Regression Of Melanoma Research Articles

Estudo da espessura da regressão como fator prognóstico nos melanomas cutâneos finos

BACKGROUND: The diagnosis of thin cutaneous malignant melanomas has been increasingly more frequent. These lesions, initially associated with excellent prognosis, have presented recurrence or metastases and sometimes have been fatal. Many variables have been studied and, although none of them has explained this behaviour, regression and its possible negative impact have been focused on recently. According to some authors, late regression bears major relevance in the prognosis. OBJECTIVE: To correlate the maximum regression thickness of thin cutaneous malignant melanomas with disease-free survival time. MATERIALS AND METHOD: Retrospective study of 84 cases of thin cutaneous malignant melanomas. The criteria of Kang et al. (1993) for identification and evolutionary classification (early, intermediate and late) of the regression were applied. RESULTS: Regression (in any phase) was observed in 70 out of 84 thin cutaneous malignant melanomas (83.3%), and 30 cases (35.7%) showed late regression. The maximum regression thickness measurement ranged from 0.16 to 1.53 mm. Disease-free survival time ranged from 17 days to 108 months. Five cases (5.9%) had an unfavorable outcome, from which three were in situ melanomas. There was no correlation between the studied variables (p > 0.05). DISCUSSION: The meaning of regression in thin cutaneous malignant melanomas is controversial, probably due to the different methods applied in the few studies carried out about the subject and the wide variety of size and composition of the samples. There is no medical consensus as to a standardized regression measurement system, which partially explains the controversial results obtained to date. CONCLUSIONS: There was no statistical correlation between regression thickness in thick cutaneous melanomas and disease-free survival time (p > 0.05). Future studies with wider samples may contribute to a better understanding of this phenomenon.

Melanoma Regression Alone Doesn't Justify an SLN Biopsy

Melanoma Regression Alone Doesn't Justify an SLN Biopsy

Melanoma vaccines

Over the last century, vaccine studies have demonstrated that the human immune system, with appropriate help, can limit or prevent infection against otherwise lethal pathogens. Encouraged by these results, success in animal models and numerous well-documented reports of immune-mediated melanoma regression in humans, investigators developed melanoma vaccines. However, despite considerable laboratory evidence for vaccine-induced immune responses, clinical responses remain poor. Recent studies have elucidated several mechanisms that hinder or prevent the creation of successful vaccines and suggest novel approaches to overcome these barriers. Unraveling the mechanisms of autoimmunity, dendritic cell activation, regulatory T cells and Toll-like receptors will generate novel vaccines that, when used in conjunction with standard adjuvant therapies, may result in improved clinical outcomes. The objective of this review is to provide an overall summary of recent clinical trials with melanoma vaccines and highlight novel vaccine strategies to evaluate in the near future.

S155 – Spontaneous Regression of Mucosal Melanoma

Objectives Spontaneous regression of melanoma is a rare phenomenon, and it has yet to be described in the literature for mucosal melanomas, which ordinarily have a grim prognosis with a 10–15%, 5-year survival rate. We present a case of a hard palate melanoma that spontaneously regressed. Methods We present a case report, review of the literature, and a discussion. Results A 49-year-old female presented with a pigmented lesion recently on her hard palate that was biopsy-proven to be spindle-cell type malignant melanoma with a depth of 2.3 mm. It stained positive for S-100 and Melan-A. Subsequent PET/CT imaging did not show hypermetabolic activity either at the lesion or elsewhere. A wide local excision of the lesion was performed. The histopathology showed oral mucosa with focal cicatrix formation, chronic inflammation, and pigmented macrophages, but no evidence of residual melanoma. Conclusions The case illustrates histopathologic findings in a mucosal melanoma undergoing spontaneous regression. These findings point to a potentially critical role for histiocytes in effecting tumor elimination. Analysis of spontaneous melanoma regression may help understand this phenomenon better and may lead to improved immunotherapy.

Gene Expression Signature for Spontaneous Cancer Regression in Melanoma Pigs

Incomplete spontaneous regression of melanoma is common. However, complete melanoma regression is still a very rare phenomenon. Because melanoma is the most immunogenic human malignancy, the mechanisms leading to regression, based on accumulative evidence, are the host's immune responses. Unfortunately, therapies aiming to enhance the patient's natural immunity against melanoma have yet to meet their expectations. Reasons for failure include various immune escape mechanisms, induced by the tumor, that subsequently lead to tolerance. Here, we performed time-dependent gene expression profiling to unravel molecular changes involved in the transition of progressive melanoma to complete tumor regression using a porcine model. The melanoblastomabearing Libechov minipigs are highly suitable for this study because these animals exhibit naturally occurring and regressing melanomas. We were able to identify a molecular signature of the melanoma regression process. Genes regulated in this signature were associated with 1) cell cycle, 2) immune response, and 3) melanocyte differentiation. These genes may shed light on molecular mechanisms involved in complete melanoma regression and indicate what improvements are needed for successful antimelanoma therapy.

