Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma

ABSTRACT: The recent findings brought the necessity of testing the mutational status of a series of genes which had been already identified as responsible for melanomas development and progression, such as BRAF, CKIT and PTEN: the consequent results are, in fact, essential to guide the assessment of the novel treatment protocols based on tailored targeted therapies. We present here the case of a 66 year-old male patient, diagnosed with an advanced melanoma in June 2011, and treated with Dabrafenib for double mutant metastatic disease. The patient was referred to our attention for a large exophytic malignant melanoma on the left shoulder. After complete surgical excision and elective lymph node dissection for presence of metastatic sentinel lymph node, the patient has started high-dose interferon alfa- 2b injections as adjuvant therapy for a complete negative staging. The treatment was interrupted in August 2011 due to the appearance of metastatic lymph nodes. Tumor burden was rapidly growing reaching in few months the size of a tennis ball for the tumor mass located in the shoulder. Mutational study of the tumor revealed a double BRAF mutation on V-600E and V600M. This finding incited us to enroll the patient in compassionate Dabrafenib clinical trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost surprisingly for the rapidity of the effect, one week later the lesion on the shoulder has reduced its size by 60% and one month later it has completely disappeared from sight. CT scan of June 2012 documented the astonishing clinical response

Role of microsatellite instability, immunohistochemistry and Mismatch Repair germline aberrations in immunosuppressed transplant patients: a phenocopy dilemma in Muir-Torre Syndrome.

Sebaceous tumours and keratoacanthomas are uncommon neoplasms that constitute important clinical criteria for Muir-Torre Syndrome (MTS) diagnosis. In MTS patients, the increased risk of developing synchronous or metachronous visceral malignancies is characterized by autosomal dominant inheritance. However, there are further conditions, other than MTS, that increase the risk of sebaceous neoplasms, e.g. iatrogenic immunosuppression. In this latter scenario, the sebaceous tumours can present Microsatellite instability (MSI) and loss of Mismatch-Repair (MMR) proteins, characteristic of hereditary syndromes, even in the absence of MMR germline mutations. In this paper we examine transplant probands in which the immunosuppressive therapies unmask the MTS cutaneous phenotypes, showing microsatellite instability (MSI) and loss of MMR protein expression, as demonstrated by immunohistochemistry (IHC). Furthermore, mismatch repair genes (MMR) sequencing analysis identified the presence of germline mutations in MTS-suspected individuals, in the absence of a visceral MTS phenotype. It is well known that immunosuppression plays a central role in the development of sebaceous tumours in both MTS and in non-syndromic settings. Sebaceous skin tumours MSI status and IHC profiles can be influenced by epigenetic or iatrogenic factors, however they constitute valuable tools and a cost-effective approach to screen individuals who otherways should undergo MMR genes direct sequencing in the context of immunosuppression. In this complex setting, the choice of the immunosuppressive drug becomes a critical decision for the management of both MTS and sporadic transplant patients, that may benefit from the administration of immunosuppressive drugs, resulting in a low impact on skin cancerogenesis

Skeletal stigmata as keys to access to the composite and ancient Gorlin-Goltz syndrome history: The Egypt, Pompeii and Herculaneum lessons

There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to cutaneous and visceral benign and malignant neoplasms. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant systemic disease with almost complete penetrance and high intra-familial phenotypic variability, caused by germline mutations of the gene PTCH1. The syndrome is characterized by unusual skeletal changes and high predisposition to the development of multiple basal cell carcinomas, odontogenic keratocysts tumors and other visceral tumors. The Gorlin syndrome, clinically defined as distinct syndrome in 1963, existed during Dynastic Egyptian times, as revealed by a costellation of skeletal findings compatible with the syndrome in mummies dating back to 3000years ago and, most likely, in the ancient population of Pompeii. These paleogenetic and historical evidences, together with the clinical and biomolecular modern evidences, confirm the quite benign behavior of the syndrome and the critical value of the multiple and synchronous skeletal anomalies in the recognition of these rare and complex genetic disease

Microsatellite instability, immunohistochemistry and germline mismatch repair gene mutations for the diagnosis of Muir-Torre syndrome in immunosuppressed patients

Although rare sebaceous tumors and keratoacanthomas are clinical criteria for Muir-Torre syndrome (MTS), they can also be found in the context of immunosuppression. We present here two patients who underwent organ transplantation in which immunosuppression unmasked MTS through the early appearance of the cutaneous sebaceous neoplasms. In all of their sebaceous tumors we detected microsatellite instability (MSI) e loss of mutS protein homolog 2 (MSH2) and 6 (MSH6) expression at immunohistochemistry (IHC). Although in the absence of visceral MTS phenotype, we performed the sequencing analysis for mismatch repair genes (MMR) identifying two novel MSH2 and MSH6 germline mutations. The combination of MSI and IHC status can therefore be considered useful for the recognition of MTS, even in case of incomplete MTS phenotype and/or in immunosuppressed patients. It would allow a costeffective approach to identify individuals who should undergo MMR genes direct sequencing

Giuseppe Moscati: a man, a physician and a scientist

The life of Giuseppe Moscati (1880-1927) as a man, as a physician and as a scientist may be framed within the cultural climate of Positivism, which spread over the last years of the 19th century and the beginning of the 20th Century. His activity contributed to patients' care improvement; in addition to meticulous drug regimens, he also prescribed a methodology of spiritual care, involving meditation and self-control as part of an holistic approach to healthcare. Our review deals with his published researches, highlighting the innovative findings on the juvenile diabetes treatment and extensive clinical changes consequent upon nephritis. This extraordinary man put considerable emphasis on primary care and holistic health in Italy, pioneering a new patient-centred, and holistic approach to medicine

