Early Diagnosis of Melanoma and Breast Cancer in Women: Influence of Body Image Perception.

The diagnosis of melanoma and breast cancer may impact many aspects of life with significant reductions in emotional functioning and quality of life. The aim of the study was to analyze the emotional traits of female patients with oncological in early-stage diagnosis, investigating predictors for psychological distress and analyzing body image perception. An observational study was conducted, A sample of 84 female cancer patients (age range 30-55 years) with melanoma (n = 42) and breast cancer diagnosis (n = 42). The examined emotional variables were psychological distress; depression, stress, and anxiety; metacognitions; and body self-perception. Findings showed higher psychological distress in breast cancer than in melanoma patients (p = 0.00), which was related to lower positive self-perception of body image (p = 0.03). Furthermore, psychological distress was negatively correlated with consequences of clinical treatment on body image, and low well-being affected the social interaction and well-being with own body. There was no significant difference between cancer staging and timing from diagnosis. Prevention and therapeutic psychological protocols might be adapted and tailored to the unmet needs of the patients in medical treatments to promote and enhance the Quality of Life in survivorship.

Merkel cell carcinoma: an updated overview of clinico-pathological aspects, molecular genetics and therapy.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma of uncertain origin. MCC incidence varies by country and has been increasing among white populations over the last three decades. MCC occurs most commonly in elderly men and typically arises on sun-exposed areas. It is associated with a high mortality rate due to rapid growth and significant metastatic potential. Clinical and histopathological diagnosis are challenging, but prompt recognition of the disease is imperative for a correct management. Several hypotheses have been proposed to define the cell of origin, which still remains controversial. The discovery of Merkel cell polyoma virus, identified in the majority of MCCs, led to the hypothesis of the existence of two tumour subtypes showing biological, clinico-pathological and prognostic differences. Significant interest is nowadays directed to characterize MCC genomic alterations and microRNA (miRNA) expression profiles. Current treatment strategies for MCC depend on staging, and typically consist of surgery, radiation therapy, chemotherapy and/or, more recently, immunotherapy. The aim of this review is to provide an updated overview of MCC with a special focus on clinico-pathological aspects, molecular-genetics and therapy.

Transimmunization restores immune surveillance and prevents recurrence in a syngeneic mouse model of ovarian cancer.

Ovarian cancer accounts for most deaths from gynecologic malignancies. Although more than 80% of patients respond to first-line standard of care, most of these responders present with recurrence and eventually succumb to carcinomatosis and chemotherapy-resistant disease. To improve patient survival, new modalities must, therefore, target or prevent recurrent disease. Here we describe for the first time a novel syngeneic mouse model of recurrent high-grade serous ovarian cancer (HGSOC), which allows immunotherapeutic interventions in a time course relevant to human carcinomatosis and disease course. Using this model, we demonstrate the efficacy of Transimmunization (TI), a dendritic cell (DC) vaccination strategy that uses autologous and physiologically derived DC loaded with autologous whole tumor antigens. TI has been proven successful in the treatment of human cutaneous T cell lymphoma and we report for the first time its in vivo efficacy against an intra-peritoneal solid tumor. Given as a single therapy, TI is able to elicit an effective anti-tumor immune response and inhibit immune-suppressive crosstalks with sufficient power to curtail tumor progression and establishment of carcinomatosis and recurrent disease. Specifically, TI is able to inhibit the expansion of tumor-associated macrophages as well as myeloid-derived suppressive cells consequently restoring T cell immune-surveillance. These results demonstrate the possible value of TI in the management of ovarian cancer and other intra-peritoneal tumors.

Predictive role of vitamin A serum concentration in psoriatic patients treated with IL-17 inhibitors to prevent skin and systemic fungal infections.

The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.

Melanocytic lesion in children and adolescents: an Italian observational study.

Malignant melanoma is a rare neoplasm in the pediatric age group. One of the main risks factors is represented by the presence of a high number of melanocytic nevi. Sun exposure in pediatric age represents a predictor of melanocytic nevi number in the adult age and there is a direct correlation between the presence of melanocytic moles in early childhood and the development of many nevi in adults, suggesting that a high number of nevi in childhood should be considered as a predictor of melanoma development during adult life. The predominance of dermoscopic types of melanocytic nevi varies according to the individual's age and depends on endogenous or exogenous signaling, suggesting different pathways of nevogenesis. We evaluated the total amount of melanocytic nevi of pediatric patients and their prevalent dermoscopic pattern. We investigated the reasons for dermatological examination, pointing out the role of older parents' populations in the decision to refer to a dermatological consultant. We performed a prospective observational study on 295 pediatric outpatients consecutively enrolled from July 2018 to July 2019. Descriptive and inferential statistical analyses were performed using logistic and linear regression. 49% of children were characterized by less than 10 nevi, 45% of children by a number of nevi between 10 and 30, whilst 17 patients (5%) had a number of nevi between 30 and 50. The most prevalent dermoscopic pattern was the globular one. An older parenting age was correlated with an autonomous reason for referral and a later first visit. Our data agreed with previous suggestions demonstrating a strong influence of latitude, sun exposure and ethnic background in the development of the number of nevi. To our knowledge, this is the first study, which evaluated the reasons for dermatological examination and the role of older parents' populations in the decision to refer to a dermatological consultant.

