Functional recovery in senior adults undergoing surgery for colorectal cancer: Assessment tools and strategies to preserve functional status.

Colorectal cancer is a widely-recognized aging-associated disease. Recent advances in the care of senior colorectal cancer patients has led to similar cancer-related life expectancy for older patients when compared to their younger counterparts. Recent data suggests that onco-geriatric patients place as much value on maintenance of functional independence and quality of life after treatment as they do on the potential improvements in survival that a treatment might offer. As a result, there has been significant interest in the geriatric literature surrounding the concept of "functional recovery," a multidimensional outcome metric that takes into account several domains, including physical, physiologic, psychological, social, and economic wellbeing. This review introduces the concept of functional recovery and highlights a number of predictors of post-treatment functional trajectory, including several office-based tools that clinicians can use to help guide informed decision making surrounding potential treatment options. This review also highlights a number of validated metrics that can be used to assess a patient's progress in functional recovery after surgery. While the timeline of each individual's functional recovery may vary, most data suggests that if patients are to return to their pre-operative functional status, this could occur up to 6 months post-surgery. For those patients identified to be at risk for post-operative functional decline this review also delineates strategies for prehabilitation and rehabilitation that may improve functional outcomes.

Antibiofilm properties of triclosan with EDTA or cranberry as Foley Catheter lock solutions.

AIMS: To investigate the efficiency of triclosan, ethylenediaminetetraacetic acid (EDTA) and cranberry alone or in combinations against Escherichia coli strains as urinary catheter lock solutions to reduce catheter-associated urinary tract infections. METHODS AND RESULTS: Viable counting was used to assess antibiofilm activities for triclosan, EDTA and cranberry alone or in combinations against E. coli strains embedded in biofilm onto all-silicon Foley catheter surface. The results revealed that combination of triclosan (10 mg ml-1 /EDTA 30 mg ml-1 ) when filling the catheter balloon was able to eradicate and prevent biofilm formation among all tested E. coli including the resistant strains, whereas triclosan (8·5 mg ml-1 )/ cranberry (103 mg ml-1 ) combination was a successful catheter lock solution by preventing all tested strains from adhering onto catheter surface when filled via the eye hole. CONCLUSIONS: The combinations of triclosan/EDTA and triclosan/cranberry were significantly effective in eradicating and preventing biofilm formation of the tested E. coli strains on Foley catheters. SIGNIFICANCE AND IMPACT OF THE STUDY: Combinations of triclosan/EDTA and triclosan/cranberry have a promising application as nonantibiotic catheter lock solution.

Effect of time interval between surgery and preoperative chemoradiotherapy with 5-fluorouracil or 5-fluorouracil and oxaliplatin on outcomes in rectal cancer.

BACKGROUND AND OBJECTIVES: Preoperative chemoradiotherapy for locally advanced rectal cancer is now considered "standard of care." However, the optimal time interval for resection after neoadjuvant therapy is unknown. METHODS: Between 11/90 and 11/04, 107 patients with rectal adenocarcinoma underwent preoperative chemo/RT at the University of Pennsylvania. Fifty-six percent had LAR and 40% had APR. Chemotherapy consisted of 5-FU/oxaliplatin in 28% and 5-FU in 72% of patients. All patients received preoperative RT. RESULTS: A longer time interval between chemo/RT and surgery was associated with tumor downstaging (OR 1.24, P = 0.02). A longer time interval was not associated with: nodal downstaging (OR 1.00, P = 0.98); pathologic complete response (PCR) (OR 0.97, P = 0.80); likelihood of performing an LAR (OR 0.90, P = 0.47); improved disease free survival (DFS), local control, or distant control (HR 1.05, P = 0.49; HR 1.14, P = 0.22; HR 1.06, P = 0.52, respectively). The PCR rate was 34.5% in the 5-FU/oxaliplatin/radiation group, and 13.7% in the 5-FU/radiation group. If patients with microscopic CR were excluded, then the PCR rate for 5FU/OX was 21.4% and for 5-FU was 12.2%. CONCLUSIONS: Time interval between surgery and chemo/RT appeared to have little effect on PCR or LAR rates. Patients receiving 5 FU/oxaliplatin/RT had a high PCR rate. A prospective randomized trial to test superiority of 5 FU/oxaliplatin is warranted.

Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis.

Menopausal hormone replacement therapy has been widely used to alleviate the symptoms of menopause and to decrease the detrimental effects of ovarian hormone loss on bone density and cardiovascular health. Multiple studies of colorectal cancer epidemiology also support a role for hormone replacement therapy in prevention of colorectal cancer. We studied the effect of ovariectomy and estrogen replacement on tumor formation in C57BL/6J-Min/+ (Min/+) mice, animals that bear a germline mutation in murine Apc. These mice develop multiple intestinal tumors that show loss of wild-type Apc protein. After ovariectomy, intestinal adenomas in Min/+ mice increased by 77% (P = 0.0004). Ovariectomized Min/+ mice that were treated with a replacement dose of 17beta-estradiol had the same number of tumors as Min/+ mice that were neither castrated nor treated with estrogen replacement (P = 0.85). Examination of estrogen receptor (ER) levels in intestinal tissue by immunoblot showed changes in relative expression levels of ERalpha and ERbeta, with highest ERalpha and lowest ERbeta expression in the normal-appearing intestine of Min/+ mice, and lowest ERalpha and highest ERbeta expression in the enterocytes of animals that received 17beta-estradiol. These results suggest that endogenous estrogens protect against Apc-associated tumor formation and that tumor prevention by 17beta-estradiol is associated with an increase in ERbeta and a decrease in ERalpha expression in the target tissue.

Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.

Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.

Administration of an unconjugated bile acid increases duodenal tumors in a murine model of familial adenomatous polyposis.

Intestinal carcinogenesis involves the successive accumulation of multiple genetic defects until cellular transformation to an invasive phenotype occurs. This process is modulated by many epigenetic factors. Unconjugated bile acids are tumor promoters whose presence in intestinal tissues is regulated by dietary factors. We studied the role of the unconjugated bile acid, chenodeoxycholate, in an animal model of familial adenomatous polyposis. Mice susceptible to intestinal tumors as a result of a germline mutation in Apc (Min/+ mice) were given a 10 week dietary treatment with 0.5% chenodeoxycholate. Following this, the mice were examined to determine tumor number, enterocyte proliferation, apoptosis and beta-catenin expression. Intestinal tissue prostaglandin E2 (PGE2) levels were also assessed. Administration of chenodeoxycholate in the diet increased duodenal tumor number in Min/+ mice. Promotion of duodenal tumor formation was accompanied by increased beta-catenin expression in duodenal cells, as well as increased PGE2 in duodenal tissue. These data suggest that unconjugated bile acids contribute to periampullary tumor formation in the setting of an Apc mutation.

Genotype-phenotype correlation in murine Apc mutation: differences in enterocyte migration and response to sulindac.

The adenomatous polyposis coli (APC) gene product mediates coordinated cell growth in the intestinal mucosa. In humans, germ-line mutations of APC are associated with colorectal carcinogenesis, a process that varies in severity depending on the length of the protein resulting from the mutant allele. In a previous study of the C57BL/6J-Min/+ (Min/+) mouse, we found that the protein fragment resulting from truncation at codon 850 of murine Apc was associated with changes in enterocyte migration, proliferation, apoptosis, and beta-catenin expression. This effect was reversed upon treatment of Min/+ mice with the chemopreventive drug sulindac sulfide. In this study, we measured enterocyte migration in the Apc1638N mouse, an animal with an Apc mutation that yields no detectable APC protein. We found no difference in enterocyte migration, proliferation, apoptosis, or beta-catenin levels in the Apc1638N mouse when compared to wild-type littermates bearing two normal Apc alleles. Furthermore, administration of sulindac sulfide to Apc1638N mice did not alter enterocyte migration. These observations suggest that a dominant negative effect altering cell migration is exerted by the truncated APC protein present in the Min/+ mouse. These data also suggest that the effectiveness of chemopreventive agents in preventing Apc-related tumor formation may depend on which type of mutation is present.

Aspirin prevents tumors in a murine model of familial adenomatous polyposis.

