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J N Myers

Publications and source records attributed to J N Myers.

At least 19 recordsLinked to original sources
PubMed2006

Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.

Constitutively activated nuclear factor-kappaB (NF-kappaB) has been associated with a variety of aggressive tumor types, including head and neck squamous cell carcinoma (HNSCC); however, the mechanism of its activation is not fully understood. Therefore, we investigated the molecular pathway that mediates constitutive activation of NF-kappaB in a series of HNSCC cell lines. We confirmed that NF-kappaB was constitutively active in all HNSCC cell lines (FaDu, LICR-LON-HN5 and SCC4) examined as indicated by DNA binding, immunocytochemical localization of p65, by NF-kappaB-dependent reporter gene expression and its inhibition by dominant-negative (DN)-inhibitory subunit of NF-kappaB (IkappaBalpha), the natural inhibitor of NF-kappaB. Constitutive NF-kappaB activation in HNSCC was found to be due to constitutive activation of IkappaBalpha kinase (IKK); and this correlated with constitutive expression of phosphorylated forms of IkappaBalpha and p65 proteins. All HNSCC showed the expression of p50, p52, p100 and receptor-interacting protein; all linked with NF-kappaB activation. The expression of constitutively active NF-kappaB in HNSCC is mediated through the tumor necrosis factor (TNF) signaling pathway, as NF-kappaB reporter activity was inhibited by DN-TNF receptor-associated death domain (TRADD), DN-TNF receptor-associated factor (TRAF)2, DN-receptor-interacting protein (RIP), DN-transforming growth factor-beta-activated kinase 1 (TAK1), DN-kappa-Ras, DN-AKT and DN-IKK but not by DN-TRAF5 or DN-TRAF6. Constitutive NF-kappaB activation was also associated with the autocrine expression of TNF, TNF receptors and receptor-activator of NF-kappaB and its ligand in HNSCC cells but not interleukin (IL)-1beta. All HNSCC cell lines expressed IL-6, a NF-kappaB-regulated gene product. Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated constitutively active NF-kappaB, and this was associated with inhibition of IL-6 expression and cell proliferation. Our results clearly demonstrate that constitutive activation of NF-kappaB is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway, making TNF a novel target in the treatment of head and neck cancer.

Carcinoma, Squamous Cell↗
PubMed2005

The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells.

The phosphatidylinositol 3' kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

Apoptosis↗
PubMed2005

ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion!

ICAM-5 (telencephalin) is an intercellular adhesion molecule reported to be expressed only in the somatodendritic membrane of telencephalic neurons. We recently identified high ICAM-5 expression in a cDNA array study of head and neck neoplasms with a propensity for perineural invasion. To determine the association of this gene in tumorigenesis and perineural invasion, we analyzed the expression and functional status of ICAM-5 mRNA transcripts in 30 different human cancer cell lines and 25 head and neck squamous carcinoma specimens by reverse-transcriptase polymerase chain reaction (cell lines and specimens) and in vitro functional assays (cell lines). ICAM-5 transcripts were detected in 28 (93%) of 30 cell lines derived from primary head and neck, colon, thyroid, cervical, pancreatic, skin, and adenoid cystic carcinomas. In cell lines, small interfering RNA blocked ICAM-5 expression and inhibited cell proliferation. Treatment with the phosphatidylinositol 3'-kinase (PBK) inhibitor LY294002 resulted in ICAM-5 down-regulation. In tissue specimens, none of the 25 histologically normal oral mucosal specimens had detectable ICAM-5 level, whereas 16 (64%) of the 25 matched primary squamous carcinomas showed expression. Carcinoma specimens high ICAM-5 expression had a high incidence of perineural invasion. Our study indicates that ICAM-5 may play a role in tumorigenesis and perineural invasion, most likely through the P13K/Akt-signaling pathway.

Adult↗
PubMed2001

Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue.