Transglutaminase 3 Reduces the Severity of Psoriasis in Imiquimod-Treated Mouse Skin.

Four transglutaminase (TG) isoforms have been detected in epidermal keratinocytes: TG1, TG2, TG3, and TG5. Except for TG1 and TG3, their contribution to keratinocyte development and structure remains undefined. In this paper, we focused on the roles of TG2 and TG3 in imiquimod-induced psoriasis in mouse skin. We evaluated the severity of psoriasis markers in the skin of imiquimod-treated TG3 null and TG2 null mice. Our results showed that compromised TG3KO mouse skin was more responsive than WT or TG2KO mouse skin to the action of the pro-inflammatory drug imiquimod.

Safety and efficacy of certolizumab pegol in a real-life cohort of patients with psoriasis and psoriatic arthritis.

Background: The aim of this observational study was to assess safety and efficacy of certolizumab pegol (CZP) in a real-life cohort of patients affected by psoriasis (PsO) and psoriatic arthritis (PsA), who had an inadequate response to previous systemic immunosuppressive treatments, with a follow-up of 24 weeks.Materials and methods: Twelve patients with PsO and PsA, referring to our Dermatology/Rheumatology combined outpatient clinic, were enrolled. Primary endpoints were safety and efficacy of CZP, defined as statistically significant improvement of DAPSA, clinical DAPSA and PASI. Secondary endpoints validated clinical and laboratory measures and patient-reported outcomes.Results: CZP injections were well-tolerated. We observed a rapid and significant improvement in all primary endpoints, in the 24-week treatment period of the study. We described positive effects of CZP in several domains, including joint and skin involvement, pain, patient and physician global assessment, physical function, and health-related quality of life. CZP was effective and safe in patients who were either naïve or previously unresponsive to other anti-TNFα. No difference was found in terms of efficacy and safety between patients treated with CZP monotherapy and patients in combination therapy with methotrexate.Conclusions: CZP was safe and effective in a real-life cohort of patients affected by PsO and PsA, who have had an inadequate response to previous systemic treatments.

Intra-patient Heterogeneity of BRAF and NRAS Molecular Alterations in Primary Melanoma and Metastases.

Mutations in MAPK signalling genes are driver events in melanoma, and have therapeutic relevance in the metastatic and adjuvant setting. This study evaluated the intra-patient heterogeneity of BRAF, NRAS and c-KIT mutational status between 30 primary melanomas and 39 related metastases, using molecular analysis and immunohistochemistry. BRAF mutations were identified in 46.7% of primary melanomas and 48.7% of metastases and NRAS mutations in 20% and 25.6%, respectively. Intra-patient heterogeneity was detected in 13.3% of patients for both BRAF and NRAS genes and was not associated with clinico-pathological characteristics of melanomas or metastases. High consistency was observed between immunostaining and molecular methods for BRAFV600E (k = 0.90; p < 0.001) and NRASQ61R (k = 0.87; p < 0.001). These findings demonstrate a relevant intra-patient heterogeneity between primary and metastatic lesions that is independent of clinical variables and methodological approach.

Rapid Production of Physiologic Dendritic Cells (phDC) for Immunotherapy.

Generation of large numbers of dendritic cells (DC) for research or immunotherapeutic purposes typically involves in vitro conversion of murine bone marrow precursors or human blood monocytes to DC via cultivation with supraphysiologic concentrations of cytokines such as GM-CSF and IL-4 for up to 7 days. Alternatively, our group has recently established a new approach, based on the underlying mechanism of action of a widely used cancer immunotherapy termed Extracorporeal Photochemotherapy (ECP). Our method of rapid and cytokine-free production of therapeutically relevant DC populations, leveraging the innate physiologic programs likely responsible for DC differentiation from blood monocytes in vivo, potentially offers a novel, inexpensive, and easily accessible source of DC for clinical and research uses. This approach involves ex vivo physiologic reprogramming of blood monocytes to immunologically tunable dendritic antigen-presenting cells, which we term "phDC," for physiological DC. To facilitate access and utilization of these new DC populations by the research community, in this chapter, we describe the use of a scaled-down version of the clinical ECP leukocyte-treatment device termed the Transimmunization (TI) chamber or plate, suitable for processing both mouse and human samples. We highlight the methodological sequences necessary to isolate mouse or human peripheral blood mononuclear cell (PBMC) from whole blood, and to expose those PBMC to the TI chamber for facilitating monocyte activation and conversion to physiological DC (phDC) through interaction with blood proteins and activated platelets under controlled flow conditions. We then provide sample protocols for potential applications of the generated DC, including their use as vaccinating antigen-presenting cells (APC) in murine in vivo antitumor models, and in human ex vivo T-cell stimulation and antigen cross-presentation assays which mimic clinical vaccination. We additionally highlight the technical aspects of loading mouse or human phDC with tumor-associated antigens (TAA) in the form of peptides or apoptotic tumor cells. We provide a simple and clinically relevant means to reprogram blood monocytes into functional APC, potentially replacing the comparatively expensive and clinically disappointing cytokine-derived DC which have previously dominated the dendritic cell landscape.

