Rongxin Zhang

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

BACKGROUND Hand-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). METHODS We 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. RESULTS Grade 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). CONCLUSIONS Celecoxib can be used effectively and safely to prevent capecitabine-related HFS.BACKGROUND Hand-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). METHODS We 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. RESULTS Grade 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). CONCLUSIONS Celecoxib 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.

Indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 expression prediction for adverse prognosis in colorectal cancer

AIM To evaluate indoleamine-2,3-dioxygenase 1/cyclooxygenase 2 (IDO1/COX2) expression as an independent prognostic biomarker for colorectal cancer (CRC) patients. METHODS We retrospectively studied the medical records of 95 patients who received surgical resection from August 2008 to January 2010. All patients were randomly assigned to adjuvant treatment with or without celecoxib groups after surgery. We performed standard immunohistochemistry to assess the expression levels of IDO1/COX2 and evaluated the correlation of IDO1/COX2 with clinicopathological factors and overall survival (OS) outcomes. RESULTS The expression of nuclear IDO1 was significantly correlated with body mass index (P < 0.001), and IDO1 expression displayed no association with sex, age, tumor differentiation, T stage, N stage, carcinoembryonic antigen, cancer antigen 19-9, CD3+ and CD8+ tumor infiltrating lymphocytes, and COX2. In univariate analysis, we found that nuclear IDO1 (P = 0.039), nuclear/cytoplasmic IDO1 [hazard ratio (HR) = 2.044, 95% confidence interval (CI): 0.871-4.798, P = 0.039], nuclear IDO1/COX2 (HR = 3.048, 95%CI: 0.868-10.7, P = 0.0049) and cytoplasmic IDO1/COX2 (HR = 2.109, 95%CI: 0.976-4.558, P = 0.022) all yielded significantly poor OS outcomes. Nuclear IDO1 (P = 0.041), nuclear/cytoplasmic IDO1 (HR = 3.023, 95%CI: 0.585-15.61, P = 0.041) and cytoplasmic IDO1/COX2 (HR = 2.740, 95%CI: 0.764-9.831, P = 0.038) have significantly poor OS outcomes for the CRC celecoxib subgroup. In our multivariate Cox model, high coexpression of cytoplasmic IDO1/COX2 was found to be an independent predictor of poor outcome in CRC (HR = 2.218, 95%CI: 1.011-4.48, P = 0.047) and celecoxib subgroup patients (HR = 3.210, 95%CI: 1.074-9.590, P = 0.037). CONCLUSION Our results showed that cytoplasmic IDO1/COX2 coexpression could be used as an independent poor predictor for OS in CRC.

Genetic variations in the PI3K/PTEN/AKT/mTOR pathway predict tumor response and disease-free survival in locally advanced rectal cancer patients receiving preoperative chemoradiotherapy and radical surgery

Objective: Although preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC), the clinical efficacy differs among patients. This study was conducted to determine the association between genetic variations in the PI3K/PTEN/AKT/mTOR pathway and clinical outcomes in LARC patients. Methods: Sixteen tagging single-nucleotide polymorphisms (SNPs) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) were genotyped. The associations of these SNPs with tumor response to preoperative CRT, postoperative disease-free survival (DFS) and overall survival (OS) were identified. Crude odds ratios (ORs) and hazard ratios (HRs) were adjusted by age, sex, clinical stage, tumor differentiation, tumor location, cycles of preoperative chemotherapy and time interval from CRT completion to surgery. Results: In an analysis of 97 LARC patients, the G/T+G/G genotype of AKT1:rs2498804 was associated with an increased tumor response rate (adjusted OR = 2.909, 95% confidence interval (CI), 1.127-7.505, P = 0.027). At a median of 65.7 months of follow-up, the G/C+C/C genotype of AKT2:rs8100018 was associated with a reduced risk of postoperative recurrence (adjusted HR = 0.414; 95% CI, 0.187-0.914, P = 0.029). Patients carrying the G/C+C/C genotype in AKT2:rs8100018 presented a higher 5-year DFS rate than those with the wild-type genotype (79.2% vs. 62.3%, P = 0.038). None of the SNPs were significantly associated with pathological complete response (pCR) or 5-year OS. Conclusions: The current study indicates that genetic variations within the PI3K/ PTEN/AKT/mTOR signaling pathway are associated with the clinical outcomes of LARC patients undergoing preoperative CRT followed by radical surgery.

Sorafenib Monotherapy Versus Sorafenib Combined with Regional Therapies for Hepatocellular Carcinoma Patients with Pulmonary Oligometastases: A Propensity Score-matched Analysis.

