Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

Grover's Disease Association with Cutaneous Keratinocyte Cancers: More than a Coincidence?

Better mechanistic understanding of desmosome disruption and acantholysis in Grover's disease (GD) may improve management of this disease. Recent molecular studies highlighted promising pathways to be explored by directly comparing GD and selected features of associated skin diseases. The association between GD and cutaneous keratinocyte carcinomas, the most prevalent non-melanoma skin cancers (NMSC), is not completely characterized. To review the medical literature regarding GD-associated cutaneous keratinocyte cancers, focusing on molecular features, pathophysiological mechanisms, and disease associations, to help guide future research and patient management. GD has been associated with a variety of skin conditions, but its association with skin cancers has been rarely reported. Between 1983 and 2024, only nine scientific papers presented data supporting this association. Interestingly, we found that GD may mimic multiple NMSCs, as few authors reported GD cases misdiagnosed as multiple cutaneous squamous cell carcinomas for more than 4 years or the presence of superficial basal cell carcinoma-like areas associated with focal acantholysis. In conclusion: (a) GD may be an imitator of multiple NMSCs, and (b) the relationship between GD and NMSCs may reveal promising pathways for the mechanistic understanding of desmosome disruption and acantholysis in GD and may even lead to its reclassification as a distinctive syndrome.

Endothelial Dysfunction as a Key Link between Cardiovascular Disease and Frailty: A Systematic Review.

Background: Frailty is increasingly recognized as a significant health concern, particularly due to its association with cardiovascular pathologies. This study aims to examine how vascular endothelial dysfunction, a known premorbid stage in the pathophysiology of cardiovascular diseases, contributes to the link between cardiovascular illness and frailty. Methods: The inclusion criteria allowed us to focus on original clinical research articles published in English between January 2014 and January 2024, which reported quantitative assessments of the relationship between frailty and vascular endothelial dysfunction. Excluded from the study were systematic literature reviews, meta-analyses, editorials, conference articles, theses, methodological articles, and studies using animal or cell culture models. Searches were conducted of electronic databases, including Scopus, ScienceDirect, and Medline, up to 22 January 2024. The risk of bias was assessed using the Joanna Briggs Institute's critical appraisal tools. The methods used to present and synthesize the results involved data extraction and categorization based on biomolecular and clinical findings of endothelial dysfunction. Results: Following the application of the inclusion and exclusion criteria, a total of 29 studies were identified. Vascular endothelial dysfunction was associated with increased frailty phenotypes, and we also identified SGLT-2 inhibitors' potential role as an anti-fragility treatment that affects endothelial dysfunction. This study found that the physical and biomolecular markers of endothelial dysfunction are associated with frailty measures and have predictive value for incident frailty. Furthermore, some studies have shown inflammation to have an impact on endothelial dysfunction and frailty, and an innovative age-related chronic inflammation measure has been proven to predict frailty scores. Conclusions: The current evidence suggests an association between endothelial dysfunction and frailty, highlighting the need for further research to elucidate the underlying mechanisms.

Frailty and Loneliness in Older Adults: A Narrative Review.

(1) Background: In a society with an advancing aging rate, medical systems are coming under pressure due to an increasing flow of older patients with multiple somatic diseases, exacerbated by their psychological and sociological backgrounds. We aimed to investigate the relationship between frailty and loneliness in older adults and to provide a holistic perspective on these concepts. Our research question was "Is there a link between the loneliness and frailty in older people?" (2) Methods: To assess the link between loneliness and frailty, we conducted a search accessing Index Medicus and PubMed; the timeframe of our research was from 2013 until 2023. Data regarding the study population, as well as loneliness and frailty assessments and approaches, were extracted. (3) Results: A positive relationship between loneliness and the appearance and progression of frailty in older adults is argued for. (4) Conclusions: Frailty and loneliness in older adults are often interconnected and can have a significant impact on their overall well-being. Early identification of frailty by assessing risk factors (including loneliness and/or social isolation) should become a standard of care for older patients. Appropriate combined interventions that effectively address both frailty and loneliness (physical exercises, psychological support, and social engagement) can promote healthier aging, prevent health deterioration, maintain independence, and reduce healthcare costs.

