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Michael Murphy

Publications and source records attributed to Michael Murphy.

At least 37 records · Page 2Linked to original sources
PubMed2004

Cytokine-modified Mycobacterium smegmatis as a novel anticancer immunotherapy.

Intravesical administration of live M. bovis BCG organisms for carcinoma in situ of the urinary bladder is the most successful immunotherapy for solid malignancy. Nevertheless BCG-therapy is associated with significant toxicity and is ineffective in 30-40% of cases. Recently it has been proposed that cytokine-modified mycobacteria may give greater efficacy. As any immunotherapy involving administration of live BCG organisms (wild-type or recombinant) is likely to have associated toxicity (notably in the immunocompromised), we examined the anti-tumour potential of the closely related nonpathogenic organism, Mycobacterium smegmatis, and a TNFalpha gene-modified recombinant M. smegmatis. When wild-type M. smegmatis were delivered to immunocompetent C57Bl/6 mice bearing the transplantable MB49 bladder tumour, efficacy comparable to live BCG was observed with 10-20% long-term survival. However, this effect was lost in both Nude and Beige mice, lacking functional T and NK cells, respectively. Recombinant M. smegmatis secreting TNFalpha, however, gave a 70% durable tumour-free survival. Lymphocytes from draining lymph-nodes and spleens of these mice exhibited pronounced IFNgamma production to mycobacterial-antigen and tumour-lysate, indicating a bias towards cell-mediated immunity. This was further supported by histopathological examination of the tumour site, which revealed significantly increased numbers of CD3+ lymphocytes in animals receiving the recombinant vaccine, but not in those receiving wild-type bacteria. Importantly, tumour rejection following M. smegmatis/TNFalpha was independent of T lymphocytes, as athymic Nude mice efficiently eradicated MB49 tumours. In contrast, the therapeutic efficacy of M. smegmatis/TNFalpha was reduced in animals deficient in NK cytolytic function, suggesting a role for NK-cells in initial tumour destruction. Furthermore the absence of NK-function in Beige mice did not prevent the establishment of tumour-protective memory. No toxicity was observed with wild-type or recombinant M. smegmatis in immunocompetent, T-deficient or NK-deficient models. We demonstrate for the first time that recombinant mycobacteria expressing mammalian cytokines have markedly increased anti-tumour properties. The lack of toxicity suggests that M. smegmatis is a "safe" vehicle for use in immunocompromised patients.

Animals↗
PubMed2004

Subfrontal schwannoma: a case report and literature review.

Subfrontal schwannomas are rare and usually misdiagnosed preoperatively. We present the third reported case of a schwannoma arising from the olfactory nerve. The neuroradiological and pathological features of the case, as well as the origin of the tumour are discussed.

Adult↗
PubMed2004

The genetic basis for smoking behavior: a systematic review and meta-analysis.

Considerable evidence indicates that smoking behavior is under a degree of genetic influence. We conducted a systematic review of candidate gene studies of smoking behavior and, where sufficient studies existed, combined reported data using meta-analytic techniques. A total of 41 studies were identified by the search strategy, of which 28 contributed to the meta-analysis. The meta-analysis included data on the DRD2, DAT, 5HTT, and CYP2A6 genes and smoking behavior. Categorical data were extracted on smoking status (never-smoker, ex-smoker, current smoker). Continuous data were extracted on number of cigarettes smoked per day. Evidence indicated effects of the DRD2 Taq1A polymorphism and smoking initiation, the 5HTT LPR and CYP2A6 reduced-activity polymorphisms and smoking cessation, and the DRD2 Taq1A and CYP2A6 reduced-activity polymorphisms and cigarette consumption. The evidence for an effect of specific genes was modest, however, and evidence indicated substantial between-study heterogeneity in most cases, with the exception of the effects of the 5HTT and CYP2A6 genes on smoking cessation. When a random-effects model was applied to analyses in which evidence indicated significant heterogeneity, the effects were in all cases no longer statistically significant. The evidence for a contribution of specific genes to smoking behavior remains modest. Implications for the design of future studies are discussed, such as the need for the development of more specific phenotypes to increase the genetic signal in candidate gene studies.