INTRODUCTION: The presence of nodal metastases remains the most significant predictive factor for regional recurrence and survival in patients treated for squamous cell carcinoma of the head and neck. Survival rates are further decreased in patients with nodal metastases that have spread beyond the lymph node capsule, or extracapsular spread (ECS). To the authors' knowledge, this is the first report on the impact of ECS in a large series of patients treated for squamous cell carcinoma of the oral tongue (SCCOT) at a single institution using surgery as the primary treatment modality. METHODS: The authors retrospectively reviewed the medical records of all patients treated for SCCOT with resection of the primary and neck dissection at a single institution between 1980 and1995. RESULTS: Two hundred sixty-six patients were included in the study. Of that number, 146 patients (55%) were pathologically node-negative (pN0), 75 patients (28%) were pathologically node-positive (pN+) without ECS (pN+/ECS-), and 45 patients (17%) were pN+ with ECS (pN+/ECS+). The 5-year disease-specific and overall survival rates for pN0 patients were 88% and 75%; for pN+/ECS- patients, 65% and 50%; and 48% and 30% for pN+/ECS+ patients. The patterns of failure for the pN0, pN+/ECS- and, pN+/ECS+ groups showed overall recurrence rates of 19.8%, 34.2%, and 51.1% with regional failure rates of 11.5%, 19.2%, and 28.9%, respectively, and distant metastases rates of 3.3%, 8.2%, and 24.4%. CONCLUSIONS: ECS is the most significant predictor of both regional recurrence and development of distant metastasis accounting for decreased survival of patients with SCCOT in the current study. Therefore, intensive regional and systemic adjuvant therapy may be indicated for patients with ECS. Future studies should focus on identifying molecular mediators involved in ECS to determine targets for adjuvant therapies in this subset of patients.

Adult↗
PubMed2001

Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Thalidomide has been shown to have antiangiogenic effects in preclinical models as well as a significant antitumor effect in hematologic tumors such as multiple myeloma. The authors performed this Phase II study to determine the activity, toxicity profile, and antiangiogenic effect of thalidomide in patients with locoregionally recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: Twenty-one patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with single-agent thalidomide. All patients had received radiation therapy, and most had undergone surgery (95%) and/or chemotherapy (90%). Thalidomide was initiated at 200 mg;3>daily and increased to a target dose of 1000 mg daily. Patients continued treatment until disease progression, unacceptable toxicity, or death occurred. RESULTS: All 21 patients eventually developed progressive disease. Median time to progression was 50 days (95% confidence interval, 28-70), with median overall survival time of 194 days (95% lower confidence boundary, 151), similar to the progression and survival times reported for this patient group with other agents. Thalidomide was generally well tolerated, with few patients experiencing Grades 3 to 4 toxicities. Serum vascular endothelial growth factor and basic fibroblast growth factor levels increased in six of seven patients, for whom paired serum samples were available and all of whom had progressive disease. CONCLUSIONS: In this heavily pretreated population of patients with advanced squamous cell carcinoma of the head and neck, thalidomide does not appear to have single-agent antitumor activity. Further evaluation of the mechanism of action of thalidomide is indicated. Potentially, future evaluations of thalidomide may be performed in combination with other antiangiogenic or cytotoxic agents in patients with earlier stage disease or in patients with minimal residual disease.

Administration, Oral↗
PubMed2001

Predictors of weight loss during radiation therapy.

OBJECTIVE: To define risk factors for weight loss or dehydration during radiation therapy (RT). STUDY DESIGN AND SETTING: Retrospective chart review, academic tertiary care center. RESULTS: The incidence of severe weight loss during RT was 32.7%, the incidence of dehydration was 10.9%, and the rate of prophylactic feeding gastrostomy tube placement was 32%. The patients most likely to suffer severe weight loss included patients with tumor sites of nasopharynx and base of tongue, those treated with chemoradiation, and patients with severe pretreatment weight loss. Prophylactic feeding gastrostomy tube placement before RT significantly reduced the incidence of severe weight loss and hospitalization during RT. CONCLUSION: Severe weight loss and dehydration during RT for head and neck cancer is common. Prophylactic feeding gastrostomy tubes significantly reduce the incidence of severe weight loss and hospitalization for dehydration during RT when placed before onset of RT. Patients at risk for severe weight loss include those with severe pretreatment weight loss, tumors of the nasopharynx and base of tongue, or treatment with chemoradiation.

