Genomic landscape defines peritoneal metastatic pattern and related target of peritoneal metastasis in colorectal cancer.

The primary objective of this study is to develop a prediction model for peritoneal metastasis (PM) in colorectal cancer by integrating the genomic features of primary colorectal cancer, along with clinicopathological features. Concurrently, we aim to identify potential target implicated in the peritoneal dissemination of colorectal cancer through bioinformatics exploration and experimental validation. By analyzing the genomic landscape of primary colorectal cancer and clinicopathological features from 363 metastatic colorectal cancer patients, we identified 22 differently distributed variables, which were used for subsequent LASSO regression to construct a PM prediction model. The integrated model established by LASSO regression, which incorporated two clinicopathological variables and seven genomic variables, precisely discriminated PM cases (AUC 0.899; 95% CI 0.860-0.937) with good calibration (Hosmer-Lemeshow test p = .147). Model validation yielded AUCs of 0.898 (95% CI 0.896-0.899) and 0.704 (95% CI 0.622-0.787) internally and externally, respectively. Additionally, the peritoneal metastasis-related genomic signature (PGS), which was composed of the seven genes in the integrated model, has prognostic stratification capability for colorectal cancer. The divergent genomic landscape drives the driver genes of PM. Bioinformatic analysis concerning these driver genes indicated SERINC1 may be associated with PM. Subsequent experiments indicate that knocking down of SERINC1 functionally suppresses peritoneal dissemination, emphasizing its importance in CRCPM. In summary, the genomic landscape of primary cancer in colorectal cancer defines peritoneal metastatic pattern and reveals the potential target of SERINC1 for PM in colorectal cancer.

Development and Validation of a Post-Radiotherapy Prediction Model for Bowel Dysfunction After Rectal Cancer Resection.

BACKGROUND & AIMS: The benefit of radiotherapy for rectal cancer is based largely on a balance between a decrease in local recurrence and an increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features. METHODS: Eligible patients more than 1 year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score at 3 national hospitals in China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by means of logistic regression on the basis of key factors with proportional weighs. The accuracy of the model for major LARS prediction was internally and externally validated. RESULTS: A total of 868 patients reported a mean LARS score of 28.4 after an average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathologic nodal stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835; 95% CI, 0.800-0.870, n = 521) and external dataset (0.884; 95% CI, 0.848-0.921, n = 347). The model achieved both sensitivity and specificity >0.83 in the external validation. In addition, PORTLARS outperformed the preoperative LARS score for prediction of major events. CONCLUSIONS: PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to identify patients who need additional support for long-term dysfunction in the early stage. CLINICALTRIALS: gov, number NCT05129215.

CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis.

Radiation enteritis (RE) is a prevalent complication of radiotherapy for pelvic malignant tumors, characterized by severe intestinal epithelial destruction and progressive submucosal fibrosis. However, little is known about the pathogenesis of this disease, and so far, there is no specific targeted therapy. Here, we report that CXCL16 is upregulated in the injured intestinal tissues of RE patients and in a mouse model. Genetic deletion of Cxcl16 mitigates fibrosis and promotes intestinal stem cell-mediated epithelial regeneration after radiation injury in mice. Mechanistically, CXCL16 functions on myofibroblasts through its receptor CXCR6 and activates JAK3/STAT3 signaling to promote fibrosis and, at the same time, to transcriptionally modulate the levels of BMP4 and hepatocyte growth factor (HGF) in myofibroblasts. Moreover, we find that CXCL16 and CXCR6 auto- and cross-regulate themselves in positive feedback loops. Treatment with CXCL16 neutralizing monoclonal antibody attenuates fibrosis and improves the epithelial repair in RE mouse model. Our findings emphasize the important role of CXCL16 in the progression of RE and suggest that CXCL16 signaling could be a potential therapeutic target for RE. © 2022 The Pathological Society of Great Britain and Ireland.

Extensive involvement of indolent T-cell lymphoma in a patient with ulcerative colitis.

Indolent T-cell lymphoma is a rare disease. Here we presented a 53-year-old male patient initially diagnosed as ulcerative colitis in 2000 that finally developed into extensive indolent T-cell lymphoma in 2022. We also described the differences between indolent T-cell lymphoma and inflammatory bowel disease, and the possible disease progression into lymphoma after biological therapy.

Modified FOLFOXIRI With or Without Cetuximab as Conversion Therapy in Patients with RAS/BRAF Wild-Type Unresectable Liver Metastases Colorectal Cancer: The FOCULM Multicenter Phase II Trial.

