Development and validation of a competitive risk model in patients with rectal cancer: based on SEER database.

BACKGROUND: Rectal cancer is one of the most common malignancies. To predict the specific mortality risk of rectal cancer patients, we constructed a predictive nomogram based on a competing risk model. METHODS: The information on rectal cancer patients was extracted from the SEER database. Traditional survival analysis and specific death analysis were performed separately on the data. RESULTS: The present study included 23,680 patients, with 16,580 in the training set and 7100 in the validation set. The specific mortality rate calculated by the competing risk model was lower than that of the traditional survival analysis. Age, Marriage, Race, Sex, ICD-O-3Hist/Behav, Grade, AJCC stage, T stage, N stage, Surgery, Examined LN, RX SUMM-SURG OTH, Chemotherapy, CEA, Deposits, Regional nodes positive, Brain, Bone, Liver, Lung, Tumor size, and Malignant were independent influencing factors of specific death. The overall C statistic of the model in the training set was 0.821 (Se = 0.001), and the areas under the ROC curve for cancer-specific survival (CSS) at 1, 3, and 5 years were 0.842, 0.830, and 0.812, respectively. The overall C statistic of the model in the validation set was 0.829 (Se = 0.002), and the areas under the ROC curve for CSS at 1, 3, and 5 years were 0.851, 0.836, and 0.813, respectively. CONCLUSIONS: The predictive nomogram based on a competing risk model for time-specific mortality in patients with rectal cancer has very desirable accuracy. Thus, the application of the predictive nomogram in clinical practice can help physicians make clinical decisions and follow-up strategies.

An Updated Review on Imaging and Staging of Anal Cancer-Not Just Rectal Cancer.

Anal cancer is a rare disease, but its incidence has been increasing steadily. Primary staging and assessment after chemoradiation therapy are commonly performed using MRI, which is considered to be the preferred imaging modality. CT and PET/CT are useful in evaluating lymph node metastases and distant metastatic disease. Anal squamous-cell carcinoma (ASCC) and rectal adenocarcinoma are typically indistinguishable on MRI, and a biopsy prior to imaging is necessary to accurately stage the tumor and determine the treatment approach. This review discusses the histology, MR technique, diagnosis, staging, and treatment of anal cancer, with a particular focus on the differences in TNM staging between anal and rectal carcinomas. PURPOSE: This review discusses the histology, MR technique, diagnosis, staging, and treatment of anal cancer, with a particular focus on the differences in TNM staging between anal squamous-cell carcinoma (ASCC) and rectal adenocarcinoma. METHODS AND MATERIALS: To conduct this updated review, a comprehensive literature search was performed using prominent medical databases, including PubMed and Embase. The search was limited to articles published within the last 10 years (2013-2023) to ensure their relevance to the current state of knowledge. INCLUSION CRITERIA: (1) articles that provided substantial information on the diagnostic techniques used for ASCC, mainly focusing on imaging, were included; (2) studies reporting on emerging technologies; (3) English-language articles. EXCLUSION CRITERIA: articles that did not meet the inclusion criteria, case reports, or articles with insufficient data. The primary outcome of this review is to assess the accuracy and efficacy of different diagnostic modalities, including CT, MRI, and PET, in diagnosing ASCC. The secondary outcomes are as follows: (1) to identify any advancements or innovations in diagnostic techniques for ASCC over the past decade; (2) to highlight the challenges and limitations of the diagnostic process. RESULTS: ASCC is a rare disease; however, its incidence has been steadily increasing. Primary staging and assessment after chemoradiation therapy are commonly performed using MRI, which is considered to be the preferred imaging modality. CT and PET/CT are useful in evaluating lymph node metastases and distant metastatic disease. CONCLUSION: ASCC and rectal adenocarcinoma are the most common histological subtypes and are typically indistinguishable on MRI; therefore, a biopsy prior to imaging is necessary to stage the tumor accurately and determine the treatment approach.

Magnetic resonance imaging accuracy in staging early and locally advanced rectal cancer.