Combined Optokinetic Treatment and Vestibular Rehabilitation to Reduce Visually Induced Dizziness in a Professional Ice Hockey Player After Concussion: A Clinical Case.

Background: The appropriate detection and therapy of concussion symptoms are of great importance to avoid long-term impairment and absence from pre-concussive activities, such as sport, school or work. Post-traumatic headache and dizziness are known as risk factors of persistent symptoms after a concussion. Dizziness has even been classified as a predictor for symptom persistence. One type of dizziness, which has never been considered is visually induced dizziness (VID) often develops as a consequence of vestibular impairment. This manuscript presents the clinical case of a 25-year-old male, professional ice hockey player, whereby a therapeutic approach to VID after concussion is demonstrated. Case: A detailed interdisciplinary clinical and laboratory-assisted neurological, neurovestibular and ocular-motor examination was performed 20 days post-concussion, which indicated VID symptoms. Thus, the player qualified for a 5-day combined vestibular, balance and optokinetic therapy, which aimed to reduce the player's increased sensitivity to visual information. Each treatment day consisted of two sessions: vestibular/ocular-motor training and exposure to optokinetic stimuli combined with postural control exercises. The optokinetic stimulus was delivered in the form of a rotating disk. VID symptoms were recorded daily via posturography and a visual analog scale prior to the optokinetic sessions. The player improved over the course of each treatment day and was able to return to ice hockey 15 days after the final treatment session. Three months later the player reported no symptoms in the follow up questionnaire. Conclusion: The combination of vestibular, balance and optokinetic therapy led to remission of VID symptoms in a professional ice hockey player after multiple concussions, within a short time frame after his last concussion. Thus, this case study highlights the significant benefit of treating post-concussive VID symptoms utilizing a multi-modal approach.

Efficacy and safety of Vismodegib treatment in patients with advanced basal cell carcinoma and multiple comorbidities.

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians, and its incidence is increasing. Most BCCs are treated surgically, nevertheless surgery is not an effective treatment for locally advanced or metastatic BCC. Alterations in hedgehog signaling pathway, a key regulator of cell growth and differentiation during development, are implicated in the pathogenesis of basal-cell carcinoma. Vismodegib is a small-molecule inhibitor of smoothened (SMO), a key component of the hedgehog (Hh) signaling pathway, administered in BCC patients, especially when surgery and radiotherapy treatments have failed. We report a series of eight elderly patients treated with vismodegib for advanced BCC and affected by concomitant multiple comorbidities. The efficacy and tolerability of vismodegib in patients with single and/or multiple comorbidities has been poorly studied. In our observation an overall high safety and tolerability has been observed over the course of treatment, with side effects of grade I and II and no changes in vital parameters, electrocardiography and echocardiogram. Vismodegib has been shown to be a safe and well tolerated treatment option for elderly patients affected by multiple comorbidities and advanced BCC.

Novel Protocol for Generating Physiologic Immunogenic Dendritic Cells.

Extracorporeal photochemotherapy (ECP) is a widely used cancer immunotherapy for cutaneous T cell lymphoma (CTCL), operative in over 350 university centers worldwide. While ECP's clinical efficacy and exemplary safety profile have driven its widespread use, elucidation of the underlying mechanisms has remained a challenge, partly owing to lack of a laboratory ECP model. To overcome this obstacle and create a simple, user-friendly platform for ECP research, we developed a scaled-down version of the clinical ECP leukocyte-processing device, suitable for work with both mouse models, and small human blood samples. This device is termed the Transimmunization (TI) chamber, or plate. In a series of landmark experiments, the miniaturized device was used to produce a cellular vaccine that regularly initiated therapeutic anti-cancer immunity in several syngeneic mouse tumor models. By removing individual factors from the experimental system and ascertaining their contribution to the in vivo anti-tumor response, we then elucidated key mechanistic drivers of ECP immunizing potential. Collectively, our results revealed that anti-tumor effects of ECP are initiated by dendritic cells (DC), physiologically generated through blood monocyte interaction with platelets in the TI plate, and loaded with antigens from tumor cells whose apoptotic cell death is finely titrated by exposure to the photoactivatable DNA cross-linking agent 8-methoxypsoralen and UVA light (8-MOPA). When returned to the mouse, this cellular vaccine leads to specific and transferable anti-tumor T cell immunity. We verified that the TI chamber is also suitable for human blood processing, producing human DCs fully comparable in activation state and profile to those derived from the clinical ECP chamber. The protocols presented here are intended for ECP studies in mouse and man, controlled generation of apoptotic tumor cells with 8-MOPA, and rapid production of physiologic human and mouse monocyte-derived DCs for a variety of applications.

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma.

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen's disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75⁻85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32⁻70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.