Alan Meagher - Academia.edu (original) (raw)

Papers by Alan Meagher

Research paper thumbnail of Vaginal support pessary in treatment of rectal prolapse Case series and review

Research paper thumbnail of Co-ordinate epigenetic silencing of a cluster of 3p22 genes flanking MLH1 in sporadic microsatellite unstable colorectal cancer

LB-207 Somatically acquired biallelic methylation of the MLH1 promoter and accompanying transcrip... more LB-207 Somatically acquired biallelic methylation of the MLH1 promoter and accompanying transcriptional silencing occurs in most sporadic colorectal cancers exhibiting microsatellite instability due to failed DNA mismatch repair function. Long-range epigenetic silencing of contiguous genes has recently been found on chromosome 2q14 in colorectal cancer. We hypothesized that epigenetic silencing of MLH1 could occur on a regional scale affecting additional genes within 3p22, rather than as a focal event. We found concordant CpG island hypermethylation and transcriptional inactivation of MLH1 with a specific cluster of flanking genes spanning >1Mb in primary microsatellite unstable colorectal cancers, which included additional tumour suppressor genes. This hypermethylated region was interspersed with genes that escaped methylation, but were nevertheless also transcriptionally repressed. Epigenetic silencing of the >1Mb cluster was observed in a proportion of adenomas, suggesting ...

Research paper thumbnail of How often are patients with clinically apparent inguinal hernias referred to a surgeon accompanied with an ultrasound? A prospective multicentre study

Australian Health Review, 2020

ObjectivesThis study estimated the frequency of ultrasounds ordered for clinically obvious inguin... more ObjectivesThis study estimated the frequency of ultrasounds ordered for clinically obvious inguinal hernias in patients referred to surgeons and evaluated the clinical value of ultrasonography for this patient population. MethodsThe present study was a prospective diagnostic and therapeutic impact study conducted in district, rural and tertiary referral hospitals in Sydney, Hawkesbury and Wagga Wagga, Australia. The study included adult patients (≥18 years of age) who had been referred to one of the participating surgeons for an elective inguinal hernia repair. The study determined the proportion of: (1) patients who underwent an inguinal hernia repair for a clinically obvious hernia and also had an ultrasound; (2) ultrasounds ordered by general practitioners (GPs); and (3) these ultrasounds that altered diagnosis and consequent surgical management from the surgeon’s perspective. ResultsIn all, 144 participants were included in this study. Of these patients, 134 had a clinically app...

Research paper thumbnail of Colorectal carcinoma with an oncocytic component occurring in a patient with Birt–Hogg–Dubé syndrome

Pathology, 2016

nodes or other organs. An accumulation of cases is needed to determine the clinical outcome of th... more nodes or other organs. An accumulation of cases is needed to determine the clinical outcome of this unusual SCC variant. In summary, we describe the first case of acantholytic SCC of the oesophagus showing extreme acantholysis, signet ring cells, and osteoclast-like giant cells. Our case highlights the histological diversity of SCC, and will be a helpful reference in surgical pathology practice.

Research paper thumbnail of Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorect... more The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 a...

Research paper thumbnail of Comparison of Reduced Volume Versus Four Liters Sulfate-Free Electrolyte Lavage Solutions for Colonoscopy Colon Cleansing

American Journal of Gastroenterology, 2003

In an attempt to improve patient tolerance for colonoscopy cleansing, a reduced volume lavage reg... more In an attempt to improve patient tolerance for colonoscopy cleansing, a reduced volume lavage regimen with 2 L sulfate-free electrolyte lavage solution (SF-ELS, Nu-LYTELY, Braintree Laboratories, Braintree, MA) plus 20 mg p.o. bisacodyl (Half Lytely, Braintree Laboratories) was compared with standard 4 L SF-ELS lavage for safety and efficacy. METHODS: At two centers, 200 patients undergoing colonoscopy for routine indications were randomized to receive the reduced volume or standard 4 L method. The day before scheduled colonoscopy, study subjects were allowed a normal breakfast and clear liquids for lunch and dinner. Those randomized to receive the reduced volume method received four 5-mg bisacodyl tablets p.o. at noon. Six hours later, they received 2 L SF-ELS given as 10 oz every 10 min. Subjects randomized to receive 4 L SF-ELS also drank their solution at 6:00 PM in a similar fashion. Colonoscopists, unaware as to the randomized preparation received, rated efficacy of cleansing. Patient tolerance and various hematological and biochemical parameters were assessed. RESULTS: Physician assessment of colon cleansing showed no differences between those patients randomized to receive reduced volume (n ϭ 93) or 4 L (n ϭ 93) SF-ELS cleansing (p ϭ 0.16). There was a profound reduction in preparation side effects. The reduced volume preparation had less fullness (p Ͻ 0.01), nausea (p Ͻ 0.01), vomiting (p ϭ 0.01), and overall discomfort (p Ͻ 0.01). There were no clinically significant changes in hematology or blood chemistry associated with either preparation. CONCLUSIONS: Reduced volume preparation with 2 L SF-ELS and bisacodyl is safe and effective. Clinical symptoms from the reduced volume preparation are significantly reduced compared with traditional 4 L gut lavage.

