All for one: Collaboration between dermatologist, radiation oncologist and radiologist in the clinical management of "difficult to treat" non melanoma skin cancer.

This series introduces the clinical management of difficult-to-treat non-melanoma skin cancers (NMSCs) through a multidisciplinary approach, emphasizing the integration of dermoscopy and Ultra high-frequency ultrasound (UHFUS) for accurate diagnosis and treatment planning, particularly in cases referred for radiotherapy (RT). Dermoscopy aids in diagnosing both pigmented and non-pigmented skin lesions, guiding treatment margins and reducing the benign-to-malignant biopsy ratio. UHFUS provides valuable insights into tumor size, depth, and vascularity, complementing clinical evaluations and assisting in RT planning. Three challenging cases are presented, highlighting the pivotal role of dermoscopy and UHFUS in decision-making and treatment optimization. Collaboration between dermatologists, radiation oncologists, and radiologists enhances diagnostic accuracy, tailoring treatment plans to individual patient needs and preferences, ultimately improving patient outcomes and experience. The integration of these imaging techniques holds promise for optimizing non-surgical treatments like RT and monitoring treatment progress, offering a personalized approach to NMSC management.

Parecoxib decreases cellular growth and Bcl-2 protein levels in primary cultures of keloid fibroblasts.

Keloids seem to overexpress cyclo-oxygenase-2 (COX-2), suggesting a role in its deregulated pathway in inducing an altered epithelial-mesenchymal interaction, which may be responsible for the overgrowth of dermal components resulting in scars or keloid lesions. This study aimed to evaluate the effect of Parecoxib, a COX-2 inhibitor, on cell growth in fibroblast primary cultures obtained from human keloid tissues. Tissue explants were obtained from patients who underwent intralesional excision of untreated keloids; central fractions were isolated from keloid tissues and used for establishing distinct primary cultures. Appropriate aliquots of Parecoxib, a COX-2 inhibitor were diluted to obtain the concentration used in the experimental protocols in vitro (1, 10 or 100 µM). Treatment with Parecoxib (at all concentrations) caused a significant decrease in cellular growth from 24 hours onwards, and with a maximum at 72 hours (P < .02). Moreover, at 72 hours Parecoxib significantly reduced cellular vitality. Parecoxib treatment also induced an increase in fragmented nuclei with a maximum effect at 100 µM and a significant decrease in Bcl-2 and an increase in activated caspase-3 protein levels at 72 hours compared with control untreated cultures. Our findings suggest a potential use of the COX-2 inhibitor, Parecoxib, as the therapy for keloids.

The Role of Sentinel Node Biopsy in the Era of Adjuvant Therapy for Melanoma.

Sentinel lymph node biopsy (SLNB) is a surgical procedure aimed to detect nodal metastases in patients with clinically occult disease. Since the advent of new systemic therapies, its role in melanoma has been extensively debated over the last years. In this article, three possible scenarios are discussed, considering the SLNB impact on the management of melanoma patients. First, pT1b and pT2a patients with negative SLNB (stages IA and IB) and those with positive SLNB (stage IIIA) would all not benefit from adjuvant treatment. Therefore, SLNB might be avoided in these categories of patients. Second, in IIB and IIC, melanoma patients are already candidates for adjuvant treatment; therefore, SLNB in patients with T3b, T4a, or T4b melanoma would not change treatment decisions. On the other end of the spectrum, patients with pT2b and pT3a melanomas (clinical stage IIA) represent the only two groups whose management would be significantly affected by the SLNB status, being adjuvant therapy only indicated for SLN-positive patients. Further studies are needed to investigate which melanoma patient deserves SLNB.

Multiple Foci of Basal Cell Carcinoma Arising in Rhinophyma: A Case Report and Literature Review.

