Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Neferine alleviates ovariectomy-induced osteoporosis by enhancing osteogenic differentiation of bone marrow mesenchymal stem cells via regulation of the p38MAPK pathway.

OBJECTIVE: Osteoporosis, a skeletal ailment marked by bone metabolism imbalance and disruption of bone microarchitecture, Neferine, a bisbenzylisoquinoline alkaloid with diverse pharmacological activities, has received limited attention in the context of osteoporosis treatment. METHODS: We employed a bilateral ovariectomy (OVX) rat model to induce osteoporosis and subsequently administered Neferine treatment for four weeks following successful model establishment. Throughout the modeling and treatment phases, we closely monitored rat body weights. We assessed alterations in bone tissue microstructure through micro-CT, HE staining, and safranin O-fast green staining. Levels of bone formation and resorption markers in serum were evaluated using ELISA assay. Western blot analysis was employed to determine the expression levels of p38MAPK, p-p38MAPK, and bone formation-related genes in bone tissue. We isolated and cultured OVX rat BMSCs (OVX-BMSCs) and induced osteogenic differentiation while simultaneously introducing Neferine and the p38MAPK inhibitor SB203580 for intervention. RESULTS: Neferine treatment effectively curbed the rapid weight gain in OVX rats, ameliorated bone loss, and decreased serum levels of TRAP, CTX-I, PINP, and BALP. Most notably, Neferine promoted the expression of bone formation-related factors in bone tissue of OVX rats, while concurrently activating the p38MAPK signaling pathway. In in vitro experiments, Neferine facilitated the expression of bone formation-related factors in OVX-BMSCs, increased the osteogenic differentiation potential of OVX-BMSCs, and activated the p38MAPK signaling pathway. Nevertheless, SB203580 partially reversed Neferine's promotive effect. CONCLUSION: Neferine can boost the osteoblastic differentiation of BMSCs and alleviate OVX-induced osteoporosis in rats by activating the p38MAPK signaling pathway.

Safety and Efficacy Analysis of Radical Surgery for 403 Patients with Colon Cancer over 80 Years Old.

Aim: To investigate the safety and efficacy of radical surgery in colon cancer patients over 80 years old. Methods: Data from colon cancer patients aged ≥80 years who underwent radical surgery at the Cancer Hospital of the Chinese Academy of Medical Sciences and affiliated Heji Hospital of Changzhi Medical College from January 2011 to December 2022 were retrospectively analysed. Data on clinical characteristics, pathological features, perioperative data, and long-term prognosis were collected. Severe complications were classified as grade III-V. Logistic regression models were used to identify the risk factors for severe postoperative complications, and a Cox regression model was used to determine prognostic variables. Results: A total of 403 eligible patients were included in the study. A total of 118 (29.3%) patients developed postoperative complications, of which 51 (12.7%) experienced grade 3-5 severe complications. Two (0.5%) patients died of pulmonary embolism and myocardial infarction during the perioperative period. The multivariate logistic regression analysis showed that preoperative albumin levels <35 g/L and right colon cancer were independent risk factors for grade 3-5 postoperative complications. In terms of prognosis, multivariate analysis revealed that overall survival was significantly affected by TNM stage III and grade 3-4 postoperative complications. In addition, TNM stage III and perineural invasion were the independent prognostic factors for disease-free survival. Conclusion: Radical surgery can be performed safely in elderly colon cancer patients aged over 80 years, with an acceptable morbidity and mortality. Patients with preoperative albumin levels <35 g/L or tumors in the right colon should be alerted to the development of severe postoperative complications. In addition, the occurrence of severe complications can significantly affect the prognosis of elderly colon cancer patients.

A novel web-based dynamic prognostic nomogram for gastric signet ring cell carcinoma: a multicenter population-based study.

