Short-term outcomes of short- and long-course chemoradiotherapy prior to total mesorectal excision for locally advanced rectal tumors: A single-center study in Taiwan utilizing propensity score matching.

BACKGROUND: Locally advanced rectal tumors are typically treated with neoadjuvant chemoradiotherapy. Short-course chemoradiotherapy (SCRT, 2,500 cGy in five fractions) is a convenient alternative to concurrent chemoradiotherapy with long-course radiotherapy (CCRT, 4,500 cGy in 25 fractions) without sacrificing efficacy. We aimed to compare the short-term outcomes of SCRT and CCRT in patients with mid- and low- rectal tumors who underwent total mesorectal excision using real-world data. METHODS: We retrospectively reviewed the data of patients with locally advanced rectal cancer who underwent radical resection after neoadjuvant chemoradiotherapy from 2011 to 2022. We analyzed the clinicopathological findings and prognostic factors for disease-free and overall survival in the SCRT and CCRT groups and compared the outcomes using propensity score matching. RESULTS: Among the 66 patients in the two groups, no disparities were noted in the demographic features, pathological remission, or downstaging rates. Nonetheless, the SCRT group exhibited superior 3-year disease-free survival (81.8% vs. 62.1%, p = 0.011), whereas the overall survival did not differ significantly between the two groups. The initial carcinoembryonic antigen (CEA) levels and neoadjuvant SCRT were associated with the recurrence rates [hazard ratio (HR) 1.13-4.10; HR 0.19-0.74], but the harvested lymph node count was not (HR 0.51-1.97). CONCLUSION: Among patients with locally advanced rectal cancer, SCRT combined with four cycles of FOLFOX was shown to enhance short-term disease-free survival. Factors impacting recurrence include the initial CEA level and SCRT, but not the harvested lymph node count.

The salvage lenvatinib-based regimen provides survival benefit in patients with refractory metastatic colorectal cancer.

Salvage treatment for refractory metastatic colorectal cancer (mCRC) has yet to be identified. We aimed to evaluate the efficacy of a salvage lenvatinib-based regimen for refractory mCRC. In total, 371 patients were categorized into lenvatinib-based and non-lenvatinib-based groups. In the lenvatinib-based group, patients who received lenvatinib at a dosage of 10 mg/day were categorized into lenvatinib/chemotherapy and lenvatinib/immunotherapy subgroups. We reported overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. OS1 was used to measure the time from disease progression after TAS-102 and regorafenib treatment to death, while OS2 was used to measure the time from TAS-102 or regorafenib treatment to death. Propensity score matching analysis was employed to compare the characteristics between the lenvatinib-based and non-lenvatinib-based groups. Next-generation sequencing (NGS) information was analyzed using R software. The lenvatinib-based group exhibited longer OS than did the non-lenvatinib-based group (OS1, 11.4 vs. 3.7 months; OS2, 27.2 vs. 8.2 months). The disease control rate (DCR) and objective response rate (ORR) of the lenvatinib-based regimens were 69.4% and 6.1%, respectively. Lenvatinib/chemotherapy and lenvatinib/immunotherapy had similar PFS, OS, DCR, and ORR. The adverse effects were manageable. After propensity score matching, the lenvatinib-based group continued to exhibit significantly longer OS1 and OS2 than did the non-lenvatinib-based group. NGS analysis revealed that GNAS and KRAS alterations were associated with a worse treatment response and prolonged survival, respectively. In conclusion, a moderate-dose salvage lenvatinib-based regimen demonstrated promising clinical activity and tolerability in treating refractory mCRC.

The survival outcome differs between left-sided colon cancer and middle/low rectal cancer after colorectal hepatic metastasectomy.

BACKGROUND: The clinical outcomes between left-sided colon cancer and middle/low rectal cancer seem to be different. This study aimed to examine the effect of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of patients who underwent colorectal hepatic metastasectomy. METHODS: Patients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into 2 groups according to the primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were analyzed using the Student t test. Survival was analyzed using the Kaplan-Meier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. RESULTS: Overall, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio [HR], 0.725; P = .018), with median OS estimates of 48 and 38 months, respectively. In the subgroup analysis of RAS mutations, patients with left-sided colon cancer had significantly prolonged OS compared with those with middle/low rectum cancer (HR, 0.608; P = .034), with median OS estimates of 49 and 26 months, respectively. This observation was limited to patients with RAS mutations. CONCLUSION: According to our findings, patients with middle/low rectal cancer had poorer survival outcome and should not be categorized together with patients with left-sided colon cancer in terms of OS after colorectal hepatic metastasectomy.

