Judy W. C. Ho

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS–RAF–MEK–ERK–MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Summary Background Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. Methods In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. Results 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35–1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32–0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19–0·86, p=0·02) and an IRR of 0·37 (0·18–0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. Interpretation 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. Funding European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

Physical activity for cancer survivors: meta-analysis of randomised controlled trials

Objective To systematically evaluate the effects of physical activity in adult patients after completion of main treatment related to cancer. Design Meta-analysis of randomised controlled trials with data extraction and quality assessment performed independently by two researchers. Data sources Pubmed, CINAHL, and Google Scholar from the earliest possible year to September 2011. References from meta-analyses and reviews. Study selection Randomised controlled trials that assessed the effects of physical activity in adults who had completed their main cancer treatment, except hormonal treatment. Results There were 34 randomised controlled trials, of which 22 (65%) focused on patients with breast cancer, and 48 outcomes in our meta-analysis. Twenty two studies assessed aerobic exercise, and four also included resistance or strength training. The median duration of physical activity was 13 weeks (range 3-60 weeks). Most control groups were considered sedentary or were assigned no exercise. Based on studies on patients with breast cancer, physical activity was associated with improvements in insulin-like growth factor-I, bench press, leg press, fatigue, depression, and quality of life. When we combined studies on different types of cancer, we found significant improvements in body mass index (BMI), body weight, peak oxygen consumption, peak power output, distance walked in six minutes, right handgrip strength, and quality of life. Sources of study heterogeneity included age, study quality, study size, and type and duration of physical activity. Publication bias did not alter our conclusions. Conclusions Physical activity has positive effects on physiology, body composition, physical functions, psychological outcomes, and quality of life in patients after treatment for breast cancer. When patients with cancer other than breast cancer were also included, physical activity was associated with reduced BMI and body weight, increased peak oxygen consumption and peak power output, and improved quality of life.

Risk factors for anastomotic leakage after low anterior resection with total mesorectal excision.

BACKGROUND This study aims to analyze the risk factors for anastomotic leakage after low anterior resection with the technique of total mesorectal excision (TME). METHODS From September 1993 to November 1998, 196 patients with rectal cancer from 3 to 12 cm from the anal verge were treated with low anterior resection with TME. The data were entered in a prospective manner, and the factors that might affect anastomotic leakage were analyzed. RESULTS The mean level of anastomosis was 3.6 cm from the anal verge (range 1 to 5 cm). The leakage rate was 10.2%. Female gender (P = 0.01; 95% confidence interval [CI] 1.3 to 14.3; odds ratio 4.3) and presence of a diversion stoma (P = 0.01; 95% CI 1.4 to 14.2; odds ratio 4.5) were independent significant factors for lower anastomotic leakage. The absence of a stoma was associated with significantly increased leakage in male (P = 0.001) but not in female (P = 0.51) patients. CONCLUSIONS With low anastomosis after low anterior resection with TME, diversion stoma construction should be performed routinely in men. In women, the need for diversion can be more selective.

Prospective Evaluation of Selective Defunctioning Stoma for Low Anterior Resection with Total Mesorectal Excision

Abstract. Low anterior resection with total mesorectal excision for rectal carcinoma is associated with a high anastomotic leakage rate, and the effectiveness of a defunctioning stoma in preventing anastomotic leakage remains controversial. In this study a policy of selective defunctioning stoma for stapled colorectal anastomosis after low anterior resection with total mesorectal excision in 148 consecutive patients was evaluated prospectively. A defunctioning stoma was performed in 61 patients (41%) considered at high risk of anastomotic leakage. Clinical leakage occurred in 2 patients (3.3%) with a stoma and 11 patients (12.6%) without a stoma (p= 0.047). Among those without a stoma, the leakage rate among male patients (20.9%) was significantly higher than that for female patients (4.5%) (p= 0.022). Leakage subsided with conservative treatment in the two patients with a stoma, but seven patients without a stoma developed peritonitis requiring laparotomy. No deaths resulted from leakage, and there was one hospital death (0.6%) in the whole group. Median hospital stay was similar with and without a stoma (13.0 vs. 12.0 days) (p= 0.290). Closure of the stoma was associated with no mortality, a morbidity rate of 8.7%, and a median hospital stay of 6.0 days. In conclusion, a defunctioning stoma is effective in preventing clinical anastomotic leakage after low anterior resection with total mesorectal excision. The relatively high incidence of leakage in the low risk group indicates the difficulty of predicting anastomotic leakage and hence the need for more liberal use of a defunctioning stoma especially in male patients.

