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Biomedical subjects

John H Scholefield

Publications and source records attributed to John H Scholefield.

At least 19 recordsLinked to original sources
PubMed2006

A neoadjuvant/adjuvant randomized trial of colorectal cancer patients vaccinated with an anti-idiotypic antibody, 105AD7, mimicking CD55.

PURPOSE: To assess the tolerability and effectiveness of 105AD7 vaccination in colorectal cancer patients. 105AD7 is a human anti-idiotypic antibody mimicking CD55, a glycoprotein, which is more than expressed on colorectal cancer cells and protects them from attack by complement. EXPERIMENTAL DESIGN: Colorectal cancer patients (n = 67) eligible for primary surgery were randomized to receive the anti-idiotypic antibody 105AD7+/-Bacillus Calmette-Guerin/alum or to no treatment (control group). The immunizations were given i.d./i.m. before surgery and continued for a period of 2 years. The patients were monitored in enzyme-linked immunospot (ELISPOT; gamma-IFN), proliferation assay, and Luminex cytokine assays. RESULTS: No serious adverse events were recorded. Of the 32 investigated immunized patients, 14 (44%) were considered to be responders in the ELISPOT assay. Induced proliferative responses were noted in 17 of 40 (43%) monitored patients. There was no correlation between the ELISPOT and proliferation assays. Luminex analyses revealed tumor necrosis factor-alpha and granulocyte macrophage colony-stimulating factor responses not only to the vaccine but also toward the native antigen CD55 in 9 of 13 (69%) patients. CONCLUSIONS: Immune responses to vaccination were induced in a majority of monitored patients measured by ELISPOT and proliferation assay. The lack of correlation between the ELISPOT and proliferation assays may reflect the fact that the two methods measure different T-cell responses and highlights the importance of multiple readouts in evaluating a potential cancer vaccine. Responses to both the anti-idiotype and the CD55 antigen were measurable, adding support to the use of CD55 as a target in cancer treatment.

Adjuvants, Immunologic↗
PubMed2006

Cytoplasmic expression of p27(kip1) is associated with a favourable prognosis in colorectal cancer patients.

AIM: To evaluate the prognostic significance of p27(kip1) in colorectal cancer patients. METHODS: Cytoplasmic and nuclear p27(kip1) expression was evaluated in 418 colorectal cancers using tissue microarrays. Data were associated with known patient and tumor variables and long-term patient outcomes, providing further insight into the mechanisms by which p27(kip1) may influence tumor development. RESULTS: Nuclear and cytoplasmic p27(kip1) expressions were detected in 59% and 19% of tumors respectively. Cytoplasmic p27(kip1) was almost invariably associated with positive nuclear p27(kip1) expression. Neither case correlated with known clinical or pathological variables, including tumor stage, grade or extramural vascular invasion. Furthermore, nuclear p27(kip1) expression had no impact on survival. However, we identified a significant correlation between expression of cytoplasmic p27(kip1) and longer disease-specific survival times. On multivariate analysis, TNM stage and extramural vascular invasion were highly significant independent prognostic factors, with positive cytoplasmic p27 expression showing a trend towards improved patient survival (P = 0.059). CONCLUSION: These findings support the recent evidence that cytoplasmic p27(kip1) has a distinct and important biological role that can influence tumor outcome.

Aged↗
PubMed2006

Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients.

The realization of targeted cancer therapy has driven the need to improve selection of patients with colorectal cancer for adjuvant therapy, leading to a search for potential new prognostic markers. There is accumulating evidence that immunosurveillance acts as an extrinsic tumor suppressor. As genetic instability is an early event in colorectal cancer, this can lead to altered expression of molecules conferring resistance to immune attack. Hence, molecules up or downregulated in this process may impact on patient survival. In our study, 449 colorectal tumors were screened for expression of the stress-related protein MICA, which functions as a ligand for the NKG2D receptor and whose expression confers susceptibility to both T- and NK-cell attack. Intensity of MICA expression was quantified using automated image analysis and MICA expression showed no correlation with conventional clinicopathological variables. In contrast, survival analysis showed a significant correlation between higher levels of MICA expression and improved disease-specific survival, with independent prognostic significance in multivariate analysis. Thus, patients with low levels of MICA and a poor prognosis may be good candidates for aggressive chemotherapy. In contrast, patients with high expression of MICA may be candidates for the antibody therapies, as they should be susceptible to NK killing by antibody dependent cellular cytotoxicity.