Research paper thumbnail of Pathological and Genetic Correlates of Apoptosis in the Progression of Colorectal Neoplasia

Tumor Biology, 1997

Apoptosis is commonly observed in a variety of human tumors, and some of the genetic events which... more Apoptosis is commonly observed in a variety of human tumors, and some of the genetic events which control this process have been identified in vitro. The aim of this study was to determine the frequency of apoptosis in colorectal neoplasms and to examine its relationship to a number of pathological parameters, to the presence of mutations in the p53 tumor suppressor gene, and to overexpression of the bcl-2 oncoprotein. A total of 109 colorectal neoplasms (26 adenomas 83 carcinomas) were examined. An in situ end-labelling assay was used to detect apoptosis in paraffin-embedded tumor sections, and scores were determined by light microscopy. The p53 and bcl-2 status were determined by immunohistochemistry. Apoptotic frequency increased with tumor progression. Normal mucosa contained significantly fewer apoptotic cells than adenomas or carcinomas. Similarly adenomas showed less apoptosis than carcinomas, and the frequency of apoptosis increased with Dukes' stage. Overall, changes in apoptotic frequency were inversely related to the level of bcl-2 expression, but were not related to the p53 status of the tumors. The frequency of apoptosis in colorectal neoplasia appears to increase in the course of tumor progression in association with a decline in bcl-2 expression, but is not influenced by p53 gene mutations.

Research paper thumbnail of Twelve-year experience with the long intestinal tube

World Journal of Surgery, 1995

A number of surgical methods, including use of the long intestinal tube, have been designed to de... more A number of surgical methods, including use of the long intestinal tube, have been designed to decrease the incidence of recurrent small bowel obstruction. The aim of the present study was to review the indications, morbidity, and long-term results of the long intestinal tube at the Mayo Clinic. During the 12-year period 1981-1992, 47 patients had such tubes placed. The patients formed a complex surgical group: 46 patients had previously undergone at least one laparotomy (median 4, range 1-10); 41 patients had been hospitalized at least once for small bowel obstruction (median 3, range 1-15); and all 41 of these patients had undergone at least one previous laparotomy for obstruction (median 2, range 1-7). Eleven patients had a history of inflammatory bowel disease, and eight had a history of irradiation. In addition to dense adhesions in 46 patients, operative findings included large bowel tumors in six patients, intraperitoneal carcinomatosis in four, intraabdominal abscess in four, and small bowel stricture in three. Twenty patients required either a small bowel or large bowel resection, and three had a stoma fashioned. Only one case of morbidity (tube retraction) was related to tube placement. Among the 36 patients with complete follow-up, nine patients developed episodes of recurrent adhesional small bowel obstruction after a mean follow-up of 48 months, although only one required laparotomy. Of the remaining 11 patients it is known that two developed small bowel obstruction, one of whom required laparotomy. Use of the long intestinal tube has generally been reserved for surgically complex cases. In light of the diverse and complicated nature of the patients in this series, the long-term reoperation rate for adhesional small bowel obstruction appears to be low.

Research paper thumbnail of Surgical and oncology trials for rectal cancer: Who will participate?

Surgery, 2007

The assessment of patients&am... more The assessment of patients' and clinicians' willingness to participate in clinical trials is advisable as part of a feasibility exercise prior to the commencement of randomized controlled trials (RCTs) to ensure adequate support in terms of likely accrual to achieve the required sample size in a timely fashion. Furthermore, understanding why patients are unwilling to enter RCTs is imperative before the current trend of low participation can be reversed. Patients, colorectal surgeons, and medical and radiation oncologists, were presented with 5 different, detailed treatments for locally advanced rectal cancer. They were asked whether they would be willing to enter an RCT comparing each treatment choice. Patients who would not participate were asked to indicate their reason for refusal. Patients' willingness to participate in each trial was consistently low (19% to 32%). Similar low levels of participation were indicated by each clinical subspecialty (15% to 38%). Of the scenarios, patients and clinicians were most willing to enter a trial investigating surgery plus preoperative radiotherapy. A dislike of randomization, a desire to be involved in decision-making, and quality of life considerations were the most commonly stated reasons for refusal. This study highlights the difficulties in performing RCTs in surgery and oncology. However, results suggest that improvements in communication regarding randomization and clinical trial processes and the actual, rather than perceived, side effects of treatments are strategies that may enhance patient participation.