Circular RNA ZNF800 (hsa_circ_0082096) regulates cancer stem cell properties and tumor growth in colorectal cancer.

BACKGROUND: Cancer stem cells form a rare cell population in tumors that contributes to metastasis, recurrence and chemoresistance in cancer patients. Circular RNAs (circRNAs) are post-transcriptional regulators of gene expression that sponge targeted microRNA (miRNAs) to affect a multitude of downstream cellular processes. We previously showed in an expression profiling study that circZNF800 (hsa_circ_0082096) was up-regulated in cancer stem cell-enriched spheroids derived from colorectal cancer (CRC) cell lines. METHODS: Spheroids were generated in suspension spheroidal culture. The ZNF800 mRNA, pluripotency stem cell markers and circZNF800 levels were determined by quantitative RT-PCR. CircZNF800-miRNA interactions were shown in RNA pulldown assays and the miRNA levels determined by stem-loop qRT-PCR. The effects of circZNF800 on cell proliferation were tested by EdU staining followed by flowcytometry. Expression of stem cell markers CD44/CD133, Lgr5 and SOX9 was demonstrated in immunofluorescence microscopy. To manipulate the cellular levels of circZNF800, circZNF800 over-expression was achieved via transfection of in vitro synthesized and circularized circZNF800, and knockdown attained using a CRISPR-Cas13d-circZNF800 vector system. Xenografted nude mice were used to demonstrate effects of circZNF800 over-expression and knockdown on tumor growth in vivo. RESULTS: CircZNF800 was shown to be over-expressed in late-stage tumor tissues of CRC patients. Data showed that circZNF800 impeded expression of miR-140-3p, miR-382-5p and miR-579-3p while promoted the mRNA levels of ALK/ACVR1C, FZD3 and WNT5A targeted by the miRNAs, as supported by alignments of seed sequences between the circZNF800-miRNA, and miRNA-mRNA paired interactions. Analysis in CRC cells and biopsied tissues showed that circZNF800 positively regulated the expression of intestinal stem cell, pluripotency and cancer stem cell markers, and promoted CRC cell proliferation, spheroid and colony formation in vitro, all of which are cancer stem cell properties. In xenografted mice, circZNF800 over-expression promoted tumor growth, while circZNF800 knockdown via administration of CRISPR Cas13d-circZNF800 viral particles at the CRC tumor sites impeded tumor growth. CONCLUSIONS: CircZNF800 is an oncogenic factor that regulate cancer stem cell properties to lead colorectal tumorigenesis, and may be used as a predictive marker for tumor progression and the CRISPR Cas13d-circZNF800 knockdown strategy for therapeutic intervention of colorectal cancer.

Surgical strategy for colorectal cancer with synchronous liver and extrahepatic metastases: A scoring system and decision tree model.

BACKGROUND: The role of hepatectomy in a specific group of patients with synchronous colorectal cancer with liver metastases (SCRLM) and synchronous extrahepatic disease (SEHD) is still unclear. The aim of this study was to evaluate the efficacy of liver surgery and define the selection criteria for surgical candidates in patients with SCRLM + SEHD. METHODS: Between July 2007 and October 2018, 475 patients with colorectal cancer with liver metastases (CRLM) who underwent liver resection were retrospectively reviewed. Sixty-five patients with SCRLM + SEHD were identified and included in the study. Clinical pathological data of these patients were analyzed to evaluate the influence on survival. Important prognostic factors were identified by univariate and multivariate analyses. The risk score system and decision tree analysis were generated according to the important prognostic factors for better patient selection. RESULTS: The 5-year survival rate of patients with SCRLM + SEHD was 21.9%. The most important prognostic factors were SCRLM number of more than five, site of SEHD other than the lung only, inability to achieve SCRLM + SEHD R0 resection, and BRAF mutation of cancer cells. The proposed risk score system and decision tree model easily discriminated between patients with different survival rates and identified the profile of suitable surgical patients. CONCLUSION: Liver surgery should not be a contraindication for patients with SCRLM + SEHD. Patients with complete SCRLM + SEHD R0 resection, SCRLM number less than or equal to five, SEHD confined to the lung only, and wild-type BRAF could have favorable survival outcomes. The proposed scoring system and decision tree model may be beneficial to patient selection in clinical use.

