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.

Survival outcomes of stage I colorectal cancer: development and validation of the ACEPLY model using two prospective cohorts.

BACKGROUND: Approximately 10% of stage I colorectal cancer (CRC) patients experience unfavorable clinical outcomes after surgery. However, little is known about the subset of stage I patients who are predisposed to high risk of recurrence or death. Previous evidence was limited by small sample sizes and lack of validation. METHODS: We aimed to identify early indicators and develop a risk stratification model to inform prognosis of stage I patients by employing two large prospective cohorts. Prognostic factors for stage II tumors, including T stage, number of nodes examined, preoperative carcinoma embryonic antigen (CEA), lymphovascular invasion, perineural invasion (PNI), and tumor grade were investigated in the discovery cohort, and significant findings were further validated in the other cohort. We adopted disease-free survival (DFS) as the primary outcome for maximum statistical power and recurrence rate and overall survival (OS) as secondary outcomes. Hazard ratios (HRs) were estimated from Cox proportional hazard models, which were subsequently utilized to develop a multivariable model to predict DFS. Predictive performance was assessed in relation to discrimination, calibration and net benefit. RESULTS: A total of 728 and 413 patients were included for discovery and validation. Overall, 6.7% and 4.1% of the patients developed recurrences during follow-up. We identified consistent significant effects of PNI and higher preoperative CEA on inferior DFS in both the discovery (PNI: HR = 4.26, 95% CI: 1.70-10.67, p = 0.002; CEA: HR = 1.46, 95% CI: 1.13-1.87, p = 0.003) and the validation analysis (PNI: HR = 3.31, 95% CI: 1.01-10.89, p = 0.049; CEA: HR = 1.58, 95% CI: 1.10-2.28, p = 0.014). They were also significantly associated with recurrence rate. Age at diagnosis was a prominent determinant of OS. A prediction model on DFS using Age at diagnosis, CEA, PNI, and number of LYmph nodes examined (ACEPLY) showed significant discriminative performance (C-index: 0.69, 95% CI:0.60-0.77) in the external validation cohort. Decision curve analysis demonstrated added clinical benefit of applying the model for risk stratification. CONCLUSIONS: PNI and preoperative CEA are useful indicators for inferior survival outcomes of stage I CRC. Identification of stage I patients at high risk of recurrence is feasible using the ACEPLY model, although the predictive performance is yet to be improved.

MiR-143-3p targets ATG2B to inhibit autophagy and promote endothelial progenitor cells tube formation in deep vein thrombosis.

Deep vein thrombosis (DVT) is a common disease in vascular surgery. In recent study, microRNA (miRNA) plays a regulatory role in function of Endothelial progenitor cells (EPCs), which showed promising therapeutic choice for DVT. However, the function of miR-143-3p in EPCs remains incomplete. Flow cytometry was used to identify EPCs surface markers. Cell viability, migration, invasion and tube formation of EPCs were detected by 3-[4,5-dimethylthylthiazol-2-yl]-2,5 diphenyltetrazolium broide (MTT), wound healing, transwell and tube formation assay, respectively. TargetScan was used to predict miR-143-3p targeting genes. Dual-luciferase report assay was used to verify the interactions between miR-143-3p and autophagy-related 2B (ATG2B). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to examine the mRNA expression levels of ATG2B and miR-143-3p. Western blot was used to examine the protein expression levels of ATG2B, LC3 and p62. The cultured EPCs showed cobblestone morphology and were identified by cell surface markers. Overexpression of miR-143-3p enhanced the viability, migration, invasion and tube formation of EPCs, but low expression of miR-143-3p obtained the reverse results. ATG2B directly bound to miR-143-3p. Overexpression of miR-143-3p reduced the expression of ATG2B, but low expression of miR-143-3p increased. Overexpression of miR-143-3p decreased the expression of LC3I/II, but increased the expression of p62. Overexpression of ATG2B reversed the above-mentioned effects of EPCs which regulated by overexpression of miR-143-3p. MiR-143-3p targets ATG2B to modulate the function of EPCs and recanalization and resolution of DVT.

Clinical Decision Support for High-Risk Stage II Colon Cancer: A Real-World Study of Treatment Concordance and Survival.

