Surgery For Melanoma Research Articles

Serum YKL-40 is elevated in a subgroup of patients after surgery for stage IIb-III melanoma

8574 Background: High serum YKL-40 is associated with poor prognosis in patients with adeno- and squamous cell carcinoma, glioblastoma, and stage I-II and IV melanoma. YKL-40 is secreted by cancer cells, macrophages and neutrophils. YKL-40 is a growth and differentiation factor, and plays a role in tissue remodelling and angiogenesis. The aim of our study was to compare serum YKL-40 in patients after surgery for stage IIb-III melanoma with healthy individuals and with clinical and histological prognostic parameters. Methods: YKL-40 was determined by ELISA (Quidel, CA) in serum samples from 231 patients, with stage IIb-III melanoma. The 74 women and 157 men had a median age of 50 (range 22–76 years), and they were enrolled in a Nordic adjuvant protocol, randomizing to observation or interferon therapy (1 or 2 years). Baseline samples were drawn <70 days after primary biopsy, but prior to start of therapy. Results: Serum YKL-40 was increased (p=0.003) in the 231 patients (median 47 μg/l, range 20–1,416 μg/l) compared to healthy individuals (43 μg/l, range: 20–184 μg/l, n=245). Serum YKL-40 was higher than the age-corrected 95th percentile of s-YKL-40 in healthy individuals in 19% of the patients with melanoma thickness >4 mm and no lymph node metastasis (n=27), in 8% with sentinel lymph node metastasis (n=89) and in 14% with clinical lymph node metastasis at time of surgery or as recurrence in the follow-up period (n=111). Comparison of serum YKL-40 in the 3 groups showed no significant differences (p=0.22). No difference was found comparing serum YKL-40 between the three groups of Breslow thickness (< 1 mm, 1–2 mm, > 2 mm)(p=0.66), and the two groups of Clark′s level (II-III, IV-V)(p=0.88) was found. A weak association (p=0.045) was found between s-YKL-40 and localization of primary tumor, with trunc having the highest median concentration of s-YKL-40. No association between an elevated s-YKL-40 with number of positive lymph nodes (0.36), ulceration (p=0.81), extranodal growth (p=0.56), or histologic subtype of primary tumor (p=0.48) was observed. Conclusion: Serum YKL-40 is elevated in a subgroup of melanoma patients with stage IIb-III and not associated with classical clinical and histological parameters. It is not known if the increased YKL-40 reflects the biological behaviour of the disease. No significant financial relationships to disclose.

Reliability and validity of the Functional Assessment of Cancer Therapy-melanoma (FACT-M)

8554 Background: Our group has developed a disease-specific module for the Functional Assessment of Cancer Therapy (FACT) instrument to assess quality of life (QOL) in melanoma patients. The purpose of this study was to assess the reliability and validity of the melanoma subscale (MS) and melanoma surgery subscales (MSS) as well as the total FACT-M, which includes the FACT combined with the MS and MSS. Methods: 273 melanoma patients (stages I-IV) attending an outpatient melanoma clinic completed a battery of questionnaires at baseline assessment. The scores from the MS, MSS, and total FACT-M were compared to patient performance status (ECOG and Karnofsky scales), disease stage, treatment status, and other instruments with related domains including the Profile of Mood States, Marlowe-Crowne Social Desirability Scale, and the EORTC Quality of Life Questionnaire - melanoma module. Patients were assessed 1 week after baseline to assess test-retest reliability, and 163 patients completed assessments at 3 months to evaluate the responsiveness to change in performance status. Results: Internal consistency and test-retest reliability for the MS (Cronbach's a = 0.85, r = 0.81), MSS (a = 0.85, r = 0.82), and the total FACT-M (a = 0.95, r = 0.90) were excellent. Overall, the scales correlated with other measures and correlations were in the hypothesized direction. As predicted, FACT-M, MS, and MSS scores were lower for patients with advanced (stage III/IV) melanoma, patients with poor performance status, and patients who were receiving active treatment. In addition, total FACT-M, MS, and MSS scores were highly sensitive to changes in performance status (p = 0.0012, 0.0004, and 0.0006, respectively). Conclusions: The FACT-M is a reliable and valid QOL assessment tool for patients with melanoma. This disease-specific instrument should be utilized for melanoma QOL assessment in clinical trials. No significant financial relationships to disclose.

