine the best predictive factors for patient prognosis. METHODS: Patients who underwent surgery for colorectal cancer (CRC) between 2010 and 2016 were included in this study. Preoperative computed tomography images were analysed using an automatic segmentation program. Body composition parameters for muscle, muscle adiposity, subcutaneous fat (SF) and abdominal visceral fat (AVF) were assessed using 2D images at the third lumbar (L3) level and 3D images of the abdominal waist (L1-L5). The cut-off points for each parameter were determined using X-tile software. A Cox proportional hazards regression model was used to identify the association between the parameters and the treatment outcomes, and the relative influence of each parameter was compared using a gradient boosting model. RESULTS: Overall, 499 patients were included in the study. At a median follow-up of 59 months, higher 3D parameters of the abdominal muscles and SF from the abdominal waist were found to be associated with longer overall survival (OS) and disease-free survival (all P < 0.001). Although the 3D parameters of AVF were not related to survival outcomes, patients with a high AVF volume and mass experienced higher rate of postoperative complications than those with low AVF volume (27.4% vs. 18.7%, P = 0.021, for mass; 27.1% vs. 19.0%, P = 0.028, for volume). Low muscle mass and volume (hazard ratio [HR] 1.959, P = 0.016; HR 2.093, P = 0.036, respectively) and low SF mass and volume (HR 1.968, P = 0.008; HR 2.561, P = 0.003, respectively), both in the abdominal waist, were identified as independent prognostic factors for worse OS. Along with muscle mass and volume, SF mass and volume in the abdominal waist were negatively correlated with mortality (all P < 0.001). Both AVF mass and volume in the abdominal waist were positively correlated with postoperative complications (P < 0.05); 3D muscle volume and SF at the abdominal waist were the most influential factors for OS. CONCLUSIONS: 3D volumetric parameters generated using an automatic segmentation program showed higher correlations with the short- and long-term outcomes of patients with CRC than conventional 2D parameters.

Cystic lymphangioma causing intussusception of the right colon: a case report and review of current literature.

Among intraabdominal lymphangiomas, colonic lymphangiomas are rare. These cystic tumors are generally asymptomatic and incidentally found but may present with bleeding or obstructive symptoms. Intussusception by such tumors is scarcely reported, with only nine previously reported cases listed in Pubmed. We report a case of a 41-year-old female Asian patient who presented with acute abdomen and was diagnosed with colonic intussusception caused by lymphangioma. She received emergent right hemicolectomy, recovered well without complications, and was discharged on the 5th postoperative day.

A 3 mm Port Reduces Postoperative Pain After Laparoscopic Colon Cancer Surgery: A Case-control Matched Study.

BACKGROUND: Recently, smaller-size trocars and instruments have been developed for laparoscopic colon cancer surgery; however, their effectiveness and safety have not been elucidated. This study aimed to investigate whether 3 mm trocars and instruments have benefits compared with conventional trocars and instruments. PATIENTS AND METHODS: Patients with colon cancer who underwent laparoscopic anterior resection or right hemicolectomy were included. Patients who underwent combined resections of other organs and those with conversion to open surgery were excluded. In the 3 mm group, three 5 mm trocars were replaced by 3 mm trocars. The numeric rating scale (NRS) immediately postoperatively at 24, 48, and 72 hours, respectively, after surgery and the use of additional analgesics and perioperative outcomes were analyzed. Case-control matched analysis was used to reduce bias according to the type of surgery. RESULTS: A total of 207 patients (conventional: n = 158, 3 mm: n = 49) were included. Before matching, NRS 48 hours postoperatively ( P = 0.049), proportion of patients using additional intravenous (IV) analgesics ( P = 0.007), postoperative hospital stay ( P < 0.001), and blood loss ( P < 0.001) were lower in the 3 mm group. In multivariable analysis, trocar type significantly impacted the proportion of patients using additional IV analgesics (odds ratio: 0.330; 95% CI: 0.153-0.712; P = 0.005). After case-control matching, NRS immediately postoperatively ( P = 0.015) and 24 hours postsurgery ( P = 0.043), patients using additional IV analgesics ( P = 0.019), postoperative hospital stay ( P = 0.010), intraoperative blood loss ( P < 0.001), and postoperative complication rate ( P = 0.028) were significantly lower in the 3 mm group compared with the 5 mm group. CONCLUSIONS: The use of 3 mm trocars and instruments in laparoscopic colon cancer surgery can effectively reduce postoperative pain while maintaining perioperative safety.

