Treating low-risk febrile neutropenia: Jenny's story.
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Anti-Bacterial Agents↗
Biomedical subjects
R Phillips
Publications and source records attributed to R Phillips.
Neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy followed by docetaxel in refractory patients with locally advanced breast cancer.
The objective of this study was to evaluate the clinical response of locally advanced breast cancer (LABC) to neoadjuvant (NA) chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and to study the role of docetaxel in patients who fail to respond to first-line chemotherapy. Patients were enrolled who had primary tumours without distant metastasis that were too extensive for conservative surgery. All underwent NA chemotherapy for breast cancer and thereafter surgery and/or radical radiotherapy. NA chemotherapy with FEC was administered to 88 patients between February 1998 and June 2005. A median of 6 cycles of FEC (range 1-8) was given, followed in 21 cases by a median of 4 cycles (range 2-6) of docetaxel. Where clinically established, with FEC the clinical complete response (cCR) was 22/81 (27%), clinical partial response (cPR) 41/81 (51%), clinical stable disease (cSD) 18/81 (22%). In patients where the response to FEC was regarded as insufficient, docetaxel was given. Response rates were cCR 3/21 (14%); cPR 10/21 (48%), cSD 8/21 (38%). There were 11 cases of pathological complete response (pCR), 9 in the FEC-only group and 2 in the docetaxel group. Following chemotherapy 49 (56%) patients underwent mastectomy, 32 (36%) breast conserving surgery and 5 (6%) radical radiotherapy, giving a breast conservation rate of 42%. Two patients died before receiving surgery or radical radiotherapy. The results show that neoadjuvant FEC is a reasonable NA therapy in breast cancer and that docetaxel is effective in FEC refractory cases. Only 8 of 81 (10%) assessable patients did not respond to any chemotherapy, giving an overall clinical response rate of 90%, which is comparable to studies in which taxanes were given irrespective of response to preceding therapy with antracycline including regimes.
Adult↗
Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation.
BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5', 3', and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein. METHODS AND RESULTS: We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5' Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes ("third hits") in some polyps. We found that the "third hit" probably initiated tumorigenesis. Somatic mutation spectra were similar in 5' and 3' mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, "third hits" were more common. Most "third hits" left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele. CONCLUSIONS: We propose that mutations, such as nt4661insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need "three hits" however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele.
Adenomatous Polyposis Coli↗
Video capsule endoscopy in peutz-jeghers syndrome: a blinded comparison with barium follow-through for detection of small-bowel polyps.
BACKGROUND AND STUDY AIMS: Video capsule endoscopy has shown promise for the surveillance of significant small-bowel polyps in patients with Peutz-Jeghers syndrome. In this study the yield of significant small-bowel polyps by capsule endoscopy was compared to the yield of these polyps by barium follow-through in adults with Peutz-Jeghers syndrome. PATIENTS AND METHODS: A total of 19 adults with Peutz-Jeghers syndrome who were undergoing surveillance underwent both capsule endoscopy and barium follow-through examinations, and the number of small-bowel polyps of at least 1 cm in diameter that were detected was recorded for each method. The two methods were assessed in terms of comfort and convenience for the patients and their preferred future surveillance method, using a questionnaire. RESULTS: Capsule endoscopy detected a median of four significant small-bowel polyps while barium follow-through detected a median of one (P = 0.008). There was a trend towards more participants having at least one significant small-bowel polyp detected by capsule endoscopy than was the case with barium follow-through, though capsule endoscopy seemed to be less reliable for accurate sizing of polyps that were at the limit of clinical significance. Most participants expressed a preference for capsule endoscopy for future surveillance. CONCLUSIONS: Capsule endoscopy should replace barium follow-through for the surveillance of small-bowel polyps in adults with Peutz-Jeghers syndrome, but the findings of this study should be interpreted with caution until a more reliable means of sizing polyps by capsule endoscopy is available.
Administration, Oral↗
Cytokine response to antigen stimulation of whole blood from patients with Mycobacterium ulcerans disease compared to that from patients with tuberculosis.