Repigmentation after Surgery of Melanoma in a Burn Scar: Dermoscopy as Aid for the Management Decision

Repigmentation after Surgery of Melanoma in a Burn Scar: Dermoscopy as Aid for the Management Decision

The Density and Distribution of Melanocytes Adjacent to Melanoma and Nonmelanoma Skin Cancers

The determination of clear margins during Mohs surgery for melanoma in situ arising on sun-damaged skin is often made difficult by the presence of background atypical melanocytic hyperplasia. To determine the density and distribution patterns of melanocytes adjacent to melanoma and nonmelanoma skin cancers. 180 skin specimens obtained during the routine repair of defects resulting from the removal of melanoma and nonmelanoma skin cancers were analyzed using H and E-stained permanent sections to determine the quantity and distribution of epidermal melanocytes. The mean melanocyte density was 7.97 melanocytes per 1 mm of epidermis (SD,+/-6.7). Contiguous melanocytes were found in 30 (16.7%), atypical melanocytes were observed in 8 (4.4%), and follicular extension of melanocytes was observed in 11 (6.1%) of the specimens. These features were significantly associated with higher melanocyte densities (p< .001) and were more commonly observed in specimens from patients with melanoma. There is a high degree of variability in melanocyte densities seen adjacent to melanoma and nonmelanoma skin cancers. Contiguous melanocytes, atypical melanocytes, and follicular melanocytes can be seen in the sun-damaged skin surrounding both melanoma and nonmelanoma skin cancers, but especially with melanoma. Because some of the features of melanoma in situ can be seen in chronically sun-damaged skin, the Mohs surgeon should be cautious when assessing the margins for melanoma in this setting.

Current status of sentinel lymph node navigation surgery in breast and gastrointestinal tract

Sentinel lymph node biopsy (SLNB) has been developed as a new diagnostic and therapeutic modality in melanoma and breast cancer surgery. The purpose of the SLNB include preventing the operative morbidity and improving the pathologic stage by focusing on fewer lymph nodes using immunocytochemic and molecular technology has almost achieved in breast cancer surgery. The prognostic meaning of immunocytochemically detected micrometastases is also evaluating in the SLN and bone marrow aspirates of women with early-stage breast cancer. SLNB using available techniques have suggested that the lymphatic drainage of the gastrointestinal tract is much more complicated than other sites, skip metastasis being rather frequent because of an aberrant lymphatic drainage outside of the basin exist. At the moment, the available data does not justify reduced extent of lymphadenectomy, but provides strong evidence for an improvement in tumor staging on the basis of SLNB. Two large scale prospective multi-center trials concerning feasibility of gamma-probe and dye detection for gastric cancer are ongoing in Japan. Recent studies have shown favorable results for identification of SLN in esophageal cancer. CT lymphography with endoscopic mucosal injection of iopamidol was applicable for SLN navigation of superficial esophageal cancer. The aim of surgical treatment is complete resection of the tumor-infiltrated organ including the regional lymph nodes. Accurate detection of SLN can achieve a selection of a more sophisticated tailor made approach. The patient can make a individualized choice from a broader spectrum of therapeutic options including endoscopic, laparoscopic or laparoscopy-assisted surgery, modified radical surgery, and typical radical surgery with lymph node dissection. Ultrastaging by detecting micrometastasis at the molecular level and the choice of an adequate treatment improve the postoperative quality of life and survival. However these issues require further investigation.

A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma–Trans Tasman Radiation Oncology Group (TROG) Study 96.06

Background The role of adjuvant postoperative therapy after resection of localised malignant melanoma involving regional lymph nodes remains controversial. There are no randomised trials that confirm that postoperative radiation conveys a benefit in terms of regional control or survival. Methods Two hundred and thirty-four patients with melanoma involving lymph nodes were registered on a prospective study to evaluate the effect of postoperative radiation therapy. The regimen consisted of 48 Gy in 20 fractions to the nodal basin using recommended treatment guidelines for each of the major node sites. The primary endpoints were regional in-field relapse and late toxicity. Secondary endpoints were adjacent relapse, distant relapse, overall survival, progression-free survival and time to in-field progression. Results Adjuvant radiation therapy was well tolerated by all of the patients. As the first site of relapse, regional in-field relapses occurred in 16/234 patients (6.8%). The overall survival was 36% at 5 years. The progression-free survival and regional control rates were 27% and 91%, respectively, at 5 years. Patients with more than 2 nodes involved had a significantly worse outcome in terms of distant relapse, overall and progression-free survival. Conclusion We believe that adjuvant radiation therapy following nodal surgery could offer a possible benefit in terms of regional control. These results require confirmation in a randomised trial.

