Effectiveness of pudendal nerve block in the management of acute post-haemorrhoidectomy pain in Asian individuals using inverse probability of treatment weighting (IPTW).

BACKGROUND: Inadequate management of acute post-haemorrhoidectomy pain is a major concern. Optimal pain management is necessary to reduce acute postoperative pain and improve care quality. Therefore, we investigated the efficacy of postoperative pudendal nerve block (PNB) in reducing acute post-haemorrhoidectomy pain in Asian individuals. METHODS: This retrospective cohort study analysed 108 adult patients with grade 3 haemorrhoids. Patients with anorectal cancer were excluded from this study. Among the 108 patients, 79 and 29 received spinal anaesthesia (SA) with PNB (SAPNB) and SA alone, respectively. Propensity score matching and inverse probability of treatment weighting were performed to adjust for the effects of confounders. RESULTS: Patients receiving SAPNB had significantly lower postoperative pain scores 6, 12, and 18 h after haemorrhoidectomy but significantly higher postoperative pain scores 24 and 48 h after haemorrhoidectomy than did patients receiving SA alone. PNB, older age, female sex, reduced operation time, and absence of cardiovascular disease reduced the risk of moderate to severe postoperative pain. Only the addition of PNB was consistently associated with a reduced risk of moderate to severe pain 6, 12, and 18 h after haemorrhoidectomy. Patients receiving SAPNB had significantly lower risks of perianal swelling and urinary retention but a significantly higher risk of nausea than did those receiving SA alone. The two groups exhibited similarity in their rates of postoperative readmission because of poor pain management and their lengths of stay upon readmission. CONCLUSION: The addition of PNB to SA may effectively reduce acute post-haemorrhoidectomy pain.

Modified enhanced recovery after surgery protocol in octogenarians undergoing minimally invasive colorectal cancer surgery.

BACKGROUND: Colorectal cancer (CRC) is a major health issue worldwide. As the population ages, more older patients including octogenarians will require CRC treatment. However, this vulnerable group has decreased functional reserves and increased surgical risks. Enhanced recovery after surgery (ERAS) pathways aim to reduce surgical stress and complications, but concerns remain about applying ERAS protocols to older patients. We assessed whether a modified ERAS (mERAS) protocol combined would improve outcomes in octogenarian CRC patients undergoing minimally invasive surgery. METHODS: In this retrospective cohort study, we compared 360 non-octogenarians aged 50-64 years and 114 octogenarians aged 80-89 years before and after mERAS protocol implementation. Outcomes including postoperative functionary recovery, length of stay, complications, emergency department visits, and readmissions were analyzed. RESULTS: Despite comparable tumor characteristics, octogenarians had poorer nutrition, American Society of Anesthesiologists status, and more comorbidities. After mERAS, octogenarians had reduced complications, faster return of bowel function, and shorter postoperative length of stay, similar to non-octogenarians. mERAS implementation improved recovery in both groups without increasing emergency department visits or readmissions. CONCLUSION: Although less remarkable than in non-octogenarians, mERAS protocols mitigated higher complication rates and improved recovery in octogenarians after minimally invasive surgery for CRC, confirming protocol feasibility and safety in this vulnerable population.

Diode laser hemorrhoidoplasty versus conventional Milligan-Morgan and Ferguson hemorrhoidectomy for symptomatic hemorrhoids: Meta-analysis.

