Local excision for middle-low rectal cancer after neoadjuvant chemoradiation:A retrospective study from a single tertiary center

BACKGROUND Rectal cancer has become one of the leading malignancies threatening people’s health.For locally advanced rectal cancer(LARC),the comprehensive strategy combining neoadjuvant chemoradiotherapy(NCRT),total mesorectal excision(TME),and adjuvant chemotherapy has emerged as a standard treatment regimen,leading to favorable local control and long-term survival.However,in recent years,an increasing attention has been paid on the exploration of organ preservation strategies,aiming to enhance quality of life while maintaining optimal oncological treatment outcomes.Local excision(LE),compared with low anterior resection(LAR)or abdominal-perineal resection(APR)was introduced dating back to 1970’s.LE has historically been linked to a heightened risk of recurrence compared to TME,potentially due to occult lymph node metastasis and intraluminal recurrence.Recent evidence has demonstrated that LE might be an alternative approach,instead of LAR or APR,in cases with favorable tumor regression after NCRT with potentially better quality of life.Therefore,a retrospective analysis of clinicopathological data from mid-low LARC patients who underwent LE after NCRT was conducted,aiming to evaluate the treatment's efficacy,safety,and oncologic prognosis.AIM To explore the safety,efficacy,and long-term prognosis of LE in patients with mid-low rectal cancer who had a good response to NCRT.METHODS Patients with LE between 2012 to 2021 were retrospectively collected from the rectal cancer database from Gastro-intestinal Ward III in Peking University Cancer Hospital.The clinicopathological features,postoperative complications,and long-term prognosis of these patients were analyzed.The Kaplan-Meier method was used to create cancer-specific survival curve,and the log-rank test was used to compare the differences regarding outcomes.RESULTS A total of 33 patients were included in this study.The median interval between NCRT and surgery was 25.4(range:8.7-164.4)weeks.The median operation time was 57(20.0-137.0)minutes.The initial clinical T staging(cT):9(27.3%)patients were cT2,19(57.6%)patients were cT3,and 5(15.2%)patients were cT4;The initial N staging(cN):8 patients(24.2%)were cN negative,25 patients(75.8%)were cN positive;The initial M stage(cM):2 patients(6.1%)had distant metastasis(ycM1),31(93.9%)patients had no distant metastasis(cM0).The pathological results:18(54.5%)patients were pathological T0 stage(ypT0),6(18.2%)patients were ypT1,7(21.2%)patients were ypT2,and 2(6.1%)patients were ypT3.For 9 cT2 patients,5(5/9,55.6%)had a postoperative pathological result of ypT0.For 19 cT3 patients,11(57.9%)patients were ypT0,and 2(40%)were ypT0 in 5 cT4 patients.The most common complication was chronic perineal pain(71.4%,5/7),followed by bleeding(43%,3/7),stenosis(14.3%,1/7),and fecal incontinence(14.3%,1/7).The median follow-up time was 42.0(4.0-93.5)months.For 31 patients with cM0,the 5-year disease-free survival(DFS)rate,5-year local recurrence-free survival(LRFS)rate,and 5-year overall survival(OS)rate were 88.4%,96.7%,and 92.9%,respectively.There were significant differences between the ycT groups concerning either DFS(P=0.042)or OS(P=0.002)in the Kaplan-Meier analysis.The LRFS curve of ycT≤T1 patients was better than that of ycT≥T2 patients,and the P value was very close to 0.05(P=0.070).The DFS curve of patients with ypT≤T1 was better than that of patients with ypT≥T2,but the P value was not statistically significant(P=0.560).There was a significant difference between the ypT groups concerning OS(P=0.014)in the Kaplan-Meier analysis.The LRFS curve of ypT≤T1 patients was better than that of ypT≥T2 patients,and the P value was very close to 0.05(P=0.070).Two patients with initial cM1 were alive at the last follow-up.CONCLUSION LE for rectal cancer with significant tumor regression after NCRT can obtain better safety,efficiency,and oncological outcome.Minimally invasive or nonsurgical treatment with patient participation in decision-making can be performed for highly selected patients.Further investigation from multiple centers will bring better understanding of potential advantages regarding local resection.