Aged↗
PubMed2006

Immunosurveillance is active in colorectal cancer as downregulation but not complete loss of MHC class I expression correlates with a poor prognosis.

Many colorectal tumors lose or downregulate cell surface expression of MHC class I molecules conferring resistance to T-cell-mediated attack. It has been suggested that this phenomenon is due to in vivo immune-tumor interactions. However, evidence of the impact of MHC class I loss on outcomes from colorectal cancer is scarce. In our study of more than 450 colorectal cancers in tissue microarray format, we have shown that both high levels of MHC class I expression and absent MHC class I expression are associated with similar disease-specific survival times, possibly due to natural killer cell-mediated clearance of MHC class I-negative tumor cells. However, tumors with low level expression of MHC class I were found to confer a significantly poorer prognosis, retaining independent significance on multivariate analysis. The existence of these poor prognosis tumors, which may avoid both NK- and T-cell-mediated immune surveillance, has important implications for the design of immunotherapeutic strategies in colorectal cancer.

Aged↗
PubMed2005

Expression of the membrane complement regulatory protein CD59 (protectin) is associated with reduced survival in colorectal cancer patients.

It has been known for some time that the immune system can recognise growing tumours, and that tumours may respond by modulation of molecules, which make them resistant to further attack. Expression, over-expression, or loss of these molecules may function as markers of tumour progression and prognosis. Among such molecules are the membrane-bound complement regulatory proteins (mCRP), which protect cells from bystander attack by autologous complement. These include CD59 (protectin), which prevents formation of the MAC complex in the terminal stages of complement activation. In the present study, we evaluated immunohistochemical expression of CD59 in a series of over 460 well-characterised colorectal cancers using tissue microarrays (TMA), and related this information to known tumour and patient variables and to survival. The CD59 expression was observed in 69 (15%) of cases overall, and was significantly associated with tumour grade. In contrast, no associations were noted with tumour site, stage or histological type. On survival analysis, a further correlation was observed between expression of CD59 by the colorectal tumours and a reduction in disease-specific patient survival. This observation was strongest for patients with early stage disease. However, a negative impact on survival was also seen in those patients with late stage disease. These results indicate that TMA linked to good clinicopathological databases with good long term follow up are useful tools for determining new prognostic indicators that can be used in future patient management. Immune surveillance may result in immune-editing that induces variable expression of a range of target antigens, and these may be useful prognostic markers. This study has identified CD59 expression as a marker of poor prognosis in colorectal cancer patients.

Adenocarcinoma↗
PubMed2005

Evidence that the p53 negative / Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: a tissue microarray study of 460 patients.

BACKGROUND: Advances in our understanding of the molecular biology of colorectal cancer have fuelled the search for novel molecular prognostic markers to complement existing staging systems. Markers assessed in combination may perform better than those considered individually. Using high-throughput tissue microarray technology, we describe the prognostic value of combined p53 / Bcl-2 status in colorectal cancer. PATIENTS AND METHODS: Tumour samples from 462 patients who underwent elective surgery to resect a primary colorectal cancer between 1994 and 2000 (mean follow-up of 75 months) were assembled in tissue microarray format. Clinico-pathological data including tumour grade, stage, vascular invasion status along with disease specific survival data has been collected prospectively. Immunohistochemical analysis of p53 and Bcl-2 expression was performed using antibodies DO-7 (p53) and 124 (Bcl-2), and results correlated with known clinico-pathological variables and outcomes. RESULTS: Abnormal nuclear p53 accumulation and Bcl-2 overexpression were detected in 221/445 (49.6%) and199/437 (45.5%) tumours respectively, with a significant inverse correlation between the two markers (p = 0.023). On univariate analysis no correlations were found between either marker and standard clinico-pathological variables, however nuclear p53 expression was associated with a significantly reduced survival (p = 0.024). Combined analysis of the two markers indicated that 112/432 (24.2%) cases displayed a p53(-)/Bcl-2(+) phenotype, this occurring more frequently in earlier stage tumours. Kaplan-Meier analysis revealed a significant survival advantage in these p53(-)/Bcl-2(+) tumours compared with the remaining cases (p = 0.0032). On multivariate analysis using the Cox proportional hazards model, neither p53 expression nor Bcl-2 expression alone were of independent prognostic significance, however the combined p53(-)/Bcl-2(+) phenotype was significantly associated with a good prognosis in this series (HR 0.659, 95%CI 0.452-0.959, p = 0.029). CONCLUSION: Patient stratification by combined p53 / Bcl-2 phenotype provides stage-independent prognostic information in colorectal cancer. Specifically, that up to a quarter of patients display a good prognosis p53(-)/Bcl-2(+) phenotype. This may indicate a more clinically indolent phenotype and a subset of patients for whom less aggressive adjuvant treatment appropriate.

