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Objective We conducted this multicenter cohort study to evaluate the current tumor‐node‐metastasis staging system and treatment modality by analyzing the survival outcomes of patient groups with stage III and IV colon cancer. Patients and Methods Stage III and IV colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database (SEER cohort) and prospectively maintained Sun Yat‐sen University (SYSU) cohort were included in this study. Kaplan‐Meier method was used to estimate the cumulative rate of overall survival (OS) between patient groups, and the inverse probability weighting method was used to calculated age and sex‐adjusted survival curves. The Cox regression model was used to identify the risk factors for OS. Results A total of 17,911 and 1135 stage III–IV cases were included in the SEER and SYSU cohorts, respectively. Among them, 1448 and 124 resectable stage IV cases underwent curative‐intent treatment in the SEER and SYSU cohorts, respectively. The T4N2b group showed a significantly worse survival outcome compared with the M1a subset receiving curative‐intent treatment (HR, 1.46; p, By analyzing the Surveillance, Epidemiology, and End Results database and in‐house cohorts, several stage III subgroups were identified in a high risk of death, especially the T4N2b group that had significantly worse overall survival than that of the M1a subset. When further categorized by risk factors, the survival of the high‐risk T4N2b patients was worse than that of the M1b subset.

Background The local recurrence of rectal cancer has been improved by total mesorectal excision following neoadjuvant chemoradiotherapy. However, in patients with low locally advanced rectal cancer, lateral pelvic recurrence remains to be addressed. Objective This study aimed to determine the efficiency of neoadjuvant radiotherapy in addressing lateral pelvic recurrence and which subgroup of patients might be optimal to receive lateral lymph node dissection. Design The MRI/CT images were reassessed for lateral lymph node status. The lateral lymph nodes with short axis ≥5 mm and ≥4 mm were considered positive in pretreatment and restaging MRI/CT. Setting This was a post hoc analysis of a prospective randomized controlled trial (FOWARC, NCT01211210). Patients A total of 495 patients with stage II or III rectal adenocarcinoma were included in the original trial. According to the excluding criteria, the finally included population consists of 253 patients; of these, 195 patients received neoadjuvant chemoradiotherapy and 94 received chemotherapy alone. Main outcomes and measures The primary outcome was the 5-year lateral pelvic recurrence rate. Results Compared with patients receiving chemotherapy alone, patients receiving additional radiotherapy had a marginal significance of lower lateral pelvic recurrence rate (6.6% vs 13.0%; p = 0.051). In the subset with pretreatment positive lateral lymph nodes, patients had a lateral pelvic recurrence rate of 22.6% and 45.1% after neoadjuvant chemoradiotherapy and chemotherapy alone. Of note, 34.9% of the pretreatment positive lateral lymph nodes were persistent after neoadjuvant chemoradiotherapy, culminating in a lateral pelvic