Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by genomic integration of the Merkel cell polyomavirus (MCPyV). MCPyV-negative cases often present as combined MCCs, which represent a distinctive subset of tumors characterized by association of an MCC with a second tumor component, mostly squamous cell carcinoma. Up to now, only exceptional cases of combined MCC with neuroblastic differentiation have been reported. Herein we describe two additional combined MCCs with neuroblastic differentiation and provide comprehensive morphologic, immunohistochemical, transcriptomic, genetic and epigenetic characterization of these tumors, which both arose in elderly men and appeared as an isolated inguinal adenopathy. Microscopic examination revealed biphasic tumors combining a poorly differentiated high-grade carcinoma with a poorly differentiated neuroblastic component lacking signs of proliferation. Immunohistochemical investigation revealed keratin 20 and MCPyV T antigen (TA) in the MCC parts, while neuroblastic differentiation was confirmed in the other component in both cases. A clonal relation of the two components can be deduced from 20 and 14 shared acquired point mutations detected by whole exome analysis in both combined tumors, respectively. Spatial transcriptomics demonstrated a lower expression of stem cell marker genes such as SOX2 and MCM2 in the neuroblastic component. Interestingly, although the neuroblastic part lacked TA expression, the same genomic MCPyV integration and the same large T-truncating mutations were observed in both tumor parts. Given that neuronal transdifferentiation upon TA repression has been reported for MCC cell lines, the most likely scenario for the two combined MCC/neuroblastic tumors is that neuroblastic transdifferentiation resulted from loss of TA expression in a subset of MCC cells. Indeed, DNA methylation profiling suggests an MCC-typical cellular origin for the combined MCC/neuroblastomas. (c) 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

To assess the impact of various local pathologies on facial alveolar bone dimensions at tooth sites. Cone-beam computed tomography images of 60 patients were analyzed. Healthy teeth and teeth with local pathologies (i.e., endodontically treated, periodontally diseased teeth, and teeth with periapical lesions) were included. The thickness of the facial alveolar bone was measured at five locations: (1) the bone crest (W0), (2) 25% (W25), (3) 50% (W50), (4) 75% (W75) of the distance from the bone crest to the root apex (A), and (5) in the A region (W100). The results were considered statistically significant at p < 0.0008 (adjustment according to the statistical correction for multiple testing). A total of 1174 teeth (707 healthy and 467 with the local pathologies) were assessed. Periodontally diseased maxillary premolars and anterior teeth in the mandible in the W0 position, as well as maxillary molars in the W25 position, tended to have a lower facial bone thickness when compared to the healthy teeth (0.68 mm vs. 0.84 mm, p = 0.008; 0.47 mm vs. 0.55 mm, p = 0.004; and 1.27 mm vs. 1.72 mm; p = 0.009, respectively). In contrast, the observed tendency pointed towards thicker facial bone wall for the periodontally diseased mandibular anterior teeth in the W50 position (0.74 vs. 0.52, p = 0.001). Healthy maxillary molars tended to display a thicker facial alveolar bone compared to the teeth with local pathologies in the W25, W50, and W75 positions (p = 0.001, p = 0.005, and p = 0.004, respectively). The present analysis has indicated that local pathologies are commonly associated with a compromised socket morphology. The facial bone thickness was particularly reduced at periodontally diseased teeth, which may challenge implant therapy.

