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Biomedical subjects

G S Wood

Publications and source records attributed to G S Wood.

At least 19 recordsLinked to original sources
PubMed2005

Genomic instability in radial growth phase melanoma cell lines after ultraviolet irradiation.

BACKGROUND/AIMS: Although ultraviolet (UV) irradiation, apoptosis, and genomic instability are all potentially involved in the pathogenesis of melanoma, in vitro studies investigating these changes in the radial growth phase of this neoplasm are still lacking; therefore, this study was designed to investigate these changes. METHOD: An in vitro system consisting of three radial growth phase Wistar melanoma cell lines (WM35, WM3211, and WM1650) was established. Cells were UV irradiated (10 mJ/cm2 for UVB and 6 J/cm2 for UVA), harvested after UV exposure, and evaluated for viability and apoptosis using Trypan blue and terminal deoxynucleotidyl transferase mediated dUTP digoxigenin nick end labelling assays, respectively. Polymerase chain reaction based microsatellite assays were used to examine the cell lines for the presence of microsatellite instability (MSI) using 21 markers at the 1p, 2p, 3p, 4q, 9p, and 17p regions. RESULTS: Exposure to UV initiated progressive cell death associated with pronounced apoptosis, with UVA having a greater effect than UVB. MSI was found in UVB (WM35 and WM3211) and UVA (WM35) irradiated cell lines at 1p, 9p, and 17p, but not in non-irradiated cells. The prevalence of MSI was higher after UVB irradiation (14%) than UVA irradiation (4.7%), and was most frequently found at D1S233. CONCLUSIONS: The ability of erythemogenic UV irradiation to induce both apoptosis and MSI in radial growth phase melanoma cells is suggestive of its role in melanoma pathogenesis. This instability may reflect a hypermutability state, oxidative stress induced DNA damage, replication infidelity, or a combination of these factors.

Apoptosis↗
PubMed2003

p53-related pathways and the molecular pathogenesis of melanoma.

Cutaneous malignant melanoma (CMM) is a life-threatening cancer that can have a poor prognosis with high metastatic potential. Its incidence is rapidly increasing worldwide. Its molecular alterations involve multiple pathways, including those related to p53. Since 1981, more than 380 papers containing the terms 'p53 and melanoma' as key words in the Abstract have been published in the literature. However, in spite of these extensive investigations, a review of p53 and associated genes in CMM is still lacking. To remedy this issue, this review seeks to provide a brief overview of p53 and discuss the genes targeted along its related pathways.

Animals↗
PubMed2001

The clonality of tumor-infiltrating lymphocytes in African Kaposi's sarcoma.

BACKGROUND: African Kaposi's sarcoma (KS) lesions contain human herpesvirus-8 (HHV-8) and Epstein-Barr virus (EBV), both of which are associated with various types of non-Hodgkin's lymphomas and are known to produce several factors suspected of lymphomagenic potential. The aim of this study was to evaluate tumor-infiltrating lymphocytes for the evidence of clonal expansion in African KS. METHODS: We used polymerase chain reaction (PCR)-based assays to determine the clonality of tumor-infiltrating lymphocytes in African KS lesions and compared the results to similar studies of patient-matched uninvolved skin and peripheral blood. RESULTS: T cells were polyclonal in all samples tested. Peripheral blood B cells were also polyclonal; however, a minority of lesional and uninvolved skin samples exhibited evidence of restricted B-cell clonality. Correlation with immunohistological analysis revealed that this clonal B-cell restriction was secondary to the sparse nature of lesional B cells rather than their clonal overgrowth. CONCLUSIONS: We conclude that, despite the putative lymphomagenic potential of HHV-8 and EBV and their co-existence in African KS lesions, tumor-infiltrating lymphocytes in these cases do not show evidence of clonal expansion that might be an early manifestation of lymphoma. Nevertheless, these studies are a case in point that sparse lymphoid subpopulations in lesional and uninvolved extranodal tissues can give rise to restricted clonal patterns that must be interpreted carefully to avoid the misdiagnosis of occult lymphoma.

Africa↗
PubMed2001

Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi.