BACKGROUND: Both human and murine studies suggest that anti-inflammatory drugs prevent intestinal neoplasia. The purpose of this study was to investigate the role of aspirin as a chemopreventive agent for colorectal cancer. METHODS: We administered aspirin to the Min/+ mouse, an animal with a germline mutation in Apc, a gene that is essential for normal epithelial cell growth and differentiation. Apc mutation increases cytoplasmic beta-catenin, a regulatory protein associated with the cytoskeleton. Min/+ mice develop multiple intestinal adenomas and exhibit altered cell growth in the preneoplastic intestinal epithelium. RESULTS: Aspirin decreased the rate of tumor formation in Min/+ mice by 44%. Aspirin also normalized enterocyte growth by increasing apoptosis and proliferation in the preneoplastic intestinal mucosa. Finally, aspirin produced a decrease in intracellular beta-catenin levels, suggesting that modulation of this protein is associated with tumor prevention. CONCLUSIONS: These data confirm a role for aspirin in suppression of Apc-associated intestinal carcinogenesis.

The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis.

Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in treating intestinal adenomas in humans with Familial Adenomatous Polyposis (FAP) and in preventing intestinal tumors in the C57Bl/6J-Min+ (Min) mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the liver and intestinal flora to a sulfone, which has no anti-inflammatory activity, and a sulfide, which is the active anti-inflammatory metabolite. In this study, we determined which of these metabolites is responsible for the anti-tumor effect of sulindac in Min mice. Min mice were treated with either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation (+/+) were used as controls. At 110 days of age, all mice were euthanized and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6 tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte apoptosis was observed in Min control mice and Min mice treated with sulindac sulfone. Sulindac sulfide restored to normal the level of apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the small intestine of treated Min animals by 59% (P < 0.001). These data suggest that the anti-tumor effect of sulindac in Apc-deficient animals is mediated by the sulfide metabolite and correlates with suppression of tissue prostaglandin synthesis.

Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration.

Apc-associated intestinal tumor formation appears to require functional loss of both Apc alleles. Apc has, therefore, been classified as a tumor suppressor gene. Loss of APC protein function results in increased intracellular beta-catenin, a molecule important to both cell-cell adhesion and regulation of cellular growth. In mice bearing a germ-line Apc mutation, we found that enterocyte beta-catenin expression was also increased in histologically normal intestinal mucosa. Enterocyte crypt-villus migration was decreased by 25%, and treatment of Min/+ animals with sulindac sulfide normalized both beta-catenin expression and enterocyte migration. Our data suggest that alterations in enterocyte migration occur in cells bearing a single mutant Apc allele, and that sulindac sulfide may normalize enterocyte growth in these cells.

Surgical aspects of colorectal carcinoma.

Colorectal surgery remains the cornerstone of curative therapy for colorectal carcinoma. The development of new instruments permitting technical advances, however, as well as the advent of effective adjuvant therapies and the progress in staging and early detection, have changed some of the indications for surgery as well as surgical methods. Even so, emphasis has always been placed on thorough preoperative evaluation and staging. This article explores the current state of standard surgical care of the colorectal cancer patient with special attention given to preoperative evaluation, standard and controversial surgical therapies, and postoperative surveillance.

Rapid analysis of mitotic histone H1 phosphorylation by cationic disc electrophoresis at neutral pH in minigels.

A new method is described for analysis of histone H1 and other basic proteins by cationic disc electrophoresis in polyacrylamide gels at neutral pH. The multiphasic buffer (disc) system uses Na+ as leading ion, L-histidine as trailing ion, and Hepes as buffering counterion. These "Hepes/histidine gels" have three advantages over conventional acid-urea gels for studies of H1 phosphorylation and dephosphorylation: speed, convenience, and the need for only small amounts of cells or chromatin. Core histones and their acetylated forms can also be separated in gels containing 0.4% Triton X-100. The difference in electrophoretic mobility between mitotic (superphosphorylated) and interphase H1 from HeLa cells is approximately twice as great at neutral pH as at pH 4.5, making it possible to separate these two H1 forms rapidly and easily in Hepes/histidine "minigels" only 5-cm long. Total histones can be rapidly prepared by simply neutralizing 0.2 N HCl extracts, and the entire analysis, from harvesting cells to destaining gels, can be carried out in 1 day. The stacking effect of the disc system produces sharp bands and high resolution even with relatively dilute samples.