PURPOSE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI (mFOLFOXIRI: 5-fluorouracil/folinic acid, oxaliplatin, irinotecan) as conversion therapy in a two-group, nonrandomized, multicenter, phase II trial in patients with initially technically unresectable colorectal liver-limited metastases (CLM) and BRAF/RAS wild-type. PATIENTS AND METHODS: Patients were enrolled to receive cetuximab (500 mg/m2 ) plus mFOLFOXIRI (oxaliplatin 85 mg/m2 , irinotecan 165 mg/m2 , folinic acid 400 mg/m2 , 5-fluorouracil 2,800 mg/m2 46-hour infusion, every 2 weeks) (the cetuximab group) or the same regimen of mFOLFOXIRI alone (the control group), in a 2:1 ratio allocation. The primary endpoint was the rate of no evidence of disease (NED) achieved. Secondary endpoints included resection rate, objective response rate (ORR), survival, and safety. RESULTS: Between February 2014 and July 2019, 117 patients were registered for screening at six centers in China, and 101 of these were enrolled (67 cetuximab group, 34 control group). The rate of NED achieved was 70.1% in the cetuximab group and 41.2% in the control group (difference 29.0%; 95% confidence interval [CI], 9.1%-48.8%; p = .005). Patients in the cetuximab group had improved ORR (95.5% vs. 76.5%; difference 19.1%; 95% CI, 17.4%-36.4%; p = .010) compared with those in control group. Progression-free survival and overall survival showed the trend to favor the cetuximab group. The incidence of grade 3 and 4 adverse events was similar in the two groups. CONCLUSION: Addition of cetuximab to mFOLFOXIRI improved the rate of NED achieved. This combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable CLM. IMPLICATIONS FOR PRACTICE: This trial evaluated the addition of cetuximab to a modified FOLFOXIRI as conversion therapy in a phase II trial in patients with initially technically unresectable colorectal liver-limited metastases and BRAF/RAS wild-type. The rate of no evidence of disease achieved was 70.1% in the cetuximab plus modified FOLFOXIRI group and 41.2% in the modified FOLFOXIRI group. Objective response rates, overall survival, and progression-free survival were improved in the cetuximab group when compared with the modified FOLFOXIRI group. Addition of cetuximab to modified FOLFOXIRI increased the rate of no evidence of disease achieved, and this combination could be an option of conversion regimen for molecularly selected patients with initially technically unresectable colorectal liver-limited metastasis.

Medical Management of Inoperable Malignant Bowel Obstruction.

OBJECTIVE: To review medical management of inoperable malignant bowel obstruction. DATA SOURCES: A literature review using PubMed and MEDLINE databases searching malignant bowel obstruction, etiology, types, pathophysiology, medical, antisecretory, anti-inflammatory, antiemetic drugs, analgesics, promotion of emptying, prevention of infection, anticholinergics, somatostatin analogs, gastric antisecretory drugs, prokinetic agents, glucocorticoid, opioid analgesics, antibiotics, enema, and adverse effects. STUDY SELECTION AND DATA EXTRACTION: Randomized or observational studies, cohorts, case reports, or reviews written in English between 1983 and November 2020 were evaluated. DATA SYNTHESIS: Malignant bowel obstruction (MBO) commonly occurs in patients with advanced or recurrent malignancies and severely affects the quality of life and survival of patients. Its management remains complex and variable. Medical management is the cornerstone of MBO treatment, with the goal of reducing distressing symptoms and optimizing quality of life. Until now, there has been neither a standard clinical approach nor registered medications to treat patients with inoperable MBO. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review provides information on the etiology, type and pathophysiology, and medical treatment of MBO and related adverse reactions of the drugs commonly used, which can greatly assist clinicians in making clinical decisions when treating MBO. CONCLUSIONS: Published research shows that medical management of MBO mainly consists of antisecretory, anti-inflammatory strategies, controlling vomiting and pain, promoting emptying, preventing infection, and combination therapy. Being knowledgeable about the most current treatment options, the related adverse effects, and the evidence supporting different practices is critical for clinicians to provide individualized medical therapy for MBO patients.

Diverting colostomy is an effective procedure for ulcerative chronic radiation proctitis patients after pelvic malignancy radiation.