Research paper thumbnail of Routine testing for mismatch repair deficiency in sporadic colorectal cancer is justified

The Journal of Pathology, 2005

This study prospectively examines the accuracy of immunohistochemical staining in the identificat... more This study prospectively examines the accuracy of immunohistochemical staining in the identification of mismatch repair defective (MMRD) colorectal cancer in routine clinical practice. The potential impact of this information on decisions regarding adjuvant treatment and germline testing were quantified. A consecutive series of fresh tissue (836 cancers) was obtained from 786 individuals undergoing curative surgery for colorectal cancer at one institution. As part of normal practice, each tumour was screened for the expression of MLH1 and MSH2 by immunohistochemical staining (IHC) and relevant clinicopathological details were documented. Microsatellite instability (MSI) was assessed using standard markers. Overall, 108 (13%) tumours showed loss of staining for either MLH1 (92 tumours) or MSH2 (16 tumours). The positive predictive value of mismatch repair IHC when used alone in the detection of MSI tumours was 88%, and the negative predictive value was 97%. Specificity and positive predictive value were improved by correlation with microsatellite status. Tumour stage (HR 3.5, 95% CI 2.0-6.0), vascular space invasion (HR 1.9, 95% CI 1.2-3.0) and mismatch repair deficiency (HR 0.2, 95% CI 0.05-0.87) were independent prognostic factors in stages II and III disease. Screening by mismatch repair IHC could reasonably have been expected to prevent ineffective treatment in 3.6% of stage II and 7.6% of stage III patients. The frequency of germline mismatch repair mutations was 0.8%, representing six unsuspected hereditary non-polyposis colorectal cancer (HNPCC) cases. Routine screening of colorectal cancers by mismatch repair IHC identifies individuals at low risk of relapse, and can prevent unnecessary adjuvant treatments in a significant number of individuals. Abnormal immunohistochemistry should be confirmed by microsatellite testing to ensure that false-positive results do not adversely impact on treatment decisions.

Research paper thumbnail of Adverse Prognostic Effect of Methylation in Colorectal Cancer Is Reversed by Microsatellite Instability

Journal of Clinical Oncology, 2003

Purpose: DNA methylation is an important biologic event in colorectal cancer and in some cases is... more Purpose: DNA methylation is an important biologic event in colorectal cancer and in some cases is associated with the development of microsatellite instability (MSI). In this study, we sought to determine the prognostic significance of DNA methylation, both in univariate analysis and in concert with other clinicopathologic factors known to influence outcome. Patients and Methods: Fresh tissue (625 cancers) was obtained from 605 individuals (age range, 29 to 99 years) undergoing curative surgery for colorectal cancer at one institution during a period of 8 years. Clinicopathologic details were recorded for all tumors, including stage, grade, type, vascular space invasion, and clinical follow-up to 5 years. Microsatellite status was assessed using standard markers. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at methylated-in-tumor loci (MINT)1, MINT2, MINT12, and MINT31 loci were assessed by bisulfi...

Research paper thumbnail of Characterisation and clinicopathological correlates of serum anti-p53 antibodies in breast and colon cancer

Journal of Cancer Research and Clinical Oncology, 1996

The humoral immune response to p53 was determined in 54 individuals with colon or breast cancer a... more The humoral immune response to p53 was determined in 54 individuals with colon or breast cancer and 50 healthy subjects, in an attempt to better understand the origin and significance of anti-p53 serum antibodies. The presence of anti-p53 antibodies in serum was determined by enzyme-linked immunosorbent assay using purified recombinant human p53, and results were validated by immunoprecipitation of radiolabelled p53. Immunohistochemical analysis of 28 tumours was performed to detect the accumulation of p53 protein. Antibodies against p53 were significantly more common in patients with colorectal (10 of 42) and breast (2 of 12) cancer than in healthy individuals (2 of 50). They were of both the IgM (7 of 11) and IgG (4 of 11) isotypes. There was no significant difference in prevalence of serum antibodies against p53 with respect to the p53 immunohistochemical status of the tumour or to other pathological features, including the presence of lymph node and distant metastases. These findings provide indirect evidence that, rather than arising as a result of a specific immune response, anti-p53 antibodies in individuals with cancer may represent elevated levels of naturally occurring polyreactive antibodies.

Research paper thumbnail of Human papillomavirus (HPV) genotypes in an Australian sample of anal cancers

International Journal of Cancer, 2014

Human papillomavirus (HPV) causes most cases of anal cancers. In this study, we analyzed biopsy m... more Human papillomavirus (HPV) causes most cases of anal cancers. In this study, we analyzed biopsy material from 112 patients with anal cancers in Australia for the presence of HPV DNA by the INNO LiPA HPV genotyping assay. There were 82% (92) males and 18% (20) females. The mean age at diagnosis was significantly (p = 0.006) younger for males (52.5 years) than females (66 years). HIV-infected males were diagnosed at a much earlier mean age (48.2 years) than HIV negative (56.3 years) males (p = 0.05). HPV DNA was detected in 96.4% (108) of cases. HPV type 16 was the commonest, at 75% (81) of samples and being the sole genotype detected in 61% (66). Overall, 79% (85) of cases had at least one genotype targeted by the bivalent HPV (bHPV) vaccine, 90% (97) by the quadrivalent HPV (qHPV) vaccine and 96% (104) by the nonavalent HPV (nHPV) vaccine. The qHPV vaccine, which is now offered to all secondary school students in Australia, may prevent anal cancers in Australia. However, given the mean age of onset of this condition, the vaccine is unlikely to have a significant impact for several decades. Further research is necessary to prove additional protective effects of the nHPV vaccine.