Conventional hemorrhoidectomy is the mainstay of treatment for symptomatic haemorrhoids, but reported postoperative complications remains the main concern. On the contrary, with its minimally invasive nature, laser hemorrhoidoplasty showed the potential to reduce postoperative complications and discomfort. Therefore, we performed a systemic review and meta-analysis to evaluate the postoperative outcome of laser hemorrhoidoplasty compared to conventional hemorrhoidectomies, including Milligan-Morgan and Ferguson techniques. Of all studies from PubMed, EMBASE, Cochrane database, and Google Scholar, we included 17 trials with 1196 patients, of whom 596 (49.8 %) underwent laser hemorrhoidoplasty and 600 (50.2 %) underwent conventional hemorrhoidectomy. The primary outcomes were operative blood loss and postoperative haemorrhage, and the secondary outcomes were the operative time, postoperative pain score, complications, and haemorrhoid recurrence. In this study, we found that laser hemorrhoidoplasty showed benefits in operative blood loss (weighted mean difference [WMD]: -16.43 ml, 95 % confidence interval [CI]: -23.82 to -9.04), postoperative hemorrhage/bleeding (odds ratio [OR]: 0.16, 95 % CI: 0.10 to 0.28), operative time (WMD: -12.42 min, 95 % CI: -14.56 to -10.28), postoperative pain score on day 1 (WMD: -2.50, 95 % CI: -3.13 to -1.88), and anal stenosis (OR: 0.14, 95 % CI: 0.03 to 0.65) in comparison with conventional hemorrhoidectomy. However, incidence of fecal/flatus incontinence, urinary retention and hemorrhoid recurrence were not significantly different between the 2 groups. Consistent results were found in 5 subgroup analyses, including studies with low risk of bias, studies using 1470 nm laser, and studies using 980 nm laser, studies conducted in Asia, and studies conducted in Europe and America.

Preclinical Repurposing of Sitagliptin as a Drug Candidate for Colorectal Cancer by Targeting CD24/CTNNB1/SOX4-Centered Signaling Hub.

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating CD24+ cancer-associated fibroblasts (CAFs), suggesting that the CD24/SOX4-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the CD24/SOX4-centered signaling, ß-catenin, and DPP4. Emerging evidence indicates that DPP4 plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a DPP4 inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted CD24/SOX4-centered signaling molecules with high affinity. In vitro experimental data showed that sitagliptin treatment suppressed CRC tumorigenic properties and worked in synergy with 5FU and this study thus provided preclinical evidence to support the alternative use of sitagliptin for treating CRC.

The role of thrombomodulin in modulating ITGB3 expression and its implications for triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC) compared to other BC subtypes in clinical settings. Currently, there are no effective therapeutic strategies for TNBC treatment. Therefore, there is an urgent need to identify suitable biomarkers or therapeutic targets for TNBC patients. Thrombomodulin (TM) plays a role in cancer progression and metastasis in many different cancers. However, the role of TM in TNBC is not yet fully understood. First, silenced-TM in MDA-MB-231 cells caused an increase in proliferative and metastatic activity. In contrast, overexpression of TM in Hs578T cells caused a reduction in proliferation, invasion, and migration rate. Using RNA-seq analysis, we found that Integrin beta 3 (ITGB3) expression may be a downstream target of TM. Furthermore, we found an increase in ITGB3 levels in TM-KD cells by QPCR and western blot analysis but a decrease in ITGB3 levels in TM-overexpressing cells. We found phospho-smad2/3 levels were increased in TM-KD cells but decreased in TM-overexpressing cells. This implies that TM negatively regulates ITGB3 levels through the activation of the smad2/3 pathway. Silencing ITGB3 in TM-KD cells caused a decrease in proliferation and migration. Finally, we found that higher ITGB3 levels were correlated with poor overall survival and relapse-free survival in patients with TNBC. Our results indicated a novel regulatory relationship between TM and ITGB3 in TNBC.

Development of a social cognitive career theory scale for measuring the intention to select surgery as a career.

Background: Surgeon shortages have emerged as a prominent global issue. Although various studies have explored the factors that influence medical students in choosing surgery as a career, addressing the need for surgeons requires a multifaceted approach. However, there is currently a lack of a theoretically grounded scale to evaluate the effectiveness of surgical career development or policy promotion. Thus, this study aimed to develop a questionnaire for assessing the preference for a surgical career by adopting the Social Cognitive Career Theory (SCCT). Materials and methods: The study aimed to develop the Social Cognitive Career Theory Scale toward Surgery (SCCTSS) by adopting the framework of SCCT. The questionnaire was created through expert consensus and the content validity index (CVI) calculation. Subsequently, a pilot version of the SCCTSS was administered to 222 medical students in their clinical clerkships, and the collected data underwent item analysis. Additionally, the validation of the SCCTSS by gender was performed. Results: The SCCTSS comprised 16 items that passed expert panel evaluation, with a CVI >0.8, mean ≥ 3.00, and an interquartile range ≤1. Item analysis demonstrated that the quality of the SCCTSS met the qualifying threshold. Furthermore, the SCCTSS questionnaire effectively validated gender differences in surgical career preference. Conclusions: We developed an internally consistent and reliable scale and validated it through an expert panel method and feedback from medical students. Further research is required to evaluate the targeted interventions that may assist in recruiting medical students into the field of surgery through the application of the SCCTSS.

