A proposed modification to the McDonald 2010 criteria for the diagnosis of primary progressive multiple sclerosis.

BACKGROUND: The diagnostic criteria for primary-progressive multiple sclerosis (PPMS) have undergone revision over the last 20 years. Cerebrospinal fluid oligoclonal bands (CSFOBs) have received less emphasis in recent revisions of the McDonald criteria. The aim of this study was to examine the sensitivity of the diagnostic criteria for PPMS with particular reference to spinal cord criteria and examine the utility of CSFOBs in a cohort of PPMS patients. METHODS: All new PPMS diagnoses between 1990 and 2011 were identified. Baseline clinical details and paraclinical evaluations including MRI of the brain, spinal cord, CSF and visually evoked responses (VERs) were assessed. The proportion of patients who met the requirements for diagnosis of PPMS on the basis of Thompson's and the McDonald Criteria (2001, 2005, 2010) were determined. RESULTS: There were 88/95 PPMS patients who had at least two diagnostic investigations. The sensitivity of Thompson's and the McDonald 2001 criteria was 64%; the McDonald 2010 revisions gave the highest sensitivity (77%); the McDonald 2005 criteria had intermediate sensitivity (74%). The combination of CSFOBs and MRI of the brain yielded the greatest number of patients demonstrating dissemination in space (DIS) on only two investigations. VERs did not aid diagnosis. Reducing requirements for the number of spinal cord lesions (symptomatic or not) to one increased diagnostic sensitivity to 84%. CONCLUSION: An alternative criterion requiring two of: i) MRI of the brain with one or more lesions in two of three regions typical for demyelination; ii) the presence of one T2-weighted spinal cord plaque (typical for demyelination); iii) CSFOBs; would increase the diagnostic sensitivity for PPMS.

Effect of the circumferential resection margin on survival following rectal cancer surgery.

BACKGROUND: The aim was to determine the effect of the circumferential resection margin (CRM) on overall survival following surgical excision of rectal cancer. METHODS: The effect of CRM on survival was examined by case mix-adjusted analysis of patients undergoing potentially curative excision of a rectal cancer between 1998 and 2002. RESULTS: Of 1896 patients, 1561 (82.3 per cent) had recorded data on the CRM. In 232 patients (14.9 per cent) tumour was found 1 mm or less from the CRM. In 370 patients (23.7 per cent) it was over 1 mm but no more than 5 mm from the CRM, and in 288 (18.4 per cent) it was over 5 mm but no more than 10 mm from the CRM. The remaining 671 patients (43.0 per cent) had a CRM exceeding 10 mm. Overall 5-year survival rates for these groups were 43.2, 51.7, 66.6 and 66.0 per cent respectively. Compared with patients with a CRM exceeding 10 mm, the adjusted risk of death was significantly increased for patients with a CRM of 1 mm or less (hazard ratio (HR) 1.61, P < 0.001) and those with a margin greater than 1 mm but no larger than 5 mm (HR 1.35, P = 0.005). There was no added risk for patients with tumour more than 5 mm but 10 mm or less from the CRM (HR 1.02, P = 0.873). The adverse effect of a CRM greater than 1 mm but no larger than 5 mm was found particularly in mid-rectal cancers. CONCLUSION: A predicted CRM of 5 mm or less on preoperative staging should be considered for neoadjuvant treatment.

Impact of deprivation on short- and long-term outcomes after colorectal cancer surgery.

BACKGROUND: The aim of the study was to determine the association between short- and long-term outcomes and deprivation for patients undergoing operative treatment for colorectal cancer in the Northern Region of England. METHODS: This was a retrospective analytical study based on the Northern Region Colorectal Cancer Audit Group database for the period 1998-2002. The Index of Multiple Deprivation 2004, an area-based measure, was recalibrated and used to quantify deprivation. Patients were ranked based on their postcode of residence and grouped into five categories. RESULTS: Of 8159 patients in total, 7352 (90·1 per cent) had surgery; 6953 (94·6 per cent) of the 7352 patients underwent tumour resection and 4935 (67·7 per cent) of 7294 had a margin-negative (R0) resection. Deprivation was not associated with age, sex, tumour site, stage or other tumour-related factors. Compared with the most affluent group, the most deprived patients had fewer elective operations (72·9 versus 76·4 per cent; P = 0·014), more adverse co-morbidity (P < 0·001) and fewer curative resections (65·5 versus 71·2 per cent; P < 0·001). In multivariable analysis, deprivation was not an independent predictor of postoperative death (odds ratio (OR) 0·72, 95 per cent confidence interval 0·48 to 1·06; P = 0·101) but it was a predictor of curative resection (OR 1·24, 1·01 to 1·52; P = 0·042), overall survival (HR 0·83, 0·73 to 0·95; P = 0·006) and relative survival (HR 0·74, 0·58 to 0·95; P = 0·023). CONCLUSION: Deprivation, both independently and by influencing other surgical predictors, impacts on short- and long-term outcomes of patients with colorectal cancer.

Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) guidelines recommend a timeline of 6 weeks from referral to neurology consultation and then 6 weeks to a diagnosis of multiple sclerosis (MS). OBJECTIVES: We audited the clinical management of all new outpatient referrals diagnosed with MS between January 2007 and May 2010. METHODS: We analysed the timelines from referral to first clinic visit, to MRI studies and lumbar puncture (LP) (if performed) and the overall interval from first visit to the time the diagnosis was given to the patient. RESULTS: Of the 119 diagnoses of MS/Clinically Isolated Syndrome (CIS), 93 (78%) were seen within 6 weeks of referral. MRI was performed before first visit in 61% and within 6 weeks in a further 27%. A lumbar puncture (LP) was performed in 83% of all patients and was done within 6 weeks in 78%. In total, 63 (53%) patients received their final diagnosis within 6 weeks of their first clinic visit, with 57 (48%) patients having their diagnosis delayed. The main rate-limiting steps were the availability of imaging and LP, and administrative issues. CONCLUSIONS: We conclude that, even with careful scheduling, it is difficult for a specialist service to obtain MRI scans and LP results so as to fulfil NICE guidelines within the optimal six-week period. An improved service would require MRI scans to be arranged before the first clinic visit in all patients with suspected MS.

Volume-outcome analysis of colorectal cancer-related outcomes.

BACKGROUND: Significant associations between caseload and surgical outcomes highlight the conflict between local cancer care and the need for centralization. This study examined the effect of hospital volume on short-term outcomes and survival, adjusting for the effect of surgeon caseload. METHODS: Between 1998 and 2002, 8219 patients with colorectal cancer were identified in a regional population-based audit. Outcomes were assessed using univariable and multivariable analysis to allow case mix adjustment. Surgeons were categorized as low (26 or fewer operations annually), medium (27-40) or high (more than 40) volume. Hospitals were categorized as low (86 or fewer), medium (87-109) or high (more than 109) volume. RESULTS: Some 7411 (90.2 per cent) of 8219 patients underwent surgery with an anastomotic leak rate of 2.9 per cent (162 of 5581), perioperative mortality rate of 8.0 per cent (591 of 7411) and 5-year survival rate of 46.8 per cent. Medium- and high-volume surgeons were associated with significantly better operative mortality (odds ratio (OR) 0.74, P = 0.010 and OR 0.66, P = 0.002 respectively) and survival (hazard ratio (HR) 0.88, P = 0.003 and HR 0.93, P = 0.090 respectively) than low-volume surgeons. Rectal cancer survival was significantly better in high-volume versus low-volume hospitals (HR 0.85, P = 0.036), with no difference between medium- and low-volume hospitals (HR 0.96, P = 0.505). CONCLUSION: This study has confirmed the relevance of minimum volume standards for individual surgeons. Organization of services in high-volume units may improve survival in patients with rectal cancer.

Cell kinetics and gene expression changes in colorectal cancer patients given resistant starch: a randomised controlled trial.

OBJECTIVE: This study investigated the effects of oral supplementation of resistant starch (RS) on tumour cell and colonic mucosal cell kinetics and on gene expression in patients with colorectal cancer (CRC), and its potential role in colon cancer prevention. METHODS: 65 patients with CRC were randomised to treatment with RS or ordinary starch (OS) and were given starch treatment for up to 4 weeks. Pretreatment and post-treatment biopsies were obtained from the tumour and colonic mucosa, and the effects of the starch treatment on cell proliferation and expression of the cell cycle regulatory genes CDK4 (cyclin-dependent kinase 4) and GADD45A (growth arrest and DNA damage-inducible, alpha) were investigated. RESULTS: The proportion of mitotic cells in the top half of the colonic crypt was significantly lower following RS treatment (3.1 (1.5), mean (SEM)) as compared with OS treatment (13.7 (3.2)) (p = 0.028). However, there was no effect of RS treatment on crypt dimensions and tumour cell proliferation index. There was significant upregulation in expression of CDK4 (p<0.01) and downregulation in expression of GADD45A (p<0.001) in the tumour tissue when compared with macroscopically normal mucosa. Following RS treatment, CDK4 expression in tumours (0.88 (0.15)) was twofold higher than that in the OS group (0.37 (0.16)) (p = 0.02). The expression of GADD45A, which was downregulated in the presence of cancer, was significantly upregulated (p = 0.048) following RS treatment (1.41 (0.26)) as compared with OS treatment (0.56 (0.3)). However, there were no significant differences in the expression of these genes in the normal mucosa following starch treatment. CONCLUSIONS: Cell proliferation in the upper part of colonic crypts is a premalignant marker and its reduction by RS supplementation is consistent with an antineoplastic action of this food component. Differential expression of the key cell cycle regulatory genes may contribute to the molecular mechanisms underlying these antineoplastic effects of RS.