Research paper thumbnail of CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability

Gastroenterology, 2002

The authors thank Rachael Williams for her assistance in the collection and verification of famil... more The authors thank Rachael Williams for her assistance in the collection and verification of family history and survival data, Dr. Matthew Law for advice on statistics, Dr. Jenny Turner for review of histopathologic specimens, and Dr. Alison Todd for technical advice related to the optimization of the p16 MSP assay.

Research paper thumbnail of The Place of Elective Surgery Following Acute Diverticulitis in Young Patients

Diseases of the Colon & Rectum, 2009

Research paper thumbnail of Right hemicolectomy with a linear cutting stapler

Diseases of the Colon & Rectum, 1994

The aims of this study were to describe and evaluate a new method of performing a stapled, ftmcti... more The aims of this study were to describe and evaluate a new method of performing a stapled, ftmctional end-to-end anastomosis following right hemicolectomy. METHODS: The widely patent anastomosis is constructed by two "ftrings" of a nondisposable linear cutting stapler. The medical records and follow-up details of all patients tmdergoing this procedure were reviewed. RESULTS: This technique, which can be performed quickly and safely, has been used in 42 patients. There have been no instances of short-term or long-term anastomotic complications. CONCLUSION: The initial experience with this simplified technique of stapled anastomosis following right hemicolectomy has been favorable.

Research paper thumbnail of Colonoscopy in patients with a family history of colorectal cancer

Diseases of the Colon & Rectum, 1992

Since 1982 it has been the second author's policy to advise all patients who have presented with ... more Since 1982 it has been the second author's policy to advise all patients who have presented with a positive family history of bowel cancer and who are over the age of 30 years to undergo colonoscopy. In the period to August 1990, 600 such patients had at least one colonoscopy. Colorectal polyps or cancer were detected in 270 patients (45 percent). The incidence was essentially the same for the 171 patients with only second-degree relatives affected (43 percent), for the 194 patients with more than one affected relative (45 percent), and for the 429 patients with an affected first-degree relative (46 percent). Only the 55 patients with more than one affected first-degree relative had a higher incidence (67 percent). The incidence in the 136 totally asymptomatic patients was 36 percent but was 48 percent in the 464 with symptoms. In 37 patients carcinoma was diagnosed. Even in the 30-to 39-year age group there was a 29 percent incidence of polyps or carcinoma. Colonoscopic screening of patients with a family history of bowel cancer compares favorably with mass screening for breast cancer. It is currently advised that all patients over 30 years of age with a family history of colorectal cancer undergo colonoscopy on presentation and, if clear, every four years thereafter unless two first-degree relatives are affected, when it should be every two years.

Research paper thumbnail of Surgical management of ileosigmoid fistulas in Crohnʼs disease

Diseases of the Colon & Rectum, 1997

Research paper thumbnail of 93RD Annual Convention Podium and Poster Abstracts

Diseases of the Colon & Rectum, 1994

CM Davis, SA Strong .............. Cleveland, OH Proctectomy for severe perianal Crohn&am... more CM Davis, SA Strong .............. Cleveland, OH Proctectomy for severe perianal Crohn's disease (CD) is associated with a significant risk (15-70 percent) for an unhealed perineal wound (UPW) which is defined as more than 6 months delay in complete healing. While ...

Research paper thumbnail of Human papillomavirus 16-specific T cell responses in classic HPV-related vulvar intra-epithelial neoplasia. Determination of strongly immunogenic regions from E6 and E7 proteins

Clinical & Experimental Immunology, 2010

Summary Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was stu... more Summary Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in 16 patients affected with classic vulvar intra-epithelial neoplasia (VIN), also known as bowenoid papulosis (BP). Ten patients had blood lymphocyte proliferative T cell responses directed against E6/2 (14–34) and/or E6/4 (45–68) peptides, which were identified in the present study as immunodominant among HPV-16 E6 and E7 large peptides. Ex vivo enzyme-linked immunospot–interferon (IFN)-γ assay was positive in three patients who had proliferative responses. Twelve months later, proliferative T cell responses remained detectable in only six women and the immunodominant antigens remained the E6/2 (14–34) and E6/4 (45–68) peptides. The latter large fragments of peptides contained many epitopes able to bind to at least seven human leucocyte antigen (HLA) class I molecules and were strong binders to seven HLA-DR class II molecules. In order to build a therapeutic anti-HPV-16 vaccine, E...