Background: Gastric signet ring cell carcinoma (GSRCC) is a rare and highly malignant disease with a poor prognosis. To assess the overall survival (OS) and cancer-specific survival (CSS) of patients with GSRCC, prognostic nomograms were developed and validated using common clinical factors. Methods: This retrospective cohort study included patients diagnosed with GSRCC between 2011 and 2018 from the National Cancer Center (n = 1453) and SEER databases (n = 2745). Prognostic nomograms were established by identifying independent prognostic factors using univariate and multivariate Cox regression analyses. The calibration curve and C-index were used to assess the predictions. The clinical usefulness of the survival prediction model was further evaluated using the DCA and ROC curves. The models were internally validated in the training cohort and externally validated in the validation cohort. Two web servers were created to make the nomogram easier to use. Results: Patients with GSRCC were divided into training (n = 2938) and validation (n = 1260) cohorts. The nomograms incorporated six predictors: age, race, tumor site, tumor size, N stage, T stage, and AJCC stage. Excellent agreement was observed between the internal and exterior calibration plots for the GSRCC survival estimates. The C-index and area under the ROC curve were roughly greater than 0.7. Both nomograms had adequate clinical efficacy, as demonstrated by the DCA plots. Furthermore, we developed a dynamic web application utilizing the constructed nomograms available at https://jiangyujuan.shinyapps.io/OS-nomogram/ and https://jiangyujuan.shinyapps.io/DynNomapp-DFS/. Conclusion: We developed web-based dynamic nomograms utilizing six independent prognostic variables that assist physicians in estimating the OS and CSS of patients with GSRCC.

Feasibility, Indications, and Prognostic Significance of Selective Lateral Pelvic Lymph Node Dissection After Preoperative Chemoradiotherapy in Middle/Low Rectal Cancer: Results of a Multicenter Lateral Node Study in China.

