IgG4 subclass antibodies impair antitumor immunity in melanoma.

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

The role of positron emission tomography with computed tomography in the follow-up of asymptomatic cutaneous malignant melanoma patients with a high risk of disease recurrence.

The aim of this study was to evaluate the role of [F] fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) as a surveillance tool in asymptomatic patients with primary cutaneous melanoma with the American Joint Committee on Cancer stage 3 disease. Thirty-four patients with primary cutaneous malignant melanoma with American Joint Committee on Cancer stage 3 disease, who underwent at least one annual surveillance PET/CT scan, were retrospectively identified from our PET Centre Database in May 2008 and their characteristics, PET/CT results and disease course were reviewed. In 20 patients with microscopic stage 3 disease at diagnosis, annual surveillance PET/CT detected two of three recurrences and detected one incidental breast carcinoma. In 14 patients with macroscopic stage 3 disease at, or subsequent to, their initial diagnosis, annual PET/CT detected four of four recurrences, detected metastases in one patient who remains asymptomatic and detected one incidental thyroid carcinoma. PET/CT seems to be a useful surveillance tool in patients with macroscopic stage 3 disease, although the numbers in this study are small. However, the role of PET/CT in patients initially presenting with microscopic stage 3 disease requires further confirmation.

Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies.

Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

Clinical guidelines for the recognition of melanoma of the foot and nail unit.

Malignant melanoma is a life threatening skin tumour which may arise on the foot. The prognosis for the condition is good when lesions are diagnosed and treated early. However, lesions arising on the soles and within the nail unit can be difficult to recognise leading to delays in diagnosis. These guidelines have been drafted to alert health care practitioners to the early signs of the disease so an early diagnosis can be sought.

Sentinel node positive melanoma patients: prediction and prognostic significance of nonsentinel node metastases and development of a survival tree model.

BACKGROUND: Completion lymph node dissection (CLND) following positive sentinel node biopsy (SNB) for melanoma detects additional nonsentinel node (NSN) metastases in approximately 20% of cases. This study aimed to establish whether NSN status can be predicted, to determine its effect on survival, and to develop survival tree models for the sentinel node (SN) positive population. MATERIALS AND METHODS: Sydney Melanoma Unit (SMU) patients with at least 1 positive SN, meeting inclusion criteria and treated between October 1992 and June 2005, were identified from the Unit database. Survival characteristics, potential predictors of survival, and NSN status were assessed using the Kaplan-Meier method, Cox regression model, and logistic regression analyses, respectively. Classification tree analysis was performed to identify groups with distinctly different survival characteristics. RESULTS: A total of 323 SN-positive melanoma patients met the inclusion criteria. On multivariate analysis, age, gender, primary tumor thickness, mitotic rate, number of positive NSNs, or total number of positive nodes were statistically significant predictors of survival. NSN metastasis, found at CLND in 19% of patients, was only predicted to a statistically significant degree by ulceration. Multivariate analyses demonstrated that survival was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis revealed 4 prognostically distinct survival groups. CONCLUSIONS: Patients with NSN metastases could not be reliably identified prior to CLND. Prognosis following CLND was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis defined distinctly different survival groups more accurately than use of single-factor analysis.

Cutaneous malignant melanoma arising in an acquired naevus of Ota.

Naevus of Ota is a dermal melanocytosis most commonly found in black or Asian skin and is usually a benign malformation, but with a low risk of melanoma. We describe a 32-year-old Caucasian man with an acquired naevus of Ota with subtle pigmentation, in which a melanocytic papule developed. The lesion, deceptively, had no clinically suspicious features, but investigation revealed an aggressive cutaneous malignant melanoma, extensive orbital ring melanocytosis and metastatic brain and subsequent liver disease.

Acral lentiginous melanoma of the foot and ankle: A case series and review of the literature.

BACKGROUND: Acral lentiginous melanoma (ALM) is an uncommon, cutaneous malignant tumour which may arise on the foot. Its relative rarity, atypical appearance and late presentation frequently serve as poor prognostic indicators. METHODS: At a tertiary skin tumour centre, a retrospective review was undertaken of all patients diagnosed with the tumour at the level of ankle or below. RESULTS: Over a six year period, 27 cases (20 female, 7 male) were identified with positive histology confirming the disease. The age ranged from 35-96 years of age (mean 62.7 years). The majority of the cohort were white (59%) with plantar lesions (62%). 33% of patients were initially were diagnosed incorrectly. The average time taken from the point of recognition, by the patient, to the lesion being correctly diagnosed was around 13.5 months. CONCLUSION: Earlier diagnosis of ALM requires education at both a patient and practitioner level.

Routine positron emission tomography and positron emission tomography/computed tomography in melanoma staging with positive sentinel node biopsy is of limited benefit.

Positron emission tomography (PET) is increasingly used for the staging and management of melanoma. The aim of this study was to evaluate the role of PET or PET/ computed tomography (CT) as a routine procedure in patients with positive sentinel node biopsy (SNB). Thirty patients with melanoma of Breslow thickness greater than 1 mm who had PET or PET/CT scans performed within 100 days after a positive SNB were reviewed retrospectively. Two patients (6%) had a positive PET scan, none of which were melanoma related. The first patient had a synchronous neuroendocrine thyroid tumour and the second patient had increased uptake in the chest wall, which proved to be old trauma. Lymph node dissection was positive in five cases (16%). With a median follow-up of 24 months, 21 patients remained disease free. In none of the 30 cases did the early PET scan after a positive SNB alter subsequent melanoma management. The role of PET scanning soon after a positive sentinel node biopsy seems to be of limited benefit. It is questionable whether any imaging is beneficial at this stage. The results of this review suggest that PET scanning might not be indicated for this group of patients.

Assessing response to chemotherapy in metastatic melanoma with FDG PET: Early experience.

OBJECTIVE: The management of metastatic melanoma remains challenging with only modest response rates to chemotherapy but the need to identify the best re-staging techniques remains paramount. This study evaluates our early experience in the use of FDG PET-CT in the assessment of early response to chemotherapy in metastatic melanoma. METHODS: FDG PET-CT was performed at baseline and following two or three cycles of combination or single agent chemotherapy in seven patients. Response was assessed visually as complete, partial metabolic response or progressive disease. RESULTS: There was intense FDG uptake in all metastases at baseline. Following two to three cycles of chemotherapy, there was a complete metabolic response (CMR) in one patient, partial metabolic response (PMR) in two patients and progressive metabolic disease (PMD) in the remaining three patients. Survival was 679 days in the single patient with a CMR, median of 206 and 129 days in the patients with PMR and PMD respectively. CONCLUSION: This pilot study demonstrates the potential use of FDG PET as a biomarker in early response assessment to chemotherapy in metastatic melanoma. PET-CT already plays in integral role in staging high risk melanoma patients and it may also have a promising role in assessing response to current and novel therapies. Further larger studies examining specific therapies and optimal timing are required.

Cutaneous malignant melanoma in association with mycosis fungoides.

We retrospectively analyzed the first 461 cases entered into our cutaneous lymphoma database and found 285 cases of mycosis fungoides. We also identified 6 cases of malignant melanoma, all of which were found in patients with mycosis fungoides. The crude rate of melanoma in the general population in England, United Kingdom, in 1998 was 8.8/100,000 in men and 11.4/100,000 in women. The incidence of melanoma found in our cohort of patients with mycosis fungoides was far higher, and in 4 of the 6 patients cannot be explained on the basis of prior therapy. The reason for this association is unclear, but this report emphasizes the risk of second malignancies for patients with cutaneous T-cell lymphoma and melanoma.