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Aims: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2‐fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. Methods and Results: Five patients were male and the median age was 79 years (ranges: 59–95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. Conclusion: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement. [ABSTRACT FROM AUTHOR]

Aims: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2‐fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. Methods and Results: Five patients were male and the median age was 79 years (ranges: 59–95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. Conclusion: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement. [ABSTRACT FROM AUTHOR]

Malignant PEComas are an extremely rare subtype of soft tissue sarcomas. Here, we report the case of a man presenting with a perirectal PEComa and liver metastasis. Since the tumor harbored a tumor mutational burden of 23/Mb and a programmed death-ligand 1 tumor positivity score of 50%, the patient was treated with pembrolizumab as a second line of systemic therapy, in combination with everolimus. This combined therapy led to a near-complete response of the primary tumor and a partial response of the metastasis. Radioembolization of the liver metastasis was performed due to isolated liver progression, and the pelvic tumor was treated by radiotherapy because of pelvic symptoms. The disease is still stable after 13 months of pembrolizumab plus everolimus and multimodal treatment. This case shows that malignant PEComas can display molecular features associated with sensitivity to checkpoint inhibitors. The use of checkpoint inhibitors may be a relevant therapeutic strategy in these patients. It is also the first report on selective internal radiation therapy in PEComas. Plain language summary: A case of a patient with metastatic PEComa of the rectum, a very rare tumor type, treated by immunotherapy in combination with local treatments This article reports the case of a patient presenting with a very rare tumor type called "PEComa". The tumor originated from the rectum and had disseminated to the liver. Since this tumor is very rare, there is a lack of knowledge on which treatments to use, and every case reporting the use of new treatments in PEComas is helpful. Here, the tumor displayed molecular alterations that suggested that it would respond to immunotherapy, such as a high number of mutations. Therefore, the patient was treated with an immunotherapy called pembrolizumab, in combination with another medication (everolimus). The rectal tumor nearly disappeared under treatment, and the liver metastasis decreased in size. The patient had radiotherapy of the rectum because of rectal bleeding. For the liver metastasis we used another technique called radioembolization, that consists in delivering radioactive compounds directly in the metastasis through the bloodstream. Now, he has received immunotherapy for 13 months and the disease is still under control. This case shows that immunotherapy can be a good treatment option in PEComas. It is also the first time that a medical team reports the using radioembolization to treat a PEComa. [ABSTRACT FROM AUTHOR]

This article, published in the Journal of the European Academy of Dermatology & Venereology, explores the impact of blood tumor clone frequency on the time to next treatment in mycosis fungoides (MF), the most common cutaneous T-cell lymphoma. The study used high-throughput DNA sequencing to identify T-cell clones in MF patients and determine the tumor clone frequency (TCF) in the total T-cell infiltrate. The findings suggest that an increased frequency of the malignant T-cell clone in the blood is correlated with reduced time to next treatment in MF patients. However, further validation in a larger cohort is needed to confirm these results. [Extracted from the article]

This article discusses the genomic profiling of a cohort of skin adnexal carcinomas (SACs), which are rare and challenging to diagnose due to their low incidence and morphological convergence. The study included 77 patients with SACs and used high-throughput sequencing to identify oncogenic molecular alterations. The results revealed the complexity of SACs, with various gene alterations identified in different types of SACs. The study also found that MAPK and Shh pathway alterations were common in sweat gland and hair follicle carcinomas, respectively. The findings provide insights into the oncogenic processes and potential therapeutic options for SACs. [Extracted from the article]