BACKGROUND: Chronic radiation proctitis (CRP) with rectal ulcer is a common complication after pelvic malignancy radiation, and gradually deteriorating ulcers will result in severe complications such as fistula. The aim of this study was to evaluate effect of colostomy on ulcerative CRP and to identify associated influence factors with effectiveness of colostomy. METHODS: Between November 2011 to February 2019, 811 hospitalized patients were diagnosed with radiation-induced enteritis (RE) in Sun Yat-sen University Sixth Affiliated Hospital, among which 284 patients presented with rectal ulcer, and 61 ulcerative CRP patients were retrospectively collected and analyzed. RESULTS: The overall effective rate of colostomy on ulcerative CRP was 49.2%, with a highest effective rate of 88.2% within 12 to 24 months after colostomy. 9 (31.1%) CRP patients with ulcers were cured after colostomy and 12 (19.67%) patients restored intestinal continuity, among which including 2 (3.3%) patients ever with rectovaginal fistula. 100% (55/55) patients with rectal bleeding and 91.4% (32/35) patients with anal pain were remarkably alleviated. Additionally, multivariable analysis showed the duration of stoma [OR 1.211, 95% CI (1.060-1.382), P = 0.005] and albumin (ALB) level post-colostomy [OR 1.437, 95% CI (1.102-1.875), P = 0.007] were two independent influence factors for the effectiveness of colostomy on the rectal ulcer of CRP patients. CONCLUSIONS: Colostomy was an effective and safe procedure for treating rectal ulcer of CRP patients, and also a potential strategy for preventing and treating fistula. Duration of stoma for 12-24 months and higher ALB level could significantly improve the effectiveness of colostomy on ulcerative CRP patients.

Clinical Anastomotic Leakage After Rectal Cancer Resection Can Be Predicted by Pelvic Anatomic Features on Preoperative MRI Scans: A Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: We demonstrated previously that radiation proctitis induced by preoperative radiotherapy is a predisposing factor for clinical anastomotic leakage in patients undergoing rectal cancer resection. Quantitative measurement of radiation proctitis is needed. OBJECTIVE: This study aimed to quantitate the changes of anatomic features caused by preoperative radiotherapy for rectal cancer and evaluate its ability to predict leakage. DESIGN: It was a secondary analysis of a randomized controlled trial (NCT01211210). MRI variables were retrospectively assessed. SETTINGS: The study was conducted in the leading center of the trial, which is a tertiary GI hospital. PATIENTS: Patients undergoing preoperative chemoradiation with sphincter-preserving surgery were included. MAIN OUTCOME MEASURES: Anatomic features were measured by preradiotherapy and postradiotherapy MRI. Univariate analyses were used to identify prognostic factors. Receiver operating characteristic curves were constructed to determine the cutoff value of the changes of MRI variables in predicting leakage. RESULTS: Eighteen (14.4%) of the 125 included patients developed clinical anastomotic leakage. Baseline characteristics were comparable between leakage group and nonleakage group. Relative increments of width of presacral space, thickness of rectal wall, and distal end of sigmoid colon discriminate between the 2 groups better than random chance. Relative increments of width of presacral space was the best performing predictor, with area under the curve of 0.722, sensitivity of 66.7%, specificity of 72.0%, and positive and negative predictive value of 28.6% and 92.8%. LIMITATIONS: The study was limited by its small sample size and retrospective design. CONCLUSIONS: Increments of the width of the presacral space, thickness of rectal wall, and distal part of the sigmoid colon helps to identify individuals not at risk for clinical anastomotic leakage after rectal cancer resection. The first variable is the strongest predictor. Changes of these variables should be taken into consideration when evaluating the application of defunctioning stoma. See Video Abstract at http://links.lww.com/DCR/B23. CLINICAL TRIALS IDENTIFIER: NCT1211210. LAS FUGAS ANASTOMÓTICAS CLÍNICAS DESPUÉS DE LA RESECCIÓN DEL CÁNCER DEL RECTO PUEDEN PREDECIRSE POR LAS CARACTERÍSTICAS ANATÓMICAS PÉLVICAS EN LAS IMAGENES DE RESONANCIA MAGNÉTICA PREOPERATORIA: UN ANÁLISIS SECUNDARIO DE UN ESTUDIO CONTROLADO ALEATORIZADO:: Anteriormente demostramos que la proctitis inducida por la radiación de radioterapia preoperatoria es un factor predisponente para la fuga anastomótica clínica en pacientes sometidos a resección de cáncer rectal. Es necesaria la medición cuantitativa de la proctitis por radiación.Este estudio tuvo como objetivo cuantificar los cambios en las características anatómicas causados por la radioterapia preoperatoria para el cáncer de recto y evaluar su capacidad para predecir las fugas anastomoticas.Fue un análisis secundario de un estudio controlado aleatorio (NCT01211210). Los variables de imagines de resonancia magnetica se evaluaron retrospectivamente.Se llevó a cabo en el centro principal del estudio, que es un hospital gastrointestinal terciario.Se incluyeron pacientes sometidos a quimiorradiación preoperatoria con cirugía conservadora del esfínter.Las características anatómicas se midieron mediante imagines de resonancia magnetica previa y posterior a la radioterapia. Se utilizaron análisis univariados para identificar los factores pronósticos. Las curvas de características operativas del receptor se construyeron para determinar el valor de corte de los cambios de los variables de resonancia magnetica en la predicción de fugas.Dieciocho (14.4%) de los 125 pacientes incluidos desarrollaron fugas anastomóticas clínicas. Las características basales fueron comparables entre el grupo de fugas y el grupo de no fugas. Los incrementos relativos del ancho del espacio presacro, el grosor de la pared rectal y distal del colon sigmoide discriminan entre los dos grupos mejor que la posibilidad aleatoria. Los incrementos relativos del ancho del espacio presacro fueron el mejor pronóstico con un AUC de 0.722, sensibilidad del 66.7%, especificidad del 72.0%, valor predictivo positivo y negativo del 28.6% y 92.8%.Estaba limitado por el tamaño de muestra pequeño y el diseño retrospectivo.Los incrementos en el ancho del espacio presacro, el grosor de la pared rectal y la parte distal del colon sigmoide ayudan a identificar a las personas que no tienen riesgo de fuga anastomótica clínica después de la resección del cáncer rectal. La primera variable es el predictor más fuerte. Los cambios de estos variables deben tenerse en cuenta al evaluar la aplicación del estoma para desvio. Vea el Resumen del Video en http://links.lww.com/DCR/B23.

