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Biomedical subjects

Andrew M Scott

Publications and source records attributed to Andrew M Scott.

At least 55 records · Page 3Linked to original sources
PubMed2004

Targeted bioactivity of membrane-anchored TNF by an antibody-derived TNF fusion protein.

We describe the generation and characterization of a fusion protein consisting of a humanized anti-fibroblast-activating protein (anti-FAP) Ab and human TNF replacing the IgG1 CH2/CH3 Fc domain. The construct was generated by recombinant DNA technology and preserved its IgG1-derived dimeric structure with the TNF molecule linked as a dimer. Expression in CHO cells was optimized in serum-free medium under GMP conditions to achieve production levels up to 15 mg/liter. Recognition of the FAP Ag by the construct was as good as that by the parental anti-FAP Ab. TNF signaling was induce able via both TNF receptor types. When acting in solution, the Ab-linked TNF dimer exhibited a 10- to 20-fold lower activity compared with recombinant trimeric TNF. However, after binding to FAP-expressing cells, immobilized anti-FAP-TNF dimer was equivalent to membrane-anchored TNF with regard to bioactivity. Amplification of TNF-related pathways by mimicking the membrane-integrated TNF signaling was detectable in various systems, such as apoptosis induction or tissue factor production. The difference in TNF receptor type 1 and 2 signaling by the anti-FAP-TNF construct correlated well with its Ag-bound or -soluble status. Translating the approach into a xenograft animal model (BALB/c nu/nu mice), we demonstrated low toxicity with measurable antitumor efficacy for the TNF fusion protein after i.v. application. Immunohistochemical analysis of tumor sections showed restricted TNF-mediated macrophage recruitment to the targeted tissue in a time- and dose-dependent manner. These data warrant transfer of the anti-FAP-TNF immunocytokine into clinical trials for the treatment of FAP-positive tumors.

Animals↗
PubMed2004

CR1/CR2 interactions modulate the functions of the cell surface epidermal growth factor receptor.

Recent crystallographic data on the isolated extracellular domain of the epidermal growth factor receptor (EGFR) have suggested a model for its activation by ligand. We have tested this model in the context of the full-length EGFR displayed at the cell surface, by introducing mutations in two regions (CR1 and CR2) of the extracellular domain thought to be critical for regulation of receptor activation. Mutations in the CR1 and CR2 domains have opposing effects on ligand binding affinity, receptor dimerization, tyrosine kinase activation, and signaling competence. Tyr(246) is a critical residue in the CR1 loop, which is implicated in the positioning and stabilization of the receptor dimer interface after ligand binding; mutations of Tyr(246) impair or abolish receptor function. Mutations in CR2, which weaken the interaction that restricts the receptor to the tethered (inactive) state, enhance responsiveness to EGF by increasing affinity for the ligand. However, weakening of the CR1/CR2 interaction does not result in spontaneous activation of the receptors' kinase. We have used an antibody (mAb 806), which recognizes a transition state of the EGF receptor between the negatively constrained, tethered state and the fully active back-to-back dimer conformation, to follow conformational changes in the wild-type and mutant EGF receptors after ligand binding. Our results suggest that EGFR on the cell surface can be untethered, but this form is inactive; thus, untethering of the receptor is not sufficient for activation, and ligand binding is essential for the correct positioning of the two receptor subunits to achieve kinase activation.

Animals↗
PubMed2004

Detection of occult bone metastases of lung cancer with fluorine-18 fluorodeoxyglucose positron emission tomography.

Accurate staging of cancer has a critical role in optimal patient management. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) is superior to CT in the detection of local and distant metastases in patients with non-small cell lung cancer. Although Tc-99 m methylene diphosphonate (MDP) bone scanning is well established in the evaluation of bone metastases, there are conflicting reports on the use of FDG PET in the evaluation of skeletal metastases. We report on a patient with locally advanced lung carcinoma in whom FDG PET accurately identified previously unsuspected widespread asymptomatic bone metastases (bone scan and X-rays negative, confirmed on MRI). Assessment of glucose metabolism with FDG PET might represent a more powerful tool to detect bone metastases in lung cancer compared with conventional bone scans.