BACKGROUND: Prognostic and pathologic risk factors typically guide clinicians and patients in their choice of surveillance or adjuvant chemotherapy when managing high-risk stage II colon cancer. However, variations in treatment and outcomes in patients with stage II colon cancer remain. OBJECTIVE: This study aimed to assess the survival benefits of treatments concordant with suggested therapeutic options from Watson for Oncology, a clinical decision support system. DESIGN: This is a retrospective observational study of concordance between actual treatment and Watson for Oncology therapeutic options. SETTING: This study was conducted at a top-tier cancer center in China. PATIENTS: Postoperative treatment data were retrieved from the electronic health records of 306 patients with high-risk stage II colon adenocarcinoma. MAIN OUTCOME MEASURES: The primary outcomes measured were the treatment patterns plus 3- and 5-year overall and disease-free survival for concordant and nonconcordant cases. RESULTS: Overall concordance was 90%. Most nonconcordant care resulted from adjuvant chemotherapy use (rather than surveillance) in patients with high-level microsatellite instability and ≥70 years old. No difference in overall survival (p = 0.56) or disease-free survival (p = 0.19) was observed between concordance groups. Patients receiving adjuvant chemotherapy had significantly higher 5-year overall survival than those undergoing surveillance (94% vs 84%, p = 0.01). LIMITATIONS: This study was limited by the use of retrospective cases drawn from patients presenting for surgery, the lack of complete follow-up data for 58% of patients who could not be included in the analysis, and a survival analysis that assumes no unmeasured correlation between survival and censoring. CONCLUSIONS: Watson for Oncology produced therapeutic options highly concordant with human decisions at a top-tier cancer center in China. Treatment patterns suggest that Watson for Oncology may be able to guide clinicians to minimize overtreatment of patients with high-risk stage II colon cancer with chemotherapy. Survival analyses suggest the need for further investigation to specifically assess the association between surveillance, single-agent and multiagent chemotherapy, and survival outcomes in this population. See Video Abstract at http://links.lww.com/DCR/B291. APOYO A LA DECISIÓN CLÍNICA DEL CÁNCER DE COLON EN ESTADIO II DE ALTO RIESGO: UN ESTUDIO DEL MUNDO REAL SOBRE LA CONCORDANCIA DEL TRATAMIENTO Y LA SUPERVIVENCIA: Los factores de riesgo pronósticos y patológicos generalmente guían a los médicos y pacientes en su elección de vigilancia o quimioterapia adyuvante cuando se trata el cáncer de colon en estadio II de alto riesgo. Sin embargo, las variaciones en el tratamiento y los resultados en pacientes con cáncer de colon en estadio II permanecen.Evaluar los beneficios de supervivencia de los tratamientos concordantes con las opciones terapéuticas sugeridas por "Watson for Oncology" (Watson para la oncología), un sistema de apoyo a la decisión clínica.Estudio observacional retrospectivo de concordancia entre el tratamiento real y las opciones terapéuticas de Watson para oncología.Un centro oncológico de primer nivel en China.Datos de tratamiento postoperatorio de registros de salud electrónicos de 306 pacientes con adenocarcinoma de colon en estadio II de alto riesgo.Patrones de tratamiento más supervivencia global y libre de enfermedad a 3 y 5 años para casos concordantes y no concordantes.La concordancia general fue del 90%. La mayoría de la atención no concordante resultó del uso de quimioterapia adyuvante (en lugar de vigilancia) en pacientes de alto nivel con inestabilidad de microsatélites y pacientes ≥70 años. No se observaron diferencias en la supervivencia global (p = 0,56) o la supervivencia libre de enfermedad (p = 0,19) entre los grupos de concordancia. Los pacientes que recibieron quimioterapia adyuvante tuvieron una supervivencia global a los 5 años significativamente más alta que los que fueron sometidos a vigilancia (94% frente a 84%, p = 0,01).Uso de casos retrospectivos extraídos de pacientes que se presentan para cirugía, falta de datos de seguimiento completos para el 58% de los pacientes que no pudieron ser incluidos en el análisis, y análisis de supervivencia que asume que no exite una correlación no medida entre supervivencia y censura.Watson para Oncología produjo opciones terapéuticas altamente concordantes con las decisiones humanas en un centro oncológico de primer nivel en China. Los patrones de tratamiento sugieren que Watson para Oncología puede guiar a los médicos para minimizar el sobretratamiento de pacientes con cáncer de colon en estadio II de alto riesgo con quimioterapia. Los análisis de supervivencia sugieren la necesidad de realizar mas investigaciónes para evaluar específicamente la asociación entre la vigilancia, la quimioterapia con uno solo o múltiples agentes y los resultados de supervivencia en esta población. Consulte Video Resumen en http://links.lww.com/DCR/B291. (Traducción-Dr. Gonzalo Hagerman).