Vitiligo-Thyroid Disease Association: When, in Whom, and Why Should It Be Suspected? A Systematic Review.

In most dermatological pathologies, the phenomena observed on the skin are a reflection of internal disorders. In patients with associated acral involvement on the dorsal sides of the hands, this "vitiligo phenotype" may lead to the investigation of certain associated pathologies that sometimes have no obvious clinical impact. To assess the link between skin depigmentation and autoimmune pathologies, we conducted a systematic review involving article selection from the PubMed database. Patients with coexisting thyroid pathologies were found to have a predisposition for developing acral vitiligo and depigmentation of the wrists, and autoimmune thyroid pathologies appeared to be the only coexisting autoimmune or inflammatory diseases in vitiligo patients to show a pattern of distribution. The association of concomitant thyroid dysfunction with depigmentation of the hands was found to be so strong that the absence of depigmented macules on the hands may exclude the coexistence of an autoimmune thyroid pathology. Although the frequency of acral involvement in patients with vitiligo and autoimmune pathologies is higher, the mechanism by which thyroid dysfunction influences this distribution pattern remains incompletely elucidated and requires future studies.

The prognostic significance of the clinical and histological parameters in primary cutaneous melanoma patients.

Cutaneous melanoma is the most aggressive form of skin cancer and its incidence is unfortunately increasing. In the last decades, a progressive increase of new cases of diagnosed thin melanoma has been noted. This may be due to earlier detection, better surveillance, improved diagnostic criteria or increased exposure to sunlight. Despite the fact that Breslow tumor thickness has the strongest proven prognostic significance, there are still thin melanomas that metastasize and thick melanomas with favorable evolution. Therefore, the identification of strong predictive factors for survival is mandatory, particularly for patients with thin melanoma.

Role of immunohistochemistry in the diagnosis and staging of cutaneous squamous-cell carcinomas (Review).

Non-melanoma skin cancer (NMSC) is the most common type of neoplasm affecting Caucasian individuals, with squamous-cell carcinoma (cSCC) being the second most common type of NMSC after basal-cell carcinoma. The immunohistochemical study of cSCC is of particular importance, especially for the diagnosis of its rare forms, for which accurate and early diagnosis is crucial for survival. In the present review of the literature, the potentially significant value of immunohistochemical markers were highlighted to more accurately assess the biological behaviour, the prognosis of cSCC and to optimize case management. The immunohistochemical markers were classified from a pathophysiological point of view in order to present the mechanism by which carcinogenesis occurs with its subsequent evolution and therefore, to develop a more accurate novel risk staging criteria for this type of neoplasm.

Current Challenges in Deciphering Sutton Nevi-Literature Review and Personal Experience.

Halo nevi, known as leukoderma acquisitum centrifugum, Sutton nevus, leukopigmentary nevus, perinevoid vitiligo, or perinevoid leukoderma, together with vitiligo and melanoma-associated hypopigmentation, belong to the group of dermatoses designated as immunological leukodermas. The etiology and pathogenesis of halo nevi has not been fully elucidated. There are several mechanisms through which a lymphocytic infiltrate can induce tumoral regression. In this review, we aimed to update the knowledge about Sutton nevi starting with the clinical appearance and dermoscopic features, continuing with information regarding conventional microscopy, immunohistochemistry, and the immunological mechanisms responsible for the occurrence of halo nevi. We also included in the article original unpublished results when discussing dermoscopic, pathologic and immunohistochemical results in halo nevi. Sutton nevi are valuable models for studying antitumor reactions that the human body can generate. The slow and effective mechanism against a melanocytic skin tumor can teach us important lessons about both autoimmune diseases and anticancer defenses.