recurrence rate of 63.3%. Limitations This is a post hoc analysis, and only the patients from the leading center were included, which limited the sample size. In addition, the lateral lymph node dissection was not performed in this cohort. Conclusions The addition of radiotherapy in neoadjuvant regimens could not address lateral pelvic recurrence adequately. Some subgroups of patients might need additional dissection. See Video Abstract at http://links.lww.com/DCR/B613. La inclusion de la radioterapia preoperatoria es insuficiiente en el control plvico lateral en un subgrupo de pacientes con cncer de recto inferior localmente avanzado un estudio posthoc controlado y randomizado ANTECEDENTES:La recurrencia local del cancer de recto ha disminuido al efectuar una excision mesorrectal total seguida de quimioradioterapia neoadyuvante. No obstante, en pacientes con cancer de tercio inferior de recto avanzado localmente, aun esta por controlarse la recurrencia pelvicaOBJETIVOS:Determinar la eficacia de la radioterapia neoadyuvante en el control de la recurrencia pelvica lateral y en que subgrupo de pacientes seria conveniente efecutar una excision lateral de las cadenas ganglionares.DISENO:Se reevaluaron las imagenes tomograficas y de resonancia magnetica del status de las cadenas ganglionares linfaticas laterales. Los ganglios linfaticos laterales con un eje-corto > 5 mm y ≥ 4 mm se consideraron como positivos previo al tratamiento y reestadificados con RM y TAC respectivamente.ESCENARIO:Es un analisis post hoc de un studio prospectivo randomizado controlado (FOWARC, NCT01211210).PACIENTESSe incluyeron un total de 495 pacientes en estdio II o III con adenomcarcinoma rectal en el estudio original. De acuerdo a los criterios de exclusion, la poblacion final incluida consistio en 253 pacientes; de estos, 195 recibieron quimioradioterapia neoadyuvante y 94 quimioterapia sola.EVALUACION DE LOS RESULTADOS PRINCIPALES:El parametro mas importante fue la tasa de recurrencia pelvica lateral a cinco anos.RESULTADOS:En comparacion con los pacientes que recibieron quimioterapia sola, aquellos que ademas fueron sometidos a radioterapia adicional presentaron un margen significativo de menor tasa de recurrencia pelvica lateral (6.6% vs. 13.0%; p=0.051). En el grupo de pacientes con ganglios linfaticos laterales positivos, los enfermos presentaron una tasa de recurrencia pelvica lateral de 22.6% y 45.1% despues de quimioradiaterapia neoadyuvante en comparacion con quimioterapia sola respectivamente. Cabe mencionar que el 34.9% de los pacientes con ganglios linfaticos laterales positivos antes del tratamiento persistieron despues de la quimioradioterapia neoadyuvante, reportandose finalmente una recurrencia pelvica lateral de un 63.3%.LIMITACIONES:Se trata de un analisis posthoc y solo los pacientes del hospital fueron incluidos, lo que limita el tamano de la muestra. Ademas, no se efectuo la diseccion de los ganglios linfaticos laterales en este grupo.CONCLUSIONES:La radioterapia en los esquemas de neoadyuvancia no logran controlar la recurrencia pelvica lateral en forma adecuada. Algunos subgrupos de pacientes podria requerir de diseccion adicional. Consulte Video Resumen en http://links.lww.com/DCR/B613.