Genetic Predisposition to Disease↗
PubMed2004

Plasma ropivacaine levels following scalp block for awake craniotomy.

The plasma levels of ropivacaine HCl with 5 mcg/mL epinephrine were measured in 10 patients following scalp blockade for awake craniotomy. A mean dose of 260 mg (3.6 mg/kg) resulted in peak plasma concentrations of 1.5 +/- 0.6 mcg/mL, with a median time to peak plasma concentration of 15 minutes. The pattern of rise of plasma level was similar in all patients and rapid compared with other regional blocks (epidural, intercostal, and axillary brachial plexus block). Despite this rapid rise of plasma level, no signs of cardiovascular or central nervous system toxicity were observed. In this group of patients undergoing awake craniotomy for excision of lesions in the eloquent areas of the cerebral cortex, ropivacaine HCl with epinephrine appeared to be a safe and effective local anesthetic agent in the dosages used.

Adolescent↗
PubMed2004

CD34-reactive trichodiscoma.

BACKGROUND: Trichodiscomas are rare hamartomas of the dermal portion of the hair disc, a specialized component of the perifollicular mesenchyme. They are usually found as asymptomatic multiple skin-colored papules on the face and extremities and may have an autosomal dominant inheritance pattern. However, a solitary variant has been described. CASE REPORT: A 78-year-old woman presented with a single, non-pigmented, firm papule on the left tip of the nose, measuring 3.5 mm in diameter. RESULTS: The histological examination revealed the previously described features of a trichodiscoma. The immunohistochemical analysis showed strong immunoreactivity for CD34 in the spindle cell component. Spindle cells were negative for S-100, HMB-45, Melan-A, EMA, neurofilament, desmin, and Factor XIIIa by immunohistochemistry. CONCLUSIONS: We report strong reactivity for CD34 in the spindle cell component of a trichodiscoma. We suggest that this lesion be considered in the differential diagnosis of any CD34+ dermal spindle cell proliferation, in which an adjacent epithelial component cannot be entirely excluded.

Aged↗
PubMed2004

Hypoxia regulation of the cell cycle in malignant melanoma: putative role for the cyclin-dependent kinase inhibitor p27.

BACKGROUND: Intratumor hypoxia has been shown to promote more aggressive and metastatic cancer phenotypes that are associated with treatment resistance and poor prognosis. Cellular proliferation and its control are known to be important components of tumor progression. Hypoxia induces cell-cycle arrest in cultured cell lines, possibly via up-regulation of the cyclin-dependent kinase inhibitor p27. The effect of hypoxia on cell-cycle regulation in excised human tumors has not been investigated. METHODS: We performed immunohistochemistry for p27 and Ki-67 on 10 formalin-fixed paraffin-embedded metastatic melanomas, selected on the basis of histological evidence of zonal/geographic necrosis, adjacent to areas with viable perivascular tumor cells. RESULTS: In the majority of cases, there was a significant increase in p27 staining in cells adjacent to necrotic areas compared to perivascular zones. An inverse staining pattern between Ki-67 and p27 was identified in these tumors. Tumors with no zonal increase in p27 staining demonstrated a diffuse pattern of staining for Ki-67 within tumor nests. CONCLUSIONS: While increased cellular proliferation is a characteristic of cancer, subsets of human melanomas may retain the ability to regulate their rate of proliferation in response to changes in the tumor microenvironment. The hypoxia-mediated cell-cycle arrest (decreased Ki-67) in these tumors may be mediated by p27 up-regulation.

Cell Cycle↗
PubMed2004

Skp2 and p27kip1 expression in melanocytic nevi and melanoma: an inverse relationship.