INTRODUCTION: Magnetic Resonance Imaging (MRI) is the standard pretreatment staging in patients with rectal cancer. Accurate tumor staging is paramount to determining the appropriate treatment course for patients diagnosed with rectal cancer. The current study aims to re-evaluate the accuracy of pre-operative MRI in staging of both early and locally advanced rectal cancer following completion of neoadjuvant therapy (NAT) compared to the pathologic stage. METHODS: A retrospective review of patients treated for rectal cancer between 2015 and 2020 at a single academic institution. All patients underwent rectal cancer protocol MRIs before surgical resection. Analysis was carried out in two groups: early rectal cancer: T1/2 N0 tumors with upfront surgical resection (N = 40); and locally advanced disease: T3 or greater or N+ disease receiving NAT, with restaging MRI following NAT (n = 63). RESULTS: 103 patients were included in analysis. MRI accuracy in early tumors was 35% ICC = 0.52 (95% CI 0.25-0.71) T stage and 66% ICC = 0 (95% CI -0.24, 0.29) for 29 patients with nodal data for N stage. There was 28% understaging of T2 tumors and 34% understaging of N0 stage by MRI. Post NAT MRI had 44% accuracy ICC = 0.57 (95% CI -0.15-0.20) T stage and 60% accuracy ICC = 0.32 (95% CI 0.08-0.52) N stage. Tumor invasion was overstaged on MRI: 40% T2, 29% T3, 90% T4. Nodal inaccuracy was due to overstaging, 61% N1, 90% N2. CONCLUSIONS: In locally advanced rectal cancer MRI overstaged tumors, this could be due to the continued effect of NAT from MRI to resection. This overstaging is of little clinical significance as it doesn't alter the treatment plan, except in cases of complete clinical response. In early rectal cancer, MRI had limited accuracy compared to pathology, understaging a quarter of patients who would benefit from NAT before surgery. Other adjunct imaging modalities should be considered to improve accuracy in staging early rectal cancer and consideration of complete response and enrollment in watch and wait protocols.

Predictive and Prognostic Role of Neutrophil to Lymphocyte Ratio in Rectal Cancer: A Case Control Study with Propensity Score Analysis.

Background: Neutrophil to lymphocyte ratio (NLR) is promoted as a marker reflecting the antitumoral inflammatory response. Herein, we aim to assess whether NLR at the time of diagnosis can predict response to neoadjuvant therapy and long-term survival in a matched cohort of rectal cancer patients. Methods: This is a case control study on rectal cancer patients who underwent standard oncological treatment and had NLR sampled at each stage. ROC curve was used to establish the cut off value of NLR at diagnosis. Two groups (high and low NLR) were compared. Kaplan Meier overall and disease-free survival (DFS) analysis was done comparatively between two groups of patients: low and high NLR. Pearson and Log Rank tests were used to establish statistical significance. Propensity score matching (PSM) was performed, and all variables were compared again on the matched subgroups. Results: One hundred patients were included and 54 were compared again after PSM. NLR at diagnosis did not correlate with tumor regression grade (p=0.77). High NLR at diagnosis (NLR 2.58) was not found to be significantly associated with worse overall survival (p=0.096) or DFS (p=0.128). Similar results were achieved after PSM, except when stage III subgroups were compared, where higher NLR was associated with worse DFS (p=0.04), while results for OS were borderline (p=0.05). Conclusions: Overall, a pretherapeutic high NLR ( 2.58) was not found to predict survival or response do neoadjuvant therapy in patients with rectal cancer. However, a higher NLR may be associated with worse outcomes in advanced colorectal cancer.

Simultaneous rectal neuroendocrine tumors and pituitary adenoma: A case report and review of literature.

BACKGROUND: Neuroendocrine tumors (NET) are rare heterogeneous tumors that arise from neuroendocrine cells throughout the body. Acromegaly, a rare and slowly progressive disorder, usually results from a growth hormone (GH)-secreting pituitary adenoma. CASE SUMMARY: We herein describe a 38-year-old patient who was initially diagnosed with diabetes. During colonoscopy, two bulges were identified and subsequently removed through endoscopic submucosal dissection. Following the surgical intervention, the excised tissue samples were examined and confirmed to be grade 2 NET. 18F-ALF-NOTATATE positron emission tomography-computed tomography (PET/CT) and 68Ga-DOTANOC PET/CT revealed metastases in the peri-intestinal lymph nodes, prompting laparoscopic low anterior resection with total mesorectal excision. The patient later returned to the hospital because of hyperglycemia and was found to have facial changes, namely a larger nose, thicker lips, and mandibular prognathism. Laboratory tests and magnetic resonance imaging (MRI) suggested a GH-secreting pituitary adenoma. The pituitary adenoma shrunk after treatment with octreotide and was neuroendoscopically resected via a trans-sphenoidal approach. Whole-exome sequencing analysis revealed no genetic abnormalities. The patient recovered well with no evidence of recurrence during follow-up. CONCLUSION: 18F-ALF-NOTATE PET/CT and MRI with pathological analysis can effectively diagnose rare cases of pituitary adenomas complicated with rectal NET.

