Resection Of Primary Colorectal Cancer Research Articles

Venous thromboembolism among Asian populations with localized colorectal cancer undergoing curative resection: is pharmacological thromboprophylaxis required? A systematic review and meta-analysis.

We compared the incidence of venous thromboembolism (VTE) among Asian populations with localized colorectal cancer undergoing curative resection with and without the use of pharmacological thromboprophylaxis (PTP). A comprehensive literature search was undertaken to identify relevant studies published from January 1, 1980 to February 28, 2022. The inclusion criteria were patients who underwent primary tumor resection for localized nonmetastatic colorectal cancer; an Asian population or studies conducted in an Asian country; randomized controlled trials, case-control studies, or cohort studies; and the incidence of symptomatic VTE, deep vein thrombosis, and/or pulmonary embolism as the primary study outcomes. Data were pooled using a random-effects model. This study was registered in PROSPERO on October 11, 2020 (No. CRD42020206793). Seven studies (2 randomized controlled trials and 5 observational cohort studies) were included, encompassing 5,302 patients. The overall incidence of VTE was 1.4%. The use of PTP did not significantly reduce overall VTE incidence: 1.1% (95% confidence interval [CI], 0%-3.1%) versus 1.9% (95% CI, 0.3%-4.4%; P = 0.55). Similarly, PTP was not associated with significantly lower rates of symptomatic VTE, proximal deep vein thrombosis, or pulmonary embolism. The benefit of PTP in reducing VTE incidence among Asian patients undergoing curative resection for localized colorectal cancer has not been clearly established. The decision to administer PTP should be evaluated on a case-bycase basis and with consideration of associated bleeding risks.

Clinical characteristics and prognostic impact of direct distant organ metastasis in colorectal cancer

BackgroundColorectal cancer (CRC) is the third most common type of cancer worldwide, and distant metastasis is frequently noted at diagnosis or follow-up. Notably, some patients with CRC can present with distant organ metastasis without any nodal involvement, which was defined as direct distant organ metastasis (DDOM). In this study, we evaluated the prognostic significance of DDOM for patients with CRC. MethodsThis study included 325 patients who had undergone primary colorectal cancer resection between August 2008 and December 2021. The patients with and without DDOM were compared (Kaplan–Meier analysis) in terms of overall survival (OS) and time to recurrence. Furthermore, the patients’ clinicopathological risk factors and protective factors were analyzed (multivariate Cox proportional hazards model). ResultsOf the 325 patients, 65 (20%) had DDOM (Direct+ group) and 260 (80%) did not (Direct− group). The Kaplan–Meier analysis revealed that OS was significantly better in the Direct+ group than in the Direct− group (p < 0.01). A subgroup analysis by CRC stage was performed; for the patients with non-stage-IV CRC, the rate of OS was significantly higher in the Direct+ group than in the Direct− group (p = 0.02). However, DDOM did not affect the OS of the patients with stage IV CRC. The multivariate analysis indicated DDOM, left colon tumor location, and postoperative adjuvant chemotherapy were significant protective factors for disease-related mortality in the patients with non-stage-IV CRC; by contrast, body mass index, curative resection, and postoperative adjuvant chemotherapy were identified to be significant protective factors in the patients with stage IV CRC. ConclusionsDDOM appears to be significantly associated with improved OS in patients with non-stage-IV CRC but not in those with stage IV CRC. Furthermore, the time to cancer recurrence may not vary significantly between patients with DDOM and those without it.

Clinicopathological Impact of High Preoperative CA19-9 in Early-stage Colorectal Cancer: A Single-center Retrospective Cohort Study.

This study examined the clinical significance of very high preoperative carbohydrate antigen 19-9 (CA19-9) levels in patients with early-stage colorectal cancer (CRC). We retrospectively analyzed the clinicopathological data of patients who underwent curative resection for primary CRC (c-Stage I-III) between 2004 and 2022 in our facility. The patients were classified into three groups according to the preoperative CA19-9 level: normal (≤37.0 U/ml), high (>37.0 to ≤100.0 U/ml), and very high (>100.0 U/ml). Of 971 patients, 885 (91.1%), 67 (6.9%), and 19 (2.0%) had normal, high, and very high CA19-9 levels, respectively. Overall survival (very high vs. normal: p<0.0001, very high vs. high: p=0.01) and recurrence-free survival (very high vs. normal: p<0.0001, very high vs. high: p=0.18) were significantly worse in the very high group. On multivariate analysis including TNM stage, very high preoperative CA19-9 levels were independently associated with worse overall (odds ratio=4.54; 95% confidence interval=2.03-10.16; p=0.0002) and recurrence-free survival (odds ratio=3.49; 95% confidence interval=1.82-6.69; p=0.0002). High preoperative CA19-9 levels were associated with poor survival in early-stage CRC. Careful intraoperative observation and close follow-up might be necessary.

