Advancing Cancer Research: Current Knowledge on Cutaneous Neoplasia.

Skin cancers require a multidisciplinary approach. The updated guidelines introduce new insights into the management of these diseases. Melanoma (MM), the third most common skin cancer, a malignant melanocytic tumor, which is classified into four major histological subtypes, continues to have the potential to be a lethal disease. The mortality-incidence ratio is higher in Eastern European countries compared to Western European countries, which shows the need for better prevention and early detection in Eastern European countries. Basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC) remain the top two skin cancers, and their incidence continues to grow. The gold standard in establishing the diagnosis and establishing the histopathological subtype in BCC and SCC is a skin biopsy. Sebaceous carcinoma (SeC) is an uncommon and potentially aggressive cutaneous malignancy showing sebaceous differentiation. It accounts for 0.7% of skin cancers and 3-6.7% of cancer-related deaths. Due to the rapid extension to the regional lymph nodes, SeC requires early treatment. The main treatment for sebaceous carcinoma is surgical treatment, including Mohs micrographic surgery, which has the advantage of complete margin evaluation and low recurrence rates. Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoproliferative diseases, with no evidence of extracutaneous determination at the moment of the diagnosis. PCLs have usually a very different evolution, prognosis, and treatment compared to the lymphomas that may secondarily involve the skin. The aim of our review is to summarize the important changes in the approach to treating melanoma, non-melanoma skin, cutaneous T and B cell lymphomas, and other types of skin cancers. For all skin cancers, optimal patient management requires a multidisciplinary approach including dermatology, medical oncology, and radiation oncology.

Catching Cancer Early: The Importance of Dermato-Oncology Screening.

The European Society for Medical Oncology experts have identified the main components of the long-term management of oncological patients. These include early diagnosis through population screening and periodic control of already diagnosed patients to identify relapses, recurrences, and other associated neoplasms. There are no generally accepted international guidelines for the long-term monitoring of patients with skin neoplasms (nonmelanoma skin cancer, malignant melanoma, precancerous-high-risk skin lesions). Still, depending on the experience of the attending physician and based on the data from the literature, one can establish monitoring intervals to supervise these high-risk population groups, educate the patient and monitor the general population.

A Prospective Analysis of the Retinopathy of Prematurity Correlated with the Inflammatory Status of the Extremely Premature and Very Premature Neonates.

Retinopathy of Prematurity (ROP) is a major cause of blindness in premature infants. This study aimed to evaluate the association between inflammatory markers and ROP development in extremely premature and very premature neonates and identify potential inflammatory biomarkers for ROP risk prediction. This prospective study was conducted from January 2021 to January 2023 in two clinical hospitals associated with the "Victor Babes" University of Medicine and Pharmacy Timisoara. The study population comprised neonates with a gestational age of less than 32 weeks. Various inflammatory markers, including total white blood cell count, polymorphonuclear leukocytes, C-reactive protein, interleukin-6, and lactate dehydrogenase, were analyzed from blood samples collected at birth and three days postnatally. ROP was diagnosed and classified following the International Classification of Retinopathy of Prematurity. The study included 48 neonates, 12 Extremely Premature Infants (EPI), and 36 Very Premature Infants (VPI). The EPI group had significantly higher mean interleukin-6 and lactate dehydrogenase levels at birth and three days postnatally than the VPI group. C-reactive protein levels at three days were significantly higher in the VPI group. Umbilical cord inflammation and ROP severity were found to have a statistically significant positive correlation. Half of the EPIs had moderate to severe ROP, significantly more than in the VPI group. The duration of oxygen supplementation, mechanical ventilation, Continuous Positive Airway Pressure (CPAP), gestational age less than 28 weeks, and umbilical cord inflammation at or above stage 3 were significant risk factors for developing ROP stage 2 or above. Elevated CRP and IL-6 were also significantly associated with an increased risk of developing ROP stage 2 or above, highlighting their potential as biomarkers for ROP risk prediction. This study suggests a significant association between inflammatory markers and ROP development in extremely premature and very premature neonates. These findings could contribute to the identification of potential inflammatory biomarkers for ROP risk prediction, improving early diagnosis and intervention strategies for this condition.

The Molecular and Histopathological Assessment of Inflammatory Status in Very and Extremely Premature Infants: A Prospective Study.