Background: Sorafenib has been recommended as the standard therapy for advanced HCC with extrahepatic metastasis. The purpose of this retrospective study was to investigate the difference in overall survival (OS) between treatments with sorafenib combined with regional therapies versus sorafenib monotherapy in hepatocellular carcinoma (HCC) patients with pulmonary oligometastases. Methods: The study retrospectively enrolled 95 consecutive patients who underwent sorafenib therapy. A combined group (CG) of 40 patients received regional therapy in addition to sorafenib, and a monotherapy group (MG) of 55 patients received only sorafenib. OS was the primary endpoint, and time to progression (TTP) was the secondary endpoint. Subgroup analysis was further performed to evaluate the differences between the two groups. A propensity score-matched analysis was performed to overcome the bias. Results: Median OS was significantly longer in the CG than in the MG (18.37 vs. 7.13 months; P = 0.002). Multivariate analysis identified three baseline characteristics that were prognostic indicators of OS: macrovascular invasion, regional therapy, and alpha-fetoprotein. Median TTP was significantly longer in the CG than in the MG (2.93 vs. 2.23 months; P = 0.004). Further multivariate analysis showed alpha-fetoprotein, total bilirubin, and regional therapy as prognostic indicators of TTP. After propensity score matching, 34 paired patients constituted each group. Patients in the adjusted CG showed a longer OS and TTP than those in the adjusted MG (OS: 18.37 vs. 7.37 months, P = 0.015; TTP: 3.12 vs. 2.265 months, P = 0.009). Multivariate analysis showed that combining regional therapies was still a prognostic indicator of OS (P = 0.01) and TTP (P = 0.001). Conclusions: Sorafenib combined with regional therapies may be associated with prolonged OS and TTP in HCC patients with pulmonary oligometastases compared with sorafenib monotherapy.

Right- and left-sided stage III colon cancers present different prognostic outcomes of oxaliplatin-based adjuvant chemotherapy after curative resection

Background Growing evidence has suggested that right-sided colon cancer (RCC) and left-sided colon cancer (LCC) should be considered as different tumor entities. However, stage III colon cancer is currently treated as the same entity with uniform therapy. This study was aimed at investigating the prognostic influence of tumor location in patients with stage III colon cancer receiving adjuvant chemotherapy after curative resection. Patients and methods We retrospectively analyzed 274 eligible patients with stage III colon cancer undergoing curative tumor resection followed by adjuvant chemotherapy with oxaliplatin and capecitabine between December 2007 and December 2013. Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan–Meier and log-rank tests, and prognostic factors were identified by Cox regression methods. Results Patients with RCC exhibited lower hemoglobin levels (23.6% vs. 9.8%; P = 0.002), larger tumor size (60.6% vs. 40.9%; P = 0.001), and a higher proportion of 12 or more resected lymph nodes (86.4% vs. 64.6%; P < 0.001) than patients with LCC. Grade 1 neurotoxicity was more common in patients with RCC than in those with LCC (53.6% vs. 40.9%; P = 0.037). RCC was significantly associated with a shorter 3-year OS than LCC, whereas a difference was noted only for stage IIIC and not stage IIIA or stage IIIB colon cancer. Multivariate analyses revealed that RCC was independently associated with a worse 3-year OS (hazard ratio: 2.213; 95% CI: 1.063–4.606; P = 0.002). In addition, an increase in 3-year OS and DFS after 6–8 cycles of adjuvant chemotherapy was only observed in patients with RCC and not in those with LCC. Conclusion This study indicated that RCC has a worse prognostic outcome for stage III colon cancer, and a full course of adjuvant chemotherapy should be suggested for patients with RCC.

Serum CNPY2 isoform 2 represents a novel biomarker for early detection of colorectal cancer

Since early diagnosis is very important for treating CRC, we decided to detect peripheral serum canopy fibroblast growth factor signaling regulator 2 (CNPY2) isoform 2 to verify its diagnostic value for CRC patients. Serum samples were collected from 430 CRC patients and 201 healthy controls. Enzyme-linked immunosorbent assay (ELISA) detection kits for CNPY2 isoform 2 were generated and then applied to measure serum CNPY2 isoform 2 concentrations. Serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were also measured. The median serum CNPY2 isoform 2 concentrations in all CRC patients were significantly higher than those in the healthy control group (all P<0.001). Those with stage I CRC presented the highest area under the receiver operating characteristic curve (AUC) for CNPY2 isoform 2 [0.707, 95% confidence interval (CI): 0.649–0.765, P<0.001]. The diagnostic efficiency of the combination of CNPY2 isoform 2, CEA and CA19-9 was significantly higher than that of each biomarker detected separately (all P<0.0167). Serum CNPY2 isoform 2 may be a valuable biomarker for the early detection of CRC and presents an improvement in the diagnostic efficiency by combination of CEA and CA19-9.