Nurse specialist led flexible sigmoidoscopy in an outpatient setting.

OBJECTIVE: There has been an increasing demand for diagnostic flexible sigmoidoscopy. In order to improve our diagnostic services, we established a nurse specialist led flexible sigmoidoscopy clinic in 1999. The aim of this study was to review the outcomes of this service between 1999 and 2004. METHOD: The following information was collected prospectively: source of referral, presenting symptoms, the result of the flexible sigmoidoscopy, depth of insertion, the follow-up plan and complications. RESULTS: A total of 3956 patients had a flexible sigmoidoscopy performed between 1999 and 2004. The presenting symptoms were as follows: rectal bleeding (RB) in 1915 patients, change of bowel habit (CBH) in 421 patients, RB+CBH in 814 patients. The depth of insertion of the sigmoidoscope was as follows: rectum in 85 patients, sigmoid colon in 595 patients, descending colon in 1969 patients, splenic flexure in 958 patients and transverse colon in 311 patients. The findings at sigmoidoscopy were as follows: normal in 1560 patients, cancer in 132 patients, inflammatory bowel disease in 276 patients, polyps in 415 patients, diverticular disease in 584 patients and haemorrhoids in 926 patients. Two patients sustained an iatrogenic rectal perforation. CONCLUSION: The nurse specialist led flexible sigmoidoscopy clinic offers an efficient and safe diagnostic service for patients presenting with colorectal symptoms.

The predictive value of p53 and p33(ING1b) in patients with Dukes'C colorectal cancer.

OBJECTIVE: Identification of biological markers that may predict response to chemotherapy would allow the individualization of treatment by enabling selection of patients most likely to benefit from chemotherapy. The aims of this study were to determine whether p53 mutation status and p53 and p33(ING1b) protein expression can predict which patients with Dukes' C colorectal cancer following curative surgical resection respond to adjuvant chemotherapy with 5-fluorouracil (5-FU). METHOD: Patients with Dukes'C colorectal cancer (n = 41) were studied. DNA was extracted and analysed for p53 mutation using PCR-based direct DNA sequencing. Tumours were analysed for p53 protein expression by immunohistochemistry using DO-7 monoclonal antibody and for p33(ING1b) protein expression using GN1 monoclonal antibody. RESULTS: There was a significant association between p53 mutation status analysed by gene sequencing and overall and metastasis-free survival (P = 0.03 and 0.004, respectively, log-rank test). By contrast, no significant correlation was found between p53 and p33(ING1b) protein expression and overall or metastasis-free survival. CONCLUSION: In patients with Dukes'C colorectal cancer who underwent curative surgical resection of the primary tumour, followed by 5-FU-based adjuvant chemotherapy, p53 mutation status as assessed by gene sequencing is a significant predictor of overall and metastasis-free survival.

Involvement of surgical trainees in surgery for colorectal cancer and their effect on outcome.

