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Background: Despite the dramatic advances in the management of metastatic cutaneous melanoma, there remains no consensus-based, evidence-based strategy for the management of mucosal melanoma. The rare nature of the disease, its late clinical presentation, and distinct tumour biology all complicate efforts to optimise patient outcomes. Methods: To this end, we carried out a monocentric, retrospective analysis of all patients diagnosed with mucosal melanoma and treated between 2013 and 2021. Both tumour- and patient-specific characteristics were recorded, in addition to immune-related adverse events, in order to provide real-world data on disease progression, treatment efficacy, and the identification of prognostic markers. Results: A total of 20 patients were identified (14 females and 6 males), with a mean age at diagnosis of 65.9 years. The median follow-up was 3.9 years (95% CI 1.4-6.4 years) from the initiation of systemic therapy. The median OS in the entire cohort was 1.9 years (95% CI 0.5-3.3 years). Performance status, sex, body mass index, and the presence of brain metastases were not associated with poorer outcomes. However, serum lactate dehydrogenase levels (LDH) ( p = 0.04) and an NRAS mutation were markers of a poor prognosis ( p = 0.004). Conclusuion: There is a pressing need for real-world, prospective, and clinical trial data to inform the optimal management of mucosal melanoma, and data supporting the use of adjuvant and neo-adjuvant immunotherapy are currently lacking. However, an elevated LDH is a reliable, independent negative prognostic marker. Inter-disciplinary management remains essential in order to develop optimal treatment strategies.

Background: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences., Objective: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma., Methods: A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list., Results: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients., Conclusions: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Despite the dramatic improvement in both overall survival (OS) and progression-free survival (PFS) in patients with metastatic melanoma treated with immune checkpoint inhibitors, up to 60% will develop treatment resistance and 50% will die from their disease. Therefore, although dacarbazine is no longer a mainstay of modern melanoma management, we examined the extent to, and in which context, it may still play a role. A retrospective analysis of electronic medical records of patients who had received dacarbazine treatment between October 2014 and October 2021, following innate or acquired resistance to immune checkpoint inhibitors, was performed to determine PFS and OS and examine tolerability. Nine patients with locally advanced ( n  = 1) or metastatic melanoma ( n  = 8) were identified (average age: 74 years, 4 males and 5 females). The number of cycles of dacarbazine ranged from 2 to 45 (mean = 12). One-third of patients developed a complete ( n  = 2) or partial ( n  = 1) response, two-thirds did not respond to treatment. The median PFS time was 90 days. Common adverse events included blood dyscrasias; one patient developed a grade 3 hepatitis, although it was unclear if this was due to the chemotherapy or the preceding combined immunotherapy. Dacarbazine may still be a valid option in the setting of treatment for refractory, relapsed, or progressive disease. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially restore sensitivity to immune checkpoint-based therapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Despite the dramatic improvements in recurrence-free survival in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICI), a number of patients develop metastases during adjuvant therapy. It is not currently possible to predict which patients are most likely to develop disease recurrence due to a lack of reliable biomarkers. Thus, we retrospectively analyzed the case records of all patients who commenced adjuvant ICI therapy between January 2018 and December 2021 in a single university skin cancer center (n = 46) (i) to determine the rates of disease recurrence, (ii) to examine the utility of established markers, and (iii) to examine whether re-challenge with immunotherapy resulted in clinical response. Twelve out of forty-six (26%) patients developed a relapse on adjuvant immunotherapy in our cohort, and the median time to relapse was 139 days. Adjuvant immunotherapy was continued in three patients. Of the twelve patients who developed recurrence during adjuvant immunotherapy, seven had further disease recurrence within the observation period, with a median time of 112 days after the first progress. There was no significant difference comparing early recurrence (<180 days after initiation) on adjuvant immunotherapy to late recurrence (>180 days after initiation) on adjuvant immunotherapy. Classical tumor markers, including serum lactate dehydrogenase (LDH) and S-100, were unreliable for the detection of disease recurrence. Baseline lymphocyte and eosinophil counts and those during immunotherapy were not associated with disease recurrence. Interestingly, patients with NRAS mutations were disproportionately represented (60%) in the patients who developed disease recurrence, suggesting that these patients should be closely monitored during adjuvant therapy.

Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

With more than 82 million cases worldwide and almost two million deaths, the Covid-19 global pandemic shows little sign of abating. However, its effect on quality of life (QoL) in skin cancer patients has not been systematically evaluated to date. Given that QoL impairments may be associated with increased psychological morbidity, and may interfere with engagement with cancer therapy and follow-up, we prospectively evaluated quality of life in skin cancer patients using the Covid-19 Emotional Impact Survey (C-19EIS) and the EORTC QLQ-C30 questionnaires. 101 patients (48 females and 53 males) completed both questionnaires. The mean C-19EIS score was 3.8 on a scale from 0 (no impact) to 12 (severe impact). Patients undergoing systemic therapy showed significantly impaired physical (p = 0.006) and social functioning (p = 0.003). However, when compared to the published normative EORTC QLQ-C30 data, there was no evidence that the Covid-19 pandemic had significantly impacted upon overall quality of life. Subscales of the EORTC QLQ-C30 were significantly inversely correlated with the C-19EIS, validating its use in skin cancer patients. Despite the Covid-19 pandemic, skin cancer patients in our tertiary referral center were surprisingly resilient. However, given the geographical variations in the rates of Sars-CoV-2 infection it is possible that the low incidence in Northern Germany may have resulted in a lack of general QoL impairments. Multi-center studies are required to further determine the impact of Covid-19 on psychological wellbeing in skin cancer patients in order to develop supportive interventions and to ensure that engagement with cancer care services is maintained in order to enable early detection of cancer progression and/or recurrence., Competing Interests: The authors have read the journal’s policy and have the following competing interests: GK reports speaker’s honoraria from Novartis and Kyowa Kirin. EAL reports personal fees and non-financial support from BristolMyersSquibb, personal fees and non-financial support from Novartis, meeting and travel support from Curevac and advisory board fees from Sun Pharma. PT reports speaker’s honoraria from BMS, Novartis, MSD, Pierre-Fabre, CureVac and Roche, consultant’s honoraria from BMS, Novartis, Pierre-Fabre, Merck Serono, Sanofi und Roche and travel support from BMS, Pierre-Fabre and Roche. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare. The other authors report no competing interests.

A novel ultrasonic instrumentation was successfully implemented in a compaction simulator. A through-transmission set-up was realised with longitudinal and transverse transducers being alternately positioned inside Euro-D-modified punches. Key features of the data acquisition are described. Considerable attention was paid to an accurate displacement measurement and a synchronic acquisition of the ultrasonic signal. Vivapur 102 and Di-Cafos A150 were chosen for evaluation. In contrast to other published instrumentations, production-relevant powder densification speeds were feasible whilst featuring outstanding measurement precision. Maximum ultrasonic speed was achieved at maximum density. Materials differed considerably regarding the slope of the decompression phase, which might be suitable for assessing elasticity and speed sensitivity of powders or formulations without compressing twice. The developed set-up furthermore enables in-die measurements of apparent Young's modulus and apparent Poisson's ratio (i.e. their change throughout the course of the tableting process). Young's modulus increased upon densification and values match with literature data. Poisson's ratio increased linearly as a function of solid fraction for plastically deforming Vivapur 102, whereas it was practically constant for brittle Di-Cafos A150. Increased mechanistic understanding of deformation factors (e.g. rearrangement, fragmentation, elasticity) and estimation of mechanical compatibility of mixtures, is feasible. Moreover, in-die Young's modulus and Poisson's ratio are valuable for compression simulations based on finite or discrete element method., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Tricalcium citrate (TCC) was characterized as a tableting excipient for direct compression (DC) and dry granulation (DG)., Significance: Brittle materials usually lead to tablets of inferior mechanical strength compared to plastic deforming materials. A brittle material exhibiting a high tabletability with the ability to retain that behavior during recompression would represent a valuable alternative to the commonly used microcrystalline cellulose., Methods: Tablets of TCC and other common fillers were directly compressed for the purpose of compression analysis including Heckel analysis, speed dependency, and lubricant sensitivity. DG by roller compaction of TCC was first simulated via briquetting and experiments were subsequently repeated on a roller compactor., Results: TCC appears as an excellent flowing powder of large agglomerates consisting of lower micron to submicron platelets. Despite the brittle deformation mechanism identified in the Heckel analysis, TCC demonstrated a very high mechanical strength up to 11 MPa in conjunction with an astonishingly low solid fraction of 0.85 at a compression pressure of 400 MPa. This was seen along with hardly any speed and lubricant sensitivity. Nevertheless, disintegration time was very short. TCC tablets suffered only a little from the re-compression: a slight loss in tensile strength of 1-2 MPa was observed for granules produced via roller compaction., Conclusions: TCC was found to be suitable for DC as a predominantly brittle deforming filler, nevertheless demonstrating an enormous hardness yield while being independent of lubrication and tableting speed. TCC furthermore retained enough bonding capacity after DG to maintain this pronounced tabletability.