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.

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.

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.

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.

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.

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.

Risk Prediction and Treatment of LE-DVT in Patients with Chronic Radiation Intestinal Injury: A Retrospective Case-Control Study.

BACKGROUND: Chronic radiation intestinal injury (CRII) is the most common complication after pelvic malignancy radiation. Once hemorrhagic CRII patients suffer from lower extremity deep venous thrombosis (LE-DVT), hemostasis and anticoagulation therapy will be adopted simultaneously, but the treatment strategy is a paradox, as the condition is extremely intractable and serious. The aim of this study was to investigate the prevalence of and risk factors for LE-DVT in CRII patients and explore the treatment of hemorrhagic CRII patients with LE-DVT. METHODS: This was a retrospective study, and a total of 608 hospitalized CRII patients after pelvic radiotherapy were included from November 2011 to October 2018. Univariate and multivariate analyses were conducted to investigate the potential risk factors for LE-DVT in CRII patients. Furthermore, the treatment of hemorrhagic CRII patients with LE-DVT was explored. RESULTS: Among the CRII patients, 94 (15.5%) were with suspicious symptoms of LE-DVT in the lower limbs, and 32 (5.3%) were diagnosed with LE-DVT. Among the patients with LE-DVT, 65.6% (21/32) had bleeding simultaneously, and 29 (90.6%) had anemia with 24 (75.0%) having moderate to severe anemia. Multivariate analysis showed that a recent surgical history (≤6 months) (OR = 5.761, 95% CI: 2.506~13.246, p < 0.001), tumor recurrence or metastasis (OR = 3.049, 95% CI: 1.398~6.648, p = 0.005) and the hemoglobin (Hb) level (OR = 0.960, 95% CI: 0.942~0.979, p < 0.001) were significantly associated with the development of LE-DVT. ROC curve analysis showed that the AUC of the merged risk score of the independent risk factors was 0.822 (95% CI: 0.789~0.852), and the optimal Hb cutoff was 82.5 g/L. After colostomy, obvious bleeding remission was rapidly found in 84.6% of hemorrhagic CRII patients with LE-DVT. CONCLUSION: The prevalence of LE-DVT in hospitalized CRII patients was 5.3%. A recent surgical history, tumor recurrence or metastasis and a lower Hb level were independently associated with LE-DVT development in CRII patients. Colostomy could be a good choice for intractable hemorrhagic CRII patients with LE-DVT.

Pathologic-Based Nomograms for Predicting Overall Survival and Disease-Free Survival Among Patients with Locally Advanced Rectal Cancer.

PURPOSE: Preoperative neoadjuvant therapy is standard before surgery for locally advanced rectal cancer in current clinical treatment. However, patients with the same clinical TNM stage before treatment vary in clinical outcomes. More and more studies noted that pathological findings after preoperative neoadjuvant therapy are better prognostic factors to determine prognosis than clinical TNM stage in patients with locally advanced rectal cancer. The purpose of this study is to develop and validate models based on pathological findings to predict overall survival (OS) and disease-free survival (DFS). PATIENTS AND METHODS: A total of 3026 patients from two hospitals were included. The endpoint was OS and DFS. Significant predictors of OS on multivariate analysis were used to establish the nomogram. RESULTS: The Harrell's C index for OS prediction was 0.72 (95% confidence interval [CI], 0.68 to 0.77) in the training cohort, 0.66 (95% CI, 0.60 to 0.72) and 0.68 (95% CI, 0.64 to 0.73) in the internal and external validation cohorts. Using this nomogram, high- and low-risk groups for OS were defined in the training cohort. The 3-year OS was 78.1% (95% CI: 72.4-84.2%) for the high-risk group and 95% (95% CI: 93.6-96.5%) in the low-risk group (HR: 4.42, 95% CI: 3.22-6.05; P<0.001). This finding was also applied in the two external cohorts. Similarly, a nomogram that contained the same indices was developed and validated to predict for DFS. CONCLUSION: Nomograms based on pathological findings are a reliable tool to predict 3-year OS and DFS rate in patients with locally advanced rectal cancer.