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial.

BACKGROUND: For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. METHODS: This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2-4 weeks in the TNT group and 6-10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. DISCUSSION: The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. TRIAL REGISTRATION: Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

The association between prescription drugs and colorectal cancer prognosis: a nationwide cohort study using a medication-wide association study.

BACKGROUND: With the availability of health insurance claim data, pharmacovigilance for various drugs has been suggested; however, it is necessary to establish an appropriate analysis method. To detect unintended drug effects and to generate new hypotheses, we conducted a hypothesis-free study to systematically examine the relationship between all prescription nonanticancer drugs and the mortality of colorectal cancer patients. METHODS: We used the Korean National Health Insurance Service-National Sample Cohort database. A total of 2,618 colorectal cancer patients diagnosed between 2004 and 2015 were divided into drug discovery and drug validation sets (1:1) through random sampling. Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification system: 76 drugs classified as ATC level 2 and 332 drugs classified as ATC level 4 were included in the analysis. We used a Cox proportional hazard model adjusted for sex, age, colorectal cancer treatment, and comorbidities. The relationship between all prescription nonanticancer drugs and the mortality of colorectal cancer patients was analyzed, controlling for multiple comparisons with the false discovery rate. RESULTS: We found that one ATC level-2 drug (drugs that act on the nervous system, including parasympathomimetics, addictive disorder drugs, and antivertigo drugs) showed a protective effect related to colorectal cancer prognosis. At the ATC level 4 classification, 4 drugs were significant: two had a protective effect (anticholinesterases and opioid anesthetics), and the other two had a detrimental effect (magnesium compounds and Pregnen [4] derivatives). CONCLUSIONS: In this hypothesis-free study, we identified four drugs linked to colorectal cancer prognosis. The MWAS method can be useful in real-world data analysis.

Personalised circulating tumour DNA assay with large-scale mutation coverage for sensitive minimal residual disease detection in colorectal cancer.

BACKGROUND: Postoperative minimal residual disease (MRD) detection using circulating-tumour DNA (ctDNA) requires a highly sensitive analysis platform. We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. METHODS: Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). RESULTS: In 98 CRC patients, personalised panels for ctDNA sequencing were built from tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (<0.01%). At postoperative 3-week, 21.4% of patients were positive for MRD by ctDNA. Postoperative positive MRD was strongly associated with poor disease-free survival (DFS) (adjusted hazard ratio 8.40, 95% confidence interval 3.49-20.2). Patients with a negative conversion of MRD after adjuvant therapy showed significantly better DFS (P < 0.001). CONCLUSION: Tumour-informed, hybrid-capture-based ctDNA assay monitoring a large number of patient-specific mutations is a sensitive strategy for MRD detection to predict recurrence in CRC.

Gut microbiome associated with low anterior resection syndrome after rectal cancer surgery.

This study aimed to assess the likely association of gut microbiome with low anterior resection syndrome (LARS) symptoms. Postoperative stool samples from patients with minor or major LARS after sphincter-preserving surgery (SPS) for rectal cancer were collected and analyzed using 16S ribosomal RNA sequencing method. The symptom patterns of LARS were classified into two groups (PC1LARS, PC2LARS) using principal component analysis. The dichotomized sum of questionnaire items (sub1LARS, sub2LARS) was used to group patients according to the main symptoms. According to microbial diversity, enterotype, and taxa, PC1LARS and sub1LARS were associated with frequency-dominant LARS symptoms and patients, while PC2LARS and sub2LARS were grouped as incontinence-dominant LARS symptoms and patients. Butyricicoccus levels decreased while overall LARS scores increased. The α-diversity richness index Chao1 showed a significantly negative correlation in sub1LARS and a positive correlation in sub2LARS. In sub1LARS, the severe group showed a lower Prevotellaceae enterotype and higher Bacteroidaceae enterotype than the mild group. Subdoligranulum and Flavonifractor showed a negative and a positive correlation with PC1LARS, respectively, while showing a negative relationship with PC2LARS. Lactobacillus and Bifidobacterium were negatively correlated to PC1LARS. Frequency-dominant LARS had decreased diversity of gut microbiome and showed lower levels of lactic acid-producing bacteria.

Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis.

Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.

Widespread somatic L1 retrotransposition in normal colorectal epithelium.

Throughout an individual's lifetime, genomic alterations accumulate in somatic cells1-11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12-14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.

Postoperative NSAIDs use and the risk of anastomotic leakage after restorative resection for colorectal cancer.

BACKGROUND: Although non-steroidal anti-inflammatory drugs (NSAIDs) are useful options for multimodal opioid-sparing analgesia, their effect on anastomotic leakage (AL) after colorectal surgery remains unclear. We aimed to investigate the association between early postoperative NSAID use and AL occurrence in patients who underwent colorectal cancer surgery at a high-volume tertiary care center. METHODS: This retrospective observational study included all adult patients who underwent elective colorectal cancer resection surgery during 2011-2021 at a tertiary teaching hospital. Based on NSAID use within five postoperative days, patients were classified into either NSAID or no NSAID groups. We performed multivariable logistic regression analysis for the primary outcome, AL, within the first 30 postoperative days, before and after propensity score analysis using stabilized inverse probability of treatment weighting (sIPTW). RESULTS: Among the 7928 patients analyzed, 0.6% experienced AL after surgery. The occurrence rates of AL were 1.7% (12/714) and 0.5% (37/7214) in the NSAID and no NSAID groups, respectively. Multivariable logistic regression analysis revealed that early postoperative NSAID use was significantly associated with AL [odds ratio (OR), 3.41; 95% confidence interval (CI), 1.76-6.60; P < 0.001]. Significance was maintained after sIPTW (OR, 3.65; 95% CI, 1.86-6.72; P < 0.001). CONCLUSION: Early postoperative NSAID use was significantly associated with AL in patients undergoing colorectal cancer surgery at a high-volume tertiary care center. Further prospective studies are required to investigate NSAIDs' clinically meaningful unfavorable effects following colorectal cancer surgery.

Circulating Tumor DNA Dynamics and Treatment Outcome of Regorafenib in Metastatic Colorectal Cancer.

PURPOSE: Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib. Materials and Methods: In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted next-generation sequencing platform which included 106 genes. RESULTS: A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of -31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of ≥ 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly. CONCLUSION: Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib.

Safety of early surgery after self-expandable metallic stenting for obstructive left-sided colorectal cancer.

BACKGROUND: Self-expanding metallic stenting (SEMS) is usual for the temporary resolution of obstructive left-sided colorectal cancer (CRC) as a bridge to elective surgery. However, there is no consensus regarding adequate time intervals from stenting to radical surgery. The aim of this study was to identify the optimal time interval that results in favorable short- and long-term outcomes. METHODS: Data on patients with obstructive left-sided CRC who underwent elective radical surgery after clinically successful SEMS deployment in five tertiary referral hospitals from 2004 to 2016 were analyzed, retrospectively. An inverse probability treatment-weighted propensity score analysis was used to minimize bias. Postoperative short- and long-term outcomes were compared between two groups: an early surgery (within 8 days) group and delayed surgery (after 8 days) group. RESULTS: Of 311 patients, 148 (47.6%) underwent early and 163 (52.4%) underwent delayed surgery. The median surgery interval was 9.0 days. After adjustment, the groups had similar patient and tumor characteristics. In terms of short-term outcomes, there was no difference in hospitalization length or postoperative complications. No deaths were observed. With a median follow-up of 71.0 months, no significant difference was observed between the groups in 5-year overall survival (early vs. delayed surgery: 79.6% vs. 71.3%, P = 0.370) and 5-year disease-free survival (early vs. delayed surgery: 59.1% vs. 60.4%, P = 0.970). CONCLUSIONS: In obstructive left-sided CRC, the time interval between SEMS and radical surgery did not significantly influence short- and long-term outcomes. Therefore, early surgery after SEMS could be suggested if there is no reason to postpone surgery for preoperative medical optimization.