Background: Rhinophyma is a benign condition caused by the excessive growth of sebaceous glands in the nasal tissue, presenting with symptoms such as nasal hypertrophy, erythema, and papules. Cases of basal cell carcinoma in rhinophyma have been reported in literature, but its etiological role remains unclear. It is uncertain whether rhinophyma is predisposed to neoplasm development or if their coexistence is coincidental. Material and Method: We conducted a literature survey to identify such cases reported over the years. Results: We identified 22 studies reporting a total of 47 cases in the literature, all involving male patients. The most common pattern of occurrence was the rapid growth of a nodular formation within the context of rhinophyma. Discussions and Conclusion: The elucidation of the association between basal cell carcinoma and rhinophyma remains challenging. The presence of multiple foci supports the theory that rhinophyma may play a role in their development, but larger studies are needed to establish a causal relationship.

Correction of Rippling in Implant-based Breast Reconstruction with Serratus Fascia Flap.

Implant-based breast reconstruction represents the most popular procedure for the treatment of women undergoing skin-sparing mastectomy. In selected patients, it allows for obtaining an excellent appearance of the reconstructed breast with great satisfaction to the patient. However, aesthetic and functional results can be affected by complications requiring reoperation. Among them, rippling is an undesired occurrence associated with implant-based reconstruction. It consists of a cutaneous manifestation, visible and/or palpable, of the implant wrinkles and edge which appear mostly when the patient leans forward. To treat this contour deformity, several techniques have been described such as acellular dermal matrices and autologous tissues. In this study, we intend to add the serratus anterior fascial flap within the autologous options in the treatment of implant rippling, reporting our experience.

Mondor's disease as a complication in breast surgery in a male patient. The first ever reported case in literature.

Mondor's disease (MD) is an uncommon clinical condition characterized by thrombophlebitis of the superficial veins of the anterolateral thoracoabdominal wall. In this paper we present the first ever reported case of Mondor's disease in male patient after surgical correction of gynecomastia with liposuction assisted skin sparing adenectomy.

Optimizing Fat Grafting Using a Hydraulic System Technique for Fat Processing: A Time and Cost Analysis.

Background Many authors have researched ways to optimize fat grafting by looking for a technique that offers safe and long-term fat survival rate. To date, there is no standardized protocol. We designed a "hydraulic system technique" optimizing the relationship among the quantity of injected fat, operative time, and material cost to establish fat volume cutoffs for a single procedure. Methods Thirty-six patients underwent fat grafting surgery and were organized into three groups according to material used: standard, "1-track," and "2-tracks" systems. The amount of harvested and grafted fat as well as material used for each procedure was collected. Operating times were recorded and statistical analysis was performed to establish the relationship with the amount of treated fat. Results In 15 cases the standard system was used (mean treated fat 72 [30-100] mL, mean cost 4.23 ± 0.27 euros), in 11 cases the "1-track" system (mean treated fat 183.3 [120-280] mL, mean cost 7.63 ± 0.6 euros), and in 10 cases the "2-tracks" one (mean treated fat 311[220-550] mL, mean cost 12.47 ± 1 euros). The mean time difference between the standard system and the "1-track" system is statistically significant starting from three fat syringes (90 mL) in 17.66 versus 6.87 minutes. The difference between the "1-track" system and "2-tracks" system becomes statistically significant from 240 mL of fat in 15 minutes ("1-track") versus 9.3 minutes for the "2-tracks" system. Conclusion Data analysis would indicate the use of the standard system, "1-track," and "2-tracks" to treat an amount of fat < 90 mL of fat, 90 ÷ 240 mL of fat, and ≥ 240 mL of fat, respectively.

The Impact of Direct Oral Anticoagulant Prophylaxis for Thromboembolism in Thrombophilic Patients Undergoing Abdominoplastic Surgery.

Congenital or acquired thrombophilia is observed in 10-15% of the general population; therefore, careful screening is carried out in patients at higher risk of venous thrombo-embolism (VTE). High risk of VTE is a contraindication in patients undergoing abdominoplasty. We evaluated rivaroxaban, an oral Xa inhibitor, with enoxaparin, a subcutaneously low molecular weight heparin (LMWH), in 48 female patients with documented thrombophilia, undergoing thrombo-prophylaxis after abdominoplasty. Patients were stratified into two groups according to thrombo-prophylaxis procedure: enoxaparin Group (n = 28) and rivaroxaban Group (n = 20). Hematologic outcomes were evaluated including VTE and hematoma. No episodes of VTE occurred in both groups; two patients during their course of enoxaparin presented severe hematoma for drainage and hemostasis revision. This study suggests that abdominoplasty, in patients with thrombophilia, in combination with thrombo-prophylaxis can be performed safely. Rivaroxaban was as effective as LMWH for preventing VTE, with only a moderate risk of clinically relevant bleeding. More research is needed to determine the optimal timing and duration of prophylaxis in patients undergoing plastic surgery.