Research paper thumbnail of Vaginal support pessary in treatment of rectal prolapse Case series and review

Research paper thumbnail of Co-ordinate epigenetic silencing of a cluster of 3p22 genes flanking MLH1 in sporadic microsatellite unstable colorectal cancer

LB-207 Somatically acquired biallelic methylation of the MLH1 promoter and accompanying transcrip... more LB-207 Somatically acquired biallelic methylation of the MLH1 promoter and accompanying transcriptional silencing occurs in most sporadic colorectal cancers exhibiting microsatellite instability due to failed DNA mismatch repair function. Long-range epigenetic silencing of contiguous genes has recently been found on chromosome 2q14 in colorectal cancer. We hypothesized that epigenetic silencing of MLH1 could occur on a regional scale affecting additional genes within 3p22, rather than as a focal event. We found concordant CpG island hypermethylation and transcriptional inactivation of MLH1 with a specific cluster of flanking genes spanning >1Mb in primary microsatellite unstable colorectal cancers, which included additional tumour suppressor genes. This hypermethylated region was interspersed with genes that escaped methylation, but were nevertheless also transcriptionally repressed. Epigenetic silencing of the >1Mb cluster was observed in a proportion of adenomas, suggesting ...

Research paper thumbnail of How often are patients with clinically apparent inguinal hernias referred to a surgeon accompanied with an ultrasound? A prospective multicentre study

Australian Health Review, 2020

ObjectivesThis study estimated the frequency of ultrasounds ordered for clinically obvious inguin... more ObjectivesThis study estimated the frequency of ultrasounds ordered for clinically obvious inguinal hernias in patients referred to surgeons and evaluated the clinical value of ultrasonography for this patient population. MethodsThe present study was a prospective diagnostic and therapeutic impact study conducted in district, rural and tertiary referral hospitals in Sydney, Hawkesbury and Wagga Wagga, Australia. The study included adult patients (≥18 years of age) who had been referred to one of the participating surgeons for an elective inguinal hernia repair. The study determined the proportion of: (1) patients who underwent an inguinal hernia repair for a clinically obvious hernia and also had an ultrasound; (2) ultrasounds ordered by general practitioners (GPs); and (3) these ultrasounds that altered diagnosis and consequent surgical management from the surgeon’s perspective. ResultsIn all, 144 participants were included in this study. Of these patients, 134 had a clinically app...

Research paper thumbnail of Colorectal carcinoma with an oncocytic component occurring in a patient with Birt–Hogg–Dubé syndrome

Pathology, 2016

nodes or other organs. An accumulation of cases is needed to determine the clinical outcome of th... more nodes or other organs. An accumulation of cases is needed to determine the clinical outcome of this unusual SCC variant. In summary, we describe the first case of acantholytic SCC of the oesophagus showing extreme acantholysis, signet ring cells, and osteoclast-like giant cells. Our case highlights the histological diversity of SCC, and will be a helpful reference in surgical pathology practice.

Research paper thumbnail of Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer

Clinical cancer research : an official journal of the American Association for Cancer Research, 2000

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorect... more The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 a...

Research paper thumbnail of Comparison of Reduced Volume Versus Four Liters Sulfate-Free Electrolyte Lavage Solutions for Colonoscopy Colon Cleansing

American Journal of Gastroenterology, 2003

In an attempt to improve patient tolerance for colonoscopy cleansing, a reduced volume lavage reg... more In an attempt to improve patient tolerance for colonoscopy cleansing, a reduced volume lavage regimen with 2 L sulfate-free electrolyte lavage solution (SF-ELS, Nu-LYTELY, Braintree Laboratories, Braintree, MA) plus 20 mg p.o. bisacodyl (Half Lytely, Braintree Laboratories) was compared with standard 4 L SF-ELS lavage for safety and efficacy. METHODS: At two centers, 200 patients undergoing colonoscopy for routine indications were randomized to receive the reduced volume or standard 4 L method. The day before scheduled colonoscopy, study subjects were allowed a normal breakfast and clear liquids for lunch and dinner. Those randomized to receive the reduced volume method received four 5-mg bisacodyl tablets p.o. at noon. Six hours later, they received 2 L SF-ELS given as 10 oz every 10 min. Subjects randomized to receive 4 L SF-ELS also drank their solution at 6:00 PM in a similar fashion. Colonoscopists, unaware as to the randomized preparation received, rated efficacy of cleansing. Patient tolerance and various hematological and biochemical parameters were assessed. RESULTS: Physician assessment of colon cleansing showed no differences between those patients randomized to receive reduced volume (n ϭ 93) or 4 L (n ϭ 93) SF-ELS cleansing (p ϭ 0.16). There was a profound reduction in preparation side effects. The reduced volume preparation had less fullness (p Ͻ 0.01), nausea (p Ͻ 0.01), vomiting (p ϭ 0.01), and overall discomfort (p Ͻ 0.01). There were no clinically significant changes in hematology or blood chemistry associated with either preparation. CONCLUSIONS: Reduced volume preparation with 2 L SF-ELS and bisacodyl is safe and effective. Clinical symptoms from the reduced volume preparation are significantly reduced compared with traditional 4 L gut lavage.

