Ulcerative colitis-associated colorectal cancer

The association between ulcerative colitis(UC) and colorectal cancer(CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC(UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, lowgrade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC.     

Surveillance strategies for colitis-associated cancer: state of the art and future perspectives

Introduction: Colitis-associated cancer (CAC) represents a concrete risk of morbidity and mortality in patients with long lasting inflammatory bowel diseases. Surveillance colonoscopy is a rapidly evolving research field with profound changes from the traditional approach based on scheduled controls and random biopsy protocols.

Areas covered: A literature search was performed using PubMed/Embase to review the latest evidence supporting the need for surveillance colonoscopy. By focusing on the most promising recent advances in this field, we provide a state-of-the-art overview of the current gold standards for the diagnosis and management of colitis-associated dysplasia.

Expert commentary: Evidence-based and emerging data have questioned the efficacy and effectiveness of both standard surveillance colonoscopy and random biopsy protocols. The latest guidelines endorse early initiation of surveillance programs, risk-profiling assessment of colonoscopy intervals and standardized use of advanced imaging modalities to detect early dysplasia. Current trends clearly reveal increased attention to direct visualization and endoscopic management of visible dysplastic lesions, even in patients with longstanding colitis. Emerging technological advances in gastrointestinal endoscopy are expected to change the endoscopic surveillance protocols in the near future.     

LRP-5、LRP-6在溃疡性结肠炎相关癌组织中表达的临床意义

目的:探讨脂蛋白受体相关蛋白5、6(LRP-5、LRP-6)在溃疡性结肠炎(UC)相关癌组织中的表达及意义.方法:以溃疡性结肠炎伴不典型增生(UD)和溃疡性结肠炎相关癌(UCAC)为病例组,溃疡性结肠炎(UC组)和散发性大肠癌(SCRC组)为对照组,应用免疫组织化学S-P法检测各组肠黏膜组织中LRP-5、LRP-6的表...     

Prognostic factors in patients with colorectal cancer receiving adjuvant chemotherapy or chemoradiotherapy: a pooled analysis of two randomized studies

Background. Although the TNM system is useful in predicting survival in resected colorectal cancer, heterogeneity within the same stages regarding prognosis exists. We are presenting a pooled analysis of prognostic factors from two randomized studies of adjuvant treatment conducted by the Hellenic Cooperative Oncology Group. Patients and Methods. Patients with stage II or III colon (n=279) or rectal (n=220) cancer were included in this analysis. Following surgery, patients received: 5-fluorouracil/leucovorin (5-FU/LV) (n=135), 5-FU/LV and interferon Alfa-2a (IFNA-2a) (n=138), 5-FU/LV and pelvic chemoradiotherapy (n=106), and pelvic chemoradiotherapy alone (n=108). Results. Median follow up was 92 mo. The number of involved lymph nodes (LNs), tumor differentiation, and the presence of regional implants were independent prognostic factors for both OS and TTP, while nerve invasion was only significant for TTP. Patients were stratified into three prognostic groups (low-risk: no LNs and grade 1/2; high-risk: >3 LNs and grade 3/4; intermediate-risk: remaining patients) with distinct differences in 5-yr survival (84.7% vs 57.6% vs 32.4%) and 5-yr TTP (81.2% vs 54.5% vs 28.6%). Conclusion. The combination of clinicopathological prognostic factors can be more informative than the traditional TNM staging system. Such stratification may be necessary in randomized trials and could be useful in deciding the most appropriate adjuvant treatment strategies.     

Effects of Streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis

Abstract

Background. Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. Aims. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Methods. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 10⁹ cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Results. Body weight was significantly decreased by doxorubicin compared with normal controls (p < 0.05). Histological parameters, such as crypt depth and villus height, were also significantly decreased by doxorubicin. TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. Conclusions. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens.     