BACKGROUND: S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p45(SKP2) is important in the degradation of p27kip1 (a cyclin dependent kinase inhibitor) and progression through the G1-S cell-cycle checkpoint. Low levels of p27 and high levels of Skp2 are related to poor prognosis in some cancers. METHODS: Clinicopathologic features and immunohistochemical expression of Skp2 and p27kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi, 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed. RESULTS: Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27kip1, respectively, was identified moving from melanocytic nevi (0.05 +/- 0.2/85 +/- 15) to melanoma in situ (3 +/- 2/45 +/- 20) to primary cutaneous melanoma (12 +/- 9/30 +/- 25) to metastatic melanoma (25 +/- 15/15 +/- 20) (p < or = 0.006). Expression of these proteins also significantly correlated with increasing American Joint Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (p < or = 0.01). Moreover, the level of these two proteins exhibited a significant inverse relationship (r = -0.4, p = 0.0001). Skp2 cytoplasmic labeling index of >20% predicted worse 10-year overall survival (38% vs. 86%, p = 0.04) in primary melanoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognosis. CONCLUSIONS: Gain of Skp2 and loss of p27kip1 protein expression are implicated in melanoma progression where the level of p27kip1 may be regulated by targeted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of aggressive melanomas and could represent another pathway of deregulation of the cell cycle.

Adult↗
PubMed2004

A computer-generated stereotactic "Virtual Subdural Grid" to guide resective epilepsy surgery.

BACKGROUND AND PURPOSE: In selected patients undergoing epilepsy surgery, subdural electrode grids play an important role in localizing the epileptogenic zone and identifying eloquent cortex. Determining the relationship of the electrodes to underlying brain architecture traditionally has been difficult. This report describes and validates the use of an original computer-aided method that displays a representation of the electrode positions, based on postimplantation CT or MR findings, coregistered with a 3D-rendered image of the brain, on an image-guided surgery system. METHODS: Seventeen patients underwent the procedure with visual verification of the actual and virtual grids undertaken during the second (postimplantation) surgery. The accuracy of the Virtual Grid electrode positions was further studied in a subgroup of five patients during surgery by plotting the distance from the actual electrode positions by using an infrared stereotactic probe. RESULTS: The accuracy of the Virtual Grid electrode positions by visual inspection was satisfactory in all 17 cases. In the five cases in which quantitative measurements were performed, the mean error for the CT derived electrode positions was 3.4 mm (range 0.5-5.4) compared with the mean error for the MR-derived electrode positions of 2.5 mm (range 0.5-5.2). CONCLUSION: The Virtual Grid electrode positions were highly accurate in localizing the actual position of the subdural electrodes with both CT- and MR-derived images. The MR-derived electrodes demonstrated a trend toward better accuracy, but the CT images were quicker and easier to process. This technology has the potential to minimize both human and technical errors, allowing for a more precise tailoring of the cortical resection in epilepsy surgery.

Brain Mapping↗
PubMed2004

Extracerebral cavernous hemangioma of the cavernous sinus: diagnosis with MR imaging and labeled red cell blood pool scintigraphy.

We present the case of a 64-year-old man with a presumed diagnosis of extracerebral cavernous hemangioma involving the cavernous sinus. The diagnosis was made on the basis of labeled red cell blood pool scintigraphy findings in conjunction with those of MR imaging. This lesion was not altered in appearance at 6-year follow-up MR imaging. We also present the labeled red cell blood pool scintigraphy findings obtained in three other patients with similar-appearing cavernous sinus lesions at MR imaging who underwent subsequent biopsy; histologic findings confirmed chondrosarcoma, chordoma, and meningioma, respectively.

Adult↗
PubMed2004

Improving the ascertainment of families at high risk of colorectal cancer: a prospective GP register study.

