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Neoadjuvant Treatment of Regional Stage IIIB Melanoma With High-Dose Interferon Alfa-2b Induces Objective Tumor Regression in Association With Modulation of Tumor Infiltrating Host Cellular Immune Responses

Stergios J. Moschos, Howard D. Edington, Stephanie R. Land, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood

From the Melanoma and Skin Cancer Program; Division of Medical Oncology, Department of Medicine; Department of Surgery, Division of Surgical Oncology; Department of Biostatistics, Graduate School of Public Health; Department of Pathology; and the Department of Dermatology, Division of Dermatopathology, University of Pittsburgh School of Medicine, Pittsburgh, PA

Address reprint requests to John M. Kirkwood, MD, Department of Medicine, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Avenue, Pittsburgh, PA 15213-2584; e-mail: kirkwoodjm{at}upmc.edu

	ABSTRACT

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PURPOSE: Adjuvant high-dose interferon-alfa-2b (HDI) improves disease-free and overall survival in patients with high-risk melanoma. However, its mechanism of action is largely unknown. Therefore, HDI was investigated in the neoadjuvant setting to assess clinical and pathologic responses after 4 weeks of HDI and to perform immunohistochemical evaluation of immune cell subsets and melanoma-associated antigens.

PATIENTS AND METHODS: Patients with palpable regional lymph node metastases from melanoma (American Joint Committee on Cancer stage IIIB-C) underwent surgical biopsy at study entry and then received standard intravenous HDI (20 million units/m², 5 days per week) for 4 weeks followed by complete lymphadenectomy and standard maintenance subcutaneous HDI (10 million units/m² 3 times per week) for 48 weeks. Biopsy samples were obtained before and after intravenous HDI and subjected to immunohistochemical analysis as well as routine pathologic study.

RESULTS: Twenty patients were enrolled, and biopsy samples were informative for 17. Eleven patients (55%) demonstrated objective clinical response, and 3 patients (15%) had complete pathologic response. At a median follow-up of 18.5 months (range, 7 months to 50 months) 10 patients had no evidence of recurrent disease. Clinical responders had significantly greater increases in endotumoral CD11c⁺ and CD3⁺ cells and significantly greater decreases in endotumoral CD83⁺ cells compared with nonresponders. No changes in the expression of melanoma-associated lineage antigens, tumor cell proliferation, angiogenesis, or apoptosis were evident.

CONCLUSION: Neoadjuvant HDI is highly effective for the treatment of palpable stage IIIB-C melanoma, and the findings of this study implicate an indirect immunomodulatory mechanism rather than a direct antitumor mechanism.

	INTRODUCTION

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The risk of relapse and death for patients with clinically palpable regional lymph node metastases (American Joint Committee on Cancer [AJCC] stage IIIB-C cutaneous melanoma) is high and approaches 70% at 5 years.^1-3 Surgery is the cornerstone of treatment at this stage of disease, and only high-dose interferon alfa-2b (HDI) has ever shown a consistent, significant, and durable relapse-free survival benefit when given as adjuvant therapy in multicenter randomized controlled trials of the US Cooperative Groups.^4-6 Two of these trials demonstrated that HDI significantly prolonged overall survival, the first of which led to US Food and Drug Administration approval of HDI in 1996. This clinical benefit of HDI has been reaffirmed in several regulatory reviews over the past 9 years, but its acceptance in the medical community has not been uniform. Despite 20 years of clinical research, the antitumor mechanism of action for interferon alfa-2b (IFN-2b) therapy in patients with melanoma has not been universal. A better understanding of the antitumor mechanism of action would enable more selective application of this therapy to those patients who are most likely to benefit and may improve the therapeutic index and cost effectiveness of HDI.

Murine models and clinical correlative studies of IFN-2b therapy have suggested that the indirect immunomodulatory activity of IFN-2b may be more important than direct cytotoxic, proapoptotic, or antiangiogenic effects.^7-10 Unfortunately, no strong link has been established between the clinical antitumor effects of HDI in patients with metastatic melanoma and any of the immunomodulatory, antiproliferative, or antiangiogenic effects that are otherwise well-documented for IFN-. This is in part attributable to the low frequency of antitumor response in patients with advanced unresectable metastatic disease.⁹ Unfortunately, the mechanism cannot be studied in tumor tissue for postoperative adjuvant settings where HDI therapy has been most extensively investigated.