溃疡性结肠炎相关性大肠癌P53、K-ras及hMSH2蛋白表达的研究

目的 探讨溃疡性结肠炎相关性大肠癌组织中P53、K-ras及hMSH2蛋白表达。方法 以溃疡性结肠炎伴不典型增生(UD)和溃疡性结肠炎相关性大肠癌(UCACRC)组织为实验组，溃疡性结肠炎(UC)和散发性大肠癌(SCRC)组织为对照组，应用免疫组化法检测组织中P53、K-ras、hMSH2蛋白的表达状况；聚合酶链式反应一单链构象多态性分析法(PCR-SSCP)检测组织中的微卫星不稳定性(MSI)状态(6个位点)，并进行统计学分析。结果 P53蛋白过表达的阳性率在UC(1／25例)与UD(3／7例)组间，UC与UCACRC(4／8例)组间差异均有统计学意义(P＜0．05，P＜0．01)，UCACRC与SCRC(17／30例)组间差异无统计学意义(P＞0．05)；突变型K-ras表达的阳性率在UC(4／25例)与UD(4／7例)组间，UC与UCACRC(7／8例)组间差异均有统计学意义(P＜0．05，P＜0．01)，UCACRC与SCRC(24／30例)组间差异无统计学意义(P＞0．05)；hMSH2蛋白缺失率在UC(2／25例)与UD(0／7例)组间、UD与UCACRC(4／8例)组间、UCACRC与SCRC(13／30例)组间差异均无统计学意义(P＞0．05)。MSI阳性率在UC(0／25例)与UD(3／7例)组间差异有统计学意义(P＜0．01)，在UD与UCACRC(2／8例)组间、UCACRC与SCRC(7／30例)组间差异无统计学意义(P＞0．05)。结论 P53、K-ras基因突变、MSI在UCACRC的发生发展过程中可能是一早期事件。UCACRC中MSI与hMSH2蛋白的缺失可能无关。     

Tamoxifen inhibits colorectal cancer metastases in the liver: A study in a murine model

Liver metastases account for over 70% of deaths resulting from colorectal carcinoma, with survival rates varying between 6–18 months. At present, surgical resection offers the only hope for a cure, while chemotherapy, focal destructive techniques and selective internal radiation offer palliative care. Tamoxifen, a non-steroidal anti-oestrogen is primarily known for treating oestrogen receptor (ER)-positive breast cancer. Some studies suggest that tamoxifen may have beneficial effects in malignancies other than breast cancer. These inhibitory effects, which have been shown to be independent of the ER, highlight new mechanisms of therapeutic action. Using an intrasplenic animal model we report the efficacy of tamoxifen on experimental liver metastases. In this model, a dimethyl hydrazine-induced colon carcinoma cell suspension is introduced into the portal circulation via the spleen, which results in secondary tumour deposits in the liver in virtually all animals. Tamoxifen was administered at a dose of 1 mg/kg suspended in 1.0% methyl cellulose. The control group received an equal volume of the vehicle. The reagents were administered s.c. on the day of metastases induction and were continued daily over a 4 week period. The effect of tamoxifen on tumour growth was assessed by stereology and bromodeoxyuridine immunohistochemistry at selected time points. Data were assessed by a multiple analysis of variance where P < 0.05 was considered significant. In the control group the volume of metastases increased from 44 ± 41 mm³ at day 10 to 517 ± 380 mm³, 1394 ± 598 mm³ and 2082 ± 675 mm³ by days 16, 22 and 28, respectively. Daily administration of tamoxifen exerted an inhibitory effect on tumour growth during the first 3 weeks, recording a volume of 421 ± 299 mm³ by day 22 compared with the control group at that time point (P= 0.00004). The inhibitory effect diminished by the fourth week recording a tumour volume of 1344 ± 674 mm³ by day 28. Inhibition of tumour growth at day 22 coincides with a reduction of cells in the S phase of the cell cycle. The percentage of brdU-positive nuclear profiles in metastases of tamoxifen-treated mice at 3 weeks was 35.87 ± 5.60% compared with 48.01 ± 3.96% in the control group (P=0.001). These data suggest that tamoxifen has a potent inhibitory action on colorectal liver metastases by exerting an effect on cell proliferation.     