Simultaneous Resection for Colorectal and Liver Metastases, new equipment and personalized medicine.

Nowadays we perform synchronous colorectal cancer resection along with synchronous liver metastases. We investigated whether colon resection first is safer than liver resection first and if simultaneous surgeries are in general safe. Patients and Methods: Twenty patients were included in our multicenter study. In our study patients had simultaneous laparoscopic resection of primary colorectal cancer and liver metastases. The patients included were divided into two groups based on their first surgery. Group A had colon resection first (n = 10) and group B had liver resection first (n = 10). All adverse effects and outcomes were compared after the first day of hospitalization. Results: The only difference between the two groups was the operative blood loss. It was observed to be less in group B. Conclusion: In our study we did not observe any significant difference regarding the order of the operation.

A prospective, single-centre, randomized, double-blind controlled study protocol to study whether long-term oral metronidazole can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer

IntroductionFifteen to 25% of patients with colorectal cancer have combined liver metastases at the time of diagnosis, whereas an additional 15 to 25% will develop liver metastases after curative resection of primary colorectal cancer, with the vast majority (80–90%) of liver metastases unresponsive to curative resection at first. Colorectal cancer liver metastasis is also the leading cause of death in patients with colorectal cancer. In recent years, several studies have demonstrated that intestinal flora, especially Fusobacterium nucleatum, plays a crucial role in the development of colorectal cancer liver metastasis, so we hypothesized that long-term metronidazole use could effectively reduce the incidence of postoperative liver metastasis in colorectal cancer patients.Methods/designThis study is a prospective, single-centre, randomized, double-blind controlled study in which 300 patients will be randomly assigned to the test group or the control group in a 1:1 allocation ratio. The aim of this trial is to demonstrate that long-term oral antibiotics can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer.Ethics and disseminationEthics approval was obtained from the Ethics Committee at the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20210229). The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals.Trial registrationChinese Clinical Trial Registry ChiCTR2100046201. Registered on July 05, 2021.

Prediction of disease recurrence or residual disease after primary endoscopic resection of pT1 colorectal cancer—results from a large nationwide Danish study

PurposeRisk assessment of disease recurrence in pT1 colorectal cancer is crucial in order to select the appropriate treatment strategy. The study aimed to develop a prediction model, based on histopathological data, for the probability of disease recurrence and residual disease in patients with pT1 colorectal cancer.MethodsThe model dataset consisted of 558 patients with pT1 CRC who had undergone endoscopic resection only (n = 339) or endoscopic resection followed by subsequent bowel resection (n = 219). Tissue blocks and slides were retrieved from Pathology Departments from all regions in Denmark. All original slides were evaluated by one experienced gastrointestinal pathologist (TPK). New sections were cut and stained for haematoxylin and eosin (HE) and immunohistochemical markers. Missing values were multiple imputed. A logistic regression model with backward elimination was used to construct the prediction model.ResultsThe final prediction model for disease recurrence demonstrated good performance with AUC of 0.75 [95% CI 0.72–0.78], HL chi-squared test of 0.59 and scaled Brier score of 10%. The final prediction model for residual disease demonstrated medium performance with an AUC of 0.68 [0.63–0.72].ConclusionWe developed a prediction model for the probability of disease recurrence in pT1 CRC with good performance and calibration based on histopathological data. Together with lymphatic and venous invasion, an involved resection margin (0 mm) as opposed to a margin of ≤ 1 mm was an independent risk factor for both disease recurrence and residual disease.

Do resected colorectal cancer patients need early chest imaging? Impact of clinicopathologic characteristics on time to development of pulmonary metastases.

For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.

Upfront primary tumor resection versus upfront systemic therapy for metastatic colorectal cancer: a systematic review and meta-analysis.

