Elena Marra

Extracorporeal photopheresis for the treatment of erythrodermic cutaneous T‐cell lymphoma: a single center clinical experience with long‐term follow‐up data and a brief overview of the literature

Extracorporeal photopheresis (ECP) is a therapeutic procedure in which leukapheresed peripheral blood mononuclear cells are exposed to ultraviolet A in the presence of the photosensitizer 8‐methoxypsoralen and then reinfused. Several guidelines recommend ECP as a treatment of choice in erythrodermic primary cutaneous T‐cell lymphomas (E‐CTCL). However, the level of evidence is low due to the rarity of this disease and the lack of randomized controlled trials. We performed a review of the English literature, restricting our analysis to studies including erythrodermic patients and more than 10 cases. Based on these criteria, we identified 28 studies, with a total of 407 patients. The median response rate in erythrodermic patients was 63% (range 31–86%), with a complete response rate ranging between 0 and 62% (median 20%). In our experience, we treated 51 patients with E‐CTCL since 1992. A clinical response was obtained in 32 of 51 patients (63%), with a 16% complete response rate. The median time for response induction was eight months (range: 1–23). The median response duration was 22.4 months (range six months to 11 years). The treatment was generally well tolerated without systemic toxicities grade III–IV. The pretreatment parameters significantly associated with a higher likelihood to obtain a clinical response were the B‐score in the peripheral blood, CD4/CD8 ratio, and amount of circulating CD3+CD8+ cells. Literature data together with our personal experience clearly support the clinical activity and tolerability of ECP in patients with E‐CTCL. Prospective controlled clinical trials are strongly recommended to better document the evidence.

Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years

In many centers, Stage I–II melanoma patients are considered “cured” after 10 years of disease‐free survival and follow‐up visits are interrupted. However, melanoma may relapse also later. We retrospectively analyzed a cohort of 1,372 Stage I–II melanoma patients who were disease‐free 10 years after diagnosis. The aim of this study was to characterize patients who experienced a late recurrence and to compare them to those who remained disease‐free to identify possible predictive factors. Multivariate Cox proportional‐hazards regression analyses were carried out to evaluate the influence of different factors on the risk of recurrence. Seventy‐seven patients out of 1,372 (5.6%) relapsed, 52 in regional sites and 25 in distant ones. The majority of patients (31 out of 52) experienced late recurrence in regional lymph nodes. Brain and lung were the most common site of single distant recurrence (24% each). Patients with multiple distant metastases showed a brain and lung involvement in, respectively, 40 and 48% of cases. A Cox proportional‐hazards regression model analysis showed the independent role of age under 40 years, Breslow thickness >2 mm, and Clark Level IV/V in increasing the risk of Late Recurrence. These patients should be followed‐up for longer than 10 years. The pattern of recurrence suggests that melanoma cells can be dormant preferentially in lymph nodes, brain and lung. A particular attention should be reserved to these anatomic sites during the follow‐up after 10 years of disease‐free.

Prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis

The prognostic significance of histological regression in primary melanoma has been debated for many years. We aim to review the evidence to see how histological regression may affect prognosis. A systematic review was performed by searching in MEDLINE, Scopus and the Cochrane Library from 1 January 1966 to 1 August 2015. All studies reporting hazard ratios or data on survival and histological regression were included. Primary random‐effects meta‐analyses were used to summarize outcome measures. Heterogeneity was assessed using the χ2‐test and I2‐statistic. To assess the potential bias of small studies we used funnel plots and the Begg and Mazumdar adjusted rank correlation method. Summaries of survival outcomes were measured as hazard ratios or relative risk of death at 5 years according to the presence of histological regression of primary melanoma. In total, 183 articles were reviewed out of 1876 retrieved. Ten studies comprising 8557 patients were included. Patients with histological regression had a lower relative risk of death (0·77, 95% confidence interval 0·61–0·97) than those without. Examination of the funnel plot did not provide evidence of publication bias. The results showed that histological regression is a protective factor for survival.

Treatment of metastatic melanoma: A multidisciplinary approach

The prognosis of stage IV metastatic melanoma is poor. An overall 1-year survival of 25.5% and a median survival of 6.2 months were reported without any significant improvement during the last 30 years before the introduction of new drugs (immune checkpoint inhibitors and targeted therapies) which completely modified the therapeutic approach and induced an overwhelming improvement on the survival rates of these patients. This review will analyze the therapeutic tools available for the treatment of patients with metastatic melanoma, including adjuvant interferon and locoregional therapies (surgery, radiotherapy and electrochemotherapy) and will mainly focus on the presentation of results obtained by the new treatments (checkpoint inhibitors and targeted therapies).

Current status and perspectives in immunotherapy for metastatic melanoma

Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.

Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors

The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive. However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed.

Arrhythmias in metastatic melanoma patient treated with targeted therapy and ICD implant

Metastatic melanoma is an aggressive and rapidly progressive disease. Heart metastases were shown in over 50% of autopsy. However, these metastases are usually clinically silent and reported in less than 2% of living patients1.2. There are no specific guidelines for the treatment of cardiac metastases as the therapeutic approach varies with the clinical features of the patient. This article is protected by copyright. All rights reserved.

Confocal microscopy and dermoscopy for the monitoring of BRAF inhibitor therapy of melanoma skin metastases.

Herein we demonstrated the utility of dermoscopy and RCM in the monitoring of BRAF inhibitore therapy for melanoma skin metastases. Dermoscopically, after therapy all nodules and papules were typified by the presence of bluish colour with crystalline structures and peppering feature. RCM revealed a honeycombed pattern as typical finding of healthy skin; at dermal level, grossly arranged collagen fibers were detected along with small bright particles corresponding to inflammatory cells. Notably, no atypical melanocytes or any other malignant features were seen at all skin levels. This article is protected by copyright. All rights reserved.

Atopic dermatitis in a phenylketonuric untreated patient

Phenylketonuria (PKU) is an autosomal recessive metabolic disease, which is seen in approximately 1:12,000– 1:18,000 newborn. PKU results from a deficiency of phenylalanine hydroxylase, the enzyme converting phenylalanine into tyrosine. Hyperphenylalaninemia is the biochemical hallmark of PKU. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity; without dietary restriction of phenylalanine, patients will develop profound and irreversible intellectual disability and neurological disturbances. The natural history of this disorder has been changed since newborn screening was introduced in the late 1960s, and affected children are now maintained on a phenylalanine restricted diet, which must commence as soon as possible after birth and should continue for life. Skin disorders linked with PKU are principally scleroderma-like changes with guttate or generalized morphea and hypopigmentation; dermatitis is also described in these patients. An accurate description of clinical features of this dermatitis cannot be found in the literature, and the relationship with atopic dermatitis, a multifactorial, inflammatory skin disease with a chronic or relapsing course, has never been analyzed thoroughly.