Regional therapies for locoregionally advanced and unresectable melanoma

Locoregionally advanced and unresectable disease can be seen in up to 10% of melanoma patients. Treatment options for these patients have been evolving most notably over the past few decades and have demonstrated efficacy through multiple intra-arterial as well as intralesional therapies. Isolated limb perfusions and isolated limb infusions have been utilized to treat locoregionally advanced melanoma of the extremity with overall response rates up to 90% in some reports. Intralesional therapies, for in transit metastatic melanoma, such as Bacille Calmette–Guerin, talimogene laherparepvec, and PV-10 (Rose Bengal) have all demonstrated efficacy in the treatment of unresectable cutaneous melanoma. The treatment effect due to intralesional injection has been identified in directly injected lesions as well as in distant uninjected “bystander lesions” with some injectables. This bystander effect is likely an immunologic reaction due to tumor antigen release, antigen-presenting cell uptake, T cell activation and subsequent bystander tumor destruction in uninjected lesions. Treatment options for unresectable melanoma metastases limited to the liver include isolated hepatic perfusion, which can now be performed through a minimally invasive approach known as percutaneous hepatic perfusion. These intra-arterial and intralesional regional therapies offer a variety of effective treatment modalities for unresectable disease and may potentially be combined with systemic treatments, such as immunotherapy, in the future treatment of locoregionally advanced melanoma.     

Molecular clonality of in-transit melanoma metastasis

In-transit melanoma is characterized by an aggressive pattern of recurrence that is associated with a poorer prognosis. Because in-transit melanoma is considered to result from the intralymphatic trapping of melanoma cells between the primary tumor and regional lymph nodes, it provides an excellent model to assess genetic events associated with early metastasis. The hypothesis of this study was to determine whether in-transit metastases are clonal in origin and therefore, may have specific genetic alterations uniquely associated with this disease and the development of early metastasis. This was assessed using loss of heterozygosity (LOH) analysis for specific DNA microsatellite loci. Seventy-nine paraffin-embedded in-transit melanoma lesions from 25 patients (range, 2 to 9 lesions per patient; average, 3.4 lesions per patient) were assessed for LOH using eight microsatellite DNA markers on six chromosomes. In 19 of 25 patients (76%) LOH was demonstrated for at least one marker. The most frequent microsatellite marker demonstrating LOH was D9S157 (56%). Using LOH microsatellite markers to assess intertumor heterogeneity, six of 79 tumors (7.6%) demonstrated different profiles when compared to other lesions from the same patient. In-transit metastases from those patients demonstrating intertumor heterogeneity were further assessed using laser capture microdissection and DNA analysis, and revealed no significant intratumor heterogeneity. In conclusion, LOH was frequently observed in in-transit melanoma metastasis. Based on LOH analysis, in-transit metastases are clonal in origin. The establishment of clinically successful in-transit melanoma metastasis requires specific genetic events that seem to be unique and homogeneous for each patient.     

Genetic factors in metastatic progression of cutaneous melanoma: the future role of circulating melanoma cells in prognosis and management

The greatest potential for improvement of outcome for patients with Cutaneous Malignant Melanoma lies in the prevention of systemic metastasis. Despite extensive investigation, current prognostic indicators either alone or in combination, although related to melanoma progression, are not sufficient to accurately predict the pattern of progression and outcome for any individual patient. Metastasis related death has been recorded in patients initially diagnosed with early stage tumour as well as in patients many years after initial tumour removal. The trouble finding a predictable pattern in the puzzle of melanoma progression may be linked to the fact that most of the material studied for prognosis is either, cutaneous primaries or metastatic deposits, rather than the melanoma cells in the circulatory system which are responsible for disease progression. In this review article we discuss the potential use of circulating tumour cell (CTC) detection and quantification for identifying patients at risk of metastatic deposits. We also discuss current therapies for the treatment of metastatic melanoma and analyse how CTCs may be used to evaluate the effectiveness of current therapies and to pinpoint patients who require further treatment.     

Topical immunotherapy with diphencyprone (DPCP) for in-transit and unresectable cutaneous melanoma lesions: an inaugural Canadian series

Background: Diphencycprone (DPCP) is an immune contact sensitizer applied to melanoma lesions. Early studies show favorable efficacy. We present the first North-American series of patients treated with DPCP.

Methods: A single center retrospective study of patients with in-transit or unresectable melanoma lesions treated with DPCP from December 1,2014 to December 31,2015 was completed. Primary objectives were response rate and toxicity. Secondary objective was health-related quality of life assessment with the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire.

