Zhizhong Pan

The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer

BackgroundOne of the putative mechanisms of tumor immune escape is based on the hypothesis that carcinomas actively create an immunosuppressed state via the expression of indoleamine 2,3-dioxygenase (IDO), both in the cancer cells and in the immune cells among the tumor-draining lymph nodes (TDLN). In an attempt to verify this hypothesis, the patterns of expression of IDO in the cancer cells and the immune cells among colon cancers were examined.MethodsSeventy-one cases of pathologically-confirmed colon cancer tissues matched with adjacent non-cancerous tissues, lymph node metastases, and TDLN without metastases were collected at the Sun Yat-sen Cancer Center between January 2000 and December 2000. The expression of IDO and Bin1, an IDO regulator, was determined with an immunohistochemical assay. The association between IDO or Bin1 expression and TNM stages and the 5-year survival rate in colon cancer patients was analyzed.ResultsIDO and Bin1 were detected in the cytoplasm of cancer cells and normal epithelium. In primary colon cancer, the strong expression of IDO existed in 9/71 cases (12.7%), while the strong expression of Bin1 existed in 33/71 cases (46.5%). However, similar staining of IDO and Bin1 existed in the adjacent non-cancerous tissues. Among the 41 cases with primary colon tumor and lymph node metastases, decreased expression of IDO was documented in the lymph node metastases. Furthermore, among the TDLN without metastases, a higher density of IDO+cells was documented in 21/60 cases (35%). Both univariate and multivariate analyses revealed that the density of IDO+cells in TDLN was an independent prognostic factor. The patients with a higher density of IDO+cells in TDLN had a lower 5-year survival rate (37.5%) than the cells with a lower density (73.1%).ConclusionThis study demonstrated paradoxical patterns of expression of IDO in colon cancer. The high density IDO+cells existed in TDLN and IDO was down-regulated in lymph nodes with metastases, implying that IDO in tumor and immune cells functions differently.

Long noncoding RNA XIST expedites metastasis and modulates epithelial–mesenchymal transition in colorectal cancer

Tumor progression and metastasis is the main cause of death in colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer. In this study, we found that lncRNA XIST was overexpressed in CRC cell lines and tissues. High expression of lncRNA XIST was associated with adverse overall survival in CRC patients. Knockdown of lncRNA XIST remarkably inhibited CRC cell proliferation, invasion, epithelial–mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and metastasis in vivo. Further study indicated that knockdown of lncRNA XIST markedly increased the expression of microRNA-200b-3p (miR-200b-3p) that has been found to be downregulated in CRC tissues and cell lines, and luciferase activity assay indicated that lncRNA XIST could bind directly with miR-200b-3p. Moreover, knockdown of lncRNA XIST significantly reduced the expression of ZEB1, which was the direct target of miR-200b-3p, and the tumor suppressive effects caused by knockdown of lncRNA XIST could be rescued by re-expression of ZEB1 in CRC cells. Overall, our study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1. lncRNA XIST may be used as a biomarker to predict prognosis in CRC patients.

Intraoperative Blood Loss Independently Predicts Survival and Recurrence after Resection of Colorectal Cancer Liver Metastasis

Background Although numerous prognostic factors have been reported for colorectal cancer liver metastasis (CRLM), few studies have reported intraoperative blood loss (IBL) effects on clinical outcome after CRLM resection. Methods We retrospectively evaluated the clinical and histopathological characteristics of 139 patients who underwent liver resection for CRLM. The IBL cutoff volume was calculated using receiver operating characteristic curves. Overall survival (OS) and recurrence free survival (RFS) were assessed using the Kaplan–Meier and Cox regression methods. Results All patients underwent curative resection. The median follow up period was 25.0 months (range, 2.1–88.8). Body mass index (BMI) and CRLM number and tumor size were associated with increased IBL. BMI (P=0.01; 95% CI = 1.3–8.5) and IBL (P<0.01; 95% CI = 1.6–12.5) were independent OSOs predictors. Five factors, including IBL (P=0.02; 95% CI = 1.1–4.1), were significantly related to RFS via multivariate Cox regression analysis. In addition, OSOs and RFS significantly decreased with increasing IBL volumes. The 5-year OSOs of patients with IBL≤250, 250–500, and >500mL were 71%, 33%, and 0%, respectively (P<0.01). RFS of patients within three IBL volumes at the end of the first year were 67%, 38%, and 18%, respectively (P<0.01). Conclusions IBL during CRLM resection is an independent predictor of long term survival and tumor recurrence, and its prognostic value was confirmed by a dose–response relationship.

