Effects of sodium sulfate on fecal pH and proliferation of colonic mucosa in patients at high risk for colon cancer.

High fecal pH level has been suggested as a risk factor for colorectal cancer. We previously demonstrated that, although sodium sulfate did not affect the proliferation rate of colonic mucosa, as indicated by thymidine-labeling index, it did lower fecal pH in subjects at average risk for colon cancer. In the current study, we evaluated the effects of sodium sulfate on fecal pH and proliferation of colonic mucosa in subjects at high risk for colon cancer. Fifty-seven patients who had had colonic polyps removed were randomly assigned to two groups to receive either sodium sulfate (27 patients) or a placebo (25 patients) at a mean dose of 4 g/day for 14 days. Age, sex, height, and weight were comparable in both groups. Before intervention, levels of fecal pH were similar in the two groups, but after intervention, fecal pH was reduced only in the sodium sulfate group (mean decrease, 0.3 U; P less than .01). Thymidine-labeling index (number of labeled cells per number of cells counted) was similar in the two groups prior to intervention and did not change significantly after intervention (mean increase, 0.9%; P = .35). Regression analysis revealed no correlation between the change in labeling index and the change in fecal pH. We conclude that high fecal pH level is only indirectly associated with the development of colon cancer and, therefore, may be a secondary, rather than a primary, measure of cancer risk.

Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons.

Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomatous polyps, the precursors to colorectal cancer. APC and ras gene mutations have been shown to be important early molecular events in the development of colorectal neoplasms. The objective of this study was to establish the nature and frequency of these two genetic alterations in ACF harvested from human colorectal resection specimens. One hundred and fifty-four ACF comprised of between 1 and 56 crypts were harvested from the grossly normal mucosa of colorectal resection specimens of 28 patients with varying pathological diagnoses. One hundred and twenty-five ACF from 20 colons were screened for the presence of K-ras codon 12 mutations with a polymerase chain reaction/restriction enzyme-based method. The APC gene mutation cluster region was screened in 65 ACF from 20 colons using a polymerase chain reaction/single strand conformation polymorphism technique. Putative mutations were confirmed by direct sequencing. K-ras codon 12 mutations were identified in 13% (16 of 125) of ACF. We also identified APC mutations in 4.6% (3 of 65) of ACF. The results of this study demonstrate that both APC and K-ras mutations occur in ACF. These observations support the role of the ACF as a colorectal cancer precursor and provide further insight into the early genetic changes which occur during colorectal tumorigenesis.

Comparative dual label study of first and second generation antitumor-associated glycoprotein-72 monoclonal antibodies in colorectal cancer patients.

Radiolabeled first-generation anti-tumor-associated glycoprotein-72 (TAG-72) monoclonal antibody (MAb), B72.3, has proven useful in detecting primary and secondary colorectal carcinoma. It has been anticipated that the development of second-generation, higher affinity, anti-TAG-72 MAbs, CC49 and CC83, would be of greater use in cancer detection and of value in radioimmunotherapy of human cancer. We compared the pharmacokinetics, biodistribution, and immune responses of 131I-labeled CC49 and CC83 to 125I-labeled B72.3 by preoperatively coninjecting dual-labeled MAbs into 16 colorectal cancer patients. The imaging properties of radiolabeled CC49 and CC83 were also assessed. Pharmacokinetics of all three MAbs were identical, and there were no differences in the uptake of any of three MAbs in tumor and normal tissues. Maximum tumor uptake was 0.0041% of the injected dose/g for 125I-B72.3, 0.0024% for 131I-CC49, and 0.0029% for 131I-CC83. Radiolabeled CC49 and CC83 detected most known tumor sites on scintigrams without any clear advantage for either MAb. Nonspecific splenic and testicular uptake was frequently observed. Anti-idiotypic human anti-mouse antibody responses were seen more frequently with B72.3 than with CC49 or CC83. We conclude that higher affinity, radiolabeled anti-TAG-72 MAbs can detect colorectal cancer but do not penetrate these tumors more effectively than B72.3. Improvements in tumor detection and radioimmunotherapeutic strategies will likely require the administration of smaller fragments of MAb molecules or novel delivery systems rather than the continued development of higher affinity MAbs.

Wheat-bran and oat-bran supplements' effects on blood lipids and lipoproteins.