Microsecretory adenocarcinoma (MSA) is a newly described salivary gland tumor harboring a characteristic balanced chromosomal translocation resulting in MEF2C::SS18 gene fusion. Six primary cutaneous MSA cases have been recently described. We report three additional cases confirming the relevance of this recently identified entity of primary cutaneous adnexal tumor. Three patients aged 53‐, 64‐ and 78‐year‐old were retrospectively diagnosed with MSA of the skin (MSAS) as consultation cases of the CARADERM (CAncers RAres DERMatologiques) national network. The clinical presentation was an indolent nodule on the upper extremities. There was no history of salivary gland tumor. Histopathologically, the tumors presented as dermal nodular proliferation with slightly infiltrative borders, composed of cribriform and microcystic structures with abundant myxoid intraluminal secretion embedded in a fibromyxoid stroma. They diffusely expressed cytokeratin 8 and SOX10, focally p63 and heterogeneously smooth muscle actin. All tumors harbored the MEF2C::SS18 gene fusion. A complete surgical excision was performed. No local recurrence or distant metastases were observed so far (follow‐up: 17, 38, and 45 months). MSAS is the cutaneous homologue of MSA of the salivary gland, a low‐grade adnexal neoplasm whose prognosis seems to be excellent once the complete removal of the tumor is assured. [ABSTRACT FROM AUTHOR]

This article discusses two cases of patients with cutaneous T-cell lymphoma (CTCL) who experienced severe relapses after receiving ruxolitinib, a JAK1/2 inhibitor, for the treatment of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (allo-HSCT). The patients initially showed positive responses to ruxolitinib for GVHD, but their CTCL worsened, leading to erythroderma and skin tumors. The authors suggest that ruxolitinib may have a deleterious effect on CTCL after allo-HSCT, possibly impairing the graft versus leukemia (GVL) response. Further investigation is needed to evaluate the use of JAK inhibitors in CTCL treatment after allo-HSCT. [Extracted from the article]

Introduction: Considering the growing interest in matched cancer treatment, our aim was to evaluate the ability of a comprehensive genomic profiling (CGP) assay to propose at least one targeted therapy given an identified genomic alteration or signature (actionability), and to collect the treatment modifications based on the CGP test results in clinical practise for solid tumors. Methods: This retrospective, multicentre French study was conducted among 25 centres that participated in a free of charge program between 2017 and 2019 for a tissue CGP test. Data were collected on the patient, disease, tumor genomic profile, treatment suggested in the report (related to the genomic profile results) and subsequent therapeutic decisions according to the physician's declaration. Results: Among the 416 patients, most had lung cancer (35.6%), followed by biliary tract cancer (11.5%) or rare cancers (11.1%); 75% had a metastatic disease. The actionability was 75.0% (95% CI [70.6%-78.9%]) for all patients, 85.1% and 78.4%, respectively in lung cancer and metastatic patients. After exclusion of clinical trial suggestions, the actionability decreased to 62.3% (95% CI [57.5%-66.8%]). Treatment modification based on the test results was observed in 17.3% of the patients and was more frequent in metastatic disease (OR = 2.73, 95% CI [1.31–5.71], p = 0.007). The main reasons for no treatment modification were poor general condition (33.2%) and stable disease or remission (30.2%). The genomic-directed treatment changes were performed mostly during the first six months after the CGP test, and interestingly a substantial part was observed from six to 24 months after the genomic profiling. Conclusion: This French study provides information on the real-life actionability of a CGP test based on tissue samples, and trends to confirm its utility in clinical practice across the course of the disease, in particularly for patients with lung cancer and/or advanced disease. [ABSTRACT FROM AUTHOR]

Aims: Poroma is a benign adnexal neoplasm with differentiation towards the upper portion of the sweat gland apparatus. In 2019, Sekine et al. demonstrated recurrent YAP1::MAML2 and YAP1::NUTM1 fusion in poroma and porocarcinoma. Follicular, sebaceous and/or apocrine differentiation has been reported in rare cases of poroma and whether these tumours constitute a variant of poroma or represent a distinctive tumour is a matter to debate. Herein we describe the clinical, immunophenotypic, and molecular features of 13 cases of poroma with folliculo‐sebaceous differentiation. Methods and results: Most of the tumours were located on the head and neck region (n = 7), and on the thigh (n = 3). All presented were adults with a slight male predilection. The median tumour size was 10 mm (range: 4–25). Microscopically, lesions displayed features of poroma with nodules of monotonous basophilic cells associated with a second population of larger eosinophilic cells. In all cases, ducts and scattered sebocytes were identified. Infundibular cysts were present in 10 cases. In two cases high mitotic activity was noted, and in three cases cytologic atypia and areas of necrosis were identified. Whole transcriptome RNA sequencing demonstrated in‐frame fusion transcripts involving RNF13::PAK2 (n = 4), EPHB3::PAK2 (n = 2), DLG1::PAK2 (n = 2), LRIG1::PAK2 (n = 1), ATP1B3::PAK2 (n = 1), TM9SF4::PAK2 (n = 1), and CTNNA1::PAK2 (n = 1). Moreover, fluorescence in situ hybridisation (FISH) analysis revealed PAK2 rearrangement in an additional case. No YAP1::MAML2 or YAP1::NUTM1 fusion was detected. Conclusion: Recurrent fusions involving the PAK2 gene in all analysed poroma with folliculo‐sebaceous differentiation in this study confirms that this neoplasm represents a separate tumour entity distinct from YAP1::MAML2 or YAP1::NUTM1 rearranged poromas. [ABSTRACT FROM AUTHOR]