Prematurity comes with a varying range of complications, implying a high prevalence of complications and mortality and depending on the severity of prematurity and the sustained inflammation among these infants, which recently sparked an important scientific interest. The primary objective of this prospective study was to establish the degree of inflammation in very (VPIs) and extremely preterm infants (EPIs) in association with the histology findings of the umbilical cord (UC), while the secondary objective was to study the inflammatory markers in the neonates' blood as predictors of fetal inflammatory response (FIR). A total of thirty neonates were analyzed, ten of them being born extremely premature (<28 weeks of gestation) and twenty very premature (28-32 weeks of gestation). The EPIs had considerably higher levels of IL-6 at birth than VPIs (638.2 pg/mL vs. 151.1 pg/mL). The CRP levels at delivery did not vary substantially across groups; however, after days, the EPIs had significantly higher CRP levels (11.0 mg/dL vs. 7.2 mg/dL). In contrast, the LDH was considerably higher in the extremely preterm infants at birth and four days after birth. Surprisingly, the proportions of infants with pathologically increased inflammatory markers did not differ between the EPIs and VPIs. The LDH increased considerably in both groups, although the CRP levels increased exclusively among the VPIs. The stage of inflammation in the UC did not vary substantially between the EPIs and VPIs. The majority of infants were identified with Stage 0 UC inflammation (40% in EPI vs. 55% in VPIs). There was a substantial correlation link between gestational age and newborn weight and a significant inverse correlation among gestational age and IL-6 and LDH levels. There was a strong negative association between weight and IL-6 (rho = -0.349) and LDH (rho = -0.261). The stage of the UC inflammation demonstrated a statistically significant direct connection with IL-6 (rho = 0.461) and LDH (rho = 0.293), but none with the CRP. Further studies involving a bigger population size of preterm newborns are required to validate the findings and analyze more inflammatory markers, while prediction models on inflammatory markers that are measured expectantly, before the onset of preterm labor, need to be created.

"Face(s)" of a PHACE(S) Syndrome Patient before and after Therapy: Particular Case Report and Review of Literature.

A rare, uncommon disorder called PHACE(S) (P-posterior fossa anomalies, H-hemangioma, A-arterial anomalies, C-cardiac anomalies, E-eye anomalies, and S-sternal cleft) of unknown etiology was rarely reported. Children are susceptible to developing PHACE(S) syndrome from the moment they are born. It may be challenging for a physician to appropriately diagnose and treat children with PHACE due to the multifaceted nature of the disease and the extensive range of consequences that may be associated with it. A one-month-old newborn girl was admitted to hospital with extensive, multiple facial infantile hemangiomas, ulceration of the lower lip hemangioma-like lesion, cardiovascular, sternal, and neurological concomitant malformations. Five days following the initial application of the medication, systemic treatment with propranolol and topical treatment with silver sulfadiazine produced their first noticeable benefits. The lip ulceration was mostly healed and facial hemangioma started to regress. The regression continued under therapy and this effect persists for 6 months since Propranolol therapy ended. No cardiovascular or neurological clinical events have been registered during follow-up. The present case has three peculiarities: (1) high number of facial hemangiomas; (2) presence of subependymal cyst not yet reported in the literature associated with PHACE syndrome; and (3) lack of cardiovascular events during therapy knowing that these events frequently appear in PHACE syndrome patients.

VEGF Pathway Gene Expression Profile of Proliferating versus Involuting Infantile Hemangiomas: Preliminary Evidence and Review of the Literature.

Background. Infantile hemangiomas may have unexpected behavior. Initial regression (spontaneously or drug-induced) may be followed by unexplained recurrences. At this moment, there are no well-established criteria to predict infantile hemangioma reccurrences. Methods. We compared the VEGF pathway gene expression profile for one case of involuting infantile hemangioma versus one case of recurrent proliferative infantile hemangioma using TaqMan Array. Results. We found ten genes upregulated for both involuting and recurrent proliferative hemangiomas: ACTB, KRAS, MAP2K1, HRAS, NOS3, BAD, HSPB1, HPRT1, GUSB, and CASP9. Thirteen genes were downregulated for both involuting and proliferative hemangiomas: FIGF, ACTG1, GRB2, MAPKAPK2, ACTG2, MAP2K2, MAPK3, HSP90AA1, MAP2K6, NRAS, ACTA1, KDR, and MAPK1. Three genes showed divergent expression between proliferating and involuting hemangiomas. Proliferating hemangioma had MAPK14 and AKT1 gene upregulation and ACTA2 downregulation. Involuting infantile hemangioma was characterized by ACTA2 upregulation and AKT1 and MAPK14 downregulation. Conclusions. Three genes, AKT1, p38/MAPK14, and ACTA2, were found to have divergent expression in proliferating and involuting infantile hemangiomas. Excepting AKT1, which was mentioned in the last ISSVA classification (strictly related to Proteus Syndrome), none of the other genes were reported. An accurate gene expression profile mapping of infantile hemangiomas together with a gene expression-based hemangioma classification is stringently needed.

