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Biomedical subjects

Gary L Clayman

Publications and source records attributed to Gary L Clayman.

At least 19 recordsLinked to original sources
PubMed2007

Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma.

BACKGROUND: The objective of this phase II trial was to investigate the safety and efficacy of autologous heat shock protein-peptide complex 96 (HSPPC-96) vaccines prepared from tumor specimens of patients with newly diagnosed or previously treated indolent non-Hodgkin lymphoma (NHL). METHODS: The study was for patients with indolent B-cell NHL with measurable lesions. HSPPC-96 vaccines were prepared from patients' resected tumor specimens and administered as a 25-microg intradermal injection in the absence of disease progression every week for 4 weeks and then every 2 weeks until the vaccine supply was exhausted. RESULTS: Twenty patients were enrolled in this trial. The median patient age was 59 years. Ten patients had been treated previously (median, 2 regimens; range, 1 to 7). Eighteen (90%) patients had stage III or IV disease. Autologous vaccines were successfully prepared for 17 (85%) patients and all received at least 1 dose. The treatment was very well tolerated. One patient experienced a response with biopsy-proven clearance of the lymphoma cells in 2 of the skin nodules at 3.0 months that lasted for 7.0 months. Eight patients had stable disease for 6.0 to 19.8 months. The median failure-free survival duration in patients who received vaccine therapy was 5.2 months. CONCLUSIONS: HSPPC-96 can be prepared from tumor specimens for the majority of lymphoma patients, but it had limited efficacy in inducing responses in patients with active diseases. Further studies of HSPPCs, therefore, should be considered in adjuvant settings or in combination with other immunomodulatory agents to assess survival benefit.

Aged↗
PubMed2007

Transoral resection of thyroid cancer metastasis to lateral retropharyngeal nodes.

BACKGROUND: Lymph node metastasis from differentiated thyroid carcinoma may occur outside of the basins at greatest risk of spread, such as the lateral retropharyngeal lymph nodes. The extensive surgery of traditional approaches to the retropharyngeal space are rarely justified in the treatment of metastatic differentiated thyroid cancer. Therefore, a less invasive surgical approach is advantageous in resection of metastatic lateral retropharyngeal nodes. METHODS: To assess feasibility and safety, we report transoral excision guided by preoperative ultrasonography in a series of 3 consecutive patients with differentiated thyroid cancer metastatic to the retropharyngeal space. RESULTS: In all cases, the metastatic lateral retropharyngeal lymph node was successfully removed by transoral retropharyngotomy without complications. CONCLUSIONS: We advocate a transoral approach guided by preoperative ultrasonography for resection of differentiated thyroid cancer metastatic to the retropharyngeal lymph nodes. The approach is feasible, minimally invasive, and safe in achieving the goals in management of regionally metastatic disease.

Adult↗
PubMed2006

A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation.

Desquamation of the stratum corneum is a serine protease-dependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13, and KLK14 to desquamation by examining their interactions, in vitro, with: 1) colocalized SPI, lympho-epithelial Kazal-type-related inhibitor (LEKTI, four recombinant fragments containing inhibitory domains 1-6 (rLEKTI(1-6)), domains 6-8 and partial domain 9 (rLEKTI(6-9')), domains 9-12 (rLEKTI(9-12)), and domains 12-15 (rLEKTI(12-15)), secretory leukocyte protease inhibitor, and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1. KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13, and KLK14 were potently inhibited by rLEKTI(1-6), rLEKTI(6-9'), and rLEKTI(9-12) with Ki values in the range of 2.3-28.4 nm, 6.1-221 nm, and 2.7-416 nm for each respective fragment. Only KLK5 was inhibited by rLEKTI(12-15) (Ki = 21.8 nm). No KLK was inhibited by secretory leukocyte protease inhibitor or elafin. Apart from KLK13, all KLKs digested the ectodomain of desmoglein 1 within cadherin repeats, Ca2+ binding sites, or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.

Carrier Proteins↗
PubMed2006

Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein.