An unexpected side-effect of a dermal regeneration dressing

Wide surgical excisions performed for skin tumour removal often need a graft to obtain good quality closure. In some cases, a residual depression is observed, leading to a poor cosmetic result. Recently, the use of a dermal regeneration template-type dressing (Integra, Integra Lifescience Corp, Plainsboro, NJ, US) has been proposed to give a better functional and cosmetic result of the graft. We report here on an unexpected side-effect observed in a patient who underwent surgery for a malignant melanoma and was subsequently treated with this dressing.

Chemokine Receptor CXCR4 Expression in Patients With Melanoma and Colorectal Cancer Liver Metastases and the Association With Disease Outcome

To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative real-time RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P < 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P = 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P = not significant). CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (+) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome.

Re: Questionable Utility of Melan-A/Mart-1 Immunoperoxidase Staining while Doing Mohs Surgery for Melanoma

Re: Questionable Utility of Melan-A/Mart-1 Immunoperoxidase Staining while Doing Mohs Surgery for Melanoma

The sentinel node biopsy in early gastric cancer: a preliminary study

Sentinel node biopsy is currently used in surgery of malignant melanoma and breast cancer. The feasibility of sentinel node mapping in gastrointestinal cancers and its diagnostic sensitivity is unclear. It could be of particular value in the management of early gastric cancer in which radical D2 lymphadenectomy may be unnecessary. From January 2004 to June 2005, ten patients with preoperative diagnosis of early gastric cancer and no nodal involvement (cT1N0) were submitted to sentinel node biopsy using the dual mapping procedure with endoscopic blue dye and 99mTc radio colloid injection. All the patients underwent standard radical gastrectomy and D2 lymphadenectomy. The resected nodes were evaluated by routine (hematoxylin-eosin) histopathological examination; the sentinel (blue or hot) nodes, in addition, were evaluated with immunohistochemistry for cytokeratin. The detection rate of this procedure was 100%. The preliminary results and perspectives for feasibility of sentinel node biopsy and its accuracy in predicting the nodal status in early gastric cancer are discussed.

Delivery of gadolinium-labeled nanoparticles to the sentinel lymph node: Comparison of the sentinel node visualization and estimations of intra-nodal gadolinium concentration by the magnetic resonance imaging

Sentinel node imaging is commonly performed prior to surgery for breast cancer and melanoma. While current methods are based on radio-lymphoscintigraphy, MR lymphangiography (MRL) offers the benefits of better spatial resolution without ionizing radiation. However, the optimal nanoparticle for imaging the sentinel nodes remains unclear. Gadolinium-labeled (Gd) contrast agents ranging in diameter from < 1 to 12 nm were evaluated to determine which size provides the most rapid and most concentrated delivery of contrast agent to the lymph nodes in a mouse model of lymphatic metastases. Specifically, PAMAM-G2, -G4, -G6 and -G8, and DAB-G5 Gd-dendrimer agents, as well as Gadomer-17 and Gd-DTPA, were compared. Among these agents, the G6 Gd dendrimer depicted the lymphatics and lymph nodes with the highest peak concentrations and this occurred 24–36 min post-injection ( p < 0.01; all except G8). Based on ex vivo concentration phantoms, high accumulations of Gd(III) ions occurred within lymph nodes (1.7–4.4 mM Gd/270–680 ppm Gd) with high target to background ratios (> 100). These concentrations are sufficient to contemplate the use of Gd-neutron capture therapy of regional lymph nodes. Thus, when injected interstitially, the PAMAM-G6 Gd dendrimer not only provides excellent opacification of sentinel lymph nodes, but also provides the potential for targeted therapy of sentinel lymph nodes.