Modeling the survival of colorectal cancer patients based on colonoscopic features in a feature ensemble vision transformer.

The prognosis of patients with colorectal cancer (CRC) mostly relies on the classic tumor node metastasis (TNM) staging classification. A more accurate and convenient prediction model would provide a better prognosis and assist in treatment. From May 2014 to December 2017, patients who underwent an operation for CRC were enrolled. The proposed feature ensemble vision transformer (FEViT) used ensemble classifiers to benefit the combinations of relevant colonoscopy features from the pretrained vision transformer and clinical features, including sex, age, family history of CRC, and tumor location, to establish the prognostic model. A total of 1729 colonoscopy images were enrolled in the current retrospective study. For the prediction of patient survival, FEViT achieved an accuracy of 94 % with an area under the receiver operating characteristic curve of 0.93, which was better than the TNM staging classification (90 %, 0.83) in the experiment. FEViT reduced the limited receptive field and gradient disappearance in the conventional convolutional neural network and was a relatively effective and efficient procedure. The promising accuracy of FEViT in modeling survival makes the prognosis of CRC patients more predictable and practical.

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability.

BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.

Protective loop ileostomy or colostomy? a risk evaluation of all common complications.

Purpose: Protective ileostomy and colostomy are performed in patients undergoing low anterior resection with a high leakage risk. We aimed to compare surgical, medical, and daily care complications between these 2 ostomies in order to make individual choice. Methods: Patients who underwent low anterior resection for rectal tumors with protective stomas between January 2011 and September 2018 were enrolled. Stoma-related complications were prospectively recorded by wound, ostomy, and continence nurses. The cancer stage and treatment data were obtained from the Taiwan Cancer Database of our Big Data Center. Other demographic data were collected retrospectively from medical notes. The complications after stoma creation and after the stoma reversal were compared. Results: There were 176 patients with protective colostomy and 234 with protective ileostomy. Protective ileostomy had higher proportions of high output from the stoma for 2 consecutive days than protective colostomy (11.1% vs. 0%, P<0.001). Protective colostomy resulted in more stoma retraction than protective ileostomy (21.6% vs. 9.4%, P=0.001). Female sex, open operation, ileostomy, and carrying stoma more than 4 months were also significantly associated with a higher risk of stoma-related complications during diversion. The incidence of complication after stoma reversal did not differ between colostomy group and ileostomy group (24.3% vs. 20.9%, P=0.542). Conclusion: We suggest avoiding colostomy in patients who are female and potential prolong diversion when stoma retraction is a concern. Otherwise, ileostomy should be avoided for patients with impaired renal function. Wise selection and flexibility are more important than using one type of stoma routinely.

The Negative Prognostic Impact of Lymph Node Skip Metastasis in Stage III Colon Cancer With pN1 Disease: A Single-Center and Retrospective Cohort Study.