Clinical epigenetics and restoring of metabolic health in severely obese patients undergoing batriatric and metabolic surgery.

Epigenetic-sensitive mechanisms, mainly DNA methylation, mirror the relationship between environmental and genetic risk factors able to affect the sensitiveness to development of obesity and its comorbidities. Bariatric and metabolic surgery may reduce obesity-related cardiovascular risk through tissue-specific DNA methylation changes. Among the most robust results, differential promoter methylation of ACACA, CETP, CTGF, S100A8, and S100A9 genes correlated significantly with the levels of mRNA before and after gastric bypass surgery (RYGB) in obese women. Additionally, promoter hypermethylation of NFKB1 gene was significantly associated with reduced blood pressure in obese patients after RYGB suggesting useful non-invasive biomarkers. Of note, sperm-related DNA methylation signatures of genes regulating the central control of appetite, such as MC4R, BDNF, NPY, and CR1, and other genes including FTO, CHST8, and SH2B1 were different in obese patients as compared to non-obese subjects and patients who lost weight after RYGB surgery. Importantly, transgenerational studies provided relevant evidence of the potential effect of bariatric and metabolic surgery on DNA methylation. For example, peripheral blood biospecimens isolated from siblings born from obese mothers before bariatric surgery showed different methylation signatures in the insulin receptor and leptin signaling axis as compared to siblings born from post-obese mothers who underwent surgery. This evidence suggests that bariatric and metabolic surgery of mothers may affect the epigenetic profiles of the offspring with potential implication for primary prevention of severe obesity. We update on tissue-specific epigenetic signatures as potential mechanisms underlying the restoration of metabolic health after surgery suggesting useful predictive biomarkers.

MiR-200c-3p maintains stemness and proliferative potential in adipose-derived stem cells by counteracting senescence mechanisms.

Adipose-derived mesenchymal stem cells (ASCs) are promising therapeutic tools in regenerative medicine because they possess self-renewal, differentiation and immunomodulatory capacities. After isolation, ASCs are passaged multiple times in vitro passages to obtain a sufficient amount of cells for clinical applications. During this time-consuming procedure, ASCs become senescent and less proliferative, compromising their clinical efficacy. Here, we sought to investigate how in vitro passages impact ASC proliferation/senescence and expression of immune regulatory proteins. MicroRNAs are pivotal regulators of ASC physiology. Particularly, miR-200c is known to maintain pluripotency and targets the immune checkpoint Programmed death-ligand 1 (PD-L1). We therefore investigated its involvement in these critical characteristics of ASCs during in vitro passages. We found that when transiently expressed, miR-200c-3p promotes proliferation, maintains stemness, and contrasts senescence in late passaged ASCs. Additionally, this miRNA modulates PD-L1 and Indoleamine 2,3-Dioxygenase (IDO1) expression, thus most likely interfering with the immunoregulatory capacity of ASCs. Based on our results, we suggest that expression of miR-200c-3p may prime ASC towards a self-renewing phenotype by improving their in vitro expansion. Contrarily, its inhibition is associated with senescence, reduced proliferation and induction of immune regulators. Our data underline the potential use of miR-200c-3p as a switch for ASCs reprogramming and their clinical application.

Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update.