Neoadjuvant therapy has potential advantages over standard adjuvant therapy in patients with locally advanced disease.¹¹ For example, in breast, bladder, and esophageal cancer, neoadjuvant chemotherapy improves survival outcomes compared with surgery alone^12-14 and may be as good or even better than the same therapy given postoperatively.

We, therefore, investigated the efficacy of neoadjuvant HDI in melanoma patients with palpable regional lymph node metastases either presenting with clinical AJCC stage IIIB-C (T_anyN_2,3) disease or with recurrent regional lymphadenopathy. Our goals were to evaluate the clinical and pathologic response to neoadjuvant HDI and to identify immunologic and histologic correlates of tumor response.

	PATIENTS AND METHODS

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Patients
Eligible patients had histopathologically confirmed, palpable, regional lymph node metastatic melanoma (AJCC stage IIIB-C; N_1b-3) either at initial presentation or at regional lymph node recurrence. Other eligibility criteria included normal findings from routine radiographic studies (computed tomography [CT] scans of the chest, abdomen and pelvis, and brain magnetic resonance imaging), unimpaired performance status (Eastern Cooperative Oncology Group 0 or 1), adequate hematologic, hepatic, and renal function. Patients were excluded if they had in-transit disease or matting of nodal tissue that might compromise complete lymphadenectomy, or had received prior radiotherapy, chemotherapy, or immunotherapy. Other exclusion criteria were active ischemic cardiac or cerebrovascular disease, infections requiring antibiotics, autoimmune disease or other disorders requiring immunosuppressive therapy, psychiatric illnesses requiring therapy, or lack of effective contraception for women of childbearing potential and sexually active males. All patients signed informed consent to obtain both pre- and post-treatment biopsies, and the study was approved by the University of Pittsburgh (Pittsburgh, PA) institutional review board.

Treatment Plan
The treatment plan is illustrated in Figure 1. A surgical lymph node biopsy (sample 1) was performed within 14 days of study entry to confirm the presence of melanoma. Subsequently, patients received standard outpatient induction HDI (IFN-2b 20 million units/m² per day intravenously [IV], 5 days per week, Monday to Friday) for 4 weeks. During the induction period, patients underwent physical examination every week for 4 weeks to assess toxicity and clinical response of palpable tumor. After completion of the 4-week induction phase, patients underwent radical lymph node dissection (sample 2). Surgical procedures were performed by the same surgeon (H.D.E.). Therefore, differences in surgical management and technique are unlikely to account for differences in patient outcome. Pathology material was assessed for evidence of residual disease and apportioned by the reference surgical pathologist (U.N.R.) for additional immunohistochemical (IHC) studies. After recovery from surgery and wound healing, standard outpatient maintenance IFN-2b therapy (10 million units/m², subcutaneously [SC], 3 times per week) was administered for 48 weeks. Patients were observed over time (monthly for the first 3 months and then every 3 months) for treatment-related toxicity and melanoma recurrence.

View larger version (10K): [in this window] [in a new window]   Fig 1. Treatment schema. Tumor biopsies are obtained before and immediately after the induction phase of high-dose interferon alfa-2b (HDI). IV, intravenous; IFN, interferon alfa; TIW, three times per week.

Histologic Evaluation
All tissue sections were scored at x20 magnification by independent observers, including a surgical pathologist (U.N.R.), a dermatopathologist (D.J.), a medical oncologist specialized in melanoma (J.M.K.), and a fellow in medical oncology (S.J.M.). All four observers were blinded to the patient and treatment status (both pre- and post-treatment) when they examined tissue samples. Given the variation in the amount of tissue available for IHC stains, as well as the amount of viable tumor present in a given section, a single field with the maximum viable tumor density was selected by the surgical pathologist for scoring. The total numbers of endotumoral, peritumoral, and perivascular mononuclear cell infiltrates (CD3⁺, CD4⁺, CD8⁺, CD11c⁺, CD56⁺, CD83⁺, CD86⁺, and CD123⁺) were scored.