CWH43 Is a Novel Tumor Suppressor Gene with Negative Regulation of TTK in Colorectal Cancer.

Colorectal cancer (CRC) ranks among the most prevalent forms of cancer globally, and its late-stage survival outcomes are less than optimal. A more nuanced understanding of the underlying mechanisms behind CRC's development is crucial for enhancing patient survival rates. Existing research suggests that the expression of Cell Wall Biogenesis 43 C-Terminal Homolog (CWH43) is reduced in CRC. However, the specific role that CWH43 plays in cancer progression remains ambiguous. Our research seeks to elucidate the influence of CWH43 on CRC's biological behavior and to shed light on its potential as a therapeutic target in CRC management. Utilizing publicly available databases, we examined the expression levels of CWH43 in CRC tissue samples and their adjacent non-cancerous tissues. Our findings indicated lower levels of both mRNA and protein expressions of CWH43 in cancerous tissues. Moreover, we found that a decrease in CWH43 expression correlates with poorer prognoses for CRC patients. In vitro experiments demonstrated that the suppression of CWH43 led to increased cell proliferation, migration, and invasiveness, while its overexpression had inhibitory effects. Further evidence from xenograft models showed enhanced tumor growth upon CWH43 silencing. Leveraging data from The Cancer Genome Atlas (TCGA), our Gene Set Enrichment Analysis (GSEA) indicated a positive relationship between low CWH43 expression and the activation of the epithelial-mesenchymal Transition (EMT) pathway. We conducted RNA sequencing to analyze gene expression changes under both silenced and overexpressed CWH43 conditions. By identifying core genes and executing KEGG pathway analysis, we discovered that CWH43 appears to have regulatory influence over the TTK-mediated cell cycle. Importantly, inhibition of TTK counteracted the tumor-promoting effects caused by CWH43 downregulation. Our findings propose that the decreased expression of CWH43 amplifies TTK-mediated cell cycle activities, thus encouraging tumor growth. This newly identified mechanism offers promising avenues for targeted CRC treatment strategies.

Identification of Moesin (MSN) as a Potential Therapeutic Target for Colorectal Cancer via the ß-Catenin-RUNX2 Axis.

CRC is the second leading cause of cancer-related death. The complex mechanisms of metastatic CRC limit available therapeutic choice. Thus, identifying new CRC therapeutic targets is essential. Moesin (MSN), a member of the ezrin-radixin-moesin family, connects the cell membrane to the actin-based cytoskeleton and regulates cell morphology. We investigated the role of MSN in the progression of CRC. GENT2 and oncomine were used to study MSN expression and CRC patient outcomes. MSN-specific shRNAs or MSN-overexpressed plasmid were used to establish MSN-KD and MSN overexpressed cell lines, respectively. SRB, migration, wound healing, and flow cytometry were used to test cell survival and migration. Propidium iodide and annexin V stain were used to analyze the cell cycle and apoptosis. MSN expression was found to be higher in CRC tissues than in normal tissues. Higher MSN expression is associated with poor overall survival, disease-free survival, and relapse-free survival rates in CRC patients. MSN silencing inhibits cell proliferation, adhesion, migration, and invasion in vitro, whereas MSN overexpression accelerates cell proliferation, adhesion, migration, and invasion. RNA sequencing was used to investigate differentially expressed genes, and RUNX2 was discovered as a possible downstream target for MSN. In CRC patients, RUNX2 expression was significantly correlated with MSN expression. We also found that MSN silencing decreased cytoplasmic and nuclear ß-catenin levels. Additionally, pharmacological inhibition of ß-catenin in MSN-overexpressed cells led to a reduction of RUNX2, and activating ß-catenin signaling by inhibiting GSK3ß rescued the RUNX2 downregulation in MSN-KD cells. This confirms that MSN regulates RUNX2 expression via activation of ß-catenin signaling. Finally, our result further determined that RUNX2 silencing reduced the ability of MSN overexpression cells to proliferate and migrate. MSN accelerated CRC progression via the ß-catenin-RUNX2 axis. As a result, MSN holds the potential to become a new target for CRC treatment.