BACKGROUND: Lateral pelvic lymph node dissection after preoperative chemoradiotherapy can decrease local recurrence to lateral compartments, thereby providing survival benefits. OBJECTIVE: The safety of lateral pelvic lymph node dissection after preoperative chemoradiotherapy was investigated, and the surgical indications and survival benefits of lateral pelvic lymph node dissection were established on the basis of preoperative characteristics. DESIGN: A multicenter retrospective study. SETTINGS: Three hospitals in China. PATIENTS: Four hundred nine patients with clinical evidence of lateral pelvic lymph node metastasis. INTERVENTIONS: Patients who received lateral pelvic lymph node dissection were divided into 2 groups depending on whether they received chemoradiotherapy (n = 139) or not (n = 270). MAIN OUTCOME MEASURES: The safety, indications, and survival benefits of lateral pelvic lymph node dissection after preoperative chemoradiotherapy were investigated. RESULTS: The surgery times were significantly prolonged by preoperative chemoradiotherapy (291.3 vs 265.5 min; p = 0.021). Multivariate analysis demonstrated that poor/mucinous/signet-ring adenocarcinoma (OR = 4.42, 95% CI, 2.24-11.27; p = 0.031) and postchemoradiotherapy lateral pelvic lymph node short-axis diameter ≥7 mm (OR = 15.2, 95% CI, 5.89-53.01; p < 0.001) were independent predictive factors for lateral pelvic lymph node metastasis. Multivariate prognostic analysis showed that swollen lateral pelvic lymph nodes beyond the obturator or internal iliac as well as the involvement of 3 or more lateral pelvic lymph nodes were independent adverse prognostic factors. LIMITATIONS: The retrospective nature of the study and the small sample size were the limitations of this study. CONCLUSIONS: Preoperative chemoradiotherapy combined with lateral pelvic lymph node dissection is a practicable procedure with acceptable morbidity. Postchemoradiotherapy lateral pelvic lymph node short-axis diameter ≥7 mm and poor/signet/mucinous adenocarcinoma could be used for predicting lateral pelvic lymph node metastasis after chemoradiotherapy. However, lateral pelvic lymph node dissection should be carefully considered in patients with swollen lateral pelvic lymph nodes beyond the obturator or internal iliac region or involvement of multiple lateral pelvic lymph nodes. See Video Abstract at http://links.lww.com/DCR/C133 . VIABILIDAD, INDICACIONES E IMPORTANCIA PRONSTICA DE LA DISECCIN SELECTIVA DE GANGLIOS LINFTICOS PLVICOS LATERALES DESPUS DE QUIMIORRADIOTERAPIA PREOPERATORIA EN CNCER DE RECTO MEDIO/INFERIOR RESULTADOS DE UN ESTUDIO MULTICNTRICO DE GANGLIOS LATERALES EN CHINA: ANTECEDENTES:La disección de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia preoperatoria puede disminuir la recurrencia local en los compartimentos laterales, lo que brinda beneficios de supervivencia.OBJETIVO:Se investigó la seguridad de la disección de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia preoperatoria, y se establecieron las indicaciones quirúrgicas y los beneficios de supervivencia de la disección de los ganglios linfáticos pélvicos laterales en función de las características preoperatorias.DISEÑO:Estudio retrospectivo multicéntrico.ESCENARIO:Tres hospitales en China.PACIENTES:Cuatrocientos nueve pacientes con evidencia clínica de metástasis en los ganglios linfáticos pélvicos laterales.INTERVENCIONES:Los pacientes que recibieron disección de ganglios linfáticos pélvicos laterales se dividieron en dos grupos dependiendo de si recibieron quimiorradioterapia (n = 139) o no (n = 270).PRINCIPALES MEDIDAS DE RESULTADO:Se investigaron la seguridad, las indicaciones y los beneficios de supervivencia de la disección de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia preoperatoria.RESULTADOS:Los tiempos de cirugía se prolongaron significativamente con la quimiorradioterapia preoperatoria (291,3 vs 265,5 min, p = 0,021). El análisis multivariable demostró que el adenocarcinoma mal diferenciado/mucinoso/en anillo de sello (odds ratio = 4,42, intervalo de confianza del 95%, 2,24-11,27; p = 0,031) y el diámetro del eje corto de los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia ≥7 mm (odds ratio = 15,2, intervalo de confianza del 95%, 5,89-53,01; p < 0,001) fueron factores predictivos independientes de metástasis en los ganglios linfáticos pélvicos laterales. El análisis pronóstico multivariable mostró que la inflamación de los ganglios linfáticos pélvicos laterales más allá del obturador o la ilíaca interna, así como la afectación de tres o más ganglios linfáticos pélvicos laterales, eran factores pronósticos adversos independientes.LIMITACIONES:La naturaleza retrospectiva del estudio y el pequeño tamaño de la muestra.CONCLUSIONES:La quimiorradioterapia preoperatoria combinada con la disección de los ganglios linfáticos pélvicos laterales es un procedimiento practicable con una morbilidad aceptable. Posterior a la quimiorradioterapia, el diámetro del eje corto de los ganglios linfáticos pélvicos laterales ≥7 mm y el adenocarcinoma pobre/en sello/mucinoso podrían usarse para predecir la metástasis en los ganglios linfáticos pélvicos laterales después de la quimiorradioterapia. Sin embargo, la disección de los ganglios linfáticos pélvicos laterales debe considerarse cuidadosamente en pacientes con ganglios linfáticos pélvicos laterales inflamados más allá del obturador o de la región ilíaca interna o compromiso de múltiples ganglios linfáticos pélvicos laterales. Consulte Video Resumen en http://links.lww.com/DCR/C133 . (Traducción-Dr. Felipe Bellolio ).

Survival nomograms for simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy in patients with resectable colorectal liver metastasis.

Background: No well-performing nomogram has been developed specifically to predict individual-patient cancer-specific survival (CSS) and overall survival (OS) among patients with resectable colorectal liver metastasis (CRLM) who undergo simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy (NAC). We aim to investigate the prognosis of patients with resectable CRLM undergoing simultaneous resection of primary and hepatic lesions without NAC. Methods: Data of patients with CRLM in the Surveillance, Epidemiology and End Results Program (cohort, n = 225) were collected as the training set, and data of patients with CRLM treated at the National Cancer Center (cohort, n = 180) were collected as the validation set. The prognostic value of the clinicopathological parameters in the training cohort was assessed using Kaplan‒Meier curves and univariate and multivariate Cox proportional hazards models, and OS and CSS nomograms integrated with the prognostic variables were constructed. Calibration analyses, receiver operating characteristic (ROC) curves, and decision curve analyses (DCAs) were then performed to evaluate the performance of the nomograms. Results: There was no collinearity among the collected variables. Three factors were associated with OS and CSS: the pretreatment carcinoembryonic antigen (CEA) concentration, pathologic N (pN) stage, and adjuvant chemotherapy (each p < 0.05). OS and CSS nomograms were constructed using these three parameters. The calibration plots revealed favorable agreement between the predicted and observed outcomes. The areas under the ROC curves were approximately 0.7. The DCA plots revealed that both nomograms had satisfactory clinical benefits. The ROC curves and DCAs also confirmed that the nomogram surpassed the tumor, node, and metastasis staging system. Conclusion: The herein-described nomograms containing the pretreatment CEA concentration, pN stage, and adjuvant chemotherapy may be effective models for predicting postoperative survival in patients with CRLM.