BACKGROUND: Lymph node skip metastasis is a subgroup of lymph node metastatic patterns with low incidence in node-positive colon cancer. Its clinical significance is still unclear. OBJECTIVE: This study aimed to investigate the prognostic impact of lymph node skip metastasis in stage III colon cancer. DESIGN: This is a retrospective observational analysis. SETTINGS: The study was conducted at the Taipei Veterans General Hospital. PATIENTS: This study included patients with stage III colon cancer who underwent D3 lymphadenectomy between 2006 and 2015. MAIN OUTCOME MEASURES: The patients were divided into a lymph node skip metastasis-positive group and a negative group. Recurrence-free survival and overall survival were compared using Kaplan-Meier curves and log-rank test. Cox regression was applied to identify related risk factors influencing survival. RESULTS: A total of 461 patients were reviewed, and lymph node skip metastasis-positive patients represented 13.2% of our sample. Patients with lymph node skip metastasis tended to present with a higher proportion of right-sided cancer, lower positive lymph nodes, lower lymph node ratio, and higher mean BMI. Liver recurrence was more prevalent in the lymph node skip metastasis group ( p = 0.028) than in the negative group. The presence of lymph node skip metastasis was a negative prognostic factor for 5-year recurrence-free survival (51.4% vs 68.7%; p = 0.002) and 5-year overall survival (66.4% vs 80.4%; p = 0.024) in Kaplan-Meier curves and multivariate Cox regression. Subgroup analysis revealed the survival significance of recurrence-free survival ( p = 0.001) and overall survival ( p = 0.011) in lymph node skip metastasis with pN1 disease. LIMITATIONS: This study was limited by its retrospective design, single-center nature, and sampling error. CONCLUSIONS: Lymph node skip metastasis is an independent negative prognostic factor in stage III colon cancer with pN1 disease. More intensive surveillance may be necessary for patients of this subgroup. See Video Abstract at https://links.lww.com/DCR/C60 . IMPACTO PRONSTICO NEGATIVO DE LAS METSTASIS DISCONTNUAS GANGLIONARES LINFTICAS EN CASOS DE CNCER DE COLON ESTADIO III CON ENFERMEDAD PN ESTUDIO DE COHORTES RETROSPECTIVO MONOCENTRICO: ANTECEDENTES:Las metástasis discontínuas ganglionares linfáticas, son un subgrupo de patrones metastásicos en los ganglios linfáticos con baja incidencia en el cáncer de colon con nódulos positivos. Su significado clínico aún no está claro.OBJETIVO:Estudio que tiene por objetivo el investigar el impacto pronóstico de las metástasis discontínuas de los ganglios linfáticos en el cáncer de colon de estadio III.DISEÑO:Análisis observacional retrospectivo.AJUSTES:El estudio se realizó en el Hospital General de Veteranos de Taipei.PACIENTES:Pacientes con cáncer de colon en estadio III que se sometieron a linfadenectomía D3 entre 2006 y 2015.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes se dividieron en un grupo positivo de metástasis discontínuas en los ganglios linfáticos y un otro grupo negativo. La sobrevida libre de recidiva y la sobrevida global, fueron comparadas mediante las curvas de Kaplan-Meier y la prueba de rango logarítmico. Se aplicó la regresión de Cox para identificar los factores de riesgo relacionados que influyeron en la sobrevida.RESULTADOS:Se revisaron un total de 461 casos, donde los pacientes positivos con metástasis en los ganglios linfáticos representaron el 13,2% de nuestra muestra. Los pacientes con metástasis discontínuas ganglionares linfáticas tendían a presentar una mayor proporción de cáncer localizado en el lado derecho del colon, presentar un menor numéro de ganglios linfáticos positivos y una proporción menor de ganglios linfáticos con un IMC promedio más alto. Las recidivas hepáticas fueron más prevalentes en el grupo de metástasis discontínuas ganglionares linfáticas ( p = 0,028) que en el grupo negativo. La presencia de metástasis discontínuas ganglionares linfáticas fué un factor de pronóstico negativo en la sobrevida libre de recidiva a 5 años (51,4% frente a 68,7%, p = 0,002) y la sobrevida general a 5 años (66,4% frente a 80,4%, p = 0,024) evaluada por las curvas de Kaplan-Meier y la regresión multivariada de Cox. El análisis de subgrupos reveló la importancia de la sobrevida libre de recidiva ( p = 0,001) y la sobrevida general ( p = 0,011) en los casos con metástasis discontínuas ganglionares linfáticas con enfermedad pN1.LIMITACIONES:Diseño retrospectivo, naturaleza de centro único y error de muestreo.CONCLUSIONES:Las metástasis discontínuas ganglionares linfáticas son un factor pronóstico negativo independiente en los casos de cáncer de colon estadio III con enfermedad pN1. Tal vez sea necesaria una mayor vigilancia de los pacientes en este subgrupo.Consulte Video Resumen en https://links.lww.com/DCR/C60 . (Traducción-Dr. Xavier Delgadillo ).

Clinical outcome of local treatment and radical resection for pT1 rectal cancer.

