Cannabidiol oxidation product HU-331 is a potential anticancer cannabinoid-quinone: a narrative review.

Cannabidiol and related cannabinoids are under exploration for the treatment of a number of disease states. The cannabinoid-quinone HU-331 has been studied as a potential anticancer therapeutic. Previous studies provide evidence that HU-331 displays anticancer activity without some of the known adverse events associated with traditional anticancer agents. In this brief review, we will explore the literature related to the activity of HU-331 in purified systems, cancer cell lines, and animal models. For example, HU-331 displays inhibitory activity against human topoisomerase IIα, a known anticancer drug target. Further, in multiple cell model systems, the IC50 value for HU-331 was less than 10 µM. In addition, mouse model systems demonstrate the ability of HU-331 to shrink tumors without causing cardiotoxicity. In addition, we will briefly review the activity of some key analogs and derivatives of HU-331 for various disease states. Taken together, the published studies support further exploration of HU-331 for the treatment of cancer and possibly other disease states.

Efficacy of postoperative oral metronidazole for haemorrhoidectomy pain: a randomized double-blind, placebo-controlled trial.

AIM: The aim of this work was to examine the efficacy of oral metronidazole in reducing posthaemorrhoidectomy pain versus placebo. METHOD: Forty patients were randomized to either metronidazole and standard care or placebo and standard care (21 metronidazole, 19 placebo) in a double-blinded, randomized controlled trial. The main outcome measure was posthaemorrhoidectomy pain scores over 21 days, measured on a 10-point Likert scale. RESULTS: There were no significant differences between groups with regards to age, gender, smoking status, self-reported general health or quality of life, haemorrhoid-related pain, haemorrhoid-related impact on quality of life, reported satisfaction with surgery, experience of surgery, median overall pain score or likelihood of recommending surgery to others. For reported median worst pain scores and defaecation-related pain, a trend to significance was identified between groups on days 16 and 18-21, with the metronidazole group reporting less pain. However, these differences were not significant when prespecified Bonferroni correction criteria were used. Using multilevel mixed effects modelling, the impact of time on median worst pain score was identified to be highly significant (P < 0.0001) whereas treatment allocation (placebo versus metronidazole) did not significantly affect the improvement in patients' reported pain (P = 0.8837). CONCLUSION: Our data do not support the hypothesis that postoperative metronidazole has a clinically meaningful effect on posthaemorrhoidectomy pain. This study adds to the previous literature, and implies that it should not be routinely used as an adjunct to analgesia.

Clarifying the Mechanism of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα and IIß.

Topoisomerase II is a nuclear enzyme involved in the maintenance of DNA and is an effective anticancer drug target. However, several clinical topoisomerase II-targeted agents display significant off-target toxicities and adverse events. Thus, it is important to continue characterizing compounds with activity against topoisomerase II. We previously analyzed α-(N)-heterocyclic thiosemicarbazone copper(II) complexes against human topoisomerase IIα (TOP2A), but humans also express topoisomerase IIß (TOP2B), which has distinct functional roles. Therefore, we examined two α-(N)-heterocyclic thiosemicarbazone copper [Cu(II)] complexes for activity against TOP2B in a purified system. The Cu(II) complexes, Cu(APY-ETSC)Cl and Cu(BZP-ETSC)Cl, were examined using plasmid DNA cleavage, supercoiled DNA relaxation, enzyme inactivation, protein cross-linking, DNA ligation, and ATP hydrolysis assays with TOP2B to determine whether these compounds act similarly against both enzymes. Both of the Cu(II) thiosemicarbazone (Cu-TSC) complexes we tested disrupted the function of TOP2B in a way similar to the effect on TOP2A. In particular, TOP2B DNA cleavage activity is increased in the presence of these compounds, while the relaxation and ATPase activities are inhibited. Further, both Cu-TSCs stabilize the N-terminal DNA clamp of TOP2A and TOP2B and rapidly inactivate TOP2B when the compounds are present before DNA. Our data provide evidence that the Cu-TSC complexes we tested utilize a similar mechanism against both isoforms of the enzyme. This mechanism may involve interaction with the ATPase domain of TOP2A and TOP2B outside of the ATP binding pocket. Additionally, these data support a model of TOP2 function where the ATPase domain communicates with the DNA cleavage/ligation domain.

Postoperative recurrence of Crohn's disease: impact of endoscopic monitoring and treatment step-up.