High-sensitivity troponin T levels before and after cardiac surgery and the 30-day mortality: a retrospective cohort study.

Background: The suggested threshold level of cardiac troponin T elevation after cardiac surgery is not very clear, and the values recommended by various guidelines and literature reports are quite different. Methods: In this retrospective cohort study, we collected clinical data of patients who underwent heart surgery at Tsinghua University First Hospital between January 2015 and December 2022. Using the high-sensitivity cardiac troponin T levels (reference upper limit: 14 ng/L) measured at 1-3 days postoperation, the relationship between the cardiac troponin T level and the 30-day mortality risk was evaluated using Cox regression analysis. Results: Among the 3,128 patients included in this study, the types of operations mainly consisted of coronary artery bypass graft (CABG, 1,164, 37.2%), aortic valve replacement (AVR, 735, 23.5%), and other cardiac operations (1,229, 39.3%). Within 30 days postoperation, 57 patients (1.8%) died and 72 patients (2.3%) developed major vascular complications. In patients undergoing CABG or AVR, the cardiac troponin T threshold level measured within one day postoperation related to an increased 30-day mortality was determined to be 3,012 ng/L (95% CI: 1,435-3,578 ng/L), which is 218 times higher than the reference upper limit. In patients undergoing other cardiac operations, this threshold was 5,876 ng/L (95% CI: 2,458-8,119 ng/L), which is 420 times higher than the reference upper limit. Conclusion: The high-sensitivity cardiac troponin T level associated with an increased 30-day mortality risk after cardiac surgery is significantly higher than the current recommendations for defining clinically important perioperative myocardial injury.

Distant Metastasis is the Dominant Cause of Treatment Failure after Lateral Lymph Node Dissection in Patients with Lateral Lymph Node Metastasis: Results of the Large Multicenter Lateral Node Study in China.

Background: Lateral lymph node (LLN) metastases (LLNM) are often associated with poor prognosis. This study aimed to investigate the prognostic significance and postoperative recurrence pattern in rectal cancer patients with LLNM after LLN dissection (LLND). Materials and Methods: This is a multicenter retrospective case-control study where propensity score-matched (PSM) analysis was introduced. From January 2012 to December 2019, 259 patients with clinical suspicion of LLNM who underwent LLND without neoadjuvant therapy were included in the study. They were divided into the negative (n = 197) and positive (n = 62) LLN groups. Primary endpoints were 3-year recurrence-free survival (RFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Results: After PSM, the DMFS rate in the positive LLN group was significantly worse (67.9 vs. 52.5%, P = 0.012). Pathological LLNM (HR, 3.07; 95% CI, 1.55-6.05; P = 0.001) were independent prognostic factors for DMFS. Patients in the positive LLN group had a higher proportion of distant metastases in all recurrence patterns (92.3% vs 82.6%). Among patients with LLN metastasis, metastases to the common iliac and external iliac arteries were the independent prognostic factor for DMFS (HR: 2.85; 95% CI, 1.31-4.67; P = 0.042). No significant different was observed for prognosis between patients with metastases to the obturator or internal iliac vessels and patients with a N2b stage. Conclusion: Distant metastasis is the main cause of treatment failure after LLND in patients with LLNM. Because of the low completion rate of adjuvant chemotherapy, preoperative chemotherapy or total neoadjuvant therapy may be considered before LLND. In addition, patients with metastasis to external iliac and common iliac vessels have an extremely poor prognosis, and systemic chemotherapy instead of LLND should be recommended.

miR-3195 suppresses the malignant progression of osteosarcoma cells via targeting SOX4.

