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Biomedical subjects

Edward J Fox

Publications and source records attributed to Edward J Fox.

14 recordsLinked to original sources
PubMed2025

CSF proteogenomics implicates novel proteins and humoral immunity in Alzheimer's disease risk.

We profiled 2,961 cerebrospinal fluid (CSF) proteins in 1,005 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 1,066 proteins not measured in prior studies, using mass spectrometry (MS). We mapped protein quantitative trait loci (pQTLs) in CSF, compared them with brain and plasma pQTLs, and integrated them with Alzheimer's disease (AD) genome-wide association study (GWAS) data. We identified 1,417 index cis pQTLs for 654 unique genes and 130 index trans pQTLs for 94 unique genes. Cross-tissue and cross-proteomic-platform comparisons show broad consistency between MS-based CSF pQTLs and MS-based brain pQTLs as well as affinity-based CSF and plasma pQTLs. Lastly, through integrating CSF pQTLs with the largest AD GWAS, we identified 24 candidate AD causal proteins in CSF, including 10 novel and 14 previously identified in either brain, CSF, or plasma using similar approaches. These CSF AD candidate causal proteins are involved in immune response - notably humoral immunity (3 of 24) - that expands the role of the immune system in AD beyond innate immunity, as well as lysosomal function and neurovascular growth and remodeling. Together, our findings provide novel insights into AD biology and new targets for biomarker and therapeutic development.

Journal Article↗
PubMed2006

Management of worsening multiple sclerosis with mitoxantrone: a review.

BACKGROUND: Mitoxantrone, an intravenously administered immunosuppressant that inhibits T-cell, B-cell, and macrophage proliferation, is indicated for reducing neurologic disability and relapse frequency in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing MS, or worsening relapsing-remitting MS (RRMS). OBJECTIVE: This article reviews the pathogenesis and natural history of MS and examines the available treatment options for patients with RRMS, worsening RRMS, or SPMS, with a focus on mitoxantrone. METHODS: MEDLINE (1966-present) and the Cochrane Central Register of Controlled Trials (1994-present) were searched for relevant randomized, blinded, controlled clinical trials using the terms mitoxantrone, Novantrone, and multiple sclerosis. RESULTS: Five randomized, blinded, controlled trials and an ongoing open-label Phase IV safety study were identified and included in this review. In one randomized, double-blind trial (N=25), patients with RRMS who received mitoxantrone 8 mg/m2 monthly had significantly reduced relapse rates at 1 year compared with those who received placebo (P=0.014). In a 2-year, randomized, partially blinded trial (N=51), patients with active RRMS who received mitoxantrone 8 mg/m2 monthly had significantly fewer relapses compared with those who received placebo (P<0.001), and significantly fewer patients had confirmed progression of disability (1-point increase in Expanded Disability Status Scale [EDSS] score) (P=0.02). In a randomized, double-blind trial (N=49), patients with relapsing SPMS who received mitoxantrone 12 mg/m2 monthly for 3 months followed by 12 mg/m2 g3mo for up to 32 months had significant improvements in EDSS scores compared with those who received methylprednisolone 1 g IV monthly for 3 months followed by 1 g IV g3mo (P=0.002 at 1 year, P=0.045 at 2 years) and significant reductions in the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) (P=0.002 at 1 and 2 years, P=0.03 at 3 years). In a randomized, partially blinded Phase II trial in 42 patients with active RRMS or SPMS, patients who received mitoxantrone 20 mg IV monthly and methylprednisolone 1 g IV monthly had significantly fewer new gadolinium-enhancing lesions on MRI (P<0.001) and significantly fewer relapses (P<0.01) at 6 months compared with those who received methylprednisolone alone. In a pivotal Phase III trial (N=194), patients with worsening RRMS or SPMS who received mitoxantrone 12 mg/m2 g3mo for 2 years had significantly fewer relapses (P<0.001) and significantly less deterioration in disability, as measured by change in EDSS score (P=0.019), compared with those who received placebo. In a nonrandomized subgroup of patients from this study (n=110), those who received mitoxantrone 12 mg/m2 g3mo had a significant reduction in the number of T2-weighted MRI lesions at 24 months (P=0.027). The most common adverse events in these studies included nausea and/or vomiting (18%-85%), alopecia (33%-61%), amenorrhea (8%-53%), urinary tract infections (6%-32%), and upper respiratory tract infections (4%-53%). Leukopenia was reported in 10% to 19% of patients. Use of mitoxantrone can lead to serious adverse effects, particularly cardiotoxicity, myelosuppression, and, rarely, leukemia. Long-term use of mitoxantrone may compromise left ventricular function. Limited cardiotoxicity was reported in the clinical studies; in the pivotal clinical trial, 2 patients who received mitoxantrone 12 mg/m2 had decreases in left ventricular ejection fraction to <50% of baseline. CONCLUSIONS: In the available clinical trials, mitoxantrone provided effective treatment for worsening RRMS or SPMS. When mitoxantrone is used as recommended, the risks of substantial myelosuppressive and cardiotoxic effects can be reduced by careful patient selection, drug administration, and monitoring. The lifetime cumulative dose should be strictly limited to 140 mg/m2, or 2 to 3 years of therapy.

