Diagnosis and management of stage I/II melanoma

OBJECTIVES: To describe the clinical features and histologic subtypes of cutaneous melanoma; to review the diagnosis, clinical, and pathologic staging of melanoma and the associated prognostic factors; and to review the treatment and management of AJCC stage I and II melanoma. DATA SOURCES: Scientific and review articles, textbooks, and clinical practice. CONCLUSIONS: Management of melanoma depends on accurate diagnosis, staging, and interpretation of prognostic factors. The treatment of choice for stage I and II melanoma is surgery, ranging from simple excision to lymph node dissection. IMPLICATIONS FOR NURSING PRACTICE: Familiarity with the clinical features of melanoma assists nurses in the screening and early detection of melanoma. Knowledge of AJCC staging guides education regarding treatment and lifelong surveillance.     

Diagnosis and management of malignant melanoma

The incidence of malignant melanoma has increased in recent years more than that of any other cancer in the United States. About one in 70 people will develop melanoma during their lifetime. Family physicians should be aware that a patient with a changing mole, an atypical mole or multiple nevi is at considerable risk for developing melanoma. Any mole that is suggestive of melanoma requires an excisional biopsy, primarily because prognosis and treatment are based on tumor thickness. Staging is based on tumor thickness (Breslow's measurement) and histologic level of invasion (Clark level). The current recommendations for excisional removal of confirmed melanomas include 1-cm margins for lesions measuring 1.0 mm or less in thickness and 2-cm margins for lesions from 1.0 mm to 4.0 mm in thickness or Clark's level IV of any thickness. No evidence currently shows that wider margins improve survival in patients with lesions more than 4.0 mm thick. Clinically positive nodes are typically managed by completely removing lymph nodes in the area. Elective lymph node dissection is recommended only for patients who are younger than 60 years with lesions between 1.5 mm and 4.0 mm in thickness. In the Eastern Cooperative Oncology Group Trial, interferon alfa-2b was shown to improve disease-free and overall survival, but in many other trials it has not been shown to be effective at prolonging overall survival. Vaccine therapy is currently being used to stimulate the immune system of melanoma patients with metastatic disease.     

Population pharmacokinetic analysis of pegylated interferon alfa-2b and interferon alfa-2b in patients with chronic hepatitis C.

BACKGROUND: This study quantified pharmacokinetic changes in pegylated and nonpegylated interferon alfa-2b during 48 weeks of treatment and the influences of covariates on the basis of sparsely sampled serum concentrations and activity values. Possible relationships between pharmacokinetic and pharmacodynamic variables were investigated. METHODS: Patients with chronic hepatitis C were enrolled in a clinical trial that compared the efficacy of pegylated interferon alfa-2b with interferon alfa-2b. Single blood samples were obtained from each patient at weeks 4, 12, 24, 36, and 48. Three pharmacostatistical models were developed for 2 immunoassays and 1 bioassay. RESULTS: Apparent clearance values of pegylated interferon alfa-2b and interferon alfa-2b at the end of treatment declined 33.7% and 80.0%, respectively, from their week 4 values. Bioactivity increased 41% to 58% at week 48 for different treatment groups. Changes were greatest in the first weeks of administration and diminished during the subsequent months. Body weight had a modest positive effect on clearance values and activity. Within each dose level, no significant associations were observed between pharmacokinetic variables and any pharmacodynamic variables (hepatitis C virus--RNA responses or changes in neutrophils and platelets). CONCLUSIONS: This analysis confirms earlier observations of progressive pharmacokinetic changes in the patients with hepatitis C during 48 weeks of treatment. The absence of a relationship between toxicity or efficacy variables and interferon concentration or activity (within a dose level) suggests that clinical management of patients (eg, for efficacy or to manage toxicity) should be based on clinically derived dosing guidelines rather than on serum concentration or activity criteria.     

Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models

BACKGROUND: Combination therapy of ribavirin with interferon alfa-2b and pegylated interferon alfa-2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight. OBJECTIVE: Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles. METHODS: Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose-concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800-mg/d dose, empiric weight-adjusted doses (ie, 1000 mg/d for patients who weighed < or =75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights < or =75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65-85/>85 kg]), a dose of 13 mg/kg per day, and other per-body weight doses between 9 and 16 mg/kg per day. RESULTS: Simulation results showed that both efficacy and toxicity increased as the milligrams-per-kilogram dose of ribavirin increased. The body weight-based 800/1000/1200-mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800-mg/d dose. In particular, patients with genotype-1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200-mg/d and 13-mg/kg per day dose groups. CONCLUSIONS: This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa-2b) for patients with chronic hepatitis C should be based on body weight.     

Potential drug-drug interaction between interferon alfa-2b and gemfibrozil in a patient with malignant melanoma

BACKGROUND: In the United States, patients with high-risk stage II or III melanoma are often treated with adjuvant interferon (IFN) therapy for 1 year after surgery. Adverse events associated with IFN alfa-2b use are primarily constitutional symptoms. However, hypertriglyceridemia requiring treatment has been reported. OBJECTIVE: The aim of this report was to describe a potential drug-drug interaction between IFN alfa-2b and gemfibrozil in a patient with malignant melanoma. The possible mechanism of this potential interaction was examined. METHODS: This report presents the case of a 43-year-old male patient weighing 101 kg with newly diagnosed stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient presented to the University of California Irvine Medical Center, Orange, California with severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations at week 48 of 104 of adjuvant treatment of malignant melanoma (IFN alfa 11 MU SC TIW in combination with the investigational melanoma vaccine melanoma theraccine 1.25 mL [I mL lysate + 0.25 mL vaccine adjuvant] given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104), and IFN-induced hypertriglyceridemia (gemfibrozil 600 mg PO BID). The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medication. The possible mechanism of this potential IFN alfa-gemfibrozil interaction as related to the cytochrome P450 (CYP) enzyme system was assessed. RESULTS: In this case of a possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID in a patient undergoing treatment for IFN-induced hypertriglyceridemia, the Naranjo Adverse Drug Reactions (ADR) Probability Scale score was 7 (ie, ADR possibly related to treatment). CONCLUSIONS: Both IFN and gemfibrozil inhibit the activity of the hepatic enzymes CYP1A2 and CYP2C19. A possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia.     

Progressive vitiligo induced by recurrent melanoma

A woman had undergone excision for primary melanoma of the left heel and dissection of groin lymph nodes. The recurrent tumor on the lateral left lower leg developed six months ago and the depigmented plaques spread extensively on the left lower limb. The depigmented macules were localized to the left lower limb and were not seen in other areas. Although the left groin lymph node had been dissected, the local immune environment of anti‐tumor immunity was preserved. The cause of melanoma‐associated vitiligo is regarded to be anti‐tumor autoimmune mediated, and this phenomenon is recently recognized during the therapy with immune checkpoint inhibitors in the treatment of stage III and IV melanoma     

Detection of metastases in patients with cutaneous melanoma using FDG-PET/CT

This study aimed to detect metastases in patients with stage III or IV cutaneous melanoma by (18)F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT). Thirty-nine patients with clinically evident stage III or IV melanoma underwent whole-body FDG-PET/CT scans for metastatic disease and these results were compared with those of biopsy. Scans for 38 of the patients were evaluated; one patient's scan could not be evaluated. There were 11 true-positive, two false-positive, 24 true-negative and one false-negative scans for the detection of melanoma metastases, with sensitivity 91%, specificity 92%, accuracy 92%, and positive and negative predictive values 84% and 96%, respectively. False-positive FDG-PET/CT scans were due to sarcoidosis in the lung and infected cyst in the liver. It is concluded that FDG-PET/CT scanning has high sensitivity and specificity for detecting stage III or IV metastatic melanoma.     

Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma

This phase II study was performed to determine the induction of a specific T-cell response, the clinical response rate, and toxicity of vaccination with different HLA class I-binding peptide epitopes derived from the melanocyte differentiation antigen tyrosinase in patients with stage IV melanoma. The study population consisted of 16 patients with metastatic disease and two patients who were macroscopically free of disease at study entry after resection of recurrent skin lesions. Patients received intradermal injections of 200 microgram [corrected] peptide corresponding to their HLA type on day 3, and 75 or 150 microg granulocyte-macrophage colony-stimulating factor on days 1 to 4. Vaccinations were repeated at weeks 2, 4, 6, 10, and 14. Monitoring of peptide-specific T-cell frequencies in the peripheral blood was performed using an interferon gamma ELISPOT assay. Eleven of the 16 patients with metastatic disease went off the protocol within the first 10 weeks because of tumor progression. Of the five patients with metastatic disease who received all six vaccinations, one patient showed a mixed response with regression of some lung metastases; two patients with progressive disease before vaccination had stable disease for 6 and 18+ months; and two patients had progression of their disease. The two patients who had all their metastases resected before vaccination did not have relapses for 6 and 12+ months after vaccination. Induction of tyrosinase-reactive T cells was found in these two patients and in two others with metastatic disease, including the one who achieved a mixed response and one with stable disease. This study shows limited clinical and immunologic activity of HLA class 1-peptide vaccination in combination with granulocyte-macrophage colony-stimulating factor in stage IV melanoma patients.     

Malignant melanoma

There have been many prospective randomized clinical trials of IFNalpha as post-surgical adjuvant therapy for high-risk melanoma patients. High dose IFNalpha therapy(HDI) has been reported to be effective in disease-free survival (DFS). However, the usefulness of HDI therapy is still controversial due to its grave toxicity. Low dose IFNalpha therapy (LDI) has no consistent effects on DFS. Most trials showed little activity in patients with metastatic melanoma. In Japan, IFNbeta, in combination with chemotherapy, has been used as post-surgical adjuvant therapy, and has been considered to improve the prognosis of stage III melanoma patients. In addition, we have recently performed a phase I/IIa trial of IFNbeta gene therapy for advanced melanoma patients.     

M-Vax: an autologous,hapten-modified vaccine for human cancer

A novel approach to active immunotherapy has been devised based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). This technology is being developed by AVAX Technologies as a treatment for melanoma under the brand name, M-Vax^TM. The treatment program consists of multiple intradermal injections of DNP-modified autologous tumour cells mixed with Bacille Calmette-Guérin (BCG). DNP-vaccine administration to patients with metastatic melanoma induces a unique reaction – the development of inflammation in metastatic masses. The inflammation is mediated by IFN-γ-producing T-lymphocytes, some of which represent expansion of novel clones. Following DNP-vaccine treatment, almost all patients develop delayed-type hypersensitivity (DTH) to autologous, DNP-modified melanoma cells; approximately half also exhibit DTH to autologous, unmodified tumour cells. The toxicity of the vaccine is mild, consisting mainly of papules or pustules at the injection sites. Clinical trials have been conducted in two populations of melanoma patients: stage IV with measurable metastases and clinical stage III patients, rendered tumour-free by lymphadenectomy. In 83 patients with measurable metastases, there were 11 antitumour responses: two complete responses (CRs), four partial responses (PRs) and five mixed. Both CRs and two of four PRs occurred in patients with lung metastases. In 214 stage III patients the 5-year overall survival rate was 46% (one nodal site = 48%, in-transit metastases = 50%, two nodal sites = 36%). In both populations, the induction of DTH to unmodified autologous tumour cells was associated with significantly longer survival. This technology is applicable to other human cancers and clinical trials have been initiated with ovarian adenocarcinoma. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.     