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma.

Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.

Identification of differentially expressed genes in spontaneously regressing melanoma using the MeLiM Swine Model

Partial and some few cases of complete spontaneous regression have been observed in cutaneous melanoma patients but little is known about the molecular mechanisms involved. The Melanoblastoma-bearing Libechov Minipig (MeLiM) is a suitable animal model to study the phenomenon of spontaneous regression because MeLiM pigs exhibit naturally occurring melanomas which regress completely 6 months after birth. In this study, we used suppression subtractive hybridization (SSH) to identify molecular determinants of melanoma regression within swine melanoma tissues and melanoma cell cultures. Several markers involved in cell-adhesion, -communication, -motility, signal transduction, negative regulation of cell proliferation, transport and immune response were identified that correlated with melanoma regression whereas the main genes involved in melanin synthesis showed a strong downregulation. For the most differentially expressed genes, we validated the results obtained by SSH with qRT-PCR and with immunohistochemistry for some of them (CD9, MITF, RARRES1). Most notable, for the first time in melanoma, we identified the retinoic acid responder 1 gene (RARRES1) as a main actor of the regression process in melanoma. This first gene expression study in swine melanoma regression, may contribute to the finding of new therapeutic targets for human melanoma treatment.

Complete Regression of Primary Malignant Melanoma

Over the years, histopathologic studies to determine the nature and significance of regression in malignant melanoma have yielded different results. At least in part, this most likely reflects differences in the definition of what constitutes regression. Although partial regression is relatively common, complete regression is rare. It has been said that complete regression of a primary lesion is associated with metastatic disease, but the evidence for this is largely anecdotal-the literature contains only case reports and small series. We found 2 cases of complete regression in our dermatopathology database. Metastatic disease was identified in both cases; in 1 case, the suspicion of melanoma was raised on the initial biopsy and subsequent workup revealed lymph node metastasis. These cases illustrate the histologic features of a completely regressed primary melanoma and add credence to the theory that completely regressed melanoma is associated with a poor outcome.

Long-term Survival and Occasional Regression of Distant Melanoma Metastases after Adrenal Metastasectomy

Human melanoma cells express high-affinity glucocorticoid receptors, and adrenalectomy has been shown to have antimelanoma effects in animal models. Long-term regression of distant metastatic melanoma was observed in one patient after bilateral adrenalectomy, prompting a review of adrenalectomy for melanoma metastases performed at this center. A retrospective study in which all patients treated at the Sydney Melanoma Unit and recorded as having adrenal gland metastases between January 1987 and January 2004 were identified and their survival analyzed. One hundred eighty-six patients with adrenal gland metastases were identified. Adrenalectomy was performed in 23 patients; the other 163 patients were treated nonsurgically. The adrenal glands were the sole site of disease in five patients. All symptomatic patients were free of pain after recovery from the surgical procedure. Thirteen patients were rendered clinically and radiologically disease-free by their surgery. There was no postoperative mortality within 30 days. Median overall survival after adrenalectomy was 16 months (2-year survival, 39%), compared with 5 months for patients with documented adrenal metastases treated nonsurgically (P < .00001). In one patient, nonresected visceral metastases elsewhere regressed completely after bilateral adrenalectomy; he remained well and free of disease 80 months after adrenalectomy. Regression of distant visceral metastatic disease also occurred in a second patient after unilateral adrenalectomy. Adrenalectomy for melanoma metastatic to the adrenal gland provides good palliation of symptoms and is associated with prolonged survival in a selected cohort of patients. We report for the first time sustained complete regression of distant metastatic melanoma after bilateral adrenalectomy, suggesting a possible role for adrenal hormones in modifying melanoma progression in certain patients.

