Melanoma: Thompson JA

Coit DG, Andtbacka R, Bichakjian CK, Dilawari RA, Dimaio D, Guild V, Halpern AC, Hodi FS, Kashani-Sabet M, Lange JR, Lind A, Martin L, Martini MC, Pruitt SK, Ross MI, Sener SF, Swetter SM, Tanabe KK, Thompson JA, Trisal V, Urist MM, Weber J, Wong MK, Anonymous00048. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #19401060 No free full text.

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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.

Balch CM, Soong SJ, Atkins MB, Buzaid AC, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. · American Society of Clinical Oncology, Alexandria, VA, USA. · CA Cancer J Clin. · Pubmed #15195788 links to  free full text

Abstract: A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. · Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Semin Surg Oncol. · Pubmed #12923915 No free full text.

Abstract: The American Joint Committee on Cancer (AJCC) implemented major revisions of the melanoma TNM and stage grouping criteria in the recently published 6th edition of the Staging Manual. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include: 1) melanoma thickness and ulceration but not level of invasion to be used in the T classification, 2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of microscopic vs. macroscopic nodal metastases to be used in the N classification, 3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase (LDH) to be used in the M classification, 4) an upstaging of all patients with Stage I, II, and III disease when a primary melanoma is ulcerated, 5) a merging of satellite metastases around a primary melanoma and in transit metastases into a single staging entity that is grouped into Stage III disease, and 6) a new convention for defining clinical and pathological staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. · Johns Hopkins Medical Institutions, Baltimore, MD, USA. · J Clin Oncol. · Pubmed #11504745 No free full text.

Abstract: PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

Wallen H, Thompson JA, Reilly JZ, Rodmyre RM, Cao J, Yee C. · Department of Clinical Research, Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America. · PLoS One. · Pubmed #19270751 links to  free full text

Abstract: BACKGROUND: Adoptive T cell therapy involving the use of ex vivo generated antigen-specific cytotoxic T lymphocytes provides a promising approach to immunotherapy. It has become increasingly apparent that anti-tumor efficacy using adoptively transferred T cells is linked to their duration of in vivo persistence and can only be achieved when combined with some form of pre-infusion patient conditioning regimen. An optimal conditioning regimen that provides a positive benefit without serious toxicities has yet to be defined. We have established a unique clinical model that allows for evaluation of a given conditioning regimen on adoptively transferred T cells in humans. In this first-in-human study (FHCRC #1796), we evaluate the use of fludarabine, an FDA-approved reagent with predictable lymphodepleting kinetics and duration of action, as a conditioning regimen that promotes homeostatic upregulation of cytokines and growth signals contributing to in vivo T cell persistence. METHODS/FINDINGS: We conducted a phase I study in patients with refractory metastatic melanoma. Patients received two infusions of a single tumor-reactive antigen-specific CTL clone expanded to 10(10)/m(2); the first infusion was given without fludarabine conditioning, and the second CTL infusion was given after a course of fludarabine (25 mg/m(2)/dayx5 days). This design permits intra-patient comparison of in vivo T cell persistence pre- and post-fludarabine. Nineteen CTL infusions were administered to ten patients. No serious toxicities were observed. Three of nine evaluable patients experienced minor response or stable disease for periods of 5.8-11.0 months with two additional patients demonstrating delayed disease stabilization. The median overall survival in this heavily pre-treated population was 9.7 months. Fludarabine led to a 2.9 fold improvement in the in vivo persistence of transferred CTL clones from a median of 4.5 days (range 0-38+) to 13.0 days (range 2-63+) (p<0.05). Fludarabine lymphodepletion increased plasma levels of the homeostatic cytokines IL-7 and IL-15. Surprisingly, fludarabine also increased the relative percentage of CD4+ T cells expressing the regulatory protein Foxp3. CONCLUSIONS/SIGNIFICANCE: Lymphodepletion with fludarabine enhances transferred T cell persistence but suggest that additional improvements to optimize T cell survival and address regulatory T cells are critical in providing anti-tumor efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00317759.

Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, Sievers EL, Hughes SD, DeVries TA, Hausman DF. · Seattle Cancer Care Alliance, 825 Eastlake Ave East, Mailstop G4-830, Seattle, WA 98109-1023, USA. · J Clin Oncol. · Pubmed #18347008 No free full text.

Abstract: PURPOSE: A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human interleukin-21 (rIL-21). PATIENTS AND METHODS: Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 microg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles. RESULTS: Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 microg/kg. The most common adverse events included flu-like symptoms, pruritus, and rash. Twelve patients received up to five additional two-cycle courses of treatment without cumulative toxicity, except for one patient with reversible grade 4 hepatotoxicity. Serum concentrations of rIL-21 increased in a dose-proportional manner. Dose-dependent increases in soluble CD25 reflected lymphocyte activation. Antitumor activity was observed in both MM (one complete response and 11 SD) and RCC (four partial responses, 13 SD). CONCLUSION: Outpatient therapy with rIL-21 at 30 microg/kg was well tolerated, had dose-dependent pharmacokinetics and pharmacodynamics, and was associated with antitumor activity in patients with MM and RCC.

Hutchins LF, Moon J, Clark JI, Thompson JA, Lange MK, Flaherty LE, Sondak VK. · Division of Hematology/Oncology, Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. · Cancer. · Pubmed #17932881 links to  free full text

Abstract: BACKGROUND: Southwest Oncology Group protocol 0026 evaluated interferon alpha-2b plus thalidomide in patients with disseminated melanoma. Endpoints were 6-month progression-free survival rate, response rate, and toxicity. METHODS: Twenty-six patients with Stage IV melanoma, measurable or nonmeasurable disease, performance status of 0-2, and adequate renal and hepatic functions were registered. One prior systemic therapy for Stage IV disease was required. Interferon was administered subcutaneously (1 million U) twice daily; thalidomide was orally administered (200-400 mg) each evening in a dose-escalating manner. Response evaluations using Response Evaluation Criteria in Solid Tumors were performed every 8 weeks. RESULTS: After 2 sudden deaths and 1 grade 4 treatment-related pulmonary embolism, this study was temporarily closed. One patient with deep-vein thrombosis and 2 with grade 3 cardiac arrhythmias were reported. The relationship of these events to the treatment was worrisome but not definitive. Grade 3 treatment-related adverse events occurred in 14 of 26 patients. Because of concern for patient safety the study was permanently closed. No treatment responses were seen in the 22 evaluable patients. Estimated 6-month progression-free survival rate was 15% (95% confidence interval [CI], 2%-29%), estimated 6-month overall survival was 58% (95% CI, 39%-77%), and estimated response probability was 0 of 22 (95% CI, 0%-15%). CONCLUSIONS: This regimen demonstrated a lack of response and was associated with multiple severe toxicities. Further investigation of interferon alpha-2b and thalidomide in this dose and schedule is not warranted.

Dummer R, Garbe C, Thompson JA, Eggermont AM, Yoo K, Maier T, Bergstrom B. · Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland. · J Clin Oncol. · Pubmed #16505439 No free full text.

Abstract: PURPOSE: A pegylated interferon, peginterferon alfa-2a (PEG-IFNalpha-2a; 40 kd), has the potential for improved tumor response and survival with lower toxicity than IFNalpha. This open-label, randomized study evaluated the safety, tolerability, and efficacy of subcutaneous PEG-IFNalpha-2a in patients with metastatic malignant melanoma (stage IV American Joint Committee on Cancer staging system). PATIENTS AND METHODS: PEG-IFNalpha-2a was administered subcutaneously at 180 (n = 48), 360 (n = 53), or 450 mug (n = 49) once weekly for 24 weeks, with maintenance therapy for responders. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: The major response rate (CR or PR) was 6% in the 180-mug group (CR, 2%; PR, 4%), 8% in the 360-mug group (CR, 2%; PR, 6%), and 12% in the 450-mug group (CR, 6%; PR, 6%). The times to achieve a major response, duration of major response, rate of disease progression, and 12-month survival were similar between groups, although overall median survival was significantly different among the three groups (P = .0136). More patients required dose adjustment for safety reasons in the higher dose groups, but PEG-IFNalpha-2a was generally well tolerated, with few withdrawals because of adverse events (6%, 19%, and 16% in the 180-, 360-, and 450-mug groups, respectively). The most common adverse events were fatigue, pyrexia, and nausea. CONCLUSION: PEG-IFNalpha-2a at doses up to 450 mug once weekly has shown good tolerability and similar efficacy to conventional IFNalpha and monochemotherapy in stage IV metastatic melanoma.