FOXP3 in Melanoma with Regression: Between Tumoral Expression and Regulatory T Cell Upregulation.

Cutaneous melanoma is a significant immunogenic tumoral model, the most frequently described immune phenomenon being tumor regression, as a result of the interaction of tumoral antigens and stromal microenvironment. We present a retrospective cohort study including 52 cases of melanoma with regression. There were evaluated correlations of the most important prognostic factors (Breslow depth and mitotic index) with FOXP3 expression in tumor cells and with the presence of regulatory T cells and dendritic cells in the tumoral stroma. FOXP3 expression in tumor cells seems an independent factor of poor prognosis in melanoma, while regression areas are characterized by a high number of dendritic cells and a low number of regulatory T cells. FOXP3 is probably a useful therapeutical target in melanoma, since inhibition of FOXP3-positive tumor clones and of regulatory T cells could eliminate the ability of tumor cells to escape the immune defense of the host.

Pyoderma gangrenosum and suppurative hidradenitis association, overlap or spectrum of the same disease? Case report and discussion.

Suppurative hidradenitis and pyoderma gangrenosum are rare disorders that can be seen isolated or even more rare, as part of different autoinflammatory syndromes: Pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH), pyoderma gangrenosum, acne, pyogenic arthritis, and hidradenitis suppurativa (PAPASH) or psoriatic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PsAPASH). Although they have different clinical features, suppurative hidradenitis and pyoderma gangrenosum seem to share similar pathogenic pathways involving a dysregulated innate immune system, with neutrophilic inflammation, mediated by IL-1ß, controlled by NALP3 inflammasome pathway. We report a case of a 53-year-old male patient previously diagnosed with HS in inguinal-scrotal area that developed rapidly after a traumatic injury on his left anterior calf, a painful inflammatory plaque with pustules on the surface that rapidly progressed (24-48 h) to form ulcers. The lesions ended up healing with a large scarring plaque with cribriform openings, multiple fibrous bridges, open comedones, and double-ended pseudo-comedones. Although the clinical aspect at presentation together with the aspect on the first biopsy were suggestive for pyoderma gangrenosum, the healing aspect is more commonly seen in suppurative hidradenitis. Commonly seen in acne, in the healing phase of suppurative hidradenitis but more rarely in pyoderma gangrenosum, the formation of comedones seem to be a complex process and raise the question if these entities represent in our patient an association, an overlap or the spectrum of the same disease.

Bacillary angiomatosis triggered by severe trauma in a healthy Caucasian patient: A case report.

Bacillary angiomatosis represents a cutaneous and systemic infection caused by Bartonella species, typically described in the past in HIV-positive patients or associated with immunodeficiencies. More recent case reports had brought into attention the probability that this entity may manifest in otherwise healthy individuals, triggered by trauma and skin burns. The physiopathology of this neoproliferative process is based on the production of angiogenetic molecules, such as vascular endothelial growth factor (VEGF) and IL-8. In case of an inadequate treatment, the evolution can be fatal, with a systemic dissemination of the abscesses within the gastro-intestinal tract, respiratory tract, brain and bones. The appropriate therapy is with oral erythromycin and doxycycline, but several treatments such as cephalosporins, penicillins, macrolides, aminoglycosides, rifampin, dapsone, ciprofloxacin, have been tried with favorable results. Herein we present the case of a Caucasian patient, seronegative for HIV, who developed multiple vascular papules and nodules on the face, after a severe trauma and which healed after an adequate antibiotic therapy with oral clarithromycin.