Results: Fifteen consecutive patients were identified with median age of 78 (range 43–92). 73% of patients had prior treatment. Two patients (13%) had a complete response after 25 and 32 weeks, respectively. Four patients (27%) had a partial response with a mean treatment time of 30 weeks (range 6–51 weeks). Six (40%) had stable disease. Six patients stopped DPCP – three from systemic progression and three from toxicity. The most common toxicity was blisters; one patient had significant skin ulceration that resolved on stopping DPCP. Median FACT-M score was 142.95 (possible total 172). Mean overall follow-up time was 22.7 weeks.

Conclusion: DPCP is a feasible option for in-transit and other melanoma cutaneous lesions ineligible/refractory to surgery and may delay need for systemic therapy.     

Prediction of outcome for patients with cutaneous melanoma

Pathologists continue to have a major role in the assessment of prognosis for melanoma patients. Accurate assessment of likely clinical outcome permits the planning of optimal surgery and measured deployment of potentially morbid chemotherapy and immunotherapy. Accurate diagnosis of pigmented lesions, although often difficult, avoids potentially disastrous undertreatment of melanoma and undesirably extensive surgery for benign melanocytic lesions. Assessments of single factors of primary melanoma, such as measured width of ulceration, Clark level and Breslow thickness, remain valuable and should be recorded. Completeness of excision, including excision of the radial growth phase, must be reported accurately to minimize the possibility of local and satellitic growth. Techniques that combine different prognostic factors increase predictive accuracy, but are often cumbersome. We have developed a relatively simple multifactorial approach designed to individualize prognosis assessment. The extent of regional disease, number of tumour-positive lymph nodes, and extent of involvement of the nodes (proportional area of tumour, proportional diameter of tumour and extracapsular spread) are all accurate predictors of further recurrence and death from melanoma. Similar techniques may be applied to the sentinel node to determine the likelihood that there may be tumour in the non-sentinel nodes (and thus whether the patient may need a complete regional lymph node dissection), and the probability of later recurrences and death from melanoma. Staging will become increasingly precise as newer techniques, such as real-time polymerase chain reaction are utilized. In the foreseeable future, the surgical pathologist will remain the main provider of the information on which management decisions are based.     

The morphological features of locally recurrent melanoma and cutaneous metastases of melanoma.

Local recurrence of melanoma at the primary excision site usually implies that the primary excision was incomplete or "inadequate" and that the recurrence was attributable to retained primary melanoma cells or occult melanoma metastases in the adjacent tissue. Pathologists frequently report these tumors in the scar as recurrent or residual melanoma, apparently without considering the possibility that they may be local metastases and manifestations of systemic disease. In this study of 72 cases, we have shown that the morphological features of locally recurrent melanoma, excluding persistent incompletely excised primary melanoma, and cutaneous metastases of melanoma were identical. Because the prevention of local recurrence is the main reason for wide excision of melanoma beyond complete excision of the primary tumor itself, it is essential that pathologists should classify these neoplasms precisely as either persistent incompletely excised primary melanoma or metastatic melanoma.     

T cell receptor therapy against melanoma—Immunotherapy for the future?

Malignant melanoma has seen monumental changes in treatment options the last decade from the very poor results of dacarbazine treatment to the modern-day use of targeted therapies and immune checkpoint inhibitors. Melanoma has a high mutational burden making it more capable of evoking immune responses than many other tumours. Even when considering double immune checkpoint blockade with anti-CTLA-4 and anti-PD-1, we still have far to go in melanoma treatment as 50% of patients with metastatic disease do not respond to current treatment. Alternative immunotherapy should therefore be considered. Since melanoma has a high mutational burden, it is considered more immunogenic than many other tumours. T cell receptor (TCR) therapy could be a possible way forward, either alone or in combination, to improve the response rates of this deadly disease. Melanoma is one of the cancers where TCR therapy has been frequently applied. However, the number of antigens targeted remains fairly limited, although advanced personalized therapies aim at also targeting private mutations. In this review, we look at possible aspects of targeting TCR therapy towards melanoma and provide an implication of its use in the future.     

Treatment of cutaneous mastocytosis

Therapy of cutaneous mastocytosis is directed towards skin and systemic symptoms due to mediator release and targeted on skin lesions. Symptomatic therapy of cutaneous mastocytosis involves agents that inhibit the release of mediators or antagonize H1 and H2 receptors such as antihistamines ketodifen and Aspirin. Disodium cromoglycate has no effect of the cutaneous symptoms of cutaneous mastocytosis. Skin-targeted therapies that lead to a resolution of the lesions of cutaneous mastocytosis are psoralen-photochemotherapy and topical corticosteroid therapy either by occlusion or intralesional injection for a limited number of lesions. There is no treatment that permanently cures cutaneous mastocytosis and patient selection will therefore have to be made on the basis of the clinical manifestations, onset of disease, the probability of spontaneous involution and the severity of cutaneous and systemic symptoms.     

Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm

Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.     

"All in one" cardiopulmonary bypass circuit for aortic surgery

We devised an "all in one" cardiopulmonary bypass circuit for aortic surgery, and evaluated its efficacy and safety. The circuit consisted of a venous line, reservoir, single centrifugal pump, membrane oxygenator and arterial line bifurcated into two lines for systemic perfusion and selective branch perfusion. The perfusion volume was regulated by an occluder and measured by a flow sensor. A closed partial bypass was established using a shunt line bypassing the reservoir. We applied this circuit to 25 patients with aortic disease. Regulation of both the selective cerebral perfusion (SCP) and the selective branch perfusion was easily performed. There was neither stroke nor organ dysfunction postoperatively. There are some cases in which it is difficult to decide the necessity for SCP preoperatively; the use of this circuit may resolve this problem. This circuit can be easily and safely applied to any type of aortic surgery.     

Immunohistochemistry in melanocytic proliferative lesions

Melanoma incidence is rising worldwide. Early diagnosis is very important, as the most effective treatment for melanoma still consists of excision of the tumour before onset of the metastatic growth phase. Immunohistochemistry is a valuable tool for (dermato)pathologists to aid establishing diagnosis. Melanoma markers can be classified into two main categories: melanocytic differentiation markers and melanoma progression markers. Melanocytic differentiation markers are mostly used to distinguish poorly differentiated melanomas from non-melanocytic tumours and for staging of melanocytic proliferative lesions. Melanoma progression markers are most suitable to determine the level of malignancy and/or aggressiveness of tumour cells. This review describes the classification of melanoma markers, including commonly used and recently identified antigens with potential marker function. We characterize their expression profile in melanocytic proliferative lesions and their potential usefulness for diagnosis, prognosis, microstaging, immunotherapeutic purposes and evaluation of therapies.     

Mortality and morbidity after initial diagnostic excision biopsy of cutaneous melanoma in primary versus secondary care

Background

Current UK melanoma guidelines do not support the initial diagnostic excision biopsy of pigmented lesions in primary care, although this is standard in other countries such as Australia. Previous research in Northeast Scotland found that initial diagnostic excision biopsies in primary care that prove to be melanoma were no more likely to be incomplete than those performed in secondary care, but data on longer-term outcomes were not available.

Aim

To determine whether initial diagnostic excision biopsy of cutaneous melanoma in primary versus secondary care leads to poorer survival and increased morbidity.

Design and setting

Analysis of a linked dataset comprising pathological data from melanoma cases diagnosed in Northeast Scotland between 1991 and 2007, the General Registry Office (Scotland) death registry, and an NHS Scotland episode of care database.

Method

Patient data from three sources were matched using the Community Health Index (CHI) number. Cox proportional hazards regression, with robust standard error estimates, was used to examine the hazard ratio (95% confidence interval) of key mortality and morbidity outcomes based on excision in primary versus secondary care. Analysis was conducted before and after adjustment for operator and patient-level factors, using a multilevel approach.

Results

Patients receiving their initial diagnostic excision biopsy for melanoma in primary versus secondary care were no more likely to be dead, or to have died of metastatic malignant melanoma. Patients who had their initial diagnostic excision biopsy for melanoma in primary care had significantly fewer subsequent hospital admissions and spent fewer days in hospital.

Conclusion

These findings suggest that initial diagnostic excision biopsy of melanoma in primary care does not lead to poorer long-term outcomes.     

Recombinantly engineered human proteins: transforming the treatment of psoriasis

Psoriasis is a chronic, inflammatory disease with lesions that produce considerable physical discomfort and often lead to substantial disruption in patients' daily activities. The use of currently available, nonspecific, systemic immunosuppressive therapies for patients with moderate to severe psoriasis is limited by an inability to maintain disease remission safely. Advances in recombinant DNA technology paralleled with increased understanding of the immunopathology of psoriasis have led to the development of numerous biologic agents for the treatment of this disease. These new biologic therapies target specific steps in psoriasis pathology, including direct effects on T cells, T cell activation, T cell migration, and cellular production and secretion of cytokines. By selectively targeting the activities of T cells that are directly involved in psoriasis pathogenesis, these novel agents offer improved safety profiles and enhanced efficacy. In this article, the mechanisms of T cell pathogenicity that guided the development of these new biologic therapies are reviewed along with clinical data on the progress of these agents.     