BACKGROUND: Human growth hormone (hGH) is naturally present in numerous isoforms, some of which arise from proteolytic processing in both the pituitary and periphery. The nature of the enzymes that proteolytically cleave hGH and the regulation of this process are not fully understood. Our objective is to examine if members of a newly discovered human tissue kallikrein family (KLKs) are expressed in the pituitary and if these enzymes can cleave hGH in-vitro. METHODS: Expression of 12 of the KLKs (KLKs 4-15) and serine protease inhibitor Kazal-type 5 (SPINK5) genes and their proteins in the pituitary was examined by RT-PCR and immunohistochemistry. Recombinant hGH was digested by various recombinant KLKs and fragments were characterized by N-terminal sequencing. SPINK5 recombinant fragments were used for inhibition of KLK activities. RESULTS: We here describe for the first time expression of numerous KLKs (KLKs 5-8, 10-14) and SPINK5 in the pituitary. KLK6 and SPINK5 appeared to be localized to hGH-producing cells. KLKs 4-6, 8, 13 and 14 were able to cleave hGH, yielding various isoforms, in vitro. Inhibitor SPINK5 fragments were able to suppress activity of KLKs 4, 5 and 14 in vitro. Based on these data, we propose a model for the proteolytic processing of hGH in the pituitary and the regulation of this system by SPINK5 inhibitory domains. We speculate that loss of SPINK5 inhibitory domains, as in the case of Netherton syndrome, may lead to proteolytic over-processing of hGH and to growth retardation. CONCLUSION: We conclude that many KLKs and SPINK5 are expressed in the pituitary. This serine protease-inhibitor system is likely to participate in the regulated proteolytic processing of hGH in the pituitary, leading to generation of hGH fragments. Our data suggest that KLKs 5, 6 and 14 might be involved in this process.

Carrier Proteins↗
PubMed2006

Phase I/II study of docetaxel, cisplatin, and concomitant boost radiation for locally advanced squamous cell cancer of the head and neck.

PURPOSE: To investigate the feasibility of combining concomitant boost accelerated radiation with docetaxel and cisplatin and assess the regimen's toxicity, locoregional control rate, and survival in patients with locally advanced head and neck cancer (HNSCC). PATIENTS AND METHODS: Patients with stage III-IV HNSCC were eligible. Phase I included two schedules of docetaxel and cisplatin: arm 1, once per week during weeks 1 to 4; arm 2, every 21 days for weeks 1 and 4. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (concomitant boost). RESULTS: Twenty patients were enrolled in phase I. The arm 1 maximum-tolerated dose (MTD) was defined at docetaxel 15 mg/m2 and cisplatin 20 mg/m2 based on prolonged mucositis in 29% of patients. The initial dose level in arm 2 was above the MTD. In total, 52 patients were treated using the arm 1 regimen in phase II. Acute toxicity included grade 3 mucositis and dermatitis in 81% and 44% of patients. The 2-year locoregional control rate was 71%. The 2-year progression-free and overall survival rates were 61% and 65%. Median survival was 37.8 months. Late effects included feeding tube dependence in 17% of patients alive and free of disease. CONCLUSION: Locoregional control, survival, and acute toxicity with this regimen were comparable with other trials utilizing taxanes and/or platins and concomitant conventional or altered fractionation radiation. Our data suggest that chemotherapy added to concomitant boost fractionation may increase rates of long-term feeding tube dependence. Phase III trials are needed to assess the contribution of concomitant boost fractionation to chemoradiotherapy.

Adult↗
PubMed2006

4-Nitroquinoline-1-oxide-induced mutagen sensitivity and risk of nonmelanoma skin cancer: a case-control analysis.

The UV radiation-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) is thought to induce squamous cell carcinoma (SCC) similar to those induced by UV radiation in animals. Therefore, we tested the hypothesis that cellular sensitivity to 4-NQO is associated with risk of developing skin cancer in a case-control study of 191 patients with nonmelanoma skin cancer (NMSC; 81 SCC and 110 basal cell carcinoma (BCC)) and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 microM for 24 hours and scored for chromatid breaks in 50 well-spread metaphases. We found that the mean frequency of chromatid breaks per cell (b/c) was significantly higher in the cases (mean+/-SD, 0.46+/-0.43 for SCC and 0.43+/-0.38 for BCC) than in the controls (0.25+/-0.25; P<0.001 for both comparisons) and were associated with more-than-twofold increased risk for both SCC and BCC after adjustment for known risk factors. Therefore, our findings support the notion that sensitivity to 4-NQO reflects susceptibility to UV-induced NMSC. However, there is a lack of correlation between UVB-induced b/c and 4-NQO-induced b/c in this study population. Therefore, these findings need to be verified by additional studies.