BACKGROUND: Osteosarcoma (OS) is a highly invasive primary malignancy of the bone that is common in children and adolescents. MicroRNAs (miRNAs) are novel diagnostic and predictive biomarkers for cancers. The miRNA miR-3195 is aberrantly expressed in multiple types of tumors. However, the expression levels and biological functions of miR-3195 in OS remain unclear. METHODS: Two Gene Expression Omnibus (GEO) datasets (GSE69470 and GSE16088) were used to analyze differentially expressed miRNAs and mRNAs in osteosarcoma cell lines and OS tissues. Quantitative RT-PCR was used to detect the expression levels of miR-3195 and the SRY-box transcription factor 4 (SOX4) mRNA in OS tissues and cell lines. The relationship between miR-3195 and the 3'-upstream region (3'-UTR) in the SOX4 mRNA (predicted through bioinformatics) was analyzed using Pearson's correlation analysis and confirmed by a dual-luciferase reporter gene experiment. Cell counting kit-8 assays, colony formation assays, flow cytometry, wound healing assays, transwell assays, and western blotting were performed to explore the effects of miR-3195 levels on SOX4 affected OS cell biological behavior. RESULTS: Our results revealed that miR-3195 was the most down-regulated miRNA and SOX4 was the most up-regulated mRNA by Bioinformatic analysis. It was further confirmed miR-3195 had low expression, and SOX4 had high expression levels in clinical OS tissue samples; the expression levels of both genes were negatively correlated with each other in OS tissues. Overexpression of miR-3195 in OS cell lines significantly inhibited cell proliferation, migration, and invasiveness, while promoting apoptosis; all these effects were reversed by increasing SOX4 expression levels. We also found that miR-3195 could directly bind with the SOX4 gene and down-regulate SOX4 expression. CONCLUSIONS: miR-3195 can modulate proliferation, migration, invasiveness, and apoptosis in OS cells by regulating the SOX4 gene. Thus, the miR-3195/SOX4 signaling may be a novel therapeutic target in OS treatment.

Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma.

Background: Ferroptosis is defined as an iron-dependent non-apoptotic form of programmed cell death. Dihydroorotate dehydrogenase (DHODH) is a newly discovered anti-ferroptosis molecule independent from the well-known GPX4 and AIFM2. However, the expression pattern and especially the functional roles of DHODH during cancer cell death are generally unknown. Methods: The databases of Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, and Tumor Immune Estimation Resource (TIMER), and methods of colony formation, Cell Counting Kit-8 (CCK-8), adenosine triphosphate (ATP) detection, RNA-seq, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to analyze the expression level, prognostic role, and oncogenic roles of DHODH in cancers. Results: DHODH overexpression was identified in many types of cancers including esophageal carcinoma (ESCA), colon adenocarcinoma (COAD), rectum adenocarcinoma (READ), and so on. Silence and inactivation of DHODH decreased the abilities of cell proliferation, colony formation, and cellular ATP levels both in esophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) cells. Z-VAD-FMK (an apoptosis inhibitor) partially rescued blockade of DHODH-induced death of ESCC cells, and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) together with the necroptosis inhibitor (necrostatin-1) partially rescued inhibition of DHODH-induced death of CRC cells, respectively. Pathways including rheumatoid arthritis, salmonella infection, cytokine-cytokine receptor interaction, pertussis, and nuclear factor-κB (NF-κB) were enriched in DHODH-silenced ESCC cells. Conclusions: Overexpression of DHODH augments cell proliferation and suppresses cell death in ESCC and CRC, and DHODH might be developed as a potential anticancer target.

Oncological and surgical outcomes of radical surgery in elderly colorectal cancer patients with intestinal obstruction.

