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Biomarker-guided trials have drawn considerable attention as they promise to lead to improvements in the benefit-risk ratio of treatments and enhanced opportunities for drug development. A variety of such designs have been proposed in the literature, many of which have been adopted in practice. Implementing such trial designs in practice can be challenging, and identifying those challenges was the main objective of a workshop organised by the MRC Hubs for Trials Methodology Research Network's Stratified Medicine Working Group in March 2017. Participants reflected on completed and ongoing biomarker-guided trials to identify the practical challenges encountered. Here, the key challenges identified during the workshop including those related to funding, ethical and regulatory issues, recruitment, monitoring of samples and laboratories, biomarker assessment, and data sharing and resources, are discussed. Despite the complexities often associated with biomarker-guided trials, the workshop concluded that they can play an important role in advancing the field of personalised medicine. Therefore, it is important that the practical challenges surrounding their implementation are acknowledged and addressed.

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A male newborn born by an atraumatic vaginal frank breech delivery was noted to have normal limb movement at birth. However, at 24 hours the neonate developed paraplegia with no evidence of spinal cord injury on radiographic films. Ultrasound and MRI demonstrated an epidural hematoma at the level of T8 and distal cord edema which extended to the conus medullaris. Delayed onset paraplegia following an atraumatic vaginal breech delivery is unlikely to have been caused by acute traction or torsion at birth. Traction and torsion injuries would present acutely. This infant developed a T8 epidural hematoma which has not been reported in a newborn. The pathophysiology of a spontaneous spinal epidural hematoma (SSEH) in adults is frequently related to increased abdominal/thoracic pressure which results in increased pressure in the highly anastomotic network of thin walled and valve-less vertebral venous plexus (Batson's plexus). Such increase in abdominal/thoracic pressure could occur during a frank breech delivery and result in a slow onset epidural hematoma. This report highlights the importance of considering slow onset epidural hematoma in the differential diagnosis of neonates who develop slow onset paraplegia. If diagnosed quickly, an epidural hematoma represents a potentially treatable etiology by rapid surgical decompression.

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AIM: Microglia form a high proportion of cells in glial tumours but their role in supporting or inhibiting tumour growth is unclear. Here we describe the establishment of an in vitro model to investigate their role in astrocytomas. METHODS: Rat hippocampal slices were prepared and, after 7 days to allow microglia to become quiescent, rat C6 astrocytic tumour cells were added. Over the following 7 days, infiltration and cell death were studied using fluorescent C6 tumour cells and confocal microscopy; immunophenotyping of microglia was performed using CD68 (phagocytosis), MHCII (antigen-presentation) and Iba1 (microglial marker regardless of functional state). Cell proliferation was assessed using Ki67 and qPCR to detect cytokine expression. Sham and control groups were included. RESULTS: Microscopy showed proliferation of C6 tumour cells with both infiltration of tumour cells into the hippocampal tissue and of microglia among the tumour cells. Confocal experiments confirmed increasing tumour cell infiltration into the hippocampal slice with time (P<0.001), associated with cell death (σ=0.313, P=0.022). Ki67 showed increased proliferation (P<0.001), of both tumour cells and Iba1+ microglia and increased microglial phagocytosis (CD68: P<0.001). Expression of pro-inflammatory cytokines IL1, IL6 and TNFα were downregulated with expression of the anti-inflammatory cytokine TGFß1 maintained. CONCLUSION: This model allows study of the proliferation and infiltration of astrocytic tumour cells in central nervous system tissue and their interaction with microglia. Our data suggest that microglial function is altered in the presence of tumour cells, putatively facilitating tumour progression. Manipulation of the microglial functional state may have therapeutic value for astrocytic tumours.

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OBJECTIVE: To compare the effectiveness and cost of self treatment of penile warts with a commercial preparation of podophyllotoxin 0.5% (PDX 0.5%) with podophyllin 0.5% and podophyllin 2.0% sourced from Podophyllum emodii. DESIGN: A prospective double blind randomised study. SUBJECTS: 315 patients with penile warts attending two departments of genitourinary medicine. MAIN OUTCOME MEASURES: Absence of warts, cessation of treatment due to severe side effects at 5 weeks. RESULTS: Of the 315 patients, 244 conformed to the protocol. Analysis was on an intention to treat basis. At 5 weeks no significant differences were found in the extent of healing of warts or in side effects for the three treatment groups. The costs of drug treatment (excluding staff time) are at least pounds 10.00 less for podophyllin than podophyllotoxin. A fourfold variation in the active constituents of the podophyllin preparations did not produce appreciably different clinical responses. In a subanalysis no evidence of deterioration in effectiveness of podophyllin over time was demonstrated. CONCLUSIONS: Penile warts in selected cases can be safely treated with 0.5-2.0% podophyllin self applied by the patient at a fraction of the cost of commercially available podophyllotoxin. The shelf life of the podophyllin extracts is at least 3 months. These findings may be especially relevant in countries where resources for health care are limited.