Lewis KD, Thompson JA, Weber JS, Robinson WA, O'Day S, Lutzky J, Legha SS, Floret S, Ruvuna F, Gonzalez R. · University of Colorado, Cancer Center, 1665 North Ursula St, Mail Stop F-703, Aurora, CO 80045, USA. · Invest New Drugs. · Pubmed #16379038 No free full text.

Abstract: Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective of the current study was to evaluate the efficacy and safety of continuously administered Apomine (SR-45023A), a novel bisphosphonate, in patients with previously treated metastatic malignant melanoma. Adult patients with previously treated metastatic melanoma received Apomine 100 mg orally, twice daily (total dose 200 mg per day) continuously for 28 days (defined as a cycle). Treatment was continued until disease progression or unacceptable toxicity. A total of 42 patients received at least one dose of Apomine. Stable disease was achieved in 2 patients (5%). No complete or partial responses were observed. Progression free survival of at least 16 weeks was observed in 6 patients (14%). The median overall survival was 6.1 months (95% CI, 4.9-9.4 months). Time to treatment failure was 1.7 months (95% CI, 1.6-1.8 months) with Apomine therapy. By cycle 2, Apomine concentrations reached steady-state. Apomine was well tolerated with only 37% of patients experiencing any drug-related event. Abdominal pain was the most frequent adverse event occurring in 26% of patients. In conclusion, Apomine, at the current dose studied, failed to produce a 30% progression free survival rate at 16 weeks considered to be a meaningful benefit for further development.

Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD. · Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D3-100, Seattle, WA 98109, USA. · Proc Natl Acad Sci U S A. · Pubmed #12427970 links to  free full text

Abstract: Adoptive T cell therapy, involving the ex vivo selection and expansion of antigen-specific T cell clones, provides a means of augmenting antigen-specific immunity without the in vivo constraints that can accompany vaccine-based strategies. A phase I study was performed to evaluate the safety, in vivo persistence, and efficacy of adoptively transferred CD8+ T cell clones targeting the tumor-associated antigens, MART1MelanA and gp100 for the treatment of patients with metastatic melanoma. Four infusions of autologous T cell clones were administered, the first without IL-2 and subsequent infusions with low-dose IL-2 (at 0.25, 0.50, and 1.0 x 10(6) unitsm(2) twice daily for the second, third, and fourth infusions, respectively). Forty-three infusions of MART1MelanA-specific or gp100-specific CD8+ T cell clones were administered to 10 patients. No serious toxicity was observed. We demonstrate that the adoptively transferred T cell clones persist in vivo in response to low-dose IL-2, preferentially localize to tumor sites and mediate an antigen-specific immune response characterized by the elimination of antigen-positive tumor cells, regression of individual metastases, and minor, mixed or stable responses in 8 of 10 patients with refractory, metastatic disease for up to 21 mo.

Sosman JA, Unger JM, Liu PY, Flaherty LE, Park MS, Kempf RA, Thompson JA, Terasaki PI, Sondak VK, Anonymous00059. · Vanderbilt University, Nashville, TN, USA. · J Clin Oncol. · Pubmed #11956267 No free full text.

Abstract: PURPOSE: An association between expression of > or = two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic melanoma vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this vaccine. PATIENTS AND METHODS: We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS: HLA typing was performed on 553 (80%) of the 689 enrolled patients (294 vaccinated and 259 observed). Expression of > or = two M5 antigens was associated with a superior vaccine treatment effect. Among patients who matched > or = two of the M5, the 97 vaccine-treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% v 59%; P =.0002). The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2-positive and/or HLA-C3-positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (P =.004). There was no impact of HLA-A2 and/or HLA-C3 expression among observation patients. CONCLUSION: This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing > or = two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA-C3 contributed most to this effect. Processed melanoma peptides found in Melacine may be presented by HLA-A2 and HLA-C3 and play a role in preventing relapse in vaccinated patients.