Anti-Inflammatory Agents↗
PubMed2006

Desmoid tumors and current status of management.

Desmoid tumors, also known as aggressive fibromatosis, are rare fibroblastic tumors that exhibit a wide range of local aggressiveness, from largely indolent to locally destructive. Understanding of the pathogenesis and the great heterogeneity in the natural history of desmoid tumors is invaluable to the development of therapeutic strategies. The optimal treatment protocol has not yet been established and, in many cases, a multidisciplinary approach including surgery, chemotherapy, and radiation therapy has been employed. The rarity of cases in even major tumor centers has traditionally limited the ability to study this disease. Several novel pharmacologic and biologic treatment approaches are actively being developed, although long-term follow-up is needed for their substantiation.

Adolescent↗
PubMed2006

Clinical utility of percutaneous biopsies of musculoskeletal tumors.

UNLABELLED: Percutaneous biopsies are frequently used for musculoskeletal lesions. We suspect published accuracy rates (80-97%) overestimate clinical utility. We retrospectively reviewed 120 consecutive percutaneous biopsies performed by interventional radiologists at our institution. Patients underwent core biopsy, fine-needle aspiration (FNA), or both. The biopsy interpretations were considered clinically useful if they allowed proper treatment to proceed and not useful if they were nondiagnostic or if surgical specimens disagreed with percutaneous specimen. Patients were categorized by biopsy type, tissue type, and tumor type. Ninety of 120 percutaneous biopsies were clinically useful, 27 were nondiagnostic, and three were incorrect; in these latter 30 patients we proceeded to open biopsy. Patients with both biopsies had clinically useful results (80.6%) more often than FNA or core alone(68.0% and 66.7%, respectively). Biopsies of bone lesions were clinically useful more often than those of soft tissue. Myxoid histology was associated with decreased clinical accuracy. Clinical utility was independent of tumor type. No single characteristic predicted increased probability of open biopsy. The clinical utility rate was acceptable, but below published accuracy rates. The combination of both biopsies was better than FNA alone. Myxoid findings rarely helped to guide definitive treatment. Treatment decision making requires balancing biopsy results with clinical data. LEVEL OF EVIDENCE: Diagnostic study, level IV.

Biopsy, Fine-Needle↗
PubMed2006

Mutually exclusive promoter hypermethylation patterns of hMLH1 and O6-methylguanine DNA methyltransferase in colorectal cancer.

Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancer. Many cellular pathways, including DNA repair, are inactivated by this type of epigenetic lesion, resulting in proposed mutator phenotypes. Promoter hypermethylation of hMLH1 has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI). Transcriptional silencing of O6-methylguanine DNA methyltransferase (MGMT) has also been described in a variety of neoplasms and has been associated with a consequent mutational spectrum. We investigated the relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation in 110 colorectal cancers using methylation-specific polymerase chain reaction. Expression of hMLH1 and MGMT was assessed by immunohistochemistry. MSI testing was performed using the National Cancer Institute consensus panel of five microsatellite markers. Promoter hypermethylation of hMLH1 was detected in 12% of tumors. This was significantly associated with the MSI-high phenotype (P < 0.01) and loss of hMLH1 expression (P < 0.01). Methylation of the MGMT promoter was detected in 43% of tumors, which were mostly microsatellite stable or MSI-low (P = 0.041) and showed loss of MGMT expression (P < 0.01). We demonstrated an inverse relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation (P = 0.041), suggesting that a number of distinct hypermethylation-associated pathways may exist in colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Endoprosthetic reconstructions: results of long-term followup of 139 patients.

UNLABELLED: Our primary goal in doing this study was to determine the effect of prosthesis location, patient age, periprosthetic infection, and primary versus revision placement on endoprosthetic survival. We also examined our endoprosthetic survival rates and reasons for failure. We retrospectively studied 139 endoprosthetic reconstructions performed between 1984 and 2002, including 57 distal femur, 27 proximal femur, 26 proximal tibia, 17 proximal humerus, 4 distal humerus, 3 total scapula, 3 total femur, and 2 total humerus reconstructions. Location of reconstruction and presence of periprosthetic infection significantly affected endoprosthetic survival. Survival was not affected by patient age or primary versus revision placement. Overall, Kaplan-Meier event-free endoprosthetic survival was 86%, 80%, and 69% at 3, 5, and 10-year followup. The trend for endoprosthetic survival from best to worst was proximal femur, proximal humerus, distal femur, proximal tibia, and distal humerus. Reasons for failure included mechanical failure (eight patients), tumor recurrence (eight patients), aseptic loosening (six patients), dislocation (two patients), periprosthetic infection (two patients), and endoprosthetic malalignment (one patient). Our periprosthetic infection rate was 2.2%. The local recurrence rate in patients treated for primary malignant tumors was 6.8%, similar to previous limb-salvage and amputation studies. Overall, we have found that endoprosthetic reconstruction is a reliable limb-salvage technique. LEVEL OF EVIDENCE: Therapeutic study, Level IV-2 (case series). See the Guidelines for Authors for a complete description of levels of evidence.