Fully automated volumetric modulated arc therapy planning for locally advanced rectal cancer: feasibility and efficiency.

BACKGROUND: Volumetric modulated arc therapy (VMAT) for locally advanced rectal cancer (LARC) has emerged as a promising technique, but the planning process can be time-consuming and dependent on planner expertise. We aimed to develop a fully automated VMAT planning program for LARC and evaluate its feasibility and efficiency. METHODS: A total of 26 LARC patients who received VMAT treatment and the computed tomography (CT) scans were included in this study. Clinical target volumes and organs at risk were contoured by radiation oncologists. The automatic planning program, developed within the Raystation treatment planning system, used scripting capabilities and a Python environment to automate the entire planning process. The automated VMAT plan (auto-VMAT) was created by our automated planning program with the 26 CT scans used in the manual VMAT plan (manual-VMAT) and their regions of interests. Dosimetric parameters and time efficiency were compared between the auto-VMAT and the manual-VMAT created by experienced planners. All results were analyzed using the Wilcoxon signed-rank sum test. RESULTS: The auto-VMAT achieved comparable coverage of the target volume while demonstrating improved dose conformity and uniformity compared with the manual-VMAT. V30 and V40 in the small bowel were significantly lower in the auto-VMAT compared with those in the manual-VMAT (p < 0.001 and < 0.001, respectively); the mean dose of the bladder was also significantly reduced in the auto-VMAT (p < 0.001). Furthermore, auto-VMAT plans were consistently generated with less variability in quality. In terms of efficiency, the auto-VMAT markedly reduced the time required for planning and expedited plan approval, with 93% of cases approved within one day. CONCLUSION: We developed a fully automatic feasible VMAT plan creation program for LARC. The auto-VMAT maintained target coverage while providing organs at risk dose reduction. The developed program dramatically reduced the time to approval.

Development and validation of a nomogram for predicting operating time in laparoscopic anterior resection of rectal cancer.

Aims: The goal of this study is to create and verify a nomogram estimate operating time in rectal cancer (RC) patients based on clinicopathological factors and MRI/CT measurements before surgery. Materials and Methods: The nomogram was developed in a cohort of patients who underwent laparoscopic anterior resection (L-AR) for RC. The clinicopathological and pelvis parameters were collected. Risk factors for a long operating time were determined by univariate and multivariate logistic regression analyses, and a nomogram was established with independent risk factors. The performance of the nomogram was evaluated. An independent cohort of consecutive patients served as the validation dataset. Results: The development group recruited 159 RC patients, while 54 patients were enrolled in the validation group. Independent risk factors identified in multivariate analysis were a distance from the anal verge <5 cm (P = 0.024), the transverse diameter of the pelvic inlet (P < 0.001), mesorectal fat area (P = 0.017), and visceral fat area (P < 0.001). Then, a nomogram was built based on these four independent risk factors. The C-indexes of the nomogram in the development and validation group were 0.886 and 0.855, respectively. And values of AUC were the same with C-indexes in both groups. Besides, the calibration plots showed satisfactory consistency between actual observation and nomogram-predicted probabilities of long operating time. Conclusions: A nomogram for predicting the risk of long operating duration in L-AR of RC was developed. And the nomogram displayed a good prediction effect and can be utilized as a tool for evaluating operating time preoperatively.

Dynamic Monitoring of Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer.