4-Nitroquinoline-1-oxide↗
PubMed2006

American Society of Clinical Oncology clinical practice guideline for the use of larynx-preservation strategies in the treatment of laryngeal cancer.

PURPOSE: To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. METHODS: A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. RESULTS: Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. RECOMMENDATIONS: All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

Clinical Trials, Phase III as Topic↗
PubMed2006

Fenretinide activity in retinoid-resistant oral leukoplakia.

PURPOSE: To test the hypothesis that the retinamide N-(4-hydroxyphenyl)retinamide (fenretinide) would be clinically active potentially via receptor-independent apoptosis and receptor-dependent effects in natural retinoid-resistant oral leukoplakia patients--the first test of this hypothesis in any in vivo setting. EXPERIMENTAL DESIGN: A phase II trial of fenretinide (200 mg/d for 3 months) in oral leukoplakia patients who had not responded (de novo resistance) or who had responded and then relapsed (acquired resistance) to previous treatment with natural retinoids. We analyzed apoptosis via the terminal deoxynucleotidyl transferase-mediated nick end labeling in situ DNA fragmentation assay. RESULTS: We accrued 35 evaluable patients with retinoid-resistant oral leukoplakia, 12 (34.3%) had partial responses to fenretinide (95% confidence interval, 19.2-52.4%), and response was associated with acquired resistance to natural retinoids (P = 0.015, Fisher's exact test). Nine responders progressed within 9 months of stopping fenretinide. Toxicity was minimal and compliance was excellent. Mean apoptosis values (SE) increased from 0.35% (0.25%) at baseline to 1.18% (0.64%) at 3 months (P = 0.001, sign test); this increase did not correlate with clinical response. The increases in 3-month mean serum concentrations of fenretinide (0.23 micromol/L) and N-(4-methoxyphenyl)retinamide (0.57 micromol/L) correlated with decreased retinol concentrations [Spearman correlation coefficient of -0.57 (P = 0.001) and -0.43 (P = 0.01), respectively]. CONCLUSIONS: Low-dose fenretinide was clinically active and produced a small increase in apoptosis in retinoid-resistant oral leukoplakia.

Adult↗
PubMed2006

Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome.

Mutations in the SPINK5 gene encoding the serine protease (SP) inhibitor, lymphoepithelial-Kazal-type 5 inhibitor (LEKTI), cause Netherton syndrome (NS), a life-threatening disease, owing to proteolysis of the stratum corneum (SC). We assessed here the basis for phenotypic variations in nine patients with "mild", "moderate", and "severe" NS. The magnitude of SP activation correlated with both the barrier defect and clinical severity, and inversely with residual LEKTI expression. LEKTI co-localizes within the SC with kallikreins 5 and 7 and inhibits both SP. The permeability barrier abnormality in NS was further linked to SC thinning and proteolysis of two lipid hydrolases (beta-glucocerebrosidase and acidic sphingomyelinase), with resultant disorganization of extracellular lamellar membranes. SC attenuation correlated with phenotype-dependent, SP activation, and loss of corneodesmosomes, owing to desmoglein (DSG)1 and desmocollin (DSC)1 degradation. Although excess SP activity extended into the nucleated layers in NS, degrading desmosomal mid-line structures with loss of DSG1/DSC1, the integrity of the nucleated epidermis appears to be maintained by compensatory upregulation of DSG3/DSC3. Maintenance of sufficient permeability barrier function for survival correlated with a compensatory acceleration of lamellar body secretion, providing a partial permeability barrier in NS. These studies provide a mechanistic basis for phenotypic variations in NS, and describe compensatory mechanisms that permit survival of NS patients in the face of unrelenting SP attack.

Abnormalities, Multiple↗
PubMed2006

Human tracheal reconstruction with a composite radial forearm free flap and prosthesis.