Impaired Dendritic Cell Migration and T cell Stimulation in Aging Lead to Defective Dendritic Cell‐Mediated Antitumor Immunity

We recently reported that bone marrow‐derived dendritic cells (DCs) from old C57BL/6 mice are less effective than their young counterpart in inducing the regression of B16‐OVA melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide (257–264), DCs from aged (18–20 months) mice are less efficient than those from young (3–6 months) mice in stimulating MHC class I OVA‐specific T cells in vitro (p&lt;0.0025). Phenotypic analysis revealed a selective decrease in DC‐specific/intracellular adhesion molecule type 3‐grabbing, nonintegrin (DC‐SIGN) level in aged DCs. Importantly, vaccination of young mice using old OVA‐peptide(257–264) pulsed DCs resulted in impaired activation of OVA‐specific CD8+ splenic T cells in vivo (p&lt;0.025). These splenic T cells from aged animals were able to differentiateinto IFN‐γ‐producing and cytotoxic effectors, but to a significantly less extent than those vaccinated with young OVA PP‐DCs. A decrease influx of CD8+ T cells within the tumor was also observed seven days after old DC injection. Finally, adoptive transfer experiments showed defective in vivo DC trafficking in aging, with half as many aged DCs migrated to the regional lymph nodes (p&lt;0.025). This correlates with reduced CCR7 gene expression, impaired in vitro migration of aged DCs in response to CCL21, and defective CCR7 signaling in aged DCs. Taken together, our findings suggest that defective DC migration and T cell stimulation contribute to the observed impaired DC tumor immunotherapeutic response in aging.This work id supported by the NIH (1RO1AG020628‐01A2; 3RO1 AR42525) (RY), the Ann Arbor VA Health System (VA Merit Review) (RY), and by the NIH‐NIA (AG024824, University of Michigan OAIC Pepper Center) (AG).

The correlation of regression in primary melanoma with sentinel lymph node status

Background:The significance of regression in primary melanoma has been disputed for many years. Some have suggested regression as a marker for poor prognosis while others have reported a negligible or...

High-Frequency Ultrasound Characteristics of 24 Iris and Iridociliary Melanomas

To evaluate size, characteristics, and regression of iris and iridociliary melanomas on high-frequency ultrasound images before and after plaque brachytherapy. Retrospective review of high-frequency ultrasound characteristics of 24 consecutive iris and iridociliary melanomas before and after radiation therapy. The median tumor thickness before radiation therapy was 2.3 mm (range, 1.4-4.3 mm). Nineteen iris melanomas (79%) involved the ciliary body, 18 (75%) involved the iris pigment epithelium, 11 (46%) were club shaped, and 4 (17%) caused disinsertion of the iris root. At a median follow-up of 30 months after plaque brachytherapy, the mean tumor thickness had diminished to 1.2 mm (median, 1.2 mm; range, 0.9-1.9 mm). While all tumors exhibited a reduction in thickness, no tumors showed additional regression after 30 months past treatment. Fourteen tumors (58%) were noted to have increases in internal reflectivity. There was 1 failure of local control (at 6 years), successfully treated by a second application of plaque brachytherapy. High-frequency ultrasonography revealed unique tumor characteristics, quantified tumor size, and demonstrated tumor response to radiation therapy.

Spontaneous regression of cutaneous head and neck melanoma: Implications for the immunologic control of neoplasia

Spontaneous regression of cancer in the head and neck is a rare event. Moreover, there are rare reported cases of spontaneous regression of primary head and neck melanoma with accompanying immunohistochemical analysis of the tumor. We used detailed preoperative and postoperative pathologic examination of a lesion in the right supraclavicular region. Pathologic examination of the initial specimen identified a melanoma of superficial spreading type with vertical growth and a thickness of 1.8 mm. The excised specimen demonstrated a complete regression of the melanoma with a florid host inflammatory response predominantly composed of a histiocytic reaction. The case presented illustrates histopathologic findings occurring in a head and neck melanoma as it is undergoing spontaneous regression. These findings point to a potentially critical role for histiocytes in effecting tumor elimination. Pathologic analysis of spontaneous head and neck melanoma regression will ultimately facilitate an improved understanding of naturally-occurring tumor elimination.