PURPOSE: Plasma circulating tumor DNA (ctDNA) is a valuable resource for tumor characterization and for monitoring of residual disease during treatment; however, it is not yet introduced in metastatic colorectal cancer (mCRC) routine clinical practice. In this retrospective exploratory study, we evaluated the role of ctDNA in patients with mCRC treated with chemotherapy plus bevacizumab. MATERIALS AND METHODS: Fifty-three patients were characterized for RAS and BRAF status on tumor tissue before the start of treatment. Plasma was collected at baseline, at first clinical evaluation, and at disease progression. ctDNA analysis was performed using Oncomine Colon cfDNA Assay on the Ion S5 XL instrument. RESULTS: At baseline, from a plasma sample, RAS, BRAF, or PIK3CA mutations were detected in 44 patients. A high correspondence was observed between ctDNA and tumor tissue mutations (KRAS 100%, NRAS 97.9%, BRAF 97.9%, PIK3CA 90%). Low baseline variant allele frequency (VAF) was found to be associated with longer median progression-free survival (PFS) compared with those with high VAF (15.9 v 12.2 months, P = .02). A higher PFS {12.29 months (95% CI, 9.03 to 17.9) v 8.15 months (95% CI, 2.76 to not available [NA]), P = .04} and overall survival (34.1 months [95% CI, 21.68 to NA] v 11.1 months [95% CI, 3.71 to NA], P = .003) were observed in patients with large decline in VAF at first evaluation. CONCLUSION: ctDNA analysis is useful for molecular characterization and tumor response monitoring in patients with mCRC. Quantitative variations of released ctDNA are associated with clinical outcomes.

Neoadjuvant chemoradiotherapy with capecitabine based regimen in locally advanced rectal cancer: A retrospective study.

Capecitabine-based neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer. The objective of this study is to analyze overall survival (OS), disease-free survival (DFS) and prognostic factors of patients with stage II to III rectal cancer treated with nCRT in our institution. Between March 2014 to June 2020, 121 locally advanced rectal cancer patients were retrospectively reviewed and analyzed. All of the enrolled patients were treated with capecitabine-based nCRT (pelvic radiotherapy: 45-50.4 Gy, 1.8 Gy/d plus concomitant capecitabine-based chemotherapy), total mesorectal excision surgery (surgery was carried out 8-12 weeks after the end of CRT), and capecitabine-based adjuvant chemotherapy. We examined the pathological complete response rate, 3-year OS, 3-year DFS and the other prognostic factors. Kaplan-Meier method and Log-rank test were used to estimate and compare survival rate. With a median follow-up of 36 months, 3-year DFS and 3-year OS was 74.4% and 83.2%, respectively. Among the 121 patients, 24 achieved pathological complete remission (19.8%). After multivariate analysis, ypTNM stage (TNM stage after neoadjuvant therapy) was significantly associated with DFS. Positive mesorectal fasciae (MRF) status on magnetic resonance imaging and ypTNM stage were significantly related to OS. CRT with capecitabine based regimen provides high rates of survival and sphincter preservation with acceptable toxicity. YpTNM stage was significantly associated with DFS; magnetic resonance imaging MRF status and ypTNM stage were significant factors for OS after multivariate analysis. Distant metastasis is the dominant mode of treatment failure, and it is crucial to optimize systemic treatment for newly diagnosed patients.

A unique case of rectal cancer with coexistence of multiple pathways of carcinogenesis.

BACKGROUND: Colorectal cancer with a global incidence of 10% has multiple pathways implicated in its carcinogenesis. WNT signaling is the principal underlying pathway via APC gene, while defective mismatch repair genes and epigenetic changes also are known to contribute. CASE PRESENTATION: Here, we present an unusual case of rectal adenocarcinoma in a woman, with germline MSH6 and PMS1 mutations, and simultaneous somatic APC and TP53 mutations treated with surgery and adjuvant capecitabine. CONCLUSIONS: The case is unique suggesting a possible interaction between the two pathways and contributing to carcinogenesis in this patient. This also suggests need for a thorough germline and somatic mutation evaluation in select colorectal cancer patients to direct a tailored therapy.

Predictors and survival outcomes of having less than 12 harvested lymph nodes in proctectomy for rectal cancer.

