Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial.

PURPOSE: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. METHODS AND MATERIALS: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). CONCLUSIONS: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Outcomes of a modified Bresler procedure for the treatment of rectocele with rectal intussusception.

BACKGROUND: Obstructed defecation syndrome (ODS) is a condition that is frequently caused by rectocele and rectal intussusception. This study aimed to evaluate the effectiveness of a modified Bresler procedure for the treatment of ODS. The outcomes of this modified procedure were compared with the stapled transanal rectal resection (STARR) procedure. METHODS: We performed a retrospective analysis of the clinical data from 76 female patients who presented with ODS between June 2014 and June 2016. The patients were divided into two treatment groups, namely Modified and STARR. Patients in the Modified group (n = 36) underwent the modified Bresler procedure, which involved posterior rectal-wall resection using a circular tubular stapler with multilevel purse-string sutures. Patients in the STARR group (n = 40) underwent the standard STARR procedure. We analysed post-operative complications, Wexner constipation scores (WCS), rectocele depths, and four-point post-operative satisfaction scales. RESULTS: Patients in the Modified group exhibited shorter operative times and fewer post-operative complications (both P < 0.05). At 12 months post-operatively, both the Modified and STARR groups displayed a significant improvement in the Wexner constipation score and the depth of rectocele. The post-operative WCS for the Modified group were significantly improved compared to those for the STARR group (P < 0.05), while there was no significant difference in the rectocele depth between the two groups (P > 0.05). Post-operative interviews at post-operative 12 months showed that patients in the Modified group had a better satisfaction (P = 0.05). CONCLUSIONS: Our modified procedure may be an effective treatment strategy for patients experiencing ODS caused by rectocele and rectal intussusception, with fewer complications and effective relief of symptoms.

Fast-track multidisciplinary treatment versus conventional treatment for colorectal cancer: a multicenter, open-label randomized controlled study.

BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.

The accuracy of computed tomography in the pretreatment staging of colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent cancers around the world. Multimodality therapies are used for CRC including surgery, chemotherapy, radiotherapy and targeted therapy. Correct treatment plan depends greatly on the accurate pretreatment staging. Computed tomography (CT) is a widely used detection and staging modality for CRC patients in clinical practice. The role of CT in assessing the patients with CRC has been well established, but the accuracy of pretreatment staging by CT varies in different reports. With the development of CT techniques, some reformations such as multi-detector CT (MDCT), CT with water enema or air insufflations, multiple planner reconstruction (MPR) help to give us higher resolution images in shorter time. The accuracy of CT for N staging was still not so ideal, but CT played an important role in chest and liver staging. Magnetic resonance imaging (MRI) and endorectal ultrasound (ERUS) may provide more precise images and evaluation of local T and N staging for rectal cancer. And positron emission tomography (PET) or PET/CT is recommended as a complement of CT, only for cases suspected of residual or recurrent colorectal carcinoma or before metastasectomy, not for routine use.

Transsacral excision with pre-operative imatinib mesylate treatment and approach for gastrointestinal stromal tumors in the rectum: A report of two cases.

Gastrointestinal stromal tumors (GISTs) are rare in the rectum. Radical surgery, such as an abdominoperineal resection, is necessary for large rectal GISTs, which can result in the loss of function of involved organs. Imatinib mesylate can be used as perioperative therapy and may reduce tumor size, and it is now approved for use in the adjuvant therapy of locally resected anorectal GISTs. The present study describes two cases of large rectal GISTs, for which abdominoperineal resections were initially planned. The two patients received pre-operative imatinib mesylate treatment, and the therapeutic response was assessed by magnetic resonance imaging. Finally, transsacral local resection was successfully performed for these two GISTs. A macroscopically complete resection was achieved, and microscopically, the resection margin was negative. One patient experienced the complication of rectal leakage, which was successfully managed by drainage. No recurrence occurred in the two patients after more than two years. Pre-operative imatinib mesylate therapy with subsequent transsacral local resection for selected rectal GISTs is a feasible treatment modality and can prevent extended surgery.

Suppression of cellular apoptosis susceptibility (CSE1L) inhibits proliferation and induces apoptosis in colorectal cancer cells.

The cellular apoptosis susceptibility (CSE1L) gene has been demonstrated to regulate multiple cellular mechanisms including the mitotic spindle check point as well as proliferation and apoptosis. However, the importance of CSE1L in human colon cancer is largely unknown. In the present study, we examined expression levels of CSE1L mRNA by semiquantitative RT-PCR. A lentivirus-mediated small interfering RNA (siRNA) was used to knock down CSE1L expression in the human colon cancer cell line RKO. Changes in CSE1L target gene expression were determined by RT-PCR. Cell proliferation was examined by a high content screening assay. In vitro tumorigenesis was measured by colony-formation assay. Cell cycle distribution and apoptosis were detected by flow cytometric analysis. We found CSE1L mRNA to be expressed in human colon cancer cells. Using a lentivirus based RNAi approach, CSE1L expression was significantly inhibited in RKO cells, causing cell cycle arrest in the G2/M and S phases and a delay in cell proliferation, as well as induction of apoptosis and an inhibition of colony growth capacity. Collectively, the results suggest that silencing of CSE1L may be a potential therapeutic approach for colon cancer.