Background: Identifying the arterial variation of the lateral circumflex femoral artery (LCFA) is a vital step in planning surgical and radiological approach. The aim of the study was to evaluate the variations and discuss the clinical correlates of the LCFA. Materials and methods: Fifty eight adult cadavers (male 45, female 13) with 115 usable sides were used to assess and classify the origin and branches of the LCFA. Also its external diameter, distance from mid-inguinal ligament to sites of origin from the profunda femoris artery or femoral arteries. Results: There were seven types of LCFA variations in this sample. We classified them as types A to G, of which type A was normal, that is, the one showing a single LCFA arising from the profunda femoris artery. Nearly 50.43% of the sample had type B–G variations, each having 13, 10, 23, 4, 4, and 3 cases, accounting for 11.30%, 8.70%, 20.00%, 3.48%, 3.48%, and 2.61%, respectively. Conclusions: There are many variant types in the LCFA. To avoid iatrogenic injuries, clinicians must have a sound understanding of the variation types of this important blood vessel.

The incidence of colorectal cancer is increasing among young adults and more rectal cancers are reported. This study aimed to identify the clinical features specific for early-onset rectal cancer and provide insights on cancer management.Early-onset (50 years) and late-onset (≥50 years) rectal cancer patients from a referral tertiary care center (SYSU cohort) and Surveillance Epidemiology and End Results database (SEER cohort) were included to perform a comprehensive comparison on clinical information.A total of 552 and 80,341 patients with stages I-III rectal cancer were included in the SYSU and SEER cohorts, respectively. In the SYSU cohort, early-onset diseases had significantly higher prevalence of family history of cancer and history of HBV infection and lower incidence of comorbidities (p 0.05). In addition, early-onset patients presented more frequently with advanced node stage (N2 stage: 16.9 vs. 9.3%, p = 0.017) and high-risk features, including mucinous or signet cell carcinomas (21.8 vs. 12.9%, p = 0.014), poorly differentiated tumors (28.8 vs. 15.4%, p = 0.002), and perineural invasion (14.5 vs. 7.9%, p = 0.027) compared with late-onset patients. However, early-onset patients received more neoadjuvant (18.5 vs. 11.2%, p = 0.032) and adjuvant treatments (71.0 vs. 45.8%, p 0.001), and they had better overall survival in both SYSU (HR 0.57, 95% CI: 0.34-0.95; p = 0.029) and SEER (HR 0.38, 95% CI: 0.37-0.40; p 0.001) cohorts.Early-onset rectal cancers are distinct from late-onset cases in clinicopathological features, treatment modalities, and outcomes. The clinical trials and studies that are specific for young populations are needed to develop optimal strategies for cancer screening, treatment, and surveillance.

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world. More comprehensive studies of key molecular alterations in CRC progression were urgent. DNA methylation promotes tumor progression. However, the mechanism of the ANKRD13 gene methylation that drives colorectal cancer evolution remains largely unknown. This was the first study focused on the role of ANKRD13 and the hypermethylated mechanisms in colorectal cancer. Methods: Chi-Square tests were utilized to the comparison of the baseline characteristics of patients with hypomethylation ANKRD13B and hypermethylated ANKRD13B. Kaplan-Meier analysis were used to estimate the difference of overall survival between the two groups patients. The methylation level of ANKRD13B was quantified by qMSP in colorectal cancer, normal colon epitheliums and colorectal adenoma tissues. CRISPR/dCas9-DNMT3A and CRISPR/dCas9-TET1-CD methylation editing tools were applied to enable targeted and specific CpG methylation at the CpG loci near stop codon of ANKRD13B. Transwell-migrated assay, wound scratch assay and colony formation assay were preformed to ascertain the abilities of viability, migration and invasion in the editing CRC cell lines. The methylated RNA immunoprecipitation (MeRIP) assays, chromatin immunoprecipitation (ChIP) assays and 5-AZA treatment assays were performed combined with qPCR to quantify the m6A levels of ANKRD13B mRNA following hypermethylated-editing. Results: Here, we identified a novel oncogenic gene, ANKRD13B, encoding ankyrin repeat domain 13B. This gene was frequently hypermethylated in CpG islands surrounding the stop codon region of colorectal cancer. This hypermethylation was associated with poor clinical outcomes in patients diagnosed with colorectal cancer. Compared with normal tissue (4.2%), this type of epigenetic alteration upregulated ANKRD13B expression in both adenoma (73.0%) and adenoma cancer tissues (83.3%) (P< 0.0001), and it also promoted colorectal cancer cell growth, invasion, and migration. Demethylation treatment can reduce the ANKRD13B expression and the growth, migration, and invasion of the cancer cell. Moreover, we found that the aberrant ANKRD13B methylated surrounding the stop codon, and it can promote RNA N6-methyladenosine methylation modification, suggesting that aberrant DNA 5mC methylation promotes ANKRD13B expression and tumor progression in an RNA m6A-dependent manner. Conclusions: In summary, our findings illustrated that ANKRD13B is an oncogenic gene of colorectal cancer that is commonly methylated and overexpressed in colorectal cancer whose function in the pathogenesis of colorectal cancer depends on RNA m6A-dependent manner. Aberrant DNA 5mC methylation promotes ANKRD13B expression and tumor progression in an RNA m6A-dependent Manner. Key words: ANKRD13B, DNA methylation, Epigenetic regulation, Colorectal cancer Citation Format: JingRong Weng, JinXin Lin, YuMo Xie, GuanNan Tang, LiangLiang Bai, JinHua Chen, ZengHong Huang, ZhuoKai Zhuang, ShaoYong Peng, Heng Wang, GaoPo Xu, Yu Zhang, XiaoXia Liu, MeiJin Huang, YanXin Luo, XiaoLin Wang, Huichuan Yu. RNA m6A methylation relay the oncogenic flow from DNA methylationto gene expression of ANKRD13B [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 6006.

