Search Results (323)

Background/Objectives: Orbital reconstruction remains one of the most demanding procedures in maxillofacial surgery. It requires not only precise anatomical knowledge but also poses multiple intraoperative challenges. Limited surgical visibility—especially in transconjunctival or transcaruncular approaches—demands exceptional precision from the surgeon. At the same time, the complex anatomical structure of the orbit, its rich vascularization and innervation, and the risk of severe postoperative complications—such as diplopia, sensory deficits, impaired ocular mobility, or in the most serious cases, post-traumatic blindness due to nerve injury or orbital compartment syndrome—necessitate the highest level of surgical accuracy. In this context, patient-specific implants (PSIs), commonly fabricated from zirconium oxide or ultra-high-density polyethylene, have become invaluable. Within CAD-based reconstructive planning, especially for orbital implants, critical factors include the implant’s anatomical fit, passive stabilization on intact bony structures, and non-interference with orbital soft tissues. Above all, precise replication of the orbital dimensions is essential for optimal clinical outcomes. This study compares the morphological accuracy of orbital structures based on anthropometric measurements from 3D models generated from fan-beam computed tomography (FBCT) and cone-beam computed tomography (CBCT). Methods: A cohort group of 500 Caucasian patients aged 8 to 88 years was analyzed. 3D models of the orbits were generated from FBCT and CBCT scans. Anthropometric measurements were taken to evaluate the morphological accuracy of the orbital structures. The assessed parameters included orbital depth, orbital width, the distance from the infraorbital rim to the infraorbital foramen, the distance between the piriform aperture and the infraorbital foramen, and the distance from the zygomatico-orbital foramen to the infraorbital rim. Results: Statistically significant differences were observed between virtual models derived from FBCT and those based on CBCT in several key parameters. Discrepancies were particularly evident in measurements of orbital depth, orbital width, the distance from the infraorbital rim to the infraorbital foramen, the distance between the piriform aperture and the infraorbital foramen, and the distance from the zygomatico-orbital foramen to the infraorbital rim. Conclusions: The statistically significant discrepancies in selected orbital dimensions—particularly in regions of so-called thin bone—demonstrate that FBCT remains the gold standard in the planning and design of CAD/CAM patient-specific orbital implants. Despite its advantages, including greater accessibility and lower radiation dose, CBCT shows limited reliability in the context of orbital and infraorbital reconstruction planning. Full article

Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), represents the most common type of cancer worldwide, particularly among Caucasians. While BCC is locally invasive with minimal metastatic potential, cSCC is a highly aggressive tumor with a significant potential for metastasis, particularly in elderly populations. Tumor development and progression and the metastasis of cSCC are influenced by a complex interplay between tumor cells and the tumor microenvironment. Recent research highlights the importance of various immune cell subsets, including T cells, tumor-associated macrophages (TAMs), and dendritic cells, in influencing tumor progression, immune evasion, and treatment resistance. This review outlines key regulatory mechanisms in the immune tumor microenvironment (TME) of cSCC and explores the role of cytokines, immune checkpoints, and stromal interactions. We further discuss the relevance of three-dimensional (3D) in vitro models such as spheroids, organoids, and tumor-on-chip systems as tools to mimic immune–tumor interactions with higher physiological relevance, such as macrophage activation and polarization against cSCC cells. Globally, 3D models offer new opportunities for immunotherapy screening and mechanistic studies. Understanding the immune landscape in cSCC through advanced modeling techniques holds strong clinical potential for improving diagnostic and therapeutic strategies. Full article

Basal cell carcinoma (BCC), the most common skin cancer, is primarily driven by Hedgehog (Hh) and TP53 pathway alterations. Although additional pathways were implicated, the mutational landscape in Asian populations, particularly Koreans, remains underexplored. We performed whole-exome sequencing of BCC tumor tissues from Korean patients and analyzed mutations in 11 established BCC driver genes (PTCH1, SMO, GLI1, TP53, CSMD1/2, NOTCH1/2, ITIH2, DPP10, and STEAP4). Mutational profiles were compared with Caucasian cohort profiles to identify ethnicity-specific variants. Ultraviolet (UV)-exposed and non-UV-exposed tumor sites were compared; genes unique to non-UV-exposed tumors were further analyzed with protein–protein interaction analysis. BCCs in Koreans exhibited distinct features, including fewer truncating and more intronic variants compared to Caucasians. Korean-specific mutations in SMO, PTCH1, TP53, and NOTCH2 overlapped with oncogenic gain-of-function/loss-of-function (GOF/LOF) variants annotated in OncoKB, with some occurring at hotspot sites. BCCs in non-exposed areas showed recurrent mutations in CSMD1, PTCH1, and NOTCH1, suggesting a UV-independent mechanism. Novel mutations in TAS1R2 and ADCY10 were exclusive to non-exposed BCCs, with protein–protein interaction analysis linking them to TP53 and NOTCH2. We found unique ethnic-specific and UV-independent mutational profiles of BCCs in Koreans. TAS1R2 and ADCY10 may contribute to tumorigenesis of BCC in non-exposed areas, supporting the need for population-specific precision oncology. Full article