Summary: Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD‐PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow‐up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD‐PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain‐of‐function p.N666S variant in two. Interestingly, both patients had hyaline‐vascular UCD subtype, were in the UCD‐PNP subgroup and had FDCS. Sera from 25 UCD‐PNP patients and 6 PNP patients without UCD were tested for PNP‐associated autoantibodies. Sera from UCD‐PNP patients had a strong reactivity against the N‐terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD‐PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history. [ABSTRACT FROM AUTHOR]

Simple Summary: TERT promoter mutations are the most frequent mutations in melanoma, co-occur regularly with BRAF alterations and are associated with a poorer prognosis. Conflicting results have been published on the role of TERT promoter mutations in resistance to targeted therapy in melanoma. Our data suggest that the TERT mRNA level is associated with resistance to BRAF and MEK inhibitors and could therefore be a more reliable marker for prognosis than the promoter mutations. We showed that overexpression of TERT in a V600E-BRAF melanoma cell line drove resistance to BRAF and MEK inhibitors by a mechanism involving the reactivation of the MAPK pathway independently of telomere maintenance. Finally, we established that TERT inhibition is a therapeutic option in V600E-BRAF-mutated melanoma with acquired resistance to BRAF inhibition. Our results demonstrated the diversity of TERT biological activities in melanoma and highlight the therapeutic potential of targeting TERT in these tumors. Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering the molecular mechanisms driving resistance has been the subject of intense research. Recent in vitro and clinical data have suggested a link between expression of telomerase and resistance to targeted therapy in melanoma. TERT promoter mutations are the main mechanism for the continuous upregulation of telomerase in melanoma and co-occur frequently with BRAF alterations. To understand how TERT promoter mutations could be associated with resistance to targeted therapy in melanoma, we conducted translational and in vitro studies. In a cohort of V600E-BRAF-mutated melanoma patients, we showed that the TERT promoter mutation status and TERT expression tended to be associated with response to BRAF and MEK inhibitors. We demonstrated that TERT overexpression in BRAF-mutated melanoma cells reduced sensitivity to BRAF and MEK independently of TERT's telomer maintenance activity. Interestingly, inhibition of TERT reduced growth of BRAF-mutated melanoma including resistant cells. TERT expression in melanoma can therefore be a new biomarker for resistance to MAPK inhibitors as well as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

At best, stable disease (SD) was achieved after 13 of the treatment lines (43%), partial response (PR) after 12 (40%), CR after two (7%) and progressive disease (PD) after three (10%). GSS treatment is challenging and mostly allows patients to achieve SD or PR. At the last visit, one patient (14%) was in ongoing CR 5 years after stopping methotrexate and three patients (43%) had controlled disease, including one without treatment. [Extracted from the article]

This article discusses the failure of a second course of treatment with mogamulizumab in three patients with Sézary syndrome, a type of cutaneous T-cell lymphoma. Despite positive expression of the target receptor, CCR4, at the start of the second treatment, mogamulizumab did not result in any blood or cutaneous responses. The patients were quickly switched to alternative treatments. The study suggests that acquired resistance to mogamulizumab may be independent of receptor expression and calls for further investigation into the underlying mechanisms. [Extracted from the article]