The standard initial treatment for metastatic colorectal cancer (mCRC) remains debated. This study investigated whether upfront primary tumor resection (PTR) or upfront systemic therapy (ST) provides better survival outcomes for patients with mCRC. The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for studies published at any time from January 1, 2004, to December 31, 2022. Randomized controlled trials (RCTs) and prospective or retrospective cohort studies (RCSs) utilizing propensity score matching (PSM) or inverse probability treatment weighting (IPTW) were included. We evaluated overall survival (OS) and short-term (60-day) mortality in these studies. After reviewing 3,626 articles, we identified 10 studies including a total of 48,696 patients. OS differed significantly between the upfront PTR and upfront ST arms (hazard ratio [HR] 0.62; 95% CI: 0.57-0.68; p < 0.001). However, a subgroup analysis identified no significant difference in OS in RCTs (HR 0.97; 95% CI: 0.7-1.34; p = 0.83), whereas significant difference in OS occurred between the treatment arms in RCSs with PSM or IPTW (HR 0.59; 95% CI: 0.54-0.64; p < 0.001). Short-term mortality was analyzed in three RCTs, and 60-day mortality differed significantly between the treatment arms (risk ratio [RR] 3.52; 95% CI: 1.23-10.10; p = 0.02). In RCTs, upfront PTR for mCRC did not improve OS and enhanced the risk of 60-day mortality. However, upfront PTR seemed to increase OS in RCSs with PSM or IPTW. Therefore, whether upfront PTR should be used for mCRC remains unclear. Further large RCTs are required.

Surgical resection for second primary colorectal cancer: a population-based study.

Second primary colorectal cancer (CRC) is attributed to a crucial component of the CRC population. Still, its treatments remain unclear due to the troublesome conditions originating from multiple primary cancers and the lack of quality evidence. This study aimed to determine that which type of surgical resection is the eligible treatment for second primary CRC among patients with a prior cancer history. This cohort study retrospectively collected patients with second primary stage 0-III CRC in the Surveillance, Epidemiology, and End Results database from 2000 to 2017. Prevalence of surgical resection in second primary CRC, overall survival (OS) and disease-specific survival (DSS) of patients who received different surgical interventions were estimated. A total of 38,669 patients with second primary CRC were identified. Most of the patients (93.2%) underwent surgical resection as initial treatment. Approximately 39.2% of the second primary CRCs (N = 15,139) were removed with segmental resection, while 54.0% (N = 20,884) were removed through radical colectomy/proctectomy. Surgical resection was associated with a significantly favorable OS and DSS compared to those not receiving any surgical operations for second primary CRC [OS: adjusted Hazard ratios (adjusted HR): 0.35; 95% CI: 0.34-0.37, p < 0.001; DSS: adjusted HR: 0.27; 95% CI: 0.25-0.29, p < 0.001]. Segmental resection considerably outperformed radical resection in terms of OS and DSS (OS: adjusted HR: 0.97; 95% CI: 0.91-1.00, p = 0.07; DSS: adjusted HR: 0.92; 95% CI: 0.87-0.97, p = 0.002). Segmental resection was also associated with a significantly reduced cumulative mortality of postoperative non-cancer comorbidities. Surgical resection demonstrated excellent oncological superiority for second primary CRC and was used to remove the vast majority of second primary CRCs. In comparison to radical resection, segmental resection offered a better prognosis and reduced postoperative non-cancer complications. The second primary colorectal cancers should be resected if the patients can afford surgical operations.

Simultaneous laparoscopic resection of primary colorectal cancer and synchronus liver metastases: Initial experience of single institute

Simultaneous laparoscopic resection of primary colorectal cancer and synchronus liver metastases: Initial experience of single institute

Poly-G for tumor matched samples chronicles the evolution of human colorectal cancer