Remote ischemic perconditioning prevents liver transplantation-induced ischemia/reperfusion injury in rats: Role of ROS/RNS and e NOS

AIM To investigate the underlying mechanisms of the protective role of remote ischemic perconditioning (RIPerC) in rat liver transplantation. METHODS Sprague-Dawley rats were subjected to sham, orthotopic liver transplantation (OLT), ischemic postconditioning (IPostC) or RIPerC. After 3 h reperfusion, blood samples were taken for measurement of alanine aminotransferase, aspartate aminotransferase, creatinine (Cr) and creatinine kinase-myocardial band (CK-MB). The liver lobes were harvested for the following measurements: reactive oxygen species (ROS), H2O2, mitochondrial membrane potential (Delta psi m) and total nitric oxide (NO). These measurements were determined using an ROS/H2O2, JC1 and Total NOx Assay Kit, respectively. Endothelial NO synthase (eNOS) was analyzed by reverse transcription-polymerase chain reaction (RTPCR) and western blotting, and peroxynitrite was semiquantified by western blotting of 3-nitrotyrosine. RESULTS Compared with the OLT group, the grafts subjected to RIPerC showed significantly improved liver and remote organ functions (P < 0.05). ROS (P < 0.001) including H2O2 (P < 0.05) were largely elevated in the OLT group as compared with the sham group, and RIPerC (P < 0.05) reversed this trend. The collapse of Delta psi m induced by OLT ischemia/reperfusion (I/R) injury was significantly attenuated in the RIPerC group (P < 0.001). A marked increase of NO content and phosphoserine eNOS, both in protein and mRNA levels, was observed in liver graft of the RIPerC group as compared with the OLT group (P < 0.05). I/R-induced 3-nitrotyrosine content was significantly reduced in the RIPerC group as compared with the OLT group (P < 0.05). There were no significant differences between the RIPerC and IPostC groups for all the results except Cr. The Cr level was lower in the RIPerC group than in the IPostC group (P < 0.01). CONCLUSION Liver graft protection by RIPerC is similar to or better than that of IPostC, and involves inhibition of oxidative stress and up-regulation of the PI3K/Akt/eNOS/NO pathway.

Tumor regression grades:Potential outcome predictor of locally advanced rectal adenocarcinoma after preoperative radiotherapy

AIM:To analyze tumor regression grade(TRG)for prognosis of locally advanced rectal adenocarcinoma(LARA)treated with preoperative radiotherapy.METHODS:One hundred and ninety patients with clinical stageⅡ/ⅢLARA were studied.All patients underwent radical surgery(between 2004 and 2010)after 30-Gy/10-fraction preoperative radiotherapy(preRT).All 190 patients received a short course of preRT and were reassessed for disease recurrence and survival;the slides of surgical specimens were reviewed and classified according to Mandard TRG.We compared patients with good response(Mandard TRG1 or TRG2)vs patients with bad/poor response(Mandard TRG3-5).Outcomes evaluated were 5-year overall survival(OS),5-year disease-free survival(DFS),and local,distant and mixed recurrence.Fisher’s exact test orχ2 test,logrank test and proportional hazards regression analysis were used to calculate the probability that Mandard TRG was associated with patient outcomes.RESULTS:One hundred and sixty-six of 190 patients(87.4%)were identified as Mandard bad responders(TRG3-5).High Mandard grade was correlated with tumor height(41.7%<6 cm vs 58.3%≥6 cm,P=0.050),yp T stage(75%yp T0-2 vs 25%yp T3-4,P=0.000),and yp N stage(75%yp N0 vs 25%yp N1,P=0.031).In univariate survival analysis,Mandard grade bad responders had significantly worse OS and DFSthan good responders(TRG1/2)(OS,83.1%vs 96.4%,P=0.000;DFS,72.3%vs 92.0%,P=0.002).In multivariate survival analysis,Mandard bad responders had significantly worse DFS than Mandard good responders(DFS 3.8 years(95%CI:1.2-12.2 years,P=0.026).CONCLUSION:Mandard grade good responders had a favorable prognosis.TRG may be a potential predictor for DFS in LARA after pre-RT.

