Neoadjuvant immunotherapy in microsatellite stability or mismatch repair proficient colorectal cancer / 中华胃肠外科杂志

Immunotherapy has become an important treatment option for microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) colorectal cancer. From late-line to first-line treatment, and even in neoadjuvant setting for early stage colorectal cancer, promising efficacy was observed with immunotherapy. In microsatellite stability (MSS) or mismatch repair proficient (pMMR) colorectal cancer, the researches of neoadjuvant immunotherapy have been conducted constantly. This paper focuses on the recent researches and progress of neoadjuvant immunotherapy for MSS or pMMR colorectal cancer. Neoadjuvant immunotherapy alone led to a good pathological response in a subset of patients. Studies of induction or consolidation immunotherapy before or after neoadjuvant chemoradiotherapy or concurrent immunotherapy during radiotherapy showed higher pathological complete remission (pCR) rates as compared to standard chemoradiotherapy. Studies on sequential dual immunotherapy after radiochemotherapy and targeted therapy combined with neoadjuvant immunotherapy are ongoing. At present, most of these are pilot studies with small sample size. More researches and long-term follow-up are needed to prove the efficacy of neoadjuvant immunotherapy in MSS or pMMR colorectal cancer.

Clinical value of MR diffusion weighted imaging in prediction of pathological complete response of rectal cancer after neoadjuvant therapy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the application value of magnetic resonance diffusion-weighted imaging (DWI) combined with routine T2WI sequence in the determination of pathological complete response (pCR) after neoadjuvant therapy for rectal cancer.</p><p><b>METHODS</b>Clinical data of 51 cases with locally advanced mid-low rectal cancer undergoing neoadjuvant therapy plus radical resection in the Rectal Cancer Center at The Sixth Affiliated Hospital of Sun Yat-sen University from June 2012 to April 2013 were analyzed retrospectively. Magnetic resonance DWI and T2WI sequences scanning were performed within 1 week before neoadjuvant therapy and within 1 week before operation. Routine single T2WI sequence and DWI combined with T2WI sequence were used separately to predict the residual tumor and to compare with postoperative pathological examination. The prediction values of two methods were compared.</p><p><b>RESULTS</b>Of 51 patients, 12 cases had pathological complete response (pCR). Prediction of DWI combined T2WI sequence was correct in 8 cases of pCR, whose sensitivity and specificity were higher than those of routine single T2WI sequence (66.7%, 94.9% vs. 33.3%, 84.6%). Prediction value of DWI combined T2WI sequence for pCR was significantly higher as compared to routine single T2WI sequence (AUC, 0.808 vs. 0.590, P=0.001).</p><p><b>CONCLUSION</b>Compared with the routine single T2WI sequence, DWI combined with T2WI sequence can improve the prediction accuracy of pathological complete response.</p>

Lymph nodes distribution and metastatic pattern of ultra-low rectal cancer after neoadjuvant therapy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the lymph nodes distribution and metastatic pattern of the ultra-low rectal cancer after neoadjuvant therapy.</p><p><b>METHODS</b>A total of 21 rectal cancer gross specimen after neoadjuvant therapy and 23 rectal cancer gross specimen without neoadjuvant therapy were investigated by whole mount section and tissue microarray techniques with CK20. All the patients were treated by abdominoperineal resection.</p><p><b>RESULTS</b>There were 138 lymph nodes retrieved from the mesorectum in the neoadjuvant group including 39 metastatic lymph nodes and 12 micro-metastatic lymph nodes. Among these nodes, there were 7 rectal cancer cases with lymph nodes and 2 cases with micro-metastatic lymph nodes, and 6 cases had pathological complete remission. There were 415 lymph nodes retrieved from the mesorectum in the group without neoadjuvant therapy including 169 metastatic lymph nodes and 59 micro-metastatic lymph nodes. Among these nodes, there were 12 rectal cancer cases with lymph nodes and 4 cases with micro-metastatic lymph nodes. The proportions of metastatic lymph nodes in outer zone between the two groups were 21.5% and 29.0%, and those in pre-zone were 17.6% and 17.2% respectively. The ratio of metastatic lymph nodes in ischiorectal fossa between the two groups were 25.0% vs. 22.2% respectively. The rate of metastatic or micro-metastatic lymph nodes cases between the two groups were 4.8% vs. 13.0% respectively.</p><p><b>CONCLUSIONS</b>The lymph nodes distribution and metastatic pattern of the ultra-low rectal cancer are affected by neoadjuvant therapy. The proportions of the anal sphincter invasion and metastatic or micro-metastatic lymph nodes in ischiorectal fossa are lower after neoadjuvant therapy. Abdominoperineal resection as the standard treatment of the ultra-low rectal cancer after neoadjuvant therapy should be re-evaluated.</p>