Vaccine therapy for melanoma: Current status and future directions

A vaccine is typically defined as any preparation used as a preventive inoculation to confer immunity against a specific disease. Vaccines for infectious diseases are highly effective, acting by inducing antigen-specific immunity that prevents subsequent infection. Unfortunately, the success of vaccines in infectious diseases has not been mirrored in oncology. This failure is the result of several challenges facing cancer vaccines, including the conceptual shift from disease prevention to disease treatment, tumor-induced immunosuppression and other mechanisms of immune escape, the similarity between tumor antigens and self antigens to which the patient is tolerant, unfavorable effector-to-target ratios in patients with established tumors, and financial and regulatory issues. Despite this, cancer remains a promising target for vaccine therapy. Melanoma in particular is known for its inherent immunogenicity on the basis of many anecdotal reports of spontaneous immune-based tumor regression, and thus has been the focus of immunotherapeutic approaches. Rare but significant vaccine-induced clinical regression of melanoma has spurred intensive investigations to augment vaccine efficacy. This review explores the many vaccine strategies that have been clinically tested for the treatment of melanoma and considers future approaches of cancer immunotherapy.

Improved survival following lymphadenectomy for nodal metastasis from an unknown primary melanoma

8515 Background: It is not possible to identify a primary site in 10–20% of melanoma patients presenting with palpable nodal metastases. The explanation for this phenomenon is unknown but could reflect an endogenous antimelanoma immune response that causes complete regression of the primary melanoma. If so, then these patients should have a better survival than patients whose primary melanoma has been identified. Methods: We reviewed our 13,000-patient prospective melanoma database (1971–2005) to identify patients managed with regional lymphadenectomy for palpable nodal metastases from unknown primary melanoma (MUP) or known primary cutaneous melanoma (MKP). Multivariate analysis was performed to identify prognostic factors significant for survival. MUP and MKP patients were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis. Results: Among 1571 patients with palpable nodal metastases who underwent regional lymphadenectomy, multivariate analysis identified 5 significant covariates: age (HR=1.294, P=0.0017), sex (HR=1.335, P=0.0004), nodal tumor burden (HR=1.256, P&lt;0.0001), decade of diagnosis (HR=0.989, P=0.0131), and unknown/known primary (HR=1.507; 95% CI=1.220 to 1.862; P=0.0001). Five-year OS was significantly higher for the 262 MUP patients than 1309 MKP patients (55±6% vs. 44±3%; P=0.0021). Computerized matching of MUP and MKP patients by four significant covariates (age, sex, nodal tumor burden, and decade of diagnosis) yielded 221 matched pairs. Median OS and 5-year OS rates were 165 months and 58±7%, respectively, for MUP as compared with 34 months and 40±6%, respectively, for MKP (P=0.0008). Conclusions: Our results strongly support the effectiveness of lymphadenectomy for nodal metastasis from MUP. Risk of death dropped significantly when regional lymphadenectomy was performed for metastases from MUP as compared with MKP. This result is compatible with an immunologic rejection of the primary melanoma due to a strong host antitumor immune response. Immunologic studies to identify cell-mediated and antibody components of this response are underway. No significant financial relationships to disclose.

Absence de valeur prédictive des signes de régression histologique sur l’envahissement du ganglion sentinelle

The predictive value of regression in melanoma is debated. A retrospective single-centre study to evaluate the correlation between regression in primary skin tumor and the presence of micrometastases in sentinel lymph nodes. Histological signs of regression in 84 melanomas (>1 mm) with corresponding sentinel lymph nodes were studied by two independent pathologists. Regression was seen in 40 skin melanoma tumors while micrometastasis was seen in 24. Of the tumors with micrometastasis, only 10 were regressive (RR: 0.47, p=0.49). Breslow value>2 mm and male sex were predictive for node micrometastasis (RR: 4.6, p=0.03 and RR: 7.6, p=0.006, respectively). On multivariate analysis, these two factors were independent. These data suggest that regression in primary cutaneous melanoma is not predictive for lymph node metastasis.

A Randomized Phase 2 Trial of Bevacizumab with or without Daily Low-Dose Interferon Alfa-2b in Metastatic Malignant Melanoma