Mycobacterium ulcerans disease (Buruli ulcer) is a skin-ulcerating infection common in some parts of the tropics. We have investigated cytokine secretion after stimulation of whole blood from Buruli ulcer (BU) patients in a region of endemicity in Ghana with M. ulcerans sonicate or culture filtrate antigens to investigate the development of the response over time and its specificity by comparison with the response to Mycobacterium tuberculosis sonicate in human immunodeficiency virus-negative tuberculosis patients. Significant gamma interferon (IFN-gamma) production in response to whole-blood stimulation with M. ulcerans sonicate was detected in patients with ulcers, which was higher than that in patients with nodules but similar to subjects with healed BU. The mean IFN-gamma response in household contacts of BU patients was not significantly different from that in healthy control subjects from an area of nonendemicity. Results in patients with untreated, smear-positive pulmonary tuberculosis and tuberculosis patients on treatment for more than 2 weeks showed that BU patients responded better to M. ulcerans antigens than tuberculosis patients. In contrast, interleukin-10 results were higher in patients with active M. ulcerans disease than in those with healed lesions, but the pattern of response was similar to that seen in tuberculosis. A similar pattern of cytokine secretion was found using M. tuberculosis sonicate as an antigen. Neither of the two culture filtrate antigens of M. ulcerans appeared to be more specific than M. ulcerans sonicate. In the early stages of M. ulcerans disease there was a mixed Th1 and Th2 cytokine response, but the Th1 response emerged as the dominant type.
Adolescent↗
Cytokine mRNA expression in Mycobacterium ulcerans-infected human skin and correlation with local inflammatory response.
Cytokine mRNA expression in biopsies of Mycobacterium ulcerans-infected human tissue was investigated using real-time PCR, and the findings were correlated with the clinical stages of disease and histopathologies. A broad range of cytokine mRNAs were detected in 16 early nodules and 28 late-stage ulcers, including those for the Th1 cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) and the Th2 cytokine interleukin 10 (IL-10). IFN-gamma was strongly expressed in both nodules and ulcers, suggesting that a Th1 response begins early in the disease. There was a significantly higher expression of IL-8 and other proinflammatory cytokines in results from 32 biopsies with neutrophilia than in those from 12 biopsies without acute inflammation. Ten tissue samples containing granulomas showed high mRNA expression for IFN-gamma, IL-1beta, IL-12p35, IL-12p40, IL-15, and TNF-alpha relative to 34 tissue samples without granulomas. These results suggest that the human immune response to M. ulcerans is similar to that seen with some other mycobacteria despite the presence of the toxin mycolactone in the tissues.
Cytokines↗
Three dimensional stereolithography models of cancellous bone structures from muCT data: testing and validation of finite element results.
Stereolithography (STL) models of complex cancellous bone structures have been produced from three-dimensional micro-computed tomography data sets of human cancellous bone histological samples from four skeletal sites. The STL models have been mechanically tested and the derived stiffness compared with that predicted by finite element analysis. The results show a strong correlation (R2 = 0.941) between the predicted and calculated stiffnesses of the structures and show promise for the use of STL as an additional technique to complement the use of finite element models, for the assessment of the mechanical properties of complex cancellous bone structures.
Biomimetics↗
Smart tool for force measurements during knee arthroscopy: in vivo human study.
This paper describes the magnitude and patterns of forces obtained by using a probe, equipped with a six-axis force torque sensor, in knee arthroscopy. The probe was used by orthopaedic surgeons and trainees, who performed 11 different tasks in 10 standard knee arthroscopies. The force magnitude and patterns generated are presented; which can support the development of virtual arthroscopy systems with realistic haptic feedback. The results were compared across both groups of surgeons. A difference in the force patterns generated by senior versus junior surgeons was noted which can aid in the development of an objective assessment system for arthroscopy skills. The results could potentially be useful to assess future performance in real arthroscopy.
Arthroscopy↗
Factors affecting targeting using the computer assisted orthopaedic surgery system (CAOSS).