Clinical Response
Response was assessed both clinically and histologically after completion of the 4-week induction phase of HDI. After 14 patients were enrolled, radiological assessment was also performed by coregistered positron emission tomography (PET)/CT scans, but the predetermined primary end point was the clinicopathologic response, not the radiographic response. Clinical complete response (CR) was defined as the disappearance of all clinical evidence of tumor, whereas clinical partial response (PR) was defined as 50% or more decrease in the product of the greatest perpendicular diameters of nodal disease (WHO).¹⁵ No clinical response was defined as no change, reduction of less than 50% in the product of the greatest perpendicular diameter of nodal disease, or unequivocal increase in size of measurable lesions.¹⁵

Statistical Methods
The median follow-up was estimated with reverse censoring using the Kaplan-Meier method. Associations of clinical response (responders v nonresponders) with changes in IHC measurements of cell surface antigens present in pretreatment and post-treatment tissue samples were assessed using the Wilcoxon rank sum test. The effect of treatment was assessed for the whole group using the Wilcoxon signed-rank test. The log-rank test was used to compare the survival outcome by clinical response in an intention-to-treat analysis. For grading of adverse effects, the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 was used. Given the exploratory nature of the study, corrections for multiple testing were not performed, and statistical tests were considered significant at P = .05 and suggestive at P = .10. Analyses of IHC data were performed for patients with assessable IHC data. Survival and clinical response analyses were performed for all patients with confirmed melanoma pretreatment. Safety analyses were performed for all enrolled patients.

	RESULTS

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Patients
Twenty patients were enrolled between January 2001 and February 2005, and their baseline characteristics are shown in Table 1. The median age of the cohort entering the study was 59 years (range, 40 years to 78 years), and 13 patients were male. Clinically palpable regional lymphadenopathy was recurrent in 11 patients (55%), and these patients had experienced recurrence at a median of 27 months (range, 7 months to 150 months) after the original diagnosis of melanoma. One patient was deemed ineligible because the pretreatment biopsy did not show evidence of melanoma (patient 2; Table 1). Fifteen patients completed 4 weeks of induction HDI therapy.

At a median follow-up of 18.5 months (range, 7 months to 50 months), 10 patients had no evidence of disease, seven patients died from metastatic disease, and three patients were alive with metastatic disease. Figure 2 shows the Kaplan-Meier estimates of disease-free and overall survival for clinical responders versus nonresponders for the 19 eligible patients. This analysis excludes patient 2, whose pretreatment biopsy did not show evidence of melanoma; therefore, clinical response could not be defined. Disease-free and overall survival are longer among patients with clinical response compared with nonresponders, although the results did not reach statistical significance (log-rank P = .15; P = .17, respectively). For disease-free survival, the median survival times were 32 months for responders versus 10 months for nonresponders.

View larger version (5K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimates of (A) disease-free survival and (B) overall survival for clinical responders (dashed lines) versus nonresponders (solid lines) in all eligible patients (N = 19).

IHC Analysis
IHC analysis of pre- and post-treatment tissue biopsies was informative in 17 patients (nine responders and eight nonresponders) and demonstrated a number of changes in the mononuclear cell populations infiltrating the tumor (Figs 3 and 4). At 4 weeks of IV HDI treatment, a significant increase in the number of CD11c⁺ and CD86⁺ cells infiltrating the tumor (P = .047; P = .074, respectively) was observed, whereas the number of CD83⁺ cells decreased slightly, but the result did not reach statistical significance (P = .107). An increase of the peritumoral CD4⁺ cell infiltrate (P = .143) was also noted. Clinical responders compared with nonresponders exhibited a trend toward greater increase in the number of endotumoral CD11c⁺ and CD3⁺ cells (P = .094 and P = .094, respectively; Figs 3 and 4) and a trend toward greater reduction in endotumoral CD83⁺ cells (P = .060). Clinical responders compared with nonresponders also had an increase in endotumoral CD56⁺ cells that did not achieve significance, but it is of interest in view of the other changes observed (P = .138). HDI did not differentially alter the immune cell infiltrates in the peritumoral and perivascular cell compartments of clinical responders versus nonresponders, and there were no similar trends toward differences between clinical responders and nonresponders in the phenotype of melanoma cells, as assessed by several lineage markers (data not shown). Finally, HDI did not appear to alter angiogenesis, HLA expression (either among melanoma or mononuclear cells), or proliferation and/or apoptosis (of melanoma cells) based on IHC studies with antibodies against von Willebrand factor, HLA-ABC, HLA-DR, Ki67, and Apoptag (data not shown).