Phosphatidylinositol 3-kinase CB association with preoperative radiotherapy response in rectal adenocarcinoma

AIM: To examine the correlation of phosphatidylinositol 3-kinase (PIK3) CB expression with preoperative radiotherapy response in patients with stage II/III rectal adenocarcinoma.

High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis

AIM To develop predictive markers in blood for colorectal cancer liver metastasis.METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was ⅢC(T3-4N2M0), while another 10 patients with synchronous liver metastasis(TNM stage Ⅳ) were recruited for group B. During the surgical procedure, a 10-ml drainage vein(DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-ml peripheral vein(PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.RESULTS Univariate analysis revealed that platelet-derivedgrowth factor AA(PDGFAA) in DV blood(d PDGFAA)(P = 0.001), PDGFAA in PV blood(p PDGFAA)(P = 0.007), and human epidermal growth factor receptor-2 in PV blood(p HER2)(P = 0.001), p MMP7(P = 0.028), pR ANTES(P = 0.013), and pE GF(P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified d PDGFAA(HR = 1.001, P = 0.033) and p HER2(HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance(P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA(r = 0.794, P < 0.001), but not for HER2(r = 0.189, P = 0.424).CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.

Surgical intervention for malignant bowel obstruction caused by gastrointestinal malignancies

BACKGROUND Malignant bowel obstruction(MBO)is a common event for end-stage gastrointestinal cancer patients.Previous studies had demonstrated manifestations and clinical management of MBO with mixed malignancies.There still lack reports of the surgical treatment of MBO.AIM To analyze the short-term outcomes and prognosis of palliative surgery for MBO caused by gastrointestinal cancer.METHODS A retrospective chart review of 61 patients received palliative surgery between January 2016 to October 2018 was performed,of which 31 patients underwent massive debulking surgery(MDS)and 30 underwent ostomy/by-pass surgery(OBS).The 60-d symptom palliation rate,30-d morbidity and mortality,and overall survival rates were compared between the two groups.RESULTS The overall symptom palliation rate was 75.4%(46/61);patients in the MDS group had significantly higher symptom palliation rate than OBS group(90%vs 61.2%,P=0.016).Patients with colorectal cancer who were in the MDS group showed significantly higher symptom improvement rates compared to the OBS group(overall,76.4%;MDS,61.5%;OBS,92%;P=0.019).However,patients with gastric cancer did not show a significant difference in symptom palliation rate between the MDS and OBS groups(OBS,60%;MDS,80%;P=1.0).The median survival time in the MDS group was significantly longer than in the OBS group(10.9 mo vs 5.3 mo,P=0.05).CONCLUSION For patients with MBO caused by peritoneal metastatic colorectal cancer,MDS can improve symptom palliation rates and prolong survival,without increasing mortality and morbidity rates.

Trans-anal minimally invasive surgery for rectal neoplasia:Experience from single tertiary institution in China

AIM To evaluate the feasibility and safety of trans-anal minimally invasive surgery(TAMIS) from single institute in China. METHODS A retrospective review was conducted for patients with rectal neoplasia, who underwent TAMIS using single incision laparoscopic surgery-Port from January 2013 till January 2016 by a group of colorectal surgeons from Gastrointestinal Center Unit Ⅲ, Peking University Cancer Hospital. Patients' demographic data, surgical related information, post-operational pathology, as well as perioperative follow-up were all collected. RESULTS Twenty-five patients with rectal neoplasia were identified consequently. Complete full-thickness excision was achieved in all cases without conversion. 22(88%) cases had rectal malignancies [6 were adenocarcinomas and 16 were neuroendocrine tumors(NET)], while 3 patients had adenomas. Mean surgical duration was 61.3 min, and mean post-operative stay were 2.7 d. Post-operational examination demonstrated 5 cases had positive resection margin: 2 adenocarcinoma cases and 1 NET case with positive lateral margin, and the other 2 NET cases with positive basal margin. The curve of operation time for TAMIS cases suggested a minimum of 10 cases for a laparoscopic surgeon proficient withthis technique. CONCLUSION TAMIS was demonstrated to be reproducible and safe,with a relatively short learning process for laparoscopic surgeons in selected cases for rectal neoplasia. Longterm oncological outcome needs to be determined by further investigation.