An advantage of CAOS over traditional surgery is improved precision of implant position and trajectories in 3D space. However, the implementation of these trajectories often adds an extra step to the operation that increases operative time and requires extra training. This paper reports a study of variation in time-to-task and learning curve in performing a standard task of targeting in 3D space using Hull's CAOSS. It shows that time-to-task can be reduced by replacing a 3D targeting task with multiple independent 2D targeting tasks whilst potentially reducing targeting error. Based on this better understanding of targeting a novel jig was developed for performing dynamic hip Screw (DHS) insertion using CAOSS that would provide improved targeting performance by the surgeon.
Hip↗
Finite-temperature quasicontinuum: molecular dynamics without all the atoms.
Using a combination of statistical mechanics and finite-element interpolation, we develop a coarse-grained (CG) alternative to molecular dynamics (MD) for crystalline solids at constant temperature. The new approach is significantly more efficient than MD and generalizes earlier work on the quasicontinuum method. The method is validated by recovering equilibrium properties of single crystal Ni as a function of temperature. CG dynamical simulations of nano-indentation reveal a strong dependence on temperature of the critical stress to nucleate dislocations under the indenter.
Journal Article↗
Can pathological complete response in the primary tumour following pre-operative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision?
INTRODUCTION: Local excision is considered inappropriate treatment for T3-T4 rectal adenocarcinomas, as it cannot provide prognostic information regarding lymph node involvement and has a high risk of pelvic recurrence. Preoperative chemoradiation (CRT) studies in rectal cancer suggest that a pathological complete response (pCR) in the primary tumour provides an excellent long-term outcome. If downstaging to stage pT0 predicts a tumour response within the perirectal and pelvic lymph nodes, this may allow local excision to be performed without increased risk of pelvic recurrence. This retrospective study aimed to determine the incidence of involved lymph nodes following pCR (ypT0) after preoperative CRT and total mesorectal excision. METHOD: The outcome and treatment details of 211 patients undergoing preoperative CRT for clinically staged T3-T4 unresectable rectal adenocarcinomas between 1993 and 2003 at Mount Vernon Hospital were reviewed. RESULTS: Data were recorded from the 143 patients who completed treatment with a median follow-up of 25 months. Twenty-three patients (18%) were found to have had a pCR. Four out of 23 patients (17%) had involved lymph nodes. No pelvic recurrences developed after a ypCR. Overall survival was similar for patients with ypT0 or residual tumour. CONCLUSION: Pathological complete response in the primary tumour failed to predict a response in the perirectal lymph nodes (p=0.08). The degree of response predicted a lymph node response (p=0.02). The detection of ypCR identified patients with a low rate of pelvic recurrence. This may in the future allow selection of patients for whom local excision can be performed without a higher risk of local relapse.
Adenocarcinoma↗
[Non-invasive determination of cardiac output by continuous wave Doppler in air rescue service].
BACKGROUND: Determination of cardiac output (CO) enables to assess the hemodynamic situation as well as to administer optimal catecholamine therapy especially in critically compromised patients with hemodynamic instability. Invasive determination of CO is possible via a Swan-Ganz-catheter with its associated risk of implantation in the hospital. Using the Doppler technique, we evaluated the feasibility of the USCOM-system for non-invasive CO determination in preclinical emergency medicine in air rescue service. METHODS: In 32 patients (17 months to 92-years-old) cardiac output was determined non-invasively (USCOM) at the scene and during the helicopter transport at Christoph 4, based at Hannover Medical School. Simultaneously, blood pressure, ECG and oxygen saturation were determined. Non-invasive CO was assessed by a suprasternal access aiming at the aorta ascendens. 19 patients were unconscious due to cardial and non-cardial reasons, and 13 were conscious (sepsis, status epilepticus, anaphylactic reaction). 7 patients were hemodynamically unstable. In three patients the monitor was used during interhospital transfer by helicopter. RESULTS: Non-invasively determined CO via the USCOM system was 4.8 +/- 0.7 l/min with a cardiac index of 2.4 +/- 0.3 l/m (2). Highest CO values were determined in a patient with sepsis and during a grand-mal-status in epilepsy (CO 8.2 l/min). All examinations were done by the same emergency physician of the emergency helicopter Christoph 4 immediately after arrival at the scene. The examination took on average 25 seconds. During the helicopter transport, several consecutive CO measurements were performed to assess volume and catecholamine therapy with increase of stroke volume after volume load with colloidal fluids. CONCLUSIONS: Using the USCOM system it is possible to determine the beat-to-beat cardiac output in air rescue service non-invasively. The emergency physician gains additional crucial hemodynamic information to diagnose and treat adequately by administration of volume load and catecholamines at the scene and during flight conditions. Further preclinical prospective trials are mandatory to elucidate the value of this novel device in emergency medicine.