Dehydration↗
PubMed2001

Phase II trial of systemic recombinant interleukin-2 in the treatment of refractory nasopharyngeal carcinoma.

BACKGROUND: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. METHODS: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5-6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-alpha, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. RESULTS: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3x) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. CONCLUSION: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.

Adult↗
PubMed2001

Malignant melanoma arising within a burn scar case report and review of the literature.

Burn scar carcinomas, also called Marjolin's ulcers, are uncommon tumors that arise from an antecedent burn. Most burn scar carcinomas are diagnosed about 30 years after the burn, and most are well-differentiated squamous cell carcinomas. We report a case in which a squamous cell carcinoma developed within a burn scar on the cheek and then a malignant melanoma arose within the burn scar after the squamous cell carcinoma had been excised. We also review the available literature on burn scar carcinoma, covering the demographics, pathogenesis, diagnosis, prognosis, and treatment of the disease. Given the multifocality of this disease process, we advocate aggressive resection of the entire burn scar, as well as the tumor, to prevent the development of further cancers within the wound.

Abdomen↗
PubMed2000

Cancer of the oral cavity.

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Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Squamous cell carcinoma of the tongue in young adults: increasing incidence and factors that predict treatment outcomes.

OBJECTIVE: This study was designed to determine whether the incidence of squamous cell carcinoma of the oral tongue (SCCOT) in young adults has changed during the past 25 years and to determine prognostic factors for young adult patients (aged < 40 years) with SCCOT. METHODS AND PATIENTS: A retrospective review of young adults with SCCOT who sought treatment at the M. D. Anderson Cancer Center between 1973 and 1995 was undertaken. RESULTS: The percentage of young adult SCCOT patients at M. D. Anderson increased from 4% in 1971 to 18% in 1993. T stage, N stage, perineural invasion, and lymphatic invasion were all associated with decreased survival. Patients who received a neck dissection as part of their primary treatment had a better chance of survival than patients who did not. CONCLUSIONS: The incidence of SCCOT in the young adult population is increasing in the United States. Appropriate surgical management for young adults with SCCOT includes resection of the primary tumor along with a selective node dissection.

Adult↗
PubMed1999

Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis.

MMAC/PTEN, a tumor suppressor gene located on chromosome 10q, has recently been shown to act as a phosphatidylinositol 3,4,5-triphosphate phosphatase and to modulate cell growth and apoptosis. Somatic mutations of MMAC/PTEN have been reported in a number of human cancers, especially in glioblastoma multiforme (GBM), although the number of identified mutations (approximately 10-35%) is significantly lower than the frequency of LOH affecting the MMAC/PTEN locus in the specimens (approximately 75-95%). To further investigate the possible alterations that may affect MMAC/PTEN, we examined the expression of the gene by reverse transcription-PCR in a series of gliomas. A significant difference (P < 0.001) was observed between the expression of MMAC/PTEN in GBMs versus lower grades of gliomas, thus mimicking the difference in allelic deletion associated with the locus in these tumors. Furthermore, Kaplan-Meier survival plots, adjusted for age and tumor grade, showed a significantly better prognosis for patients whose tumors expressed high levels of MMAC/PTEN. Additionally, immunostaining of GBMs revealed little or no MMAC/PTEN expression in about two-thirds of the tumors, whereas the other approximately one-third of tumors had significantly higher levels of expression. However, in about two-thirds of the high-expressing specimens, a heterogeneous pattern of expression was observed, indicating that certain cells within the tumor failed to express MMAC/PTEN. The combination of these results suggest that, in addition to molecular alterations affecting the gene, altered expression of MMAC/PTEN may play a significant role in the progression of GBM and patient outcome.

Biomarkers, Tumor↗
PubMed1999

Biochemoprevention for dysplastic lesions of the upper aerodigestive tract.