AIM: Eighty per cent of patients with Crohn's disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of postoperative colonoscopy and treatment adjustment is unknown. METHOD: Patients with a bowel resection over a 10-year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step-up in drug therapy. RESULTS: Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow-up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty-nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step-up of drug therapy [antibiotics (n =10), aminosalicylates (n=2), thiopurine (n=5), methotrexate (n=1)] and 76% had no step-up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step-up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS). CONCLUSION: Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.

Faecal diversion in the management of perianal Crohn's disease.

AIM: Severe perianal Crohn's disease remains an uncommon but important indication for faecal diversion (FD). The advent of biological therapy such as infliximab for Crohn's disease is considered to have improved the outcome for these patients. The aim of this study was to assess the outcome of patients undergoing FD for perianal Crohn's disease and the impact of biological therapy (infliximab). METHOD: Retrospective chart review was undertaken of patients who underwent FD for management of perianal Crohn's disease at two tertiary centres between 1990 and 2007. Patient demographics, disease extent and use of biological therapy were recorded. Subsequent surgery was assessed. The impact of infliximab on rates of proctocolectomy and restoration of intestinal continuity was assessed. RESULTS: Twenty-one patients (one male, 20 female), median age 34 years (range 21-67 years), underwent FD for perianal Crohn's disease. At a median follow-up time of 22 months (range 4-121 months), four patients had undergone stoma closure, 11 had had proctocolectomy and six had a stoma in situ. The effects of the procedure on severity of perianal disease were no effect in four (19%), temporary improvement in six (29%), initial improvement with later plateau in seven (33%) and healing in four patients (19%). Eleven patients (52%) received infliximab. In this group, four underwent proctocolectomy and two had intestinal continuity restored. This was not significantly different from the noninfliximab group. CONCLUSION: Patients undergoing FD for perianal Crohn's disease have <20% likelihood of restoration of intestinal continuity. This is not improved with biological therapy.

Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is recognized in children but the etiology is unknown. Abnormalities in substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide (NO) have been implicated. The density of nerve fibers in circular muscle containing these transmitters was examined in colon from children with STC and compared to other pediatric and adult samples. METHODS: Fluorescence immunohistochemistry using antibodies to NO synthase (NOS), VIP and SP was performed on colonic biopsies (transverse and sigmoid colon) from 33 adults with colorectal cancer, 11 children with normal colonic transit and anorectal retention (NAR) and 51 with chronic constipation and slow motility in the proximal colon (STC). The percentage area of nerve fibers in circular muscle containing each transmitter was quantified in confocal images. KEY RESULTS: In colon circular muscle, the percentage area of nerve fibers containing NOS > VIP > SP (6 : 2 : 1). Pediatric groups had a higher density of nerve fibers than adults. In pediatric samples, there were no regional differences in NOS and VIP, while SP nerve fiber density was higher in sigmoid than proximal colon. STC children had lower SP and VIP nerve fiber density in the proximal colon than NAR children. Twenty-three percent of STC children had low SP nerve fiber density. CONCLUSIONS & INFERENCES: There are age-related reductions in nerve fiber density in human colon circular muscle. NOS and VIP do not show regional variations, while SP nerve fiber density is higher in distal colon. 1/3 of pediatric STC patients have low SP or VIP nerve fiber density in proximal colon.

Enterocutaneous fistula: a single-centre experience.

BACKGROUND: Enterocutaneous fistulae (ECFs) present a difficult management problem and can cause significant morbidity. The aim of the study was to assess the outcome of these patients. METHODS: A retrospective chart review of all patients with ECF managed at a tertiary centre between 1996 and 2006 was performed. Demographic, management and outcome data including ECF closure, morbidity and mortality were recorded. RESULTS: A total of 33 patients (17 male) were identified with ECF (median age: 63 years, range: 27-84). The primary aetiology was Crohn's (30%), anastomotic leak (24%), iatrogenic (18%), mesh (6%), neoplasia (6%) and other (16%). Definitive surgery was undertaken in 21 (64%) at a median of 6.4 months (0.4-72 range) following presentation. Twenty percent of patients required emergency surgical intervention and 5 patients required preoperative total parenteral nutrition (TPN). Surgical management was formal resection and reanastomosis in all patients, with a mean operative time of 4.75 h (standard deviation = 1.8). The median hospital stay for the operative group was 19 days (7-85). Four patients required post-operative TPN with one patient requiring home TPN. Fistula closure rate was 97% (operative group: 21 out of 21; non-operative group: 11 out of 12). Mean follow-up was 37.3 months (0.5-217). Six (19%) operative patients developed fistula recurrence. There were two deaths at 2 and 5 months (fistula aetiology malignant colonic fistula and radiation enteritis, respectively). CONCLUSION: Patients with ECF can be treated with low morbidity and low recurrence rate in a multidisciplinary setting. We believe that patients with ECF should be referred to specialist units for management.