View larger version (11K): [in this window] [in a new window]   Fig 3. Numbers of (A) CD3+, (B) CD4+, (C) CD11c+, (D) CD56+, (E) CD83+, and (F) CD86+ cells present in lymph node tumor tissue per high power field pre- (x-axis) and post-treatment with high-dose interferon alfa-2b (HDI) for 4 weeks (y-axis) for responders (black diamonds) versus nonresponders (gray circles).

View larger version (128K): [in this window] [in a new window]   Fig 4. Immunohistochemical staining for CD3 (A, B) and CD11c (C, D) in melanoma-infiltrated lymph nodes from a clinical responder before (A, C) and after (B, D) treatment with high-dose interferon alfa-2b for 4 weeks. Peritumoral (pt) and endotumoral (et) compartments are shown.

	DISCUSSION

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Despite the small size of this study, the 55% clinical and 15% pathologic response rates observed are notable for several reasons. First, patients with stage IIIB-C melanoma have the highest risk for relapse and mortality of all the risk groups included in prior adjuvant trials conducted by the cooperative groups.¹ Second, most patients enrolled in this study had regional lymph node recurrence after initial therapy for melanoma rather than synchronous nodal disease at initial diagnosis. Recurrent disease has a worse prognosis than disease initially presenting in stage III, as documented in multiple trials of the US Cooperative Groups (E1684 and E1690).^4,5 Third, the high clinical response rate with neoadjuvant HDI therapy observed in this study is to be contrasted to the response rates observed in clinical assessment during earlier phase I/II studies of HDI for stage IV melanoma. In the setting of advanced stage IV disease, response rates of less than 20% were achieved, although a number of patients had durable responses ranging from 26 to more than 30 months.²³ Finally, although this study was not designed to study the effect of neoadjuvant IFN on surgical outcome, it did not appear to compromise surgical management and the reduction of tumor burden may favorably influence the management of patients with clinical response to HDI.²⁴

Pathologic and clinical response were not perfectly correlated, and pathologic response was also imperfectly correlated with radiographic assessment of response for PET-CT, where two of five patients evaluated by coregistered PET/CT scan had no evidence of radiographic response while pathology demonstrated response (data not shown). These discrepancies may be attributed to at least two confounding factors. First, patients vary in terms of extent of disease and the likely kinetics of tumor and host response; the single point of clinical, radiological, and pathologic evaluation at day 29 in this study may not have accurately represented the dynamic process of tumor regression, which may take longer intervals in patients with high initial tumor volume or slower tumor response kinetics. Second, the influx of immune cells infiltrating the tumor may lead to inflammatory swelling, confounding the assessment of clinical response at day 29, as in patient 6 of our study. In support of this interpretation we observed several different phases of the immune response process in evaluating the post-treatment samples: these ranged from perivascular immune cell infiltrates to the appearance of melanophages, and the appearance of later phases of fibrosis/necrosis (data not shown).

This trial was not powered to detect increases in disease-free and overall survival among clinical responders compared with nonresponders. The prolongation of disease-free survival, while not statistically significant for patients responding to IFN at 4 weeks assessment in this trial, is supported by several large phase III trial experiences in the United States. The consistent and highly significant disease-free survival benefit observed in three previous Eastern Cooperative Oncology Group/Intergroup adjuvant trials of HDI for melanoma was in fact part of the rationale for our pursuit of this investigation. The results of this study suggest two hypotheses. First, assessment of response to HDI at 4 weeks may predict the ultimate impact of HDI on disease. If so, this decision, made early in treatment might allow us to avoid the toxicity of therapy in patients who are not destined to derive benefit from additional treatment with the remaining 11 months of therapy. Second, the study suggests that the benefit of IFN may derive from the 4 weeks of IV induction HDI, without requirement of maintenance therapy for an additional 11 months. This has important implications for the intergroup E1697 international trial of 4 weeks of induction IV HDI currently under way. While this trial of neoadjuvant therapy was underpowered to define the role of response at 4 weeks in terms of overall survival benefit, the E1697 trial targeting 1,490 patients will have ample power to detect relapse-free benefits of as little as 7.5%. While clinical and radiological response of disease at 4 weeks may not correspond perfectly with histopathologic responses in the setting of bulky regional lymph node metastasis (stage IIIB), the clinical, radiological, and pathologic findings we have reported here will be relevant to the Intergroup study E1697, where 4 weeks of induction IV HDI is being tested in comparison to observation for patients with earlier stages of deeper primary (stage IIA-B) and microscopic nodal disease (stage IIIA).

