Zhenhai Lu

Elevated expressions of MMP7, TROP2, and survivin are associated with survival, disease recurrence, and liver metastasis of colon cancer

PurposeColorectal cancer is one of the most common cancers worldwide. We tested the hypothesis that differences in the expression of certain molecular markers of colon cancer may account for different clinical outcomes.MethodsTissue microarray technology was used to assay the expression of 17 biological markers [β-catenin, CD44v7, c-myc, cyclin D1, estrogen receptor β, mitogen-activated protein kinase/extracellular signal-regulated kinase, maspin, matrix metalloproteinase-7 (MMP7), p53, Pin1, peroxisome proliferators-activated receptor-gamma, survivin, T cell transcription factor 4 (TCF4), transforming growth factor beta receptor II (TGFβR II), TGFβ, TROP2, and Wnt] by immunohistochemistry in 620 colon cancer patients. The Cox proportional hazards regression model was applied to analyze the lifetime data, including time to death, time to recurrence, and time to liver metastasis.ResultsAll the markers were present at significantly higher expression levels in tumor specimens than in normal colonic specimens. Kaplan–Meier analysis showed that high expression of TROP2, MMP7, and survivin were related to decreased survival; TCF4 and TROP2 were related to disease recurrence; and CD44v7, cyclin D1, MMP7, p53, survivin, and TCF4 were related to liver metastasis. However, the results of the multivariate analysis only showed that expression of MMP7, survivin, and TROP2 were significant predictors of lower patient survival, while TROP2 and MMP7 were significantly related to disease recurrence and liver metastasis, respectively.ConclusionsWe conclude that elevated survivin, MMP7, and TROP2 expression levels are related to decreased survival. In addition, elevated MMP7 and TROP2 expression levels are predictors of disease recurrence and liver metastasis, respectively.

Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial

BACKGROUNDnHand-foot syndrome (HFS) is the most common adverse event induced by capecitabine. Some clinicians think that HFS is a type of inflammation limited to the hands and feet and can be prevented with a COX-2 inhibitor (celecoxib).nnnMETHODSnWe designed a single-center, prospective randomized clinical trial to test the hypothesis. From August 2008 to December 2010, stage II and III colorectal cancer patients receiving capecitabine-based chemotherapy enrolled in the trial voluntarily. All patients were divided randomly into two groups treated with or without celecoxib. All adverse events were recorded.nnnRESULTSnGrade 1 and grade 2 HFS were more common in the capecitabine group than in the capecitabine/celecoxib group (74.6% versus 57.4%, P = 0.034, 29.6% versus 14.7% P = 0.035). The use of celecoxib (P < 0.001, P = 0.003) and the level of dihydropyrimidine dehydrogenase (P = 0.048, P = 0.014) affected the incidence of grade 1 and 2 HFS, as determined by log-rank analysis. Multivariate Cox proportional hazards regression analysis indicated that the use of celecoxib was the only factor that affected the incidence of ≥ grade 1 HFS [Hazard Ratio (HR): 0.556, P = 0.001] and ≥ grade 2 HFS (HR: 0.414, P = 0.005).nnnCONCLUSIONSnCelecoxib can be used effectively and safely to prevent capecitabine-related HFS.BACKGROUNDnHand-foot syndrome (HFS) is the most common adverse event induced by capecitabine. Some clinicians think that HFS is a type of inflammation limited to the hands and feet and can be prevented with a COX-2 inhibitor (celecoxib).nnnMETHODSnWe designed a single-center, prospective randomized clinical trial to test the hypothesis. From August 2008 to December 2010, stage II and III colorectal cancer patients receiving capecitabine-based chemotherapy enrolled in the trial voluntarily. All patients were divided randomly into two groups treated with or without celecoxib. All adverse events were recorded.nnnRESULTSnGrade 1 and grade 2 HFS were more common in the capecitabine group than in the capecitabine/celecoxib group (74.6% versus 57.4%, P = 0.034, 29.6% versus 14.7% P = 0.035). The use of celecoxib (P < 0.001, P = 0.003) and the level of dihydropyrimidine dehydrogenase (P = 0.048, P = 0.014) affected the incidence of grade 1 and 2 HFS, as determined by log-rank analysis. Multivariate Cox proportional hazards regression analysis indicated that the use of celecoxib was the only factor that affected the incidence of ≥ grade 1 HFS [Hazard Ratio (HR): 0.556, P = 0.001] and ≥ grade 2 HFS (HR: 0.414, P = 0.005).nnnCONCLUSIONSnCelecoxib can be used effectively and safely to prevent capecitabine-related HFS.

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.