BACKGROUND: Rectal cancer is mainly cured by radical resection with neoadjuvant chemoradiation or adjuvant chemotherapy. Pathological T1 lesions can be managed by local treatment and radiotherapy thereafter. Lower morbidity is the key benefit of these local treatments. Since nodal metastasis is important for staging, radical resection (RR) is suggested. Rectal cancer has higher surgical morbidity than colon cancer; local treatment has been the preferred choice by patients. METHODS: We retrospectively enrolled data of 244 patients with pT1 rectal adenocarcinoma. A total of 202 patients (82.8%) underwent RR, including low anterior resection (LAR) and abdomino-perineal resection (APR), and 42 patients (17.2%) underwent LT, including transanal excision and colonoscopic polypectomy. RESULTS: In our study, seven patients (16.7%) had loco-regional recurrence and distant metastasis from the LT group while eight patients (4.0%) had distant metastasis without loco-regional recurrence from the RR group. The lymph node metastasis rate in RR group was 8.4%. Forty-seven patients (24.2%) underwent LAR with temporary stoma, and its reversal rate was 100%. In the RR group, postoperative complication rate was 10.4% with a mortality rate of 0.5%. Recurrence-free survival (RFS) was 95.7% for RR and 80.2% for LT (P = 0.001), and overall survival (OS) was 93.7% for RR and 70.0% for LT (P = 0.001). CONCLUSION: This study found that RFS and OS in patients of pT1 rectal adenocarcinoma that had received RR were better than receiving LT. Further adjuvant chemotherapy was possible for some RR patients. A higher recurrence rate after LT must be balanced against the morbidity and mortality associated with RR.

A Long-Term and Large-Scale Real-World Study in Taiwan: Efficacy of Target Therapy in Stage IV Colorectal Cancer.

This study expands the understanding of the role of target therapy in improving survival of patients with mCRC based on real-world study results. These data represent potential survival outcomes of Taiwanese patients with mCRC in clinical practice. CRC is the most commonly diagnosed cancer and the third leading cause of cancer-related death in Taiwan. The aim of this study was to evaluate the efficacy of target therapy in combination with chemotherapy for mCRC in Taiwan. This was a real-world, retrospective, observational study in patients diagnosed with mCRC (N=1583). A total of 792 patients received chemotherapy plus target therapy (anti-EGFR therapy, n=180; anti-VEGF therapy, n=612) and 791 patients who received chemotherapy alone. Overall survival (OS) and progression-free survival (PFS) were examined. For RAS wild-type patients, the median OS (mOS) was 34.3 months in the EGFR L (left-sided colon) group, 27.3 months in the VEGF L group, 18.4 months in VEGF R (right-sided colon) group, and 13.8 months in EGFR R group (P<0.001). Median PFS (mPFS) was 9.8 months in the EGFR L group, 8.9 months in the VEGF L group, 6.8 months in VEGF R group, and 5.8 months in EGFR R group. In patients with a RAS mutation, mOS was 25.4 months in the VEGF L group and 19.4 months in the VEGF R group (P=0.167). Judicious treatment allocation in Taiwanese patients with mCRC can result in an mOS of 34.3 months using cetuximab plus chemotherapy for left-sided tumors. An mOS of 48.5 months can be achieved using cetuximab plus chemotherapy in the neoadjuvant setting in mCRC patients with left-sided tumors. This study expands our understanding of the role of target therapy in improving survival of mCRC patients based on real-world study results.

Prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on low-grade appendiceal mucinous neoplasm: A single tertiary hospital experience.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is a rare disease, which prognostic factors were difficult to evaluate. Inflammation markers, like neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were used as prognosticators for various cancers. This study aimed to investigate the prognostic value of pretreatment NLR and PLR on LAMN. METHODS: From January 2000 to September 2018, there were 57 patients diagnosed with LAMN in Taipei Veterans General Hospital. Patients diagnosed with mucinous cystadenoma, mucinous tumor with uncertain malignant potential before 2010 were also included based on previous classification. Clinical and pathological data were collected. Patients were separated into high-NLR (NLR-H) and low-NLR (NLR-L) groups according to cutoff value of 3. Similarly, they were separated into high-PLR (PLR-H), and low-PLR (PLR-L) groups with cutoff value of 300. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. RESULTS: Among all patients, the median follow-up time was 42 months. Age, gender, clinical manifestations, type of surgery, and T stage were similar in different NLR and PLR groups. Both NLR-H and PLR-H groups had higher rate of M1 stage of diseases (22.7% vs 9.4%, p = 0.04; 57.1% vs 8.8%, p < 0.01, respectively). PLR-H group had more presence of pseudomyxoma peritonei (PMP) (57.1% vs 15.2%, p = 0.03). In univariate analysis, factors such as age, gender, tumor perforation, and operation did not have impact on OS nor RFS. On the other hand, M1b stage is the only significantly poor prognostic factor on RFS (hazard ratio, 57.96, 95% CI, 5.16-651.23, p < 0.01). CONCLUSION: Both NLR-H and PLR-H had more M1 stage of diseases, but they were not correlated to OS nor RFS. PLR-H group had higher rate of presence PMP. Nevertheless, patients with LAMN and cellular PMP (M1b stage) had a higher rate of recurrence, and other factors showed no statistical difference in OS nor RFS.