Background: Immune checkpoint inhibitor (ICI) treatment in patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) tumors holds promise in reshaping organ preservation in rectal cancer. However, the benefits are accompanied by distinctive patterns of response, introducing a dilemma in the response evaluation for clinical decision-making. Patients and Methods: Patients with locally advanced rectal cancer with MSI-H/dMMR tumors receiving neoadjuvant ICI (nICI) treatment (n=13) and matched patients receiving neoadjuvant chemoradiotherapy (nCRT; n=13) were included to compare clinical response and histopathologic features. Results: Among the 13 patients receiving nICI treatment, in the final radiologic evaluation prior to surgery (at a median of 103 days after initiation of therapy), progressive disease (n=3), stable disease (n=1), partial response (n=7), and complete response (n=2) were observed. However, these patients were later confirmed as having pathologic complete response, resulting in pseudoprogression and pseudoresidue with incidences of 23.1% (n=3) and 76.9% (n=10), respectively, whereas no pseudoprogression was found in the 13 patients receiving nCRT. We further revealed the histopathologic basis underlying the pseudoprogression and pseudoresidue by discovering the distinctive immune-related regression features after nICI treatment, including fibrogenesis, dense lymphocytes, and plasma cell infiltration. Conclusions: Pseudoprogression and pseudoresidue were unique and prevalent response patterns in MSI-H/dMMR rectal cancer after nICI treatment. Our findings highlight the importance of developing specific strategies for response evaluation in neoadjuvant immunotherapy to identify patients with a good response in whom sphincter/organ-preserving or watch-and-wait strategies may be considered.

Background Colorectal cancer (CRC) patients with different molecular phenotypes, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS gene, vary in treatment response and prognosis. However, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes. Methods Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI, CIMP, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype. Results The incidences of MSI, CIMP, BRAF mutation and KRAS mutation were 25.3% (72/285), 2.5% (7/270), 3.4% (10/293), and 34.8% (96/276) respectively. In the multivariate Logistic analysis, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation, proximal tumor, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI, CIMP, BRAF mutation and KRAS mutation were developed based on these independent predictors, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%), 95.57% (95% CI: 95.20-95.94%), 83.56% (95% CI: 81.54-85.58%), and 69.12% (95% CI: 68.30-69.94%) respectively. Conclusion We established four nomograms using easily accessible variables that could well predict the presence of MSI, CIMP, BRAF mutation and KRAS mutation in CRC patients.

Background: Serum CEA has been widely used to screen for potential recurrent disease after resection in rectal cancer. However, the influence of baseline CEA on the performance of CEA in recurrence surveillance needs to be investigated. Patients and Methods: This longitudinal cohort study included 484 patients with nonmetastatic rectal cancer from 18,013 patients in a prospectively enrolled institutional database program of colorectal disease. Baseline CEA levels were determined before treatment, and CEA-based follow-up tests and examinations were applied in the surveillance after treatment. Results: A total of 62.6% (62/99) overall, 53.5% (23/43) local, and 64.9% (50/77) distant recurrences were seen in patients who had similar CEA levels with their baseline statuses. The sensitivity of elevated CEA levels during surveillance for overall recurrence was significantly lower in patients with negative baseline CEA than in those with elevated baseline CEA levels (41.3% vs 69.4%; P =.007). Moreover, similar results were observed in the surveillance for local (50% vs 61.5%; P =.048) and distant (39.6% vs 72.4%; P =.005) recurrences between these 2 patient groups. However, CEA had comparable and excellent specificity during surveillance for recurrent disease in these groups. The addition of CA19-9 to the CEA assay significantly improved the sensitivity in recurrence surveillance for patients with negative baseline CEA (49.2% vs 41.3%; P =.037). Finally, we identified a subgroup of CEA-turn recurrences characterized by negative CEA at baseline, elevated CEA at recurrence, and worse survival outcomes after recurrence (hazard ratio, 1.88; 95% CI, 1.07–3.30; P =.026). Conclusions: In patients with rectal cancer with negative baseline CEA, serum CEA had insufficient sensitivity in recurrence surveillance after treatment, and additional surveillance may improve oncologic outcomes. Baseline CEA should be considered before CEA-based surveillance can be applied in the follow-up trials.