Optimization of Complete Rat Heart Decellularization Using Artificial Neural Networks.

Whole organ decellularization techniques have facilitated the fabrication of extracellular matrices (ECMs) for engineering new organs. Unfortunately, there is no objective gold standard evaluation of the scaffold without applying a destructive method such as histological analysis or DNA removal quantification of the dry tissue. Our proposal is a software application using deep convolutional neural networks (DCNN) to distinguish between different stages of decellularization, determining the exact moment of completion. Hearts from male Sprague Dawley rats (n = 10) were decellularized using 1% sodium dodecyl sulfate (SDS) in a modified Langendorff device in the presence of an alternating rectangular electric field. Spectrophotometric measurements of deoxyribonucleic acid (DNA) and total proteins concentration from the decellularization solution were taken every 30 min. A monitoring system supervised the sessions, collecting a large number of photos saved in corresponding folders. This system aimed to prove a strong correlation between the data gathered by spectrophotometry and the state of the heart that could be visualized with an OpenCV-based spectrometer. A decellularization completion metric was built using a DCNN based classifier model trained using an image set comprising thousands of photos. Optimizing the decellularization process using a machine learning approach launches exponential progress in tissue bioengineering research.

Expression of ß1 adrenergic receptor in vascular anomalies in children.

OBJECTIVE: Controversial, heterogeneous, and inconsistent responses to beta-blockers have been reported in some cases of infantile proliferative hemangiomas. On the basis of these clinical observations, we aimed to examine the ß1 adrenergic receptor (ß1-AR) protein expression distribution among different types of pediatric vascular anomalies. METHODS: Immunohistochemistry (IHC) was performed for ß1-AR on 43 surgical specimens. RESULTS: We found positive ß1-AR IHC staining in all intramuscular hemangiomas, capillary-lymphatic, lymphatic, venous, and combined malformations, and Masson's tumor cases, as well as in 7 of 10 cases of proliferative infantile hemangiomas. CONCLUSIONS: Our research demonstrates, for the first time, the degree of heterogeneous expression of ß1-AR among pediatric vascular malformations. Our results support the need for ß1-AR assessment in pediatric vascular anomalies to select cases with a robust response to ß1-selective blockers. ß1-AR assessment may have a strong impact on therapeutic refinement for pediatric vascular anomalies by selecting cases with a stronger response to beta-blockers.

Osteogenic Potential of Bovine Bone Graft in Combination with Laser Photobiomodulation: An Ex Vivo Demonstrative Study in Wistar Rats by Cross-Linked Studies Based on Synchrotron Microtomography and Histology.

BACKGROUND: Alveolar bone defects are usually the main concern when planning implant treatments for the appropriate oral rehabilitation of patients. To improve local conditions and achieve implant treatments, there are several methods used for increasing bone volume, among which one of the most successful, versatile, and effective is considered to be guided bone regeneration. The aim of this demonstrative study was to propose an innovative analysis protocol for the evaluation of the effect of photobiomodulation on the bone regeneration process, using rat calvarial defects of 5 mm in diameter, filled with xenograft, covered with collagen membrane, and then exposed to laser radiation. METHODS: The animals were sacrificed at different points in time (i.e., after 14, 21, and 30 days). Samples of identical dimensions were harvested in order to compare the results obtained after different periods of healing. The analysis was performed by cross-linking the information obtained using histology and high-resolution synchrotron-based tomography on the same samples. A comparison was made with both the negative control (NC) group (with a bone defect which was left for spontaneous healing), and the positive control (PC) group (in which the bone defects were filled with xenografts and collagen membrane without receiving laser treatment). RESULTS: We demonstrated that using photobiomodulation provides a better healing effect than when receiving only the support of the biomaterial. This effect has been evident for short times treatments, i.e., during the first 14 days after surgery. CONCLUSION: The proposed analysis protocol was effective in detecting the presence of higher quantities of bone volumes under remodeling after photobiomodulation with respect to the exclusive bone regeneration guided by the xenograft.