INTRODUCTION: the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors. MATERIAL AND METHODS: To investigate the prevalence and frequency of MSI in melanocytic lesions, the polymerase chain reaction (PCR)-based microsatellite assay was used to examine formalin-fixed, paraffin-embedded tissues of 30 benign melanocytic nevi, 60 melanocytic dysplastic nevi (MDN), and 22 primary vertical growth phase cutaneous malignant melanomas (CMM). Twenty-four microsatellite markers at the 1p, 2p, 3p, 4q and 9p chromosomal regions were used. RESULTS: MSI was found at 1p and 9p in MDN and CMM but not in benign melanocytic nevi. The overall prevalence of MSI was 17/60 (28%) in MDN and 7/22 (31%) in CMM. The frequency of MSI ranged from 2/24 (9%) to 4/24 (17%) and was most commonly found at D9S162. There was a statistically significant correlation between degree of atypia and frequency of MSI (p<0.001) in MDN. There were two MSI banding patterns: band shifts and additional bands. CONCLUSIONS: The data presented revealed the presence of low-frequency MSI (MSI-L) at the 1p and 9p regions in both MDN and CMM. Whether the MSI-L pattern reflects a defect in mismatch repair genes is still to be determined.

Chromosome Mapping↗
PubMed2001

Absence of Borrelia burgdorferi DNA in cutaneous B-cell lymphomas from the United States.

BACKGROUND: An association between Borrelia burgdorferi and cutaneous B-cell lymphoma (CBCL) has been made in several European countries. The evidence in favor of such an association has recently been based on more definitive tests for the pathogenetic role of B. burgdorferi in CBCL, including positive cultures or polymerase chain reaction (PCR) amplification of borrelial DNA from lesional skin. However, there is only one report of B. burgdorferi in four North American cases of B-cell lymphoma. METHODS: We retrieved 38 cases of primary and secondary CBCL from different geographic regions of the United States. Two separate techniques were used to detect borrelial DNA by PCR, a nested PCR method to amplify a B. burgdorferi-specific gene as well as a borrelial chromosomal Ly-1 clone amplification method. Southern blot hybridization was used for confirmation of the PCR results. RESULTS: No B. burgdorferi-specific DNA was detected in any of the 38 CBCL cases, whereas detectable PCR products were obtained with our positive controls. CONCLUSIONS: Our findings, in light of previous studies, suggest that B. burgdorferi plays a minimal role in the development or pathogenesis of CBCL in the United States. The findings also suggest that the geographic variations in the clinical manifestations of B. burgdorferi are indeed real and may be secondary to the genetic and phenotypic differences between B. burgdorferi strains present in Europe and North America.

Borrelia burgdorferi↗
PubMed2001

Anetoderma arising in cutaneous B-cell lymphoproliferative disease.

Anetoderma is circumscribed atrophy of the skin due to a localized deficiency in elastic tissue. It can follow inflammatory skin diseases of several types, and occasionally is present in the skin around neoplasms. There are a few reports of anetoderma in the lesional skin of cutaneous lymphoma. We report on two patients who presented with multiple lesions of anetoderma and who later proved to have low-grade cutaneous B-cell lymphomas. One patient (Patient 1) is a 39-year-old man and the other patient is a 26-year-old woman who is a renal transplant recipient (Patient 2). Some biopsy specimens from the anetodermic skin of Patient 1 appeared to show an urticarial reaction, although plasma cells were present. A large nodule showed lymphoid follicles surrounded by plasmacytoid lymphocytes, with loss of elastic tissue in the adjacent dermis. The plasmacytoid cells stained overwhelmingly for lambda light chain, and staining of the urticarial lesions from this patient also showed a marked majority of lambda positive cells. Immunoglobulin heavy chain gene (IgH) rearrangements showed a dominant clonal pattern in the nodular lesion. We classified the disease in Patient 1 as marginal zone lymphoma and the disease in Patient 2 as a post-transplant lymphoproliferative disorder. Because of the intimate association of anetoderma and cutaneous B-cell lymphoproliferative disorders in these two patients, it seems possible that anetoderma could result from either a local effect of the neoplastic cells or associated inflammatory cells, especially neutrophils as in Case 1. The infiltrates of Case 1 had many interstitial neutrophils and only a few clonal plasmacytoid lymphocytes, indicating that this presentation of B-cell lymphoma can be a diagnostic pitfall. Given these two cases and similar ones in the literature, biopsy of lesional skin in anetoderma should be performed to ensure that lymphomatous infiltrates are not present. Even if plasma cells are sparse, studies to detect clonality are appropriate. Cutaneous B-cell lymphoma can be added to the list of associations of elastolysis and cutaneous lymphoma, which includes granulomatous slack skin (T-cell lymphoma) and cutis laxa (myeloma).