BACKGROUND: Systemic inflammation markers have shown prognostic values with variability in rectal cancer. Considering the association of serum calcium with inflammation, we aimed to examine whether it could improve systemic inflammation markers for survival prediction. METHODS: We enrolled 508 patients with stage I to III rectal cancer who underwent curative resection. The cohort was grouped by corrected serum calcium (cCa), platelet-to-lymphocyte ratio (PLR), and CaPLR (a score model combining cCa with PLR) for survival analysis. The LR (likelihood ratio) test and AIC (Akaike information criterion) were applied to compare models in survival prediction. The primary endpoint was disease-free survival (DFS). RESULTS: A total of 26.7% (136/508) patients reached recurrence after curative surgery. Both high cCa (HR 1.486; 95% CI, 1.018–2.171; P=0.040) and high PLR (HR 1.452; 95% CI, 1.059–1.991; P=0.021) were significantly associated with worse DFS. In model comparison, the AIC and LR were improved after cCa was added to PLR model in DFS prediction (AIC: 1,704.83 vs. 1,707.14 vs. 1,707.15; LR: 8.68 vs. 4.37 vs. 4.36; P=0.037). The CaPLR was developed for DFS prediction with adjusted HRs of 2.216 (95% CI, 1.256–3.909; P=0.006) and 1.679 (95% CI, 1.004–2.836; P=0.047) for high and intermediate score group respectively compared to low score group. A nomogram for predicting DFS was generated by using CaPLR and other clinical predictors, with a concordance index of 0.705 (95% CI, 0.620–0.789; P

Background We aimed to develop a radiomic model based on pre-treatment computed tomography (CT) to predict the pathological complete response (pCR) in patients with rectal cancer after neoadjuvant treatment and tried to integrate our model with magnetic resonance imaging (MRI)-based radiomic signature. Methods This was a secondary analysis of the FOWARC randomized controlled trial. Radiomic features were extracted from pre-treatment portal venous-phase contrast-enhanced CT images of 177 patients with rectal cancer. Patients were randomly allocated to the primary and validation cohort. The least absolute shrinkage and selection operator regression was applied to select predictive features to build a radiomic signature for pCR prediction (rad-score). This CT-based rad-score was integrated with clinicopathological variables using gradient boosting machine (GBM) or MRI-based rad-score to construct comprehensive models for pCR prediction. The performance of CT-based model was evaluated and compared by receiver operator characteristic (ROC) curve analysis. The LR (likelihood ratio) test and AIC (Akaike information criterion) were applied to compare CT-based rad-score, MRI-based rad-score and the combined rad-score. Results We developed a CT-based rad-score for pCR prediction and a gradient boosting machine (GBM) model was built after clinicopathological variables were incorporated, with improved AUCs of 0.997 [95% CI 0.990–1.000] and 0.822 [95% CI 0.649–0.995] in the primary and validation cohort, respectively. Moreover, we constructed a combined model of CT- and MRI-based radiomic signatures that achieve better AIC (75.49 vs. 81.34 vs.82.39) than CT-based rad-score (P = 0.005) and MRI-based rad-score (P = 0.003) alone did. Conclusions The CT-based radiomic models we constructed may provide a useful and reliable tool to predict pCR after neoadjuvant treatment, identify patients that are appropriate for a 'watch and wait' approach, and thus avoid overtreatment. Moreover, the CT-based radiomic signature may add predictive value to the MRI-based models for clinical decision making.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to block tumor-associated inflammation in rectal cancer. However, the perioperative use of NSAIDs remains controversial. This study was designed to investigate whether the perioperative use of NSAIDs influences outcomes and to provide a predictive marker to identify patients who would benefit from NSAIDs. We enrolled 515 patients with stage I to III rectal cancer in this retrospective study. Patients were classified into the NSAID and non-NSAID groups according to their perioperative use of NSAIDs. The whole cohort was stratified by platelet-to-lymphocyte ratio (PLR). The primary endpoints were disease-free survival (DFS) and overall survival (OS). The NSAID group had a 12.6% lower risk of recurrence than the non-NSAID group (P = 0.015), while the association with survival was nonsignificant. In the high-PLR subset, the NSAID group had a 17.3% lower risk of recurrence (P = 0.003) and a better DFS (P = 0.033) outcome than the non-NSAID group. Multivariate analysis confirmed this independent significant association with DFS (P = 0.023). In the low-PLR subset, the association of NSAID use with survival was nonsignificant. Perioperative use of NSAIDs was associated with improved survival outcomes in rectal cancer patients with high PLR.