Objective: To analyze poly-guanine (poly-G) genotypes and construct the phylogenetic tree of colorectal cancer (CRC) and provide an efficient and convenient method for the study of intra-tumor heterogeneity and tumor metastasis pathway. Methods: The clinicopathological information of patients with primary colorectal cancer resection with regional lymph node metastases were retrospectively collected in the Department of General Surgery, General Hospital of Tianjin Medical University from January 2017 to December 2017. The paraffin sections of the paired tumor samples were performed consecutively, and multi-region microdissection was performed after histogene staining. The phenol-chloroform extraction and ethanol precipitation scheme was used to obtain DNA, and Poly-G multiplex PCR amplification and capillary electrophoresis detection were performed. The correlation between Poly-G mutation frequency and clinicopathological parameters was analyzed. Based on the difference of Poly-G genotypes between paired samples, the distance matrix was calculated, and the phylogenetic tree was constructed to clarify the tumor metastasis pathway. Results: A total of 237 paired samples were collected from 20 patients including 134 primary lesions, 66 lymph node metastases, 37 normal tissues, and Poly-G mutation was detected in 20 patients (100%). The mutation frequency of Poly-G in low and undifferentiated patients was (74.10±23.11)%, higher than that in high and medium differentiated patients [(31.36±12.04)%, P<0.001]. In microsatellite instability patients, the mutation frequency of Poly-G was (68.19±24.80)%, which was higher than that in microsatellite stable patients [(32.40±14.90)%, P=0.003]. The Poly-G mutation frequency was not correlated with age, gender, and pathological staging (all P>0.05). Based on Poly-G genotype difference of the paired samples, the phylogenetic trees of 20 patients were constructed, showing the evolution process of the tumor, especially the subclonal origins of lymph node metastasis. Conclusion: Poly-G mutations accumulate in the occurrence and development of CRC, and can be used as genetic markers to generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure.

A novel risk prediction nomogram for early death in patients with resected synchronous multiple primary colorectal cancer based on the SEER database

BackgroundSynchronous multiple primary colorectal cancer (SMPCC) involves the simultaneous occurrence of 2 or more independent primary malignant tumors in the colon or rectum. Although SMPCC is rare, it results in a higher incidence of postoperative complications and mortality compared to patients with single primary colorectal cancer (SPCRC).MethodsThe clinical factors and survival outcomes of SMPCC patients registered on the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2017 were extracted. The patients were divided into the training and validation cohorts using a ratio of 7:3. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors for early death. The performance of the nomogram was evaluated using the concordance index (C-index), calibration curves, and the area under the curve (AUC) of a receiver operating characteristics curve (ROC). A decision curve analysis (DCA) was used to evaluate the clinical utility of the nomogram and standard TNM system.ResultsA total of 4386 SMPCC patients were enrolled in the study and randomly assigned to the training (n = 3070) and validation (n = 1316) cohorts. The multivariate logistic analysis identified age, chemotherapy, radiotherapy, T stage, N stage, and M stage as independent risk factors for all-cause and cancer-specific early death. The marital status was associated with all-cause early death, and the tumor grade was associated with cancer-specific early death. In the training cohort, the nomogram achieved a C-index of 0.808 (95% CI, 0.784–0.832) and 0.843 (95% CI, 0.816–0.870) for all-cause and cancer-specific early death, respectively. Following validation, the C-index was 0.797 (95% CI, 0.758–0.837) for all-cause early death and 0.832 (95% CI, 0.789–0.875) for cancer-specific early death. The ROC and calibration curves indicated that the model had good stability and reliability. The DCA showed that the nomogram had a better clinical net value than the TNM staging system.ConclusionOur nomogram can provide a simple and accurate tool for clinicians to predict the risk of early death in SMPCC patients undergoing surgery and could be used to optimize the treatment according to the patient's needs.

Laparoscopic versus open resection of primary colorectal cancers and synchronous liver metastasis: a systematic review and meta-analysis

PurposeCombined resection of primary colorectal cancer and associated liver metastases is increasingly common. This study compares peri-operative and oncological outcomes according to surgical approach.MethodsThe study was registered with PROSPERO. A systematic search was performed for all comparative studies describing outcomes in patients that underwent laparoscopic versus open simultaneous resection of colorectal primary tumours and liver metastases. Data was extracted and analysed using a random effects model via Rev Man 5.3ResultsTwenty studies were included with a total of 2168 patients. A laparoscopic approach was performed in 620 patients and an open approach in 872. There was no difference in the groups for BMI (mean difference: 0.04, 95% CI: 0.63–0.70, p = 0.91), number of difficult liver segments (mean difference: 0.64, 95% CI:0.33–1.23, p = 0.18) or major liver resections (mean difference: 0.96, 95% CI: 0.69–1.35, p = 0.83). There were fewer liver lesions per operation in the laparoscopic group (mean difference 0.46, 95% CI: 0.13–0.79, p = 0.007). Laparoscopic surgery was associated with shorter length of stay (p < 0.00001) and less overall postoperative complications (p = 0.0002). There were similar R0 resection rates (p = 0.15) but less disease recurrence in the laparoscopic group (mean difference: 0.57, 95% CI:0.44–0.75, p < 0.0001).ConclusionSynchronous laparoscopic resection of primary colorectal cancers and liver metastases is a feasible approach in selected patients and does not demonstrate inferior peri-operative or oncological outcomes.