There was a dominant skin T-cell clone by HTS of TCRB genes in the skin (17% of skin T-cells), different from the initial tumour clone, and a second-dominant T-cell clone (2% of skin T-cells) identical to the initial tumour clone. Dear Editor, Toxic epidermal necrolysis (TEN) is a rare and life-threatening mucocutaneous drug adverse event. The patient's clinical presentation, initial histopathological examination of a lesional skin biopsy and blood workup were consistent with SS, with 1712/mm SP 3 sp CD4 SP + sp CD26 SP - sp T-cells in blood and an identical dominant T-cell clone in skin and blood by high-throughput sequencing (HTS) of TCRB genes. [Extracted from the article]

Summary: Background: Mogamulizumab, an anti‐CCR4 monoclonal antibody, has been shown to increase progression‐free survival in cutaneous T‐cell lymphoma. Objectives: We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment. Methods: Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality. Results: Prior to mogamulizumab, the benign subset of CD4+ T cells displayed exhausted phenotypes, with an increased gradient in programmed death‐1, TIGIT, DNAM‐1, CD27, CD28 and CD70 expression from age‐matched controls to patients' benign CD4+ T cells and to SCs. All patients presented SCs with heterogeneous phenotypes, and differential expression of individual markers was found within distinct malignant subsets. Early complete blood response was observed in 17 of 26 patients and was associated with higher baseline CCR4 expression. A drastic decrease in benign T cells and activated regulatory T‐cell counts was observed during the first 4 weeks. Long‐term follow‐up revealed the emergence of an immune restoration involving CD8+ and naive and stem memory CD4+ T cells, with almost complete disappearance of exhausted lymphocytes. Development of resistance or tumour escape to mogamulizumab was associated with the emergence of CCR4− SCs in blood and skin, displaying significant changes in their heterogeneity patterns, and not explained only by mutations within CCR4 coding regions. Conclusions: Mogamulizumab likely contributes to the restoration of efficient immunity and reshapes not only the malignant lymphocyte subset but also the benign subset. These results have potential implications for optimal therapeutic sequences and/or combinations. What is already known about this topic?Management of Sézary syndrome (SS) involves successive therapies that participate as cause and consequence in the emergence of resistant clones, on a background of immunodeficiency.We and others have reported the complex and dynamic heterogeneity of Sézary cells (SCs) during disease progression.Mogamulizumab therapy, by targeting the skin‐homing receptor CCR4, mainly expressed by SCs, has been shown to increase progression‐free survival in patients with SS. What does this study add?Using multicolour flow cytometry, we provide quantification of CCR4 and immune checkpoint molecules on malignant SCs and benign CD4+ T cells from patients with SS, separated using KIR3DL2 and TCRVβ expression.Mogamulizumab is not only aimed at eradicating malignant SCs but potentially contributes to the restoration of efficient immunity.Tumour escape is associated with the emergence of CCR4− SCs, not explained only by mutations within CCR4 coding regions. [ABSTRACT FROM AUTHOR]

The tumour-promoting role of long-lasting inflammation is well established in the skin where it promotes cutaneous squamous cell carcinoma (cSCC).[[1]] The implication of acute inflammation in cSCC is less described.[3] Generalized eruptive keratoacanthomas of Grzybowski (GEKA) is a rare variant of acquired eruptive keratoacanthomas (KA) displaying generalized eruption on photoexposed areas of hundreds of keratotic-centred follicular papules with severe pruritus. The largest skin lesions were surgically removed, and the patient was successfully treated with oral acitretin.[4] Other patients underwent surgical resection of tumours and received topical steroids on inflammatory lesions. Histopathological examination of skin tumours revealed invasive cSCC or KA, and biopsy specimens of eczematiform eruptions showed arguments for lichenoid or eczematiform lesions. [Extracted from the article]

Wnt/β-catenin signaling plays crucial roles in melanocyte biology and may be implicated in melanoma progression. In this study, we retrospectively examined a real-life cohort of melanomas mutated for β-catenin (CTNNB1), in association or not with a MAPK mutation (of BRAF or NRAS), and analyzed their clinical, histopathological, and molecular characteristics. Our results indicate that, regardless of the presence of a concurrent MAPK mutation, CTNNB1mut cutaneous primary melanomas display more proliferative hallmarks (increased Breslow thickness, mitotic index, and ulceration) than their CTNNB1 wild-type counterparts. Accordingly, they often progress to the metastatic stage. Furthermore, concurrent CTNNB1 and MAPK mutations do not necessarily confer a deep penetrating nevi phenotype. Altogether, this study provides evidence that CTNNB1 mutations in melanomas are associated with specific clinical and pathological features. [ABSTRACT FROM AUTHOR]