Downregulation of miR-222-3p Reverses Doxorubicin-Resistance in LoVo Cells Through Upregulating Forkhead Box Protein P2 (FOXP2) Protein.

BACKGROUND Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat colon cancer. Despite impressive initial clinical responses, drug resistance has dramatically compromised the effectiveness of DOX. However, the underlying mechanisms of chemotherapeutic resistance in colon cancer remain poorly understood. MATERIAL AND METHODS In this study, we compared the expression of miR-222-3p in DOX-resistant colon cancer cells (LoVo/ADR) with the corresponding DOX-sensitive parental cells (LoVo/S) using quantitative real-time PCR. In addition, miR-222-3p inhibitors were infected into LoVo/ADR cell lines and the effects of this treatment were assessed. The Cell Counting Kit 8 assay was employed to verify the sensitivity of colon cancer cell lines to DOX. EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry, and in vivo subcutaneous tumorigenesis were used to assess cell proliferation and apoptosis. Transwell and wound healing assays were used to investigate cell migration after adding DOX. Additionally, the expression of forkhead box protein P2 (FOXP2), P-glycoprotein (P-gp) and caspase pathway-associated markers was assessed by western blotting. RESULTS Our results showed that miR-222-3p was upregulated in LoVo/ADR compared with the expression in LoVo/S cells. Additionally, downregulation of miR-222-3p in LoVo/ADR cells increased their sensitivity to DOX, reduced P-gp expression, and activated the caspase pathway. However, the downregulation of FOXP2 could efficiently reverse the effect of miR-222-3p inhibitors on LoVo/ADR cells. CONCLUSIONS Taken together, our results showed that miR-222-3p induced DOX resistance via suppressing FOXP2, upregulating P-gp, and inhibiting the caspase pathway.

Role of Angiogenesis in Chronic Radiation Proctitis: New Evidence Favoring Inhibition of Angiogenesis Ex Vivo.