Adolescent↗
PubMed2005

Intralesional curettage for grades II and III giant cell tumors of bone.

UNLABELLED: Grade III Campanacci lesions are traditionally treated with wide resections based on their postulated aggressiveness and potential for local recurrence and metastasis. The purpose of this study was to determine if there was a difference in local recurrence rates of Grade II and III lesions treated with intralesional curettage, burring, phenol cauterization, and polymethylmethacrylate application. Sixty-three patients (26 Campanacci Grade II and 37 Grade III lesions) met the inclusion criteria. No pathologic fractures, including intraarticular fractures, were included in this study. Followup averaged 108 months (range, 25-259 months). The overall local recurrence rate was 6% (4 of 63 patients), with no observed difference between Grade II and III lesions. The average Musculoskeletal Tumor Society functional score was 27.9/30 (93%). The mean range of motion of the adjacent joint was 97%. Patients with radiographic signs of osteoarthritis before treatment did not show substantial progression, and only one patient developed radiographic signs of degenerative arthritis postoperatively. Our distal metastatic rate was 3.2%. These data support the use of intralesional curettage and burring with adjuvant phenol and polymethylmethacrylate even in Grade III lesions, in the absence of pathologic fracture, regardless of the presence or extent of extraosseous extension. LEVEL OF EVIDENCE: Therapeutic study, Level III-1 (retrospective cohort). See the Guidelines for Authors for a complete description of levels of evidence.

Bone Neoplasms↗
PubMed2004

Mechanism of action of mitoxantrone.

Mitoxantrone, a synthetic anthracenedione, was developed in the 1980s as a doxorubicin analogue in a program to find a cytotoxic agent with decreased cardiotoxicity compared with doxorubicin. It was approved by the FDA in 1987 for the treatment of adult acute myeloid leukemia and in 1996 for symptomatic hormone-refractory prostate cancer. In 2000, mitoxantrone was approved by the FDA for the treatment of worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive-relapsing MS. Mitoxantrone is taken up rapidly by tissues, from which it is released slowly, and the terminal half-life ranges from 8.9 hours to 9 days. The highest concentrations of the drug are typically found in the thyroid, liver, and heart, and the drug persists in the body for as long as 272 days. Mitoxantrone is effective in reducing disease progression through a variety of different mechanisms of action. For example, it suppresses the proliferation of T cells, B cells, and macrophages. It impairs antigen presentation and decreases the secretion of proinflammatory cytokines. Mitoxantrone enhances T-cell suppressor function and inhibits B-cell function and antibody production. Finally, it inhibits macrophage-mediated myelin degradation. Compared with interferon betas, mitoxantrone has a broad range of actions and has effects on many different types of immune cells.

Animals↗
PubMed2004

Mitoxantrone for multiple sclerosis in clinical practice.

Patients with worsening relapsing-remitting multiple sclerosis (MS), secondary progressive MS, and progressive relapsing MS are potential candidates for treatment with mitoxantrone. Early identification of these patients is essential because there is emerging evidence that early and aggressive treatment might delay or limit long-term disability. Treatment with mitoxantrone is associated with certain adverse events, such as cardiotoxicity. However, the possible benefits of treatment (e.g., reduction in disease progression) outweigh the risks for patients with aggressive or worsening disease. With the selection of appropriate patients and careful monitoring for adverse events, mitoxantrone can be safely administered.

Contraindications↗
PubMed2004

Immunopathology of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disease of the CNS that is characterized by inflammation, demyelination, and axon loss. The inflammation in MS appears to be caused by an overactive pro-inflammatory T(H)1 profile in T cells. Demyelination can result as a consequence of direct damage to myelin by inflammatory cells or indirectly because of the environment produced by inflammation. Axon loss occurs in MS lesions starting early in the disease. Treatments now approved by the FDA are most effective in the inflammatory phase of the disease. Because axon loss is irreversible and is responsible for long-term disability, therapies are also needed that enhance remyelination or are neuroprotective.

Apoptosis↗
PubMed2002

Long-term followup of proximal femoral allografts.

Between 1972 and 1999, the orthopaedic service at the authors' institution treated 137 patients with proximal femoral bone lesions by resection and reconstruction with frozen allografts from cadavers. The data were entered into a computer program allowing a comprehensive analysis. Thirty-eight patients had proximal femoral osteoarticular allografts, 69 had allograft-endoprosthesis composites, 22 had intercalary allografts, and eight had an allograft arthrodesis. There were 74 complications in 54 of the 137 patients with allografts, which included 26 allograft fractures (19%), 15 infections (11%), and 20 nonunions (15%). The overall success rate for the patients with these procedures was 103 of 137 (75%) at a mean followup of 7.9 years +/- 5.6 years. If the eight patients with tumor recurrences (surgical failures rather than allograft failures) are not included, the success rate is 103 of 129 (80%). Eighty-three of these patients (55%) without any allograft complications who have been treated and followed up for at least 2 years had a 92% success rate. It is concluded that although allograft reconstruction after resection of the proximal femur for patients with aggressive or malignant tumors has a high complication rate, approximately 80% of the patients have a successful outcome.

Adolescent↗