Comparison of two-stage and three-stage surgery for obstructing left-sided colon cancer.

BACKGROUND: Whether the timing of stoma reversal after emergency diversion for obstructive left-sided colon cancer affects patient outcomes is unknown. Our study compared the short- and long-term outcomes of two- and three-stage operations for obstructive left-sided colon cancer. METHODS: Patients with obstructive left-sided colon cancer who underwent staged resection at a referral hospital between January 2002 and December 2015 were retrospectively identified. Patient demographics and outcomes were analysed and compared between the two groups. Statistical significance was set as p < 0.05. RESULTS: A total of 191 patients were reviewed. The overall complication rate was higher for two-stage surgery than for three-stage surgery (57.1% versus 36.0%, p < 0.01). Surgical site infection and/or wound dehiscence were the most common complications. Other complications, including anastomotic leakage, ileus, and bowel obstruction, were not significantly different between the two groups. The five-year overall survival and disease-free survival in stage II and III patients were comparable. CONCLUSION: Among patients with obstructive left-sided colon cancer who underwent staged resection, two-stage surgery was associated with a higher complication rate, especially for surgical site infection and/or wound dehiscence, which could be managed by local treatment. The timing of stoma reversal was not associated with survival differences in patients with stage II and III disease. However, issues such as the location of the tumour and diverting stoma, along with the need to resect other upper abdominal organs, should all be considered when deciding between two- and three-stage surgeries.

Three-dimensional versus conventional two-dimensional laparoscopic colectomy for colon cancer: A 3-year follow-up study.

Background: Three-dimensional (3D) laparoscopy was developed to overcome the drawbacks of two-dimensional (2D) laparoscopy, namely lack of depth perception. However, the benefit of 3D laparoscopy in colorectal surgery is inconclusive. Here, we compare the 3-year follow-up outcomes of 3D and 2D laparoscopic colectomy. Patients and Methods: A total of 91 consecutive patients who underwent either 3D or 2D laparoscopy colectomy from October 2015 to November 2017 by a single surgical team for colon cancer were enrolled. Data were collected from a prospectively constructed database, including clinico-pathological features and operative parameters. The pathological results, recurrence, survival and systemic treatment were collected from the Taiwan Cancer Database. Results: There were 47 patients in the 3D group and 44 in the 2D group. There were no significant differences in characteristics of patients, operation data, pathological results, complications, operative time, blood loss or the number of lymph node harvested between the two groups. In addition, disease-free survival and overall survival were equal between the two groups. Conclusions: This is the first long-term result of a 3D laparoscopic colectomy. In our 3-year follow-up, there was no difference in long-term outcomes between 2D and 3D laparoscopy for colorectal surgery in an experienced centre.

Strategic Decoy Peptides Interfere with MSI1/AGO2 Interaction to Elicit Tumor Suppression Effects.

Peptide drugs that target protein-protein interactions have attracted mounting research efforts towards clinical developments over the past decades. Increasing reports have indicated that expression of Musashi 1 (MSI1) is tightly correlated to high grade of cancers as well as enrichment of cancer stem cells. Treatment failure in malignant tumors glioblastoma multiform (GBM) had also been correlated to CSC-regulating properties of MSI1. It is thus imperative to develop new therapeutics that could effectively improve current regimens used in clinics. MSI1 and AGO2 are two emerging oncogenic molecules that both contribute to GBM tumorigenesis through mRNA regulation of targets involved in apoptosis and cell cycle. In this study, we designed peptide arrays covering the C-terminus of MSI1 and identified two peptides (Pep#11 and Pep#26) that could specifically interfere with the binding with AGO2. Our Biacore analyses ascertained binding between the identified peptides and AGO2. Recombinant reporter system Gaussian luciferase and fluorescent bioconjugate techniques were employed to determine biological functions and pharmacokinetic characteristics of these two peptides. Our data suggested that Pep#11 and Pep#26 could function as decoy peptides by mimicking the interaction function of MSI1 with its binding partner AGO2 in vitro and in vivo. Further experiments using GMB animal models corroborated the ability of Pep#11 and Pep#26 in disrupting MSI1/AGO2 interaction and consequently anti-tumorigenicity and prolonged survival rates. These striking therapeutic efficacies orchestrated by the synthetic peptides were attributed to the decoy function to C-terminal MSI1, especially in malignant brain tumors and glioblastoma.