Bone Neoplasms↗
PubMed2003

Antitumor efficacy of cytotoxic drugs and the monoclonal antibody 806 is enhanced by the EGF receptor inhibitor AG1478.

Blockade of epidermal growth factor receptor (EGFR) signaling with specific inhibitors of the EGFR tyrosine kinase retards cellular proliferation and arrests the growth of tumor xenografts. AG1478, an inhibitor of the EGFR tyrosine kinase, is used in laboratory studies; however, its therapeutic potential has not been elucidated. Therefore, we evaluated an aqueous form of AG1478 for its antitumor activity in mice bearing human xenografts expressing the WT EGFR or a naturally occurring ligand-independent truncation of the EGFR [delta2-7 (de2-7) EGFR or EGFRvIII]. Parenteral administration of soluble AG1478 blocked phosphorylation of the EGFR at the tumor site and inhibited the growth of A431 xenografts that overexpress the WT EGFR and glioma xenografts expressing the de2-7 EGFR. Strikingly, even subtherapeutic doses of AG1478 significantly enhanced the efficacy of cytotoxic drugs, with the combination of AG1478 and temozolomide displaying synergistic antitumor activity against human glioma xenografts. AG1478 was also examined in combination with mAb 806, an anti-EGFR antibody that was raised against the de2-7 EGFR but unexpectedly also binds a subset of the EGFR expressed in cells exhibiting amplification of the EGFR gene. The combination of AG1478 and mAb 806 displayed additive, and in some cases synergistic, antitumor activity against tumor xenografts overexpressing the EGFR. Here, we demonstrate that different classes of inhibitors to the EGFR can have synergistic antitumor activity in vivo. These results establish the antitumor efficacy of the EGFR inhibitor AG1478 and provide a rationale for its clinical evaluation in combination with both chemotherapy and other EGFR therapeutics.

Animals↗
PubMed2003

A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR) has attracted considerable attention as a target for cancer therapy. Wild-type (wt)EGFR is amplified/overexpressed in a number of tumor types, and several mutant forms of the coding gene have been found, with DeltaEGFR, a deletion mutation lacking exons 2-7 of the external domain, being the most common and particularly associated with glioblastoma. We generated monoclonal antibodies (mAbs) against NR6(DeltaEGFR) (mouse fibroblast line NR6 transfected with DeltaEGFR). mAb 806 with selective reactivity for NR6(DeltaEGFR) in mixed hemadsorption assays, fluorescence-activated cell sorting, Western blot, and immunohistochemistry was analyzed in detail and compared with mAbs 528 (anti-wtEGFR) and DH8.3 (anti-DeltaEGFR). In xenograft tumors and molecularly pretyped glioblastomas, the reactivity pattern was as follows: 528 reactive with amplified and nonamplified wtEGFR; DH8.3 reactive with DeltaEGFR; and 806 reactive with amplified/overexpressed wtEGFR (with or without DeltaEGFR). In normal tissues, 528 but not DH8.3 or 806 was widely reactive with many organs, e.g., liver expressing high EGFR levels. In glioblastoma and non-CNS tumor panels, 806 was reactive with a high proportion of glioblastomas and a substantial number of epithelial cancers of lung and of head and neck. DH8.3 reactivity was restricted to DeltaEGFR-positive glioblastoma. Thus, 806 represents a category of mAbs that recognizes tumors with EGFR amplification/overexpression but not normal tissues or tumors with normal EGFR levels. Our study also indicates that DeltaEGFR is restricted to glioblastoma, in contrast to other reports that this mutation is found in tumors outside the brain.

Animals↗
PubMed2003

Generation of anti-idiotype antibodies for application in clinical immunotherapy laboratory analyses.