Background: The treatment strategy for elderly colorectal cancer patients with intestinal obstruction remains controversial. The choice of reasonable treatment and surgical method directly affects perioperative safety and prognosis. This study investigated the safety and long-term efficacy of radical surgery in elderly colorectal cancer patients over 80 years old with intestinal obstruction. Methods: The clinicopathological data of elderly patients over 80 years old with intestinal obstruction who underwent colorectal cancer surgery from January 2012 to December 2021 were retrospectively collected and analysed. Patients were assigned to a radical group and a palliative group according to the surgical method. Propensity score matching (PSM) was performed to match patients in the radical group 1:1 with those in the palliative group. The perioperative-related indexes and prognosis were compared between the two groups. Results: A total of 187 patients were enrolled in this study. After PSM, 58 matched pairs were selected, and the radical and palliative groups were well balanced in terms of the clinical and surgical characteristics (P > 0.05). The proportion of patients transferred to the ICU after surgery in the radical group was significantly higher than that in the palliative group (17.2% vs. 5.2%, P = 0.039). In terms of postoperative complications, the incidence of grade 1-5 complications in the radical group was significantly higher than that in the palliative group (37.9% vs. 15.5%, P = 0.006); however, there was no significant difference in the incidence of grade 3-5 complications between the two groups (6.9% vs. 1.7%, P = 0.364). In addition, the complications were subclassified, and it was found that the incidence of gastrointestinal disorders (20.7% vs. 6.9%, P = 0.031) after surgery was significantly higher in the radical group. The 3-year OS rates were 55.2% and 22.6% in the radical and palliative groups, respectively (P < 0.001). Multivariate analysis revealed that radical surgery was an independent prognostic factor for OS (HR: 4.32; 95% CI, 1.93-12.45; P < 0.001). Conclusion: Although elderly colorectal cancer patients over 80 years of age with intestinal obstruction are more likely to be admitted to the ICU and develop more postoperative complications after radical surgery, long-term survival benefits can be achieved.

Optimized screening of DNA methylation sites combined with gene expression analysis to identify diagnostic markers of colorectal cancer.

BACKGROUND: The prognosis of patients with colorectal cancer is related to early detection. However, commonly used screening markers lack sensitivity and specificity. In this study, we identified diagnostic methylation sites for colorectal cancer. METHODS: After screening the colorectal cancer methylation dataset, diagnostic sites were identified via survival analysis, difference analysis, and ridge regression dimensionality reduction. The correlation between the selected methylation sites and the estimation of immune cell infiltration was analyzed. The accuracy of the diagnosis was verified using different datasets and the 10-fold crossover method. RESULTS: According to Gene Ontology, the main enrichment pathways of genes with hypermethylation sites are axon development, axonogenesis, and pattern specification processes. However, the Kyoto Encyclopedia of Genes and Genomes (KEGG) suggests the following main enrichment pathways: neuroactive ligand-receptor interaction, calcium signaling, and cAMP signaling. In The Cancer Genome Atlas (TCGA) and GSE131013 datasets, the area under the curve of cg07628404 was > 0.95. For the NaiveBayes machine model of cg02604524, cg07628404, and cg27364741, the accuracies of 10-fold cross-validation in the GSE131013 and TCGA datasets were 95% and 99.4%, respectively. The survival prognosis of the hypomethylated group (cg02604524, cg07628404, and cg27364741) was better than that of the hypermethylated group. The mutation risk did not differ between the hypermethylated and hypomethylated groups. The correlation coefficient between the three loci and CD4 central memory T cells, hematological stem cells, and other immune cells was not high (p < 0.05). CONCLUSION: In cases of colorectal cancer, the main enrichment pathway of genes with hypermethylated sites was axon and nerve development. In the biopsy tissues, the hypermethylation sites were diagnostic for colorectal cancer, and the NaiveBayes machine model of the three loci showed good diagnostic performance. Site (cg02604524, cg07628404, and cg27364741) hypermethylation predicts poor survival for colorectal cancer. Three methylation sites were weakly correlated with individual immune cell infiltration. Hypermethylation sites may be a useful repository for diagnosing colorectal cancer.

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

The safety and prognosis of radical surgery in colorectal cancer patients over 80 years old.