Adult↗
PubMed2001

Alterations of mismatch repair protein expression in benign melanocytic nevi, melanocytic dysplastic nevi, and cutaneous malignant melanomas.

Immunoperoxidase-staining methods were used to examine the expression of hMLH1, hMSH2, and hMSH6 mismatch repair (MMR) proteins in 50 melanocytic lesions. Microsatellite instability (MSI), screened previously in these lesions by polymerase chain reaction-based microsatellite assay, showed low-level microsatellite instability (MSI-L) in 11 of 22 melanocytic dysplastic nevi (MDN) and two of nine primary cutaneous malignant melanomas (CMMs) but not in the benign melanocytic nevi (BN). Mismatch repair proteins were widely expressed in the epidermis and adnexal structures. All lesions showed positive immunoreactivity with a gradual decrease in the MMR staining values during the progression from BN to MDN to CMMs. The average percentage of positively (PP) stained cells for hMLH1, hMSH2, and hMSH6 in BN was 85.50 +/- 1.95, 77.90 +/- 4.50, and 87.11 +/- 1.85, respectively. The PP cell values in CMMs were significantly reduced as compared with BN (75.22 +/- 3.57, p= 0.01; 56.11 +/- 8.73, p= 0.02; 65.22 +/- 6.47, p = 0.0002 for hMLH1, hMSH2, and hMSH6, respectively). No comparable significant difference was found between microsatellite stable and MSI-L lesions (p = 0.173, p = 0.458, and p = 0.385), suggesting a lack of correlation between MMR expression and MMR function. There was a direct correlation between PP cell values of hMSH2 and hMSH6 (R = 0.39, p = 0.008), implying that their expression could be regulated by a common mechanism. Thus, an important finding of these studies was the reduction of MMR protein levels in CMMs; whether this reflects underlying genetic or epigenetic mechanisms is still to be determined.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The role for interleukin-12 therapy of cutaneous T cell lymphoma.

Recent phase I and phase II trials using recombinant human interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been completed. Observations on 32 evaluable patients revealed an overall response rate approaching 50 percent. Biopsy of regressing lesions revealed an increase in numbers of CD8+ and/or TIA-1+ T cells. These results suggest that rhIL-12 may induce lesion regression by augmenting antitumor cytotoxic T cell responses. Future trials will be focused on strategies for further immune enhancement by the concomitant use of additional immune augmenting cytokines with rhIL-12.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2001

Differentiation and clonality of lesional lymphocytes in pityriasis lichenoides chronica.

BACKGROUND: Pityriasis lichenoides chronica (PLC) and pityriasis lichenoides et varioliformis acuta (PLEVA) are benign T-cell diseases that share several overlapping clinicopathologic features, leading many to believe that they exist as a spectrum rather than as single entities. Previous molecular studies have shown that PLEVA is a clonal lymphoproliferative disorder. To further characterize the immunohistologic features of PLC and to determine whether PLC demonstrates clonality, we studied 6 cases of PLC using a frozen section-immunoperoxidase technique and polymerase chain reaction/denaturing gradient gel electrophoresis. OBSERVATIONS: All 6 cases showed a mild to moderate superficial and deep perivascular infiltrate composed predominantly of CD4(+) T cells, admixed with Langerhans cells and macrophages; most were associated with an HLA-DR(+) epidermis. Three of 6 cases involved monoclonal T-cell receptor gamma (TCR gamma) gene rearrangements detected by V gamma 1-8/J gamma 1-2 and V gamma 9/J gamma 1-2 primers. CONCLUSIONS: Our findings enhance existing data showing that PLC shares many immunohistologic features with PLEVA and indicating that PLC is frequently a clonal T-cell disease. This provides further evidence that PLC and PLEVA are interrelated processes within the larger group of T-cell lymphoproliferative disorders.

Adult↗
PubMed2001

Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma.