以羟基喜树碱为主联合治疗晚期大肠癌

目的 评价以羟基喜树碱（HCPT）为主联合5-FU、CF治疗晚期大肠癌疗效及毒副反应。方法 将56例病人随机分为Ⅰ组20例,采用HCPT 5-FU CF方案;Ⅱ组18例,应用CDDP 5-FU CF方案;Ⅲ组18例,采用5-FU CF方案,4周为1周期,共完成6个周期,比较各组疗效及毒副作用。结果 Ⅰ组有效率（CR PR）50%,Ⅱ组33.3%,Ⅲ组11.1%,各组之间比较有显著性差异。结论 在无条件行体外肿瘤细胞药敏试验的情况下,以HCP为主联合方案治疗晚期大肠癌疗效肯定。病人耐受性好,值得推广应用。     

Topoisomerase I protein expression in primary colorectal cancer and recurrences after 5-FU-based adjuvant chemotherapy

Purpose Our aim was to investigate whether chemotherapy with 5-FU induces an alteration in the levels of topoisomerase I (topo I) in colorectal neoplastic tissues Methods Twenty-five colorectal cancer patients were included in our study; these had undergone surgical resection of the primary tumor, received post-operatively 5-FU-based adjuvant chemotherapy and then suffered from recurrences. In a standard three-step immunohistochemical procedure, a monoclonal antibody to topo I was applied in both specimens from each patient (one from the primary location and a second one from the recurrence). Statistical analysis was subsequently performed. Results Malignant cells from the recurrences displayed a statistical significant increase, concerning the levels of topoisomerase I, by comparison with the primary tumors (P = 0.01). The increase in topo I levels did not demonstrate significant correlations with Duke’s stage (Fisher’s Exact Test P value = 0.496), differentiation grade (P value = 0.661), localization (P value = 0.072), patient sex (P value = 0.434), nor with relapse free interval (P value = 0.493). There was a statistically significant relationship between the age of patients and increase in topo I levels (P = 0.011). Conclusions Topo I expression may be part of the malignant cells’ phenotype in recurrent colorectal carcinomas, suggesting a potential role for Topo I in the acquisition of a metastatic phenotype. The increase of topo I immunohistochemical status is likely to be attributed to 5-FU and given the fact that high levels of topo I correlate with sensitivity to camptothecin, advanced colorectal cancer patients seem to benefit from topo I targeted anticancer drug therapy.     

Pine-cone and villi patterns are endoscopic signs suggestive of ulcerative colitis-associated colorectal cancer and dysplasia

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Neoadjuvant intra-arterial versus intravenous chemotherapy in colorectal cancer

To investigate the clinical benefits of transcatheter arterial infusion chemotherapy compared with intravenous chemotherapy in patients with colorectal cancer (CRC).From May 2013 to March 2018, 83 patients (50 men and 33 women) with surgically proven CRC were retrospectively included. Before surgery, 62 patients received conventional systemic chemotherapy, and 21 transcatheter arterial chemotherapy. Basic characteristics, disease control rate (DC), adverse reactions, postoperative complications, and toxicity profiles were collected and compared between the 2 groups.The sigmoid colon (43.37%) was the most common primary tumor location, and the least was the transverse colon (6.02%). Most lesions invaded the subserosa or other structures T3-4 (78.31%), and other lesions invaded the muscular layer T1-2 (21. 69%). The overall DC was 80.65% in the intravenous chemotherapy group and 90.48% in the arterial chemotherapy group (P < .05). Adverse events included myelosuppression and gastrointestinal reactions such as nausea, vomiting, diarrhea, abnormal liver function, and neurotoxicity, which were significantly less common in the intra-arterial group than in the intravenous group (P < .05). Postoperative complications included abdominal infection (11.29% vs 14.29%), intestinal obstruction (6.45% vs 4.76%), anastomotic bleeding (1.61% vs 0.00%), and anastomotic fistula (6.45% vs 4.76%) in the intravenous and intra-arterial groups, respectively (P > .05).Preoperative transcatheter arterial infusion chemotherapy is a safe and effective neoadjuvant chemotherapy measure for CRC with fewer adverse reactions and a higher overall DC.     

溃疡性结肠炎相关性结肠癌差异表达的miRNA的筛选研究

[目的]分析结肠癌与正常结肠黏膜、结肠炎肠黏膜的微小RNA（miRNA）表达谱差异.[方法]通过建立溃疡性结肠炎（ulcerative colitis,UC）及UC相关性结肠癌（ulcerative colitis related colorectal cancer,UCRCC）小鼠模型,抽提、纯化RNA,加入荧光标记后与miRNA寡核甘酸基因芯片（Affymetrix公司）杂交,应用SAM软件进行数据分析,对有显著差异的miRNA进行实时荧光定量PCR验证,采用靶基因分析软件分析miRNA功能.[结果]has-miR-194、has-miR-215、has-miR-93、has-miR-192、has-miR-92a、has-miR-29b、has-miR-20a等7个miRNA在肿瘤组织中显著上调[中位假基因验出率（FDR）＜5％],has-miR-1231、has-miR-195、has-miR-143、has-miR-145等4个miRNA显著下调（FDR＜5％）.[结论]UCRCC与正常结肠黏膜、UC肠黏膜之间存在明显的miRNA差异表达,这些miRNA的差异性表达可能与UCRCC的发病有关.     