Prognostic value of nucleotyping, DNA ploidy and stroma in high-risk stage II colon cancer.

BACKGROUND: Heterogeneity with respect to recurrence and survival in high-risk stage II colon cancer patients still exists, and further classification is urgently required. This study aimed to ascertain the prognostic value of DNA ploidy, stroma-tumour fraction and nucleotyping in the prognosis of high-risk stage II colon cancer. METHODS: A total of 188 high-risk stage II colon cancer patients received radical surgery in Peking University Cancer Hospital, from 2009 to 2015. Status of mismatch repair proteins in tumours was analysed using immunohistochemistry. DNA ploidy, stroma-tumour fraction and nucleotyping were estimated by automated digital imaging systems. RESULTS: Nucleotyping and DNA ploidy were significant prognostic factors, while stroma-tumour fraction were not significantly prognostic in the univariate analysis. In the multivariable model, the dominant contributory factor of disease-free survival was chromatin heterogeneous vs. chromatin homogeneous [HR 3.309 (95% CI: 1.668-6.564), P = 0.001]. CONCLUSIONS: Our study indicates that nucleotyping is an independent prognostic factor in high-risk stage II colon cancer. Therefore, it may help subdivide patients into different subgroups and give them different strategies for follow-up and treatment in the future.

Circular RNA circCTNNA1 promotes colorectal cancer progression by sponging miR-149-5p and regulating FOXM1 expression.

Circular RNAs (circRNAs) are an emerging class of non-coding RNAs, identified to participate in multiple malignancies. Nevertheless, the clinical significance, biological function, and regulatory mechanisms of circRNAs in colon cancer (CC) remain largely unclear. In this study, the circRNA expression profile in CC and matched normal tissues was analyzed using circRNA microarrays. A novel circRNA, circCTNNA1, was significantly upregulated in CC, and its level was associated with advanced tumor-node-metastasis stage and poor prognosis of patients with CC. Functional experiments, including Cell Counting Kit-8, colony formation, 5-ethynyl-2'-deoxyuridine, transwell, wound healing, flow cytometric analysis, and in vivo tumorigenesis assay were then performed to investigate the oncogenic role of circCTNNA1. The results revealed that circCTNNA1 promoted CC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, RNA pull-down, RNA immunoprecipitation, dual-luciferase reporter assays, and fluorescent in situ hybridization were performed to unveil that circCTNNA1 can serve as a competing endogenous RNA of miR-149-5p to counteract the suppressive effect of miR-149-5p on downstream target Forkhead Box M1 (FOXM1). In summary, our study demonstrated that circCTNNA1 facilitated CC proliferation and invasion via the circCTNNA1/miR-149-5p/FOXM1 axis, and it might function as a novel diagnostic or therapeutic target for patients with CC.

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.

WITHDRAWN: Circular RNA circUBA1 promotes gastric cancer proliferation and metastasis by acting as a competitive endogenous RNA through sponging miR-375 and regulating TEAD4.

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Expert consensus on multidisciplinary therapy of colorectal cancer with lung metastases (2019 edition).

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

[Effect of adjuvant chemotherapy on the prognosis of stage II( colon cancer patients with high risk factors].