OBJECTIVES: To determine the safety and efficacy of oral bexarotene (Targretin capsules; Ligand Pharmaceuticals Incorporated, San Diego, Calif). DESIGN: The effects of 2 randomized doses of 6.5 mg/m(2) per day (with crossover for progression) vs 650 mg/m(2) per day (later modified to 300 mg/m(2) per day) were evaluated in an open-label, multicenter, phase 2 and 3 study conducted between February 1997 and November 1998. SETTING: Eighteen international cutaneous T-cell lymphoma clinics at academic referral centers. PATIENTS: Fifty-eight patients with biopsy-proven stage IA through IIA cutaneous T-cell lymphoma that was refractory to (or patients were intolerant of) treatment or had reached at least a 6-month response plateau under at least 2 forms of prior therapy (median of 3.5 prior therapies). INTERVENTION: Bexarotene (Targretin capsules) administered once daily with meal for 16 weeks or longer. MAIN OUTCOME MEASURES: Primary end point classification of overall response rate of complete and partial remissions determined by either the Physician's Global Assessment of Clinical Condition or the objective Composite Assessment of Index Lesion Severity. Body surface area, time to response, duration of disease control, time to disease progression, individual index lesion signs and symptoms, and quality of life parameters were secondary outcomes. RESULTS: Responses (> or = 50% improvement) were seen in 3 (20%) of 15 patients with an initial dose at 6.5 mg/m(2) per day (95% confidence interval [CI], 0%-40%), 15 (54%) of 28 patients at 300 mg/m(2) per day (95% CI, 35%-72%), and 10 (67%) of 15 patients at above 300 mg/m(2) per day (95% CI, 43%-91%). The rate of progressive disease was 47%, 21%, and 13% at the same dose levels, respectively. Eight (73%) of 11 patients crossing over from 6.5 mg/m(2) per day to higher doses subsequently responded. The median duration of response from start of therapy could not be estimated for the 15 patients at 300 mg/m(2) per day owing to low relapse rates in 2 patients (13%); at higher doses it was 516 days. The following drug-related adverse effects were reversible and treatable: hypertriglyceridemia (46 patients [79%]), hypercholesterolemia (28 patients [48%]), headache (27 patients [47%]), central hypothyroidism (23 patients [40%]), asthenia (21 patients [36%]), and leukopenia (16 patients [28%]). No cases of drug-related neutropenic fever, sepsis, or death occurred. Pancreatitis occurred in 3 patients with triglyceride levels higher than 14.69 mmol/L (1300 mg/dL), all of whom were taking 300 mg/m(2) or more of oral bexarotene per day. CONCLUSIONS: Bexarotene (Targretin capsules) (the first retinoid X receptor-selective rexinoid) was well tolerated and effective as an oral treatment for 15 (54%) of 28 patients with refractory or persistent early-stage cutaneous T-cell lymphoma at doses of 300 mg/m(2) per day. Hypertriglyceridemia and hypothyroidism require monitoring but are reversible and manageable with concomitant medication.

Administration, Oral↗
PubMed2001

Analysis of clonality in cutaneous T cell lymphoma and associated diseases.

The T cell receptor (TCR) is the antigen-specific receptor for T cells. During its differentiation, each T cell undergoes rearrangement of its TCR genes. This results in novel nucleotide sequences that constitute a unique signature or fingerprint for each T cell and all its clonal progeny. Analysis of TCR gene rearrangements in cutaneous T cell lymphoma (CTCL) has lead to several findings concerning CTCL tumor biology. First, like most other lymphomas, CTCL is a monoclonal lymphoproliferative disorder. Second, rather than being truly a cutaneous lymphoma, CTCL is actually a lymphoma of the skin-associated lymphoid tissue (SALT). Even when disease appears confined to the skin clinically, there can be low-level trafficking of tumor cells through the peripheral lymph nodes via the lymphatics and blood vessels. Furthermore, CTCL is a mature SALT lymphoma capable of trafficking to sites of cutaneous inflammation analogous to normal SALT T cells. Third, the earliest manifestation of CTCL may be "clonal dermatitis." This is a form of chronic dermatitis that harbors a dominant T cell clone but lacks histologic features diagnostic for CTCL. About 25% of clonal dermatitis cases progress to overt CTCL within five years. Fourth, other lymphoproliferative disorders that are associated with CTCL share the same TCR gene rearrangements and therefore arise as subclones of the original tumor. These include lymphomatoid papulosis, large-cell lymphoma, and Hodgkin's disease.

Clone Cells↗
PubMed2000

Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc.