TPS9592 Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive human skin cancer often caused by the Merkel cell polyomavirus or extended exposure to sunlight. Since the approvals of avelumab globally and subsequently pembrolizumab (US only), anti–PD–(L)1 antibody therapies have become the standard of care for advanced/metastatic MCC patients in recent years. Still, a significant proportion of MCC patients do not respond to or relapse on anti–PD–(L)1 antibody monotherapy. Recent preclinical data suggest that the small molecule, selective class I histone deacetylase inhibitor (HDACi) domatinostat can overcome critical mechanisms of MCC resistance to checkpoint inhibitors. These escape mechanisms include the epigenetic downregulation of the antigen processing and presentation machinery, hence treatment with domatinostat is thought to favorably modulate the tumor environment allowing a reintroduction of anti–PD–(L)1 therapy for an improved and sustained clinical benefit. Methods: The study is a phase II, multicenter, single arm clinical trial of the orally administered HDACi domatinostat in combination with the anti–PD–(L)1 antibody avelumab for patients with advanced unresectable/metastatic MCC that are progressing on previous anti–PD–(L)1 therapy. ClinicalTrials.gov Identifier: NCT04393753. Key Inclusion Criteria are: histologically confirmed MCC, an ECOG performance status ≤ 1, MCC in an advanced, unresectable stage III or metastatic stage IV, and progressing on previous anti–PD–(L)1 antibody monotherapy within the last 12 weeks before planned first administration of study medication. Key Exclusion Criteria are: history of serious anti–PD–(L)1 therapy related adverse reactions prohibiting further avelumab treatment, more than one line of previous systemic anti neoplastic therapy other than anti–PD–(L)1 antibody monotherapy (excluded: palliative radiation therapy of single lesions within 2 weeks before planned administration of study medication), significant active or chronic disease (infections, immunodeficiencies, cardiovascular, psychiatric disorders). A total of 40 patients will be enrolled in up to 46 clinical study sites in Europe and USA. Anti-tumor activity will be primarily assessed by the objective response rate according to RECIST v1.1 as an exploratory analysis. Secondary objectives include additional efficacy assessments, safety, quality of life and pharmacokinetics of domatinostat in combination with avelumab. Correlative aims include evaluating biomarkers for association with clinical benefit. The first patient was enrolled on Oct. 16, 2020, 21 of 46 clinical sites are active and 4 out of 40 planned patients have been enrolled as of Feb. 15, 2021. Clinical trial information: NCT04393753.

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL.

Aim The aim of this systematic review was to critically evaluate the currently existing clinical evidence on the efficacy of autogenous teeth (AT) for the reconstruction of alveolar ridge deficiencies. Materials and methods A search protocol was developed to answer the focused question: “In patients exhibiting alveolar ridge deficiencies and being in need of an implant retained restoration, what is the efficacy of reconstructive procedures employing AT on changes in ridge dimensions compared with control measures?” Uncontrolled studies were also included to assess the overall efficacy of AT for specific procedures. Results A total of six studies (one randomized, one non-randomized controlled, two observational, one controlled case series, one retrospective) were identified. Two studies used AT for staged lateral augmentation, whereas four studies used AT as a demineralized dentin matrix (AutoBT) for the simultaneous grafting of dehiscence-type defects, vertical augmentation of post-extraction sockets, and lateral/transcrestal sinus floor elevation. The reported clinical outcomes following the application of either AT or AutoBT were within the range of those data noted in the respective control groups. Adverse events were commonly not observed. Conclusions The available limited studies involved relatively small patient samples and short follow-up periods but pointed to the potential of AT to serve as an alternative material for the reconstruction of alveolar ridge deficiencies. Clinical relevance AT appear to be effective in reconstructing alveolar ridge deficiencies.

Merkel cell carcinoma (MCC) is an aggressive metastatic neuroendocrine skin cancer associated with high recurrence rates as well as regional and distant metastasis resulting in a high mortality. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid playing a decisive role in promoting tumor cell survival, proliferation, migration and metastasis via intracellular and extracellular targets. SPHK1 and 2 are the enzymes that phosphorylate pro-apoptotic sphingosine to form pro-survival S1P and are upregulated in different cancer entities. The objective of this study was to determine the importance of intracellular S1P in MCC cell survival and proliferation. The SPHK1 and 2 expressions were analyzed by qRT-PCR in 16 MCC cell lines. The well characterized MCC cell lines MKL1 and WaGa were used for functional studies in vitro. Since the cell of origin of MCC is still controversial, normal human dermal fibroblasts (NHDF) were used as non-transformed control cells. Treatment with SKI-II, an inhibitor of SPHK1 and 2, on MKL1 and WaGa resulted in dose dependent decrease of cell viability and increased apoptosis. In contrast, we did not see any effect of SKI-II inhibitor on NHDF cell viability as determined by CellTiter-Glo 3D cell viability assay and FITC Annexin V FACS analysis. Further, S1P-ELISA showed a decrease in intracellular S1P concentration and LC/MS analysis revealed an increase in ceramide and sphingomyelin species upon treatment with SKI-II in both MKL1 and WaGa cell lines. In addition, immunoblotting revealed decrease in pAKT levels and increased Caspase3 and PARP cleavage in SKI-II treated MKL1 and WaGa. In conclusion our in vitro data suggest that targeting the S1P axis represents a potential therapeutic strategy in MCC.