OBJECTIVE: To investigate the effect of adjuvant chemotherapy on the prognosis of stage II( colon cancer patients with high risk factors. METHODS: Clinicopathological and follow-up data of stage II( colon cancer patients undergoing radical surgery from January 2001 to March 2012 at Gastrointestinal Cancer Center of Peking University Cancer Hospital were retrospectively analyzed. The effect of adjuvant chemotherapy (within postoperative 2 month, fluorine uracil as main drugs) on the prognosis of high-risk patients was analyzed. High risk factors were defined as having at least one of the following factors: (1) tumor stage T4; (2) poor differentiation; (3) with vascular cancer embolus; (4) number of harvested lymph node less than 12; (5) complicated with obstruction or perforation. RESULTS: A total of 497 patients with stage II( colon cancer were included in this study, of whom 258 cases(51.9%) had high risk factors, including stage T4 tumor in 80 cases(16.1%), poor differentiation in 80 cases (16.1%), cancer embolus in 37 cases (7.4%), lymph node harvested number less than 12 in 88 cases (17.7%), and obstruction or perforation in 85 cases (17.1%). Among 497 patients, number of cases with 1 to 4 high risk factors was 170 (34.2%), 68 (13.7%), 16 (3.2%) and 4 (0.8%), respectively. The last follow-up time was December 2016. The 5-year overall survival rate of all the 497 patients was 81.7%. The 5-year overall survival rate of 239 patients without high risk factors was 87.0%. The 5-year survival rate in patients with 1 to 4 risk factors was 81.9%, 73.7%, 66.7% and 25.0%, respectively (P=0.001). There was no significant difference in 5-year survival rate between 103 patients with adjuvant chemotherapy and 394 patients without adjuvant chemotherapy (79.6% vs. 82.8%, P=0.814). In patients with high risk factors, 80(31.0%) received adjuvant chemotherapy. There was no significant difference of 5-year survival rate between 80 patients with adjuvant chemotherapy and 178 patients without adjuvant chemotherapy (81.4% vs. 74.7%, P=0.147). Multivariate analysis showed that preoperative CEA level, T4 stage, lymph node harvested number, and tumor differentiation were the independent prognostic factors of patients with stage II( colon cancer (all P<0.05). CONCLUSIONS: The proportion of patients with at least one risk factor is quite high in stage II( colon cancer cases. Adjuvant chemotherapy can not prolong the overall survival time of high risk patients.

[Gastrointestinal surgeons should master the adjuvant therapy of colorectal cancer].

The diagnosis and treatment of colorectal cancer is one of the main diseases of gastrointestinal surgeons. It is very important to master the adjuvant chemotherapy of colorectal cancer for gastrointestinal surgeons. In recent years, with the development of a number of clinical trials and the appearance of new drugs, fluorouracil combined with oxaliplatin had been established as the standard regimen of adjuvant chemotherapy for colorectal cancer. In the current guidelines, stage III( colon cancer is the indication for adjuvant chemotherapy, while stage II( colon cancer should receive adjuvant chemotherapy is uncertain. Unlike colon cancer, adjuvant therapy of rectal cancer is not evidence-based. Especially, the indication and duration of adjuvant chemotherapy for rectal cancer after neoadjuvant chemoradiotherapy remain controversial. Adjuvant therapy of colorectal cancer still needs further investigation.

[Clinical characteristics and prognosis of colon cancer patient with extremely elevated carcinoembryonic antigen level].

OBJECTIVE: To explore the clinicopathological characteristics and prognosis of colon cancer patients with extremely elevated serum carcinoembryonic antigen(CEA) level before operation(>50 µg/L). METHODS: Clinicopathological and follow-up data of 1250 patients with colonic adenocarcinoma undergoing primary tumor resection between January 2001 and December 2011 were retrospectively analyzed. All the patients were divided into three groups according to the preoperative serum CEA levels as normal group (0-5 µg/L, 721 cases), elevated group(5-50 µg/L, 408 cases) and extremely elevated(>50 µg/L, 121 cases). Kaplan-Meier method was used to analyze the overall survival and disease-free survival. Log-rank test was used to compare the survival between groups. Cox regression was used to screen the independent prognostic factors of colon cancer. RESULTS: Compared with normal and elevated groups, patients with extremely elevated CEA had more advanced T,N,M stages (P<0.01), more palliative surgery (P<0.01) and more lymphovascular invasion(P<0.01). During the follow-up, patients with extremely elevated CEA demonstrated significantly higher ratio of distant metastases and liver metastases (both P=0.001). After radical surgery, 5-year overall survival rate of patients with normal, elevated and extremely elevated CEA levels was 70.1%, 54.4% and 42%, respectively, with statistically significant difference among three groups (P<0.001). Multivariate analysis showed that tumor differentiation, TNM staging, preoperative CEA levels, lymphovascular invasion and adjuvant chemotherapy were independent prognostic factors for colon cancer (all P<0.01). CONCLUSIONS: Colon cancer patients with extremely elevated preoperative CEA levels are associated with more unfavorable pathological factors, advanced TNM stage and more distant metastases (especially the liver metastases) during the follow-up. The elevated degree of preoperative CEA level is an independent poor prognostic factor of patients with colon cancer.

[Retrospective analysis of 856 cases with stage 0 to III rectal cancer underwent curative surgery combined modality therapy].