Background: The aim of the study was to probe the morphological features of the proximal segment (V1) of vertebral artery (VA) in a sample of Chinese cadavers. Materials and methods: The origin, course and outer diameter at origin of the pre-vertebral part of the VAs were evaluated in 119 adult cadavers. Results: It was found that 94.12% of the VAs originated from the subclavian arteries, bilaterally. The variant origins were present in 5.88% of the cadavers and all originated directly from the arch of the aorta. All the variations were observed on the left side of male cadavers. The average outer diameters at origin of the normal and variation groups were 4.35 ± 1.00 mm and 4.82 ± ± 1.42 mm, respectively, p = 0.035. In the normal group, but not in the variation group, the average diameter in the males was significantly larger than that in the females (4.50 ± 0.99 mm, 3.92 ± 0.92 mm, respectively, p = 0.000). In addition, only 5 cadavers in the normal group had hypoplastic VAs (4.20%, 4 males, 3 right-sided). Vertebral artery dominance (VAD) was present in 91 (69 males) out of 112 cadavers and more common on the left (n = 48). In addition, 3 cadavers satisfied conditions for coexistence of VAD and vertebral artery hypoplasia. All 7 cadavers in the variation group exhibited VAD, which was more common on the right side (n = 5). Conclusions: The morphologic variations and frequencies described above have implications for the early prevention, abnormal anatomy detection, accurate diagnosis, safe surgery and endovascular treatment of cardiovascular and neurological disease.

Objectives The aim of this study is to determine the incidence and explore the types of aortic arch branch variations found in our cadavers. Methods The types and incidence of aortic branch variations in 120 cadavers were analysed after careful dissection. Results One hundred and six of 120 cadavers had normal aortic arch branches and gave rise to usual branches, namely the brachiocephalic trunk, the left common carotid artery and the left subclavian artery. The remaining 14 cadavers had 2 basic types of branch variations, thus accounting for an incidence of 11.67%. A total of 9 aortic arches emitted 4 branches; the brachiocephalic trunk, the left common carotid artery, the left vertebral artery and the left subclavian artery (incidence 7.5%). The second subgroup of 5 cadavers also emitted 4 aortic branches: the right common carotid artery, the left common carotid artery, the left subclavian artery and the right subclavian artery (incidence 4.16%). In this group, the right subclavian artery sprung as a distal branch of the aortic arch (descending), thus making a vascular ring that takes a superoposterior course round the back of the trachea and the oesophagus to reach the right side. There was a single cadaver, different from the other 4 aortic branches of the second group which had a common origin for the common carotid arteries, while the left subclavian artery and distally placed right subclavian artery were present. We did not observe any Kommerell's aortic diverticula. Conclusions The variations of aortic arch branching are complex and diverse due to varied possible alterations in the embryological processes. There is an imperative need for further research on these variations to elucidate the possible relationships with clinical diagnostic or surgical events.