Comparative analysis of CEACAM1 expression in thin melanomas with and without regression.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a key molecule in several intracellular and intercellular signaling pathways, with multiple functional and structural roles. CEACAM1 expression in melanoma is often described in the invading part of the tumor and has been associated with increased melanoma cells invasion and migration. We studied CEACAM1 expression in regressing versus non-regressing thin melanomas, knowing that phenomenon of regression represents a valuable model for understanding tumor immunity. In melanoma, through homophilic interactions, CEACAM1 inhibits natural killer cell activity, inhibits effector functions of tumor infiltrating lymphocytes, such as cytotoxicity and interferon-γ release. We present a retrospective study including 53 consecutive cases of thin melanoma, 21 with regression and 32 without regression. Comparative analysis of CEACAM1 expression in regressed and non-regressed areas from melanomas with regression and in non-regressed melanomas was performed. We used three different clones of CEACAM1: AA 1-428, extracellular domain, rabbit; AA 1-428, mouse, clone 8B6E2F4; and AA 1-468, full length, mouse, clone 2F6. All three clones had similar reactivity. We identified membrane positivity of tumor cells in non-regressed melanomas and in non-regressed areas in melanomas with regression. Remaining tumor cells in regressed areas were mostly negative for CEACAM1. In non-regressed lesions, there was a stronger positivity of CEACAM1 in the deep invasive front. In thin melanomas, CEACAM1 overexpression is related with invasiveness, suggesting that CEACAM1-positive melanomas are more aggressive. Also, in areas of regression tumor cells lose CEACAM1 expression, probably correlated with the presence of natural killer cells.

Tumor infiltrating lymphocytes: The regulator of melanoma evolution.

Melanoma is the most severe type of skin cancer and its incidence has increased in the last decades. In the United States, it is the 6th most common cancer in both men and women. Prognosis for patients with melanoma depends on the stage of the disease at the time of diagnosis and it can be influenced by the immunologic response. Melanoma has been historically considered an immunogenic malignancy. It often contains great amount of immune cells (different subsets of T-cells, dendritic cells, macrophages, neutrophils, mast cells, B lymphocytes), which may reflect a continuous intercommunication between host and tumor. It is not established if tumor-infiltrating lymphocytes (TILs) are induced by tumor cells or by other components of the microenvironment or when they are a host direct immunologic reaction. It has been observed that in many cases, the presence of a dense TIL is associated with good prognosis. The pattern and activation state of the cells which constitute TIL is variable and modulates the clinical outcome. An important step in the understanding of tumor immunobiology is the analysis of the populations and subsets of immune cells that form TIL. Besides its prognostic significance, after approval of cytotoxic T lymphocyte antigen 4, programmed cell death-1 and programmed death-1 ligand antibodies for the treatment of melanoma, the assessment of immune infiltrate composition has become even more captivating, as it could provide new target molecules and new biomarkers for predicting the effect of the treatment and disease outcome in patients treated with immunotherapy. In this review we discuss current state of knowledge in the field of immune cells that infiltrate melanoma, resuming the potential of TIL components to become prognostic markers for natural evolution, for response to drugs or valuable targets for new medication.

Epithelial-Mesenchymal Transition in Skin Cancers: A Review.

Epithelial-mesenchymal transition (EMT) is involved in physiologic processes such as embryogenesis and wound healing. A similar mechanism occurs in some tumors where cells leave the epithelial layer and gain mesenchymal particularities in order to easily migrate to other tissues. This process can explain the invasiveness and aggressiveness of these tumors which metastasize, by losing the epithelial phenotype (loss of E-cadherin, desmoplakin, and laminin-1) and acquiring mesenchymal markers (N-cadherin). Complex changes and interactions happen between the tumor cells and the microenvironment involving different pathways, transcription factors, altered expression of adhesion molecules, reorganization of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in specific microRNAs. The purpose of this review is to determine particularities of the EMT process in the most common malignant cutaneous tumors (squamous cell carcinoma, basal cell carcinoma, and melanoma) which still have an increasingly high incidence. More studies are required on this topic in order to establish clear correlations. High costs related to skin cancer therapies in general as well as high impact on patients' quality of life demand finding new, reliable prognostic and therapeutic markers with significant public health impact.