Cerebrospinal Fluid Levels of Soluble Amyloid Precursor Protein and β-Amyloid 42 in Patients with Multiple Sclerosis, Neuromyelitis Optica and Clinically Isolated Syndrome

Amyloid precursor protein (APP) accumulation in axonal ovoids is a sensitive marker for acute axonal injury in multiple sclerosis (MS) lesions. This study measured levels of α-cleaved soluble APP (αsAPP) and β-amyloid 42 (Aβ42) in the cerebrospinal fluid (CSF) of 42 MS, 10 neuromyelitis optica and 25 clinically isolated syndrome patients and 21 healthy controls, and analysed the correlation between αsAPP and Aβ42 levels and relevant clinical parameters. The CSF concentrations of αsAPP and Aβ42 in patients and controls were not significantly different. There was a significant inverse correlation in patients between CSF asAPP concentration and the Expanded Disability Status Scale (EDSS), but no significant correlation between CSF Aβ42 concentration and EDSS. The concentration of αsAPP in the CSF of statin-treated patients was significantly higher than in those not treated with statins, suggesting that statins may have a neuroprotective effect. In conclusion, αsAPP was present at similar levels in the CSF of patients with neuromyelitis optica, MS and clinically isolated syndrome and healthy controls, and an inverse correlation existed between CSF αsAPP concentration and neurological disability.

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.

Phase i trial of hepatic arterial infusion (HAI) of floxuridine with modified oxaliplatin, 5-fluorouracil and leucovorin (m-FOLFOX6) in Chinese patients with unresectable liver metastases from colorectal cancer

AbstractPurposenTo determine the maximum tolerated dose (MTD) and preliminary efficacy of concurrent hepatic arterial infusion (HAI) of floxuridine (FUDR) and systemic modified oxaliplatin, 5-fluorouracil and leucovorin (m-FOLFOX6) in Chinese patients with unresectable hepatic metastases from colorectal cancer.nPatients and methodsThirty-five patients with unresectable liver metastases with or without extrahepatic disease were treated with concurrent HAI and systemic m-FOLFOX6. HAI FUDR was delivered in a 14-day infusion with escalating dose levels, and each cycle was repeated every 4xa0weeks.ResultsThe MTD for FUDR was 0.12xa0mg/kg/day when combined with systemic m-FOLFOX6. The dose-limited toxicities were neutropenia (8.6xa0%), alanine aminotransferase/aspartate aminotransferase elevation (5.7xa0%) and diarrhea (11.4xa0%). The overall response rate was 68.6xa0% for hepatic metastases and 14.3xa0% for extrahepatic metastases. The median progression-free survival and overall survival were 8.23 and 25xa0months, respectively.ConclusionThe recommended dose of FUDR was 0.12xa0mg/kg/day when combined with systemic m-FOLFOX6. This combination achieved a high response rate in hepatic disease and a high control rate in extrahepatic disease. Further study is needed to assess the potential additional value of HAI therapy in converting patients with hepatic metastases to candidates for resection.

High preoperative serum CA19-9 level is predictive of poor prognosis for patients with colorectal liver oligometastases undergoing hepatic resection

Oligometastasis is defined as a transitional state between localized and widespread systemic metastatic cancers. In colorectal cancer, the prognostic factors and prognostic value of preoperative serum carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) for patients with colorectal liver oligometastases (CLOM) undergoing hepatic resection have not been well explored. Therefore, the present study included 141 patients with CLOM (≤5 liver metastases) who underwent R0 resection from 2005 to 2012. The association of clinicopathological factors including preoperative CA19-9 and CEA levels with overall survival (OS) was analyzed with univariate and multivariate analyses. Kaplan–Meier analysis showed that patients with high CA19-9 levels tended to have poorer OS than those with low levels (median OS 21.5 vs. 64.0xa0months, Pxa0=xa00.002). Preoperative CEA levels were not significantly associated with OS (Pxa0>xa00.05). Univariate and multivariate analyses demonstrated that larger tumor size of liver metastases (HR 1.911; 95xa0% CI 1.172–3.114; Pxa0=xa00.009), bilobar distribution (HR 1.776; 95xa0% CI 1.097–2.873; Pxa0=xa00.019), and higher preoperative CA19-9 levels (HR 1.954; 95xa0% CI 1.177–3.242; Pxa0=xa00.010) were independent predictors of poor OS for patients with CLOM. Our study identified tumor size, distribution, and preoperative CA19-9 levels as independent prognostic factors for OS of patients with CLOM. In particular, measurement of preoperative CA19-9 levels offers an easy tool that could help identify high-risk patients and aid in improving the management of patients with CLOM.