Effect of Aspirin or Resistant Starch on Colorectal Neoplasia in the Lynch Syndrome

BACKGROUND Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. METHODS In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. RESULTS Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. CONCLUSIONS The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)

Impact of Laparoscopic Resection for Colorectal Cancer on Operative Outcomes and Survival

Objective:This study aimed to compare the outcomes of patients who underwent laparoscopic and open resections for colorectal cancer. Comparison of colectomy in 2 consecutive periods (period 1: January 1996–May 2000; period 2: June 2000–December 2004), with laparoscopic surgery being a surgical option in period 2, was also performed. Summary Background Data:Prospective data of 1134 patients (448 in period 1; 656 in period 2) who underwent elective resection for colon and upper rectal cancer (above 12 cm from anal verge) were analyzed. Methods:The operative outcome and survival were compared between patients who underwent laparoscopic and open resection in period 2. The outcomes of colorectal resections in the 2 periods were also compared. Results:During period 2, the operative mortality rates of patients with laparoscopic (n = 401) and open resection (n = 255) were 0.8% and 3.7%, respectively (P = 0.022), and the morbidity rates were 21.7% and 15.7%, respectively (P = 0.068). The patients who underwent laparoscopic resection had significantly earlier return of bowel function, earlier resumption of diet, and shorter hospital stay. The 3-year overall survivals in those with nondisseminated disease were 74.4% and 78.8% for open and laparoscopic resection, respectively (P = 0.046). The operative morality rates were 4.4% and 2.6% in period 1 and period 2, respectively (P = 0.132). The 3-year overall survivals for patients with nondisseminated disease were 69.7% and 76.1% for period 1 and period 2, respectively (P = 0.019). The overall survivals in patients who underwent open resection in the 2 periods were similar (P = 0.284). Conclusions:The short-term favorable outcome of laparoscopic resection for colorectal cancer was confirmed and improvement of survival was observed with the practice of laparoscopic resection.

Self-expanding metallic stent in the treatment of colonic obstruction caused by advanced malignancies

INTRODUCTION: The treatment of malignant obstruction of the left colon or rectum usually requires emergency surgery on poor-risk patients, and the creation of a stoma is usually inevitable. With the use of self-expanding metallic stents, the prompt relief of large-bowel obstruction without surgery has become possible. This report describes our results in the use of self-expanding metallic stents in the treatment of left-sided colonic obstruction resulting from advanced malignancies. METHODS: From November 1997 to March 1999, insertion of self-expanding metallic stents was attempted in 24 patients with acute left-sided colonic obstruction caused by primary or recurrent malignancies. All the procedures were performed by colorectal surgeons. The guidewire was inserted through the channel of the endoscope, and its position was confirmed with fluoroscopy. Uncovered Wallstent® esophageal endoprostheses were used in all except the first case. The insertion and deployment of the stents were under both endoscopic and fluoroscopic guidance. RESULTS: There were 24 patients (15 males) with a mean age of 63.6 (range, 36–98) years. Thirteen patients had primary colorectal cancer and 11 had recurrent cancers (colorectal cancer, 5; gastric cancer, 5; other, 1). In the treatment of primary colorectal cancer, seven procedures were palliative, and no subsequent surgery was planned because of extensive liver metastasis or poor medical risk. The other six patients underwent elective resection after mechanical bowel preparation. There was no mortality related to the procedure. Stenting was successful in the relief of obstruction in 23 patients. Perforation of the colon occurred in one patient, and an emergency Hartmanns operation was performed. Migration of the stents occurred in three patients. Only 3 of the 18 patients in the palliation group required the subsequent creation of stomas. CONCLUSION: The use of the self-expanding metallic stents can achieve rapid and effective nonsurgical means to relieve left-sided colonic obstruction. It provides good palliation for unresectable advanced tumors that cause colonic obstruction. It may also have a role in the temporary relief of obstruction so that subsequent colonic resection can be performed under elective conditions.