Matrix metalloproteinases expression in lentigo maligna∕lentigo maligna melanoma - a review of the literature and personal experience.

Cutaneous melanoma is the most aggressive type of skin cancer, with high invasive potential. Lentigo maligna melanoma (LMM) is a relatively rare type, accounting for about 10% of all melanomas, while the most common subtype of melanoma on the face, typically on chronically sun-exposed skin of elderly people. Its in situ stage is lentigo maligna (LM). During the process of transformation from LM to LMM, tumor cells secrete or induce the release from neighboring cells of large amounts of matrix metalloproteinases (MMPs) that degrade the extracellular matrix. Some MMPs, as MMP3 and MMP9 expressed melanoma cells is associated with statistical significance in both in vitro and in vivo studies, with an invasive phenotype. Unfortunately, there is scarce data published about MMPs expression in LM∕LMM, as majority of research on melanoma refer to superficial spreading and nodular melanoma. Our personal, unpublished yet fully data is an attempt to complete a specific panel of immunohistochemical markers that could explain the slow growing rate of LMM.

Efficacy of methotrexate as anti-inflammatory and anti-proliferative drug in dermatology: Three case reports.

Methotrexate (MTX) is a folic acid analog with anti-proliferative (anti-neoplastic, cytotoxic), immunosuppressive and anti-inflammatory properties, which has been used in the treatment of various cutaneous disorders, such as psoriasis, keratoacanthoma, pityriasis rubra pilaris, atopic dermatitis, mycosis fungoides, bullous skin diseases, systemic sclerosis, morphea, lupus erythematosus, dermatomyositis and crusted scabies. Inhibition of cell proliferation is explained through its role in blocking DNA/RNA synthesis, by inhibiting dihydrofolate reductase, necessary for the production of pyrimidine and purine nucleotides. An anticancer effect can be related to α-oxoaldehyde metabolism (MTX increases methylglyoxal levels). Its anti-inflammatory property is based on the inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, thus increasing intracellular and extracellular adenosine, a purine nucleoside with anti-inflammatory effect. This drug can limit inflammation by scavenging free radicals and decreasing malondialdehyde-acetaldehyde protein-adduct production. Moreover, the anti-proliferative and anti-inflammatory effects can also be related to inhibition of the DNA methylation pathway, thus inhibiting methionine formation. The aim of the present study was to report various dermatological cases from our daily practice that demonstrate the efficacy of MTX in the treatment of cutaneous diseases, highlighting different mechanisms of action: its anti-inflammatory effect in psoriasis and its anti-proliferative, and anti-neoplastic effect in well-differentiated squamous cell carcinoma or in keratoacanthoma. Moreover, different administration pathways and doses are addressed. Assessment of the treatment plan, clinical improvement of cutaneous lesions, biologic evaluation, final aesthetic result, quality of life, as well as potential adverse effects and drug tolerance related to each case mentioned.

On the Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) in Human Malignancies.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein belonging to the carcinoembryonic antigen (CEA) family that is expressed on a wide variety of cells and holds a complex role in inflammation through its alternate splicing and generation of various isoforms, mediating intricate mechanisms of modulation and dysregulation. Initially regarded as a tumor suppressor as its expression shows considerable downregulation within the epithelia in the early phases of many solid cancers, CEACAM1 has been linked lately to the progression of malignancy and metastatic spread as various papers point to its role in tumor progression, angiogenesis, and invasion. We reviewed the literature and discussed the various expression patterns of CEACAM1 in different types of tumors, describing its structure and general biologic functions and emphasizing the most significant findings that link this molecule to poor prognosis. The importance of understanding the role of CEACAM1 in cell transformation stands not only in this adhesion molecule's value as a prognostic factor but also in its promising premise as a potential new molecular target that could be exploited as a specific cancer therapy.