Oncogenic circRNA C190 Promotes Non-Small Cell Lung Cancer via Modulation of the EGFR/ERK Pathway.

Lung cancers are the leading cause of cancer-related mortality worldwide, and the majority of lung cancers are non-small cell lung carcinoma (NSCLC). Overexpressed or activated EGFR has been associated with a poor prognosis in NSCLC. We previously identified a circular noncoding RNA, hsa_circ_0000190 (C190), as a negative prognostic biomarker of lung cancer. Here, we attempted to dissect the mechanistic function of C190 and test the potential of C190 as a therapeutic target in NSCLC. C190 was upregulated in both NSCLC clinical samples and cell lines. Activation of the EGFR pathway increased C190 expression through a MAPK/ERK-dependent mechanism. Transient and stable overexpression of C190 induced ERK1/2 phosphorylation, proliferation, and migration in vitro and xenograft tumor growth in vivo. RNA sequencing and Expression2Kinases (X2K) analysis indicated that kinases associated with cell-cycle and global translation are involved in C190-activated networks, including CDKs and p70S6K, which were further validated by immunoblotting. CRISPR/Cas13a-mediated knockdown of C190 decreased proliferation and migration of NSCLC cells in vitro and suppressed tumor growth in vivo. TargetScan and CircInteractome databases predicted that C190 targets CDKs by sponging miR-142-5p. Analysis of clinical lung cancer samples showed that C190, CDK1, and CDK6 expressions were significantly higher in advanced-stage lung cancer than in early-stage lung cancer. In summary, C190 is directly involved in EGFR-MAPK-ERK signaling and may serve as a potential therapeutic target for the treatment of NSCLC. SIGNIFICANCE: The circRNA C190 is identified as a mediator of multiple pro-oncogenic signaling pathways in lung cancer and can be targeted to suppress tumor progression.

Preference criteria for regorafenib in treating refractory metastatic colorectal cancer are the small tumor burden, slow growth and poor/scanty spread.

Given the unclear preference criteria for regorafenib in treating refractory metastatic colorectal cancer (mCRC), this study aimed to construct an algorithm in selecting right patients for regorafenib. This was a multicenter retrospective cohort study. Patients with pathology confirmed mCRC and administered with regorafenib for > 3 weeks were enrolled. Patients with good response were defined to have progression-free survival (PFS) of ≥ 4 months. The Kaplan-Meier plot was used to analyze survival. A Cox proportional hazards model was used to analyze univariate and multivariate prognostic factors and was visualized using forest plot. A clustering heatmap was used to classify patients according to responses. The decision tree and nomogram were used to construct the approaching algorithm. A total of 613 patients was analyzed. The median PFS and overall survival (OS) were 2.7 and 10.6 months, respectively. The partial response and stable disease rate are 2.4% and 36.4%. The interval between metastasis (M1) and regorafenib, metastatic status (number, liver, and brain), and CEA level were independent prognostics factors of PFS that classifies patients into three groups: good, bad and modest-1/modest-2 group with PFS > = 4 months rates of 51%, 20%, 39% and 30%, respectively. Results were used to develop the decision tree and nomogram for approaching patients indicated with regorafenib. The preference criteria for regorafenib in treating patients with refractory mCRC are small tumor burden (CEA), slow growth (interval between metastasis and regorafenib) and poor/scanty spread (metastatic status: number and sites of metastasis): The 3S rules.TRIAL registration ClinicalTrials.gov Identifier: NCT03829852; Date of first registration (February 11, 2019).

High concordance of mutation patterns in 10 common mutated genes between tumor tissue and cell-free DNA in metastatic colorectal cancer.

