Assessment of the perceived burden associated with Malignant Melanoma with Pictorial Representation of Illness and Self Measure (PRISM) and Melanoma Concerns Questionnaire (MCQ-28)

Purpose The impact of malignant melanoma (MM) on patients’ psychophysical well-being has been poorly addressed. We aimed to assess the perceived burden in patients with a diagnosis of MM, using two different tools, one generic and one specific for MM, such as Pictorial Representation of Illness and Self Measure (PRISM) and Melanoma Concerns Questionnaire (MCQ-28), respectively. The correlation between PRISM and MCQ-28 subscales and the relevance of disease and patient-related variables were also investigated. Methods This single-centre, cross-sectional study included all adult consecutive MM patients who attended our Dermatology Unit from December 2020 to June 2021. Demographics and disease-related data were recorded. PRISM and MCQ-28 were administered. Results One hundred and seventy-one patients were included (mean age: 59.5 ±14.9 years.; 48.0% males). Median time from MM diagnosis to inclusion was 36 months. Nearly 80% of the patients had in situ or stage I MM. Overall, 22.2% of the patients reported a PRISM score <100mm and similar percentages provided scores indicating impaired quality of life, as assessed with MCQ-28 subscales. A weak, albeit significant, correlation was found between PRISM scores and ACP, CON and SOC2 subscales. The most relevant association found was that between lower PRISM scores and higher-stage MM. Conclusions In the study population, mostly affected with superficial MM, their perception of the burden associated with MM did not appear either particularly dramatic or disabling. PRISM seems a reliable system for capturing and quantifying the domains correlated with the emotive dimension of MM, especially MM-related concerns and willingness to face life

Curative Intent Surgery of Oral Malignant Melanoma and Regional Lymph Node Biopsy Assessment in 25 Dogs: 2006–2017

Medical records were searched for dogs that had received curative intent surgery for oral malignant melanoma and ipsilateral excisional regional lymph node biopsy. Twenty-seven dogs were operated on and 25 dogs of these dogs met the inclusion criteria of signalment, post-excision margin status, presence of metastasis for each biopsied lymphocentrum, survival time post-excision, presence of recurrence or metastasis at follow-up or at death/euthanasia, location of the primary tumor, and any postoperative adjuvant treatment. These 25 dogs had complete tumor excision with tumor-free margins and 19 (76%) had postoperative adjuvant therapy. Median survival time after excision for the dogs in this study was 335.5 days. Results of this study support previous work that documents prolonged survival time following complete excision of oral malignant melanoma with tumor-free surgical margins in dogs. Additionally, 4 dogs (16%) had histologically confirmed regional lymph node metastasis at the time of definitive surgery.

TGFβ2 Induces the Soluble Isoform of CTLA-4 – Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma

Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.

Carbon ion radiotherapy with complete tumor regression for primary malignant melanoma of female urethra orifice: a case report

Primary malignant melanoma of the female urethra (PMMFU) is extremely rare, accounting for 0.2% of all melanomas, and fewer than 200 cases have been reported worldwide. Because of the small number of clinical cases and unclear biological characteristics, there is no uniform and standard treatment protocol. We herein describe the treatment of PMMFU using carbon ion radiotherapy. The radiotherapy was delivered at 60.8 Gy (RBE) in 16 fractions, once daily, five times per week. The patient achieved complete tumor disappearance within 1 year after carbon ion radiotherapy and remained disease-free thereafter. She developed acute grade 1 radiation dermatitis and urethritis, which resolved quickly; no other toxic effects were observed. At the time of this writing, her survival duration was 33 months. This case demonstrates that carbon ion radiotherapy may be a good option for primary genitourinary mucosal malignancies.

Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma

Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively.

Autoimmune colitis and neutropenia in adjuvant anti-PD-1 therapy for malignant melanoma: efficacy of Vedolizumab, a case report

Immune checkpoint inhibitors (ICIs) represent an important advance in the adjuvant treatment of patients with high-risk melanoma. Although the safety profile of anti-programmed cell death protein-1 (PD-1) is fairly acceptable, different immune-related adverse events (irAEs) are described. Herein we report for the first time a notably multidisciplinary combined approach on a malignant melanoma (MM) patient treated with anti-PD-1 antibody in adjuvant setting. In this novel approach, corticosteroid-refractory immune-mediated colitis (IMC) was effectively treated with Vedolizumab, a selective blockade of the α4β7 integrin and corticosteroids were successfully administered for autoimmune neutropenia. Notably, our patient also express HLA-B*35, a potential biomarker for predicting a genetic basis of autoimmune susceptibility. Our experience offers a possible future perspective about the use of Vedolizumab together with immunotherapy in a strategic early approach for high-risk patients genotyped for HLA.