BACKGROUND: Current recommendations suggest that a minimum of 12 lymph nodes (LNs) should be harvested during curative rectal cancer resection. We aimed to assess predictors and survival outcomes of harvesting < 12 lymph nodes in rectal cancer surgery. METHODS: A retrospective case-control analysis of factors associated with harvesting < 12 LNs in rectal cancer surgery was conducted. Data were derived from the National Cancer Database 2010-2019. Univariate and multivariate binary logistic regression analyses were performed to determine predictors of harvesting < 12 LNs. Association between harvesting < 12 LNs and 5-year overall survival (OS) was assessed using Cox regression and Kaplan Meier statistics. RESULTS: 67,529 patients (60.8% male; mean age: 61.2 ± 12.5 years) were included. Median number of harvested LNs was 15 (IQR: 11-20); 27.1% of patients had < 12 harvested LNs. Independent predictors of harvesting < 12 LNs were older age (OR: 1.016;p < 0.001), neoadjuvant systemic treatment (OR: 1.522;p < 0.001), neoadjuvant radiation treatment (OR: 1.367;p < 0.001), longer duration of radiation therapy (OR: 1.003;p < 0.001) and abdominoperineal resection (OR: 1.071;p = 0.017). Higher clinical TNM stage and tumor grade, pull-through coloanal anastomosis, and minimally invasive surgery were independently associated with ≥ 12 harvested LNs. < 12 harvested LNs was independently associated with lower 5-year OS (HR: 1.24;p < 0.001) and shorter mean OS (96.7 vs 102.8 months;p < 0.001) than ≥ 12 harvested LNs. CONCLUSIONS: Older age, open resection, and neoadjuvant therapy were independent predictors of < 12 harvested LNs. Conversely, higher clinical TNM stage and tumor grade, coloanal anastomosis, and minimally invasive surgery were predictive of ≥ 12 harvested LNs. < 12 LNs harvested was associated with lower OS.

Prediction of p53 mutation status in rectal cancer patients based on magnetic resonance imaging-based nomogram: a study of machine learning.

BACKGROUND: The current study aimed to construct and validate a magnetic resonance imaging (MRI)-based radiomics nomogram to predict tumor protein p53 gene status in rectal cancer patients using machine learning. METHODS: Clinical and imaging data from 300 rectal cancer patients who underwent radical resections were included in this study, and a total of 166 patients with p53 mutations according to pathology reports were included in these patients. These patients were allocated to the training (n = 210) or validation (n = 90) cohorts (7:3 ratio) according to the examination time. Using the training data set, the radiomic features of primary tumor lesions from T2-weighted images (T2WI) of each patient were analyzed by dimensionality reduction. Multivariate logistic regression was used to screen predictive features, which were combined with a radiomics model to construct a nomogram to predict p53 gene status. The accuracy and reliability of the nomograms were assessed in both training and validation data sets using receiver operating characteristic (ROC) curves. RESULTS: Using the radiomics model with the training and validation cohorts, the diagnostic efficacies were 0.828 and 0.795, the sensitivities were 0.825 and 0.891, and the specificities were 0.722 and 0.659, respectively. Using the nomogram with the training and validation data sets, the diagnostic efficacies were 0.86 and 0.847, the sensitivities were 0.758 and 0.869, and the specificities were 0.833 and 0.75, respectively. CONCLUSIONS: The radiomics nomogram based on machine learning was able to predict p53 gene status and facilitate preoperative molecular-based pathological diagnoses.

Predictive value of lesion morphology in rectal cancer based on MRI before surgery.

OBJECTIVE: To explore the relationship of MRI morphology of primary rectal cancer with extramural vascular invasion (EMVI), metastasis and local recurrence. MATERIALS AND METHODS: This retrospective study included 153 patients with rectal cancer. Imaging factors and histopathological index including nodular projection (NP), cord sign (CS) at primary tumor margin, irregular nodules (IN) of mesorectum, MRI-detected peritoneal reflection invasion (PRI), range of rectal wall invasion (RRWI), patterns and length of tumor growth, maximal extramural depth (EMD), histologically confirmed local node involvement (hLN), MRI T stage, MRI N stage, MRI-detected extramural vascular invasion (mEMVI) and histologically confirmed extramural vascular invasion (hEMVI) were evaluated. Determining the relationship between imaging factors and hEMVI, synchronous metastasis and local recurrence by univariate analysis and multivariable logistic regression, and a nomogram validated internally via Bootstrap self-sampling was constructed based on the latter. RESULTS: Thirty-eight cases of hEMVI, fourteen cases of synchronous metastasis and ten cases of local recurrence were observed among 52 NP cases. There were 50 cases of mEMVI with moderate consistency with hEMVI (Kappa = 0.614). NP, CS, EMD and mEMVI showed statistically significant differences in the negative and positive groups of hEMVI, synchronous metastasis, and local recurrence. Compared to patients with local mass growth, the rectal tumor with circular infiltration had been found to be at higher risk of synchronous metastasis and local recurrence (P < 0.05). NP and IN remained as significant predictors for hEMVI, and mEMVI was a predictor for synchronous metastasis, while PRI and mEMVI were predictors for local recurrences. The nomogram for predicting hEMVI demonstrated a C-index of 0.868, sensitivity of 86.0%, specificity of 79.6%, and accuracy of 81.7%. CONCLUSION: NP, CS, IN, large EMD, mEMVI, and circular infiltration are significantly associated with several adverse prognostic indicators. The nomogram based on NP has good predictive performance for preoperative EMVI. mEMVI is a risk factor for synchronous metastasis. PRI and mEMVI are risk factors for local recurrence.