Research paper thumbnail of Pathological and Genetic Correlates of Apoptosis in the Progression of Colorectal Neoplasia

Tumor Biology, 1997

Apoptosis is commonly observed in a variety of human tumors, and some of the genetic events which... more Apoptosis is commonly observed in a variety of human tumors, and some of the genetic events which control this process have been identified in vitro. The aim of this study was to determine the frequency of apoptosis in colorectal neoplasms and to examine its relationship to a number of pathological parameters, to the presence of mutations in the p53 tumor suppressor gene, and to overexpression of the bcl-2 oncoprotein. A total of 109 colorectal neoplasms (26 adenomas 83 carcinomas) were examined. An in situ end-labelling assay was used to detect apoptosis in paraffin-embedded tumor sections, and scores were determined by light microscopy. The p53 and bcl-2 status were determined by immunohistochemistry. Apoptotic frequency increased with tumor progression. Normal mucosa contained significantly fewer apoptotic cells than adenomas or carcinomas. Similarly adenomas showed less apoptosis than carcinomas, and the frequency of apoptosis increased with Dukes' stage. Overall, changes in apoptotic frequency were inversely related to the level of bcl-2 expression, but were not related to the p53 status of the tumors. The frequency of apoptosis in colorectal neoplasia appears to increase in the course of tumor progression in association with a decline in bcl-2 expression, but is not influenced by p53 gene mutations.

Research paper thumbnail of Twelve-year experience with the long intestinal tube

World Journal of Surgery, 1995

A number of surgical methods, including use of the long intestinal tube, have been designed to de... more A number of surgical methods, including use of the long intestinal tube, have been designed to decrease the incidence of recurrent small bowel obstruction. The aim of the present study was to review the indications, morbidity, and long-term results of the long intestinal tube at the Mayo Clinic. During the 12-year period 1981-1992, 47 patients had such tubes placed. The patients formed a complex surgical group: 46 patients had previously undergone at least one laparotomy (median 4, range 1-10); 41 patients had been hospitalized at least once for small bowel obstruction (median 3, range 1-15); and all 41 of these patients had undergone at least one previous laparotomy for obstruction (median 2, range 1-7). Eleven patients had a history of inflammatory bowel disease, and eight had a history of irradiation. In addition to dense adhesions in 46 patients, operative findings included large bowel tumors in six patients, intraperitoneal carcinomatosis in four, intraabdominal abscess in four, and small bowel stricture in three. Twenty patients required either a small bowel or large bowel resection, and three had a stoma fashioned. Only one case of morbidity (tube retraction) was related to tube placement. Among the 36 patients with complete follow-up, nine patients developed episodes of recurrent adhesional small bowel obstruction after a mean follow-up of 48 months, although only one required laparotomy. Of the remaining 11 patients it is known that two developed small bowel obstruction, one of whom required laparotomy. Use of the long intestinal tube has generally been reserved for surgically complex cases. In light of the diverse and complicated nature of the patients in this series, the long-term reoperation rate for adhesional small bowel obstruction appears to be low.

Research paper thumbnail of Surgical and oncology trials for rectal cancer: Who will participate?

Surgery, 2007

The assessment of patients&am... more The assessment of patients' and clinicians' willingness to participate in clinical trials is advisable as part of a feasibility exercise prior to the commencement of randomized controlled trials (RCTs) to ensure adequate support in terms of likely accrual to achieve the required sample size in a timely fashion. Furthermore, understanding why patients are unwilling to enter RCTs is imperative before the current trend of low participation can be reversed. Patients, colorectal surgeons, and medical and radiation oncologists, were presented with 5 different, detailed treatments for locally advanced rectal cancer. They were asked whether they would be willing to enter an RCT comparing each treatment choice. Patients who would not participate were asked to indicate their reason for refusal. Patients' willingness to participate in each trial was consistently low (19% to 32%). Similar low levels of participation were indicated by each clinical subspecialty (15% to 38%). Of the scenarios, patients and clinicians were most willing to enter a trial investigating surgery plus preoperative radiotherapy. A dislike of randomization, a desire to be involved in decision-making, and quality of life considerations were the most commonly stated reasons for refusal. This study highlights the difficulties in performing RCTs in surgery and oncology. However, results suggest that improvements in communication regarding randomization and clinical trial processes and the actual, rather than perceived, side effects of treatments are strategies that may enhance patient participation.