The concordance of mutation patterns between cell-free DNA (cfDNA) and tumor DNA varies in colorectal cancers (CRCs). Next-generation sequencing (NGS) by targeted sequencing can detect novel genes. We aimed to use NGS to test the concordance between cfDNA and tumor DNA in metastatic CRCs. A total of 95 paired tumor and peripheral blood samples from metastatic CRC patients were included. The tumor DNA and cfDNA were analyzed with a 10-gene NGS panel (Illumina HiSeq2500 system). The median number of mutations in tumor samples was 3 (range 0-7). The most commonly mutated gene was TP53 (63.2%), followed by APC (49.5%), KRAS (35.8%) and FAT4 (15.8%). The concordance of mutation patterns in these 10 genes was as high as 91% between cfDNA and tumor samples in these metastatic CRC patients. A sensitivity of 88.2% and specificity of 100% was found when using KRAS mutation status of cfDNA to predict KRAS mutation in tumor tissue. For tumor DNA with TP53, KRAS, or APC mutations, right-sided CRCs were more likely to develop peritoneal metastases, while for tumor DNA with TP53 mutations, left-sided tumors were more likely to have lung metastases. For cfDNA with TP53 or KRAS mutations, right-sided CRCs were more likely to have peritoneal metastases. Due to the high concordance of mutation patterns between cfDNA and tumor samples, monitoring the mutation pattern of cfDNA may be applicable in the treatment of metastatic CRC.

The efficacy of anti-EGFR therapy in treating metastatic colorectal cancer differs between the middle/low rectum and the left-sided colon.

BACKGROUND: Clinically, metastatic rectal cancer has been considered a subset of left-sided colon cancer. However, heterogeneity has been proposed to exist between high and middle/low rectal cancers. We aimed to examine the efficacy of anti-epidermal growth factor receptor (EGFR) treatment for middle/low rectal and left-sided colon cancers. METHODS: This study enrolled 609 patients with metastatic colorectal cancer who were treated with anti-EGFR therapy. They were divided into groups based on primary tumour locations: the right-sided colon, the left-sided colon or the middle/low rectum. The efficacy of first-line and non-first-line anti-EGFR treatment was analysed. Genomic differences in colorectal cancer data from The Cancer Genome Atlas (TCGA) were investigated and visualised with OncoPrint and a clustered heatmap. RESULTS: On first-line anti-EGFR treatment, patients with middle/low rectal tumours had significantly lower progression-free survival, overall survival, and overall response rates (6.8 months, 27.8 months and 43%, respectively) than those with left-sided colon cancer (10.1 months, 38.3 months and 66%, respectively). Similar outcomes were also identified on non-first-line anti-EGFR treatment. In TCGA analysis, rectal tumours displayed genetic heterogeneity and shared features with both left- and right-sided colon cancer. CONCLUSIONS: Anti-EGFR treatment has lower efficacy in metastatic middle/low rectal cancer than in left-sided colon cancer.

Clinicopathological and molecular features between synchronous and metachronous metastases in colorectal cancer.

The molecular difference between synchronous and metachronous metastases in colorectal cancer (CRC) remains unclear. Between 2000 and 2010, a total of 492 CRC patients were enrolled, including 280 with synchronous metastasis and 212 with metachronous metastasis. Clinicopathological and molecular features were compared between the two groups. Patients with synchronous metastasis were more likely to have right-sided CRC, poorly differentiated tumors, lymphovascular invasion, advanced pathological tumor (T) and node (N) categories, and liver metastases than those with metachronous metastasis. For right-sided CRC, patients with synchronous metastasis had more lymphovascular invasion and liver metastases than those with metachronous metastasis. For left-sided CRC, patients with synchronous metastasis were more likely to have poorly differentiated tumors, lymphovascular invasion, advanced pathological T and N categories, and liver metastases than those with metachronous metastasis. Regarding the genetic mutations, patients with metachronous metastasis had more mutations in TP53, NRAS, and HRAS and fewer mutations in APC than those with synchronous metastasis; for right-sided CRC, synchronous metastasis was associated with more APC mutations than metachronous metastasis, while for left-sided CRC, metachronous metastasis was associated with more TP53 and NRAS mutations than synchronous metastasis. The 5-year overall survival (OS) rates were significantly higher in metachronous metastasis patients than in synchronous metastasis patients, especially those with left-sided CRC. Multivariate analysis showed that age, sex, lymphovascular invasion, pathological N category, metachronous metastasis, and BRAF and NRAS mutations were independent prognostic factors affecting OS. CRC patients with synchronous metastasis had a worse OS than those with metachronous metastasis and exhibited distinct genetic mutations.