To compare the effects of oat-bran fiber on blood lipids, we studied 84 healthy middle-aged men and women who were placed on metabolic diets, for 2 wk, that were supplemented with either wheat bran (n = 42) or oat bran (n = 42). Fiber supplementation was 1.6 micrograms dietary fiber/J (6.8 g dietary fiber/1000 kcal) to a maximum of 16.4 g fiber/d. Significantly greater decrease with oat than with wheat were seen in total cholesterol (0.56 +/- 0.08 mmol/L and 0.29 +/- 0.08 mmol/L, P = 0.022) and low-density-lipoprotein cholesterol (0.39 +/- 0.07 mmol/L and 0.15 +/- 0.07 mmol/L, P = 0.024). No significant differences were seen in high-density lipoprotein, apolipoproteins A-1 and B, or triglyceride. We conclude that oat bran has an advantage over wheat bran in lowering serum lipids when tested in metabolic diets on large numbers of individuals with an initial mean serum cholesterol concentration above the desirable range, at 5.61 +/- 0.16 mmol/L.

Colonic fermentation and markers of colorectal-cancer risk.

The aim of this study was to determine the effect of soluble fiber on indexes of colon-cancer risk in postpolypectomy and nonpolyp patients. Forty-five postpolypectomy and 49 nonpolyp volunteers completed 2-wk metabolic studies where half of the group received oat-bran supplements and the other half took wheat-brain supplements. Colonic biopsies taken before and after the intervention showed no difference in the index of thymidine colonic-crypt-cell labeling, thymidine-labeling pattern, or nuclear aberrations. Nevertheless, fecal pH was significantly reduced by 0.23 +/- 0.07 pH units (P less than 0.002) as an index of increased colonic fermentation on oat bran. This was not associated with increased basal breath hydrogen concentrations; fecal butyrate concentrations were higher on wheat bran. We conclude that soluble fiber as oat brain appears to have no advantage over wheat bran in modifying putative risk factors for colonic cancer.

Radiation dose estimates for oral agents used in upper gastrointestinal disease.

Radiation dosimetry was calculated for a number of orally administered radiopharmaceuticals used for study of upper gastrointestinal function. These include: Tc-99m sulfur colloid in water, in a cooked egg, and in chicken liver labeled in vivo; In-111 DTPA; Tc-99m DTPA; In-113m DTPA; Tc-99m ovalbumin in cooked egg; and In-111 colloid in chicken liver labeled in vivo. Radiation burdens to the stomach, small intestine, upper and lower large intestine, ovaries, testes, and total body are calculated for each preparation.

Long-term effects of dietary calcium on risk markers for colon cancer in patients with familial polyposis.

There is conflicting evidence regarding the benefit of calcium in prevention of colon cancer. Patients who have undergone ileorectal operations for familial polyposis can be useful to study hypotheses on prevention of colon cancer. In this study we evaluated the effect of long-term calcium supplementation on risk markers of colon cancer. Thirty-one patients with familial polyposis, after subtotal colectomy, were randomized to group A, which received placebo, and group B, which received 1200 mg of calcium daily. Intervention lasted 9 months, in which they underwent four 3-monthly evaluations that included food records, fecal pH, calcium and bile acids, and rectal biopsy for thymidine labeling. Age, height, weight, macronutrients, and dietary fiber were comparable in both groups. More women were in the group that received placebo. Fecal pH, weight, and bile acid levels were similar before intervention and remained unchanged. Fecal calcium levels were similar before intervention and increased in the calcium group throughout the study (p less than 0.05). Labeling index of placebo and calcium groups was similar before intervention (4.8 and 6.1, respectively). After 3 months it was reduced in both groups (3.1 and 4.4, respectively; p less than 0.05). After 6 months it was reduced only in the calcium group (3.4; p less than 0.05). After 9 months it did not differ from the starting point (3.4 and 4.0, respectively). In a long-term intervention study with a homogenous group of patients with familial polyposis, supplemental dietary calcium did not affect mucosal risk factors for colon cancer.

The effect of lowering faecal pH on the rate of proliferation of the normal colonic mucosa.

Epidemiological and animal studies suggest that faecal pH may be a risk factor for colorectal cancer with low faecal pH associated with a lower incidence of the disease. The aim of this study was to determine whether faecal pH (or dietary fibre) affects the short-term risk factors for colon cancer. Sixty-nine normal volunteers were randomized into three equal groups (A-C). They provided food records, faecal specimens and submitted to rectal biopsy for thymidine labelling studies before and after a 2-week intervention. Group A received a placebo of fruit juice. Group B, approximately 3.0 g d-1 sodium sulphate in juice. Group C, 30 g d-1 supplementary dietary fibre as wheat bran in bread. Age, sex, weight, height and intake of macronutrients and minerals were similar in the groups prior to intervention. Faecal pH was similar for the three groups before and was reduced in Group B after intervention (P = 0.001) with a relative reduction of 0.5 pH units. The labelling index for the three groups was similar prior to intervention; after, it was lowest in Group B with a relative reduction of 0.5% points, although this difference was not statistically significant. The results thus do not support the hypothesis that an acidification of faecal pH leads to a reduction in risk markers for colon cancer.