Decrease in nerve fibre density in human sigmoid colon circular muscle occurs with growth but not aging.

BACKGROUND: Studies in animals suggest that enteric neurons decrease in density or number with increasing age. Neurons containing nitric oxide (NO), vasoactive intestinal peptide (VIP) and Substance P (SP) have been implicated. In human large intestine, NO-utilizing neurons decrease during childhood or early adulthood but it is not known if the innervation of the muscle changes. This study examined the density of nerve fibres containing these transmitters in sigmoid colon circular muscle from children and adults. METHODS: Fluorescence immunohistochemistry using antibodies to neuronal NO synthase (nNOS), VIP and SP was performed on sigmoid colon from 18 adults with colorectal cancer, two children with familial adenomatous polyposis, and normal colon from nine children with Hirschsprung's disease. The percentage area of immunoreactive (IR) nerve fibres containing each transmitter in circular muscle was quantified in confocal images. KEY RESULTS: In the adult sigmoid colon circular muscle, the percentage area of nerve fibres containing nNOS>VIP>SP (6 : 2 : 1). Paediatric groups had significantly higher percentage area of nerve fibres containing nNOS, VIP or SP-IR than adults, with the decrease in nerve fibre density occurring from birth to 30 years. Circular muscle thickness increased between 12 and 30 years. Total nerve fibre area remained constant, while the muscle increased in thickness. CONCLUSIONS & INFERENCES: In human sigmoid colon circular muscle, there are reductions in nNOS-, VIP- and SP-IR nerve fibre density with growth from newborn to late adolescence but little further change with aging. The reduction in nerve density is due to an increase in circular muscle thickness rather than a loss of nerve fibres.

Treatment of left-sided colonic emergencies: a comparison of US, UK and Australian surgeons.

BACKGROUND: This study sought to identify and compare the current practice of surgeons in Australia, the UK and the US when presented with a left-sided colonic emergency. METHODS: Questionnaires were posted to 500 US, 500 UK and 500 Australian surgeons. Demographic data were collected regarding the surgeon's age and surgical interest, as well as their preferred method of managing left-sided colonic emergencies (namely obstruction and perforation in stable and unstable patients). The results were analysed using the chi-squared test. RESULTS: Completed questionnaires were received from 224 UK surgeons (45%), 180 US surgeons (36%) and 259 Australian surgeons (52%). All the US surgeons had an interest in gastrointestinal surgery, while 31% of the UK surgeons and 22% of Australian surgeons had an interest in colorectal surgery. In a haemodynamically stable patient with a good anaesthetic risk presenting with a complete sigmoid obstruction, significantly more UK (84%) and Australian surgeons (70%) would perform a resection and anastomosis than US surgeons (54%, p<0.0001). Of those with a colorectal interest, 97% of UK surgeons and 80% of Australian surgeons would opt for resection and anastomosis. In a haemodynamically stable patient with a good anaesthetic risk with a perforation of the sigmoid colon and purulent peritonitis, 46% of UK surgeons, 32% of Australian surgeons and 33% of US surgeons would opt for resection and anastomosis, and among colorectal surgeons, 68% of UK surgeons and 50% of Australian surgeons would opt for resection and anastomosis. CONCLUSIONS: The management of left-sided colonic emergencies varies depending on geographic location and degree of colorectal subspecialization. While the literature suggests that single-stage procedures are accepted and safe, the reasons for this variation are explored.

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland.

Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

Cholinergic transmission to colonic circular muscle of children with slow-transit constipation is unimpaired, but transmission via NK2 receptors is lacking.

Tachykinins (TKs) colocalize with acetylcholine in excitatory motor neurones supplying human colonic circular muscle (CCM). Some children with slow-transit constipation (STC) have reduced TK-immunoreactivity in nerve terminals in CCM suggesting a deficit in neuromuscular transmission. This study aimed to test this possibility. Seromuscular biopsies of transverse colon were obtained laparoscopically from STC children (37, 17 with low density of TK-immunoreactivity). Specimens of transverse (17) and sigmoid colon (20) were obtained from adults undergoing colonic resection for cancer. CCM contractions were measured isotonically and responses to carbachol, neurokinin A (NKA) and electrical field stimulation (EFS) recorded. Carbachol and NKA-evoked contractions in adult and STC colon. Hyoscine (2 micromol L-1) significantly depressed responses to EFS in all preparations. Blockade of NK2 receptors (SR 48968, 2 micromol L-1) significantly depressed EFS-evoked contractions of adult transverse CCM, but had no effect on STC preparations. Thus, neuromuscular transmission in both adults and STC children is predominantly cholinergic and this component is unimpaired in the latter, indicating that reduced TK-immunoreactivity is not a marker for depressed cholinergic responses. Although pharmacologically responsive TK receptors are present in STC colon, we did not detect neuromuscular transmission mediated by release of TKs in these preparations.