BACKGROUND: Screening for colorectal cancer is effective in family members with a high risk of this condition, owing to single gene mutations. However, it is not known which is the most effective method of ascertaining these families at high risk. AIMS: To investigate whether a case-finding approach using computerised general practitioner (GP) registers would improve the ascertainment of families at high risk of colorectal cancer due to family history. DESIGN OF STUDY: Prospective GP register study. SETTING: General practices in Oxfordshire. METHOD: Identification of patients with colorectal cancer using GP registers, followed by a family history questionnaire survey to identify those at high risk. RESULTS: Using GP registers, 758 patients with a diagnosis of colorectal cancer were identified; a prevalence of 172 cases per 100 000 (95% confidence interval = 159 to 184). Of these, 305 patients, diagnosed under the age of 65 years, were sent a family history questionnaire. Two hundred and one (66%) patients responded to the survey; 10 (5%) patients were assessed as having high-risk families and 47 (23%) patients were assessed as having families at moderate risk. Eight of the high-risk patients had 34 first degree relatives who would benefit from routine disease surveillance, and 37 moderate-risk patients had 153 first degree relatives. Only two high-risk and six moderate-risk patients identified were previously known to the local Clinical Genetics Department. CONCLUSION: A case-finding approach using GP records and a family history questionnaire is an effective way of identifying families at high risk of developing colorectal cancer, who can then be offered disease surveillance.

Adult↗
PubMed2003

Modulation of plasma thiols and mixed disulfides by BNP7787 in patients receiving paclitaxel/cisplatin therapy.

BACKGROUND: BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) was evaluated in a phase I clinical trial with paclitaxel and cisplatin to assess the safety and potential efficacy for preventing or reducing cisplatin- and paclitaxel-induced toxicities. During this trial the effects of BNP7787 administration on the total concentrations (oxidized plus free) of cysteine, homocysteine and GSH in plasma, free and total GSH in WBC and rate of urinary excretion of cysteine were studied. The pharmacokinetics of ultrafilterable (free, non-protein bound) platinum were also determined after cisplatin (75 mg/m(2)) treatment which followed paclitaxel (175 mg/m(2)) and BNP7787 (8.2 to 27.6 g/m(2)). METHODS: Plasma thiols were measured by HPLC with fluorescence detection and platinum was measured by atomic absorption spectrophotometry. RESULTS: BNP7787 administration produced a significant depletion of all plasma thiols in all the patients studied. Differences were noted in the kinetics of BNP7787-induced depletion of cysteine and other thiols. A significant depletion of cysteine occurred with a time lag of about 2 h after the end of BNP7787 infusion, while a reversible depletion of GSH and homocysteine occurred immediately following the start of BNP7787 infusion, with the plasma thiol/disulfide nadir corresponding to the end of infusion. The mean half-life of cysteine depletion following BNP7787 administration was 2.2 h, significantly longer than for homocysteine (0.23 h), or GSH (0.18 h; P<0.05 for both). A several-fold increase in the urinary excretion of cysteine occurred following BNP7787 administration in all patients. The BNP7787-induced thiol/disulfide depletion in plasma was not affected by cisplatin administration ( P>0.05). BNP7787 administration had no effect on the ultrafilterable platinum pharmacokinetics. The 2-h lag in the depletion of cysteine, the most abundant thiol in plasma, suggests that the process may be related to the formation of free mesna from BNP7787 and that increased levels of mesna are not in circulation until after 2 h after BNP7787 administration. No effect of BNP7787 was seen on the GSH concentration in WBC, possibly reflecting the inability of these cells to take up BNP7787. CONCLUSION: The results suggest that BNP7787 has the potential to enhance cisplatin antitumor activity by depleting the reactive thiols in plasma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis.