Neuroprotective effect of neurotropin on chronic oxaliplatin-induced neurotoxicity in stage II and stage III colorectal cancer patients: results from a prospective, randomised, single-centre, pilot clinical trial

BackgroundOxaliplatin is effective in adjuvant and first-line colorectal cancer chemotherapy. Oxaliplatin-induced severe chronic neurotoxicity is the main dose-limiting adverse event. No standard treatment for oxaliplatin-induced chronic neurotoxicity has been identified.Materials and methodsWe conducted a prospective pilot clinical trial to explore whether neurotropin has neuroprotective effects on chronic neurotoxicity. From May 1, 2010 to May 1, 2011, 80 stage II and III colorectal cancer patients who were eligible to receive oxaliplatin-based chemotherapy voluntarily enrolled in the trial. The patients were randomly divided into two groups, one of which received neurotropin treatment.ResultsThe patients in the control group experienced significantlyu2009≥u2009grade 2 andu2009≥u2009grade 3 neurotoxicity (by NCI CTCAE grading) than those in the neurotropin group (60.9 vs. 21.1xa0%, for at least grade 2 neurotoxicity, Pu2009=u20090.001; 39 vs. 2.7xa0%, for at least grade 3 neurotoxicity, Pu2009<u20090.001). If neurotoxicity was assessed by oxaliplatin-specific neurotoxicity grading, the patients in the control group also experienced significantly moreu2009≥u2009grade 2 neurotoxicity (51.2 vs. 12.5xa0%, Pu2009=u20090.001). Neurotropin was the only factor that affected the incidence ofu2009≥u2009grade 2 neurotoxicity in the multivariate Cox proportional hazards regression analysis.ConclusionNeurotropin combined with oxaliplatin decreases chronic neurotoxicity effectively and safely.

Oxaliplatin and capecitabine concomitant with neoadjuvant radiotherapy and extended to the resting period in high risk locally advanced rectal cancer.

BackgroundConventional neoadjuvant chemoradiotherapy (CRT) is suboptimal for systemic control in locally advanced rectal cancer (LARC). To improve systemic control, we developed an alternative approach in which an intensified oxaliplatin and capecitabine (XELOX) chemotherapy regimen was administered concomitantly with radiation and extended to the resting period (consolidation chemotherapy) for high-risk LARC. The aim of the current study was to evaluate the short-term efficacy and toxicity of this strategy.MethodsPatients with high-risk LARC were treated with CRT. Two cycles of XELOX were administered concomitantly with radiation. Thereafter, an additional cycle of the same regimen was administered during the resting period after completion of CRT. Tumor response, toxicities and surgical complications were recorded.ResultsThis study includes 36xa0patients treated with the above strategy. All patients completed the planned concurrent CRT. Because of gradexa03 toxicities, 2xa0patients were unable to complete the additional chemotherapy. Gradexa03 toxicities were leucopenia (2.8u2009%), diarrhea (2.8u2009%) and radiodermatitis (2.8u2009%). All patients underwent optimal surgery with total mesorectal excision (TME) and a sphincter-saving procedure was performed in 27xa0patients (75u2009%). There was no perioperative mortality. Postoperative complications developed in 7xa0patients (19.4u2009%). Pathologic complete regression (pCR),“nearly pCR” (major regression), and moderate or minimal regression were achieved in 13xa0(36.1u2009%), 16xa0(44.4u2009%), and 7xa0patients (19.5u2009%), respectively.ConclusionThe preliminary results suggest that a XELOX regimen initially administered concomitantly with radiotherapy and then extended to the resting period in high-risk LARC patients is well tolerated. The strategy is highly effective in terms of pCR and nearly pCR rates, and thus warrants further investigation.ZusammenfassungHintergrundKonventionell neoadjuvante Radiochemotherapie (CRT) ist suboptimal für die systemische Kontrolle des lokal fortgeschrittenen Rektumkarzinoms (LARC). Um die systemische Kontrolle zu verbessern, haben wir eine alternative Herangehensweise entwickelt, in welcher wir eine intensivierte Chemotherapie mit dem XELOX-Therapieschema (Oxaliplatin und Capecitabin) begleitend zur Bestrahlung kombiniert und auf die Ruhephase des High-Risk-LARC ausgeweitet haben (Konsolidierungschemotherapie). Das Ziel der Studie stellte die Evaluierung der Kurzzeit-Wirksamkeit und der Toxizität dieser Vorgehensweise dar.Patienten und MethodenPatienten mit High-Risk-LARC wurden mit einer CRT behandelt. Begleitend zur Bestrahlung wurden 2xa0Therapiezyklen XELOX verabreicht. Anschließend wurde ein zusätzlicher Therapiezyklus über die Ruhephase nach Abschluss der CRT verabreicht. Erfasst wurden Tumorantwort, Toxizität und Komplikationen beim Eingriff.ErgebnisseEs wurden 36xa0Patienten ermittelt, welche mit dieser Methode behandelt wurden. Alle Patienten komplettierten die begleitende CRT. Aufgrund von Grad-3-Toxizitäten konnten 2xa0Patienten die zusätzliche Chemotherapie nicht abschließen. Toxizitäten dritten Grades waren Leukozytopenie (2,8u2009%), Diarrhoe (2,8u2009%) und Radiodermatitis (2,8u2009%). Allen Patienten wurde eine optimale chirurgische Therapie durch totale mesorektale Exzision („total mesorectal excision“, TME) zuteil, unter ihnen befanden sich 27xa0Patienten (75u2009%), die spinktererhaltend operiert werden konnten. Es gab keine perioperative Mortalität in der Kohorte. Bei 7xa0Patienten (19,4u2009%) traten postoperative Komplikationen auf. Eine pathologisch vollständige Regression (pCR), überwiegende Regression (“nearly pCR“) und mäßige oder minimale Regression wurde bei je 13 (36,1u2009%), 16 (44,4u2009%) und 7 (19,5u2009%) Patienten erreicht.SchlussfolgerungDie vorläufigen Ergebnisse legen den Schluss nahe, dass ein Therapieschema mit XELOX begleitend zur Radiotherapie, ausgeweitet auf die Ruhephase bei High-Risk-LARC gut toleriert wird. Die Methode ist höchst effektiv in Bezug auf pCR- und überwiegende pCR-Raten. Somit sind weitere Untersuchungen gerechtfertigt.

PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407

Colorectal cancer (CRC) is the third most common cause of cancer deaths, and has a high rate of liver and lung metastasis. Unfortunately, distant metastasis is the main barrier for advanced CRC therapy and leads to a very low survival rate. In this study, we identified WDR5, a vital factor that regulates vertebrate development and cell self-renewal and reprogramming, as a novel prognostic marker and therapeutic target for CRC patients. We demonstrate that WDR5 is upregulated in CRC tissues and promotes CRC metastasis both in vitro and in vivo. In an effort to investigate the impact of WDR5 on CRC cell fate, we treated CRC cells with growth factor and inhibitor. We report that WDR5 is a novel factor in the metastasis of CRC by triggering epithelial–mesenchymal transition (EMT) process in response to the PI3K/AKT signaling pathway. Moreover, WDR5 shows a direct binding to the ZNF407 promoter on regulating cellular EMT process, leading to CRC metastasis. Hence, our findings strongly position WDR5 as a valuable marker for CRC, and inhibiting WDR5 or the associated signaling pathways may be an effective strategy for the future development of anti-CRC therapy.

Phase II study of pre-operative radiotherapy with capecitabine and oxaliplatin for rectal cancer and carcinoembryonic antigen as a predictor of pathological tumour response

This study investigated the efficacy and tolerability of pre-operative radiotherapy with concurrent capecitabine and oxaliplatin in patients with rectal cancer. Forty-seven patients with rectal adenocarcinoma (stages T3 – T4; node-positive) were enrolled and received radiotherapy (46 Gy in 23 fractions) in combination with capecitabine (1000 mg/m2 twice daily on days 1–14 and 22–35) and oxaliplatin (130 mg/m2 on days 1 and 22) (XELOX regimen). The main endpoints were safety and efficacy, as assessed by pathological complete response (pCR). All patients received pre-operative chemoradiotherapy (CRT) as planned. The most common severe toxicity was diarrhoea (12.8%); post-operative complications were rare (9.8%). The pCR rate was 20.9% in all patients and 34.8% in patients with normal pre-CRT serum carcinoembryonic antigen (CEA < 5 ng/ml) level, compared with 5.0% in the patients with elevated CEA (> 5 ng/ml). In conclusion, pre-operative radiotherapy with concurrent XELOX regimen in rectal cancer patients is feasible and effective. Serum CEA may be a suitable predictor of pCR.

