Melanoma: Walker MJ

Houghton AN, Coit DG, Daud A, Dilawari RA, Dimaio D, Gollob JA, Haas NB, Halpern A, Johnson TM, Kashani-Sabet M, Kraybill WG, Lange JR, Martini M, Ross MI, Samlowski WE, Sener SF, Tanabe KK, Thompson JA, Trisal V, Urist MM, Walker MJ, Anonymous00370. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #16884669 No free full text.

This publication has no abstract.

Varker KA, Biber JE, Kefauver C, Jensen R, Lehman A, Young D, Wu H, Lesinski GB, Kendra K, Chen HX, Walker MJ, Carson WE. · Division of Surgical Oncology, The Ohio State University Comprehensive Cancer Center, N924 Doan Hall, 410 W 10th Avenue, Columbus, Ohio 43210, USA. · Ann Surg Oncol. · Pubmed #17534686 No free full text.

Abstract: BACKGROUND: Vascular endothelial growth factor (VEGF) is a proangiogenic molecule produced by melanoma cells. We hypothesized that administration of bevacizumab (Bev), a monoclonal antibody that neutralizes VEGF, with low-dose interferon alfa-2b (IFN-alpha2b), an inhibitor of basic fibroblast growth factor (FGF), would lead to the regression of metastatic melanoma. METHODS: Patients with metastatic melanoma were randomized to receive Bev (15 mg/kg intravenously every 2 weeks) with or without low-dose IFN-alpha2b (1 MU/m2 subcutaneously daily). Patients exhibiting a clinical response or stable disease after 12 weeks were treated until disease progression. RESULTS: Thirty-two patients (16 per arm) were accrued (18 male, 14 female; mean age 57.5 years). Both regimens were well tolerated. Six patients developed easily managed exacerbations of preexisting hypertension. Two patients developed grade 3 proteinuria that resolved after a treatment break. IFN-alpha2b therapy was associated with grade 1 to 2 constitutional symptoms. Arterial thromboembolic complications were observed in three patients (two mild myocardial infarctions, one transient ischemic attack), all of whom had risk factors. One patient (Bev plus IFN-alpha2b arm) had locally recurrent scalp disease that partially responded to therapy. Eight patients (five Bev, three Bev plus IFN-alpha2b) had prolonged disease stabilization (24 to 146 weeks). Plasma levels of VEGF and FGF did not correlate with any clinical parameter. The patient with the longest period of stable disease had the highest baseline VEGF and FGF. CONCLUSIONS: Bev was well tolerated at this dose and prolonged disease stabilization was achieved in one-quarter of metastatic melanoma patients. Low-dose IFN-alpha2b did not augment the activity of Bev.

Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. · The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute/The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA. · Cancer. · Pubmed #11135227 links to  free full text

Abstract: BACKGROUND: Dendritic cells (DCs) are potent initiators of immune responses, and the infiltration of DCs into tumors may confer an improved prognosis. Whether the injection of DCs directly into tumors can mediate biologic activity was examined. METHODS: Patients with metastatic dermal or subcutaneous tumors received granulocyte-macrophage-colony stimulating factor to increase the numbers of peripheral blood monocyte precursors. DCs were then generated from monocytes obtained by phlebotomy with granulocyte-macrophage-colony stimulating factor and interleukin-4 in autologous plasma. Tumors were injected at multiple sites with 30 million autologous DCs per tumor. RESULTS: Seven patients with melanoma and three patients with breast carcinoma were treated. Injections were well tolerated. Regression of the injected tumors, beginning as early as 4 days after injection, was observed in four patients with melanoma and in two patients with breast carcinoma. Biopsies of regressing lesions showed lymphocyte infiltration associated with DCs and necrosis. Neutrophils and macrophages were not evident. Lymphocytes expanded from the regressing tumors proliferated in response to heat shock proteins, HSP70 and gp96, derived from autologous tumor. The DCs injected produced interferon-alpha and expressed Fas ligand mRNA but did not exhibit cytolytic activity in vitro. Expression of the costimulatory molecule, B7-2 (CD86), decreased on DCs after intratumoral injection. CONCLUSIONS: This pilot study demonstrates that DCs derived in vitro can exist viably after intratumoral injection and can mediate biologic activity in situ. Tumor-derived heat shock proteins may be involved in the antitumor activity observed.

Zimmerer JM, Lesinski GB, Ruppert AS, Radmacher MD, Noble C, Kendra K, Walker MJ, Carson WE. · Integrated Biological Sciences Graduate Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA. · Clin Cancer Res. · Pubmed #18794103 No free full text.