M-Vax: an autologous, hapten-modified vaccine for human cancer

A novel approach to active immunotherapy has been devised based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). This technology is being developed by AVAX Technologies as a treatment for melanoma under the brand name, M-Vax(TM). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumour cells mixed with Bacille Calmette-Guérin (BCG). DNP-vaccine administration to patients with metastatic melanoma induces a unique reaction - the development of inflammation in metastatic masses. The inflammation is mediated by IFN-gamma-producing T-lymphocytes, some of which represent expansion of novel clones. Following DNP-vaccine treatment, almost all patients develop delayed-type hypersensitivity (DTH) to autologous, DNP-modified melanoma cells; approximately half also exhibit DTH to autologous, unmodified tumour cells. The toxicity of the vaccine is mild, consisting mainly of papules or pustules at the injection sites. Clinical trials have been conducted in two populations of melanoma patients: stage IV with measurable metastases and clinical stage III patients, rendered tumour-free by lymphadenectomy. In 83 patients with measurable metastases, there were 11 antitumour responses: two complete responses (CRs), four partial responses (PRs) and five mixed. Both CRs and two of four PRs occurred in patients with lung metastases. In 214 stage III patients the 5-year overall survival rate was 46% (one nodal site = 48%, in-transit metastases = 50%, two nodal sites = 36%). In both populations, the induction of DTH to unmodified autologous tumour cells was associated with significantly longer survival. This technology is applicable to other human cancers and clinical trials have been initiated with ovarian adenocarcinoma. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.     

Biomarkers in melanoma: stage III and IV disease

The prognosis associated with Stage III melanoma is variable (17-65% 5-year survival) and primarily influenced by the number of lymph nodes involved, the presence of ulceration in a primary lesion, and the tumor burden present in each lymph node. In patients with metastatic (Stage IV) melanoma, the prognosis remains dismal (6-18% 5-year survival) and is influenced primarily by the sites (and extent) of metastatic involvement. Serum lactate dehydrogenase is the only prognostic biomarker useful in metastatic melanoma and it has been incorporated into the 2002 American Joint Committee on Cancer tumor, node, metastasis staging system. In this review, the known prognostic factors in Stage III and IV melanoma are reviewed. Selected investigational therapies and associated biomarkers are also discussed.     

Combination Interferon alfa-2b/ribavirin therapy for the treatment of hepatitis C: nursing implications.

An effective new therapeutic option consisting of Intron A (Interferon alfa-2b, recombinant; Schering Corporation, Kenilworth, NJ) Injection and Rebetol (Ribavirin, USP) Capsules is now available for the initial therapy of patients with hepatitis C and for patients who had previously responded to alpha interferon but subsequently relapsed. The combination of recombinant interferon alfa-2b/ribavirin therapy increases hepatitis C viral clearance 10-fold in hepatitis C relapse patients and almost threefold in previously untreated patients compared with alpha interferon monotherapy. There is no synergistic toxicity apparent with the two-drug combination. Ribavirin does not significantly worsen the side effects associated with interferon alfa-2b, which are predictable, manageable, and reversible. The major side effects of combination therapy include flulike symptoms, neutropenia, psychiatric disorders, and anemia; however, these side effects are well known and can be managed with dose modifications and nursing intervention. The assistance of nurses in patient education, in side effect management, in hematologic parameter monitoring, and in medication dosing and administration is crucial to maximizing patient compliance and therapy outcome.     