Abelson interactor 1 splice isoform-L plays an anti-oncogenic role in colorectal carcinoma through interactions with WAVE2 and fulllength Abelson interactor 1

BACKGROUND Expression of the full-length isoform of Abelson interactor 1(ABI1),ABI1-p65,is increased in colorectal carcinoma(CRC)and is thought to be involved in one or more steps leading to tumor progression or metastasis.The ABI1 splice isoform-L(ABI1-SiL)has conserved WAVE2-binding and SH3 domains,lacks the homeodomain homologous region,and is missing the majority of PxxP-and Pro-rich domains found in full-length ABI1-p65.Thus,ABI1-SiL domain structure suggests that the protein may regulate CRC cell morphology,adhesion,migration,and metastasis via interactions with the WAVE2 complex pathway.AIM To investigate the potential role and underlying mechanisms associated with ABI1-SiL-mediated regulation of CRC.METHODS ABI1-SiL mRNA expression in CC tissue and cell lines was measured using both qualitative reverse transcriptase-polymerase chain reaction(RT-PCR)and realtime quantitative RT-PCR.A stably ABI1-SiL overexpressing SW480 cell model was constructed using Lipofectamine 2000,and cells selected with G418.Image J software,CCK8,and transwell assays were used to investigate SW480 cell surface area,proliferation,migration,and invasion.Immunoprecipitation,Western blot,and co-localization assays were performed to explore intermolecular interactions between ABI1-SiL,WAVE2,and ABI1-p65 proteins.RESULTS ABI1-SiL was expressed in normal colon tissue and was significantly decreased in CRC cell lines and tissues.Overexpression of ABI1-SiL in SW480 cells significantly increased the cell surface area and inhibited the adhesive and migration properties of the cells,but did not alter their invasive capacity.Similar to ABI1-p65,ABI1-SiL still binds WAVE2,and the ABI1-p65 isoform in SW480 cells.Furthermore,co-localization assays confirmed these intermolecular interactions.CONCLUSION These results support a model in which ABI1-SiL plays an anti-oncogenic role by competitively binding to WAVE2 and directly interacting with phosphorylated and non-phosphorylated ABI1-p65,functioning as a dominant-negative form of ABI1-p65.

Abdominoperineal excision following preoperative radiotherapy for rectal cancer: Unfavorable prognosis even with negative circumferential resection margin

AIM: To evaluate whether an abdominoperineal excision (APE) is associated with increased local recurrence (LR) and shortened disease-free survival (DFS) in mid-low rectal cancer with a negative circumferential resection margin (CRM).

Long-term follow-up of HER2 overexpression in patients with rectal cancer after preoperative radiotherapy:A prospective cohort study

BACKGROUND The role of HER2 overexpression in rectal cancer is controversial.AIM To assess the role of HER2 overexpression in the long-term prognosis of rectal cancer.METHODS Data from patients with locally advanced rectal cancer who underwent total mesorectal excision after short-course radiotherapy at Beijing Cancer Hospital between May 2002 and October 2005 were collected.A total of 151 tissue samples of rectal cancer were obtained using rigid proctoscopy before neoadjuvant radiotherapy,followed by immunohistochemistry and fluorescence in situ hybridisation to determine the patients’HER2 expression status.Univariate and multivariate analyses of the associations between the clinicopathological factors and HER2 status were performed.Survival was estimated and compared using the Kaplan-Meier method based on HER2 expression status,and the differences between groups were verified using the log-rank test.RESULTS A total of 151 patients were enrolled in this study.A total of 27(17.9%)patients were ultimately confirmed to be HER2-positive.The follow-up duration ranged from 9 mo to 210 mo,with a median of 134 mo.Distant metastasis and local recurrence occurred in 60(39.7%)and 24(15.9%)patients,respectively.HER2 positivity was significantly associated with the pre-treatment lymph node stage(pre-N)(P=0.040),while there were no differences between HER2 status and age,sex,preoperative CEA levels(pre-CEA),T stage,and lympho-vascular invasion.In terms of prognosis,HER2 overexpression was correlated with distant meta stasis(P=0.002)rather than local recurrence(P>0.05).The multivariate analysis demonstrated that elevated pre-CEA[P=0.002,odds ratio(OR)=3.277,97.5%confidence interval(CI):1.543-7.163],post N(+)(P=0.022,OR=2.437,97.5%CI:1.143-5.308)and HER2(+)(P=0.003,OR=4.222,97.5%CI:1.667-11.409)were risk factors for distant metastasis.The survival analysis showed that there were significant differences between rectal cancer patients in terms of disease-free survival(DFS)[hazard ratio:1.69(95%CI:0.91-3.14);P=0.048]and overall survival(OS)[1.95(1.05-3.63);P=0.0077].CONCLUSION HER2 overexpression is a potential biomarker for predicting lymph node metastasis and distant metastasis,which are associated with worse long-term DFS and OS in rectal cancer patients with locally advanced disease.