The infiltrate was CD3 SP + sp CD4 SP + sp with CD7 loss, the Ki67 index was 30-40% and a dominant T-cell clone was found in skin. In Sézary syndrome, the immunophenotypic abnormalities of blood tumour CD4 SP + sp T cells may include CD7 loss, and CD3 and/or CD4 downregulation. Four had no detectable blood CD3 SP - sp CD4 SP + sp , but a CD3 SP + sp CD4 SP + sp CD7 SP - sp population. [Extracted from the article]

Background: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations.Methods: DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models.Results: The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128-868) fmol/punch, corresponding to an estimated intake of 8-12 tablets per month (2-3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P < 0.001). In multivariate analysis, only systematic use of PrEP during SI and more frequent episodes of SI in the past 4 weeks were significantly associated with higher TFV-DP levels [OR (95% CI): 11.30 (3.62-35.33) and 1.46 (1.19-1.79), respectively; P < 0.001].Conclusions: Among participants using on-demand PrEP, estimated pill intake reached 8-12 tablets per month and was correlated with frequency and systematic use of PrEP for SI. [ABSTRACT FROM AUTHOR]

Background: Tumor molecular deciphering is crucial in clinical management. Pan-cancer next-generation sequencing panels have moved towards exhaustive molecular characterization. However, because of treatment resistance and the growing emergence of pharmacological targets, tumor-specific customized panels are needed to guide therapeutic strategies.Objective: The objective of this study was to present such a customized next-generation sequencing panel in melanoma.Methods: Melanoma patients with somatic molecular profiling performed as part of routine care were included. High-throughput sequencing was performed with a melanoma tailored next-generation sequencing panel of 64 genes involved in molecular classification, prognosis, theranostic, and therapeutic resistance. Single nucleotide variants and copy number variations were screened, and a comprehensive molecular analysis identified clinically relevant alterations.Results: Four hundred and twenty-one melanoma cases were analyzed (before any treatment initiation for 94.8% of patients). After bioinformatic prioritization, we uncovered 561 single nucleotide variants, 164 copy number variations, and four splice-site mutations. At least one alteration was detected in 368 (87.4%) lesions, with BRAF, NRAS, CDKN2A, CCND1, and MET as the most frequently altered genes. Among patients with BRAFV600 mutated melanoma, 44.5% (77 of 173) harbored at least one concurrent alteration driving potential resistance to mitogen-activated protein kinase inhibitors. In patients with RAS hotspot mutated lesions and in patients with neither BRAFV600 nor RAS hotspot mutations, alterations constituting potential pharmacological targets were found in 56.9% (66 of 116) and 47.7% (63 of 132) of cases, respectively.Conclusions: Our tailored next-generation sequencing assay coupled with a comprehensive analysis may improve therapeutic management in a significant number of patients with melanoma. Updating such a panel and implementing multi-omic approaches will further enhance patients' clinical management. [ABSTRACT FROM AUTHOR]

Melanoma is a highly malignant skin cancer with high propensity to metastasize and develop drug resistance, making it a difficult cancer to treat. Current therapies targeting BRAF (V600) mutations are initially effective, but eventually tumors overcome drug sensitivity and reoccur. This process is accomplished in part by reactivating alternate signaling networks that reinstate melanoma proliferative and survival capacity, mostly through reprogramming of receptor tyrosine kinase (RTK) signaling. Evidence indicates that the discoidin domain receptors (DDRs), a set of RTKs that signal in response to collagen, are part of the kinome network that confer drug resistance. We previously reported that DDR1 is expressed in melanomas, where it can promote tumor malignancy in mouse models of melanoma, and thus, DDR1 could be a promising target to overcome drug resistance. In this review, we summarize the current knowledge on DDRs in melanoma and their implication for therapy, with emphasis in resistance to MAPK inhibitors. [ABSTRACT FROM AUTHOR]

The discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family that signals in response to collagen and that has been implicated in cancer progression. In the present study, we investigated the expression and role of DDR1 in human melanoma progression. Immunohistochemical staining of human melanoma specimens (n = 52) shows high DDR1 expression in melanoma lesions that correlates with poor prognosis. DDR1 expression was associated with the clinical characteristics of Clark level and ulceration and with BRAF mutations. Downregulation of DDR1 by small interfering RNA (siRNA) in vitro inhibited melanoma cells malignant properties, migration, invasion, and survival in several human melanoma cell lines. A DDR tyrosine kinase inhibitor (DDR1‐IN‐1) significantly inhibited melanoma cell proliferation in vitro, and ex vivo and in tumor xenografts, underlining the promising potential of DDR1 inhibition in melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Keratoacanthomas (KA) are common cutaneous skin tumors originating from the hair follicles. Unlike squamous cell carcinoma, KA can regress spontaneously and have a benign evolution. Solitary KA is the most common form but familial multiple KA (Ferguson–Smith type), genetically predisposed KA (such as in xeroderma pigmentosum, or Muir–Torre syndrome), or sporadic multiple eruptive KA (Grzybowski type) have been described. Generalized eruptive KA of Grzybowski (GEKA) is a rare condition (around 40 reported cases). The pathophysiology is still unclear. Human papillomavirus (HPV) has been detected in sporadic KA but the presence of HPV39 has never been reported, to our knowledge, in GEKA. Case Report: GEKA in an 80-year-old woman was successfully treated with acitretin (0.5 mg/kg/day) combined with surgical removal of the largest lesions. Treatment was well tolerated and led to decreased pruritus and tumor regression within 6 months. The presence of HPV39 was detected in a lesion by polymerase chain reaction and Sanger sequencing. No genetic alteration was found, in particular in the genes usually altered in squamous cell carcinoma (including NOTCH1, NOTCH2, CDKN2A, TP53). Conclusion: We report a case of GEKA associated with the presence of HPV39 and the successful use of acitretin combined with surgical removal of the larger lesions. [ABSTRACT FROM AUTHOR]

Gorlin syndrome comprises multiple basal cell carcinomas (BCCs), basal cell naevi (BCNs), odontogenic keratocysts, skeletal abnormalities and other features (1). Identification of the PTCH1 gene as the candidate gene for Gorlin syndrome demonstrated that activation of the Hedgehog (Hh) pathway is the key driver in the physiology and pathology of BCC formation (2). Gorlin syndrome has been linked to germline mutations of various members of the Hh pathway, including mainly PTCH1 and also PTCH2 and SUFU; however, to date, SMO germline mutations have not been described. Recently, a case of Gorlin syndrome type 1 mosaicism presented a somatic mutation of SMO L412F (3). This mutation has been described as oncogenic, conferring constitutive activation of the Hh pathway (4). This paper describes a second case of Gorlin syndrome mosaicism with the same SMO L412F mutation observed in affected skin. A detailed molecular assessment of multiple BCNs and BCCs was performed to analyse the oncogenic steps of BCC formation in this patient. [ABSTRACT FROM AUTHOR]

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level. [ABSTRACT FROM AUTHOR]

Purpose: Central nervous system (CNS) dissemination occurs in 4.1% of mantle cell lymphoma (MCL) patients and clinically significant CNS involvement in chronic lymphocytic leukemia (CLL) patients reaches 4%. Ibrutinib, an orally administered Bruton's tyrosine kinase (BTK) inhibitor, has shown substantial activity in CLL or MCL patients with CNS localization, and in primary central nervous system lymphoma (PCNSL). The drug efficacy to treat primary or secondary CNS impairments relies on its brain distribution through the blood-brain barrier (BBB), the aim of the present work was to study the brain distribution of ibrutinib using an in vivo mice model.Methods: Brain and plasma pharmacokinetics of ibrutinib were assessed in a healthy Swiss mice model. Brain accumulation of ibrutinib was evaluated through an escalation single-dose study and a multiple-dose study in whole brain and in its specific anatomic structures. Ibrutinib plasma and brain quantification was performed using a validated liquid-chromatography mass tandem spectrometry method.Results: Maximal concentration of ibrutinib in plasma and brain were close thus showing that ibrutinib rapidly crosses the BBB in 0.29 h (0.2-0.32 h) [median (min-max)]. Ibrutinib brain exposure was also correlated to the dose, and correlated to plasma exposure. AUC0-t brain to AUC0-t plasma ratio average for ibrutinib was found to reach 0.7 and ibrutinib accumulates in the ventricle area.Conclusion: The high level of ibrutinib brain distribution supports the clinical efficacy of this drug in CNS localization of MCL, CLL or PCNSL. [ABSTRACT FROM AUTHOR]