Merkel cell carcinoma (MCC) is an aggressive metastatic neuroendocrine skin cancer associated with high recurrence and mortality rates. Sphingolipids (SL) represent a major class of bioactive lipids potently regulating cell proliferation, migration, and apoptosis. In particular pro-survival sphingosine 1-phosphate (S1P) plays a prominent role in tumor biology. De novo synthesis of S1P and its precursor ceramide begins from condensation of serine and palmitoyl-CoA catalysed by serine palmitoyltransferases (SPTLC) 1-3. The objective of this study was to elucidate whether pharmacological interference with S1P synthesis would impact MCC cell proliferation, survival, and apoptosis. MKL1 and WaGa cell lines (reflecting phenotypic properties of primary MCC tumors) were used as in vitro MCC models. Since the cell of origin of MCC is still controversial, normal human dermal fibroblasts (NHDF) were used as non-transformed control cells. qPCR and Western blotting revealed the expression of SPTLC 1-3. Myriocin, a pharmacological inhibitor of SPTLC1-3, was used to inhibit the first step of SL synthesis. Using CellTiter-Glo assay and flow cytometry, we observed dose dependent decrease in cell viability and induction of apoptosis in MCC cells. Of note, NHDF viability was unaffected by myriocin. LC/MS analysis and S1P-ELISA showed significant reduction in intracellular ceramide and S1P concentrations in myriocin treated MCC cells. This was accompanied by decreased phosphorylation of AKT and increased Caspase3 and PARP cleavage. In conclusion our in vitro data suggest that targeting the S1P axis in MCC could represent a potential anti-proliferative strategy in MCC.

ABSTRACT Solid tumors are more than an accumulation of cancer cells. Indeed, cancerous cells create a immune permissive microenvironment by exploiting non-transformed host cells. Thus, solid tumors rather resemble abnormal organs composed of the tumor cells itself and the stroma providing the supportive framework. The stroma can be divided into the extracellular matrix consisting of proteoglycans, hyaluronic acid, and fibrous proteins, as well as stromal cells including mesenchymal and immune cells; moreover, it contains various peptide factors and metabolites. Each of these components may exert immune modulating effects. More recent advances have further revealed that tumor-host interactions extend well beyond the local microenvironment. Indeed, similar to organs tumors are not existing on their own, but take up residence in the host, i.e. the patient. Moreover, tumors not only respond to, but actively perturb host organs at distant anatomic sites in order to facilitate immune escape and metastatic spread, e.g. by modification of fibroblasts and the extracellular matrix at premetastatic sites. However, the detailed modus operandi of the crosstalk between tumor cells, the tumor microenvironment and the host macroenvironment to date is not completely understood. Emerging mechanisms of communication include miRNAs as well as tumor-derived exosomes. The latter contribute to metastatic invasion by carrying both messenger proteins (as well as mRNAs, miRNAs, and DNA) that direct bone marrow–derived cells toward a prometastatic phenotype or do generate a state of chronic inflammation. Consequently, many aspects of tumor biology and tumor immunology can only be explained by a detailed understanding of both local and systemic interactions. Disclosure: The author has declared no conflicts of interest.

Amac: Radyografide curuk tanisinin konmasi bazen kolay olmayabilir. Bu calismada ayni sartlar altinda degerlendirilen dort adet fosfor plaka sisteminin ve iki film esasli sistemin curuk tanisindaki yerinin arastirilmasi amaclanmistir. Yontem: Iki yuz adet dis beserli gruplar halinde plastik Lego® bloklara yerlestirildi. Her bir bloktan standart sartlarda dental rontgen apareyi ile radyografik goruntu alindi. Fosfor plakalarla (Dentsply DenOptics®, Durr Vistascan II®, Soredex Digora FMX®, Soredex Digora Optime®) 60 kV ve 7 mA isinlamayla goruntu elde edildi. Curuk derinligi on bir gozlemci tarafindan degerlendirildi. Histolojik bulgulari karsilastirmak icin mikroskobik inceleme yapildi. Mikroskobik ve radyolojik bulgular arasindaki farklar degerlendirilerek curuk derinligi belirlendi. Bulgular: Curuk tanisinda farkli sensorlerin cok az etkisi oldugu goruldu. En buyuk farki DenOptix ve Digora FMX sistemleri gosterdi. Tum yuzeyler hesaplandiginda etkinin istatistiksel olarak anlamli olmadigi bulundu. Sonuc: Dort fosfor plaka sistemi de curuk tanisinda kabul edilebilir sonuclar gostermistir. Mine curugundeki histolojik derinlik radyografik olcumlerle uyumlu bulunmamistir. Anahtar Kelimeler : Dis curugu, dis curugu tanisi, fosfor plaka