Intra-rectal injection of tumour cells: a novel animal model of rectal cancer.

The purpose of this study was to develop an animal model of rectal cancer. Three murine-derived cell lines, B16 melanoma, CT26 and MCA38 colon carcinoma, as well as the human colon cancer cell line LS174T were injected into the submucosa of the mouse rectum. Subcutaneous CT26 anbd B16 tumours and intra-caecal CT26 tumours served as controls for tumourigenicity of the cell lines. B16 melanoma produced a locally aggressive rectal tumour as well as skin and para-aortic lymph node metastases. CT26 produced local tumour when injected intra-rectally and colon tumours and liver metastases when injected into the caecum. MCA38 and LS174T intra-rectal injections resulted in large rectal carcinomas without metastases. We believe that growth of a colon cancer cell line in the rectum approximates the human disease more closely than other models of colorectal cancer. We would expect that the model could similarly be utilized to assess the effects of novel adjuvant treatments for rectal cancer as well as in the study of the tumour biology of rectal cancer.

Primary prevention: what can you tell your patient?

Colorectal cancer, with its high incidence and significant morbidity and mortality, remains one of the leading causes of cancer-related deaths worldwide. Primary prevention of colorectal cancer may be more cost-effective and practical than secondary prevention. The primary prevention of colorectal cancer involves dietary and environmental modifications, chemoprevention, and in some cases prophylactic surgery.

The use of multiple imputation for the analysis of missing data.

This article provides a comprehensive review of multiple imputation (MI), a technique for analyzing data sets with missing values. Formally, MI is the process of replacing each missing data point with a set of m > 1 plausible values to generate m complete data sets. These complete data sets are then analyzed by standard statistical software, and the results combined, to give parameter estimates and standard errors that take into account the uncertainty due to the missing data values. This article introduces the idea behind MI, discusses the advantages of MI over existing techniques for addressing missing data, describes how to do MI for real problems, reviews the software available to implement MI, and discusses the results of a simulation study aimed at finding out how assumptions regarding the imputation model affect the parameter estimates provided by MI.

Local recurrence and intracerebral spread of squamous cell carcinoma of the scalp.

This case of squamous cell carcinoma of the scalp and malar region highlights the possibilities of therapeutic failure at the excisional, reconstructive, or histopathologic stage despite the performance of the appropriate, clinically indicated procedures and customary close examination of carcinoma patients and specimens. The extent of local recurrence and rapid intracerebral spread emphasize the occasionally aggressive nature of squamous cell carcinoma of the scalp and the need for early excision.

Progressive hemifacial atrophy associated with Lyme disease.

A case is described of progressive hemifacial atrophy occurring in a child with Lyme disease. Borrelial infection may have been an etiologic factor in the progressive hemifacial atrophy, which was ultimately treated with an SIEA free-flap transfer.

Free-flap reconstruction of large defects of the scalp and calvarium.

Beyond a certain size, full-thickness defects of scalp are not amenable to local flap repair. Staged distant flaps have now been virtually eliminated by free-flap reconstruction. The authors present 12 patients in whom full-thickness scalp defects with an average area of 275 cm2 were reconstructed utilizing free flaps. Nine patients had corresponding large calvarial defects. Ten patients had reconstruction with free latissimus dorsi muscle flaps and overlying skin grafts, and one patient had reconstruction with a scapular free flap. Of the 12 patients, 8 had extirpative surgery for tumor with immediate reconstruction and the remaining 4 had reconstruction for chronic radionecrosis of the scalp, usually associated with infected osteoradionecrosis of the calvarium. Of this latter group, 2 patients underwent simultaneous acrylic cranioplasty. The technique and results are discussed.

Spontaneous rupture of the flexor carpi radialis tendon.

Three cases of closed rupture of the flexor carpi radialis tendon associated with scapho-trapezio-trapezoidal arthritis are reported. Carpal tunnel surgery preceded all three ruptures. Local steroid injection preceded two ruptures. Long-term disability was minimal.

The Canadian Familial Adenomatous Polyposis Registry: past, present and future.

The advent of the molecular world opening up for familial adenomatous polyposis and other genetically predisposed cancers has now provided us with wonderful tools to study these diseases. The challenges, however, clearly remain to transfer discoveries in the laboratory to improvements in the care of these patients.