BACKGROUND: Chronic radiation proctitis (CRP), a common complication after radiotherapy for pelvic malignancies, compromises patient quality of life. Vascular damage and aberrant angiogenesis in the mucosal layer are essential histological features, but changes to the submucosal layer are unclear. Thus, we evaluated the histological characteristics and distribution changes of key angiogenic factors in full-layered human CRP samples. METHODS: Thirty paraffin-embedded CRP and twenty-nine non-CRP tissues were used to evaluate histopathological changes. Immunohistochemistry with anti-CD34 antibody was performed to calculate microvascular density (MVD). Frozen tissues from eight CRP patients and five non-CRP controls were collected and analyzed by antibody array, which contained sixty human angiogenesis-related factors. Quality controls with positive and negative controls were performed during antibody array analysis. Two differentially expressed factors were confirmed by ELISA. RESULTS: CRP lesions showed vasculopathy, fibrosis, mucosal ulceration, edema, and inflammatory cell infiltration. Human angiogenesis antibody array and ELISA confirmed the increased angiostatin in CRP lesions. Immunohistochemical staining showed dispersed distribution of angiostatin throughout the mucosal and submucosal layers in CRP lesions, while angiostatin accumulated within the vessel lumens in non-CRP tissues. MVD significantly decreased in the submucosal layer of CRP, suggesting a potential association with increased angiostatin. CONCLUSIONS: Angiostatin increased and had a distinct distribution in CRP lesions. Compensatory telangiectasia in the mucosa, vessel stenosis, and reduced MVD might attenuate blood flow in the submucosa and contribute to CRP progression. Restoration of vascular functionality by promoting angiogenesis in the submucosal layer may help alleviate CRP in clinical practice.

Bowel Dysfunction After Low Anterior Resection With Neoadjuvant Chemoradiotherapy or Chemotherapy Alone for Rectal Cancer: A Cross-Sectional Study from China.

BACKGROUND: Neoadjuvant therapy plays a vital role in the treatment of locally advanced rectal cancer but impairs bowel function after restorative surgery. Optimal decision making requires adequate information of functional outcomes. OBJECTIVE: This study aimed to assess postoperative bowel function and to identify predictors for severe dysfunction. DESIGN: The study included a cross-sectional cohort and retrospective assessments of pelvic anatomic features. SETTINGS: The study was conducted at a tertiary GI hospital in China. PATIENTS: Included patients underwent neoadjuvant chemoradiotherapy or chemotherapy without radiation and curative low anterior resection for rectal cancer between 2012 and 2014. MAIN OUTCOME MEASURES: Bowel function was assessed using the validated low anterior resection syndrome score. The thicknesses of the rectal wall, obturator internus, and levator ani were measured by preoperative MRI. RESULTS: A total of 151 eligible patients were identified, and 142 patients (94.0%) participated after a median of 19 months from surgery. Bowel dysfunction was observed in 71.1% (101/142) of patients, with 44.4% (63/142) reporting severe dysfunction. Symptoms of urgency and clustering were found to be major disturbances. Regression analysis identified preoperative long-course radiotherapy (p < 0.001) and a lower-third tumor (p = 0.002) independently associated with severe bowel dysfunction. Irradiated patients with a lower-third tumor (OR = 14.06; p < 0.001) or thickening of the rectal wall (OR = 11.09; p < 0.001) had a markedly increased risk of developing severe dysfunction. LIMITATIONS: The study was based on a limited cohort of patients and moderate follow-up after the primary surgery. CONCLUSIONS: Bowel function deteriorates frequently after low anterior resection for rectal cancer. Severe bowel dysfunction is significantly associated with preoperative long-course radiotherapy and a lower-third tumor, and the thickening of rectal wall after radiation is a strong predictor. Treatment decisions and patient consent should be implemented with raising awareness of bowel symptom burdens. See Video Abstract at http://links.lww.com/DCR/A317.

Restorative resection of radiation rectovaginal fistula can better relieve anorectal symptoms than colostomy only.

BACKGROUND: Radiation-induced rectovaginal fistula (RVF) is a severe and difficult complication after pelvic malignancy radiation. This study was to retrospectively compare the outcomes of restorative resection and colostomy only in remission of anorectal symptoms. METHODS: We enrolled a cohort of 26 consecutive cases who developed RVF after pelvic radiation. Two main procedures for these patients in our institution were used: one was restorative resection and pull-through coloanal anastomosis with a prophylactic colostomy, and another was a simple colostomy without resection. Thus, we divided these patients into these two groups. Anorectal symptoms including rectal pain, bleeding, tenesmus, and perineal mucous discharge were recorded and scored prior to surgery and at postoperative multiple time points. RESULTS: The baseline was similar among the two groups. All patients acquired good efficacy with improved symptoms at postoperative 6, 12, and 24 months, when compared to baseline. In addition, the resection group showed a better remission of tenesmus (6 months 33.3 vs 0%; 12 months 66.7 vs 16.7%) and perineal mucous discharge (6 months 88.9 vs 6.7%; 12 months 77.8 vs 15.4%; 24 months 85.7 vs 25.0%). Furthermore, three (30%) patients in the resection group successfully reversed stomas while no stoma was closed in the simple colostomy group. CONCLUSIONS: Both restorative resection procedure and colostomy only can improve anorectal symptoms of radiation-induced RVF, but restorative resection can completely relieve anorectal symptoms in selected cases.