Monocytes-based in vitro assay for a preliminary biocompatibility assessment of blood-contacting devices

The biological evaluation of biomaterials is currently defined by the ISO-10993 norm in which parts four and five are dedicated to emo-compatibility and cell toxicity, respectively. Our study will provide a novel in vitro experimental approach for the biocompatibility assessment of biomaterials or medical devices using human primary monocytes as cellular model. In these new settings, human monocytes are exposed to a medium containing the extractable compounds derived from materials or devices; subsequently, cell toxicity and pro-inflammatory effects are analysed through MTT assay, flow cytometry and enzyme-linked immunosorbent assay (ELISA) methodologies. These experimental procedures offer the advantage to use a human and primary cell context belonging to the immune system, in order to accurately predict the nature of blood/device interaction occurring during a clinical application. To validate the reliability of this method, we also reported a comparative study between two different membranes showing a different level of biocompatibility. On the bases of these data, it is possible to state that this new experimental model represents a good approach to investigate the effects induced by a biomaterial on cell death and inflammation using human, primary monocytes

A Proteomic Analysis of Discolored Tooth Surfaces after the Use of 0.12% Chlorhexidine (CHX) Mouthwash and CHX Provided with an Anti-Discoloration System (ADS)

Chlorhexidine (CHX) is considered the gold standard for the chemical control of bacterial plaque and is often used after surgical treatment. However, CHX employment over an extended time is responsible for side effects such as the appearance of pigmentations on the teeth and tongue; the discoloration effects are less pronounced when using a CHX-based mouthwash with added an anti-discoloration system (ADS). The aim of this study was to evaluate, using one- and two-dimensional gel electrophoresis combined with mass spectrometry, the possible proteomic changes induced by CHX and CHX+ADS in the supragingival dental sites susceptible to a discoloration effect. The tooth surface collected material (TSCM) was obtained by curettage after resective bone surgery from three groups of patients following a supportive therapy protocol in which a mechanical control was combined with placebo rinses or CHX or a CHX+ADS mouthwash. The proteomic analysis was performed before surgery (basal conditions) and four weeks after surgery when CHX was used (or not) as chemical plaque control. Changes in the TSCM proteome were only revealed following CHX treatment: glycolytic enzymes, molecular chaperones and elongation factors were identified as more expressed. These changes were not detected after CHX+ADS treatment. An ADS could directly limit TSCM forming and also the CHX antiseptic effect reduces its ability to alter bacterial cell permeability. However, Maillard's reaction produces high molecular weight molecules that change the surface properties and could facilitate bacterial adhesion

Fibroepithelioma of Pinkus: Solitary tumor or sign of a complex gastrointestinal syndrome

Fibroepithelioma of Pinkus (FEP), which is considered to be an uncommon variant of basal cell carcinoma, has been described in association with other systemic diseases. However, no specific studies are currently available on this subject. The aim of our study was to evaluate the clinical and morphological characteristics of FEP and investigate whether this rare tumor is a single entity or seen in the context of a more complex syndrome. We retrospectively analyzed 49 cases of FEP diagnosed and excised in a single academic institution from 1995 to 2011. The tumors were mainly located on the trunk (77.55%), followed by the lower extremities (12.20%) and the head and neck (10.20%). In 9 of the 49 cases (18%), FEP was associated with gastrointestinal tumors. The abovementioned cases are presented in an attempt to make clinicians more aware of a possible association between FEP and gastrointestinal cancer. Although a possible underlying common genetic background between FEP and gastrointestinal tumors was not provided, our study suggests that patients with FEP should be screened for the occurrence of gastrointestinal tumors

ICON: an Ontology for Comprehensive Artistic Interpretations

In this work, we introduce ICON, an ontology that models artistic interpretations of artworks’ subject matter (i.e. iconographies) and meanings (i.e. symbols, iconological aspects). Developed by conceptualizing authoritative knowledge and notions taken from Panofsky’s levels of interpretation theory, ICON ontology focuses on the granularity of interpretations. It can be used to describe an interpretation of an artwork from the Pre-iconographical, Icongraphical, and Iconological levels. Its main classes have been aligned to ontologies that come from the domains of cultural descriptions (ArCo, CIDOC-CRM, VIR), semiotics (DOLCE), bibliometrics (CITO), and symbolism (Simulation Ontology), to grant a robust schema that can be extendable using additional classes and properties coming from these ontologies. The ontology was evaluated through competency questions that range from simple recognition on a specific level of interpretation to complex scenarios. Data written using this model was compared to state-of-the-art ontologies and schemas to both highlight the current lack of a domain-specific ontology on art interpretation and show how our work fills some of the current gaps. The ontology is openly available and compliant with FAIR principles. With our ontology, we hope to encourage digital art historians working for cultural institutions in making more detailed linked open data about the content of their artefacts, to exploit the full potential of Semantic Web in linking artworks through not only subjects and common metadata, but also specific symbolic interpretations, intrinsic meanings, and the motifs through which their subjects are represented. Additionally, by basing our work on theories made by different art history scholars in the last century, we make sure that their knowledge and studies will not be lost in the transition to the digital, linked open data era