2,3,5,4'-Tetrahydroxystilbene (TG1), a Novel Compound Derived from 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), Inhibits Colorectal Cancer Progression by Inducing Ferroptosis, Apoptosis, and Autophagy.

BACKGROUND: Colorectal cancer (CRC) is one of the deadliest cancers worldwide and long-term survival is not guaranteed in metastatic disease despite current multidisciplinary therapies. A new compound 2,3,5,4'-Tetrahydroxystilbene (TG1), derived from THSG (2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-Glucoside), has been developed, and its anticancer ability against CRC is verified in this study. METHODS: HCT116, HT-29, and DLD-1 were treated with TG1 and the IC50 was measured using a sulforhodamine B assay. A Xenograft mouse model was used to monitor tumor growth. Apoptosis and autophagy, induced by TG1 in CRC cells, were examined. RNA-sequencing analysis of CRC cells treated with TG1 was performed to discover underlying pathways and mechanisms. RESULTS: The results demonstrated that treatment with TG1 inhibited CRC proliferation in vitro and in vivo and induced apoptotic cell death, which was confirmed by Annexin V-FITC/PI staining and Western blotting. Additionally, TG1 treatment increased the level of autophagy in cells. RNA-sequencing and GSEA analyses revealed that TG1 was associated with MYC and the induction of ferroptosis. Furthermore, the ferroptosis inhibitor Bardoxolone abrogated the cytotoxic effect of TG1 in CRC cells, indicating that ferroptosis played a crucial role in TG1-induced cytotoxicity. CONCLUSIONS: These findings suggest that TG1 might be a potential and potent compound for clinical use in the treatment of CRC by inhibiting proliferation and inducing ferroptosis through the MYC pathway.

Novel heavily fucosylated glycans as a promising therapeutic target in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is highly prevalent and lethal globally, and its prognosis remains unsatisfactory. Drug resistance is regarded as the main cause of treatment failure leading to tumor recurrence and metastasis. The overexpression of fucosylated epitopes, which are usually modifications of glycoproteins, was reported to occur in various epithelial cancers. However, the effects of treatments that target these antigens in colorectal cancer remain unclear. METHODS: This study investigated the expression of heavily fucosylated glycans (HFGs) in 30 clinical samples from patients with CRC and other normal human tissues. The complement-dependent cytotoxicity was explored in vitro through treatment with anti-HFG monoclonal antibody (mAb) alone or in combination with chemotherapeutic agents. In vivo inhibitory effects were also examined using a xenograft mouse model. RESULTS: Immunohistochemistry staining and western blotting revealed that HFG expression was higher in human colorectal cancer tissues than in normal tissues. In DLD-1 and SW1116 cells, which overexpress fucosylated epitopes, anti-HFG mAb produced observable cytotoxic effects, especially when it was combined with chemotherapeutic agents. The xenograft model also demonstrated that anti-HFG mAb had potent and dose-dependent inhibitory effects on colorectal tumor growth. CONCLUSIONS: As a novel cancer antigen, HFGs are a promising treatment target, and the implementation of anti-HFG mAb treatment for CRC warrants further investigation.