The lack of a precise stratification algorithm for predicting patients at high risk of graft rejection challenges the current solid organ transplantation (SOT) clinical setting. In fact, the established biomarkers for transplantation outcomes are unable to accurately predict the onset time and severity of graft rejection (acute or chronic) as well as the individual response to immunosuppressive drugs. Thus, identifying novel molecular pathways underlying early immunological responses which can damage transplant integrity is needed to reach precision medicine and personalized therapy of SOT. Direct epigenetic-sensitive mechanisms, mainly DNA methylation and histone modifications, may play a relevant role for immune activation and long-term effects (e.g., activation of fibrotic processes) which may be translated in new non-invasive biomarkers and drug targets. In particular, the measure of DNA methylation by using the blood-based "epigenetic clock" system may be an added value to the donor eligibility criteria providing an estimation of the heart biological age as well as a predictive biomarkers. Besides, monitoring of DNA methylation changes may aid to predict acute vs chronic graft damage in kidney transplantation (KT) patients. For example, hypermethylation of genes belonging to the Notch and Wnt pathways showed a higher predictive value for chronic injury occurring at 12 months post-KT with respect to established clinical parameters. Detecting higher circulating cell-free DNA (cfDNA) fragments carrying hepatocyte-specific unmethylated loci in the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), insulin like growth factor 2 receptor (IGF2R), and vitronectin (VTN) genes may be useful to predict acute graft injury after liver transplantation (LT) in serum samples. Furthermore, hypomethylation in the forkhead box P3 (FOXP3) gene may serve as a marker of infiltrating natural Treg percentage in the graft providing the ability to predict acute rejection events after heart transplantation (HTx). We aim to update on the possible clinical relevance of DNA methylation changes regulating immune-related pathways underlying acute or chronic graft rejection in KT, LT, and HTx which might be useful to prevent, monitor, and treat solid organ rejection at personalized level.

Immune reactivity during COVID-19: Implications for treatment.

Clinical symptoms of COVID-19 include fever, cough, and fatigue which may progress to acute respiratory distress syndrome (ARDS). The main hematological laboratory findings associated with the severe form of disease are represented by lymphopenia and eosinopenia which mostly occur in the elderly population characterized by cardiovascular comorbidities and immunosenescence. Besides, increased levels of D-dimer, procalcitonin, and C reactive protein (CRP) seem to be powerful prognostic biomarkers helping to predict the onset of coagulopathy. The host immune response to SARS-CoV-2 can lead to an aberrant inflammatory response or "cytokine storm" which contributes to the severity of illness. At immunological level, patients affected by a severe form of COVID-19 show poor clinical trajectories characterized by differential "immunotypes" for which T cell response seems to play a critical role in understanding pathogenic mechanisms of disease. Also, patients with mild to severe COVID-19 displayed macrophage activation syndrome (MAS), very low human leukocyte antigen D related (HLA-DR) expression with a parallel reduction of CD04+ lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Corticosteroids resulted the best therapy for the immune dysregulation whereas repurposing of tocilizumab (IL-6 receptor antagonist) appears to have mixed results in patients with COVID-19. Besides, anticoagulative therapy was associated with reduced in-hospital mortality and need of intubation among COVID-19 patients. Furthermore, the beneficial use of intravenous immunoglobulin (IVIG) and passive immunotherapy with convalescent plasma needs to be validated in large controlled clinical trials. In this review, we summarize the main hematological parameters with a prognostic value in COVID-19 and the basis of immunological reactivity during COVID-19, with a focus on ongoing clinical trials evaluating immune targets as possible therapeutic strategies.

Network Medicine Approach in Prevention and Personalized Treatment of Dyslipidemias.

Dyslipidemias can affect molecular networks underlying the metabolic homeostasis and vascular function leading to atherogenesis at early stages of development. Since disease-related proteins often interact with each other in functional modules, many advanced network-oriented algorithms were applied to patient-derived big data to identify the complex gene-environment interactions underlying the early pathophysiology of dyslipidemias and atherosclerosis. Both the proprotein convertase subtilisin/kexin type 7 (PCSK7) and collagen type 1 alpha 1 chain (COL1A1) genes arose from the application of TFfit and WGCNA algorithms, respectively, as potential useful therapeutic targets in prevention of dyslipidemias. Moreover, the Seed Connector algorithm (SCA) algorithm suggested a putative role of the neuropilin-1 (NRP1) protein as drug target, whereas a regression network analysis reported that niacin may provide benefits in mixed dyslipidemias. Dyslipidemias are highly heterogeneous at the clinical level; thus, it would be helpful to overcome traditional evidence-based paradigm toward a personalized risk assessment and therapy. Network Medicine uses omics data, artificial intelligence (AI), imaging tools, and clinical information to design personalized therapy of dyslipidemias and atherosclerosis. Recently, a novel non-invasive AI-derived biomarker, named Fat Attenuation Index (FAI™) has been established to early detect clinical signs of atherosclerosis. Moreover, an integrated AI-radiomics approach can detect fibrosis and microvascular remodeling improving the customized risk assessment. Here, we offer a network-based roadmap ranging from novel molecular pathways to digital therapeutics which can improve personalized therapy of dyslipidemias.