The chimeric monoclonal antibody ch806 specifically targets the tumor-associated mutant epidermal growth factor receptor (de 2-7EGFR or EGFRVIII) and is currently under investigation for its potential use in cancer therapy. The humanised monoclonal antibody hu3S193 specifically targets the Lewis Y epithelial antigen and is currently in Phase I clinical trials in patients with advanced breast, colon, and ovarian carcinomas. To assist the clinical evaluation of ch806 and hu3S193, laboratory assays are required to monitor their serum pharmacokinetics and quantitate any immune responses to the antibodies. Mice immunized with ch806 or hu3S193 were used to generate hybridomas producing antibodies with specific binding to ch806 or hu3S193 and competitive for antigen binding. These anti-idiotype antibodies (designated Ludwig Melbourne Hybridomas, LMH) were investigated as reagents suitable for use as positive controls for HAHA or HACA analyses and for measuring hu3S193 or ch806 in human serum. Anti-idiotypes with the ability to concurrently bind two target antibody molecules were identified, which enabled the development of highly reproducible, sensitive, specific ELISA assays for determining serum concentrations of hu3S193 and ch806 with a 3 ng/mL limit of quantitation using LMH-3 and LMH-12, respectively. BIAcore analyses determined high apparent binding affinity for both idiotypes: LMH-3 binding immobilized hu3S193, Ka = 4.76 x 10(8) M(-1); LMH-12 binding immobilised ch806, Ka = 1.74 x 10(9) M(-1). Establishment of HAHA or HACA analysis of sera samples using BIAcore was possible using LMH-3 and LMH-12 as positive controls for quantitation of immune responses to hu3S193 or ch806 in patient sera. These anti-idiotypes could also be used to study the penetrance and binding of ch806 or hu3S193 to tumor cells through immunohistochemical analysis of tumor biopsies. The generation of anti-idiotype antibodies capable of concurrently binding a target antibody on each variable domain provides reagents with high sensitivity for the assessment of safety and pharmacokinetic profiles of target antibodies administered clinically.

Animals↗
PubMed2003

Noncovalent scFv multimers of tumor-targeting anti-Lewis(y) hu3S193 humanized antibody.

Single-chain variable fragments (scFvs) of anti-Lewis(y) hu3S193 humanized antibody were constructed by joining the V(H) and V(L) domains with either +2 residues, +1 residue, or by directly linking the domains. In addition two constructs were synthesized in which one or two C-terminal residues of the V(H) domain were removed (-1 residue, -2 residue) and then joined directly to the V(L) domain. An scFv construct in the reverse orientation with the V(L) joined directly to the V(H) domain was also synthesized. Upon transformation into Escherichia coli all scFv constructs expressed active protein. Binding activity, multimeric status, and multivalent properties were assessed by flow cytometry, size exclusion chromatography, and biosensor analysis. The results for hu3S193 scFvs are consistent with the paradigm that scFvs with a linker of +3 residues or more associate to form a non-covalent dimer, and those with a shorter linker or directly linked associate predominantly to form a non-covalent trimer and tetramer that are in equilibrium. While the association of V domains to form either a dimer or trimer/tetramer is governed by the length of the linker, the stability of the trimer/tetramer in the equilibrium mixture is dependent on the affinity of the interaction of the individual V domains to associate to form the larger Fv module.

Chromatography, Gel↗
PubMed2003

A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer.

PURPOSE: The purpose of this research was to determine the safety, immunogenicity, pharmacokinetics, biodistribution, and tumor uptake of repeat infusions of a complementarity-determining region grafted humanized antibody (sibrotuzumab) directed against human fibroblast activation protein (FAP). EXPERIMENTAL DESIGN: A Phase I open-label dose escalation study was conducted in patients with cancers epidemiologically known to be FAP positive. Patients were entered into one of four dosage tiers of 5, 10, 25, or 50 mg/m(2) sibrotuzumab, administered weekly for 12 weeks, with trace labeling with 8-10 mCi of (131)I in weeks 1, 5, and 9. RESULTS: A total of 26 patients were entered into the trial (15 males and 11 females; mean age, 59.9 years; age range, 41-81 years). Twenty patients had colorectal carcinoma, and 6 patients had non-small cell lung cancer. A total of 218 infusions of sibrotuzumab were administered during the first 12 weeks of the study, with 24 patients being evaluable. One patient received an additional 96 infusions on continued-use phase for a total of 108 infusions over a 2-year period, and 1 patient received an additional 6 infusions on continued use. There were no objective tumor responses. Only one episode of dose-limiting toxicity was observed. Therefore, a maximum tolerated dose was not reached. Treatment-related adverse events were observed in 6 patients during the infusional monitoring period. Four of the 6 patients, 3 of whom had associated positive serum human antihuman antibody, were removed from the study because of clinical immune responses. Gamma camera images of [(131)I]sibrotuzumab demonstrated no normal organ uptake of sibrotuzumab, with tumor uptake evident within 24-48 h after infusion. Analysis of pharmacokinetics demonstrated a similar mean terminal t(1/2) of 1.4-2.6 days at the 5, 10, and 25 mg/m(2) dose levels, and with a longer mean t(1/2) of 4.9 days at the 50 mg/m(2) dose level. CONCLUSION: Repeat infusions of the humanized anti-FAP antibody sibrotuzumab can be administered safely to patients with advanced FAP-positive cancer.