PCTAIRE Protein Kinase 1 (PCTK1) Suppresses Proliferation, Stemness, and Chemoresistance in Colorectal Cancer through the BMPR1B-Smad1/5/8 Signaling Pathway.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality worldwide. Even with advances in therapy, CRC mortality remains high. Therefore, there is an urgent need to develop effective therapeutics for CRC. PCTAIRE protein kinase 1 (PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family, and the function of PCTK1 in CRC is poorly understood. In this study, we found that patients with elevated PCTK1 levels had a better overall survival rate in CRC based on the TCGA dataset. Functional analysis also showed that PCTK1 suppressed cancer stemness and cell proliferation by using PCTK1 knockdown (PCTK1-KD) or knockout (PCTK1-KO) and PCTK1 overexpression (PCTK1-over) CRC cell lines. Furthermore, overexpression of PCTK1 decreased xenograft tumor growth and knockout of PCTK1 significantly increased in vivo tumor growth. Moreover, knockout of PCTK1 was observed to increase the resistance of CRC cells to both irinotecan (CPT-11) alone and in combination with 5-fluorouracil (5-FU). Additionally, the fold change of the anti-apoptotic molecules (Bcl-2 and Bcl-xL) and the proapoptotic molecules (Bax, c-PARP, p53, and c-caspase3) was reflected in the chemoresistance of PCTK1-KO CRC cells. PCTK1 signaling in the regulation of cancer progression and chemoresponse was analyzed using RNA sequencing and gene set enrichment analysis (GSEA). Furthermore, PCTK1 and Bone Morphogenetic Protein Receptor Type 1B (BMPR1B) in CRC tumors were negatively correlated in CRC patients from the Timer2.0 and cBioPortal database. We also found that BMPR1B was negatively correlated with PCTK1 in CRC cells, and BMPR1B expression was upregulated in PCTK1-KO cells and xenograft tumor tissues. Finally, BMPR1B-KD partially reversed cell proliferation, cancer stemness, and chemoresistance in PCTK1-KO cells. Moreover, the nuclear translocation of Smad1/5/8, a downstream molecule of BMPR1B, was increased in PCTK1-KO cells. Pharmacological inhibition of Smad1/5/8 also suppressed the malignant progression of CRC. Taken together, our results indicated that PCTK1 suppresses proliferation and cancer stemness and increases the chemoresponse of CRC through the BMPR1B-Smad1/5/8 signaling pathway.

Cytotoxic properties of unfractionated and fractionated bromelain alone or in combination with chemotherapeutic agents in colorectal cancer cells.

BACKGROUND: Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Long-term survival is not achieved in metastatic CRC despite the current multidisciplinary therapies. Bromelain, a compound extracted from the pineapple plant, has multiple functions and anticancer properties. Previously, bromelain has been chromatographically separated into four fractions. Fraction 3 (F3) exhibits the highest proteolytic activity. The anticancer effects of F3 bromelain in CRC cells is unknown. METHODS: In vitro cytotoxicity was verified through a sulforhodamine B assay. Apoptosis in CRC cells induced by unfractionated or F3 bromelain was examined using Annexin V-FITC/PI staining and Western blot analysis. ROS status, autophagy and lysosome formation were determined by specific detection kit. RESULTS: The cytotoxicity of F3 bromelain in CRC cells was found to be comparable to that of unfractionated bromelain. F3 bromelain induces caspase-dependent apoptosis in CRC cells. Treatment with unfractionated or F3 bromelain increased superoxide and oxidative stress levels and autophagy and lysosome formation. ATG5/12 and beclin-1 were upregulated, and the conversion of LC3B-I to LC3B-II was increased significantly by treatment with F3 bromelain. Treated CQ, autophagy inhibitor, with unfractionated or F3 bromelain enhances the cytotoxic effects. Finally, the combination of unfractionated and F3 bromelain with a routine chemotherapeutic agent (5-fluourouracil, irinotecan, or oxaliplatin) resulted in synergistically higher cytotoxic potency in CRC cells. CONCLUSION: Unfractionated and F3 bromelain inhibits CRC cell proliferation in vitro, and the cytotoxic effects of unfractionated bromelain are equivalent to F3 bromelain. F3 bromelain may be a potential and potent drug for clinical use due to its anticancer efficacy and high synergistic cytotoxicity when combined with a routine chemotherapeutic agent for CRC.

ALDH2 promotes cancer stemness and metastasis in colorectal cancer through activating ß-catenin signaling.