Sondak VK, Liu PY, Tuthill RJ, Kempf RA, Unger JM, Sosman JA, Thompson JA, Weiss GR, Redman BG, Jakowatz JG, Noyes RD, Flaherty LE. · University of Michigan Comprehensive Cancer Center, Ann Arbor, USA. · J Clin Oncol. · Pubmed #11956266 No free full text.

Abstract: PURPOSE: Patients with clinically negative nodes constitute over 85% of new melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative melanoma patients. PATIENTS AND METHODS: The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic melanoma vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clark's level IV if thickness unknown), clinically or pathologically node-negative melanoma (T3N0M0). RESULTS: Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the vaccine arm. Most vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patients randomized to vaccine compared with 114 among the 300 eligible patients randomized to observation (hazard ratio, 0.92; Cox-adjusted P(2) = 0.51). There was no difference in vaccine efficacy among patients with tumors < or = 3 mm or > 3 mm. CONCLUSION: This represents one of the largest randomized, controlled trials of adjuvant vaccine therapy in human cancer reported to date. Compliance with randomization was excellent, with only 2% refusing assigned therapy. There is no evidence of improved disease-free survival among patients randomized to receive vaccine, although the power to detect a small but clinically significant difference was low. Future investigations of adjuvant vaccine approaches for patients with intermediate-thickness melanoma should involve larger numbers of patients and ideally should include sentinel node biopsy staging.

Stopeck AT, Jones A, Hersh EM, Thompson JA, Finucane DM, Gutheil JC, Gonzalez R. · Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724, USA. · Clin Cancer Res. · Pubmed #11489803 links to  free full text

Abstract: Cutaneous melanoma is one of the most rapidly increasing cancers in the United States. Because of the lack of effective treatment options and toxicities of most chemotherapeutic and radiation regimes, immunotherapies such as vaccination therapy represent an attractive approach for patients with advanced melanoma. The purpose of this study was to evaluate the response rate, time to progression, and survival of patients with metastatic melanoma treated by direct intratumoral injection with Allovectin-7 (a plasmid DNA encoding the genes HLA-B7 and beta2-microglobulin complexed with a cationic lipid mixture, DMRIE/DOPE. Fifty-two patients with metastatic melanoma were enrolled in this Phase II study. Therapy consisted of six intratumoral injections of 10 microg of Allovectin-7 over a 9-week period. Treatment was well tolerated. Treatment-related adverse events were mild to moderate, the most frequent of which were ecchymosis, pruritus (and/or discomfort at the injection site), and pneumothoraces. Regression of the injected lesion was observed in 18% of patients, including one complete response, three partial responses, and five minor responses. An overall response rate of 4% (two partial responses) was documented, and nine patients (18%) maintained stable disease for at least 11 weeks. Six patients remained alive 25.1 to 39.4 months from their first injection, including two patients with local (injected tumor) responses and one patient with an overall disease partial response. This study demonstrates that intratumoral administration of Allovectin-7 in metastatic melanoma is safe and can produce both responses in injected lesions and in overall disease. Clinical trials optimizing patient selection and combining Allovectin-7 with other modalities of therapy are currently ongoing in an effort to improve response rates.

Lazovich D, Thompson JA, Mink PJ, Sellers TA, Anderson KE. · Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis 55454-1015, USA. · Epidemiology. · Pubmed #10615848 No free full text.