Impact of Preoperative Radiotherapy on Anastomotic Leakage and Stenosis After Rectal Cancer Resection: Post Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Evidence regarding the effect of preoperative radiotherapy on anastomotic integrity remains conflicting in rectal cancer surgery. Prospective comparisons with appropriate controls are needed. OBJECTIVE: This study aimed to assess the impact of preoperative radiotherapy on anastomotic leakage and stenosis after rectal cancer resection. DESIGN: This was a post hoc analysis of a randomized controlled trial (NCT01211210). SETTINGS: Data were retrieved from the leading center of the trial, which is a tertiary hospital. PATIENTS: The full analysis population of 318 patients was included. INTERVENTIONS: Patients were randomly assigned to receive preoperative radiation (50 Gy per 25 fractions) and 5-fluorouracil infusion, alone (arm A) or combined with oxaliplatin (arm B), or preoperative chemotherapy with 5-fluorouracil and oxaliplatin without radiation (arm C). MAIN OUTCOME MEASURES: The rates of anastomotic leakage and stenosis were calculated for each treatment arm. Multivariate analysis was used to verify the effect of preoperative radiotherapy. RESULTS: The treatment arms were comparable in terms of most baseline characteristics, but more diversions were used in the chemoradiotherapy arms. Anastomotic leakage occurred in 20.2% of patients in arm A, 23.6% of patients in arm B, and 8.5% of patients in arm C (p = 0.007). The corresponding rates of stenosis were 17.0%, 18.9%, and 6.8% (p = 0.02). Multivariate analysis confirmed the correlation between preoperative radiotherapy and clinical leakage (p = 0.02), which was associated with delayed stenosis (p < 0.001). For patients undergoing chemoradiotherapy, radiation proctitis was identified as an independent risk factor for clinical leakage (p = 0.01) and stenosis (p < 0.001). LIMITATIONS: The main limitations were discrepancies in stoma creation and chemotherapy regimen among the treatment arms. CONCLUSIONS: Preoperative radiotherapy increases the risk of anastomotic leakage and stenosis after rectal cancer resection. Clinical leakage independently contributes to the development of stenosis.

Molecular mechanism of acute radiation enteritis revealed using proteomics and biological signaling network analysis in rats.

BACKGROUND AND AIMS: Radiation enteritis (RE) has emerged as a significant complication that can progress to severe gastrointestinal disease and the mechanisms underlying its genesis remain poorly understood. The aim of this study was to identify temporal changes in protein expression potentially associated with acute inflammation and to elucidate the mechanism underlying radiation enteritis genesis. METHODS: Male Sprague-Dawley rats were irradiated in the abdomen with a single dose of 10 Gy to establish an in vivo model of acute radiation enteritis. Two-dimensional fluorescence difference gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight spectrometer (MALDI-TOF) tandem mass spectrometry, and peptide mass fingerprinting were used to determine differentially expressed proteins between normal and inflamed intestinal mucosa. Additionally, differentially expressed proteins were evaluated by KO Based Annotation System to find the biological functions associated with acute radiation enteritis. RESULTS: Intensity changes of 86 spots were detected with statistical significance (ratio ≥ 1.5 or ≤ 1.5, P < 0.05). Sixty one of the 86 spots were identified by MALDI-TOF/TOF tandem mass spectrometry. These radiation-induced proteins with biological functions showed that the FAS pathway and glycolysis signaling pathways were significantly altered using the KOBAS tool. CONCLUSIONS: Our results reveal an underlying mechanism of radiation-induced acute enteritis, which may help clarify the pathogenesis of RE and point to potential targets for therapeutic interventions.

Investigation on the Therapeutic Mechanism of Danbie Capsules for Endometriosis: A Network Pharmacology Approach.