Journal Article↗
PubMed2005

Pharmacological advancements in the treatment of chronic anal fissure.

Chronic anal fissure is a tear in the lining of the anal canal that, if not treated appropriately at an early stage, causes considerable anal pain during defaecation. Surgery is no longer considered the first-line treatment of this common condition, as recent advancements in medical treatment has produced promising results in the healing of fissures, thus avoiding the unwanted complications that frequently occur following operative treatment. This review looks at those pharmacological agents used commonly in the treatment of chronic anal fissures and explores alternative therapies that may be of benefit in the future.

Administration, Topical↗
PubMed2004

Smoking-related DNA adducts in anal epithelium.

Several studies have identified tobacco smoking as a risk factor for anal cancer in both women and men. Samples of anal epithelium from haemorrhoidectomy specimens from current smokers (n = 20) and age-matched life-long non-smokers (n = 16) were analysed for DNA adducts by the nuclease P(1) digestion enhancement procedure of 32P-postlabelling analysis. The study included 14 men and 22 women. Both qualitative and quantitative differences in the adduct profiles were observed between the smokers and non-smokers. The mean adduct level was significantly higher in the smokers than in the non-smokers (1.88 +/- 0.71) (S.D.) versus 1.36 +/- 0.60 adducts per 10(8) nucleotides, P = 0.02, two-tailed unpaired t-test with Welch's correction); furthermore, the adduct pattern seen in two-dimensional chromatograms revealed the smoking-related diagonal radioactive zone in 17/20 smokers, but not in any of the non-smokers (P < 0.00001, Fisher's exact test). These results indicate that components of tobacco smoke inflict genotoxic damage in the anal epithelium of smokers and provide a plausible mechanism for a causal association between smoking and anal cancer.

Adult↗
PubMed2004

Stapled hemorrhoidopexy compared with conventional hemorrhoidectomy: systematic review of randomized, controlled trials.

PURPOSE: This study was designed to determine whether conventional hemorrhoidectomy or stapled hemorrhoidopexy is superior for the management of hemorrhoids. METHODS: A systematic review of all randomized trials comparing conventional hemorrhoidectomy with stapled hemorrhoidopexy was performed. MEDLINE, EMBASE, and Cochrane Library databases were searched using the terms "hemorrhoid*" or "haemorrhoid*" and "stapl*." A list of clinical outcomes was extracted. Meta-analysis was calculated if possible. RESULTS: Fifteen trials recruiting 1,077 patients were included. Follow-up ranged from 6 weeks to 37 months. Qualitative analysis showed that stapled hemorrhoidopexy is less painful compared with hemorrhoidectomy. Stapled hemorrhoidopexy has a shorter inpatient stay (weighted mean difference, -1.02 days; 95 percent confidence interval, -1.47 to -0.57; P = 0.0001), operative time (weighted mean difference, -12.82 minutes; 95 percent confidence interval, -22.61 to -3.04; P = 0.01), and return to normal activity (standardized mean difference, -4.03 days; 95 percent confidence interval, -6.95 to -1.10; P = 0.007). Studies in a day-case setting do not prove that stapled hemorrhoidopexy is more feasible than conventional hemorrhoidectomy. Stapled hemorrhoidopexy has a higher recurrence rate (odds ratio, 3.64; 95 percent confidence interval, 1.40-9.47; P = 0.008) at a minimum follow-up of six months. CONCLUSIONS: Although stapled hemorrhoidopexy is widely used, the data available on long-term outcomes is limited. The variability in case selection and reported end points are difficulties in interpreting results. Stapled hemorrhoidopexy has unique potential complications and is a less effective cure compared with hemorrhoidectomy. With this understanding, it may be offered to patients seeking a less painful alternative to conventional surgery. Hemorrhoidectomy remains the "gold standard" of treatment.