TIMPs expression in lentigo maligna÷lentigo maligna melanoma versus aged skin - a review of the literature and personal experience.

Mechanisms involved in melanoma invasiveness and metastasis are essential to understanding the behavior of this aggressive melanocytic skin cancer. The epithelial-mesenchymal transition (EMT) is considered fundamental for overcoming the in situ stage of melanoma and its proliferation beyond the basal membrane. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are key molecules involved in EMT about whose expression in lentigo maligna (LM) and lentigo maligna melanoma (LMM) little has been studied so far. In this article, our main aim was to review the role of TIMPs in invasiveness and aggressiveness of LM÷LMM in order to detect EMT modifications in this type of melanoma. We also presented some partial personal unpublished results. It is well established by now that progression of melanoma depends on ECM remodeling, TIMPs family being one of the most important regulators of this process. Considering the multitude of molecules involved in cancer invasiveness and their complex interaction, it is too early to analyze and to conclude upon the significance of different expression of TIMPs in LM÷LMM. We consider some correlations are needed to be done also with other consecrated histological (as Clark level, Breslow indexes, presence of ulceration, mitotic index, intratumor inflammatory infiltrate, etc.) and immunohistochemical markers [cadherins, vascular endothelial growth factor (VEGF), bcl-2, etc.] of prognosis and metastasis. In this light, we consider that our study could further clarify the significance of TIMPs expression in this specific type of melanoma.

Immunohistochemical Aspects of Cell Death in Diabetic Nephropathy.

INTRODUCTION: Diabetes Mellitus causes ultrastructural changes triggered by partially clarified cellular mechanisms. Since cell death is an important mechanism in the appearance and progression of diabetic nephropathy, we studied alteration of several markers of apoptotic pathways signaling in renal tissue of diabetic or prediabetic patients. METHODS: We analyzed 48 human kidney tissue samples divided into two study groups: the research group (43 renal tissue samples from diabetic or prediabetic patients), and the control group (5 renal tissue samples from patients without diabetes). Immunohistochemistry revealed expression of Bcl-2, APAF-1, CD-95 and Caspase-9 in the renal cortical structures. Statistical analysis was also performed (significance level P < 0.05). RESULTS: We found a variable expression of the antiapoptotic Bcl-2 with a decrease of Bcl-2 expression in diabetes. The control samples render evident intensely positive immunostaining for CD-95. In diabetes and diabetic nephropathy, there was positive immunostaining for APAF-1 at tubular cell level. Nuclear and cytoplasmic positivity for Caspase-9 was more frequently recorded as kidney damage progresses. APAF-1 and Caspase-9 positivity are arguments for an intrinsic apoptotic mechanism of cell death in diabetic nephropathy. CONCLUSION: The mechanisms of apoptotic cell death identified in diabetic kidney samples prove that Bcl-2, CD-95, APAF-1 and Caspase-9 represent reliable markers of cell death in human renal tissue. Our results support the hypothesis that apoptosis is a pathogenic and initiator mechanism of renal remodeling in diabetic kidney disease.

CEACAM1: Expression and Role in Melanocyte Transformation.

Metastases represent the main cause of death in melanoma patients. Despite the current optimized targeted therapy or immune checkpoint inhibitors the treatment of metastatic melanoma is unsatisfactory. Because of the poor prognosis of advanced melanoma there is an urgent need to identify new biomarkers to differentiate melanoma cells from normal melanocytes, to stratify patients according to their risk, and to identify subgroups of patients that require close follow-up or more aggressive therapy. Furthermore, melanoma progression has been associated with the dysregulation of cell adhesion molecules. We have reviewed the literature and have discussed the important role of the expression of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in the development of melanoma. Thus, novel insights into CEACAM1 may lead to promising strategies in melanoma treatment, in monitoring melanoma patients, in assessing the response to immunotherapy, and in completing the standard immunohistochemical panel used in melanoma examination.