Abstract: Results from case-control studies suggest that induced abortion may be associated with a small increase in risk of breast cancer. While risk estimates from cohort studies have generally not observed such an association, these studies have had limited information regarding abortion and possible confounding variables. Therefore, we conducted a study among a cohort of post-menopausal women from whom detailed information regarding pregnancy outcomes as well as risk factors for breast cancer had been collected. The study sample included 37,247 Iowa Women's Health Study participants, 55-64 years of age at baseline in 1986, who reported no history of breast, or other, cancer (except non-melanoma skin cancer), and for whom information regarding pregnancy outcomes (that is, live birth, stillbirth, spontaneous abortion, ectopic pregnancy or induced abortion) was available. We used linkage with records of the State Health Registry of Iowa, part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, to estimate the incidence of breast cancer among cohort members through 1995. We calculated age-adjusted relative risks and 95% confidence intervals using Cox proportional hazards regression. Only 653 women (1.8%) reported an induced abortion. The age-adjusted relative risk of breast cancer among women with prior induced abortion compared with those without was 1.1 (95% CI = 0.8-1.6). Relative risks were higher among women whose age at first abortion was less than 20 or at least 30 years, for those whose abortion took place after their first birth or who never gave birth, and for those with early termination (0-2 months). These estimates varied from 1.3-1.7, but the confidence intervals around each were wide. Since most women in this cohort were beyond their reproductive years when abortion became legal in 1973, the low prevalence of induced abortion argues for a cautious interpretation.

Bhatia S, Tykodi SS, Thompson JA. · Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington 98109, USA. · Oncology (Williston Park). · Pubmed #19544689 No free full text.

Abstract: The 10-year survival rate for patients with metastatic melanoma is less than 10%. Although surgery and radiation therapy have a role in the treatment of metastatic disease, systemic therapy is the mainstay of treatment for most patients. Single-agent chemotherapy is well tolerated but is associated with response rates of only 5% to 20%. Combination chemotherapy and biochemotherapy may improve objective response rates but do not extend survival and are associated with greater toxicity. Immunotherapeutic approaches such as high-dose interleukin-2 are associated with durable responses in a small percentage of patients. In this article, we review the treatments for metastatic melanoma including promising investigational approaches.

Bhatia S, Huber BR, Upton MP, Thompson JA. · Department of Medical Oncology, University of Washington, Seattle, WA 98109, USA. · J Immunother. · Pubmed #19238020 No free full text.

Abstract: Ipilimumab (MDX-010), a human anti-cytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody, is currently being investigated for the treatment of patients with melanoma. The most frequent toxicities observed with ipilimumab involve the gastrointestinal tract and are attributed to activation of the immune system. Constipation has been reported as a symptom in the clinical trials of anti-CTLA-4 antibody and is mostly low grade. However, it is not traditionally perceived as an immune-mediated toxicity. We report the case of a patient who developed severe refractory constipation during treatment with ipilimumab for metastatic melanoma. Biopsies of the colonic wall revealed prominent inflammatory infiltrates of mononuclear lymphocytes associated with the myenteric nervous system. There was a pathologic complete remission of melanoma. To our knowledge, this is the first clinical report of either inflammatory enteric neuropathy or constipation as an immune-related adverse event from anti-CTLA-4 antibody treatment. We discuss the pathophysiology and suggest careful monitoring of patients for development of this complication from ipilimumab therapy.

Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C. · Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. · N Engl J Med. · Pubmed #18565862 links to  free full text

Abstract: We developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.

Mitchell MS, Abrams J, Thompson JA, Kashani-Sabet M, DeConti RC, Hwu WJ, Atkins MB, Whitman E, Ernstoff MS, Haluska FG, Jakowatz JG, Das Gupta TK, Richards JM, Samlowski WE, Costanzi JJ, Aronson FR, Deisseroth AB, Dudek AZ, Jones VE. · University of California, San Diego, School of Medicine and Cancer Center, San Diego, CA, USA. · J Clin Oncol. · Pubmed #17513813 No free full text.