Reconstruction of large tracheal defects has been largely unsuccessful. We report a novel single-stage tracheal reconstruction for a 6.5-cm long defect involving the anterior two thirds of the tracheal circumference in a patient with deeply infiltrative thyroid cancer into the tracheal lumen. The reconstruction was completed using a conduit composed of a radial forearm free flap for lining with a combined PolyMax mesh (Synthes, Paoli, PA) and Hemashield vascular graft (Boston Scientific, Natick, MA) for rigid support. At a 6-month follow-up the patient has normal swallowing and preoperative voice quality, and she maintains a patent, non-stented airway.

Female↗
PubMed2006

Stent fabrication for graft immobilization following wide surgical excision of myofibroblastic sarcoma of the buccal mucosa: a clinical report.

Sarcomas of the head and neck are rare tumors derived from cells of mesenchymal origin. This article briefly discusses the epidemiology, etiology, and classification of head and neck sarcomas. Emphasis is placed on myofibrosarcoma, a malignant tumor of the myofibroblasts. Histologic criteria, prognostic factors, and the multidisciplinary management of these tumors are reviewed. A situation of a surgically excised myofibrosarcoma of the buccal mucosa is reported. In this patient, a stent was fabricated to stabilize a split-thickness skin graft used for the buccal mucosa reconstruction.

Adult↗
PubMed2005

In vitro sensitivity to ultraviolet B light and skin cancer risk: a case-control analysis.

BACKGROUND: Mutagen sensitivity, measured as mutagen-induced chromatid breaks per cell in primary lymphocytes in vitro, has been used to study susceptibility to various epithelial cancers. Patients with xeroderma pigmentosum are highly sensitive to ultraviolet (UV) light due to inherited defects in DNA repair and have a 1000-fold higher risk of UV-induced skin cancer than the general population. However, an association between UV-induced chromosomal aberrations and risk of skin cancer in the general population has not been established. METHODS: We assessed in vitro UVB-induced chromatid breaks in a hospital-based case-control study. The study included 469 patients with skin cancer (231 with nonmelanoma skin cancer [NMSC] and 238 with cutaneous malignant melanoma [CMM]) and 329 cancer-free control subjects. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Compared with the frequency of UVB-induced chromatid breaks per cell in control subjects (mean = 0.28 breaks per cell, 95% CI = 0.27 to 0.30), that in NMSC patients (basal cell carcinoma [BCC], n = 143, mean = 0.36 breaks per cell, 95% CI = 0.33 to 0.39 and squamous cell carcinoma [SCC], n = 88, mean = 0.35 breaks per cell, 95% CI = 0.32 to 0.38) was higher (P = .001 and P < .001, respectively), but that in CMM case patients (mean = 0.30 breaks per cell, 95% CI = 0.28 to 0.33) was not (P = .22). A frequency of chromatid breaks per cell above the median of control subjects was associated with nearly threefold increased risks for BCC (OR = 2.78, 95% CI = 1.79 to 4.30) and SCC (OR = 2.62, 95% CI = 1.50 to 4.60), but not with an increased risk of CMM. A dose-response relationship was evident between mutagen sensitivity and risk for both BCC (Ptrend < .001) and SCC (Ptrend < .001). Multiplicative interactions between mutagen sensitivity and sun exposure variables on risk, particularly for sunburn in BCC and hair color, tanning ability, and family history of skin cancer in SCC, were seen for NMSC but not CMM. CONCLUSIONS: UVB-induced mutagen sensitivity may play a role in susceptibility to NMSC but not to CMM.

Adult↗
PubMed2005

Headpin: a serpin with endogenous and exogenous suppression of angiogenesis.