Pretreatment TACC3 expression in locally advanced rectal cancer decreases the response to neoadjuvant chemoradiotherapy

Chemoradiotherapy combined with surgical resection is the standard treatment for locally advanced rectal cancer, but not all the patients respond to neoadjuvant treatment. Transforming acidic coiled-coil protein-3 (TACC3) is frequently aberrantly expressed in rectal cancer tissue. In this study, we investigated whether TACC3 could serve as a biomarker predictive of the efficacy of chemoradiotherapy. In all, 152 rectal cancer patients with tumor tissue collected at biopsy and set aside before treatment were enrolled in this study. All patients received chemoradiotherapy and surgical resection. Immunohistochemically detected tumoral TACC3 expression significantly decreased sensitivity to chemoradiotherapy [risk ratio (RR) = 2.236, 95% confidence interval (CI): 1.447–3.456; P = 0.001] and thus the pathological complete response rate (P = 0.001). TACC3 knockdown using specific siRNA enhanced radiotherapy-induced decreases in proliferation and colony formation by HCT116 and SW480 cells and increased the incidence of radiotherapy-induced apoptosis. Cox multivariate analysis showed that TACC3 was a significant prognostic factor for overall survival (P = 0.017) and disease-free survival (P = 0.020). These findings suggest TACC3 expression may be predictive of chemoradiotherapy sensitivity and prognosis in locally advanced rectal cancer.

Laparoscopic total mesorectal excision (TME) with electric hook for rectal cancer

Procedures of laparoscopic total mesorectal excision (TME) with electric hook for rectal cancer are described. Laparoscopy requires cooperation between the surgeon, first assistant surgeon and second assistant surgeon, in order to recognize the inferior mesenteric artery (IMA), the inferior mesenteric vein (IMV), the neurovascular bundle (NVB), and the fibrous tissues between the mesorectum and the surrounding tissues or organs. Some important organs, such as the autonomic nerves, left ureter, left gonadal vessels, and pancreas, should be avoided being injured. Comparing with ultrasound knife, the advantage of electric hook is obvious. Less smog will be produced if the electric hook is used within 2 seconds, and clearer dissectible layer will appear during the TME surgery with electric hook.

Density of CD8+ lymphocytes in biopsy samples combined with the circulating lymphocyte ratio predicts pathologic complete response to chemoradiotherapy for rectal cancer

Objectives The systemic status and local immune status, as determined by the neutrophil–lymphocyte ratio (NLR) or the lymphocyte ratio (LYMR) and tumor-infiltrating lymphocyte (TIL) count, respectively, have been suggested as predictors of the tumor response to neoadjuvant chemoradiotherapy (nCRT) in rectal cancer, although the utility of these measures remains controversial. We aimed to investigate the values of the LYMR, NLR and TIL count and their combinations (TIL–LYMR/TIL–NLR) in predicting pathologic complete response (pCR) after nCRT. Patients and methods Pretreatment biopsy samples and data from the blood tests of 92 patients with rectal cancer who underwent curative resection after nCRT were retrospectively obtained. CD8+ TILs were immunostained using an antibody against CD8. The density of CD8+ TILs was recorded as the number of CD8+ T cells per square millimeter, and the results were classified as either “high” or “low”. The LYMR and NLR were calculated using pretreatment blood test data and categorized into either “high” or “low” groups. TIL–LYMR was graded as “low,” “mid” or “high” when neither, one or both the CD8+ TIL count and LYMR were “high,” respectively. TIL–NLR was graded similarly. The associations between TILs and LYMR, NLR and their combinations (TIL–LYMR/TIL–NLR) were evaluated. Results pCR was significantly associated with a high LYMR, a low NLR and increased chemotherapy cycles (P=0.039, P=0.043 and P=0.015, respectively), but not with the CD8+ TIL count or carcinoembryonic antigen (CEA) level (P=0.100 and P=0.590, respectively). Additionally, 40% of patients with high LYMR and 40.7% with low NLR achieved pCR, whereas only 19.7% with low LYMR and 20.3% with high NLR did so. When the combinations were assessed, TIL–LYMR showed a positive correlation with pCR (P=0.038), while no association between TIL–NLR and pCR was found (P=0.916). In multivariate analysis, TIL–LYMR remained an independent predictor of pCR (odds ratio [OR]=1.833, 95% confidence interval [CI]=1.069–3.142, P=0.028). Conclusion High LYMR, low NLR and high TIL–LYMR at baseline are predictive of pCR to nCRT for patients with rectal cancer. These parameters may help identify pCR patients and provide additional information for therapeutic decision-making.