Abstract 4691: Spatially resolved transcriptomics deconvolutes histological prognostic subgroups in patients with colorectal cancer and synchronous liver metastases

Abstract Patients demonstrating strong immune responses to primary colorectal cancer (CRC) have a survival benefit following surgery, while those with predominantly stromal microenvironments do poorly. Biomarkers to identify patients with colorectal cancer liver metastases (CRLM) who have good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary CRC and CRLM, and to interrogate the underlying functional biology that drives disease progression. Patients undergoing synchronous resection of primary CRC and CRLM underwent detailed histological assessment, panel genomic and bulk transcriptomic assessment, immunohistochemistry (IHC) and GeoMx Spatial Transcriptomics (ST) analysis. Integration with genomic features, pathway enrichment analysis and immune deconvolution were performed. High-immune metastases were associated with improved cancer specific survival (HR, 0.36, P=0.01). Bulk transcriptomic analysis was confounded by stromal content but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for Type II Interferon signaling (NES=-2.05 P.Adj&amp;lt;0.005) and MHC-Class II Antigen Presentation (NES=-2.09 P.Adj&amp;lt;0.005). In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T-cells and neutrophils with enrichment of Notch (NES=2.2 P.Adj=0.022) and TGF-β (NES=2.2 P.Adj=0.02) signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcome in patients undergoing synchronous resection of CRLM and ST analysis has revealed significant intra-tumoral and inter-lesional heterogeneity with underlying transcriptomic programs identified in driving each phenotype. Citation Format: Colin S. Wood, Kathryn A. Pennel, Holly Leslie, Assya Legrini, Andrew J. Cameron, Paul Horgan, Joanne Edwards, Colin W. Steele, Nigel B. Jamieson. Spatially resolved transcriptomics deconvolutes histological prognostic subgroups in patients with colorectal cancer and synchronous liver metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4691.

Risk factors for small-bowel obstruction after colectomy for colorectal cancer: a retrospective study.

Postoperative adhesions are a concerning complication of abdominal surgery with major implications on quality of life. This study aimed to investigate the risk factors for postoperative small-bowel obstruction (SBO) after colectomy for colorectal cancer. We reviewed the clinicopathological variables of 1646 patients who underwent colectomy for colorectal cancer between 2009 and 2018. SBO occurred following primary tumor resection for colorectal cancer in 67 (4.1%) of the 1646 patients. The median observation period was 7.5 (range: 3.0-12.0) years. Multivariate analysis revealed that rectal tumors, anastomotic leakages, previous abdominal surgeries, and longer operating times were all correlated with postoperative SBO, but there were no differences in the incidence of SBO between laparoscopic vs. open surgery. The use of adhesion prevention material had no effect on SBO. Our data showed that the onset of SBO tended to be relatively early, within a year after surgery (89.5%). Tumor localization in the rectum is associated with several problems, including a wide resection area, prolonged operative duration, and high risk of anastomotic leakage, which may increase the risk of SBO. Laparoscopic surgery and adhesion prevention material did not demonstrate a clear preventive effect against SBO.

Distinct role of tumor-infiltrating lymphocytes between synchronous and metachronous colorectal cancer.