Vascular endothelial growth factor (VEGF) is a proangiogenic molecule produced by melanoma cells. We hypothesized that administration of bevacizumab (Bev), a monoclonal antibody that neutralizes VEGF, with low-dose interferon alfa-2b (IFN-alpha2b), an inhibitor of basic fibroblast growth factor (FGF), would lead to the regression of metastatic melanoma. Patients with metastatic melanoma were randomized to receive Bev (15 mg/kg intravenously every 2 weeks) with or without low-dose IFN-alpha2b (1 MU/m2 subcutaneously daily). Patients exhibiting a clinical response or stable disease after 12 weeks were treated until disease progression. Thirty-two patients (16 per arm) were accrued (18 male, 14 female; mean age 57.5 years). Both regimens were well tolerated. Six patients developed easily managed exacerbations of preexisting hypertension. Two patients developed grade 3 proteinuria that resolved after a treatment break. IFN-alpha2b therapy was associated with grade 1 to 2 constitutional symptoms. Arterial thromboembolic complications were observed in three patients (two mild myocardial infarctions, one transient ischemic attack), all of whom had risk factors. One patient (Bev plus IFN-alpha2b arm) had locally recurrent scalp disease that partially responded to therapy. Eight patients (five Bev, three Bev plus IFN-alpha2b) had prolonged disease stabilization (24 to 146 weeks). Plasma levels of VEGF and FGF did not correlate with any clinical parameter. The patient with the longest period of stable disease had the highest baseline VEGF and FGF. Bev was well tolerated at this dose and prolonged disease stabilization was achieved in one-quarter of metastatic melanoma patients. Low-dose IFN-alpha2b did not augment the activity of Bev.

Regression of Lung and Colon Cancer Xenografts by Depleting or Inhibiting RLIP76 (Ral-Binding Protein 1)

Ral-binding protein 1 (RALBP1) is a stress-responsive and stress-protective multispecific transporter of glutathione conjugates (GS-E) and xenobiotic toxins. It is frequently overexpressed in malignant cells and plays a prominent antiapoptotic role selectively in cancer cells through its ability to control cellular concentration of proapoptotic oxidized lipid byproducts. In the absence of chemotherapy, depletion or inhibition of RALBP1 causes regression of syngeneic mouse B16 melanoma. Because RALBP1 transports anthracycline and Vinca alkaloid drugs, as well as GS-E, and because it confers resistance to these drugs, we proposed that depletion or inhibition of RALBP1 should cause regression of human solid tumors that overexpress RALBP1 and augment chemotherapy efficacy. Non-small-cell lung cancer (NSCLC) H358 and H520 and colon SW480 cell lines were used. Cytotoxic synergy between anti-RALBP1 immunoglobulin G (IgG), cis-diammine-dichloroplatinum (II) [CDDP], and vinorelbine was examined in cell culture and xenografts of NSCLC cells. Effects of RALBP1 depletion by antisense were examined in xenografts of NSCLC H358, NSCLC H520, and colon SW480 cells. RALBP1 depletion by phosphorothioate antisense was confirmed and was associated with rapid, complete, and sustained remissions in established s.c. human lung and colon xenografts. RALBP1 inhibition by anti-RALBP1 IgG was equally as effective as antisense and enhanced CDDP-vinorelbine in lung cancer xenografts. These studies show that RALBP1 is a transporter that serves as a key effector function in cancer cell survival and is a valid target for cancer therapy, and confirm that inhibitory modulation of RALBP1 transport activity at the cell surface is sufficient for antitumor effects.

Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease

Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions. Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an L-glutamine--enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-alpha, and IFN-gamma were administered as a combination therapy. Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P<0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (>120 days) without recurrence in 90% of mice receiving the full therapy. Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities. Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.

Defective CCR7 function in aging: implications for dendritic cell migration (B156)

Abstract We recently reported that bone marrow-derived dendritic cells (DCs) from old C57BL/6 mice are less effective than their young counterpart in inducing the regression of pre-established B16-OVA melanomas. However, the mechanisms for this are unclear. DCs migration to lymphoid organs is essential to effective DC anti-tumor activity and is regulated by interactions between CCR7 and its ligands CCL21 and CCL19. We therefore examined the effect of aging on DC migration, CCR7 expression and function. Young (3–6 months) and old (18–20 months) DCs were labeled with CFSE and CMPTX, and their in vivo migration quantified by fluorescent microscopy. Half as many aged DCs were present in the popliteal lymph nodes (p&amp;lt;0.025). DCs from aged mice express 50% less CCR7 compared to young DCs (p&amp;lt; 0.0005). Surprisingly, the reduced gene expression did not result in any significant change in CCR7 surface expression on DCs. Nevertheless, the reduced CCR7 gene expression correlated with the impaired in vitro migration of aged DCs in response to CCL21 (p&amp;lt; 0.05). Finally, we showed that aged DCs have impaired signaling following exposure to CCL21. In conclusion, our data showed that old DCs have defective in vivo migration that correlates with reduced CCR7 gene expression, as well as impaired in vitro CCL21 migratory response and signaling. These findings may contribute to the observed impaired DC tumor immunotherapeutic response in aging.