Adult↗
PubMed2003

Targeting primary human Ph(+) B-cell precursor leukemia-engrafted SCID mice using radiolabeled anti-CD19 monoclonal antibodies.

UNLABELLED: The Philadelphia chromosome translocation (Ph(+)) confers a poor prognosis in patients with acute lymphocytic leukemia (ALL). CD19 is highly expressed (CD19(+)) on ALL cells and is an attractive target for antibody-based therapies. CLB-CD19 is an IgG1kappa murine monoclonal antibody (mAb) directed against an epitope on the CD19 antigen. METHODS: Radiolabeled CLB-CD19 antibody was evaluated for targeting ALL in a severe combined immunodeficient (SCID) mouse model engrafted with primary human leukemia cells. Lodgment of CD19(+) ALL cells in spleen and liver was confirmed using immunohistochemistry analyses. Circulating CD19(+) ALL cells in blood were also detected by flow cytometry. RESULTS: Antibody was labeled directly with the radiohalogen (125)I and radiometal (111)In via the bifunctional metal ion chelate CHX-A"-diethylenetriaminepentaacetic acid (DTPA) with retention of immunoreactivities. After intravenous injection of radioconjugates, biodistribution studies showed rapid localization of the (111)In-conjugate to leukemia-infiltrated spleen, reaching a maximum (mean +/- SD) of 72.78 +/- 13.67 % injected dose per gram of tissue (%ID/g) by 24 h after injection. In contrast, peak localization of coinjected (125)I-CLB-CD19 occurred by 4 h and was significantly lower (11.41 +/- 12.79 %ID/g) (P < 0.001). Uptake of (111)In-conjugate in the liver containing tumor was also evident but not in other normal tissues. Uptake of radiolabeled CLB-CD19 in tumor-bearing organs was specific, as uptake of radiolabeled isotype-matched antibody control was low. Gamma-camera imaging detected the uptake of (111)In-CHX-A"-DTPA CLB-CD19 in enlarged tumor-bearing spleen of engrafted mice. A single injection of 32 micro g CLB-CD19 mAb had a delayed suppressive effect on the level of circulatory leukemia cells in surviving mice and extended the median survival from 48.5 to 58 d (n = 8; P = 0.03). CONCLUSION: The radiolabeled anti-CD19 antibody showed specific targeting and rapid internalization in ALL cell-engrafted SCID mice and may also be used for selective intracellular delivery of cytotoxic radionuclides with beta-, Auger, or alpha-emissions.

Animals↗
PubMed2003

Expression and targeting of human fibroblast activation protein in a human skin/severe combined immunodeficient mouse breast cancer xenograft model.

Antigens and receptors that are highly expressed on tumor stromal cells, such as fibroblast activation protein (FAP), are attractive targets for antibody-based therapies because the supporting stroma and vessel network is essential for a solid neoplasm to grow beyond a size of 1-2 mm. The in vivo characterization of antibodies targeting human stromal or vessel antigens is hindered by the lack of an appropriate mouse model system because xenografts in standard mouse models express stromal and vessels elements of murine origin. This limitation may be overcome by the development of a human skin/mouse chimeric model, which is established by transplanting human foreskin on to the lateral flank of severe combined immunodeficient mice. The subsequent inoculation of breast carcinoma MCF-7 cells within the dermis of the transplanted human skin resulted in the production of xenografts expressing stromal and vessel elements of human origin. Widespread expression of human FAP-positive reactive stromal fibroblasts within xenografts was seen up to 2 months posttransplantation and postinjection of cells. Human blood vessel antigen expression also persisted at 2 months posttransplantation and postinjection of cells with murine vessels coexisting with the human vascular supply. The model was subsequently used to evaluate the biodistribution properties of an iodine-131-labeled humanized anti-FAP monoclonal antibody (BIBH-7). The results showed high specific targeting of the stromal compartment of the xenograft, indicating that the model provides a useful and novel approach for the in vivo assessment of the immunotherapeutic potential of molecules targeting human stroma and angiogenic systems.