Colorectal cancer (CRC) is the primary cause of death from gastrointestinal cancers. Aldehyde dehydrogenase 2 (ALDH2), a crucial mitochondrial enzyme for the oxidative pathway of alcohol metabolism, plays a dual role in cancer progression. In some cancers, it is tumor suppressive; in others, it drives cancer progression. However, whether targeting ALDH2 has any therapeutic implications or prognostic value in CRC is still unclear. Here, we investigated the role of ALDH2 in CRC progression by targeting its enzymatic activity rather than gene expression. We found that inhibiting ALDH2 by CVT-10216 and daidzein significantly decrease migration and stemness properties of both DLD-1 and HCT 116 cells, whereas activating ALDH2 by Alda-1 enhances migration rate. Concomitantly, ALDH2 inhibition by both CVT-10216 and daidzein downregulates the mRNA levels of fibronectin, snail, twist, MMP7, CD44, c-Myc, SOX2, and OCT-4, which are oncogenic in the advanced stage of CRC. Furthermore, Gene Set Enrichment Analysis (GSEA) on ALDH2 co-expressed genes from The Cancer Genome Atlas (TCGA) revealed that MYC target gene sets are upregulated. We found that ALDH2 inhibition decreased the nuclear protein levels of pGSK3ß serine 9 and c-Myc. This suggests that ALDH2 probably targets ß-catenin signaling in CRC cells. Together, our results demonstrate the prognostic value of ALDH2 in CRC as it regulates both CRC stemness and migration. Our findings also propose that the plant-derived isoflavone daidzein could be a potential chemotherapeutic drug targeting ALDH2 in CRC.

The Role of Thrombomodulin in Estrogen-Receptor-Positive Breast Cancer Progression, Metastasis, and Curcumin Sensitivity.

Estrogen and estrogen receptors (ER) play a key role in breast cancer progression, which can be treated with endocrine therapy. Nevertheless, resistance to endocrine therapies is developed over time. The tumor expression of thrombomodulin (TM) is correlated with favorable prognosis in several types of cancer. However, this correlation has not yet been confirmed in ER-positive (ER+) breast cancer. This study aims to evaluate the role of TM in ER+ breast cancer. Firstly, we found that lower TM expression correlates to poor overall survival (OS) and relapse-free survival (RFS) rates in ER+ breast cancer patients through Kaplan-Meier survival analysis (p < 0.05). Silencing TM in MCF7 cells (TM-KD) increased cell proliferation, migration, and invasion ability. Additionally, TM-KD MCF7 cells showed higher sensitivity (IC50 15 µM) to the anti-cancer agent curcumin than the scrambled control cells. Conversely, overexpression of TM (TM-over) in T47D cells leads to decreased cell proliferation, migration, and invasion ability. Furthermore, TM-over T47D cells showed more resistance (IC50 > 40 µM) to the curcumin treatment. The PI staining, DAPI, and tunnel assay also confirmed that the curcumin-induced apoptosis in TM-KD MCF7 cells was higher (90.34%) than in the scrambled control cells (48.54%). Finally, the expressions of drug-resistant genes (ABCC1, LRP1, MRP5, and MDR1) were determined by qPCR. We found that the relative mRNA expression levels of ABCC1, LRP1, and MDR1 genes after curcumin treatment were higher in scrambled control cells than in TM-KD cells. In conclusion, our results demonstrated that TM plays a suppressive role in the progression and metastasis of ER+ breast cancer, and it regulates curcumin sensitivity by interfering with ABCC1, LRP1, and MDR1 gene expression.

Tn as a potential predictor for regional lymph node metastasis in T1 colorectal cancer.

BACKGROUND: Approximately 10 percent of T1 colorectal cancer (CRC) has lymph node metastasis. In this study, we aimed to determine possible predictors for nodal involvement in order to aid selection of appropriate patients for organ-preserving strategies. METHODS: We retrospectively reviewed CRC patients underwent radical surgery from January 2009 to December 2016, with final pathology report disclosed as T1 lesion. The paraffin-embedded samples were achieved for glycosylated proteins expression analysis by immunohistochemistry. RESULTS: Totally, 111 CRC patients with T1 lesion were enrolled in this study. Of these patients, seventeen patients had nodal metastases, with the lymph node positive rate of 15.3%. Semiquantitative analysis of immunohistochemical results indicated that mean value of Tn protein expression in T1 CRC specimens was significantly different between patients with and without lymph node metastasis (63.6 vs. 27.4; p = 0.018). CONCLUSIONS: Our data shown that Tn expression may be applied as a molecular predictor for regional lymph node metastasis in T1 CRC. Moreover, the organ-preserving strategy could be improved by proper classification of patients. The mechanism involved in expression of Tn glycosylation protein and CRC metastasis need further investigation.