Abstract: PURPOSE: The precise molecular targets of IFN-alpha therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-alpha would be similar to the in vivo response to treatment with high-dose IFN-alpha. EXPERIMENTAL DESIGN: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-alpha were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-alpha. RESULTS: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-alpha in vitro for 18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-alpha-treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-alpha-2b (20 MU/m(2) i.v.) revealed significant up-regulation (>2-fold) of 21 genes (P < 0.001). Also, the gene expression profile of in vitro IFN-alpha-stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-alpha therapy. CONCLUSIONS: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-alpha and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-alpha immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-alpha may be a useful predictor of the in vivo response of immune cells to IFN-alpha immunotherapy.

Zimmerer JM, Lehman AM, Ruppert AS, Noble CW, Olencki T, Walker MJ, Kendra K, Carson WE. · Integrated Biological Sciences Graduate Program, The Ohio State University, Columbus, Ohio 43210, USA. · Clin Cancer Res. · Pubmed #18316567 links to  free full text

Abstract: PURPOSE: The precise molecular targets of IFN-alpha therapy of melanoma are unknown but likely involve signal transducer and activator of transcription (STAT) 1 signal transduction within host immune effector cells. We hypothesized that intermediate and high doses of IFN-alpha would be equally effective in activating patient immune cells. EXPERIMENTAL DESIGN: Eleven metastatic melanoma patients who were enrolled in a clinical trial of bevacizumab in combination with escalating doses of IFN-alpha-2b (5 megaunits/m(2) and then 10 megaunits/m(2)) were included in the study. Peripheral blood mononuclear cells (PBMC) were procured from patient blood just before therapy and again 1 h after each dose of IFN-alpha-2b and analyzed for the presence of phosphorylated STAT1, phosphorylated STAT2, and the induction of IFN-stimulated gene (ISG) transcripts. RESULTS: Phosphorylated STAT1 was significantly greater at the 5 megaunits/m(2) dose compared with the 10 megaunits/m(2) dose of IFN-alpha-2b (P = 0.02). In contrast, no significant difference in phosphorylated STAT2 was observed at a dose of 5 megaunits/m(2) compared with 10 megaunits/m(2) (P = 0.20). There were also no significant differences in the induction of ISGs within PBMCs between the two doses (P > 0.4 for all ISGs). Suppressor of cytokine signaling 1 and 3 (two inhibitors of IFN-alpha signaling) transcripts were significantly higher among patient PBMCs following the 10 megaunits/m(2) dose of IFN-alpha (P < 0.001). CONCLUSION: These results suggest that lower doses of IFN-alpha-2b are as effective as higher doses with respect to the induction of Janus-activated kinase-STAT signal transduction and the transcription of ISGs within immune effector cells.

Povoski SP, Hall NC, Martin EW, Walker MJ. · Division of Surgical Oncology, Department of Surgery, Arthur G, James Cancer Hospital and Richard J, Solove Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. · World J Surg Oncol. · Pubmed #18186915 links to  free full text

Abstract: BACKGROUND: The use of diagnostic 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging for the staging, restaging, and treatment monitoring of melanoma patients has become a well-recognized standard of care. It plays a key role in detecting sites of occult disease and is widely utilized in the medical and surgical planning of such patients. In the current report, we describe an innovative multimodality approach of perioperative 18F-FDG PET/CT imaging, intraoperative 18F-FDG handheld gamma probe detection, and intraoperative ultrasound for tumor localization and verification of resection of all sites of hypermetabolic tumor foci in a case of occult recurrent metastatic melanoma. CASE PRESENTATION: This report discusses a case of occult recurrent metastatic melanoma, isolated to three separate sites within the subcutaneous tissues of the left thigh region, which was not clinically apparent but was found on diagnostic restaging whole body 18F-FDG PET/CT scan utilizing an intravenous injection of 14.8 mCi 18F-FDG. Then, on the day of surgery, the patient received an intravenous injection of 12.8 mCi 18F-FDG. A multimodality approach of intraoperative handheld gamma probe detection, intraoperative ultrasound tumor localization, specimen PET/CT imaging, and postoperative PET/CT imaging was utilized for accomplishing and verifying the excision of all three sites of occult recurrent metastatic melanoma within the left thigh region. CONCLUSION: This innovative multimodality approach of perioperative 18F-FDG PET/CT imaging, intraoperative 18F-FDG handheld gamma probe detection, and intraoperative ultrasound is promising combined technology for aiding in tumor localization and verification of excision and may ultimately impact positively upon long-term outcome of selected patients.