Adolescent↗
Efficacy of the combination rifampin-streptomycin in preventing growth of Mycobacterium ulcerans in early lesions of Buruli ulcer in humans.
Mycobacterium ulcerans disease is common in some humid tropical areas, particularly in parts of West Africa, and current management is by surgical excision of skin lesions ranging from early nodules to extensive ulcers (Buruli ulcer). Antibiotic therapy would be more accessible to patients in areas of Buruli ulcer endemicity. We report a study of the efficacy of antibiotics in converting early lesions (nodules and plaques) from culture positive to culture negative. Lesions were excised either immediately or after treatment with rifampin orally at 10 mg/kg of body weight and streptomycin intramuscularly at 15 mg/kg of body weight daily for 2, 4, 8, or 12 weeks and examined by quantitative bacterial culture, PCR, and histopathology for M. ulcerans. Lesions were measured during treatment. Five lesions excised without antibiotic treatment and five lesions treated with antibiotics for 2 weeks were culture positive, whereas three lesions treated for 4 weeks, five treated for 8 weeks, and three treated for 12 weeks were culture negative. No lesions became enlarged during antibiotic treatment, and most became smaller. Treatment with rifampin and streptomycin for 4 weeks or more inhibited growth of M. ulcerans in human tissue, and it provides a basis for proceeding to a trial of antibiotic therapy as an alternative to surgery for early M. ulcerans disease.
Adolescent↗
Sensitivity of PCR targeting the IS2404 insertion sequence of Mycobacterium ulcerans in an Assay using punch biopsy specimens for diagnosis of Buruli ulcer.
Punch biopsy specimens from Mycobacterium ulcerans disease lesions were used to compare the sensitivities and specificities of direct smear, culture, PCR, and histopathology in making a diagnosis of M. ulcerans disease in a field setting. PCR for the insertion element IS2404 was modified to include uracil-N-glycosylase and deoxyuridine triphosphate instead of deoxythymidine triphosphate to reduce the risk of cross contamination. The "gold standard" for confirmation of clinically diagnosed Buruli ulcer was a definite histological diagnosis, a positive culture for M. ulcerans, or a smear positive for acid-fast bacilli (AFB), together with a possible histological diagnosis. For 70 clinically diagnosed cases of M. ulcerans disease, the modified PCR was 98% sensitive and gave a rapid result. The sensitivities of microscopy, culture, and histology were 42%, 49%, and 82%, respectively. The use of a 4-mm punch biopsy specimen was preferred to a 6-mm punch biopsy specimen since the wound was less likely to bleed and to need stitching. Given adequate technical expertise and the use of controls, the PCR was viable in a teaching hospital setting in Ghana; and in routine practice, we would recommend the use of Ziehl-Neelsen staining of biopsy specimens to detect AFB, followed by PCR, in AFB-negative cases only, in order to minimize costs. Histology and culture remain important as quality control tests, particularly in studies of treatment efficacy.
Adolescent↗
Method for large scale isolation, culture and cryopreservation of human monocytes suitable for chemotaxis, cellular adhesion assays, macrophage and dendritic cell differentiation.