Headpin is a novel serine proteinase inhibitor (serpin) with constitutive mRNA expression in histologically normal oral mucosa but with lost or down-regulated expression in head and neck squamous cell carcinoma. Several serpin family members are similarly lost in multiple cancer types and hold tumor suppressor functions including the inhibition of angiogenesis. However, the functional significance for the loss of headpin expression in cancer is not known. Using immunohistochemical analysis of invasive squamous cell carcinoma and matched normal squamous mucosa of patient specimens, headpin expression was lost or down-regulated in the vast majority of tumor specimens. We investigated the functions of exogenous recombinant headpin and endogenously expressed headpin related to angiogenesis. In a rat corneal assay of neovascularization, recombinant headpin protein blocked in vivo angiogenesis mediated by interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF). In assays of cellular events in angiogenesis, headpin blocked the invasion, migration, and tube formation of endothelial cells. In light of our findings of nuclear subcellular localization of headpin, we investigated the expression and secretion of angiogenic factors and found reduced mRNA, protein, and promoter activities of IL-8 and VEGF. Finally, using a murine flank tumor model, headpin expression reduced growth and microvessel density in tumors derived from headpin-expressing UMSCC1 cells relative to those from vector control cells. These findings of nuclear regulatory functions of a serpin in the inhibition of angiogenesis bring new understanding to the cellular and molecular mechanisms of serpins. Therefore, this novel serpin targets diverse mechanisms against tumor angiogenesis on which to base therapeutic strategies.

Animals↗
PubMed2005

Management of the N0 neck--reference or preference.

For patients with squamous cell carcinoma of the upper aerodigestive tract, appropriate management of the regional lymph nodes is an important and often controversial issue that has significant influence on survival. Over the years radical treatment either by surgery or radiotherapy contributed to improvement in prognosis. Recently, a more conservative approach has achieved a similar level of cancer control with less morbidity. This review considers the issues of selection of patients for treatment of the neck, choice of modality and extent of therapy, treatment of the contralateral neck, management of recurrence and influence of the site and status of the primary lesion.

Carcinoma, Squamous Cell↗
PubMed2005

Elective and therapeutic selective neck dissection.

Selective neck dissection is a modification of the more comprehensive modified radical or radical neck dissection that is designed to remove only those nodal levels considered to be at risk for harboring nodal metastases. The role of selective neck dissection continues to evolve: while initially designed as a staging and diagnostic procedure for patients without clinical evidence of nodal disease, a growing body of literature suggests that selective neck dissection has a therapeutic role in patients with clinical and histologic evidence of nodal metastases. The rationale behind selective neck dissection, its application in the clinically negative but histologically node-positive neck and the extended application of selective neck dissection in patients with clinical evidence of nodal disease are discussed.

Carcinoma, Squamous Cell↗
PubMed2005

Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types.

STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control-a process critical for all cancer types-we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR=1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR=1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value=0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value<0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk.

Animals↗
PubMed2005

Consequences of C-terminal domains and N-terminal signal peptide deletions on LEKTI secretion, stability, and subcellular distribution.

The secretory lympho-epithelial Kazal-type-inhibitor (LEKTI) is synthesized as a pro-LEKTI protein containing an N-terminal signal peptide and 15 potentially inhibitory domains. This inhibitor is of special interest because of its pathophysiological importance for the severe congenital disease Netherton syndrome. We showed that LEKTI is a potent inhibitor of a family of serine proteinases involved in extracellular matrix remodeling and its expression is downregulated in head and neck squamous cell carcinomas. To assess the role of C-terminal domains and N-terminal signal peptide in LEKTI secretion, we constructed deletion mutants of LEKTI, expressed them in HEK 293T cells, and analyzed their secretion behavior, stability, subcellular distribution, and proteinase inhibitory function. Pro-LEKTI is processed and secreted into the medium. On the basis of partial N-terminal sequencing and immunoblotting, the cleavage products are ordered from amino- to carboxy-terminal as follows: 37, 40, and 60kDa. Inhibitors of furin lead to enhanced secretion of unprocessed LEKTI, suggesting that processing was not required for secretion. Deletion of the N-terminal signal peptide of pro-LEKTI caused altered distribution of LEKTI from endoplasmic reticulum (ER) to cytoplasm and markedly reduced its stability, consistent with its failure to become secreted into the medium. Interestingly, when we deleted the C-terminal domains, stable partial LEKTI (LD-1-6) accumulated and still retained its association with ER but was not secreted. Recombinant LD-1-6 specifically inhibited the trypsin activity. We conclude that N-terminal signal peptide is required for LEKTI import into ER and elements present in C-terminal domains may have a role in regulating LEKTI secretion.

Amino Acid Sequence↗