The neoadjuvant study design adopted for this trial allowed us to study the effects of HDI on tumor tissue and to examine immunologic and molecular biomarkers in tumor tissue as potential correlates of tumor response. IHC analysis of tumor tissue revealed that HDI did not appear to influence the tumor cell phenotype, proliferation rate, or apoptotic fraction of cells in tumor biopsies, and did not significantly affect tumor vasculature, irrespective of clinical response. In contrast, IHC analysis of immunologic markers including T lymphocytes (CD3, CD4, and CD8), natural killer cells (CD56), and dendritic cells (CD11c, CD83, and CD86) showed that clinical response to HDI was consistently associated with augmented numbers of mononuclear immune cells infiltrating the tumor, but not those in the peritumoral or perivascular cellular compartments. These changes exhibited strong trends approaching nominal significance in regard to CD3, and CD11c, as well as CD83/86 positive populations.

IHC analysis did not demonstrate significant alterations of the numbers of mononuclear cells infiltrating the tumor in general, but rather showed changes in the endotumoral compartment that we and others have previously shown to be most closely correlated to the impact of earlier immunotherapeutic agents^25-27; the findings of this study do not suggest any change in the expression of lineage or other antigens of melanoma with IFN. This suggests that the primary antitumor mechanism of HDI is an indirect immunomodulatory mechanism rather than a direct and/or cytotoxic mechanism. Specifically, clinical response to HDI was associated with a consistent trend toward significantly greater numbers of CD3⁺ and CD11c⁺ cells infiltrating the tumor. The changes observed in tumor-infiltrating CD11c⁺ and CD83⁺ cells likely represent monocyte-derived dendritic cell subpopulations and are in agreement with the differential expression of CD83 and CD86 in monocyte-derived dendritic cells from healthy donors in vitro.²⁸

In summary, neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy results in high clinical and pathologic response rates without increased morbidity. In fact, neoadjuvant treatment of patients studied in this series may have improved the surgical outcomes and facilitated rather than impeded surgery. The present results suggest that neoadjuvant HDI therapy exerts its effects through immunomodulatory rather than direct cytotoxic mechanisms in patients with stage IIIB-C melanoma, and has antitumor effects in a greater proportion of patients with regionally advanced disease than previously noted in studies of distant metastatic disease we and others have conducted over the past 20 years. These results suggest that the beneficial effects of HDI in the adjuvant setting for high-risk resected melanoma are also likely to derive from immunomodulatory effects, which now deserve a more careful prospective evaluation in the context of additional studies of stage IIIB or resectable stage IV (eg, M1a or M1b) disease. They have implications for the current intergroup trial E1697, targeting earlier stages of disease in which the microscopic tumor burden will not permit similar biopsy studies of mechanism, but the relevance of changes induced by 4 weeks of IV HDI will be definitively tested in terms of impact on disease-free survival.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Howard D. Edington Schering Plough (A) Janice Shipe-Spotloe Schering Plough (A) John M. Kirkwood Schering Plough (A) Schering Plough (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Administrative support: Stergios J. Moschos, Howard D. Edington, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood Provision of study materials or patients: Stergios J. Moschos, Howard D. Edington, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood Collection and assembly of data: Stergios J. Moschos, Howard D. Edington, Stephanie R. Land, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood Data analysis and interpretation: Stergios J. Moschos, Stephanie R. Land, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood Manuscript writing: Stergios J. Moschos, Stephanie R. Land, John M. Kirkwood Final approval of manuscript: Stergios J. Moschos, Howard D. Edington, Stephanie R. Land, Uma N. Rao, Drazen Jukic, Janice Shipe-Spotloe, John M. Kirkwood

 

	ACKNOWLEDGMENTS

 
We thank Ruth Mascari, Cindy Sander, and Megan Renstrom for their excellent technical assistance.