Animals↗
PubMed2002

Cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity mediated by chimeric anti-GD3 monoclonal antibody KM871.

The chimeric KM871 monoclonal antibody targets the GD3 disialoganglioside antigen and is under investigation for its immunotherapeutic potential in melanoma. Preclinical and phase I studies have demonstrated the biodistribution and specific tumour targeting of KM871 to metastatic melanoma in vivo, with a long half-life and lack of immunogenicity making it an attractive candidate for further clinical trials. In vitro studies have demonstrated KM871 induces high levels of cytotoxicity in both antibody-dependent cellular-cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. In order to investigate the potential for cytokine upregulation of KM871-mediated ADCC, freshly isolated healthy donor PBMC effector cells were cultured in the presence or absence of the cytokines interleukin-2, interleukin-12 and granulocyte/macrophage-colony stimulating factor and the ADCC determined over a 10-day period. In the absence of these cytokines, ADCC activity of 1 micro g/ml KM871 on (51) Cr-labeled SK-MEL-28 target cells could not be detected after 72 hrs of culture of PBMC effector cells in media. In contrast, ADCC mediated by KM871 was significantly enhanced and maintained for the 10-day study period upon culturing PBMCs with media containing IL-2 and/or IL-12, but not with GM-CSF. FACS analysis of the effector cell population indicated CD3-/CD16+56+ NK cells were primarily responsible for the KM871-mediated ADCC activity and a direct correlation was observed between the percentage of NK cells and the level of cytotoxicity mediated by the PBMCs. Furthermore, ADCC was significantly reduced using NK-depleted PBMCs. These results suggest combining IL-2 or IL-12 with KM871 may enhance KM871 immune-mediated cell killing in patients with metastatic melanoma.

Antibodies, Monoclonal↗
PubMed2002

Novel monoclonal antibody specific for the de2-7 epidermal growth factor receptor (EGFR) that also recognizes the EGFR expressed in cells containing amplification of the EGFR gene.

In some respects, the EGFR appears to be an attractive target for tumor-targeted antibody therapy: it is overexpressed in many types of epithelial tumor and inhibition of signaling often induces an anti-tumor effect. The use of EGFR specific antibodies, however, may be limited by uptake in organs that have high endogenous levels of the wild type EGFR such as the liver. The de2-7 EGFR (or EGFRvIII) is a naturally occurring extracellular truncation of the EGFR found in a number of tumor types including glioma, breast, lung and prostate. Antibodies directed to this tumor specific variant of the EGFR provide an alternative targeting strategy, although the lower proportion of tumors that express the de2-7 EGFR restricts this approach. We describe a novel monoclonal antibody (MAb 806) that potentially overcomes the difficulties associated with targeting the EGFR expressed on the surface of tumor cells. MAb 806 bound to de2-7 EGFR transfected U87MG glioma cells (U87MG.Delta 2-7) with high affinity (approximately 1 x 10(9) M(-1)), but did not bind parental cells that express the wild type EGFR. Consistent with this observation, MAb 806 was unable to bind a soluble version of the wild type EGFR containing the extracellular domain. In contrast, immobilization of this extracellular domain to ELISA plates induced saturating and dose response binding of MAb 806, suggesting that MAb 806 can bind the wild type EGFR under certain conditions. MAb 806 also bound to the surface of A431 cells, which due to an amplification of the EGFR gene express large amounts of the EGFR. Interestingly, MAb 806 only recognized 10% of the total EGFR molecules expressed by A431 cells and the binding affinity was lower than that determined for the de2-7 EGFR. MAb 806 specifically targeted U87MG.Delta 2-7 and A431 xenografts grown in nude mice with peak levels in U87MG.Delta 2-7 xenografts detected 8 h after injection. No specific targeting of parental U87MG xenografts was observed. Following binding to U87MG.Delta 2-7 cells, MAb 806 was rapidly internalized by macropinocytosis and subsequently transported to lysosomes, a process that probably contributes to the early targeting peak observed in the xenografts. Thus, MAb 806 can be used to target tumor cells containing amplification of the EGFR gene or de2-7 EGFR but does not bind to the wild type EGFR when expressed on the cell surface.