Platelet-derived growth factor C signaling is a potential therapeutic target for radiation proctopathy.

Radiation proctopathy (RP) is characterized by inflammation of colorectal tissue and is a common complication of radiation therapy for pelvic malignancies with high incidence but lacking effective treatment. Here, we found that platelet-derived growth factor C (PDGF-C) and fibrosis markers were up-regulated in tissue samples from patients with RP and in rectal tissues after irradiation in a mouse model of RP. Genetic deletion of Pdgf-c in mice ameliorated RP-induced injuries. Genome-wide gene expression profiling and in vitro assays revealed that the promotive effect of PDGF-C in RP development was mediated by activation of PDGF receptors (PDGFRs) and C-X-C motif chemokine receptor 4, a proinflammatory chemokine regulated by transcription factor ETS variant transcription factor 1. Treatment with crenolanib, a selective inhibitor of PDGFRs, prevented or reduced RP in mice after irradiation. These results reveal that inhibition of PDGF-C signaling may have therapeutic value for the treatment of RP.

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.

KRAS and PIK3CA bi-mutations predict a poor prognosis in colorectal cancer patients: A single-site report.

STUDY RATIONALE: The coexistence of KRAS and PIK3CA mutations in cells implies potential synergistic hyperactivation of the Ras/MAPK and PI3K/Akt oncogenic pathways. Therefore, it is desirable to investigate the concomitant mutations of KRAS and PIK3CA in colorectal cancer (CRC) samples and whether the concomitant mutations are associated with a poor prognosis in CRC patients. AIM: To investigate the clinicpathological characteristics and prognostic value of concomitant mutations of KRAS and PIK3CA in CRC samples. METHODS: In this study, a total of 655 CRC patients from the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled from January to December 2015. Sanger sequencing was applied to survey the mutational status of hotspot regions in the open reading frames (ORFs) of the KRAS and PIK3CA genes. Clinicpathological parameters were collected and analyzed. The Kaplan-Meier method and Cox regression model were applied to determine the correlation between the KRAS and PIK3CA mutation statuses and survival. RESULTS: We found that KRAS and PIK3CA bi-mutations were significantly associated with aggressive clinicpathological features. Among the studied CRC patients, those with either KRAS mutations (P = 0.004) or KRAS and PIK3CA bi-mutations (P = 0.033) had poor overall survival (OS). In the multivariable analysis, KRAS mutations in exons 3 and 4 but not exon 2 with concomitant PIK3CA mutations were associated with a high risk of death (univariate HR = 8.05; 95% CI, 1.926-33.64, P = 0.004; multivariate HR = 10.505; 95% CI, 2.304-47.905, P = 0.002). CONCLUSION: The concomitant mutation statuses of KRAS and PIK3CA should be considered when the prognostic value of gene mutations is consulted in CRC patients.

Quantitative CT measurement of left colonic and pelvic mesenteric adipose volume in radiation proctitis.

BACKGROUND: The edema of left colonic and pelvic mesenteric adipose tissues has long been recognized in surgery as a characteristic feature of radiation proctitis (RP). However, the correlation between mesenteric adipose volume and RP has not been extensively clarified. The purpose of this study was thus to assess the variation of left colonic and pelvic mesenteric adipose volume in RP. METHODS: From March 2013 to June 2015, the data of 52 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy, including 23 patients with RP and 29 with non-RP (nRP), were retrieved. The mesenteric adipose volume was quantified via a computed tomography (CT) reconstruction method. Corresponding analyses were conducted to observe the correlation between the relative change of mesenteric adipose volume and the thickening degree of the rectal wall. RESULTS: The baseline data of the RP group and the nRP group were comparable. There was no significant difference in the relative change of the left colonic mesenteric adipose volume in each vertebral space from the third lumbar vertebra to the first sacral vertebra before and after radiotherapy. The relative change of pelvic mesenteric adipose volume (ΔVp%) was notably higher in the RP group compared to the nRP group. With a ΔVp% cutoff value of 3.67%, the sensitivity and specificity for the diagnosis of RP were 65.2% and 86.2%, respectively. According to the correlation analysis, ΔVp% in the RP group was significantly correlated with the thickening degree of the rectal wall after radiotherapy (r=0.47, P=0.024). CONCLUSIONS: The increment of the relative change of pelvic mesenteric adipose volume quantitatively measured by CT can be clinically useful in identifying RP.