Digestive System Surgical Procedures↗
PubMed2003

Patterns of pain in diverticular disease and the influence of acute diverticulitis.

BACKGROUND: While the association of recurrent bouts of abdominal pain with colonic diverticulosis is well recognized, the cause of this pain is obscure since in most cases it occurs without obvious diverticulitis or other potential causes. AIMS: To define the patterns of pain in diverticular disease and the influence of acute diverticulitis. METHODS: Two studies were undertaken to establish the relationship between bouts of prolonged abdominal pain (> 24 h) presumed to be due to inflammatory diverticulitis and recurrent short-lived pain. In Study 1, 261 patients with a barium enema showing diverticulosis completed a postal questionnaire concerning episodes of both prolonged and short-lived pain. In Study 2, 26 patients previously admitted to hospital with a firm diagnosis of diverticulitis were interviewed for details of their bowel habits since discharge. RESULTS: Study 1: 94/261 patients experienced recurrent, short-lived pain on a median of five days a month, with a median duration of 3 h. In addition, 51/261 patients described episodes of prolonged pain with a median duration of three days. Of these, 31/51 (61%) experienced recurrent, short-lived pain compared with 63/210 (30%) who had not had an episode of prolonged pain. More specifically, 12/17 (71%) who received antibiotic treatment for presumed acute diverticulitis during their bout of prolonged pain experienced recurrent pain compared with 82/244 (34%) who did not experience such an episode. Study 2: 18/26 patients hospitalized for acute diverticulitis developed new, recurrent, short-lived abdominal pain following discharge, with a median duration of 4 h. CONCLUSION: Episodes of prolonged, presumed inflammatory pain due to diverticulitis are frequently followed by recurrent, short-lived pain similar to that seen in irritable bowel syndrome.

Abdominal Pain↗
PubMed2003

Laparoscopic colorectal cancer surgery.

Colorectal cancer remains the second most common cause of cancer death in the USA and western Europe, with more than 34,000 new cases per year in the UK alone. Annual expenditure is in excess of pounds sterling 300 million, required for surgical, adjuvant and palliative treatment. Laparoscopic colorectal surgery has yet to gain the widespread support observed with gallbladder surgery. Randomized controlled trials are ongoing, evaluating the short- and long-term risks and benefits of laparoscopic versus conventional open surgery. Although long-term results are awaited, there is evidence of short-term benefits and no obvious evidence of laparoscopic techniques conferring any additional harm in terms of tumor recurrence or disease-free survival. This review explores the likely benefits and areas of continued concern. Information resources provide a background to colorectal cancer for nonclinicians and new strategies and a 5-year view are presented.

Colorectal Neoplasms↗
PubMed2003

The use of glyceryl trinitrate (GTN) in the treatment of chronic anal fissure in children.

BACKGROUND: 0.2 per cent topical glyceryl trinitrate (GTN) ointment heals up to two-thirds of chronic anal fissures in adults although many patients experience troublesome headaches. This double blind randomised pilot study assessed the efficacy and side effects of 0.1 and 0.05 per cent GTN ointment in treatment of chronic anal fissures in children. MATERIAL/METHODS: 15 consecutive children with chronic anal fissures were randomised to receive either 0.05 or 0.1 per cent GTN ointment applied topically twice daily for eight weeks. Clinical review was undertaken at weeks 4 and 8 and questions relating to symptoms and the incidence of headache were asked. RESULTS: The median age of the 15 (8 male) patients was 6 years (range 3-13). There were 5 anterior and 10 posterior fissures. The median duration of symptoms was 9 (3-30) months. 13/15 (86.7%) patients were taking laxatives at the time of referral. Fissure healing was complete at 8 weeks in all seven patients who received 0.05% and in 5/8 (62.5%) patients using the 0.1% ointment (Fisher's exact test, not significant). One patient from each arm experienced headaches during the first week of the trial which resolved without treatment and did not affect compliance. There were no other side effects. CONCLUSIONS: Topical glyceryl trinitrate ointment is effective in healing chronic anal fissures in children. Healing rates and side effect profile are comparable when either 0.05 or 0.1 per cent ointment is used.

Adolescent↗