Cyclin D1 and p16 alterations in advanced premalignant lesions of the upper aerodigestive tract: role in response to chemoprevention and cancer development.

PURPOSE: To better understand the role of G(1)-S transition regulator abnormalities in the pathogenesis of advanced premalignant lesions of the upper aerodigestive tract and the biological effects of chemoprevention, we studied biopsies obtained sequentially from participants in a prospective trial using 13-cis retinoic acid, IFN-alpha, and alpha-tocopherol for 12 months. EXPERIMENTAL DESIGN: Cyclin D1 and p16 expression were analyzed by immunohistochemistry, loss of heterozygosity by polymerase chain reacting amplification, and then electrophoretic separation of the products, methylation of the p16 promoter by methylation-specific polymerase chain reacting, and cyclin D1 gene amplification by fluorescence in situ hybridization. RESULTS: Baseline dysregulation of cyclin D1 expression was found in 50% (14 of 28) and was reversed in 6 of 14 cases, whereas p16 expression was lost in 46% (13 of 28) and regained in 2 of 13 cases. Loss of heterozygosity at 9p21 occurred in 68% and p16(INK4a) promoter methylation occurred in 75% of cases, with increasing frequency from mild to severe dysplasia. Cyclin D1 gene amplification was identified in two cases. Cyclin D1 protein dysregulation at last follow-up alone and in combination with p16 loss was associated with histological progression and cancer development (P < 0.01). CONCLUSIONS: Additional study of these alterations in a larger sample and exploration of the upstream signaling partners of these cell cycle regulators in vivo is warranted to identify cancer risk profiles that would be meaningful targets for chemopreventive intervention.

Modeling categorical variables by logistic regression.

OBJECTIVE: To demonstrate the use of logistic regression in health care research. METHOD: Forward and backward stepwise logistic regression algorithms were systematically applied to a real-world data set comprising 301 cancer patients and a set of explanatory variables. RESULTS: Four variables were identified as effective predictors of pain reporting by cancer patients during chemotherapy: fatigue, depression, severity of colds or viral infections, and insomnia. The 4-predictor model was validated by (a) significance tests of regression coefficients at p<0.05, (b) significant improvement of this model over competing models, and (c) goodness of fit indices. CONCLUSIONS: Logistic regression is useful for health-related research in which outcomes of interest are often categorical.

Music and the PACU environment.

Pain is a common problem in the PACU, resulting in negative respiratory, cardiovascular, gastrointestinal, renal, neuroendocrine, and autonomic nervous system consequences for patients. Pain relief contributes to improved patient outcomes and is also an important component of patient satisfaction, particularly in light of today's environment of high competition among hospitals for patients. Music and quiet conversation by staff, contributing to low noise levels in the PACU environment, have the potential to provide pain relief and improve patient satisfaction with the PACU experience. This study investigated the effect of soothing music and lowering noise levels on the pain experience of patients during their PACU stay. A quasiexperimental study was conducted with 2 groups of patients, one who listened to music on a day when staff kept extraneous noise at a minimum in the PACU (the experimental group) and one who experienced the typical PACU day (the control group). The study was conducted at a large Veterans Administration hospital in the Midwest. The sample consisted of 97 individuals undergoing same-day surgery from all surgery services except open heart. Pain was measured by using the 11-point Numerical Rating Scale (NRS). The experimental group experienced a significant reduction in pain from admission to the PACU until discharge. There was no significant decrease for the control group. Approximately 65% of both groups reported no pain on admission to PACU. The percentage of those in the experimental group with no pain increased to 74% at time of discharge. The percentage of those in the control group who reported no pain on discharge had decreased to 58%. A total of 99% of the participants remembered their PACU stay. When asked to remember aspects of comfort during the PACU stay, the experimental group reported (1) significantly less noise caused by staff voices and equipment, (2) greater perception of availability of nurses, and (3) significantly more positive perception of their PACU stay. The study findings support the potential for music played throughout the PACU stay to positively affect the pain experience and improve comfort among patients having surgery.