Optimal use of adjuvant chemotherapy in stage II colorectal cancer

Background and objectiveThe prognosis of stage II colorectal cancer varies. Whether or not to perform adjuvant chemotherapy on patients with stage II colorectal cancer is a controversial issue. The aims of this study were to identify relevant risk factors for the prognosis of stage II colorectal cancer and to evaluate the need for adjuvant chemotherapy.MethodBetween January 2000 and January 2005, 443 patients with stage II colorectal cancer who had received radical surgery at the Sun Yat-sen University Cancer Center were retrospectively analyzed. The overall survival rates and survival curves were analyzed using the Kaplan–Meier method and log–rank test. Univariate and multivariate prognostic analyses were performed using the Cox regression model. Patients with certain important risk factors were analyzed according to whether they received adjuvant chemotherapy, and four chemotherapeutic regimens were classified into sub-groups and analyzed.ResultsUnivariate analyses showed that intestinal obstruction or perforation, type 2 diabetes mellitus, an inadequate surgical margin, and sampling of less than 12 lymph nodes were risk factors that correlated with poor prognosis. Patients with an intestinal obstruction or perforation and insufficient lymph node samples achieved higher 5-year survival rates with adjuvant chemotherapy than with surgery alone.ConclusionIntestinal obstruction or perforation, sampling of less than 12 lymph nodes, and inadequate surgical margins were identified as risk factors for poor survival, and patients with either of the first two factors benefited from adjuvant chemotherapy. Moreover, the use of capecitabine alone may be insufficient for patients with an intestinal obstruction or perforation.

Preoperative lymphocyte-to-monocyte ratio represents a superior predictor compared with neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios for colorectal liver-only metastases survival

Systemic inflammation was recognized as an essential factor contributing to the development of malignancies. This study aimed to investigate the prognostic value of pre-operative lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in patients with colorectal liver-only metastases (CLOM) undergoing hepatectomy. We retrospectively enrolled 150 consecutive patients with CLOM between 2000 and 2012. The optimal cutoff values of continuous LMR, NLR, and PLR were determined using the receiver operating characteristic curve analysis. Recurrence-free survival (RFS) and overall survival (OS) related to the LMR, NLR, and PLR were analyzed using both Kaplan–Meier and multivariate Cox regression methods. Elevated LMR (≥2.82) and lower NLR (<4.63) were significantly associated with better RFS and OS in patients with CLOM after hepatectomy, instead of lower PLR (<150.17). Multivariate Cox analysis identified elevated LMR as the only independent inflammatory factor for better RFS (hazard ratio, 0.591; 95% CI, 0.32–0.844; P=0.008) and OS (hazard ratio, 0.426; 95% CI, 0.254–0.716; P=0.001). In the subgroup analysis, elevated LMR was a significant favorable factor in both 5-year RFS and OS of patients with male gender, lymph node metastases, colon cancer, liver tumor with the largest diameter <5 cm, preoperative carcinoembryonic antigen level <200 ng/mL, negative hepatitis B virus infection, non-anatomic liver resection, postoperative chemotherapy, and non-preoperative chemotherapy. This study demonstrated that the preoperative LMR was an independent predictor of RFS and OS in patients with CLOM undergoing hepatic resection, and it appeared to be superior to the NLR and PLR.

Pathological Assessment of the AJCC Tumor Regression Grading System After Preoperative Chemoradiotherapy for Chinese Locally Advanced Rectal Cancer

Abstract We used American Joint Committee on Cancer (AJCC) Staging Manual system to assess the prognostic significance of tumor regression grading (TRG) for locally advanced rectal cancer (LARC) (T3/4 or N+) patients who were treated with preoperative chemoradiotherapy (CRT). The 4 AJCC-TRG classifications were evaluated on surgical specimens from 295 LARC patients receiving CRT. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were estimated using Kaplan–Meier method and Cox regression model. Classifications of TRG 0, 1, 2, and 3 were found in 27.5%, 19.3%, 45.7%, and 7.5% of the resected specimens, respectively. Three-year OS was 95.5% for TRG0, 91.5% for TRG1, 84.8% for TRG2, and 85.7% for TRG3 (Pu200a=u200a0.035). Three-year DFS was 89.0% for TRG0, 74.4% for TRG1, 70.9% for TRG2, and 62% for TRG3 (Pu200a=u200a0.018). By multivariate analysis, AJCC-TRG (Pu200a=u200a0.033), residual lymph node metastasis (ypN+) (Pu200a<u200a0.001) and pretreatment CA19-9 level (Pu200a=u200a0.035) were significant predictors of OS. Pathological T category (Pu200a=u200a0.006) and nodal status (Pu200a<u200a0.001) after CRT were the most important independent prognostic factors for DFS. AJCC-TRG is a prognostic factor for LARC patients receiving CRT, independent of pathological staging.