A phase Ib/II trial of PEP503 (NBTXR3, radioenhancer) with radiotherapy and chemotherapy in patients with rectal cancer.

Aims: To investigate the safety profile, dose-limiting toxicity and antitumor activity of PEP503 (NBTXR3) nanoparticles with radiotherapy and concurrent chemotherapy in patients with locally advanced or unresectable rectal cancer. Methods: Patients will receive a single intratumoral injection of the nanoparticles, followed by radiotherapy and intravenous infusion of fluorouracil or oral capecitabine concurrently. In phase Ib (escalation phase, 3 + 3 design), volume escalation is based on the tumor volume of 5, 10, 15 and 22% of total baseline tumor volume. In phase II (expansion phase), 18 additional patients will be enrolled. Discussion: This study will be the first prospective, open-label, single-arm, nonrandomized study to investigate the efficacy and safety profile of PEP503 (NBTXR3) nanoparticles with radiotherapy and chemotherapy in these patients. Trial registration number: NCT02465593 (ClinicalTrials.gov).

Preoperative concurrent chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer. PEP503 (NBTXR3) has radioenhancement properties. Therefore, the dose per fraction during radiotherapy could be reduced, and the same therapeutic efficacy could be retained when PEP503 (NBTXR3) nanoparticles are used during radiotherapy. This study reveals the protocol of a phase Ib/II study to investigate the safety profile, dose-limiting toxicity and antitumor activity of PEP503 (NBTXR3) nanoparticles with radiotherapy combined with concurrent chemotherapy in patients with locally advanced or unresectable rectal cancer.

In silico analysis to identify miR-1271-5p/PLCB4 (phospholipase C Beta 4) axis mediated oxaliplatin resistance in metastatic colorectal cancer.

Oxaliplatin (OXA) is the first-line chemotherapy drug for metastatic colorectal cancer (mCRC), and the emergence of drug resistance is a major clinical challenge. Although there have been numerous studies on OXA resistance, but its underlying molecular mechanisms are still unclear. This study aims to identify key regulatory genes and pathways associated with OXA resistance. The Gene Expression Omnibus (GEO) GSE42387 dataset containing gene expression profiles of parental and OXA-resistant LoVo cells was applied to explore potential targets. GEO2R, STRING, CytoNCA (a plug-in of Cytoscape), and DAVID were used to analyze differentially expressed genes (DEGs), protein-protein interactions (PPIs), hub genes in PPIs, and gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. R2 online platform was used to run a survival analysis of validated hub genes enriched in KEGG pathways. The ENCORI database predicted microRNAs for candidate genes. A survival analysis of those genes was performed, and validated using the OncoLnc database. In addition, the 'clusterProfiler' package in R was used to perform gene set enrichment analysis (GSEA). We identified 395 DEGs, among which 155 were upregulated and 240 were downregulated. In total, 95 DEGs were screened as hub genes after constructing the PPI networks. Twelve GO terms and three KEGG pathways (steroid hormone biosynthesis, malaria, and pathways in cancer) were identified as being significant in the enrichment analysis of hub genes. Twenty-one hub genes enriched in KEGG pathways were defined as key genes. Among them AKT3, phospholipase C Beta 4 (PLCB4), and TGFB1 were identified as OXA-resistance genes through the survival analysis. High expressions of AKT3 and TGFB1 were each associated with a poor prognosis, and lower expression of PLCB4 was correlated with worse survival. Further, high levels of hsa-miR-1271-5p, which potentially targets PLCB4, were associated with poor overall survival in patients with CRC. Finally, we found that PLCB4 low expression was associated with MAPK signaling pathway and VEGF signaling pathway in CRC. Our results demonstrated that hsa-miR-1271-5p/PLCB4 in the pathway in cancer could be a new potential therapeutic target for mCRC with OXA resistance.

Comparison of robotic reduced-port and laparoscopic approaches for left-sided colorectal cancer surgery.