Rectal cancer presentation during the COVID-19 pandemic: Are decreasing screening rates leading to an increase in acute presentations?

Nearly 23 million adults ages 50-75 are overdue for colorectal cancer (CRC) screening. In March 2020, the Centers for Medicare & Medicaid issued guidance that all non-urgent procedures be delayed due to the COVID-19 pandemic. Screening delays may have effects on the presentation of rectal cancer and the natural history of the disease. The aim of this study was to determine if procedural suspension due to the COVID-19 pandemic was associated with an increased proportion of acute presentations or more advanced stage at diagnosis for patients with rectal cancer. We conducted a single-center, retrospective review of adult patients with new or recurrent rectal adenocarcinoma from 2016-2021. We compared patients presenting before (pre-COVID) to those diagnosed after (COVID) March 1, 2020. Of 208 patients diagnosed with rectal cancer, 163 were diagnosed pre-COVID and 45 patients in the COVID group. Cohorts did not differ among age, sex, race, insurance status, marital status, rurality, or BMI. There was no difference in stage at presentation with the majority diagnosed with stage III disease (40.0% vs 33.3%, p = 0.26). Similar proportions of patients presented acutely (67.5% vs 64.4%, p = 0.71). Presenting symptoms were also similar between cohorts. On adjusted analysis, male sex, white race, and uninsured status were found to have significant impact acuity of presentation, while diagnosis before or after the onset of the pandemic remained non-significant (OR 1.25, 95% CI0.57-2.72; p = 0.59). While screening rates have decreased during the COVID pandemic, patients with rectal cancer did not appear to have an increased level of acuity or stage at presentation. These findings could result from the indolent nature of the disease and may change as the pandemic progresses.

Neoadjuvant chemoradiation therapy combined with immunotherapy for microsatellite stable ultra-low rectal cancer (CHOICE II): study protocol of a multicentre prospective randomised clinical trial.

INTRODUCTION: Neoadjuvant chemoradiotherapy (nCRT) could bring tumour shrinking and downstaging and increase the probability of organ preservation for patients with low rectal cancer. But for ultra-low rectal cancer, there is little possibility for organ preservation. Immunotherapy has been shown to have significant survival benefits in microsatellite instability-high patients but poor response in microsatellite stable (MSS) patients. Studies have demonstrated that radiotherapy and immunotherapy have synergistic effects in cancer treatment. There is no existing evidence about the clinical efficacy of immunotherapy combined with nCRT for patients with MSS ultra-low rectal cancer. METHOD AND ANALYSIS: This trial is an open-labelled multicentre prospective randomised controlled trial (NCT05215379) with two parallel groups and allocation ratio 1:1 (nCRT+immunotherapy vs nCRT group). Eligible participants will be aged 18-75 years, with a desire for anus preservation, confirmed cT1-3aN0-1M0 rectal adenocarcinoma, confirmed MSS type, inferior margin of ≤5 cm from the anal verge. The primary endpoint of this trial is complete clinical response (cCR) rate. Immunotherapy is added after 1 week of chemoradiotherapy for two cycles, and then the patients will be administered two cycles of immunotherapy and CAPOX. The evaluations will be carried out after the completion of the whole neoadjuvant therapy. We expect the programme to improve the cCR rate and the quality of life for patients with ultra-low rectal cancer. ETHICS AND DISSEMINATION: This trial was approved by the Ethics committee of Changhai Hospital and other medical centres (Grant number:CHEC2022-118). The results of this study will provide further insight into the clinical efficacy of immunotherapy in combination with nCRT in patients with MSS ultra-low rectal cancer. TRIAL REGISTRATION NUMBER: NCT05215379.

Maintenance Therapy With Cetuximab After FOLFIRI Plus Cetuximab for RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

Importance: The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated. Objective: To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy. Design, Setting, and Participants: The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022. Interventions: After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen. Main Outcomes and Measures: The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile. Results: Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]). Conclusion and Relevance: The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC. Trial Registration: ClinicalTrials.gov Identifier: NCT02404935.

The benefits of adjuvant chemotherapy are associated with the kind of neoadjuvant therapy in stage ypI rectal cancer: evidence based on population analysis.