Animals↗
PubMed2002

Anti-renal cell carcinoma chimeric antibody G250: cytokine enhancement of in vitro antibody-dependent cellular cytotoxicity.

The chimeric monoclonal antibody cG250 targets the G250 antigen, a transmembrane protein which is expressed on renal carcinoma cells and is identical to the MN/CAIX antigen. In vitro studies have previously demonstrated that cG250 induces antibody-dependent cellular cytotoxicity (ADCC) of G250-positive targets. In order to investigate the upregulation of ADCC mediated by cG250, ADCC was examined using effector cells cultured in the presence or absence of the cytokines interferon-gamma (IFN-gamma), interferon-alpha isoforms IFN-alpha (2a) and IFN-alpha (2b) and interleukin-2 (IL-2), and the time course of effects over a 7-day period was determined. Renal cell carcinoma lines expressing high (SK-RC-52) and low (SK-RC-09) G250 antigen levels were used as target cells, and freshly isolated peripheral blood mononuclear cells (PBMC) from a healthy donor were used as the effector cells. PBMC were incubated with the respective cytokine at a range of concentrations or with a media alone control for a period of 7 days. The ADCC activity mediated by cG250 or control isotype matched huA33 with the different PBMC treatment groups was assessed in triplicate daily. Corresponding lymphokine activated killing (LAK) activity was measured concurrently for each treatment group. Chimeric G250 specifically recognised G250 antigen on high and low expressing cell lines SK-RC-52 and SK-RC-09, and mediated specific in vitro ADCC of both lines. In the absence of cytokine stimulation, the specific ADCC of cG250 declined rapidly within three days. IL-2 strongly enhanced and maintained cG250-mediated ADCC activity and K562 cytotoxicity when applied to PBMC in culture for seven days. IFN-gamma also enhanced the ADCC of cG250 throughout the study period, but was not as effective as the IL-2 treatment, and the SK-RC-09 line displayed lower specific cytotoxicity than the SK-RC-52 cell line. In contrast, IFN-alpha 2a and 2b increased cG250-mediated ADCC and K562 cytotoxicity for only three days of the study period. The potent and sustained immune effector activity observed with cG250 and cytokines in this in vitro study suggests that the combination immunotherapy of cG250 with cytokines such as IL-2 shows promise in the treatment of renal cell carcinoma (RCC).

Animals↗
PubMed2002

Imaging and quantitation of the hypoxic cell fraction of viable tumor in an animal model of intracerebral high grade glioma using [18F]fluoromisonidazole (FMISO).

We have demonstrated that FMISO uptake is significantly higher in tumor tissue in the C6 intracerebral glioma rat model compared to normal brain, and that there is persisting hypoxia in gliomas independent of tumor size. FMISO uptake was observed homogeneously throughout viable glioma tissue in tumor sizes ranging from 2mm to almost 1cm. Quantitation of uptake of FMISO showed a tumor/brain ratio of 1.9 and a tumor/blood ratio of 2.6 at 2 hours post injection.

Animals↗
PubMed2002

Positron emission tomography and epilepsy.