New Approach to Rare Pediatric Multicystic Mesenteric Lymphangioma; Would It Guide the Development of Targeted Therapy?

In children, lymphangiomas are extremely rare pathologic entities that are characterized by unusual locations. The mesenteric localization is extremely rare in children, and the clinical signs usually mimic an acute abdominal syndrome. For most of the cases, their diagnosis is established by the radiologist, and the main therapeutic option is represented by surgery for lesion removal. We hereby describe the case of a 4 year old girl admitted to the pediatric emergency department for continuous abdominal pain, more intense in the orthostatic position, associated with abdominal distension, nausea, and vomiting. These symptoms raised the clinical suspicion of acute abdominal syndrome. The patient had no previous clinically significant events. Radiologic examination suggested a mesenteric multicystic lymphangioma certified by surgical and histopathological evaluation. No specific targeted therapy is currently available; moreover, no specific criteria for recurrences have been stated. A new approach of infantile lymphangiomas following surgery, regarding the use of specific lymphatic markers panel including D2-40, Prox-1, VEGFR-3, PDGFs, and Ki67 may improve the characterization of such lesions regarding their prognosis, recurrence rate and targeted therapy implementation especially for those with a more aggressive or recurrent behavior.

Histologic recovery among children with celiac disease on a gluten-free diet. A long-term follow-up single-center experience.

INTRODUCTION: Celiac disease (CD) is defined by gluten-induced immune-mediated enteropathy, affecting approximately 1% of the genetically predisposed population. The immunologic response to gluten causes characteristic intestinal alterations with gradual development. Histologic recovery of intestinal architecture was reported to occur within 6-12 months after starting a gluten-free diet, simultaneously with clinical remission. The aim of this study was to assess the rate and timing of histologic recovery among children with CD on a gluten-free diet, diagnosed and followed in an academic referral pediatric center during a 10-year period. MATERIAL AND METHODS: 105 biopsy-confirmed CD children underwent follow-up small intestinal biopsies within at least 1 year after dietary gluten withdrawal. Further biopsies were performed if villous alterations were persistent. The Marsh classification modified by Oberhuber was used to score the histologic injuries. RESULTS: In all 19 cases with Marsh type II at diagnosis, villous alterations normalized to Marsh type 0 within the first year. From 86 children enrolled with Marsh type III lesions, histologic remission was observed in 81.4% after 1 year, 91.8% within 2-3 years and 97.6% in long-term follow up (≥ 3 years). Two (2.3%) patients with concomitant selective IgA deficiency had symptoms of malabsorption and persisting villous atrophy lasting more than 3 years despite a gluten-free diet. There was a significant statistic difference between the proportion of children with Marsh type IIIA, type IIIB and Marsh type IIIC respectively that achieved histologic recovery within 1 to 2 years after gluten withdrawal. There were more children with partial 25 (92.6%) and subtotal villous atrophy 30 (88.2%) showing histologic improvement, compared to only 15 (60%) patients with total villous atrophy that recovered within the first 2 years of diet (p = 0.01 and p = 0.02 respectively). CONCLUSIONS: Histologic recovery in CD after starting a gluten-free diet in children takes at least 1 year and might be incomplete only in a small proportion of children, mainly associated with IgA immunodeficiency. Systematic follow-up of children with CD and persistent malabsorption syndrome is needed in order to avoid secondary complications.

Vascular aging and subclinical atherosclerosis: why such a "never ending" and challenging story in cardiology?

The true onset of atherosclerosis remains one of the biggest challenges for cardiologists. Is atheroma plaque development considered the earliest step of vascular aging? If so, when it starts? Before or after birth? If it starts before birth or early during childhood, it seems that Thomas Sydenham was right: "A man is as old as his arteries." Except disorganization of elastic fibers, less is known about the morphology of vascular aging and also about the molecular events influencing the age of arteries, arterial stiffness, and their role in the appearance of future complications. Cellular and molecular events responsible for the switch from physiologic to pathologic aging of human arteries are less known. Epigenetic, genetic, and environmental influences at the onset of early vascular aging (EVA) should specifically influence the process. This paper briefly reviews the controversial data regarding vascular aging with an emphasis on the less known facts about the morphology of EVA.