Quality-of-life evaluation in an interferon therapy after radical surgery in cutaneous melanoma patients

Melanoma is the fastest growing solid tumor in men and women, and despite accounting for only 4% of skin cancer cases, it accounts for more than 79% of skin cancer-related deaths. The present study was designed to evaluate the impact of interferon (IFN) treatment on patients' quality of life (QOL) after radical surgery of cutaneous melanoma. The tests were carried out in a group of patients treated in the Department of Soft Tissue and Bone Cancer, Institute of Oncology, in Warsaw. The present study included 2 groups of the patients, 110 persons each. One group consisted of patients who had been subjected to radical surgery of cutaneous melanoma, and the other one consisted of 110 patients treated with a supplementary interferon alfa-2b (IFN-alpha-2b) therapy. Data were collected by means of an anonymous QLQ-C30 (version 2.0.) questionnaire elaborated and provided by the European Organisation for Research and Treatment of Cancer. The QLQ-C30 questionnaire consisted of 43 questions. The IFN-alpha-2b treatment significantly affected patients' physical condition, mental health, and social life. The emotional state of the patients was more affected during IFN-alpha-2b treatment. Somatic symptoms were also increased in those patients. The IFN-alpha-2b therapy also significantly affected family and social life. In spite of several adverse effects, the patients assessed their QOL as good. The IFN-alpha-2b treatment is troublesome for the melanoma patients. It is important that the treating physician and nurse should be aware of the 4 major categories of IFN-alpha-2b toxicity: constitutional, neuropsychiatric, hepatic, and hematologic. A number of steps can be taken to minimize the morbidity associated with IFN-alpha-2b therapy, resulting in an improvement in both QOL and patient compliance.     

Simultaneous analysis of tyrosinase mRNA and markers of tyrosinase activity in the blood of patients with metastatic melanoma.

Determination of blood tyrosinase mRNA by RT-PCR and markers of tyrosinase activity (L-DOPA/L-tyrosine ratio) by HPLC have been proposed as biological tools for the detection of metastases in melanoma patients. We prospectively evaluated their significance and clinical value in a group of 30 stage III (n = 10) and IV (n = 20) melanoma patients and one with melanosis of Dubreuilh. L-DOPA/L-tyrosine ratio was elevated in 30% of stage III, 41% of stage IV patients (range: 7.5-261.0 x 10(5)) and in melanosis of Dubreuilh (184.8) (reference values: 6-16 X 10(5)). One stage III and four stage IV melanoma patients were positive for tyrosinase mRNA. In stage IV patients, tyrosinase mRNA positivity was associated with disease progression (P<0.01). The presence of tyrosinase mRNA in blood is more related to clinical status than level of melanin precursors, which probably reflects tumor burden.     

Side effects in melanoma patients receiving adjuvant interferon alfa-2b therapy: a nurse’s perspective

Purpose

The aim of this review was to examine the toxicity profile of adjuvant interferon (IFN) alfa-2b in melanoma patients from a nursing perspective and to summarize practical information to guide the effective management of common IFN toxicities to improve patient comfort.

Methods

This is a narrative summary of both research and review articles identified by searching PubMed, National Cancer Institute, and American Cancer Society websites. It also assesses recognized guidelines on the management of adjuvant IFN toxicity relevant to nurses who are caring for patients receiving adjuvant IFN therapy.

Results

Adjuvant high-dose IFN alfa-2b (HDI) as compared with observation significantly prolongs relapse-free survival in patients with melanoma at high risk for recurrence after surgical resection; however, treatment compliance and patient quality of life can be compromised by its toxicity profile. HDI toxicities affect a number of organ systems and the majority of patients will experience some side effects. Common toxicities such as flu-like symptoms, fatigue, anorexia, neuropsychiatric symptoms, and laboratory abnormalities are discussed, along with both pharmacological and nonpharmacological management strategies.

Conclusions

The considerable side effects of HDI can be managed using established strategies. Oncology nurses play a significant role in the management of patients with melanoma receiving adjuvant HDI, and their prompt recognition of side effects, together with an understanding of effective pharmacological and nonpharmacological interventions, will improve patient comfort; this has the potential to positively influence treatment adherence and completion of the recommended treatment course.     