Meta-analysis of efficacy and safety on neoadjuvant therapy for rectal cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To assess the value of neoadjuvant therapy for resectable rectal cancer and the impact on postoperative complications.</p><p><b>METHODS</b>Literature search was performed in PubMed, Ovid, Web of Science, Springer-Link and Elsevier ScienceDirect for randomized controlled trials published before May 2010 that compared neoadjuvant therapy with surgery alone or postoperative adjuvant therapy. The computer search was supplemented with hand search of reference lists for available primary studies. Inclusion criteria and quality assessment were performed.</p><p><b>RESULTS</b>Eleven studies including 7407 patients were enrolled for analysis. Neoadjuvant therapy group had significant advantages in local recurrence (OR=0.43, 95%CI:0.37-0.50, P<0.01), distant recurrence (OR=0.85, 95%CI:0.76-0.95, P<0.01), 5-year overall survival (RR=1.15, 95%CI:1.04-1.28, P<0.01), and sphincter-saving surgery (RR=1.48, 95%CI:1.17-1.87, P<0.01). There were no significant difference in postoperative mortality rate(OR=1.20, 95%CI:0.68-2.13, P=0.53) and anastomotic complications (OR=1.04, 95%CI:0.73-1.48, P=0.84).</p><p><b>CONCLUSION</b>Neoadjuvant therapy improves local control, distant recurrence and long-term survival without increasing postoperative complications.</p>

The effects of curcumin derivative on experimental steatohepatitis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To observe the effects of curcumin derivative on non-alcoholic steatohepatitis (NASH).</p><p><b>METHODS</b>60 SD male rats were randomly divided into 5 groups. The NASH model was induced by high fat diet combined with carbon tetrachloride. These rats were then treated with curcumin and curcumin derivative, saline treating group as control. The serum biochemical parameters and liver histological examinations were observed. The TNF alpha, NF-kappa B and HMG-CoA reductase mRNA transcriptions of liver tissue were detected with RT-PCR. The protein expressions of TNF alpha and NF-kappa B were detected by western blot.</p><p><b>RESULTS</b>Compared with the saline group, A remarkable reduction was observed in serum ALT (U/L), AST (U/L) and TC (mmol/L) in rats treated with curcumin derivatives [(69.20 +/- 27.58) vs (102.43 +/- 47.29), (158.00 +/- 39.15) vs (229.50 +/- 105.20) and (2.08 +/- 0.30) vs (2.58 +/- 1.02), P < 0.05]. The degrees of fibrosis were significantly alleviated; Compared with curcumin group, liver index and serum ALT, AST of curcumin derivative group were also significantly decreased [(4.88 +/- 0.62) vs (5.16 +/- 0.61); (69.20 +/- 27.58) vs (82.5 +/- 33.23); (158.00 +/- 39.15) vs (211.75 +/- 106.30), P < 0.05]; The liver steatosis and inflammation grade were also significantly improved .The gene transcriptions of TNF alpha, NF-kappa B and HMG-CoA reductase in curcumin derivative group were significantly lower than those in curcumin and saline group (P < 0.05).</p><p><b>CONCLUSION</b>These results indicate that the water-soluble curcumin derivative displays superior bioavailability to the parent curcumin, which can effectively improve the lipid metabolism and delay the progression of hepatic fibrosis in rats with steatohepatitis.</p>