What is the role of locoregional anesthesia in breast surgery? A systematic literature review focused on pain intensity, opioid consumption, adverse events, and patient satisfaction.

BACKGROUND: Breast surgery in the United States is common. Pain affects up to 50% of women undergoing breast surgery and can interfere with postoperative outcomes. General anesthesia is the conventional, most frequently used anaesthetic technique. Various locoregional anesthetic techniques are also used for breast surgeries. A systematic review of the use of locoregional anesthesia for postoperative pain in breast surgery is needed to clarify its role in pain management. OBJECTIVES: To systematically review literature to establish the efficacy and the safety of locoregional anesthesia used in the treatment of pain after breast surgery. METHODS: Embase, MEDLINE, Google Scholar and Cochrane Central Trials Register were systematically searched in Mars 2020 for studies examining locoregional anesthesia for management of pain in adults after breast surgery. The methodological quality of the studies and their results were appraised using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist and specific measurement properties criteria, respectively. RESULTS: Nineteen studies evaluating locoregional anesthesia were included: 1058 patients underwent lumpectomy/mastectomy, 142 breast augmentation and 79 breast reduction. Locoregional anesthesia provides effective anesthesia and analgesia in the perioperative setting, however no statistically significant difference emerged if compared to other techniques. For mastectomy only, the use of locoregional techniques reduces pain in the first hour after the end of the surgery if compared to other procedures (p = 0.02). Other potentially beneficial effects of locoregional anesthesia include decreased need for opioids, decreased postoperative nausea and vomiting, fewer complications and increased patient satisfaction. All this improves postoperative recovery and shortens hospitalization stay. In none of these cases, locoregional anesthesia was statistically superior to other techniques. CONCLUSION: The results of our review showed no differences between locoregional anesthesia and other techniques in the management of breast surgery. Locoregional techniques are superior in reducing pain in the first hour after mastectomy.

Differential DNA Methylation Encodes Proliferation and Senescence Programs in Human Adipose-Derived Mesenchymal Stem Cells.

Adult adipose tissue-derived mesenchymal stem cells (ASCs) constitute a vital population of multipotent cells capable of differentiating into numerous end-organ phenotypes. However, scientific and translational endeavors to harness the regenerative potential of ASCs are currently limited by an incomplete understanding of the mechanisms that determine cell-lineage commitment and stemness. In the current study, we used reduced representation bisulfite sequencing (RRBS) analysis to identify epigenetic gene targets and cellular processes that are responsive to 5'-azacitidine (5'-AZA). We describe specific changes to DNA methylation of ASCs, uncovering pathways likely associated with the enhancement of their proliferative capacity. We identified 4,797 differentially methylated regions (FDR < 0.05) associated with 3,625 genes, of which 1,584 DMRs annotated to the promoter region. Gene set enrichment of differentially methylated promoters identified "phagocytosis," "type 2 diabetes," and "metabolic pathways" as disproportionately hypomethylated, whereas "adipocyte differentiation" was the most-enriched pathway among hyper-methylated gene promoters. Weighted coexpression network analysis of DMRs identified clusters associated with cellular proliferation and other developmental programs. Furthermore, the ELK4 binding site was disproportionately hyper-methylated within the promoters of genes associated with AKT signaling. Overall, this study offers numerous preliminary insights into the epigenetic landscape that influences the regenerative capacity of human ASCs.

Clinical epigenetics and multidrug-resistant bacterial infections: host remodelling in critical illness.