PURPOSE: This review examines the current role of positron emission tomography (PET) in the investigation and management of patients with epilepsy. PROCEDURES: A literature review utilizing MEDLINE(R) and other sources was undertaken. For the comparison of the accuracy of PET with magnetic resonance imaging (MRI) for seizure focus localization, only publications since 1994 were examined. Individual patient data was tabulated to provide figures for seizure focus localization rates for different types of focal epilepsy and the prognostic value of PET findings for epilepsy surgery outcome. RESULTS: The majority of PET studies used 2-deoxy-2-[18F]fluoro-D-glucose (FDG). The epileptogenic sites typically show reduced FDG uptake (hypometabolism). In patients with intractable temporal lobe epilepsy (TLE), unilateral temporal lobe hypometabolism (UTH) corresponding to the seizure focus was seen in 86% of patients. In the same population, MRI demonstrated relevant abnormalities in 76%. UTH contralateral to the seizure focus was rarely seen (3%). Following temporal lobectomy, 86% of patients with ipsilateral UTH had a good outcome. When MRI was normal, UTH predicted a good outcome in 82%. Fifty percent with bitemporal hypometabolism had independent bilateral foci, and in those who proceeded to surgery only 50% had a good result. In extratemporal epilepsy, hypometabolism relevant to the focus was seen in 67% but, as in TLE, it was often more extensive than pathological abnormality. Recently evidence of a role for 11C-Flumazenil has emerged with reduced binding in the primary epileptogenic site. 11C-Flumazenil abnormalities appear more restricted to abnormal cortex and may be a better guide to the extent of resection required for surgical success. CONCLUSIONS: FDG-PET has a key role in the evaluation of patients with intractable partial epilepsy, particularly when surgery is a treatment option. Development and application of more specific biochemical probes may further improve the clinical value of PET for the understanding and treatment of epilepsy.

Journal Article↗
PubMed2002

Evaluation of 18 F-fluorodeoxyglucose positron emission tomography and computed tomography with histopathologic correlation in the initial staging of head and neck cancer.

OBJECTIVE: To prospectively evaluate the use of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) in the initial staging of squamous cell head and neck carcinoma. SUMMARY BACKGROUND DATA: The status of cervical lymph nodes is an important prognostic factor and determinant of management approach in squamous cell head and neck cancer. METHODS: FDG-PET findings were compared with those of computed tomography (CT) before removal of the primary tumor and/or neck dissection. Histopathologic analysis was used as the gold standard for assessment of the sensitivity and specificity of these modalities. RESULTS: FDG-PET correctly identified the primary tumor in 35 of 40 patients in whom the site of the primary was known clinically and still present (sensitivity 88%). None of four unknown primaries were detected. Tumors not detected by FDG-PET were generally superficial, with depths of less than 4 mm. CT correctly identified 18 of the 35 primary tumors (sensitivity 51%). Eleven of 17 CT false-negative tumors were detected by FDG-PET. The sensitivity and specificity for the presence of metastatic neck disease on FDG-PET were 82% and 100%, respectively; those for CT were 81% and 81%, respectively. FDG-PET was true positive for metastatic neck disease in two of the three CT false-negative patients. CONCLUSIONS: FDG-PET shows promise in the initial staging of head and neck cancer and provides additional accuracy to a conventional staging process using CT.

Adult↗
PubMedDate not supplied

Impact of 2-deoxy-2[F-18]fluoro-D-glucose Positron Emission Tomography on the management of patients with advanced melanoma.

OBJECTIVES: Accurate staging of patients with melanoma is vital to guide appropriate treatment. 2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) has been reported to be a sensitive and specific technique for the staging of advanced melanoma, however, few studies provide information regarding its impact on patient management. METHODS: We retrospectively reviewed the FDG-PET scan results of 92 patients with melanoma who had 126 scans performed over a six-year period. These patients were seen at the specialist melanoma clinic at our Institution, and 84 patients (92%) had stage III or IV disease. FDG-PET scan results were correlated with computed tomography (CT) scans and other imaging when available, and with clinical follow-up of a minimum of three to six months. The impact of FDG-PET scans on patient management was also assessed. RESULTS: On a lesion-by-lesion analysis, FDG-PET had a sensitivity of 92%, a specificity of 88%, and an accuracy of 91%. FDG-PET correctly affected the clinical decision-making process in 40 of 126 patient studies (32%), particularly assisting in the selection of patients for surgery. CONCLUSION: FDG-PET has an important role in guiding the management of patients with advanced melanoma, particularly when surgery is contemplated.

Adult↗