This paper presents an improved method of isolating, culturing and cryopreserving human monocytes in large quantity with high purity using standard laboratory centrifuges. Monocytes were isolated from 300 to 360 ml of heparinized human blood using a Double Density technique employing Ficoll Isopaque and 46% iso-osmotic Percoll. Yields of monocytes ranged from 75 to 205 million (from 300 to 360 ml of blood) with an average purity of 90.6%. The ability of fresh or frozen monocytes to adhere to endothelial cells in the presence of oxidized L-alpha-1-palmitoyl-2-arachidonosyl-sn-glycero-3-phosphocholine (oxPAPC) or lipopolysaccharide (LPS) did not differ and no significant difference in response to the chemotactic stimulant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) was observed. We define a useful method for the culture and differentiation of fresh or frozen monocytes isolated by this method, into macrophages as judged by morphology, expression of the macrophage marker SRA-1 and induction of inflammatory genes TNF-alpha, IL-6 and COX-2. Also, fresh or frozen Double Density isolated cells can be successfully differentiated into dendritic cells in the presence of GM-CSF and IL-4 as judged by the expression of the hallmark surface proteins CD1a and DC-sign and the absence of CD14. This method also yields a pure population of lymphocytes.
Cell Adhesion↗
How can paediatric epilepsy services best be delivered in secondary care?
OBJECTIVE: To produce practical evidence-based guidelines for the management of paediatric epilepsy in secondary care settings. DESIGN: Question-specific systematic literature review and local service audit. MAIN OUTCOME MEASURES: Grade of recommendation for specific management issues. RESULTS: There is little good quality research to support many existing epilepsy guidelines for secondary care. CONCLUSION: Practical guidelines for the provision of children's epilepsy services can be evidence influenced but until more relevant research is undertaken, not evidence based.
Adolescent↗
Cost implications of sexual dysfunction: the female picture.
This study examined the clinical workload, outcome and direct costs of managing women with sexual dysfunction in an NHS clinic in the UK. A retrospective analysis of a 3-month period showed that of 47 referrals to the clinic, 38 undertook treatment. The therapists' assessments suggested that over 80% of patients improved on treatment. The average cost per patient was pound 472 (compared to pound 335 per annum for erectile dysfunction, which included physician's and drug costs). The average cost by type of practitioner was pound 278 (psychologist), pound 322 (physician), pound 532 (physician and psychologist) and pound 597 (sex therapist). Patients required between 1 and 51 treatment sessions, which were mainly restricted to psychological therapy. Female sexual dysfunction (FSD) represents a significant economic burden to the NHS. Further research on the potential role and cost effectiveness of pharmacological agents for FSD is warranted.
Adult↗
Ethical issues in social research: difficulties encountered gaining access to children in hospital for research.
BACKGROUND: This paper recounts the difficulties experienced when the authors sought access to children in hospital for social research interviews. These were part of a 2-year study, funded by the Joseph Rowntree Foundation, aiming to explore the numbers, circumstances and experiences of children who spend prolonged periods in health care settings. METHODS: As the intention was to carry out 'guided conversations' with 24 young people in various different NHS locations, permission to do so was sought from a multi-site research ethics committee (MREC), and from several local research ethics committees (LRECs). Agreement was then necessary from NHS trusts, which were asked to nominate a liaison person to help identify and recruit children to the study. Consent was also required from individual parents and children. A series of unexpected delays encountered during this process are discussed in some detail. Eventually a sample of 15 children was achieved. DISCUSSION: The second part of the paper locates this experience within a wider context, noting that similar difficulties gaining access to children in NHS settings have recently been reported by other social researchers. Several possible reasons for this trend are identified and discussed. These relate to the role of MRECs and LRECs in screening social research proposals, recently implemented legislation about data protection, heightened concerns within the NHS about confidentiality and consent, and increasing awareness of the risk of child abuse in health care settings. CONCLUSION: Finally, some suggestions for facilitating the access process are discussed. They include the sensitive and appropriate application of research governance frameworks to social research - including studies within health care settings. Ethical considerations and adequate protection of children are vital but, the authors argue, wherever possible children themselves should be encouraged to decide whether or not to participate in research. In addition, unnecessarily complex access procedures may adversely affect research outcomes.
Attitude↗