Agnese DM, Maupin R, Tillman B, Pozderac RD, Magro C, Walker MJ. · Department of Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, 410 W 10th Avenue, Columbus, OH 43210, USA. · Arch Otolaryngol Head Neck Surg. · Pubmed #18025316 links to  free full text

Abstract: OBJECTIVE: To determine whether, in the era of sentinel lymph node (SLN) biopsy, head and neck melanoma (HNM) has a poorer outcome than melanomas at other sites (OMS). DESIGN: Prospective database, 1994 to 2004. Characteristics and outcomes of patients with HNM vs those with OMS were analyzed by Fisher test, paired t test, and chi(2) test. SETTING: Tertiary referral center. PATIENTS: A total of 755 patients with melanoma who had undergone SLN biopsy. MAIN OUTCOME MEASURES: Differences between patients with HNM and those with OMS. RESULTS: A total of 17.4% of patients had HNM vs 82.6% with OMS. There was a male HNM preponderance: 68.7% vs 50.3% for females (P < .01). Patients with HNM were older (mean [SD] age, 57.1 [16.6] years vs 53.3 [16.2] years; P < .01). There were fewer cases of superficial spreading melanoma in patients with HNM (29.0% vs 53.7%; P < .01). There were more diagnoses of lentigo maligna in patients with HNM (26.0% vs 1.9%; P < .01). The mean thickness of the primary lesion was 2.32 (1.9) mm vs 2.31 (2.9) mm; P = .49. Fewer patients with HNM had Clark level involvement lower than level IV (13.3% vs 24.0%; P < .01). More SLNs were harvested from patients with HNM (3.72 [3.2] vs 2.89 [2.6]; P < .01), but a lower percentage of positive SLNs was found (9.2% vs 16.0%; P < .05). There was no difference in local, regional, or distant recurrence (5.3%, 6.9%, and 5.3%, respectively, in patients with HNM and 3.4%, 5.5%, and 6.7%, respectively, in patients with OMS). The 2- and 5-year survival rates for patients with HNM were 96.2% and 72.6%, respectively, vs 93.6% and 79.0%, respectively, in patients with OMS (P = .40). CONCLUSIONS: Most patients with HNM are older males with more SLNs harvested. They do not seem to have poorer outcome than patients with OMS.

Lesinski GB, Trefry J, Brasdovich M, Kondadasula SV, Sackey K, Zimmerer JM, Chaudhury AR, Yu L, Zhang X, Crespin TR, Walker MJ, Carson WE. · Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA. · Clin Cancer Res. · Pubmed #17785551 links to  free full text

Abstract: PURPOSE: IFN-alpha is administered to melanoma patients and its endogenous production is essential for immune-mediated tumor recognition. We hypothesized that a reduced capacity for signal transducer and activator of transcription (STAT) 1 activation allows melanoma cells to evade the direct actions of IFN-alpha. EXPERIMENTAL DESIGN: Tyr(701)-phosphorylated STAT1 (P-STAT1) was measured by flow cytometry in IFN-alpha-stimulated human melanoma cell lines, melanoma cells derived from patient tumors, and peripheral blood mononuclear cells (PBMC). Expression of other Janus-activated kinase (Jak)-STAT intermediates (STAT1, STAT2, Jak1, tyrosine kinase 2, IFN-alpha receptor, STAT3, and STAT5) was evaluated by flow cytometry, immunoblot, or immunohistochemistry. RESULTS: Significant variability in P-STAT1 was observed in human melanoma cell lines following IFN-alpha treatment (P < 0.05) and IFN-alpha-induced P-STAT1 correlated with the antiproliferative effects of IFN-alpha (P = 0.042). Reduced formation of P-STAT1 was not explained by loss of Jak-STAT proteins or enhanced STAT5 signaling as reported previously. Basal levels of P-STAT3 were inversely correlated with IFN-alpha-induced P-STAT1 in cell lines (P = 0.013). IFN-alpha-induced formation of P-STAT1 was also variable in melanoma cells derived from patient tumors; however, no relationship between P-STAT3 and IFN-alpha-induced P-STAT1 was evident. Because IFN-alpha acts on both tumor and immune cells, we examined the ability of IFN-alpha to induce P-STAT1 in patient-derived melanoma cells and PBMCs. IFN-alpha induced significantly lower levels of P-STAT1 in melanoma cells compared with matched PBMCs (P = 0.046). Melanoma cells and human melanocytes required 10-fold higher IFN-alpha doses to exert P-STAT1 levels comparable with PBMCs. CONCLUSIONS: Melanoma cells are variable in their IFN-alpha responsiveness, and cells of the melanocytic lineage exhibit a lower capacity for IFN-alpha-induced Jak-STAT signaling compared with immune cells.

