Health-related quality of life and its influencing factors in patients with primary cutaneous B-cell lymphomas: A multicentric study in 100 patients.

BACKGROUND: Primary cutaneous B-cell lymphomas (CBCL) are a group of rare malignant skin diseases that represent approximately 20%-30% of all primary cutaneous lymphomas (PCL). Previous studies revealed impaired health-related quality of life (HRQoL) in patients diagnosed with primary cutaneous T-cell lymphoma (CTCL). Currently, only small-sized studies investigated HRQoL in CBCL patients and lacked detailed analysis of respective subtypes. OBJECTIVES: This study aims to investigate HRQoL in CBCL patients to identify independent factors of HRQoL impairment in CBCL patients. METHODS: One hundred CBCL patients were recruited from eight German PCL centres in this multicentric, cross-sectional study from 2021 to 2022. The patients completed the dermatologic HRQoL questionnaire Skindex-29 and an investigator-designed 'CBCL-Questionnaire' with additional questions on HRQoL and clinical characteristics. RESULTS: The Skindex-29 revealed that HRQoL in CBCL patients is impaired on a mild to moderate level. The multiple regression analysis identified parameters like worries about dying, feeling prejudiced/discriminated and impairment of daily activities to be independently associated with impairment of HRQoL. Highest scores for HRQoL impairment were found in patients with primary cutaneous follicle centre lymphoma while on rituximab treatment and in patients with primary cutaneous marginal zone lymphoma while on watchful waiting. CONCLUSIONS: HRQoL is impaired in CBCL patients, even though, in the face of indolent disease course and favourable prognosis in the majority of cases. Of note, our investigator-designed tool identified worries about dying, feeling prejudiced/discriminated, and the type of treatment to have a negative impact on patients' HRQoL. Our study highlights the importance of a thorough patient-doctor communication to capture overall disease burden because generic HRQoL tools might lack of disease-specific items.

Management of partial and non-responding cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma are the most common types of skin cancer. For patients with locally advanced and metastatic cSCC, the programmed cell death 1 (PD-1) inhibitor cemiplimab is approved for systemic treatment. Despite this revolutionary immunomodulatory therapeutic approach, tumours may fail to respond either completely or partially. In addition to the previously established local treatment with radiotherapy or systemic treatment with chemotherapy and epidermal growth factor receptor inhibitors, ongoing trials are currently focussed on re-stimulating the antitumour immune response in patients with advanced cSCC refractory to PD-1 inhibitors. In this review, ongoing and recently finished trials with different therapeutic approaches will be discussed.

Checkpoint immunotherapy of cutaneous squamous cell carcinoma in patients suffering from chronic lymphocytic leukaemia: divergent outcomes in two men treated with PD-1 inhibitors.

Cutaneous squamous cell carcinoma (cSCC) numbers among the most common types of skin cancer and is known as one of the cancer entities with the highest mutational burden among all solid tumours. Due to the positive correlation between mutational burden and response rate to inhibitors of the programmed cell death 1 (PD-1), those inhibitors are considered promising candidates for the systemic therapy of cSCC. Recently, the PD-1 inhibitors pembrolizumab, nivolumab and cemiplimab demonstrated efficacy in the systemic treatment of locally advanced or metastatic cSCC leading to the approval of cemiplimab by the FDA (U.S. Food and Drug Administration) in 2018 and the EMA (European Medicines Agency) in 2019. Patients with haematological malignancies tend to develop skin cancers of high aggressiveness, enhanced cumulative recurrence rate and higher rates of metastases with subsequent death. Chronic lymphocytic leukaemia (CLL) is the most frequent type of leukaemia in the United States and Europe with the majority of patients older than 50 years of age. This neoplasm predominantly originates from B -cells leading to an impaired immune system of the patient. Although CLL is a B-cell malignancy, studies have also described the involvement of T cells in the pathogenesis and progression of the disease with contradictory findings on the effects of PD-1 inhibitors in CLL. Due to their underlying hematologic malignancy, these patients have commonly no access to PD-1 inhibitor trials for treatment of advanced cSCC. We report on two patients with locally advanced or metastatic cSCC. Both patients had been suffering from a CLL for many years without indication for treatment. Despite a potential immunosuppressive state of the patients due to their CLL, both were treated with the PD-1 inhibitor pembrolizumab resulting in different therapy outcomes.