Adefovir dipivoxil in the treatment of chronic hepatitis B

OBJECTIVE: To evaluate properties of the new acyclic nucleotide analog adefovir dipivoxil in the treatment of chronic hepatitis B (CHB). DATA SOURCES: MEDLINE and PubMed searches from 1966 to December 2003 were performed with the headings chronic hepatitis B, interferon alfa-2b, lamivudine, liver transplant, and adefovir dipivoxil. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled studies and meta-analyses were evaluated in detail. A manual search was performed using references from retrieved primary literature, review articles, editorials, postgraduate course syllabi from national meetings, and textbooks. Emphasis was placed on controlled, prospective, randomized trials. National meeting abstract presentations were included if the information offered was original. DATA SYNTHESIS: CHB is a major viral infection with an estimated 400 million carriers worldwide. Medications available to treat CHB include interferon alfa-2b and lamivudine, both agents having significant limitations. Adefovir dipivoxil is a novel nucleotide analog which, when given at 10 mg/day for 48 weeks, improved liver histology in 28% more patients with hepatitis B e antigen (HBeAg)-positive CHB, and in 31% more patients with HBeAg-negative CHB compared with placebo (p < 0.001). Additionally, adefovir dipivoxil therapy significantly improved virologic and biochemical parameters in both HBeAg-positive and -negative CHB patients. Adefovir dipivoxil offers important advantages over other CHB treatment options: it maintains activity against lamivudine-resistant CHB, has good efficacy against HBeAg-negative CHB, and has minimal adverse effects at the 10-mg/day Food and Drug Administration-approved dose. CONCLUSIONS: Approved medications for the treatment of CHB have many limitations, and adefovir dipivoxil provides a new important option as an initial treatment, as well as treatment in lamivudine-resistant patients.     

Isolated perfusion of extremities for metastatic melanoma from an unknown primary lesion

Since 1957, 822 patients with invasive malignant melanoma of the limbs were treated by regional perfusion at the Tulane Medical Center. Between 1958 and 1982, there were 32 patients with regional metastatic melanoma from an unknown primary site involving either the upper limb and axillary lymph nodes or lower limb and femoral or inguinal lymph nodes. This group represents 3.5% of patients with regional melanomas treated during this period. There were 16 patients with upper limb regional metastases and 14 patients with lower limb metastases. Sixteen patients had stage IIIB disease (ie, regional lymph node metastases), ten had stage IIIA disease (ie, satellitosis), and four had stage IIIAB disease. Six patients had a history of a suggestive limb lesion that had completely regressed and showed no residual tumor on biopsy. All 30 patients were treated by regional isolated perfusion and regional lymph node dissection, with surgical excision of in-transit disease when possible. The cumulative five-year survival for all patients is 50%. Interestingly, the patients with a history of a lesion that regressed had 85% cumulative five-year survival, and the patients with stage IIIB disease did almost as well, with 62% surviving for five years.     

Redirected lysis of human melanoma cells by a MCSP/CD3-bispecific BiTE antibody that engages patient-derived T cells

Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.     

Peginterferon alfa-2a (40KD) (Pegasys) for the treatment of patients with chronic hepatitis C

Compared with conventional interferon alfa, peginterferon alfa-2a (40KD) has improved pharmacokinetics, provides sustained therapeutic plasma levels, and can be administered once weekly. In randomised, multinational trials, peginterferon alfa-2a (40KD) 180 microg once weekly was significantly more effective than three times weekly interferon alfa-2a in patients with chronic hepatitis C, including patients with cirrhosis. Peginterferon alfa-2a (40KD) and ribavirin 1000/1200 mg/day for 48 weeks produced significantly higher sustained responses than three times weekly interferon alfa-2b and ribavirin 1000/1200 mg/day in patients with chronic hepatitis C including those with HCV genotype 1, genotypes 2/3 and those with high or low viral loads at baseline. The drug is well tolerated when given alone or in combination with ribavirin. Health-related quality of life was significantly less impaired during treatment with peginterferon alfa-2a (40KD) than interferon alfa-2a in randomised trials. Peginterferon alfa-2a (40KD) is widely approved for use in patients with chronic hepatitis C.