OBJECTIVE: Surgical training in the UK is undergoing substantial changes. This study assessed: 1) the training opportunities available to trainees in operations for colorectal cancer, 2) the effect of colorectal specialization on training, and 3) the effect of consultant supervision on anastomotic complications, postoperative stay, operative mortality and 5-year survival. METHOD: Unadjusted and adjusted comparisons of outcomes were made for unsupervised trainees, supervised trainees and consultants as the primary surgeon in 7411 operated patients included in the Northern Region Colorectal Cancer Audit between 1998 and 2002. RESULTS: Surgery was performed in 656 (8.8%) patients by unsupervised trainees and in 1578 (21.3%) patients by supervised trainees. Unsupervised operations reduced from 182 (12.4%) in 1998 to 82 (6.1%) in 2002 (P < 0.001). Consultants with a colorectal specialist interest were more likely than nonspecialists to be present at surgical resections (OR 1.35, 1.12-1.63, P = 0.001) and to provide supervised training (OR 1.34, 1.17-1.53, P < 0.001). Patients operated on by unsupervised trainees were more often high-risk patients, however, consultant presence was not significantly associated with operative mortality (OR 0.83, 0.63-1.09, P = 0.186) or survival (HR 1.02, 0.92-1.13, P = 0.735) in risk-adjusted analysis. Supervised trainees had a case-mix similar to consultants, with shorter length of hospital stay (11.4 vs 12.4 days, P < 0.001), but similar mortality (OR 0.90, 0.71-1.16, 0.418) and survival (HR 0.96, 0.89-1.05, P = 0.378). CONCLUSION: One third of patients were operated on by trainees, who were more likely to perform supervised resections in colorectal teams. There was no difference in anastomotic leaks rates, operative mortality or survival between unsupervised trainees, supervised trainees and consultants when case-mix adjustment was applied. This study would suggest that there is considerable underused training capacity available.

A method for localizing the early products of nonenzymatic glycosylation in fixed tissue.

The process of nonenzymatic glycosylation (NEG) may play a significant role in the development of chronic complications of diabetes. Early products of NEG can be measured by various biochemical methods. A method has been developed to localize these early products of glycosylation in vivo in fixed tissue sections of normal and diabetic skin using monoclonal antibodies specific for glucitollysine, which is formed when the early products of NEG are chemically reduced in vitro. Carnoy's-fixed, paraffin-embedded skin samples from six diabetic and 13 nondiabetic subjects were sectioned, mounted on glass slides, and reduced for one h in 100 mM NaBH4. Immunolocalization was by the avidin--biotin immunoperoxidase method. Diabetic skin consistently stained more intensely for glucitollysine than nondiabetic skin. Staining around vessels, in particular, and of the collagenous matrix in general, was markedly enhanced in diabetic skin compared with nondiabetic skin. Antigens present in both the epidermis and the eccrine structures reacted with the antibody in both diabetic and nondiabetic skin but with greater intensity in the diabetic skin. This study has shown that it is possible to localize the early products of NEG in tissue sections using monoclonal antibodies. The findings correlate with biochemical data that show increased NEG in diabetics compared with nondiabetics. This technique should prove valuable for further investigations of the role of NEG in the pathogenesis of diabetes.

Clinical experience with CA-50 in the serum of carcinoma patients.

A radioimmunoassay was used for the detection of the human carcinoma-associated antigen CA-50 in the serum of 60 normal subjects, 236 patients with benign disease and 482 patients with carcinomas of different type. Serum levels in all normal subjects and 220 of 236 patients (93%) with benign disease were below 17 units/ml, while 269 of 482 patients (56%) with carcinoma had CA-50 levels above 17 units/ml. This tumour marker may prove useful in the diagnosis and monitoring of patients with various carcinomas.

The use of CA-50 radioimmunoassay inhibition test in the differential diagnosis of benign and malignant breast disease.

The role of the tumour marker CA-50 has been studied in the differential diagnosis of benign and malignant breast disease. Serum levels of CA-50 were determined by radioimmunoassay using a level of 17 units/ml as a cut-off. All 50 normal subjects and 22 of 24 patients (92%) with benign breast disease had CA-50 levels below 17 units/ml. By contrast, 15 of 36 patients (42%) with breast carcinoma had serum CA-50 levels above 17 units/ml (P less than 0.001). There was no clear correlation with tumour stage. The data suggest that CA-50 levels may help to differentiate benign and malignant diseases of the breast.

Clinical evaluation of combined use of CEA, CA19-9 and CA50 in the serum of patients with pancreatic carcinoma.

CEA, CA19-9 and CA50 are tumour-associated antigens defined by monoclonal antibodies that have been raised against adenocarcinoma cell lines, but no single antibody is specific for the detection of pancreatic malignancy. The aim of this study was to determine whether the combined use of CEA, CA19-9 and CA50 would improve diagnostic accuracy. An immunoradiometric assay was used for the detection of CEA and CA19-9 and the Delfia system for CA50. Serum was collected from 65 normal subjects, 16 with pancreatitis and 28 with pancreatic carcinoma. Of the 28 cancer patients, 24 (85%) had a CA19-9 level above 46 mu/ml, 26 (92%) had a CA50 level above 21 mu/ml and 10 (37%) had a CEA level above 7 ng/ml. Multivariant discriminant analysis on the combined antibodies showed that 96% of the malignant group, 13% of the pancreatitis group and 11% of the normal group were positive, with an overall correct classification of 91% into the three groups (multivariant discriminant analysis P less than 0.05). Thus the combined use of CEA, CA19-9 and CA50 improves diagnostic accuracy in differentiating benign from malignant disease of the pancreas.