Fast track multi-discipline treatment (FTMDT trial) versus conventional treatment in colorectal cancer--the design of a prospective randomized controlled study.

BACKGROUND: Laparoscopy-assisted surgery, fast-track perioperative treatment are both increasingly used in colorectal cancer treatment, for their short-time benefits of enhanced recovery and short hospital stays. However, the benefits of the integration of the Laparoscopy-assisted surgery, fast-track perioperative treatment, and even with the Xelox chemotherapy, are still unknown. In this study, the three treatments integration is defined as "Fast Track Multi-Discipline Treatment Model" for colorectal cancer and this model extends the benefits to the whole treatment process of colorectal cancer. The main purpose of the study is to explore the feasibility of "Fast Track Multi-Discipline Treatment" model in treatment of colorectal cancer. METHODS: The trial is a prospective randomized controlled study with 2 × 2 balanced factorial design. Patients eligible for the study will be randomized to 4 groups: (I) Laparoscopic surgery with fast track perioperative treatment and Xelox chemotherapy; (II) Open surgery with fast track perioperative treatment and Xelox chemotherapy; (III) Laparoscopic surgery with conventional perioperative treatment and mFolfox6 chemotherapy; (IV) Open surgery with conventional perioperative treatment and mFolfox6 chemotherapy. The primary endpoint of this study is the hospital stays. The secondary endpoints are the quality of life, chemotherapy related adverse events, surgical complications and hospitalization costs. Totally, 340 patients will be enrolled with 85 patients in each group. CONCLUSIONS: The study initiates a new treatment model "Fast Track Multi-Discipline Treatment" for colorectal cancer, and will provide feasibility evidence on the new model "Fast Track Multi-Discipline Treatment" for patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547.

[Comparison of clinical and genetic phenotypes between Chinese and Korean hereditary nonpolyposis colorectal cancer families].

OBJECTIVE: To compare the clinical and genetic features between Chinese and Korean hereditary nonpolyposis colorectal cancer (HNPCC) families. METHODS: Thirty-one Chinese HNPCC families and 63 HNPCC Korean families were involved in this study. The clinical data of the probands and families were collected. Genomic DNAs were prepared from peripheral blood samples of probands for DNA test. PCR and DHPLC were employed to screen the mutations. Sequencing analysis was followed to find out the exact mutation site and feature in samples showing abnormalities in SSCP or DHPLC analysis. RESULTS: In a total, there were 136 malignant neoplasms diagnosed in the 31 Chinese families, about 77.9% of them were colorectal cancer. The mean age of colorectal cancer at diagnosis was (48.6+/- 29.0) years. Gastric cancer was the second most common cancer in these familiesîSeven pathogenic mutations (3 in hMLH1 gene and 4 in hMSH2 gene) were detected in the 31 probands, including 2 missense mutations, 2 nonsense mutations, 2 frameshift mutations and 1 large-fragment deletion. The total mutation rate was 22.6%. In the 63 Korean families, 293 malignant neoplasms were documented, 82.6% of them were diagnosed as colorectal cancer. The mean age of colorectal cancer at diagnosis was (45.9+/- 11.0) years. Gastric cancer was also the most common extracolonic cancer in these Korean families. Nineteen pathogenic mutations (17 in hMLH1 gene and 2 in hMSH2 genes) were detected in the 63 probands, including 12 frameshift mutations, 5 missense mutations, 1 nonsense mutation and 1 base-change at the splicing site. The total mutation rate was 30.2%. CONCLUSION: (1) Chinese and Korean HNPCC families had many similar clinical features, such as early-onset of colorectal cancer, predominance in distal colon and rectum, lower incidence of synchronous or metachronous colorectal cancers as compared with Western countries, and a frequent occurrence of gastric cancer in the families. (2) The total mutation rate of hMLH1 and hMSH2 gene in Chinese and Korean HNPCC families was similar and lower than that reported in Western countries. But the mutation characteristics, such as predominant gene, mutation type and mutation distribution, were different in the two populations.

Genetic characterization of Chinese hereditary non-polyposis colorectal cancer by DHPLC and multiplex PCR.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease due to germline mutations of human mismatch repair genes, mainly hMLH1 and hMSH2. The aim of the present study was to identify the point mutations and large genomic deletions of hMLH1 and hMSH2 genes in 14 Chinese HNPCC families. METHODS: Fourteen families fulfilling the Chinese HNPCC criteria were involved in this study. Genomic DNA isolated from peripheral blood samples was analyzed. Point mutations were detected by denaturing high performance liquid chromatography (DHPLC) followed by DNA sequencing. Multiplex polymerase chain reaction and GeneScan analysis were employed to detect the large genomic deletions of these two genes. RESULTS: Four of the 14 probands (29%) had sequence abnormalities that probably affect the protein function in the exonic regions of hMLH1 and hMSH2 genes. Included were one complete deletion of exons 1-7 and one missense mutation of the hMSH2 gene, and one nonsense mutation and one missense mutation of the hMLH1 gene. The large genomic deletion accounted for 25% (one out of four) of all mutations. Half (two out of four, 50%) of the mutations were missense mutation. In addition, one silent mutation, four polymorphisms in the exonic regions and four polymorphisms in the intronic regions were also discovered. CONCLUSIONS: Point mutations and large genomic deletions of the hMLH1 and hMSH2 genes were responsible for nearly one-third of Chinese HNPCC families. Detection of large genomic deletions should be involved in the routine screening manual for HNPCC families.