Lesinski GB, Valentino D, Hade EM, Jones S, Magro C, Chaudhury AR, Walker MJ, Carson WE. · Division of Human Cancer Genetics, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA. · Cancer Immunol Immunother. · Pubmed #15668815 No free full text.

Abstract: Interferon-alpha (IFN-alpha) is used as an adjuvant therapy in patients with malignant melanoma and who have undergone surgical resection of high-risk lesions. Defective expression or activation of STAT1 or STAT2 has been shown to correlate with IFN-alpha or resistance in vitro; however, recent data from our laboratory suggest that the anti-tumor effects of IFN-alpha are dependent on STAT1 signaling within host immune cells. We measured STAT1 and STAT2 expression in 28 melanoma biopsies (8 cutaneous lesions; 1 lung metastasis; 19 nodal metastases) obtained from patients prior to the initiation of adjuvant IFN-alpha therapy. Disease recurrence following IFN-alpha treatment did not correlate with the staining intensity of either STAT1 (P = 0.61) or STAT2 (P = 0.52). Tumors with minimal STAT1 or STAT2 expression (< 20% positive) were present in four patients with tumor-positive lymph nodes, who exhibited prolonged relapse-free survival (> 44 months) following adjuvant therapy. Conversely, high levels of STAT1 were present in a patient who recurred during the course of IFN-alpha therapy. A case study of one patient who experienced recurrent disease during IFN-alpha treatment revealed that STAT1 levels were greater in the recurrent tumor when compared to the original lesion. These studies provide direct evidence to suggest that levels of STAT1 and STAT2 within the tumor do not influence a patient's response to adjuvant IFN-alpha.

Agnese DM, Abdessalam SF, Burak WE, Magro CM, Pozderac RV, Walker MJ. · Ohio State University, 410 W. 10th Avenue, Columbus, OH 43210, USA. · Surgery. · Pubmed #14605613 No free full text.

Abstract: BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for thin melanomas with poor prognostic features; however, few metastases are identified. The purpose of this study was to assess the cost effectiveness of SLNB in this population. METHODS: The prospective melanoma database was reviewed to identify patients with melanomas <1.2 mm thick who had undergone SLNB. Physician and hospital charges were collected from the appropriate billing department. RESULTS: A total of 138 patients were identified over an 8-year period (1994-2002). Two patients with positive SLNs were identified (1.4%), one with a melanoma <1 mm thick. Patient charges for SLNB ranged from $10,096 to $15,223 US dollars, compared with $1000 to $1740 US dollars for wide excision as an outpatient. Using these charges, the cost to identify a single positive SLN would be between $696,600 and $1,051,100 US dollars. The cost for wide excision would be between $69,000 and $120,100 US dollars. Assuming that all patients with a positive SLN would die of melanoma, the cost per life saved would be $627,000 to $931,000 US dollars. CONCLUSIONS: The cost of performing SLNB in this population is great and only a small number will have disease identified that will alter treatment. These data call into question the appropriateness of SLNB for thin melanomas.

Zhou XP, Gimm O, Hampel H, Niemann T, Walker MJ, Eng C. · Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center and Division of Human Genetics, Department of Internal Medicine, Columbus, OH 43210, USA. · Am J Pathol. · Pubmed #11021816 links to  free full text

Abstract: A tumor suppressor gene at 10q 23.3, designated PTEN, encoding a dual specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced-stage sporadic melanomas; however, mutations or deletions in PTEN are detected mainly in melanoma cell lines. In this study, we examined PTEN expression in 34 unselected sporadic melanomas (4 primary melanomas, 30 metastases) using immunohistochemistry and correlated this with the results of structural studies of this gene. Immunostaining of 34 melanoma samples revealed no PTEN expression in 5 (15%) and low PTEN expression in 17 (50%), whereas the rest of the tumors (35%) had high levels of expression. Hemizygous deletion was found in 32% of the tumors but neither intragenic PTEN mutation nor biallelic deletion was found in any of the samples. Of the 5 melanomas showing no PTEN expression, 4 had no mutation or deletion of PTEN. Of the 13 tumors having weak PTEN immunoreactivity and informative loss of heterozygosity results, 6 had evidence of hemizygous allelic loss of PTEN while the remaining 7 had intact PTEN. These results strongly support PTEN as a major tumor suppressor on 10q involved in melanoma tumorigenesis and suggest an epigenetic mechanism of biallelic functional inactivation not previously observed in other cancers where PTEN might be involved.