OBJECTIVE: The purpose of this study was to assess the safety and feasibility of radical surgery and to investigate prognostic factors influencing in colorectal cancer (CRC) patients over the age of 80. METHODS: Between January 2010 and December 2020, 372 elderly CRC patients who underwent curative resection at the National Cancer Center were enrolled in the study. Preoperative clinical characteristics, perioperative outcomes, and postoperative pathological features were all collected. RESULTS: A total of 372 elderly patients with colorectal cancer were included in the study, including 226 (60.8%) men and 146 (39.2%) women. A total of 219 (58.9%) patients had a BMI < 24 kg/m2, and 153 (41.1%) patients had a BMI ≥ 24 kg/m2. The mean operation time and intraoperative blood loss were 152.3 ± 58.1 min and 67.6 ± 35.4 ml, respectively. The incidence of overall postoperative complications was 28.2% (105/372), and the incidence of grade 3-4 complications was 14.7% (55/372). In the multivariable Cox regression analysis, BMI ≥ 24 kg/m2 (HR, 2.30, 95% CI, 1.27-4.17; P = 0.006) and N1-N2 stage (HR: 2.97; 95% CI, 1.48-5.97; P = 0.002) correlated with worse CSS. CONCLUSION: The findings of this study showed that radical resection for CRC is safe and feasible for patients over the age of 80. After radical resection, BMI and N stage were independent prognostic factors for elderly CRC patients.

A multidimensional learning curve analysis of totally laparoscopic ileostomy reversal using a single surgeon' s experience.

Purpose: Recently, totally laparoscopic ileostomy reversal (TLAP) has received increasing attention and exhibited promising short-term outcomes. The aim of this study was to detail the learning process of the TLAP technique. Methods: Based on our initial experience with TLAP from 2018, a total of 65 TLAP cases were enrolled. Demographics and perioperative parameters were assessed using cumulative sum (CUSUM), moving average, and risk-adjusted CUSUM (RA-CUSUM) analyses. Results: The overall mean operative time (OT) was 94 min and the median postoperative hospitalization period was 4 days, and there was an estimated 10.77% incidence rate of perioperative complications. Three unique phases of the learning curve were derived from CUSUM analysis, and the mean OT of phase I (1-24 cases) was 108.5 min, that of phase II (25-39 cases) was 92 min, and that of phase III (40-65 cases) was 80 min, respectively. There was no significant difference in perioperative complications between these 3 phases. Similarly, moving average analysis indicated that the operation time was reduced significantly after the 20th case and reached a steady state after the 36th case. Furthermore, complication-based CUSUM and RA-CUSUM analyses indicated an acceptable range of complication rates during the whole learning period. Conclusion: Our data demonstrated 3 distinct phases of the learning curve of TLAP. For an experienced surgeon, surgical competence in TLAP can be grasped at around 25 cases with satisfactory short-term outcomes.

Lateral pelvic sentinel lymph node biopsy using indocyanine green fluorescence navigation: can it be a powerful supplement tool for predicting the status of lateral pelvic lymph nodes in advanced lower rectal cancer.

BACKGROUND: An innovative instrument for laparoscopy using indocyanine green (ICG) allows easy detection of sentinel lymph nodes (SLNs) in lateral pelvic lymph nodes (LPLNs). Here, we investigated the safety and efficacy of lateral pelvic SLN biopsy (SLNB) using ICG fluorescence navigation in advanced lower rectal cancer and evaluated the sensitivity and specificity of this technique to predict the status of LPLN. METHODS: From April 1, 2017 to December 1, 2020, we conducted lateral pelvic SLNB using ICG fluorescence navigation during laparoscopic total mesorectal excision and lateral pelvic lymph node dissection (LLND) in 23 patients with advanced low rectal cancer who presented with LPLN but without LPLN enlargement. Data regarding clinical characteristics, surgical and pathological outcomes, lymph node findings, and postoperative complications were collected and analyzed. RESULTS: We successfully performed the surgery using fluorescence navigation. One patient underwent bilateral LLND and 22 patients underwent unilateral LLND. The lateral pelvic SLN were clearly fluorescent before dissection in 21 patients. Lateral pelvic SLN metastasis was diagnosed in 3 patients and negative in 18 patients by frozen pathological examination. Among the 21 patients in whom lateral pelvic SLN was detected, the dissected lateral pelvic non-SLNs were all negative. All dissected LPLNs were negative in two patients without fluorescent lateral pelvic SLN. CONCLUSION: This study indicated that lateral pelvic SLNB using ICG fluorescence navigation shows promise as a safe and feasible procedure for advanced lower rectal cancer with good accuracy, and no false-negative cases were found. No metastasis in SLNB seemed to reflect all negative LPLN metastases, and this technique can replace preventive LLND for advanced lower rectal cancer.

