Garnet J. Blatchford

Cumulative incidence of metachronous colorectal cancer

The incidence of metachronous colorectal cancer has most often been reported as a crude rate: second cancers/index cancers. The reported incidence varies between 0.5 percent and 3.6 percent. However, these calculations do not take into account factors such as length of survival and length of follow-up. The cumulative incidence more accurately reflects the risk for developing a metachronous cancer and was determined in a retrospective analysis of 5,476 patients who were diagnosed with colon or rectal cancer between 1965 and 1985. The cumulative probability was calculated by determining the number of patients developing a metachronous colon cancervs.the number remaining at risk at that point in time. The calculated annual incidence for metachronous tumors was 0.35 percent per year. The cumulative incidence at 18 years was 6.3 percent. Analysis also demonstrated that metachronous cancers were diagnosed at earlier stages than were index cancers (P=0.03). Subgroup analysis was performed on patients diagnosed with metachronous cancer before and after 1980. There was a difference in the incidence of metachronous cancers between these two groups (P=0.04).

Cumulative Incidence of Colorectal and Extracolonic Cancers in MLH1 and MSH2 Mutation Carriers of Hereditary Nonpolyposis Colorectal Cancer

The extracolonic tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC) includes cancer of the endometrium, ovaries, stomach, biliary tract, and urinary tract. This study was designed to determine the penetrance of colorectal and extracolonic tumors in HNPCC mutation carriers. Forty-nine patients (22 females and 27 males) were identified with an MSH2 germline mutation, and 56 patients (28 females and 28 males) were identified with an MLH1 mutation. Cumulative incidence by age 60 (lifetime risk) and mean age of cancer diagnosis were compared. The lifetime risk of extracolonic cancers in MSH2 and MLH1 carriers was 48% and 11% respectively (P = 0.016). Extracolonic cancer risk in MSH2 females and males was 69% and 34%, respectively (P = 0.042). Mean age of extracolonic cancer diagnosis was significantly older for MSH2 males than females (55.4 vs. 39.0, P = 0.013). No difference was observed in colorectal cancer risk between MLH1 and MSH2 carriers (84% vs. 71%). Colorectal cancer risk was 96% in MSH2 males compared to 39% in MSH2 females (P = 0.034). No differences in colorectal and extracolonic cancer risks between MLH1 females and males were identified. The risk of extracolonic cancer by age 60 was greater in MSH2 mutation carriers than in MLH1 carriers. Gender differences in colorectal and extracolonic cancer risk were observed for MSH2 carriers only. These phenotypic features of HNPCC genotypes may have clinical significance in the design of genotype-specific screening, surveillance, and follow-up for affected individuals.

Positron emission tomography for preoperative staging of colorectal carcinoma

PURPOSE: Positron emission tomography (PET) is an imaging technique based onin vivo cellular metabolism. Increased glucose metabolism in neoplastic cells is detected by using fluorine-18 deoxyglucose. In an ongoing pilot study to determine the usefulness of this technique, PET is compared with computerized tomography (CT) for the preoperative staging of colorectal carcinoma. METHODS: Sixteen patients were evaluated with both PET and CT of the abdomen and pelvis. Results were compared with operative and histopathologic findings. Fifteen malignant lesions were found in 16 patients by histology. PET had a positive predictive value of 93 percent and a negative predictive value of 50 percent. By comparison CT had a positive predictive value of 100 percent and a negative predictive value of 27 percent. CONCLUSIONS: These preliminary results indicate that PET has increased sensitivity for staging colorectal carcinoma, whereas CT has higher specificity. The predictive value of a positive PET compares favorably with CT. Furthermore, the predictive accuracy for detection of colorectal carcinoma is 83 percent for PET and 56 percent for CT.

Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P<0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P<0.001,P=0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1vs. 28 percent MSH2;P=0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P=0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P=0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P=0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P<0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P=0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.

Manometric diagnosis of anal sphincter injuries

A manometric technique of anal pressure vectography has been developed for the detection of anal sphincter injuries. Manometric symmetry of the anal sphincter can be visualized on the pressure vectorgram and quantified as a vector symmetry index. The mean vector symmetry index in asymptomatic women was 0.76, compared with 0.33 in incontinent women with a known sphincter injury (p = 0.0001). Among women who were incontinent without having a recognized sphincter injury, nearly half of those who had a previous episiotomy had subnormal (less than 0.60) vector symmetry indices (p = 0.0003). The values were in the same range as those from known injuries, suggesting the presence of an occult sphincter injury. In contrast, normal symmetry indices were found in all those who had never had an episiotomy or who presented with outlet constipation. We conclude that the vector symmetry index can expose occult anal sphincter injuries and may have a role in the selection of patients for sphincter repair.