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis is a rare histiocytic disorder for which skin involvement and management are poorly described in adults. The aim of this retrospective monocentric study in a national reference centre is to describe the clinical characteristics, quality of life, BRAF mutation status and outcomes of skin involvement in adult patients with Langerhans cell histiocytosis. Twenty-five patients (14 females, mean age 47 years) were included, with a median follow-up of 33 months (range 4-420 months). Patients experienced poor dermatological quality of life despite low body surface involvement. BRAFV600 mutations were detected in 8 of the 18 patients analysed (45%). Eight patients had an associated malignancy. Several treatment options were used and consisted of surgery, topical steroids and carmustine, thalidomide, methotrexate, vinblastine and steroids and cladribine. This study highlights the need to evaluate quality of life and to screen for associated malignancy in adult patients with Langerhans cell histiocytosis. [ABSTRACT FROM AUTHOR]

Targeted therapies with MAPK inhibitors ( MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAF V 600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi. [ABSTRACT FROM AUTHOR]

CD147 has been implicated in melanoma invasion and metastasis mainly through increasing metalloproteinase synthesis and regulating VEGF/ VEGFR signalling. In this study, the prognostic value of CD147 expression was investigated in a cohort of 196 cutaneous melanomas including 136 consecutive primary malignant melanomas, 30 lymph nodes, 16 in-transit and 14 visceral metastases. A series of 10 normal skin, 10 blue nevi and 10 dermal nevi was used as control. CD147 expression was assessed by immunohistochemistry, and the association of its expression with the clinicopathological characteristics of patients and survival was evaluated using univariate and multivariate statistical analyses. Univariate analysis showed that high CD147 expression was significantly associated with metastatic potential and with a reduced overall survival ( P < 0.05 for both) in primary melanoma patients. CD147 expression level was correlated with histological factors which were associated with prognosis: Clark level, ulceration status and more particularly with Breslow index ( r = 0.7, P < 10−8). Multivariate analysis retained CD147 expression level and ulceration status as predicting factors for metastasis and overall survival ( P < 0.05 for both). CD147 emerges as an important factor in the aggressive behaviour of melanoma and deserves further evaluation as an independent prognostic biomarker. [ABSTRACT FROM AUTHOR]

Context: Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known. Objective: We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma. Methods: We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients. Results: 70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion. Conclusion: Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective. [ABSTRACT FROM AUTHOR]

Background: Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.Methods: An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.Results: Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.Conclusion: Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model.Methods: Carboplatin was administered intravenously for 60 min to a single primate following blood-brain barrier opening induced by an implantable ultrasound device. Blood and brain samples were collected after animal killing, which occurred 60 min after the end of carboplatin administration. Platinum quantification in ultrafiltrate plasma and brain samples was performed using inductively coupled plasma mass spectrometry.Results: The brain concentration of platinum was highly enhanced (5.2×) in the 3.9 cm(3) region sonicated by the US beam, with a higher concentration in more vascularized anatomical structures. At 5 and 10 mm from the US beam axis, platinum concentrations were slightly enhanced (2.2× and 1.3× respectively).Conclusions: This study demonstrates that BBB opening using an implantable ultrasound transducer enhances the brain distribution of carboplatin in a loco-regional manner. Such a treatment approach is of significant interest for the treatment of primary brain tumors and is under current evaluation in a phase 1 clinical trial (NCT02253212). [ABSTRACT FROM AUTHOR]