Iodostearic acid in the treatment of advanced gastrointestinal carcinoma.

This phase II non-comparative trial evaluated the efficacy of intramuscular iodostearic acid in the treatment of 30 patients with advanced carcinoma of the gastrointestinal tract. These included 17 patients with colorectal carcinoma, seven with pancreatic carcinoma, four with gastric carcinoma, one with hepatocellular carcinoma and one with cholangiocarcinoma. Iodostearic acid emulsion (2 ml/1.2 g) followed by depomedrone (0.5 ml/10 mg) was injected intramuscularly twice weekly. No serious toxic effects were observed, the main side effects being local pain at the injection site and hot flushes. There were no partial or complete responses. Stable disease was seen in six of 30 patients (20%) at 3 months and three of 30 patients (10%) at 6 months. In conclusion, intramuscular iodostearic acid is relatively non-toxic, however, it appears to be of little value in the treatment of patients with advanced gastrointestinal carcinomas.

Non-Hodgkin's lymphoma presenting with jaundice and hypercalcaemia.

A patient is reported with B-cell lymphoma (centroblastic high grade non-Hodgkin's) with pancreatic involvement, who presented with jaundice and hypercalcaemia. Particularly unusual features include the presentation with a pancreatic mass and the association of hypercalcaemia with centroblastic lymphoma.

Treatment of pilonidal sinus by phenol injection.

This report reviews the treatment of pilonidal sinus by phenol injection in 54 patients. Forty-four patients were treated initially by phenol injection and this was successful in 70%. The median number of injections per patient was one (range 1-5) with a median hospital stay per injection of two days (range 1-17 days). The median time to complete healing for patients treated by injection alone was two months (range 1-32 months). These results compare very favourably with more radical methods of treatment.

Laparoscopic cholecystectomy: experience in a district general hospital.

In many centres laparoscopic cholecystectomy has become the procedure of choice for symptomatic gallbladder stones. By comparison with conventional cholecystectomy it appears to be associated with minimal morbidity, shorter hospital stay, earlier return to work and a better cosmetic result. The present study reviews the results of the first 50 laparoscopic cholecystectomies performed at Altnagelvin Area Hospital.

Severe invasive group A beta-hemolytic streptococcus infection complicating pharyngitis: a case report and discussion.

Group A beta-hemolytic streptococcus (GABHS) has long been recognized as a deadly pathogen with manifestations ranging from impetigo to necrotizing fasciitis. Bacteremia from streptococcal pharyngitis is a rare complication. We report a patient presenting with septic shock and diabetic ketoacidosis from streptococcal pharyngitis. The pathophysiology, classification, and treatment of invasive group A streptococcal infection is discussed.

Economic costs associated with an MS relapse.

BACKGROUND: Multiple sclerosis (MS) commonly affects young adults and can be associated with significant disability resulting in considerable socioeconomic burden for both patient and society. AIMS: The aim was to determine the direct and indirect cost of an MS relapse. METHODS: This was a prospective audit composed of medical chart review and patient questionnaire. Relapses were stratified into 3 groups: low, moderate and high intensity. Age, gender, MS subtype, disease duration, expanded disability status scale (EDSS) score, disease modifying therapy (DMT) use and employment status were recorded. Direct costs included GP visits, investigations, clinic visit, consultations with medical staff, medication and admission costs. Indirect costs assessed loss of earnings, partner׳s loss of earnings, childcare, meals and travel costs. RESULTS: Fifty-three patients had a clinically confirmed relapse. Thirteen were of low intensity; 23 moderate intensity and 17 high intensity with mean costs of €503, €1395 and €8862, respectively. Those with high intensity episodes tended to be older with higher baseline EDSS (p<0.003) and change in EDSS (p<0.002). Direct costs were consistent in both low and moderate intensity groups but varied with length of hospital stay in the high intensity group. Loss of earnings was the biggest contributor to indirect costs. A decision to change therapy as a result of the relapse was made in 23% of cases, further adding to annual MS related costs. CONCLUSIONS: The cost of an MS relapse is dependent on severity of the episode but even low intensity episodes can have a significant financial impact for the patient in terms of loss of earnings and for society with higher annual MS related costs.