Systemic chemotherapy using cisplatin plus 5-fluorouracil for inoperable gallbladder cancer

We report a case of advanced gallbladder cancer in a 37-year-old man who presented in June 1993 with malignant obstructive jaundice. After percutaneous transhepatic biliary drainage and several diagnostic imaging examinations, the patient underwent laparotomy under a diagnosis of extremely advanced gallbladder cancer involving the confluence of the hepatic ducts. The tumor, however, was judged to be unresectable because of its massive spread into the liver along Glisson's sheath, and because of histologically proven peritoneal dissemination. After exploratory laparotomy, one course of anticancer chemotherapy (cisplatin, 100 mg/body IV, on day 1, and 5-fluorouracil, 1000 mg/body, on days 1–5, by continuous infusion) was administered and the completely obstructed hepatic duct was dramatically re-canalized. Four courses of chemotherapy were administered over a 16-month period until jaundice recurred. For these 16 months, the patient's quality of life was well maintained without biliary drainage. He died of increased peritoneal dissemination approximately 2 years after the first course of anticancer chemotherapy.     

对比晚期大肠癌三种不同化疗途径的疗效

目的对比三种不同化疗途径在治疗晚期大肠癌中的疗效。方法将我院120例晚期大肠癌患者随机分为3组,A组行全身静脉化疗;B组行口服希罗达化疗;C组行5-FU化疗粒子植入术。分别观察1、2年生存率、并发症发生率及有效率。结果A、B、C3组1、2年生存率分别为77．50％、60．00％;70．00％、50．50％;75．00％、57．50％,A、C组生存率高于B组,差异有统计学意义（X^2=6．11;P〈0．05）;3组并发症发生率分别为72．50％、70．00％、15．00％,C组并发症发生率低于A、B组,差异有统计学意义（X^2=6．83;P〈0．05）;3组治疗后有效率分别为85．00％、67．50％、92．50％,A、C组有效率高于B组,差异有统计学意义（X^2=6．29;P〈0．05）。结论5-FU化疗粒子植入治疗晚期大肠癌疗效优于全身静脉及口服化疗。     

贝伐珠单抗联合不同化疗方案治疗进展期结直肠癌54例分析

目的研究贝伐珠单抗(Bev)联合化疗治疗进展期结直肠癌的疗效和安全性。方法对2005年11月至2011年3月北京大学肿瘤医院接受Bev联合化疗治疗进展期结直肠癌54例进行分析。Bev 5 mg/kg静脉输注每2周1次或7.5 mg/kg静脉输注每3周1次,联合以奥沙利铂为基础的化疗,以伊立替康为基础的化疗,或以氟尿嘧啶类为基础的化疗进行治疗。按实体肿瘤疗效评价标准(RECIST)评价疗效,每6周评价1次。按美国癌症研究所常见毒性判定标准(NCI-CTC)3.0版评价不良反应。结果 54例中男26例,女28例;中位年龄50(24～73)岁。初治22例,21例可评价疗效,有效率(RR)为33.3%(7/21),疾病控制率(DCR)为100%(21/21);中位疾病无进展(PFS)时间11.3个月,总生存时间(OS)20.9个月。全部54例中,部分缓解(PR)12例(23.5%),稳定(SD)32例(62.7%),进展(PD)7例(13.5%),3例无法评价疗效;中位PFS 8.4个月,中位OS 15.5个月。主要3～4度不良反应为白细胞减少9例(16.7%),粒细胞减少13例(24.1%),粒细胞减少性发热1例(1.9%);3度恶心、呕吐2例(3.8%),3度腹泻3例(5.7%)。与贝伐珠单抗相关的不良反应为蛋白尿2例(3.8%),血压升高1例,鼻衄2例,痔疮出血2例,但均为1～2度。结论贝伐珠单抗联合化疗治疗进展期结直肠癌对于初治患者疗效较好,且未加重化疗的不良反应。