	NOTES

 
Supported by a research scholarship from the Robert Johnson Foundation for Melanoma Research and the Grant Channel Memorial Melanoma Research Fund (S.J.M.), and by National Institutes of Health National Cancer Institute Grant No. P30 CA4790413 (J.M.K. and S.R.L.). Costs for radiographic and laboratory analyses were funded in part by a research grant from Schering-Plough Research Institute to the University of Pittsburgh.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted January 6, 2006; accepted April 24, 2006.

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				W. Wang, H. D. Edington, U. N.M. Rao, D. M. Jukic, A. Radfar, H. Wang, and J. M. Kirkwood Effects of High-Dose IFN{alpha}2b on Regional Lymph Node Metastases of Human Melanoma: Modulation of STAT5, FOXP3, and IL-17 Clin. Cancer Res., December 15, 2008; 14(24): 8314 - 8320. [Abstract] [Full Text] [PDF]

				J. M. Zimmerer, G. B. Lesinski, A. S. Ruppert, M. D. Radmacher, C. Noble, K. Kendra, M. J. Walker, and W. E. Carson III Gene Expression Profiling Reveals Similarities between the In vitro and In vivo Responses of Immune Effector Cells to IFN-{alpha} Clin. Cancer Res., September 15, 2008; 14(18): 5900 - 5906. [Abstract] [Full Text] [PDF]

				J. M. Kirkwood, A. A. Tarhini, M. C. Panelli, S. J. Moschos, H. M. Zarour, L. H. Butterfield, and H. J. Gogas Next Generation of Immunotherapy for Melanoma J. Clin. Oncol., July 10, 2008; 26(20): 3445 - 3455. [Abstract] [Full Text] [PDF]

				J. M. Zimmerer, A. M. Lehman, A. S. Ruppert, C. W. Noble, T. Olencki, M. J. Walker, K. Kendra, and W. E. Carson III IFN-{alpha}-2b-Induced Signal Transduction and Gene Regulation in Patient Peripheral Blood Mononuclear Cells Is Not Enhanced by a Dose Increase from 5 to 10 Megaunits/m2 Clin. Cancer Res., March 1, 2008; 14(5): 1438 - 1445. [Abstract] [Full Text] [PDF]

				N. J. Ives, R. L. Stowe, P. Lorigan, and K. Wheatley Chemotherapy Compared With Biochemotherapy for the Treatment of Metastatic Melanoma: A Meta-Analysis of 18 Trials Involving 2,621 Patients J. Clin. Oncol., December 1, 2007; 25(34): 5426 - 5434. [Abstract] [Full Text] [PDF]

				G. B. Lesinski, J. Trefry, M. Brasdovich, S. V. Kondadasula, K. Sackey, J. M. Zimmerer, A. R. Chaudhury, L. Yu, X. Zhang, T. R. Crespin, et al. Melanoma Cells Exhibit Variable Signal Transducer and Activator of Transcription 1 Phosphorylation and a Reduced Response to IFN-{alpha} Compared with Immune Effector Cells Clin. Cancer Res., September 1, 2007; 13(17): 5010 - 5019. [Abstract] [Full Text] [PDF]

				Z. R. Yurkovetsky, J. M. Kirkwood, H. D. Edington, A. M. Marrangoni, L. Velikokhatnaya, M. T. Winans, E. Gorelik, and A. E. Lokshin Multiplex Analysis of Serum Cytokines in Melanoma Patients Treated with Interferon-{alpha}2b Clin. Cancer Res., April 15, 2007; 13(8): 2422 - 2428. [Abstract] [Full Text] [PDF]

				W. Wang, H. D. Edington, U. N.M. Rao, D. M. Jukic, S. R. Land, S. Ferrone, and J. M. Kirkwood Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFN{alpha}2b Clin. Cancer Res., March 1, 2007; 13(5): 1523 - 1531. [Abstract] [Full Text] [PDF]

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