Transanal ultrasound and anorectal physiology findings affecting continence after sphincteroplasty

PURPOSE: This study was undertaken to evaluate endosonographic and physiologic determinants of fecal continence after sphincteroplasty. METHODS: Sixteen female patients with severe fecal incontinence were treated with overlapping sphincteroplasty. Mean postoperative follow-up was 12 (range, 3–48) months. All patients underwent preoperative and postoperative transanal endosonography and anal manometry. Bilateral pudendal nerve terminal motor latency determinations were performed in each patient. A physiologic continence score was used to assess stool control. RESULTS: Postoperatively, continence was worse, unchanged, and improved in one, five, and ten patients, respectively. An inverse correlation was noted between endosonographic sphincter discontinuity postoperatively, in degrees, and the change in fecal continence after overlapping sphincteroplasty (r =−0.51;P =0.04). Postoperative increases in sphincter resting (r =0.6;P =0.02) and squeeze (r -0.54;P =0.03) pressures correlated with improved fecal continence. Mean pudendal nerve terminal motor latency (r = −0.34;P =0.20) and changes in anal sphincter length at rest (r =0.41;P =0.11) and squeeze (r =0.33;P =0.20) after sphincteroplasty did not significantly correlate with the change in continence. Patients with intact endosonographic anatomy postoperatively and bilateral, unilateral, or no evidence of pudendal neuropathy had a mean change in continence score of 0.5, 1.8, and 2.2, respectively (P =0.48). CONCLUSIONS: Endosonography after sphincteroplasty can identify residual sphincter defects that are significant in terms of fecal continence. Restoration of anal canal resting and squeeze pressures was related to improved fecal control after overlapping sphincteroplasty. Mean pudendal nerve terminal motor latency was not significantly related to poor postoperative continence. A trend toward less improvement in fecal continence was noted with bilateral pudendal neuropathy.

Use of preoperative ultrasound staging for treatment of rectal cancer.

INTRODUCTION: Transrectal ultrasound is the standard method for preoperative staging of rectal cancer. This study reviews the accuracy of transrectal ultrasound staging for T3 disease and its use in the selection of patients for neoadjuvant chemoradiation. METHODS: One hundred seventeen patients underwent preoperative transrectal ultrasound evaluation for rectal cancer. Accuracy of transrectal ultrasound was evaluated among 70 patients not receiving preoperative chemoradiation. Forty-seven patients received neoadjuvant chemoradiation based on transrectal ultrasound results. Tumor downstaging and early recurrence were evaluated among 45 of 47 patients receiving neoadjuvant chemoradiation. RESULTS: Among 70 nonirradiated patients, 19 were pathologic Stage pT3. Transrectal ultrasound correctly identified 18 of 19 patients with Stage pT3 (sensitivity, 94.7 percent). Transrectal ultrasound correctly identified 44 of 51 patients with less than pT3 disease (specificity, 86.3 percent). After preoperative chemoradiation in 45 patients with ultrasound Stage uT3 or uT4 tumors, 56 percent of them experienced a reduction in T stage. Residual nodal disease was found in 31 percent of patients. A complete pathologic response with no residual disease at operation was observed in 22 percent of patients. During a median follow-up period of 21 months after diagnosis, seven patients experienced a recurrence of their disease at a median of 12 months after diagnosis. Five of seven patients with recurrence were among a subgroup of ten patients who both failed to downstage T and had residual nodal disease at operation. CONCLUSION: Transrectal ultrasound is an accurate modality for selecting patients for neoadjuvant treatment. Preoperative chemoradiation produced downstaging in 56 percent of patients. Factors related to early recurrence included residual nodal disease and failure to downstage T after neoadjuvant chemoradiation.