Objective: To explore the active substances and targets of Danbie Capsules in Endometriosis therapy. Methods: This study was conducted through TCMSP and published literature screened and obtained 183 active substances of Danbie Capsules, combined and intersected with Endometriosis target genes collected and screened in the GEO database, obtained 24 target genes for Endometriosis treatment, and mapped the target network map of Danbie Capsules active substances against Endometriosis. The network was analyzed with the aid of Cytoscape version 3.9.1. With the aid of the platform of the STRING data analysis, PPI network analysis was conducted on 24 anti-Endometriosis targets of the Danbie Capsules. Results: The research results obtained three critical active substances, namely, Quercetin, ß-sitosterol, and Luteolin. Seven critical targets were identified, and two representative genes (TP53 and AKT1) have been verified in Macromolecular docking and immunohistochemical verification. Conclusion: The active substances of Danbie Capsules in the treatment of Endometriosis are Quercetin, ß-sitosterol and Luteolin, and the main targets are TP53 and AKT1.

Evaluation of transrectal ultrasound-guided tru-cut biopsy as a complementary method for predicting pathological complete response in rectal cancer after neoadjuvant treatment: a phase II prospective and diagnostic trial.

IMPORTANCE: Patients with pathological complete response (pCR) of rectal cancer following neoadjuvant treatment had better oncological outcomes. However, reliable methods for accurately predicting pCR remain limited. OBJECTIVE: To evaluate whether transrectal ultrasound-guided tru-cut biopsy (TRUS-TCB) adds diagnostic value to conventional modalities for predicting pathological complete response in patients with rectal cancer after neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated data of patients with rectal cancer who were treated with neoadjuvant treatment and reassessed using TRUS-TCB and conventional modalities before surgery. This study is registered with ClinicalTrials.gov. MAIN OUTCOMES AND MEASURES: The primary outcome was accuracy, along with secondary outcomes including sensitivity, specificity, negative predictive value, and positive predictive value in predicting tumour residues. Final surgical pathology was used as reference standard. RESULTS: Between June 2021 and June 2022, a total of 74 patients were enroled, with 63 patients ultimately evaluated. Among them, 17 patients (28%) exhibited a complete pathological response. TRUS-TCB demonstrated an accuracy of 0.71 (95% CI, 0.58-0.82) in predicting tumour residues. The combined use of TRUS-TCB and conventional modalities significantly improved diagnostic accuracy compared to conventional modalities alone (0.75 vs. 0.59, P =0.02). Furthermore, TRUS-TCB correctly reclassified 52% of patients erroneously classified as having a complete clinical response by conventional methods. The occurrence of only one mild adverse event was observed. CONCLUSIONS AND RELEVANCE: TRUS-TCB proves to be a safe and accessible tool for reevaluation with minimal complications. The incorporation of TRUS-TCB alongside conventional methods leads to enhanced diagnostic performance.

Serial Circulating Tumor DNA in Monitoring the Effect of Neoadjuvant and Adjuvant Immunotherapy in Patients With Colon Cancer: Case Series and Review of the Literature.

Although programmed death 1 blockade has significantly improved the survival of advanced colorectal cancer patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), clinical data in neoadjuvant and adjuvant setting are limited. The role of circulating tumor DNA (ctDNA) in precision oncology is promising, but its clinical significance in immunotherapy needs to be validated. We report a case series of 3 colon patients who received neoadjuvant and adjuvant immunotherapy and serial ctDNA analysis. This report summarizes clinical and molecular details for 3 patients with locally advanced or recurrent dMMR/MSI-H/polymerase epsilon ( POLE ) mutation-positive tumors treated with neoadjuvant/adjuvant immunotherapy. One stage IV recurrent colon cancer patient diagnosed with Lynch syndrome received adjuvant sintilimab monotherapy and had a progression-free survival (PFS) over 16 months, one stage Ⅲc colon cancer patient with MSI-H/high tumor mutation burden received neoadjuvant toripalimab monotherapy, was assessed as clinical complete response before surgery, continued with adjuvant sintilimab monotherapy and had a PFS over 17 months, one stage Ⅱ colon cancer patient with POLE P286R also received adjuvant sintilimab monotherapy and had a PFS over 17 months. All patients had detectable ctDNA after radical surgery and clearance of ctDNA during adjuvant immunotherapy. All 3 patients are free of tumor disease at the time of this report. Further studies are warranted to evaluate the long-term efficacy of neoadjuvant and adjuvant programmed death 1 blockade in locally advanced and metastasis in dMMR/MSI-H/ POLE mutated colorectal cancer and the role of ctDNA monitoring.