Research paper thumbnail of Routine testing for mismatch repair deficiency in sporadic colorectal cancer is justified

The Journal of Pathology, 2005

This study prospectively examines the accuracy of immunohistochemical staining in the identificat... more This study prospectively examines the accuracy of immunohistochemical staining in the identification of mismatch repair defective (MMRD) colorectal cancer in routine clinical practice. The potential impact of this information on decisions regarding adjuvant treatment and germline testing were quantified. A consecutive series of fresh tissue (836 cancers) was obtained from 786 individuals undergoing curative surgery for colorectal cancer at one institution. As part of normal practice, each tumour was screened for the expression of MLH1 and MSH2 by immunohistochemical staining (IHC) and relevant clinicopathological details were documented. Microsatellite instability (MSI) was assessed using standard markers. Overall, 108 (13%) tumours showed loss of staining for either MLH1 (92 tumours) or MSH2 (16 tumours). The positive predictive value of mismatch repair IHC when used alone in the detection of MSI tumours was 88%, and the negative predictive value was 97%. Specificity and positive predictive value were improved by correlation with microsatellite status. Tumour stage (HR 3.5, 95% CI 2.0-6.0), vascular space invasion (HR 1.9, 95% CI 1.2-3.0) and mismatch repair deficiency (HR 0.2, 95% CI 0.05-0.87) were independent prognostic factors in stages II and III disease. Screening by mismatch repair IHC could reasonably have been expected to prevent ineffective treatment in 3.6% of stage II and 7.6% of stage III patients. The frequency of germline mismatch repair mutations was 0.8%, representing six unsuspected hereditary non-polyposis colorectal cancer (HNPCC) cases. Routine screening of colorectal cancers by mismatch repair IHC identifies individuals at low risk of relapse, and can prevent unnecessary adjuvant treatments in a significant number of individuals. Abnormal immunohistochemistry should be confirmed by microsatellite testing to ensure that false-positive results do not adversely impact on treatment decisions.

Research paper thumbnail of Adverse Prognostic Effect of Methylation in Colorectal Cancer Is Reversed by Microsatellite Instability

Journal of Clinical Oncology, 2003

Purpose: DNA methylation is an important biologic event in colorectal cancer and in some cases is... more Purpose: DNA methylation is an important biologic event in colorectal cancer and in some cases is associated with the development of microsatellite instability (MSI). In this study, we sought to determine the prognostic significance of DNA methylation, both in univariate analysis and in concert with other clinicopathologic factors known to influence outcome. Patients and Methods: Fresh tissue (625 cancers) was obtained from 605 individuals (age range, 29 to 99 years) undergoing curative surgery for colorectal cancer at one institution during a period of 8 years. Clinicopathologic details were recorded for all tumors, including stage, grade, type, vascular space invasion, and clinical follow-up to 5 years. Microsatellite status was assessed using standard markers. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at methylated-in-tumor loci (MINT)1, MINT2, MINT12, and MINT31 loci were assessed by bisulfi...

Research paper thumbnail of Characterisation and clinicopathological correlates of serum anti-p53 antibodies in breast and colon cancer

Journal of Cancer Research and Clinical Oncology, 1996

The humoral immune response to p53 was determined in 54 individuals with colon or breast cancer a... more The humoral immune response to p53 was determined in 54 individuals with colon or breast cancer and 50 healthy subjects, in an attempt to better understand the origin and significance of anti-p53 serum antibodies. The presence of anti-p53 antibodies in serum was determined by enzyme-linked immunosorbent assay using purified recombinant human p53, and results were validated by immunoprecipitation of radiolabelled p53. Immunohistochemical analysis of 28 tumours was performed to detect the accumulation of p53 protein. Antibodies against p53 were significantly more common in patients with colorectal (10 of 42) and breast (2 of 12) cancer than in healthy individuals (2 of 50). They were of both the IgM (7 of 11) and IgG (4 of 11) isotypes. There was no significant difference in prevalence of serum antibodies against p53 with respect to the p53 immunohistochemical status of the tumour or to other pathological features, including the presence of lymph node and distant metastases. These findings provide indirect evidence that, rather than arising as a result of a specific immune response, anti-p53 antibodies in individuals with cancer may represent elevated levels of naturally occurring polyreactive antibodies.

Research paper thumbnail of Human papillomavirus (HPV) genotypes in an Australian sample of anal cancers

International Journal of Cancer, 2014

Human papillomavirus (HPV) causes most cases of anal cancers. In this study, we analyzed biopsy m... more Human papillomavirus (HPV) causes most cases of anal cancers. In this study, we analyzed biopsy material from 112 patients with anal cancers in Australia for the presence of HPV DNA by the INNO LiPA HPV genotyping assay. There were 82% (92) males and 18% (20) females. The mean age at diagnosis was significantly (p = 0.006) younger for males (52.5 years) than females (66 years). HIV-infected males were diagnosed at a much earlier mean age (48.2 years) than HIV negative (56.3 years) males (p = 0.05). HPV DNA was detected in 96.4% (108) of cases. HPV type 16 was the commonest, at 75% (81) of samples and being the sole genotype detected in 61% (66). Overall, 79% (85) of cases had at least one genotype targeted by the bivalent HPV (bHPV) vaccine, 90% (97) by the quadrivalent HPV (qHPV) vaccine and 96% (104) by the nonavalent HPV (nHPV) vaccine. The qHPV vaccine, which is now offered to all secondary school students in Australia, may prevent anal cancers in Australia. However, given the mean age of onset of this condition, the vaccine is unlikely to have a significant impact for several decades. Further research is necessary to prove additional protective effects of the nHPV vaccine.