Abstract: PURPOSE: To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose interferon alfa-2b (IFN-alpha-2b) with the OS achieved using high-dose IFN-alpha-2b. PATIENTS AND METHODS: An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-alpha-2b (arm 1) or high-dose IFN-alpha-2b alone for 1 year (arm 2). Active specific immunotherapy was injected subcutaneously (SC) weekly for 4 weeks, at week 8, and bimonthly thereafter. IFN-alpha-2b SC was begun on week 4 and continued thrice weekly at 5 MU/m2 for 2 years. IFN-alpha-2b in arm 2 was administered according to the Eastern Cooperative Oncology Group 1684 study regimen. RESULTS: Median follow-up time was 32 months for all patients and 42 months for surviving patients. Median OS time exceeds 84 months in arm 1 and is 83 months in arm 2 (P = .56). Five-year OS rate is 61% in arm 1 and 57% in arm 2. Estimated 5-year relapse-free survival (RFS) rate is 50% in arm 1 and 48% in arm 2, with median RFS times of 58 and 50 months, respectively. The incidence of serious adverse events as a result of treatment was the same in both arms, but more severe neuropsychiatric toxicity was seen in arm 2. CONCLUSION: OS and RFS achieved by active specific immunotherapy and low-dose IFN-alpha-2b were indistinguishable from those achieved by high-dose IFN-alpha-2b. Long RFS and OS times were observed in both treatment arms.

Bosch JJ, Thompson JA, Srivastava MK, Iheagwara UK, Murray TG, Lotem M, Ksander BR, Ostrand-Rosenberg S. · Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, USA. · Cancer Res. · Pubmed #17483366 links to  free full text

Abstract: Uveal melanoma, the most common malignancy of the eye, has a 50% rate of liver metastases among patients with large primary tumors. Several therapies prolong survival of metastatic patients; however, none are curative and no patients survive. Therefore, we are exploring immunotherapy as an alternative or adjunctive treatment. Uveal melanoma may be particularly appropriate for immunotherapy because primary tumors arise in an immune-privileged site and may express antigens to which the host is not tolerized. We are developing MHC class II (MHC II)-matched allogeneic, cell-based uveal melanoma vaccines that activate CD4(+) T lymphocytes, which are key cells for optimizing CD8(+) T-cell immunity, facilitating immune memory, and preventing tolerance. Our previous studies showed that tumor cells genetically modified to express costimulatory and MHC II molecules syngeneic to the recipient are potent inducers of antitumor immunity. Because the MHC II-matched allogeneic vaccines do not express the accessory molecule, Invariant chain, they present MHC II-restricted peptides derived from endogenously encoded tumor antigens. We now report that MHC II-matched allogeneic vaccines, prepared from primary uveal melanomas that arise in the immune-privileged eye, prime and boost IFNgamma-secreting CD4(+) T cells from the peripheral blood of either healthy donors or uveal melanoma patients that cross-react with primary uveal melanomas from other patients and metastatic tumors. In contrast, vaccines prepared from metastatic cells in the liver are less effective at activating CD4(+) T cells, suggesting that tumor cells originating in immune-privileged sites may have enhanced capacity for inducing antitumor immunity and for serving as immunotherapeutic agents.

Dissanayake SK, Thompson JA, Bosch JJ, Clements VK, Chen PW, Ksander BR, Ostrand-Rosenberg S. · Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, Maryland 21250, USA. · Cancer Res. · Pubmed #14996751 links to  free full text

Abstract: Mouse tumor cells transfected with syngeneic MHC class II and costimulatory molecule genes are therapeutic vaccines in mice, provided they do not coexpress the class II-associated invariant chain (Ii). We demonstrated previously that the vaccine cells present tumor peptides via the endogenous antigen presentation pathway to activate CD4(+) and CD8(+) T cells. Because of their efficacy in mice, we are translating this vaccine strategy for clinical use. To obtain MHC class II(+)CD80(+)Ii(-) human tumor cells, we developed retroviruses encoding HLA-DR and CD80. The HLA-DR virus encodes the DRalpha and DRbeta0101 chains using an internal ribosomal entry site to coordinate expression. SUM159PT mammary carcinoma and Mel 202 ocular melanoma cells transduced with the retroviruses DRB1/CD80 express high levels of DRB0101 and CD80 on the cell surface in the absence of Ii. Irradiated SUM159PT/DR1/CD80 vaccines stimulate proliferation of non-HLA-DRB0101 peripheral blood mononuclear cells and present an exogenous DR1-restricted tetanus toxoid (TT) peptide, indicating that the transduced DRB0101 is functional. SUM159PT/DR1/CD80 vaccines were further transduced with a retrovirus encoding the TT fragment C gene, as a model tumor antigen. These cells stimulate IFN-gamma release from TT-primed human DRB0101 peripheral blood mononuclear cells, demonstrating their ability to present "endogenous" tumor antigen. Depletion and antibody blocking experiments confirm that MHC class II-restricted, endogenously synthesized epitopes are presented to CD4(+) T cells. Therefore, the MHC class II vaccines are efficient antigen-presenting cells that activate tumor-specific MHC class II-restricted, CD4(+) T lymphocytes, and they are a novel and potential immunotherapeutic for metastatic cancers.