Significance of logistic regression scoring model based on natural killer cell-mediated cytotoxic pathway in the diagnosis of colon cancer.

Background: The poor clinical accuracy to predict the survival of colon cancer patients is associated with a high incidence rate and a poor 3-year survival rate. This study aimed to identify the poor prognostic biomarkers of colon cancer from natural killer cell-mediated cytotoxic pathway (NKCP), and establish a logistical regression scoring model to predict its prognosis. Methods: Based on the expressions and methylations of NKCP-related genes (NRGs) and the clinical information, dimensionality reduction screening was performed to establish a logistic regression scoring model to predict survival and prognosis. Risk score, clinical stage, and ULBP2 were used to establish a logistic regression scoring model to classify the 3-year survival period and compare with each other. Comparison of survival, tumor mutation burden (TMB), estimation of immune invasion, and prediction of chemotherapeutic drug IC50 were performed between low- and high-risk score groups. Results: This study found that ULBP2 was significantly overexpressed in colon cancer tissues and colon cancer cell lines. The logistic regression scoring model was established to include six statistically significant features: S = 1.70 × stage - 9.32 × cg06543087 + 6.19 × cg25848557 + 1.29 × IFNA1 + 0.048 × age + 4.37 × cg21370856 - 8.93, which was used to calculate risk score of each sample. The risk scores, clinical stage, and ULBP2 were classified into three-year survival, the 3-year prediction accuracy based on 10-fold cross-validation was 80.17%, 67.24, and 59.48%, respectively. The survival time of low-risk score group was better than that of the high-risk score group. Moreover, compared to high-risk score group, low-risk score group had lower TMB [2.20/MB (log10) vs. 2.34/MB (log10)], higher infiltration score of M0 macrophages (0.17 vs. 0.14), and lower mean IC50 value of oxaliplatin (3.65 vs 3.78) (p < 0.05). Conclusions: The significantly upregulated ULBP2 was a poor prognostic biomarker of colon cancer. The risk score based on the six-feature logistic regression model can effectively predict the 3-year survival time. High-risk score group demonstrated a poorer prognosis, higher TMB, lower M0 macrophage infiltration score, and higher IC50 value of oxaliplatin. The six-feature logistic scoring model has certain clinical significance in colon cancer.

Establishing and validating predictive nomograms for lateral pelvic lymph node metastasis in patients with rectal cancer based on radiologic factors and clinicopathologic characteristics.

INTRODUCTION: It is critical to accurately predict the occurrence of lateral pelvic lymph node (LPN) metastasis. Currently, verified predictive tools are unavailable. This study aims to establish nomograms for predicting LPN metastasis in patients with rectal cancer who received or did not receive neoadjuvant chemoradiotherapy (nCRT). MATERIALS AND METHODS: We carried out a retrospective study of patients with rectal cancer and clinical LPN metastasis who underwent total mesorectal excision (TME) and LPN dissection (LPND) from January 2012 to December 2019 at 3 institutions. We collected and evaluated their clinicopathologic and radiologic features, and constructed nomograms based on the multivariable logistic regression models. RESULTS: A total of 472 eligible patients were enrolled into the non-nCRT cohort (n = 312) and the nCRT cohort (n = 160). We established nomograms using variables from the multivariable logistic regression models in both cohorts. In the non-nCRT cohort, the variables included LPN short diameter, cT stage, cN stage, histologic grade, and malignant features, and the C-index was 0.930 in the training cohort and 0.913 in the validation cohort. In the nCRT cohort, the variables included post-nCRT LPN short diameter, ycT stage, ycN stage, histologic grade, and post-nCRT malignant features, and the C-index was 0.836 in the training dataset and 0.827 in the validation dataset. The nomograms in both cohorts were moderately calibrated and well-validated. CONCLUSIONS: We established nomograms for patients with rectal cancer that accurately predict LPN metastasis. The performance of the nomograms in both cohorts was high and well-validated.