Isolated metastasis in the gallbladder from cutaneous melanoma as shown by F-18 fluorodeoxyglucose (FDG) whole body PET/CT scan

Although malignant melanoma has the potential to spread to almost any organ of the body, isolated metastasis to the gallbladder is rare. Here, we describe a patient in whom whole body F-18 FDG PET/CT scan was performed as part of the oncological follow-up after diagnosis, radical surgery and adjuvant immunotherapy for malignant melanoma 14 months earlier. On F-18 FDG PET/CT scan an isolated mural soft tissue mass in the gallbladder wall characterized by intense F-18 FDG uptake was seen. Because the lesion was highly suspicious to be a gallbladder metastasis from the previously diagnosed cutaneous melanoma, a cholecystectomy was performed. Pathological examination confirmed the presence of melanoma. Combined F-18 FDG PET/CT has the unique opportunity to reveal F-18 FDG avidity of the lesion in the gallbladder, suggesting a malignant lesion.

Conventional histology vs. three-dimensional histology in lentigo maligna melanoma

Conventional surgery for lentigo maligna melanoma (LMM) is based on normal histological evaluation. However, such evaluation leaves diagnostic gaps. In contrast, complete three-dimensional (3D) histology of excision margins permits accurate detection of continuously spreading tumour strands like those of LMM. These can be specifically excised in tumour-positive areas with smaller excision margins, and better cosmesis and function. To date there have been no controlled studies of micrographic surgery of LMM. Clinical parameters and surgical strategies influencing the prognosis of patients with LMM were evaluated in a prospective study of melanoma patients in the Department of Dermatology of the University of Tübingen (1980-99). The 292 LMMs comprised 7.4% of 3960 primary stage I and II melanomas treated during this period. One hundred and thirty-six patients in this group (46.6%) underwent surgery on the basis of 3D histology. The geometric mean excision margins were significantly smaller in the 3D histology group (P < 0.0001). Patients with micrographic surgery had fewer recurrences. Multivariate analysis of clinical, histological and surgical variables was carried out, and tumour thickness and 3D histology proved to be independent, significant factors for the prognosis of recurrence-free survival (relative risk, RR 2.08, P < 0.0001 and RR 2.11, P = 0.0037, respectively). There were no melanoma-related deaths in the 3D histology group. All 16 melanoma-related deaths were observed among the 156 patients of the conventional histology group (10.3%). Excision of LMM using 3D histology resulted in a twofold lower probability of recurrence and twofold smaller excision margins. 3D histology is a valuable diagnostic tool and can be used in the management of LMM because of the latter's pattern of continuous tumour spread.

Surgical reconstruction after subtotal ear resection in malignant melanoma of the ear

Surgery in malignant melanoma of the external ear often leads to substantial defects where reconstruction poses a difficult challenge. We describe an option of a one-step ear reconstruction after subtotal ear resection in malignant melanoma surgery. In a patient with a high-risk melanoma of the helical rim, a wide local excision was performed. Because of a metastasis-suspect lymph node in the parotid gland, surgery included asservation of the sentinel lymph node, neck dissection and parotidectomy. A complete reconstruction of the ear was achieved using a bilobed flap from the retroauricular and neck region with acceptable cosmetic and functional results by one-step surgery. One micrometastasis was detected in the nuchal region but not in the marked sentinel lymph node. An adequate one-step ear reconstruction as described may also be performed to the benefit of patients with high-risk melanomas, allowing early adjuvant therapy.

P16 expression in primary malignant melanoma is associated with prognosis and lymph node status

Lymph node (LN) status is an important prognostic factor in melanoma patients. p16 expression and proliferation rate (MIB-1) of primary melanomas have been suggested as a marker of metastatic potential. In this study, the correlation of p16 expression and the proliferation rate (MIB-1) with LN status and tumor-specific survival was investigated in primary melanomas. MIB-1 and p16 expression were analyzed by immunohistochemistry in 64 patients with primary cutaneous melanoma. Thirty four nevi were used as control. All patients underwent sentinel lymph node staging. Three different p16 staining patterns were observed: a combination of nuclear and cytoplasmic staining, only cytoplasmic staining and absence of p16 expression. All 34 nevi displayed a nuclear and cytoplasmic p16 staining, whereas p16 was negative in 14 of 64 (22%) melanomas. The level of p16 expression gradually decreased from benign nevi to melanoma without metastasis to melanoma with metastasis. There was a significant correlation between cytoplasmic p16 expression and absence of metastasis (p < 0.05). Death of disease correlated with absence of p16 immunostaining (p = 0.01). MIB-1 expression was not associated with survival. These results confirm the relevance of p16 expression as a prognostic marker in melanoma patients. In addition, it was shown that cytoplasmic immunostaining for p16 in primary melanoma might serve as a predictor of the LN status. Therefore, immunohistochemical evaluation for p16 expression is of potential value for treatment planning in melanoma surgery.