To what extent should the intestinal be resected proximally after radiotherapy: hint from a pathological view.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is associated with post-operative anastomotic complications in rectal-cancer patients. Anastomosis involving at least one non-irradiated margin reportedly significantly reduces the risk of post-operative anastomotic complications in radiation enteritis. However, the exact scope of radiotherapy on the remaining sigmoid colon remains unknown. METHODS: We evaluated the radiation damage of proximally resected colorectal segments in 44 patients with rectal cancer, who received nCRT followed by conventional resection (nCRT-C, n = 21) or proximally extended resection (nCRT-E, n = 23). The segments from another 13 patients undergoing neoadjuvant chemotherapy (nCT) were used as control. We dissected these samples at a distance of 2 cm between the two adjacent sections. Radiation damage in proximally resected colorectal segments was evaluated using the radiation injury score (RIS) and the concentration and distribution patterns of angiostatin. RESULTS: Compared to those in the nCT group, the nCRT group showed higher RIS, levels of angiostatin, and proportion of diffuse pattern of angiostatin. With increasing distance from the tumor site, these parameters all gradually decreased; and the differences came to be not significant at the site that is over 20 cm from the tumor. The nCRT-E group showed lower RIS (median: 2 vs 4, P = 0.002) and a greater proportion of non-diffuse angiostatin (87% vs 55%, P = 0.039) at the proximal margins compared with the nCRT-C group. CONCLUSIONS: The severity of the radiation damage of the proximal colon is inversely proportional to the proximal-resection margin length. Little damage was left on the proximal margin that was over 20 cm from the tumor. Removal of an initial length of ≥20 cm from the tumor may be beneficial for rectal-cancer patients after nCRT.

Diverting colostomy is an effective and reversible option for severe hemorrhagic radiation proctopathy.

BACKGROUND: Severe chronic radiation proctopathy (CRP) is difficult to treat. AIM: To evaluate the efficacy of colostomy and stoma reversal for CRP. METHODS: To assess the efficacy of colostomy in CRP, patients with severe hemorrhagic CRP who underwent colostomy or conservative treatment were enrolled. Patients with tumor recurrence, rectal-vaginal fistula or other types of rectal fistulas, or who were lost to follow-up were excluded. Rectal bleeding, hemoglobin (Hb), endoscopic features, endo-ultrasound, rectal manometry, and magnetic resonance imaging findings were recorded. Quality of life before stoma and after closure reversal was scored with questionnaires. Anorectal functions were assessed using the CRP symptom scale, which contains the following items: Watery stool, urgency, perianal pain, tenesmus, rectal bleeding, and fecal/gas incontinence. RESULTS: A total of 738 continual CRP patients were screened. After exclusion, 14 patients in the colostomy group and 25 in the conservative group were included in the final analysis. Preoperative Hb was only 63 g/L ± 17.8 g/L in the colostomy group compared to 88.2 g/L ± 19.3 g/L (P < 0.001) in the conservative group. All 14 patients in the former group achieved complete remission of bleeding, and the colostomy was successfully reversed in 13 of 14 (93%), excepting one very old patient. The median duration of stoma was 16 (range: 9-53) mo. The Hb level increased gradually from 75 g/L at 3 mo, 99 g/L at 6 mo, and 107 g/L at 9 mo to 111 g/L at 1 year and 117 g/L at 2 years after the stoma, but no bleeding cessation or significant increase in Hb levels was observed in the conservative group. Endoscopic telangiectasia and bleeding were greatly improved. Endo-ultrasound showed decreased vascularity, and magnetic resonance imaging revealed an increasing presarcal space and thickened rectal wall. Anorectal functions and quality of life were significantly improved after stoma reversal, when compared to those before stoma creation. CONCLUSION: Diverting colostomy is a very effective method in the remission of refractory hemorrhagic CRP. Stoma can be reversed, and anorectal functions can be recovered after reversal.