Exosome-derived galectin-9 may be a novel predictor of rejection and prognosis after liver transplantation

Acute cellular rejection(ACR) remains a major concern after liver transplantation.Predicting and monitoring acute rejection by non-invasive methods are very important for guiding the use of immunosuppressive drugs.Many studies have shown that exosomes and their contents are potential biomarkers for various liver diseases.Here,we identify and validate the role of exosomes and galectin-9 in ACR after liver transplantation.Exosomes were isolated from three sets of paired patients,with and without ACR,and the proteins within the exosomes were isolated and identified.Candidate proteins were then validated using a tissue microarray containing resected liver samples from 73 ACR and 63 non-rejection patients.Finally,protein expression and clinical manifestations were included in KaplanMeier survival and Cox regression analyses.Circulating exosomes were isolated from ACR and non-rejection patients and characterized using transmission electron microscopy and western blotting for CD63/CD81.Western blotting experiments revealed higher levels of galectin-9 protein in circulating exosomes from ACR recipients.Immunohistochemical analysis of the tissue microarray showed that the expression of galectin-9 in resected liver was significantly higher in the ACR group than in the non-rejection group(P<0.05).Higher levels of galectin-9 expression in resected livers were associated with poorer prognosis(P<0.05).Exosome-derived galectin-9 may be a novel predictor of rejection and prognosis after liver transplantation.

Total neoadjuvant treatment for MRI-stratified high-risk rectal cancer:a single-center,single-arm,prospective Phase II trial(PKUCH-R02)

Background:Induction chemotherapy combined with neoadjuvant chemoradiotherapy has been recommended for patients with high-risk,locally advanced rectal cancer.However,the benefit of more intensive total neoadjuvant treatment(TNT)is unknown.This study aimed to assess the safety and efficacy of induction chemotherapy combined with chemoradiotherapy and consolidation chemotherapy for magnetic resonance imaging-stratified high-risk rectal cancer.Methods:This was a single-center,single-arm,prospective Phase II trial in Peking University Cancer Hospital(Beijing,China).Patients received three cycles of induction oxaliplatin and capecitabine(CapeOX)followed by chemoradiotherapy and two cycles of consolidation CapeOX.The primary end point was adverse event rate and the second primary end points were 3-year disease-free survival rate,completion of TNT,and pathological downstaging rate.Results:Between August 2017 and August 2018,68 rectal cancer patients with at least one high risk factor(cT3c/3d/T4a/T4b,cN2,mesorectal fascia involvement,or extramural venous invasion involvement)were enrolled.The overall compliance of receiving the entire treatment was 88.2%(60/68).All 68 patients received induction chemotherapy,65 received chemoradiotherapy,and 61 received consolidation chemotherapy.The Grade 3–4 adverse event rate was 30.8%(21/68).Nine patients achieved clinical complete response and then watch and wait.Five patients(7.4%)developed distant metastasis during TNT and received palliative chemotherapy.Fifty patients underwent surgical resection.The complete response rate was 27.9%.After a median follow-up of 49.2 months,the overall 3-year disease-free survival rate was 69.7%.Conclusions:For patients with high-risk rectal cancer,this TNT regimen can achieve favorable survival and complete response rates but with high toxicity.However,it is necessary to pay attention to the possibility of distant metastasis during the long treatment period.