OBJECTIVES: To evaluate the efficacy and secondarily the toxic effects of biochemopreventive therapy (high-dose isotretinoin [13-cis-retinoic acid], alpha-tocopherol, and interferon alfa) in the reversal of advanced premalignant lesions of the upper aerodigestive tract and to correlate the therapeutic events with modulation of biomarkers. DESIGN: Prospective, nonrandomized chemoprevention trial. SETTING: Tertiary cancer care referral center and ambulatory care. PARTICIPANTS: Thirty-six patients with advanced premalignant lesions of the upper aerodigestive tract, without cancer during the 2 years before the intervention, with evaluable lesions, and without retinoid therapy for 3 months before the trial. INTERVENTION: Administration of oral isotretinoin (100 mg/m2 per day), oral alpha-tocopherol (1200 IU/d), and subcutaneous interferon alfa (3 megaunits per square meter twice weekly) for 12 months, with serial biopsies and clinical examination at 0, 6, 12, and 18 months from study start. MAIN OUTCOME MEASURES: Clinical and histologic responses to the intervention. RESULTS: Of the 36 patients, evaluation was possible in 30 for response at 6 months and in 21 at 12 months. At 6 months, there were 10 pathologic complete responses and 7 partial responses; at 12 months, 7 complete and 3 partial responses. A striking difference in response was observed in favor of laryngeal lesions (9/19 [47%] complete response rate at 6 months and 7/14 [50%] at 12 months vs 1/11 [9%] and 0/7 [0%], respectively, for oral lesions). Toxic effects were acceptable and did not exceed grade 3. CONCLUSION: Biochemoprevention is a promising biologic approach for laryngeal dysplasia and needs to be investigated further.

Adult↗
PubMed1999

Successful use of cyclosporine in a lung transplant recipient with tacrolimus-associated hemolytic uremic syndrome.

Hemolytic-uremic syndrome (HUS) is a rare, but well-described complication in organ transplant recipients maintained on cyclosporine immunosuppression. Tacrolimus is a newer agent with similar immunosuppressant efficacy. In cases of cyclosporine-related HUS in renal transplant recipients, tacrolimus has been used successfully without recurrence of HUS. Tacrolimus has been reported to cause HUS in renal and more recently in cardiac transplant patients. We report a case of HUS in a lung transplant recipient receiving tacrolimus who was subsequently converted to cyclosporine without recurrence of HUS.

Cyclosporine↗
PubMed1999

Exercise stress testing. An overview of current guidelines.

Exercise stress testing (ET) is an inexpensive noninvasive tool that provides valuable cardiopulmonary information in healthy and diseased populations. It is most commonly used for diagnosing coronary artery disease (CAD) and developing appropriate exercise prescriptions (EP). With its widespread use and application, it is imperative that safe and appropriate guidelines and procedures are used, as there are a number of risks associated with testing in a population with or suspected of having CAD. The focus should be on the patient's safety: personnel must be properly trained and aware of all emergency procedures, contra-indications for ET and indications for test termination must be strictly adhered to. Three main types of testing are prevalent: submaximal, maximal and maximal utilising gas exchange. The maximal test is most commonly used, and the submaximal is appropriate for hospitalised patients. Gas exchange data is essential when assessing congestive heart failure and timing for heart transplantation. ET is commonly performed using a treadmill or a bicycle ergometer. The treadmill provides a more familiar exercise modality and has been shown to have greater diagnostic sensitivity than the bicycle ergometer; it is, however, more expensive and requires more space in the testing room. The bicycle ergometer is more appropriate for those individuals who are severely obese or have problems with extended periods of walking. Regardless of the modality used, an appropriate exercise protocol should be used. In North America, the Bruce protocol is the most common. However, the Bruce protocol, and others that estimate exercise capacity based on equations, tend to overestimate exercise capacity. They may be too demanding for those with limited exercise capacity, and too long for those with high exercise capacity. For these people, an exercise protocol that reaches maximal capacity in 8 to 12 minutes using smaller increments in workload should be considered. Once completed, the results of ET needs to be correctly interpreted. This includes reviewing the test results while considering the patient's history, medications and indication for the test. ET can also be used to develop an EP for the participant. An EP should take into account the intensity, modality of exercise, frequency and duration, as well as being realistic for the individual and the goals to be achieved. All the information from the test results and the pre-test examination should be presented in a report that also includes the advised EP.

British Columbia↗