Biopsy of sentinel lymph node in melanoma is not yet the standard treatment

The trend to implement sentinel node biopsy as standard of care in patients with clinically localized melanoma is encouraged by the following three factors: the technique of lymphatic mapping has matured to the point that consensus was reached on how the procedure should be carried out, surgeons showed that they can find the node in nearly 100% of patients, and tumor-status was shown to be the most powerful prognostic factor. However, recent studies revealed unfavorable new information that questions the wisdom of this trend. Three studies published in 2001 with a combined total of 1,851 patients show false-negative rates of 16-25%. Another unnerving finding is the 13-19% incidence of in-transit metastases in patients with a tumor-positive sentinel node, reported by three groups. The ultimate purpose of lymphatic mapping is to provide sentinel node positive patients with early therapeutic measures, such as regional node dissection and adjuvant systemic treatment. However, there is currently no evidence that this approach results in improved regional control and survival. Sentinel node biopsy can only become part of routine patient management if the tumor-status of the sentinel node carries clear implications of proven benefit for the manner in wich patients are managed and if regional control is not jeopardized.     

Impact of sentinel lymphadenectomy on survival in a murine model of melanoma

Lymphatic mapping and sentinel lymph node biopsy—also termed sentinel lymphadenectomy (SL)—has become a standard of care for patients with primary invasive cutaneous melanoma. This technique has been shown to provide accurate information about the disease status of the regional lymph node basins at risk for metastasis, provide prognostic information, and provide durable regional lymph node control. The potential survival benefit afforded to patients undergoing SL is controversial. Central to this controversy is whether metastasis to regional lymph nodes occurs independent of or prior to widespread hematogenous dissemination. A related area of uncertainty is whether tumor cells residing within regional lymph nodes have increased metastatic potential. We have used a murine model of primary invasive cutaneous melanoma based on injection of B16-BL6 melanoma cells into the pinna to address two questions: (1) does SL plus wide excision of the primary tumor result in a survival advantage over wide excision alone; and (2) do melanoma cells growing within lymph nodes produce a higher incidence of hematogenous metastases than do cells growing at the primary tumor site? We found that SL significantly improved the survival of mice with small primary tumors. We found no difference in the incidence of lung metastases produced by B16-BL6 melanoma cells growing exclusively within regional lymph nodes and cells growing within the pinna.     

Treatment of pemphigus vulgaris: part 2 – emerging therapies

ABSTRACT

Introduction: Corticosteroids and immunosuppressive agents have been the mainstay for the treatment of pemphigus vulgaris (PV). While they have benefited patients, they have been associated with the risks of prolonged immune suppression and a high incidence of significant and catastrophic side effects. Relapses are common. Novel agents promising targeted therapies, that may provide better outcomes, are being studied.

Areas covered: Recently rituximab with corticosteroids has been recommended as the first-line treatment for PV. A number of known and new therapeutic agents currently investigated are BAFF, P13K, BTK inhibitors along with the use of IVIg and CAR-T therapy. The possible role of these therapeutic targets in the pathophysiology appears to be the rationale for the treatment of this potentially fatal disease.

Expert opinion: While there is significant enthusiasm for these therapies, certain concerns and consequences are being under-discussed. None of the current clinical trials in progress are specific for PV, except possibly CAR-T therapy. The major issue(s) that are unclear is whether these therapies would be successful in providing long-term clinical remissions. Will these therapies require additional agents to be effective? Will the benefits be limited in duration? The answers to many questions will determine their final place in the algorithm for the treatment of PV.     

Immune-mediated inflammatory reactions and tumors as skin side effects of inflammatory bowel disease therapy

Abstract

All drugs currently used for treating patients with inflammatory bowel disease (IBD – including Crohn’s disease and ulcerative colitis) have the potential to induce skin lesions ranging from mild eruptions to more serious and widespread clinical presentations. The number of cutaneous adverse reactions due to IBD therapies is progressively increasing and the most frequently involved drugs are thiopurines and biologics like tumor necrosis factor (TNF)-α antagonists. The main drug-induced cutaneous manifestations are non-melanoma skin cancer (NMSC), notably basal cell and squamous cell carcinomas, and viral skin infections for thiopurines and psoriasiform, eczematoid and lichenoid eruptions as well as skin infections and cutaneous lupus erythematosus for biologics. Cutaneous manifestations should be promptly recognized and correctly diagnosed in order to quickly establish an adequate therapy. The main treatment for NMSC is surgical excision whereas the management of immune-mediated inflammatory skin reactions varies from topical therapy for mild presentations to the shift to another drug alone or in combination with corticosteroids for extensive eruptions.     

Recent discoveries in the genetics of melanoma and their therapeutic implications

The incidence of cutaneous malignant melanoma, tumors arising from melanocytes, has increased markedly over the past few years in many countries. Although early melanoma is curable through surgical excision, the prognosis of advanced melanoma is very poor, this tumor being resistant to current therapies. Thus there is a need for new therapies to improve the treatment of advanced melanoma. This review provides an overview of recent discoveries in the genetics of melanoma which could offer new therapeutic opportunities.