Thyroid Metastasis of Malignant Melanoma

Clinically significant metastases to the thyroid gland are very rare; however, they can present as the initial malignancy. The authors report a 53-year-old man who underwent surgery for malignant melanoma 5 years earlier, and recently presented with a thyroid nodule that turned out to be a metastasis of the primary malignancy. Fine-needle aspiration showed malignant cells, but was unable to indicate that their origin was malignant melanoma. Total thyroidectomy was the therapy chosen for the patient.

Ultrasound Mapping of Lymph Node and Subcutaneous Metastases in Patients with Cutaneous Melanoma: Results of a Prospective Multicenter Study

Background: Ultrasound (sonography, B-mode sonography, ultrasonography) examination improves the sensitivity in more than 25% compared to the clinical palpation, especially after surgery on the regional lymph node area. Objective: To evaluate the distribution of metastases during follow-up in the draining lymph node areas from the scar of primary to regional lymph nodes (head and neck, supraclavicular, axilla, infraclavicular, groin) in patients with cutaneous melanoma with or without sentinel lymph node biopsy (SLNB) or former elective or consecutive complete lymph node dissection in case of positive sentinel lymph node (CLND). Methods: Prospective multicenter study of the Departments of Dermatology of the Universities of Homburg/Saar, Tübingen and Munich (Germany) in which the distribution of lymph node and subcutaneous metastases were mapped from the scar of primary to the lymphatic drainage region in 53 melanoma patients (23 women, 30 men; median age: 64 years; median tumor thickness: 1.99 mm) with known primary, visible lymph nodes or subcutaneous metastases proven by ultrasound and histopathology during the follow-up. Results: Especially in the axilla, infraclavicular region and groin the metastases were not limited to the anatomic lymph node regions. In 5 patients (9.4%) (4 of them were in stage IV) lymph node metastases were not located in the corresponding lymph node area. 32 patients without former SLNB had a time range between melanoma excision and lymph node metastases of 31 months (median), 21 patients with SLNB had 18 months (p < 0.005). In 11 patients with positive SLNB the time range was 17 months, in 10 patients with negative SLNB 21 months (p < 0.005); in 32 patients with CLND the time range was 31 months and in 21 patients without CLND 18 months (p < 0.005). In thinner melanomas lymph node metastases occurred later (p < 0.05). Conclusions: After surgery of cutaneous melanoma, SLNB and CLND the lymphatic drainage can show significant changes which should be considered in clinical and ultrasound follow-up examinations. Especially for high-risk melanoma patients follow-up examinations should be performed at intervals of 3 months in the first years. Patients at stage IV should be examined in all regional lymph node areas clinically and by ultrasound.

Surgical Pearl: The use of endarterectomy scissors in dermatologic surgery

S urgical scissors are a necessary component of the surgical tray. It is optimal to maintain one plane of cutting or dissection when excising a lesion or undermining tissue. This is particularly important when removing a melanoma, large lesion, or Mohs micrographic surgery layer. Traditionally iris, gradle, and Stevens tenotomy scissors have been the preferred instruments for cutaneous surgery in small shallow areas. These instruments accommodate more delicate anatomic areas well. Many dermatologic surgeons use Metzenbaum or Mayo scissors when undermining larger, deeper defects and cutting thicker, more resilient skin (such as that on the scalp, back, or extremities). These scissors have a longer shank and tips than the aforementioned instruments and are more efficient in cutting and manipulating deeper tissue and larger lesions. In certain situations, however, their long tips may feel clumsy and provide less precise cutting and undermining. When used to cut the subcutaneous tissue, these scissors tend to catch a nodule of fat deep in the defect instead of maintaining a level, even cutting surface through the fat.

399 PUBLICATION Dose finding study of sequential administration of biweekly docetaxel followed by epirubicin and cyclophosphamide in high-risk breast cancer patients

For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91–1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96–1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients.

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.