BACKGROUND/OBJECTIVE: The reduced-port approach can overcome the limitations of single-incision laparoscopic surgery while maintaining its advantages. Here, we compared the effects of robotic reduced-port surgery and conventional laparoscopic approaches for left-sided colorectal cancer. METHODS: Between January 2015 and December 2016, the clinicopathological characteristics and treatment outcomes of 17 patients undergoing robotic reduced-port surgery and 49 patients undergoing laparoscopic surgery for left-sided colorectal cancer were compared. RESULTS: The two groups were comparable in almost all outcome measures except for the distal resection margin, which was significantly longer in the laparoscopic group (P < 0.001). The between-group differences in reoperation, incisional hernia development, and overall and progression-free survival were nonsignificant; however, the total hospital cost was significantly higher in the robotic group than in the laparoscopic group (US$13779.6 ± US$3114.8 vs. US$8556.3 ± US$2056.7, P < 0.001). CONCLUSION: Robotic reduced-port surgery for left-sided colorectal cancer is safe and effective but more expensive with no additional benefit compared with the conventional laparoscopic approach. This observation warrants further evaluation.

Clinical assessment for non-reversal stoma and stoma re-creation after reversal surgery for patients with rectal cancer having undergoing sphincter-saving operation.

BACKGROUND: This study aimed to identify the risk factors for permanent stoma (PS) in patients who underwent sphincter-saving operations for rectal cancer. METHODS: We retrospectively reviewed 597 consecutive patients with rectal cancer from January 2012 to December 2020 at Taipei Medical University Hospital. Univariate and multivariable analyses were used to analyze risk factors for PS. RESULTS: After a mean follow-up of 47.3 months (range 7-114 months), 59 patients (15.1%) were alive with a PS, including 46 patients who did not undergo reversal surgery and 13 patients who underwent stoma re-creation after reversal surgery. The mean period between primary surgery and stoma reversal was 6.0 months. Multivariate analysis revealed that the risk factors for PS were local recurrence [odd ratio (OR), 25.58; 95% confidence interval (CI), 4.428-147.761; p < 0.001], perirectal abscess [OR, 154.34; 95% CI, 15.806 - >999; p < 0.001], anastomosis site stenosis [OR, 187.081; 95% CI, 22.193 - >999; p < 0.001], perineural invasion [OR, 4.782; 95% CI, 1.22-18.736; p = 0.025], and operation time (min) [OR, 1.008; 95% CI, 1.002-1.014; p = 0.01]. CONCLUSIONS: Local recurrence, perirectal abscess, anastomosis site stenosis, perineural invasion, and operation time were independent risk factors for PS. Therefore, before a patient undergoes surgery for rectal cancer, surgeons should consider the possibility of the need for a PS, and patients should be informed before the operation that closure of the temporary stoma may not always be possible.

Clinical Safety and Effectiveness of Robotic-Assisted Surgery in Patients with Rectal Cancer: Real-World Experience over 8 Years of Multiple Institutions with High-Volume Robotic-Assisted Surgery.

The perioperative and short-term oncological outcomes of robotic-assisted rectal surgery (RRS) are unclear. This retrospective observational study enrolled patients with rectal adenocarcinoma undergoing RRS from three high-volume institutions in Taiwan. Of the 605 enrolled patients, 301 (49.75%), 176 (29.09%), and 116 (19.17%) had lower, middle, and upper rectal cancers, respectively. Low anterior resection (377, 62.31%) was the most frequent surgical procedure. Intraoperative blood transfusion was performed in 10 patients (2%). The surgery was converted to an open one for one patient (0.2%), and ten (1.7%) patients underwent reoperation. The overall complication rate was 14.5%, including 3% from anastomosis leakage. No deaths occurred during surgery and within 30 days postoperatively. The positive rates of distal resection margin and circumferential resection margin were observed in 21 (3.5%) and 30 (5.0%) patients, respectively. The 5-year overall and disease-free survival rates for patients with stage I-III rectal cancer were 91.1% and 86.3%, respectively. This is the first multi-institutional study in Taiwan with 605 patients from three high-volume hospitals. The overall surgical and oncological outcomes were equivalent or superior to those estimated in other studies. Hence, RRS is an effective and safe technique for rectal resection in high-volume hospitals.