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BACKGROUND: Relatively few studies have addressed the question of whether clinical estimation of melanoma thickness by palpation can accurately predict its histologic thickness. If palpability was a reliable predictor of dermal invasion, it could be used to define the surgical margin. OBJECTIVE: We sought to determine whether clinical elevation of melanoma could be used to predict the presence or absence and the degree of dermal invasion in patients with stage 1 cutaneous melanoma. METHODS: Melanomas in 165 patients were categorized by one observer as flat, just palpable, palpable, or nodular. This was compared with histologic measurements of tumor thickness. RESULTS: Overall there was significant correlation between the degree of palpability of melanoma and the presence or absence of dermal invasion (p<0.001), Breslow thickness (p<0.0001), and Clark level (p<0.001). However, the relation between palpability and Breslow thickness for invasive melanomas less than 1 mm thick was weaker (n=62, p=0.053), and the correlation between elevation and Clark level was not significant for invasive melanomas less than 4 mm thick (n=111, p>0.999). CONCLUSION: We conclude that palpability of melanoma is an inadequate guide to the presence or absence and degree of dermal invasion in melanomas less than 1 mm thick and cannot be used to determine the surgical margin.

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OBJECTIVE: To assess the prevalence and patterns of congenital heart defects in infants requiring hospital admission in a defined population and to determine the differences in ethnic groups. DESIGN: A three year retrospective analysis of all hospital admissions for paediatric congenital heart defects in a single centre. SETTING: Tertiary referral centre for infant cardiac services in the West Midlands region, United Kingdom. PATIENTS AND METHODS: Indian, Pakistani, Bangladeshi and other individuals from the Indian subcontinent constitute 5.8% of the total population of the West Midlands region. Some 9% of infants, however, are Asian because of a high birth rate. All infants with confirmed congenital heart defects resident in this region who required hospital admission between April 1990 and March 1993 were classified as Asians and non-Asian, mainly white, infants. RESULTS: Of 1111 infants with congenital heart defects born in the West Midlands and admitted to the hospital, 17.0% were Asian, significantly more than the percentage of Asian infants in the population (P < 0.0001). Asian infants had a higher proportion of complex congenital heart disease (7% v 2.1%, P < 0.001), whereas coarctation of the aorta was more common in non-Asian (3% v 9.1%, P = 0.003). Persistent arterial duct seemed to be more common in Asian children (16% v 10%, NS), but this group included preterm infants admitted for duct ligation. There was no significant difference between the two groups in the other nine categories of congenital heart defects. CONCLUSIONS: The estimated prevalence of congenital heart defects requiring hospital admission was higher in Asian infants than in non-Asian (9.45 per 1000 v 4.56 per 1000, P < 0.0001). Complex congenital heart defects were more common in Asian infants whereas coarctation of the aorta was more common in non-Asian.

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PURPOSE: This study was undertaken to identify the optimum level of stapled ileal pouch-anal anastomosis. METHOD: A prospective, randomized trial was completed to compare double-stapled ileoanal anastomosis placed at the top of anal columns (high, n = 26) with anastomosis at the dentate line (low, n = 21). RESULTS: There was no significant difference in the overall complication rate between operations (high, n = 7, vs. low, n = 8; P < 0.21). Pouch-anal functional score (scale 0-12; 0 = excellent, 12 = poor) was significantly better in the high anastomosis group (median (range): 2 (1-9) vs. 5.5 (1-12); P < 0.05). Incontinence occurred in only two patients randomized to high anastomosis compared with six in the low anastomosis group. Nocturnal soiling was reported in three patients after high anastomosis and in six patients after dentate line anastomosis. Both operations caused a significant but comparable reduction of maximum and resting pressure (31 percent after high anastomosis (P < 0.05); 23 percent after low anastomosis (P < 0.05)). However, a significant fall in functional length of the anal canal was only seen after a low pouch-anal anastomosis (P < 0.05). CONCLUSION: Stapled pouch-anal anastomosis at the top of anal columns gives better functional results compared with a stapled anastomosis at the dentate line.

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Correlation of p53 expression with 5-year survival and histopathological parameters was examined immunohistochemically in two groups of 30 patients with oesophageal carcinoma (5-year survivors versus non-survivors). Tumour type, sex, operative procedure and age were matched. Some 64 per cent of squamous carcinomas and 79 per cent of adenocarcinomas were p53 positive. Normal squamous, normal glandular and metaplastic glandular epithelia were negative. Dysplastic squamous and glandular epithelium adjacent to tumours was positive when the tumour was positive and negative when it was not. Univariate analysis showed that nodal status (P = 0.001), and grade and depth of invasion (both P = 0.01) correlated with outcome. Correlation of tumour grade with outcome, when the most poorly differentiated area is used, is a novel finding for oesophageal carcinoma. The p53 status was not significantly associated with survival or any of these parameters.

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A randomized trial was performed to compare abdominal resection rectopexy and pelvic floor repair (n = 10) with perineal rectosigmoidectomy and pelvic floor repair (n = 10) in elderly female patients with full-thickness rectal prolapse and faecal incontinence. There were no recurrences of full-thickness prolapse following resection rectopexy but one after rectosigmoidectomy. Continence to liquid and solid stool was achieved in nine patients, with faecal soiling reported in only two, after resection rectopexy and in eight, with soiling in six, following rectosigmoidectomy. The median (range) frequency of defaecation was only 1 (1-3) per day following resection rectopexy compared with 3 (1-6) per day after rectosigmoidectomy. There was an increase in the mean(s.d.) maximum resting pressure after resection rectopexy (19.3(15.28) cmH2O) compared with a reduction following rectosigmoidectomy (-3.4(13.75) cmH2O) (P = 0.003). Mean(s.d.) compliance was also greater after resection rectopexy than following rectosigmoidectomy (3.9(0.75) versus 2.2(0.78) ml/cmH2O, P < 0.001). Abdominal resection rectopexy gives better functional and physiological results than perineal rectosigmoidectomy.

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