[Cutaneous angiosarcoma clinically presenting as Quincke's edema]. / Kutanes Angiosarkom mit klinischem Bild eines Quincke-Ödems.

We report a case of a 75-year-old man with facial edema that also affected the periorbital area who was admitted to the hospital with the suspected diagnosis of Quincke's edema. The diagnosis of cutaneous angiosarcoma was made by microscopic examination and immunohistochemical staining. Chemotherapy was initially initiated because the angiosarcoma was unresectable and the radiation situation was difficult. Therapy has to be switched to second and third line therapy due to disease progression. The case illustrates the complexity of diagnosis and therapy in patients with cutaneous angiosarcoma.

Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma.

BACKGROUND: Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival. PATIENTS AND METHODS: Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n = 130; one prospectively collected multicentric validation cohort, n = 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay. RESULTS: Melanoma patients showed higher serum concentrations of PD-1 (P = 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P = 0.014, P = 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P = 0.0081, P = 0.053) and overall survival (OS; P = 0.055, P = 0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of anti-PD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P = 0.037), PFS (P = 0.048), and OS (P = 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P = 0.019; PFS, P = 0.038; OS, P = 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P = 0.010) and OS (P = 0.003) in patients treated with PD-1 inhibitors. CONCLUSION: Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.

GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma.

BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.

[Immunotherapy for malignant melanoma]. / Immuntherapie beim malignen Melanom.

Although cutaneous melanoma accounts for only about 4% of all skin cancers (including nonmelanocytic skin cancer), it is responsible for 80% of all deaths caused by skin cancer. The introduction of immune checkpoint inhibitors led to a significant improvement in long-term survival of patients in an advanced stage regardless of BRAF mutation status. In addition to targeted therapy for patients with BRAF-mutated melanoma, immunotherapies are the therapies of choice in advanced stages and, since 2018, also in the adjuvant setting. The effectiveness of combination therapies and sequences of targeted and immunotherapies are currently being tested.

Segmentally arranged seborrhoeic keratoses with impending atypia and squamous cell carcinoma in an elderly woman.

Epidermal naevi (EN) are considered mosaic disorders. Postzygotic mutations are thought to occur during early embryogenesis. They are usually arranged along Blaschko's lines and tend to be noted either at birth or shortly thereafter. Skin tumours arising on EN are occasionally reported, with ongoing discussion as to whether these are collision tumours or a malignant transformation of the EN. We describe a 76-year-old woman with segmentally arranged seborrhoeic keratoses that showed impending atypia and, in one lesion, even overt malignant transformation. In biopsies from various lesions we found FGFR3 and PIK3CA hotspot mutations but there was no consistent pattern of mutations explaining the premalignant or malignant growth. So far it is unclear whether the precancerous changes as noted in this elderly patient can be taken as an unusual manifestation of one of the established types of EN, or whether this may represent a separate disorder that could be called 'SASKIA naevus'. The acronym would stand for segmentally arranged seborrhoeic keratoses with impending atypia.

Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma.

BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.

Retarded low-dose doxycycline for EGFR or MEK inhibitor-induced papulopustular rash.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRi) and MEK inhibitors (MEKi) are notorious for causing papulopustular rash. Treatment recommendations from studies and expert panels include, amongst others, oral tetracyclines. The efficacy of retarded low-dose doxycycline (rld-doxycycline), however, has not been investigated. The objective was to review the response and development of EGFRi- and MEKi-induced rash under therapy with rld-doxycycline. PATIENTS AND METHOD: A retrospective review of all patients treated with rld-doxycyline 40 mg once daily between September 2011 and June 2012 for papulopustular rash. Rash development and severity (according to the Common Terminology Criteria of Adverse Events V4.0) were assessed. RESULTS: Seventeen patients (13 men, 4 women) were treated with rld-doxycycline while receiving EGFRi [monoclonal antibodies (mab) n = 8, tyrosine kinase inhibitors (TKi) n = 7] or MEKi (n = 2). In 47% (n = 8) the rash was reduced by at least one grade, in 29% (n = 5) the rash was stabilized, 24% (n = 4) did not profit from the treatment. All patients treated with an EGFR-TKi or a MEKi profited of the rld-doxycycline. All patients who experienced deterioration were on treatment with an EGFR-mab. CONCLUSIONS: Rld-doxycyline can improve EGFR-TKi- and MEKi-induced rash severity. Its effectiveness appears to be inferior to doxycycline 200 mg/day in more severe cases and in EGFR-mab-induced rash, but due to the advantageous side-effect profile, rld-doxycycline should be considered as a possible treatment option for papulopustular rash. Prospective, randomized trials are necessary to confirm these findings.

Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

PURPOSE: Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. METHODS: In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5 years they would require to tolerate defined side-effects. RESULTS: By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5 years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). CONCLUSION: Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

Advances and perspectives in immunotherapy of melanoma.

Immunotherapy using unspecific modulators has a long tradition in the adjuvant treatment of stage II/III melanoma. Interferon has shown a consistent effect on relapse-free survival independent of interferon dosage and duration. The results of the american Joint Committee on Cancer (AJCC) Melanoma Staging Database analysis led to a strict inclusion of additional prognostic risk factors such as ulceration of the primary and microscopic lymph node involvement explored by the sentinel node biopsy in the revised 2009 AJCC classification. These factors are now being increasingly included as stratification factors into clinical trials and yield a new hypothesis that primarily patients with both characteristics benefit from adjuvant interferon treatment. In the metastatic situation, interleukin-2 is the only immunotherapeutic agent approved by the Food and Drug administration. In combination with interferon and/or with various chemotherapeutic agents, IL-2 is associated with substantial toxic effect and poor efficacy that does not improve overall survival (OS). Ipilimumab is a fully human, monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen-4 and has recently been approved for metastatic melanoma based on two independent randomized phase III studies both demonstrating an improved OS rate after 1, 2, and 3 years compared with the control group. Based on this major step in treating metastatic melanoma, novel adjuvant strategies in stage III and combination therapies with targeted agents in stage IV are currently being explored.

Sorafenib and pegylated interferon-α2b in advanced metastatic melanoma: a multicenter phase II DeCOG trial.

BACKGROUND: The combination of sorafenib, a multikinase inhibitor, and pegylated interferon-α2b (Peg-IFN-α2b) could potentially lead to an improved antitumoral response. Previously, combinations of interferon and sorafenib have been used in renal cell cancer. PATIENTS AND METHODS: Patients with stage IV metastatic melanoma and no previous systemic therapies apart from adjuvant immunotherapy received Peg-IFN-α2b 3 µg/kg once per week, and sorafenib 400-mg b.i.d. for a minimum of 8 weeks. The primary study end point was disease control rate (DCR). RESULTS: Between February 2008 and February 2009, 55 patients were enrolled with a median age of 64 years (20-85). At 8 weeks, 2 patients (3.6%) had a partial response (PR) and 14 patients a stable disease (25.5%), for a DCR of 29.1% in the intention-to-treat (ITT) population. The median progression-free survival in the ITT population was 2.47 months (95% confidence interval 1.22-3.72 months). The toxicity of sorafenib and Peg-IFN-α2b combination was characterized by mainly hematological side-effects, including one treatment-related bleeding complication with a fatal outcome. Other grade 3/4 toxic effects were fatigue and flu-like symptoms. CONCLUSION: The combination of sorafenib and Peg-IFN-α2b showed modest clinical activity and some serious side-effects including fatal bleeding complications.

Fertility preservation and management of pregnancy in melanoma patients requiring systemic therapy.

Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients-from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.

Malignant melanoma and Wiedemann-Beckwith syndrome in childhood.

Patients with Wiedemann-Beckwith syndrome (WBS, MIM 130650), a congenital overgrowth syndrome, have a known increased tumor risk especially for embryonic tumors. WBS belongs to the "imprinting" syndromes caused by overexpression of IGF2 and/or loss of CDKN1C on chromosome 11p15.5. A 13-year-old boy with WBS developed a spitzoid malignant melanoma (Clark level V, Breslow index 4.8 mm) on the right cheek. Genetic analyses of the patient's blood showed hypermethylation at the H19 locus on chromosome 11p. The (epi)genetic changes of the WBS locus might have played a role in the pathogenesis of melanoma development.