Vascular access site thrombosis is a major cause of morbidity in patients receiving hemodialysis. The role of hypercoagulable states in recurrent vascular access site thrombosis remains poorly understood. Data are limited regarding systemic anticoagulation to improve access graft patency, because of concern about hemorrhagic complications. We determined the prevalence of hypercoagulable states and clinical outcome (thrombotic and hemorrhagic) after initiation of antithrombotic therapy in a series of patients with recurrent vascular access site thrombosis. We evaluated 31 patients who had sustained 119 thrombotic events that resulted in vascular access graft failure during the year before evaluation. Sixty-eight percent of patients tested had elevated concentrations of antibody to anticardiolipin or topical bovine thrombin, and 18% of patients tested had heparin-induced antibodies. More than 90% of patients had elevated factor VIII concentration, 62% had elevated fibrinogen concentrations, and 42% had elevated C-reactive protein concentrations. Twenty-nine patients were given antithrombotic therapy: 13 with warfarin sodium, 12 with unfractionated heparin (UFH), and 11 with low molecular weight heparin (LMWH). Seven patients received more than one antithrombotic agent, sequentially. Nineteen patients have had no thrombotic events since beginning antithrombotic therapy (10 with warfarin, 3 with UFH, 6 with LMWH). Mean follow-up was 8.6 months (median, 7 months). Eight patients sustained 10 bleeding complications (5 with warfarin, 3 with UFH, and 2 with LMWH). In conclusion, hypercoagulable states are common in patients with recurrent vascular access site thrombosis. Antithrombotic therapy may increase vascular access graft patency, but is associated with significant risk for hemorrhage. Prospective studies are needed to evaluate the role and safety of antithrombotic agents in improving vascular access graft patency.

Adult↗
PubMed2003

Patient safety and blood transfusion: new solutions.

Current risk from transfusion is largely because of noninfectious hazards and defects in the overall process of delivering safe transfusion therapy. Safe transfusion therapy depends on a complex process that requires integration and coordination among multiple hospital services including laboratory medicine, nursing, anesthesia, surgery, clerical support, and transportation. The multidisciplinary hospital transfusion committee has been traditionally charged with oversight of transfusion safety. However, in recent years, this committee may have been neglected in many institutions. Resurgence in hospital oversight of patient safety and transfusion efficacy is an important strategy for change. A new position, the transfusion safety officer (TSO), has been developed in some nations to specifically identify, resolve, and monitor organizational weakness leading to unsafe transfusion practice. New technology is becoming increasingly available to improve the performance of sample labeling and the bedside clerical check. Several technology solutions are in various stages of development and include wireless handheld portable digital assistants, advanced bar coding, radiofrequency identification, and imbedded chip technology. Technology-based solutions for transfusion safety will depend on the larger issue of the technology for patient identification. Devices for transfusion safety hold exciting promise but need to undergo clinical trials to show effectiveness and ease of use. Technology solutions will likely require integration with delivery of pharmaceuticals to be financially acceptable to hospitals.

Blood Transfusion↗
PubMed2003

Emotional and social dysfunction in patients following surgical treatment for brain tumour.

Patients following brain surgery for tumour were assessed using the Emotional and Social Dysfunction questionnaire on a self-rating and partner version of the questionnaire. Analyses were performed on those patients who had self-ratings following surgery for astrocytoma (n=13), meningioma (n=26), neuroma (n=13) and pituitary adenoma (n=17). Patients with astrocytoma were rated highest when compared to the other tumour groups, although all groups of patients performed more poorly on some of the individual scales compared to a matched control group of extra-cerebral neurosurgery patients and terminally ill cancer patients. A malignant (n=48) and benign (n=33) classification similarly showed a higher partner and self-rating of malignant tumour patients. Both diagnosis and location of lesion determined outcome independently. Some differences in profile and severity between patient self-ratings and partner ratings indicate the need to survey both perspectives. This study shows a broader based emotional dysfunction in these patients which includes such prominent features such as anger, helplessness, fatigue, emotional dyscontrol, indifference, and maladaptive behaviour. These results are discussed in terms of follow-up therapeutic care and the need to further explore the relationship between lesion location and emotional profile.

Adenoma↗