BACKGROUND: Necrolytic acral erythema is a recently described necrolytic erythema that is unique in its exclusive acral location and strong association with hepatitis C. OBSERVATION: We report the first case of necrolytic acral erythema in the United States. The patient is a 43-year-old black woman who presented with a 4-year history of tender, flaccid blisters localized to the dorsal aspect of her feet. Serum zinc and glucagon levels were normal. Serum antibodies were positive for hepatitis C, and a liver biopsy specimen showed chronic hepatitis. She was successfully treated with interferon alfa-2b and zinc. We review all previously reported cases. CONCLUSIONS: Necrolytic acral erythema is a distinct entity. In a review of the literature, most patients were between 35 and 55 years of age, although 1 patient was 12 years old. Five of 8 patients were female. Four of 7 patients described previously were treated with variable success using oral zinc sulfate and amino acids, whereas 2 were successfully treated with interferon alfa. All patients were infected with hepatitis C. Necrolytic acral erythema appears to be a skin disorder linked to infection with hepatitis C virus that responds to treatment with interferon alfa and oral zinc.

Acrodermatitis↗
PubMed2000

Cutaneous lymphoid hyperplasias.

Benign hyperplastic lymphoid infiltrates of the skin (pseudolymphoma, older term) simulate lymphoma clinically and histologically. They can be divided into B-cell predominant (typical cutaneous lymphoid hyperplasia (CLH), angiolymphoid hyperplasia, Kimura's disease, and Castleman's disease) and T-cell predominant (T-cell CLH, lymphomatoid contact dermatitis, and lymphomatoid drug eruption). Both types may represent exaggerated reactions to diverse external antigens (insect bite, tattoo, zoster, trauma, among others). A composite assessment of clinical presentation and behavior, routine histology, immunophenotyping, and molecular studies is essential for the diagnosis of benign cutaneous lymphoid infiltrates. Treatment includes antibiotics, intralesional and systemic corticosteroids, excision, radiotherapy, and immunosuppressants. Treatment depends on the assessment and biologic behavior, which is usually benign. Molecular biologic analysis has shown that a significant proportion of cases harbor occult B- or T-cell clones (clonal CLH). Progression to overt cutaneous lymphoma has been observed in a minority of cases. Patients with clonal populations of B or T cells and persistent lesions should be closely observed for emergence of a lymphoma.

Algorithms↗
PubMed2000

Detection of clonally restricted immunoglobulin heavy chain gene rearrangements in normal and lesional skin: analysis of the B cell component of the skin-associated lymphoid tissue and implications for the molecular diagnosis of cutaneous B cell lymphomas.

A monoclonal B cell population is the hallmark of B cell neoplasms including cutaneous B cell lymphomas (CBCLs). We modified and tested several polymerase chain reaction (PCR)-based assays involving amplification of immunoglobulin heavy chain (IgH) gene rearrangements to optimize assays specifically for cutaneous lymphoid infiltrates. We achieved greatest sensitivity with an assay employing IgH consensus primers complementary to the framework 3 portion of the upstream variable region and the downstream joining region. We studied 12 CBCLs, 6 nodal lymphomas and 7 cell lines. In 17/25 of these B cell neoplasms (84%), we detected one or two dominant bands, consistent with one or both IgH alleles being rearranged in the neoplastic B cell clone. As expected, IgH PCR assays produced diffuse smears in agarose gels or complex ladders in polyacrylamide gels when polyclonal B cell controls (blood and tonsil) were analyzed. However, in normal skin and non-CBCL skin lesions, one or a small number of discrete bands were sometimes detected. In certain cases, this made it difficult to distinguish true positives (monoclonal CBCL) from false positives (clonally restricted benign B cells). Correlation with immunophenotyping confirmed that false positive results were confined to samples with sparse or immunohistologically undetectable B cell infiltrates. Pseudoclonal bands showed variable sizes in repeat PCR reactions and could be distinguished from monoclonal bands by polyacrylamide gel electrophoresis of pooled triplicate PCR products. These findings suggest that molecular diagnosis using IgH PCR assays is best suited for B-cell-rich infiltrates, and can be problematic when applied to suspected T-cell-rich CBCLs, cutaneous T cell lymphomas, or other lesions containing only few B cells unless one is cognizant of the potential pitfalls. Furthermore, these results demonstrate the presence of rare B cells in normal skin and immunohistologically defined cutaneous T cell infiltrates. This correlates with recent reports of sparse B cells within the lymph draining from normal skin and may represent molecular evidence for a trafficking B cell component of the skin-associated lymphoid tissue (SALT). It also suggests a candidate B cell subset for the pathogenesis of cutaneous lymphoid hyperplasia and CBCLs.

B-Lymphocytes↗