Evaluating the implementation of a pain management flow sheet.

This study evaluated the outcome of implementing a pain flow sheet, using protocols derived from the Agency for Health Care Policy and Research (AHCPR) guidelines for pain management, for children recovering from surgery. Findings indicated the flow sheet was not used as designed; thus, implementing the flow sheet did not result in increased documentation of pain assessments, interventions, and outcomes, except in the increased documentation of nonpharmacological interventions for pain management. Rogers' Diffusion of Innovation Theory gives insight as to why this occurred and provides rationale for more intensive in-service education when new innovations are implemented.

Difficult or incomplete flexible sigmoidoscopy: implications for a screening programme.

BACKGROUND: Pilot studies are currently underway to investigate the use of flexible sigmoidoscopy as a screening tool for colorectal cancer. Estimates of the sensitivity of this investigation in detecting adenomas and carcinomas frequently assume a complete examination to 60 cm in all cases. This study seeks to determine the depth of insertion of flexible sigmoidoscopy in asymptomatic volunteers, and to examine the causes and implications of an incomplete examination. METHODS: A prospective study of flexible sigmoidoscopy in asymptomatic volunteers was conducted. The maximum depth of insertion was measured in all cases, and a database compiled of patient characteristics, discomfort and endoscopic difficulty. RESULTS: Independent risk factors for reduced depth of insertion were female sex, previous abdominal surgery in females, high expectation of pain in females and poor bowel preparation. The procedure was considered difficult in 33% of cases. CONCLUSIONS: Estimates of the efficacy of flexible sigmoidoscopy as a colorectal cancer screening modality should take into account the relatively high rate of incomplete studies, particularly in women.

Total colectomy for Crohn's disease.

BACKGROUND: Total colectomy for Crohn's disease of the colon may be restorative with ileorectal anastomosis or with an ileostomy and rectal stump. The present paper retrospectively audits the results of total colectomy and in particular assesses the number of patients who had a permanent ileostomy and whether this was related to disease in the rectum at the time of the original operation. METHODS: A retrospective case note review was undertaken of patients operated upon between 1968 and 1994. RESULTS: Thirty-eight patients were identified (mean age 35 years; range 17-65 years). One patient died perioperatively from an anastomotic leak. Median follow-up for the remaining patients was 7 years (range 1-29 years). Ileorectal anastomosis was performed in 17 patients and total colectomy and ileostomy in 20 patients. Indications for surgery were failure of medical treatment (61%); toxic colitis (18%); abscess (8%); perforation (5%); large bowel obstruction (5%); and colovesical fistula (3%). Subsequent proctectomy (14 patients, 38%) was more likely with subtotal colectomy and ileostomy (nine patients, 45%) than ileorectal anastomosis (five patients, 29%). This was not statistically significant (P = 0.33). Additionally, seven patients had diversion of the rectum making 21 with an ileostomy (57%). Rectal involvement at the time of the original procedure significantly increased the likelihood of permanent ileostomy (P = 0.001). The presence of anal disease did not increase the prospect of ileostomy. One patient died with advanced adeno carcinoma in a defunctioned rectum. CONCLUSIONS: A permanent ileostomy after total colectomy for Crohn's disease is common and significantly more likely with rectal involvement.

Early feeding after elective open colorectal resections: a prospective randomized trial.

BACKGROUND: A period of starvation after colorectal resections to allow for resolution of the clinical evidence of ileus has been an unchallenged surgical doctrine until recent times. A prospective randomized trial comparing early feeding to traditional management in patients undergoing open elective colorectal resections is reported. METHODS: Patients undergoing elective intraperitoneal colorectal resections without stoma formation were randomized to either an early feeding or control group. The early feeding group were allowed free fluids from 4 h postoperatively progressing to a solid diet from the first postoperative day as they tolerated it. The control group remained nil orally until passage of flatus or bowel motion and were then commenced on fluids progressing to solids over 24-48 h. RESULTS: There were 40 patients in each group well matched for age, sex, type and duration of operation, method of analgesia and mobilization. Thirty-two patients (80%) in the early feeding group tolerated a diet within 48 h. There was no significant difference in the rate of vomiting, nasogastric reinsertion or complications. The early feeding group tolerated a diet, passed flatus, used their bowels, and were discharged from hospital significantly earlier than the control group. CONCLUSION: Early feeding after elective open colorectal resections is successfully tolerated by the majority of patients, leading to earlier resolution of ileus and hospital discharge.