[Hypermethylation of hMLH1 promoter in sporadic colorectal cancer].

OBJECTIVE: To identify CpG island hypermethylation of 5'region of hMLH1 promotor and to explore its relationship to microsatellite instability(MSI)in sporadic colorectal carcinoma. METHODS: Forty-one pairs of tissue specimens (normal and cancer) were collected from 41 patients with colorectal cancer. Hypermethylation of hMLH1 promoter was detected by methylation specific PCR; the relationship between methylation and clinicopathological features was analyzed. Combined with BAT25 and BAT26, the MSI status was detected using an automated fluorescent DNA sequencer. RESULTS: Hypermethylation of hMLH1 promoter was detected in 75.6 % (31/41) of samples. Mean age of unmethylation cases (49.2 y) was significantly younger than that of methylation cases (63.6 y) (P<0.05), but there were no differences between two groups in other clinicopathological features. MSI was detected in 43.9 % samples (18/41); hypermethylation of hMLH1 promoter was detected in 94.4 % (17/18) of MSI(+) samples, which was higher than that in MSI(-) samples (60.9 %,14/23, P<0.05). CONCLUSION: Age-related hypermethylation is generally found in patients with sporadic colorectal cancers, which may cause MSI and might be the mechanism in the development of colorectal cancer of elderly people.

[Clinical features and mutation analysis of a poly-(A)8 tract in M3 cholinergic receptor gene in Chinese HNPCC families].

OBJECTIVE: To characterize the clinical features of Chinese HNPCC families and to screen the mutations of a poly-(A)8 tract in M3 cholinergic receptor gene in these families. METHODS: The clinical features of 15 Chinese HNPCC families were characterized. Genomic DNAs from 15 probands were prepared. PCR and direct DNA sequencing analysis were employed to examine the mutations of a poly-(A)8 tract in exon 8 of M3 cholinergic receptor gene. RESULTS: Total 55 cancer patients were found in 15 families including 41 cases of colorectal carcinoma with an average of 2.73 colorectal carcinomas developed per family. Thirty out of forty-one (73%) patients were diagnosed before age of 50 years. Proximal colon was involved in 51% of patients, while anus and rectum were 40 %. Synchronous and metachronous multiple colorectal cancers developed in 5 patients (12%). Two thirds of families belonged to Lynch II syndrome, and total 18 extracolonic malignancies in 14 patients were identified. Gastric carcinoma was the most common extracolonic types. In 15 HNPCC probands, no mutation was detected in the poly-(A)8 tract of exon 8 of M3 cholinergic receptor gene. CONCLUSION: M3 cholinergic receptor gene might have little relation with HNPCC in Chinese population. The criteria for Chinese HNPCC are useful and practical in clinical application.

Analysis for phenotype of HNPCC in China.

AIM: The aims of this study were to identify the clinicopathological features of Chinese HNPCC families and to evaluate the value of criteria for suspected HNPCC (sHNPCC) in clinical diagnosis. METHODS: According to the follow-up records, 54 HNPCC families (including 12 ICG-HNPCC families and 42 sHNPCC families) were screened out from patients with colorectal cancers (CRCs), operated upon in 2(nd) Affiliated Hospital of Zhejiang University from 1984 to 2001. Clinical data of probands and tumor spectrum in these families were listed and analyzed. RESULTS: (1) Mean age, proportion of colonic cancer, poorly differentiated cancer, multiple CRCs and Dukes' A+B of the probands in ICG-HNPCC and sHNPCC kindred were 39ys and 47.5ys, 75 % and 62 %, 0 and 12.8 %, 16.7 % and 14.3 %, 58.3 % and 81 %,respectively. Compared with sporadic colorectal cancers, probands from ICG-HNPCC and sHNPCC families were obviously different at age of onset (P=0.025 and 0.031), tumor location (P=0.001 and 0.000), differentiation(P=0.002 and 0.011) and development of multiple tumors (P=0.014 and 0.002). (2) A total of 178 malignant neoplasms were found in 54 HNPCC families, including 139 colorectal cancers. Besides of colorectal cancer, extracolonic tumors occurred in stomach, endometrium, hepatobiliary system, and so on (8 gastric cancers, 6 endometrial cancers, 6 hepatobiliary system cancers and 19 others) can also be seen in Chinese ICG-HNPCC and sHNPCC families. CONCLUSION: (1) Chinese HNPCC families have specific clinicopathological features, such as early onset, predilection for the involvement of colon, tendency of multiple CRCs, development of extracolonic tumors and well differentiation. (2) The criteria for suspected HNPCC is useful in clinical diagnosis and management of HNPCC.