5-Fluorouracil upregulates the activity of Wnt signaling pathway in CD133-positive colon cancer stem-like cells / 癌症

<p><b>BACKGROUND AND OBJECTIVE</b>CD133-positive colon cancer stem like cells (CSLCs) are resistant to the conventional cytotoxic drug 5-fluorouracil (5-FU). Wnt signaling pathway plays important roles in colon cancer carcinogenesis and metastasis, and regulates the self-renewal capacity of CSLCs. In the present study, we explored the impact of 5-FU on Wnt signaling pathway of CD133-positive colon CSLCs, and the relation between Wnt signaling pathway and drug resistance of CD133-positive colon CSLCs.</p><p><b>METHODS</b>Magnetic activation cell separation was used to collect CD133-positive cells from colon cancer cell line DLD1, which was transfected with luciferase reporter for Wnt signaling activity. The activity of Wnt signaling pathway was compared between CD133-positive and CD133-negative cells. After the treatment with 1 μg/mL of 5-FU, the cell proliferation rates of DLD1 cells, CD133-positive cells, and CD133-negative cells were compared. After the treatment with 1 μg/mL and 10 μg/mL of 5-FU for 48 h, Wnt activity was compared between CD133-positive and CD133-negative cells. The expression of CD133 and cell apoptosis of CD133-positive cells was detected after exposure to 50 ng/mL of dickkopf (DKK)-1, a Wnt pathway inhibitor.</p><p><b>RESULTS</b>After the treatment with 5-FU, the cell proliferation rate of CD133-positive cells was higher than that of CD133-negative cells and the sensitivity of CD133-positive cells to 5-FU decreased. Wnt activity was higher in CD133-positive cells than in CD133-negative cells [(46.3 ± 0.3)% vs. (33.9 ± 2.7)%, P = 0.009]. After the treatment with 1 μg/mL and 10 μg/mL of 5-FU, Wnt activity of CD133-positive cells was (90.1 ± 10.0)% (P = 0.012) and (52.9 ± 2.5)% (P = 0.047), respectively, whereas that of CD133-negative cells was (35.5 ± 3.3)% (P = 0.434) and (26.5 ± 0.4)% (P = 0.046), respectively. CD133 expression in CD133-positive cells decreased from (87.2 ± 5.3)% to (60.6 ± 3.1)% (P = 0.022) after treatment with DKK-1, whereas the cell apoptosis rate increased from (11.8 ± 0.2)% to (28.3 ± 0.6)% (P = 0.013).</p><p><b>CONCLUSIONS</b>Wnt activity is higher in CD133-positive DLD1 cells than in CD133-negative DLD1 cells. 5-FU can upregulate Wnt activity of CD133-positive colon CSLCs. Blocking Wnt activity may reverse drug sensitivity of CD133-positive cells to 5-FU.</p>

Effect of KRAS mutation on efficacy of Cetuximab combined with chemotherapy in advanced colorectal cancer patients / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the relationship between KRAS gene status and efficacy of Cetuximab (C225) combined with chemotherapy on advanced colorectal cancer in Chinese patients, and to evaluate the safety of C225.</p><p><b>METHODS</b>From May 2006 to March 2009, 81 patients with advanced colorectal cancer received Cetuximab combined with chemotherapy were enrolled in this study. The rate of KRAS mutation and the relationship of KRAS with response rate (RR), progression-free survivor (PFS), overall survival (OS) and adverse reaction of C225 were analyzed retrospectively.</p><p><b>RESULTS</b>All the 81 patients received C225 therapy, and the overall RR was 33.3%. The RR of initiate therapy was 57.1%; of the second line and over the third line therapy was 38.5% and 22.0% respectively. KRAS gene phenotype examination was performed in 44 patients whose tumor samples were available. KRAS mutation was found in 20 cases (45%). Out of 44 patients, 43 were evaluable for response. RR was 5% and 43.48% in KRAS mutation and wild KRAS patients respectively (P =0.002). The median PFS was 7.0 weeks and 18.6 weeks in mutational KRAS patients and wild KRAS patients, reaching statistical significance (P =0.003). The median OS was 15.2 months and 17.3 months in mutational KRAS patients and wild KRAS patients respectively without statistical significance (P =0.463). The common adverse reactions were leucopenia, nausea, vomiting and rash. All the adverse reactions were tolerated. The incidence of skin rash in patients with mutational KRAS and patients without KRAS mutation was 40% and 42% respectively, without statistical significance (P =0.91).</p><p><b>CONCLUSION</b>C225 combined with chemotherapy is well-tolerated in Chinese patients with advanced colorectal cancer, and it can significantly prolong PFS of patients with wild KRAS as compared to patients with KRAS mutation.</p>