Colonic anastomoses : bursting strength after corticosteroid treatment

PURPOSE: This study was designed to determine the effect of corticosteroids on healing colonic anastomoses. METHODS: Bursting pressure measurements were performed on 108 male albino rats receiving corticosteroid treatment. Twelve animals were sacrificed at time zero to determine the bursting pressure of nonoperated, nonsteroid-treated colon. The remaining 96 animals underwent division and reanastomosis of their midtransverse colon. They were then separated into four groups of 24 each. Twelve animals in each group received steroid treatment while the remaining 12 acted as controls. The groups were sacrificed at 4, 6, 8, and 20 days. The bursting pressures of the anastomoses were then noted. RESULTS: There was no significant difference in bursting strength between treated animals and controls at four days (P=0.27). A significant difference occurred at 6, 8, and 20 days (P=0.01, 0.003, 0.009, respectively). The colonic bursting pressure of operated controls returned to that of a normal, nonoperated colon by 20 days. CONCLUSION: This study demonstrates that steroids do have an adverse effect on colonic anastomotic healing.

Diagnosing anal sphincter injury with transanal ultrasound and manometry.

PURPOSE: This study was undertaken to evaluate how well anorectal manometry and transanal ultrasonography diagnose anal sphincter injury. METHODS: Anorectal manometry and transanal ultrasonography were performed in 20 asymptomatic nulliparous women and 20 asymptomatic parous women, and the results were compared with those obtained in 31 incontinent women who subsequently underwent sphincteroplasty and, thus, had operatively verified anal sphincter injury. By using computerized manometry analysis, mean maximum resting and squeeze pressures, sphincter length, and vector symmetry were determined in all women. All transanal ultrasounds were interpreted blinded as to the patients history, physical examination, and manometry results. RESULTS: Manometric resting and squeeze pressures were significantly higher in the asymptomatic nulliparous women than in the asymptomatic parous women, and both groups had significantly higher pressures than the incontinent women (P<0.001). Anal sphincter length and vector symmetry index were significantly decreased in incontinent women compared with asymptomatic women (P<0.01). Decreased resting and squeeze pressures suggestive of possible sphincter injury were found in 90 percent of incontinent women with known anal sphincter injury. Decreased anal sphincter length and vector symmetry were found in only 42 percent of women with known anal sphincter injury. Transanal ultrasound was able to identify 100 percent of the known sphincter injuries but also falsely diagnosed injury in 10 percent of the asymptomatic nulliparous women with intact anal sphincters. False identification of sphincter injury increased when transanal ultrasound scanning was performed proximal to the distal 1.5 cm of the anal canal. CONCLUSION: Although nonspecific, decreased resting and squeeze pressures were found in 90 percent of patients with anal sphincter injury. Decreased anal sphincter length or vector symmetry index were present in only 42 percent of patients with known sphincter injury. When limited to the distal 1.5 cm of the anal canal, transanal ultrasound identified all known sphincter injuries but falsely identified injury in 10 percent of women with intact anal sphincters. Transanal ultrasound in combination with decreased anal pressures correctly identified all intact sphincters and 90 percent of known anal sphincter injuries.

Preoperative chemoradiation downstages locally advanced ultrasound-staged rectal cancer

BACKGROUND This prospective study assessed the effect of preoperative radiation and chemotherapy on the pathologic staging of advanced rectal cancer. METHODS Twenty patients with rectal cancer were treated with combined chemoradiation prior to operation, after pretreatment staging of all lesions with transrectal ultrasound (TRUS). Perirectal fat invasion served as minimal criteria for preoperative neoadjuvant therapy. The pretreatment stage of these rectal lesions as defined by TRUS was then compared with the pathological stage of the surgical specimen following resection. Cancers were treated with high-dose radiation (45 to 54 Gy) in 19 of 20 patients. One patient received in excess of 60 Gy because of tumor characteristics. Chemotherapy consisted of 5-fluorouracil delivered as a continuous infusion or bolus therapy. Four to 8 weeks after neoadjuvant therapy, 13 abdominal perineal resections, 5 low anterior resections, and 2 completion proctectomies were performed. RESULTS Following resection, rectal cancer was downstaged in 14 of 20 patients. No tumor was present in the rectal wall in 8 of 20 patients. Complete pathological response was present in 7 of 20 patients. Local recurrence occurred in 2 of 20 patients. Disease-free survival in the remaining 17 of 20 patients ranges from 9 to 51 months (average 26). CONCLUSIONS Preoperative chemoradiation in the surgical management of advanced rectal cancer results in demonstrable tumor downstaging.