Schwartz AL, Thompson JA, Masood N. · Department of Primary Care, School of Nursing, Oregon Health and Science University, Portland, OR, USA. · Oncol Nurs Forum. · Pubmed #12183762 links to  free full text

Abstract: PURPOSE/OBJECTIVES: To examine the effect of exercise and methylphenidate on fatigue, functional ability, and cognitive function in patients with melanoma. DESIGN: Pilot study with comparison to historic controls. SETTING: University-based cancer center. SAMPLE: 12 patients with melanoma entered and completed the study. The mean age was 44 years. METHOD: Eligible patients were recruited before their first dose of interferon-a (IFN-a). Patients were instructed to take 20 mg sustained-release methylphenidate every morning and follow an aerobic exercise program four days a week for 15-30 minutes. Measures included a 12-minute walk, the Schwartz Cancer Fatigue Scale, Trail Maker Forms A and B, Medical Outcomes Study 36 Short Form, body weight, and daily logs. Fatigue scores were compared to usual care historical controls with melanoma receiving only IFN-a. MAIN RESEARCH VARIABLES: Fatigue, functional ability, and cognitive function. FINDINGS: 66% adhered to exercise and methylphenidate; all adhered to exercise. Fatigue was lower for the exercise and methylphenidate group than historic controls. Functional ability increased 6% for all patients and 9% for the exercise and methylphenidate group. Cognitive function was stable for the exercise and methylphenidate group. The exercise-only group showed marked cognitive slowing. CONCLUSION: The combination of aerobic exercise and methylphenidate may have a positive effect on fatigue, cognitive function, and functional ability. A larger sample size and randomized trial is needed to more rigorously evaluate the results of exercise and methylphenidate alone or in combination. IMPLICATIONS FOR NURSING: Although further study is needed, a combination of exercise and methylphenidate may be a practical intervention for patients receiving IFN-a for melanoma.

Thompson JA. · Seattle Cancer Care Alliance, WA 98109-1023, USA. · Semin Oncol. · Pubmed #12170439 No free full text.

Abstract: Substantial progress has been made in identifying the most significant clinical and pathologic characteristics of melanoma that predict for metastasis and survival. The American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma was recently revised to include these prognostic variables. Major changes in the staging include: (1) melanoma thickness and ulceration but not level of invasion will be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, "microscopic") versus clinically apparent (ie, "macroscopic") nodal metastases will be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactate dehydrogenase (LDH) will be used in the M category; (4) all patients with stage I, II, or III disease will be upstaged when a primary melanoma is ulcerated; (5) satellite metastases around a primary melanoma and in-transit metastases will be merged into a single staging entity that is grouped into stage III disease; and (6) distinct definitions for clinical and pathologic staging will take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.

Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A. · Johns Hopkins Medical Institutions, Baltimore, MD, USA. · J Clin Oncol. · Pubmed #11504744 No free full text.

Abstract: PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Yee C, Thompson JA, Roche P, Byrd DR, Lee PP, Piepkorn M, Kenyon K, Davis MM, Riddell SR, Greenberg PD. · Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. · J Exp Med. · Pubmed #11104805 links to  free full text

Abstract: Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1-specific CD8(+) T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell-specific peptide-major histocompatibility complex tetramers demonstrated a localized predominance of MART-1-specific CD8(+) T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.