Tumor-infiltrating lymphocytes (TILs) may influence the prognosis of colorectal liver metastasis (CRLM). We assessed the prognostic value of evaluating TILs in the primary and metastatic sites of synchronous CRLM as well as metachronous CRLM. We examined 90 patients who underwent curative primary and liver metastasis resection for colorectal cancer. CD8+ TILs (cytotoxic T cells) or CD45RO+ TILs (memory T cells) in both primary and metastatic sites were simultaneously evaluated by immunohistochemistry. Fifty-one patients had synchronous CRLM, and 39 patients had metachronous CRLM. In synchronous cases, the overall survival (OS) was significantly worse in patients with low CD8+ or CD45RO+ TILs in a metastatic site than in those with high CD8+ or CD45RO+ TILs (P = 0.017 and P = 0.005, respectively). Multivariate analysis showed that age ≥ 65years (P = 0.043), maximum tumor size ≥ 30mm (P = 0.003), primary N2-3 (P = 0.019), and low CD8+ TILs in metastatic site (P = 0.046) were independent poor prognostic factors. In contrast, in metachronous cases, OS was significantly worse in patients with low CD45RO+ TILs in a primary site than in those with high CD45RO+ TILs (P = 0.021). CD45RO+ TILs in a primary site (P = 0.044) were determined to be independent prognostic factor on multivariate analysis. The immune microenvironment between synchronous and metachronous CRLM might be different, and these differences may affect its prognosis.

Preoperative chemotherapy prior to primary tumor resection for asymptomatic synchronous unresectable colorectal liver-limited metastases: A multicenter randomized controlled trial.

132 Background: Most recently, there were 3 reports of prospective randomized clinical trials comparing the effects of primary tumor resection (PTR) for multiorgan metastatic colorectal cancer followed by chemotherapy with chemotherapy alone, but the results differed and unconvincing due to the prematurely study termination and research protocol changes. PTR was preferably performed for patients with asymptomatic synchronous unresectable colorectal liver-limited metastases (CRLMs) with conversion therapy purpose, including the CELIM, OLIVIA and our study (J Clin Oncol 2013;31:1931-8). This randomized phase III study investigated the superiority of preoperative chemotherapy prior to PTR for patients with asymptomatic synchronous unresectable CRLMs. Methods: Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were decided according to the RAS genotype. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), tumor response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity. Results: Between June 2012 and June 2018, a total of 320 patients were randomly assigned to arm A (160 patients) or arm B (160 patients). The cutoff date for survival data was June 2021, the median follow-up time was 36.2 months. Patients were well balanced. For the intention-to-treat population, the median PFS, median OS, and 3-year OS rates were 9.9 months, 28.0 months, and 37.0%, respectively. The median PFS in arm A was significantly improved compared with arm B (10.5 v 9.1 months; hazard ratio [95% CI, 0.60 to 0.95], 0.76; P = 0.013). Patients in arm A also had a significantly better DCR (84.4% v 75.0%; P = 0.037). The median OS was not significantly different (29.4 v 27.2 months; hazard ratio [95% CI, 0.58 to 1.01], 0.77, P = 0.058), and the objective response rates were also not significantly different (53.1% v 45.0%; P = 0.146). The actual resection rate of liver metastases was not significantly different (21.9% v 18.1%; P = 0.402). There were mild morbidities and no 30-day postoperative mortalities in both arms. The rate of complications was not significantly different (37.7% v 30.8%, P = 0.201). The incidence of Clavien–Dindo 3-4 complications also did not reach statistical significance (4.5% v 3.8%, P = 0.759). Overall the observed toxicity was mostly mild. There was no significant difference in the overall incidence of predefined grade 3/4 events (42.2% v 40.4%, P = 0.744). There were no grade 5 events in either arm. Conclusions: For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR. Clinical trial information: NCT01307878 .

Association of punctate TAK1 expression with mortality in patients with microsatellite-stable colorectal cancer.