Laparoscopic Proximally Extended Colorectal Resection With Two-Stage Turnbull-Cutait Pull-Through Coloanal Anastomosis for Late Complications of Chronic Radiation Proctopathy.

Background: Chronic radiation proctopathy (CRP) is a common complication after radiation therapy for pelvic malignancies. Compared with diversion surgery, resection surgery removes the damaged tissue completely to avoid the risks of recurrence and improve patients' outcome. Hence, resection surgery could be an optimal surgical approach when CRP is complicated by late complications. This study aimed to describe a modified surgical procedure of resection surgery and report its preliminary efficacy and safety in treating patients with CRP with late complications. Methods: We retrospectively reviewed the patients who were diagnosed with CRP with late complications and underwent the modified surgical procedure of laparoscopic proximally extended colorectal resection with two-Stage Turnbull-Cutait pull-through coloanal anastomosis (PE-Bacon) between November 2019 and October 2020 in the Sixth Affiliated Hospital of Sun Yat-sen University. Results: A total of 15 patients were performed the modified laparoscopic procedure of PE-Bacon, of which 1 patient underwent conversion from laparoscopic to open operation for intraoperative massive hemorrhage. Overall, the major (Clavien-Dindo III-V) postoperative complications occurred in 1 patient, anastomotic leakage was observed in 2 (13.3%) patients, and anastomotic stricture was observed in 4 (26.7%) patients. No patient had to be reoperated and died. Up to now, at the average follow-up of (524.40 ± 108.39) days, the preoperative symptoms of 93.3% (14/15) patients were relieved, with nine patients achieved complete remission, five patients only suffered minor symptoms. Because of the progression of radiation uropathy, one patient still had a vesicovaginal fistula as pre-operative complication. Colostomy reversal has been performed on 8 (53.3%) patients at an average postoperative duration of 299.5 ± 92.68 days, among whom only 2 patients suffered from major Low Anterior Resection Syndrome (LARS) until now. Conclusions: Laparoscopic PE-Bacon surgery is a safe and feasible surgical procedure for late complications of CRP with low morbidity and high symptom remission rate.

mFOLFOXIRI with or without bevacizumab for conversion therapy of RAS/BRAF/PIK3CA mutant unresectable colorectal liver metastases: the FORBES non-randomized phase II trial.

Background: The aim of this non-randomized single-center phase II trial was to prospectively assess the clinical efficacy of triplet chemotherapy with modified 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (mFOLFOXIRI) plus bevacizumab as conversion therapy for initially unresectable rat sarcoma viral oncogene homolog (RAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/phosphatidylinositol-3 kinase catalytic alpha (PIK3CA) mutant colorectal liver-limited metastases (CRLMs). Methods: Patients with RAS/BRAF/PIK3CA mutant initially unresectable CRLMs were recruited at a ratio of 2:1 to receive mFOLFOXIRI plus bevacizumab (experimental group) or mFOLFOXIRI alone (control group). The rate of patients attaining no evidence of disease (NED) was the primary endpoint. The secondary endpoints included objective response rate (ORR), depth of tumor response (DpR), secondary resection rate, progression-free survival (PFS), overall survival (OS), and safety. Results: The rate of NED achieved was 40.7% and 30.8%, respectively, in the experimental (n=54) and control groups (n=26); the adjusted odds ratio was 4.519 [95% confidence interval (CI): 1.247-16.375, P=0.022]. The ORR was 77.4% in the experimental group and 60.0% in the control group (P=0.112). The median DpR was significantly greater in the experimental group (45.6% vs. 34.9%, P=0.041). The median PFS was 12.6 months in the experimental group and 9.1 months in the control group [adjusted hazard ratio (HR): 0.584, 95% CI: 0.304-1.121, P=0.106]. Median OS was prolonged in the experimental group compared with the control group (42.6 vs. 35.3 months, adjusted HR: 0.443, 95% CI: 0.195-1.006, P=0.052). Thirty patients (55.6%) in the experimental group and 16 (61.5%) in the control group experienced grade 3/4 adverse events. Conclusions: We observed that the combination of mFOLFOXIRI and bevacizumab increased the rate of clinical NED and showed a trend toward improved survival compared with mFOLFOXIRI alone. This could represent a conversion therapy option for fit patients with initially unresectable RAS/BRAF/PIK3CA mutant CRLMs.

Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial.

BACKGROUND: PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. METHODS: The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS: Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8-17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. INTERPRETATION: Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. FUNDING: The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.