PURPOSE: The oncological role of adjuvant chemotherapy (ACT) remains debated in locally advanced rectal cancer (RC) after neoadjuvant therapy (NAT), especially ypI RC. In this study, we used population-based data to evaluate the benefits of ACT in stage ypI RC after NAT and surgery. Moreover, we tried to differentiate what kind of NAT (radiotherapy alone or chemoradiotherapy) was administered because this may affect the further efficacy of ACT. METHODS: All patients with stage ypI primary rectal malignancy were diagnosed in the SEER database between 2004 and 2017. The Kaplan-Meier method was applied to estimate the effects of ACT in survival analysis. Cox regression was performed to calculate the hazard ratio (HR) and the prognosis factors of survival. Propensity score matching (PSM) was used to balance the parameters between therapy groups. RESULTS: The overall cohort's median follow-up time was 105 months. For 5-year OS and CSS, there were no significant differences between the ACT ( +) and ACT (-) groups (p = 0.105; p = 0.788). However, subgroup analyses according to the kind of NAT found that ACT improved overall survival (OS) and cancer-specific survival (CSS) in patients who received neoadjuvant radiotherapy (nRT) (p < 0.001, p = 0.015). Among patients who received neoadjuvant chemoradiotherapy (nCRT), no significant survival benefits were found between the ACT ( +) and ACT (-) groups (p = 0.526, p = 0.288). CONCLUSION: Our population-based cohort study suggested that the efficacy of ACT was associated with the kind of NAT. The ACT provides survival benefits in stage ypI RC for patients who received nRT. However, among patients who received nCRT, ACT did not improve long-term survival.

Integration of single-cell RNA sequencing and bulk RNA transcriptome sequencing reveals a heterogeneous immune landscape and pivotal cell subpopulations associated with colorectal cancer prognosis.

Introduction: Colorectal cancer (CRC) is a highly heterogeneous cancer. The molecular and cellular characteristics differ between the colon and rectal cancer type due to the differences in their anatomical location and pathological properties. With the advent of single-cell sequencing, it has become possible to analyze inter- and intra-tumoral tissue heterogeneities. Methods: A comprehensive CRC immune atlas, comprising 62,398 immune cells, was re-structured into 33 immune cell clusters at the single-cell level. Further, the immune cell lineage heterogeneity of colon, rectal, and paracancerous tissues was explored. Simultaneously, we characterized the TAM phenotypes and analyzed the transcriptomic factor regulatory network of each macrophage subset using SCENIC. In addition, monocle2 was used to elucidate the B cell developmental trajectory. The crosstalk between immune cells was explored using CellChat and the patterns of incoming and outgoing signals within the overall immune cell population were identified. Afterwards, the bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) were combined and the relative infiltration abundance of the identified subpopulations was analyzed using CIBERSORT. Moreover, cell composition patterns could be classified into five tumor microenvironment (TME) subtypes by employing a consistent non-negative matrix algorithm. Finally, the co-expression and interaction between SPP1+TAMs and Treg cells in the tumor microenvironment were analyzed by multiplex immunohistochemistry. Results: In the T cell lineage, we found that CXCL13+T cells were more widely distributed in colorectal cancer tissues, and the proportion of infiltration was increased. In addition, Th17 was found accounted for the highest proportion in CD39+CD101+PD1+T cells. Mover, Ma1-SPP1 showed the characteristics of M2 phenotypes and displayed an increased proportion in tumor tissues, which may promote angiogenesis. Plasma cells (PCs) displayed a significantly heterogeneous distribution in tumor as well as normal tissues. Specifically, the IgA+ PC population could be shown to be decreased in colorectal tumor tissues whereas the IgG+ PC one was enriched. In addition, information flow mediated by SPP1 and CD44, regulate signaling pathways of tumor progression. Among the five TME subtypes, the TME-1 subtype displayed a markedly reduced proportion of T-cell infiltration with the highest proportion of macrophages which was correlated to the worst prognosis. Finally, the co-expression and interaction between SPP1+TAMs and Treg cells were observed in the CD44 enriched region. Discussion: The heterogeneity distribution and phenotype of immune cells were analyzed in colon cancer and rectal cancer at the single-cell level. Further, the prognostic role of major tumor-infiltrating lymphocytes and TME subtypes in CRC was evaluated by integrating bulk RNA. These findings provide novel insight into the immunotherapy of CRC.