220 Background: Microsatellite stable (MSS) colorectal cancer continues to have limited options for personalised therapeutic targets. The NFKB pathway is known to play an important role in inflammation-related carcinogenesis but has yet to be translated into therapies for the clinical patient. The aim of this study was to investigate the expression of cytoplasmic and punctate TAK1 (transforming growth factor β-activated protein kinase 1) in colorectal cancer and its relationship to immune checkpoint expression and prognosis. Methods: Patients undergoing primary colorectal cancer resection between 1997 and 2007 at Glasgow Royal Infirmary (UK) were studied for clinicopathological data and immunohistochemistry (IHC) performed on archival FFPE tissue from resected specimens. Antibodies for TAK1, PD-1, PD-L1, IKK alpha and other proteins were used for IHC, with digital analysis (QuPath) for quantification of cytoplasmic staining and punctate score for juxta-nuclear TAK1 assessment. Kaplan-Meier curves were created with log-rank test to determine survival. Cox-proportional hazards regression were used to determine multivariate hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 898 patients who underwent colorectal resection were identified. Higher TAK1 punctate expression was observed in left colon and rectal cancer, compared with right sided disease (p = 0.045). MMR proficient tumours had higher frequencies of high TAK1 punctate expression (p &lt; 0.001). Both cytoplasmic and punctate TAK1 expression correlated with IKK expression (p &lt; 0.050). High cytoplasmic TAK1 expression was associated with increased PD-1 and PD-L1 expression (p &lt; 0.001). Punctate TAK1 expression was associated with worse survival (p = 0.037). These differences were accentuated in patients with MSS status (p = 0.016). On multivariate analysis, high punctate TAK1 expression remained a predictor of worse cancer-specific survival (HR 1.843, CI 1.129-2.956, p = 0.011). Conclusions: TAK1 expression was associated with MSI status, and higher TAK1 expression correlates with upregulated PD-1 and PD-L1 expression. High punctate TAK1 expression predicted cancer-specific survival. In subgroup analysis of MSS patients, high punctate TAK1 expression was associated with poor survival. Further interrogation into this pathway may identify inflammation-related therapeutic targets in MSS patients with colorectal cancer.

Prognostic Potential of Cyclin D1 Expression in Colorectal Cancer.

Cyclin D1 is mainly known as an oncogenic driver in cancers, and the dysregulated cyclin D1/cyclin-dependent kinase (CDK) 4/6 axis is considered an attractive target for cancer therapy. Recent studies have reported that tumors respond to therapeutic interventions targeting altered cyclin D1 expression via application of the CDK4/6 inhibitor. However, the prognostic and therapeutic contributions of cyclin D1 to colorectal cancer (CRC) remain controversial. Herein, we assessed the associations between cyclin D1 expression and clinicopathological factors, including patients' overall survival (OS) and recurrence-free survival (RFS), in 495 surgically resected primary CRCs. We also examined previous studies for cyclin D1 in CRCs. High expressions of cyclin D1 (cyclin D1High) was observed in 389 CRC cases (78.6%). Cyclin D1High consistently predicted better patient OS and RFS in CRCs. Based on multivariate analysis, cyclin D1High and young age of patients remained as independent prognosticators of higher OS rate, whereas cyclin D1High, females, chemotherapy, absence of nodal metastasis, and lower T-category remained as independent prognosticators of better RFS. Cyclin D1 is commonly overexpressed in CRCs, and its expression can be used as a favorable prognostic indicator in patients with CRCs; this may be important for predicting responses to subsequent CDK4/6 inhibitors.

Impact of cumulative operative time on postoperative complication risk in simultaneous resections of colorectal liver metastases and primary tumors

BackgroundSimultaneous resection of colorectal liver metastases (CLM) and primary colorectal cancers (CRC) is nuanced without firm rules for selection. This study aimed to identify factors associated with morbidity after simultaneous resection. MethodsUsing a prospective database, patients undergoing simultaneous CLM-CRC resection from 1/1/2017-7/1/2020 were analyzed. Regression modeling estimated impact of colorectal resection type, Kawaguchi–Gayet (KG) hepatectomy complexity, and perioperative factors on 90-day complications. ResultsOverall, 120 patients underwent simultaneous CLM-CRC resection. Grade≥2 complications occurred in 38.3% (n = 46); these patients experienced longer length of stay (median LOS 7.5 vs. 4, p < 0.001) and increased readmission (39% vs. 1.4%, p < 0.001) compared to patients with zero or Grade 1 complications. Median OR time was 298 min. Patients within highest operative time quartile (>506 min) had higher grade≥2 complications (57%vs. 23%, p = 0.04) and greater than 4-fold increased odds of grade≥2 morbidity (OR 4.3, 95% CI (Confidence Interval) 1.41–13.1, p = 0.01). After adjusting for Pringle time, KG complexity and colorectal resection type, increasing operative time was associated with grade≥2 complications, especially for resections in highest quartile of operative time (OR 7.28, 95% CI 1.73–30.6, p = 0.007). ConclusionIn patients undergoing simultaneous CLM-CRC resection, prolonged operative time is independently associated with grade≥2 complications. Awareness of cumulative operative time may inform intraoperative decision-making by surgical teams.