The inappropriate use of antibiotics in man is driving to insurgence of pathogenic bacteria resistant to multiple drugs (MDR) representing a challenge in critical illness. The interaction of MDR bacteria with host cells can guide molecular perturbations of host transcriptional programmes involving epigenetic-sensitive mechanisms, mainly DNA methylation, histone modifications, and non-coding RNAs leading to pathogen survival. Clinical evidence of epigenetic manipulation from MDR bacteria mainly arises from Mycobacterium tuberculosis as well as Helicobacter pylori, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Legionella pneumophila infection suggesting possible biomarkers of disease. For example, DNA hypermethylation of E-cadherin (CDH1), upstream transcription factor 1/2 (USF1/2), WW domain containing oxidoreductase (WWOX), and mutL homolog 1 (MLH1) genes in gastric mucosa is correlated with malignancy suggesting useful biomarkers of early disease state. Moreover, upregulated circulating miR-361-5p, miR-889, miR-576-3p may be useful biomarkers to discriminate tuberculosis patients. Moreover, Listeria monocytogenes can indirectly induce H3 hyperacetylation leading to inflammation in human endothelial cells whereas Pseudomonas aeruginosa excretes QS 2-AA to directly induce H3 deacetylation leading to bacterial persistence in human monocytes. Remarkably, epigenetic-sensitive drugs may aid to counteract MDR in clinical setting. Trichostatin A, a histone deacetyltransferase inhibitor (HDACi), leads to AMP ß-defensin 2 (HBD2) gene up-regulation in human epithelial cells suggesting a useful 'epi-therapy' for Escherichia coli-induced intestinal diseases. We update on the most current clinical studies focusing on epigenetic changes involved in bacterial-host interactions and their putative role as biomarkers or drug targets to improve precision medicine and personalized therapy in critical illness and transplantation setting.

Large single cutaneous metastasis of colon adenocarcinoma mimicking a squamous cell carcinoma of the skin: A case report.

INTRODUCTION: Metastases represent one of the most outstanding characteristics of malignant neoplasms and are relatively rare in the skin, in spite of the great extension of the cutaneous organs. Development of cutaneous metastases from colon cancer is a rare event, usually occurring in widely disseminated disease and commonly leading to a poor prognosis. As to location, cutaneous metastases often favor areas close to the primary malignancy, such as lung cancer and skin metastases on the trunk. However, remote sites as the scalp may be also involved. CASE PRESENTATION: We present the case of a 92-year-old female patient with a massive single nodular skin lesion on her left supraclavicular area, that came back positive for cutaneous metastasis of colon adenocarcinoma. DISCUSSION: Cutaneous metastasis of colorectal cancer a rare event (2.3%-6%) that usually occur two years after the detection or resection of the primary tumor. It seldom occurs before the identification of the primary tumor and involvement of secondary organs, such as the liver. There are few cases reported with only cutaneous metastases. CONCLUSION: In conclusion, dermatological evaluation of patients who are undergoing screening or who have already been diagnosed with cancer is extremely important.

The Influence of Breast Cancer on the Distribution of Cherry Angiomas on the Anterior Thoracic Wall: A Case Series Study.

BACKGROUND/AIMS: Cherry angiomas (CAs) are one of the most common vascular manifestations of the skin. By and large, these benign lesions often only represent an aesthetic problem. In the literature, few authors have focused on the pathogenesis of these lesions, and some risk factors have been identified, such as the presence of cutaneous and non-skin neoplasias. In this study, the correlation between the distribution of CAs and breast cancer was investigated. METHODS: We carried out a study whereby 50 women with unilateral breast cancer and the presence of CAs on the anterior thoracic wall were evaluated, with a particular focus on the difference in the number of CAs between the two haemithoraces. The data was elaborated using the Wilcoxon signed-rank test in order to evaluate whether there was a statistical significance in the distribution of CAs. RESULTS: In 31 patients we found that the number of CAs was greater on the cancerous breast than on the contralateral one (p value <0.0001). This was confirmed both in the group of patients suffering from ductal breast cancer and in the group with early invasive breast tumours. CONCLUSION: It is not clear whether CAs develop prior to or following breast cancer, indicating the possibility that this cutaneous manifestation could take on a predictive, prognostic development or represent only an epiphenomenon. Further in-depth studies into the pathogenesis of CAs and the relationship with breast cancer could lead to noteworthy diagnostic-therapeutic advances.