Self-expanding metallic stent as a bridge to surgery versus emergency resection for obstructing left-sided colorectal cancer: a case-matched study.

This study aimed to compare the outcomes of patients who suffered from obstructing left-sided colorectal cancer, treated with self-expanding metallic stent (SEMS) as a bridge to surgery, with those who underwent emergency operation. Twenty patients who had acute obstruction due to left-sided colorectal cancer underwent surgical resection after insertion of SEMS (group I) were matched to 40 patients with emergency colonic resection (group II). The two groups were compared for the incidence of primary anastomosis, stoma rate, hospital stay, duration of intensive care, postoperative morbidity, and mortality. Both groups had similar preoperative comorbidity and stage of disease, but the tumors in group I were more distally located (P<0.001). In group I, one patient developed colon perforation and required Hartmann’s operation. All the other patients underwent elective operation with primary anastomosis. In group II, primary anastomosis was performed in 29 patients (72.5%; P=0.047). The operative mortality of group I and group II was 5% and 12.5%, respectively (P=0.653). Significantly shorter median postoperative hospital stay and median stay in the intensive care unit (ICU) were observed in group I (9 days [range, 5–39 days] vs. 12 days [range, 8–49 days], P=0.015 and 0 day [range, 0–17 days] vs. 0.5 day [range, 0–18 days], P=0.022, respectively). There were no differences in hospital mortality (P=0.653) or 30-day mortality (P=0.653). Both groups had similar reoperation rates, surgical complications, and medical complications. When compared with emergency resection, insertion of SEMS as a bridge to surgery for obstructing left-sided colorectal cancer is associated with a higher rate of primary anastomosis as well as a better outcome in terms of hospital stay and stay in the ICU. The wider application of this treatment option for obstructing colorectal cancer warranted further studies.

Microsatellite Instability and Mutation of DNA Mismatch Repair Genes in Gliomas

Microsatellite instability (MSI) has been identified in various human cancers, particularly those associated with the hereditary nonpolyposis colorectal cancer syndrome. Although gliomas have been reported in a few hereditary nonpolyposis colorectal cancer syndrome kindred, data on the incidence of MSI in gliomas are conflicting, and the nature of the mismatch repair (MMR) defect is not known. We established the incidence of MSI and the underlying MMR gene mutation in 22 patients ages 45 years or less with sporadic high-grade gliomas (17 glioblastomas, 3 anaplastic astrocytomas, and 2 mixed gliomas, grade III). Using five microsatellite loci, four patients (18%) had high level MSI, with at least 40% unstable loci. Germline MMR gene mutation was detected in all four patients, with inactivation of the second allele of the corresponding MMR gene or loss of protein expression in the tumor tissue. Frameshift mutation in the mononucleotide tract of insulin-like growth factor type II receptor was found in one high-level MSI glioma, but none was found in the transforming growth factor beta type II receptor and the Bax genes. There was no family history of cancer in three of the patients, and although one patient did have a family history of colorectal carcinoma, the case did not satisfy the Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome. Three patients developed metachronous colorectal adenocarcinomas, fitting the criteria of Turcots syndrome. Thus, MSI and germline MMR gene mutation is present in a subset of young glioma patients, and these patients and their family members are at risk of developing other hereditary nonpolyposis colorectal cancer syndrome-related tumors, in particular colorectal carcinomas. These results have important implications in the genetic testing and management of young patients with glioma and their families.