Preoperative chemoradiotherapy with FOLFOX in low rectal cancer: a multicenter study / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the toxicity and safety of FOLFOX regimen concurrent with radiotherapy in neoadjuvant setting in patients with low rectal cancer.</p><p><b>METHODS</b>Fifty-six patients with stage T(3-4)N(0)M(0) and T(1-4)N(1-2)M(0) were eligible from Aug. 2004 to Jul. 2007. Upon entry the study, they received 4 cycles of chemotherapy with FOLFOX regimen. Radiotherapy was added from the second cycle of chemotherapy (CT). The total dose of radiotherapy (RT) was 46 Gy (2 Gy x 23). Total mesorectal excision (TME) was performed 4-8 weeks after RT.</p><p><b>RESULTS</b>Among them, 54 cases received 4 cycles of CT, 1 patient stopped CT after the second cycle of CT because of unrecovery from neutropenia. One patient stopped chemoradiotherapy(CRT) because of complicating with active pulmonary tuberculosis after 2 cycles of CT and 10 times of RT. Two occurred liver, lung and bone metastases after CT. Totally 220 cycles of CT were administrated. Fifty-two patients received operation after CRT, 50 with anal interior sphincter reservation, 19 with prophylactic ileac stoma. Anastomotic leakage occurred in 2 patients after operation, and rectal vaginal fistula in 2 patients 1 month after operation. According to the pathologic results, 7 patients achieved complete response, 41 partial response, 4 stable disease, and the objective response rate was 85.7%.</p><p><b>CONCLUSION</b>Concomitant treatment of FOLFOX regimen and RT in neoadjuvant setting of rectal cancer was safe and tolerable, and it suggests that protective ileostomy for anastomotic leakage following anus-preserving operation should be performed.</p>

Protective efficacy and probable mechanism of ulinastatin in patients with gastrointestinal cancer undergoing adjuvant chemotherapy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate whether ulinastatin can alleviate the side effect in patients with gastrointestinal cancer undergoing adjuvant chemotherapy,and to explore the probable mechanism of its protective efficacy.</p><p><b>METHODS</b>Forty consecutive patients with gastrointestinal cancer who underwent surgical operations from May 2004 to October 2004 were recruited. The patients were randomly divided into therapeutic group and control group, receiving ulinastatin 150,000 U per day or 250 ml hydrochloric sodium before chemotherapy for 5 continuous days respectively. The prevalence of side effects and the levels IL-6 and TNF-alpha were compared between the two groups.</p><p><b>RESULTS</b>There were no differences in the clinicopathological characteristics between the two groups. The prevalences of white blood cell decline (41.2% versus 13.1%), pigmentation (23.5% versus 4.3%), baldness (17.6% versus 4.3%) were higher in the control group than those in therapeutic group (all P< 0.05). In therapeutic group, IL-6 level was significantly decreased after ulinastatin treatment, but not in the control group while the levels of TNF-alpha were not changed in the both groups.</p><p><b>CONCLUSION</b>Ulinastatin can reduce the common side effects of chemotherapy, and the mechanism may be associated with the decrease of IL-6.</p>