OBJECTIVE: To investigate the survival and prognostic factors of stage 0 to III rectal cancer in 10 years. METHODS: Clinical data and follow-up of 856 rectal cancer patients with stage 0-III underwent curative surgery from January 2000 to December 2010 were retrospective analyzed. There were 470 male and 386 female patients, with a mean age of (58 ± 12) years. Kaplan-Meier method was used to analyze the overall survival and disease free survival. Log-rank test was used to compare the survival between groups. Cox regression was used to analyze the independent prognostic factors of rectal cancer. RESULTS: The patients in each stage were stage 0 with 18 cases, stage I with 209 cases, stage II with 235 cases, and stage III with 394 cases. All patients received curative surgery. There were 296 patients evaluated as cT3, cT4 and any T with N+ received preoperative radiotherapy. 5.4% patients got pathological complete response (16/296), and the recurrence rate was 4.7% (14/296). After a median time of 41.7 months (range 4.1 to 144.0 months) follow-up, the 5-year overall survival rate in stage 0 to I of was 91.0%, stage II 86.2%, and stage III 60.0%, with a significant difference (P=0.000). The cumulative local recurrence rate was 4.8% (41/856), of which 70.7% (29/41) occurred within 3 years postoperatively, 97.6% (40/41) in 5 years. The cumulative distant metastasis rate was 16.4% (140/856), of which 82.9% (129/140) occurred within 3 years postoperatively, 96.4% (135/140) in 5 years. The incidence of abnormal imaging findings was significantly higher in pulmonary than liver and other sites metastases (75.0% vs. 21.7%, χ² =25.691, P=0.000). The incidence of CEA elevation was significantly higher in liver than lung and other sites metastases (56.8% vs. 37.8%, χ² =25.691, P=0.000). Multivariable analysis showed that age (P=0.015, HR=1.385, 95% CI: 1.066 to 1.801), surgical approach (P=0.029, HR=1.337, 95% CI: 1.030 to 1.733), differentiation (P=0.000, HR=1.535, 95% CI: 1.222 to 1.928), TNM stage (P=0.000, HR=1.349, 95% CI: 1.260 to 1.444) and lymphovascular invasion (P=0.001, HR=1.715, 95% CI: 1.258 to 2.342) are the independent prognostic factors for rectal cancer. CONCLUSIONS: Age, surgical approach, differentiation, TNM stage and lymphovascular invasion are independent prognostic factors for rectal cancer. Preoperative evaluation and combined modality therapy can significant reduce the local recurrence and improve overall survival for rectal cancer patients.

Rectal cancer patients after neoadjuvant radiotherapy (30Gy/10f) with negative lymph node may not benefit from postoperative adjuvant chemotherapy: a retrospective study.

OBJECTIVE: The purpose of this study is to evaluate whether adjuvant chemotherapy could bring oncologic benefit to all patients who underwent neoadjuvant radiotherapy (30Gy/10f). METHODS: Rectal cancer patients receiving preoperative radiotherapy between July 2002 and April 2009 were retrospectively identified. RESULTS: A total of 225 patients were enrolled in this study. One hundred thirty-one patients received postoperative adjuvant chemotherapy, and 94 patients did not. The 120 ypN+ and 105 ypN- patients were divided into chemo and non-chemo groups. Two groups of patients did not show any significant difference in terms of gender, age, ypT stage, preoperative serum carcinoembryonic antigen (CEA) level, differentiation, circumferential margin (CRM), lymphovascular invasion (LVI), surgical approach, local recurrence, and distant metastasis (P > 0.05). Survival analysis showed that in ypN+ patients, the 5-year overall survival (OS) rate and 5-year disease-free survival (DFS) rate in chemo group were both significantly higher than non-chemo group (P < 0.05). In ypN- patients, the 5-year OS rate and 5-year DFS rate did not show any significant difference in the two groups (P > 0.05). Subgroup analysis showed that the 5-year OS rate and 5-year DFS rate in ypT0-2 N- patients (P > 0.05) and ypT3-4 N- patients (P > 0.05) did not show any significant difference, either. CONCLUSIONS: Based on a Chinese protocol, patients with ypN- stage may not benefit from adjuvant chemotherapy, regardless of the ypT stage, while the ypN+ patients may benefit from adjuvant chemotherapy. More randomized clinical trials are needed in the future.

Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives.

Trying to develop potent and selective anticancer agents, two series of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives were designed and synthesized. Their antitumor activities were evaluated by MTT method against four selected human cancer cell lines (MGC-803, EC-9706, HeLa and MCF-7). Our results showed that compound 11h exhibited good anticancer activities compared to 5-fluorouracil against the four tested cell lines, with IC50 values ranging from 2.0 to 4.5 µM. Flow cytometry analysis indicated that compound 11h induced the cellular early apoptosis and cell cycle arrest at G2/M phase in EC-9706.