Research paper thumbnail of CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability

Gastroenterology, 2002

The authors thank Rachael Williams for her assistance in the collection and verification of famil... more The authors thank Rachael Williams for her assistance in the collection and verification of family history and survival data, Dr. Matthew Law for advice on statistics, Dr. Jenny Turner for review of histopathologic specimens, and Dr. Alison Todd for technical advice related to the optimization of the p16 MSP assay.

Research paper thumbnail of The Place of Elective Surgery Following Acute Diverticulitis in Young Patients

Diseases of the Colon & Rectum, 2009

Research paper thumbnail of Right hemicolectomy with a linear cutting stapler

Diseases of the Colon & Rectum, 1994

The aims of this study were to describe and evaluate a new method of performing a stapled, ftmcti... more The aims of this study were to describe and evaluate a new method of performing a stapled, ftmctional end-to-end anastomosis following right hemicolectomy. METHODS: The widely patent anastomosis is constructed by two "ftrings" of a nondisposable linear cutting stapler. The medical records and follow-up details of all patients tmdergoing this procedure were reviewed. RESULTS: This technique, which can be performed quickly and safely, has been used in 42 patients. There have been no instances of short-term or long-term anastomotic complications. CONCLUSION: The initial experience with this simplified technique of stapled anastomosis following right hemicolectomy has been favorable.

Research paper thumbnail of Colonoscopy in patients with a family history of colorectal cancer

Diseases of the Colon & Rectum, 1992

Since 1982 it has been the second author's policy to advise all patients who have presented with ... more Since 1982 it has been the second author's policy to advise all patients who have presented with a positive family history of bowel cancer and who are over the age of 30 years to undergo colonoscopy. In the period to August 1990, 600 such patients had at least one colonoscopy. Colorectal polyps or cancer were detected in 270 patients (45 percent). The incidence was essentially the same for the 171 patients with only second-degree relatives affected (43 percent), for the 194 patients with more than one affected relative (45 percent), and for the 429 patients with an affected first-degree relative (46 percent). Only the 55 patients with more than one affected first-degree relative had a higher incidence (67 percent). The incidence in the 136 totally asymptomatic patients was 36 percent but was 48 percent in the 464 with symptoms. In 37 patients carcinoma was diagnosed. Even in the 30-to 39-year age group there was a 29 percent incidence of polyps or carcinoma. Colonoscopic screening of patients with a family history of bowel cancer compares favorably with mass screening for breast cancer. It is currently advised that all patients over 30 years of age with a family history of colorectal cancer undergo colonoscopy on presentation and, if clear, every four years thereafter unless two first-degree relatives are affected, when it should be every two years.

Research paper thumbnail of Surgical management of ileosigmoid fistulas in Crohnʼs disease

Diseases of the Colon & Rectum, 1997

Research paper thumbnail of 93RD Annual Convention Podium and Poster Abstracts

Diseases of the Colon & Rectum, 1994

CM Davis, SA Strong .............. Cleveland, OH Proctectomy for severe perianal Crohn&am... more CM Davis, SA Strong .............. Cleveland, OH Proctectomy for severe perianal Crohn's disease (CD) is associated with a significant risk (15-70 percent) for an unhealed perineal wound (UPW) which is defined as more than 6 months delay in complete healing. While ...

Research paper thumbnail of Human papillomavirus 16-specific T cell responses in classic HPV-related vulvar intra-epithelial neoplasia. Determination of strongly immunogenic regions from E6 and E7 proteins

Clinical & Experimental Immunology, 2010

Summary Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was stu... more Summary Cell-mediated immunity directed against human papillomavirus 16 (HPV-16) antigens was studied in 16 patients affected with classic vulvar intra-epithelial neoplasia (VIN), also known as bowenoid papulosis (BP). Ten patients had blood lymphocyte proliferative T cell responses directed against E6/2 (14–34) and/or E6/4 (45–68) peptides, which were identified in the present study as immunodominant among HPV-16 E6 and E7 large peptides. Ex vivo enzyme-linked immunospot–interferon (IFN)-γ assay was positive in three patients who had proliferative responses. Twelve months later, proliferative T cell responses remained detectable in only six women and the immunodominant antigens remained the E6/2 (14–34) and E6/4 (45–68) peptides. The latter large fragments of peptides contained many epitopes able to bind to at least seven human leucocyte antigen (HLA) class I molecules and were strong binders to seven HLA-DR class II molecules. In order to build a therapeutic anti-HPV-16 vaccine, E...