Synthesis and biological evaluation of novel pyrimidine-benzimidazol hybrids as potential anticancer agents.

A series of pyrimidine-benzimidazol hybrids was synthesized and evaluated for anticancer activity on four human cancer cell lines including MCF-7, MGC-803, EC-9706 and SMMC-7721. Some of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 5a-b and 6a-b showed most effective activity. Compounds 5b and 6b were more cytotoxic than 5-fluorouracil against all tested four human cancer cell lines, with IC50 values ranging from 2.03 to 10.55 µM and 1.06 to 12.89 µM, respectively. Flow cytometry analysis demonstrated that treatment of MGC-803 with 6b led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death.

Expression of HER-2 in rectal cancers treated with preoperative radiotherapy: a potential biomarker predictive of metastasis.

BACKGROUND: Evidence suggests HER-2 overexpression may be predictive of prognosis in colorectal cancer patients, though this remains controversial. OBJECTIVES: This study was performed to assess the prognostic value of HER-2 expression in locally advanced rectal cancer patients after preoperative radiotherapy. PATIENTS AND METHODS: HER-2 expression was evaluated based on immunohistochemical (IHC) staining of resected specimens from 142 mid-to-low rectal cancer patients. Fluorescence in situ hybridization (FISH) was performed to confirm HER-2 overexpression in samples with an IHC score of 2+. Tumor regression grading (TRG) of the primary tumors was determined semiquantitatively using a tumor regression grading scheme advocated in the AJCC Cancer Staging Manual 7 edition. RESULTS: When the total staining intensity was evaluated, 106 samples (74.6%) showed barely-perceptible positivity (0-1+; HER-2--negative), 15 samples (10.6%) showed moderate positivity (2+) and 21 samples (14.8%) showed strong positivity (3+, HER-2 positive). FISH confirmed that 2 cases showing moderate HER-2 positivity (2+) overexpressed HER2. There was no significant difference between the HER-2 positive and -negative groups with respect to age, gender, TRG, TNM stage, downstaging status, lymphovascular invasion or tumor differentiation. A significant correlation was found between HER-2 overexpression and the incidence of distant metastasis (p = 0.005). Subgroup analysis revealed this correlation was not significant (p = 0.247) in the radiation-insensitive (TRG0-2) subgroup, whereas a significant correlation (p = 0.026) between HER-2 overexpression and distant metastasis was found in the radiation-resistant (TRG3) subgroup. Multivariate analysis identified ypN stage (OR = 0.473, p = 0.002)and overexpression of HER-2 (OR = 3.704, p = 0.008) as independent risk factors for distant metastasis. There was no correlation between HER-2 overexpression and disease-free survival or overall survival among the study population. LIMITATIONS: We reported that HER-2 overexpression was correlated with distant metastasis in rectal cancer patients, especially in the radiation-insensitive group. However, there are certain limitations. First, this study was limited due to the fact that the number of rectal patients enrolled was only 142, which is relatively small. Second, HER-2 expression was measured by IHC with a positive ratio around 15%, which is fairly high according to the literature. Also, we collected the tissue samples preoperatively. It would be interesting to know the HER-2 expression levels pre- and postradiotherapy, as well as their correlation with local recurrence or distant metastasis. Finally, in rectal cancer patients, there is little information published on HER-2 and its role in tumor progression and metastasis. Therefore, we are pursuing the regulatory molecule underlined. CONCLUSIONS: HER-2 is overexpressed in around 15% of rectal cancer patients who receive neoadjuvant radiotherapy. Moreover, HER-2 overexpression could be a predictive biomarker of distant metastasis in rectal cancer patients after preoperative radiotherapy, especially patients showing a poor response to neoadjuvant radiotherapy.

Synthesis, in vitro antimicrobial and cytotoxic activities of novel pyrimidine-benzimidazol combinations.

A series of novel 4-substituted-2-{[(1H-benzo[d]imidazol-2-yl)methyl] thio}-6-methylpyrimidine derivatives were designed, synthesized and evaluated for their cytotoxic activities against four human cancer cell lines and inhibitory activities against five type culture strains in vitro. Some of synthetic pyrimidine-benzimidazol combinations showed good inhibitory activities against Stenotrophomonas maltophilia, especially compounds 7b and 7c. Compounds 7a and 7d exhibited enhanced activities against MGC-803 in vitro, when compared to 5-Fu.