Objectives: The primary objective of this study was to determine whether motor disorders are significantly more prevalent in children with Autism Spectrum Disorder (ASD) without co-occurring genetic or neurological conditions compared to neurotypical children. Another aim was to explore the applicability of the MABC-2 test for assessing motor skills in a Polish cohort of children with ASD. Additionally, this study sought to develop a basic framework for motor skill assessment in children with autism. Methods: This study included 166 Caucasian children, both sexes, aged 5–12 years, without intellectual disability (IQ ≥ 70), without concomitant genetic or neurological disorders, particularly epilepsy or cerebral palsy. The study group consisted of children with ASD (n = 71), and the control group consisted of neurotypical children (n = 95). The participants were assessed with the Movement Assessment Battery for Children–second edition (MABC-2), MABC-2 checklist and the Developmental Coordination Disorder Questionnaire (DCDQ), used as a reference point. Results: The children with ASD obtained significantly lower MABC-2 test results in all subtests in comparison with the control group. The children with suspected or diagnosed coordination disorders were characterized by a significantly greater number of co-occurring non-motor factors than the other participants of this study. MABC-2 test showed greater consistency with DCDQ than with the MABC-2 questionnaire. Conclusions: Children with ASD present a lower level of manual dexterity and balance and greater difficulties in performing tasks, including throwing and catching, in comparison with neurotypical children. The MABC-2 test with the MABC-2 checklist and DCDQ questionnaire constitute a complementary diagnostic tool. Full article

Previous research has linked both endothelial protein changes and vitamin D with infertility. This study was undertaken to investigate the association of proteins associated with endothelial function and vitamin D status in the luteal phase at day 21 in a group of non-obese women prior to in vitro fertilization (IVF) with either unexplained infertility (UI) or male factor infertility (MFI). Twenty-five non-obese Caucasian women from a UK academic center with MFI (n = 14) and UI (n = 11) were recruited. Blood was withdrawn at day 21 of the menstrual cycle at the time of mock embryo transfer. Vitamin D parameters were measured by tandem mass spectroscopy. Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 20 protein markers of endothelial dysfunction. Baseline demographics did not differ between groups and parameters of response following IVF did not differ. Vitamins D₂ and D₃, and 1,25 Vitamin D₃ did not differ between groups. In UI, markers of endothelial activation/dysfunction were investigated; vascular cell adhesion molecule 1 (VCAM-1) decreased and this is associated with endothelial stress; vascular endothelial growth factor (VEGF) decreased and this may suggest impaired endometrial angiogenesis; while intercellular adhesion molecule 1 (ICAM-3) increased (p < 0.05) and is associated with increased immunological activity. A marker of vascular integrity, angiopoietin-1, increased while soluble angiopoietin-1 receptor (sTie-2) decreased (p < 0.05), suggesting increased vascular development. Endothelial markers of inflammation, coagulation, and endothelial progenitor cells were unchanged. Vitamin D and its metabolites show no relationship to UI, but endothelial activation/dysfunction and vascular integrity changes in VCAM-1, VEGF, sICAM-3, angiopoietin-1, and sTie-2 may contribute to UI, though the mechanisms through which they work require further evaluation; however, these protein changes have been associated with endometriosis, raising the suggestion that subclinical/undiagnosed endometriosis may have contributed to UI in these subjects. Full article

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives. Full article

Background: Donor-derived cell-free DNA (dd-cfDNA) testing offers a non-invasive approach for monitoring allograft health in transplant recipients. However, its diagnostic performance and clinical utility remain insufficiently characterized across diverse populations. Objectives: This study assesses concordance between dd-cfDNA, donor-specific antibody (DSA) testing, and biopsy, while also comparing two commercial assays (AlloSure and Prospera) in kidney and pancreas transplant recipients. Methods: We retrospectively analyzed 271 transplant patient records from 2019 to 2024 at our institution, focusing on dd-cfDNA testing. Statistical analyses evaluated assay performance in relation to DSA and biopsy results. The impact of multi-organ transplantation (MOT) on dd-cfDNA levels was also assessed. Results: In our predominantly Caucasian cohort (61.5%) with a mean age of 53 years, increased levels of dd-cfDNA were significantly associated with DSA positivity, particularly within the Prospera group (p = 0.002), and were particularly higher in patients with HLA class II DSA. Both assays showed a limited correlation with biopsy-confirmed rejection. AlloSure had high specificity (80%) but low sensitivity (19%), whereas Prospera showed higher sensitivity (75%) with moderate specificity (60%). Dd-cfDNA levels were elevated in MOT recipients in a vendor-dependent manner. Conclusions: Our findings highlight the differing clinical strengths of dd-cfDNA assays: AlloSure demonstrates greater preference for ruling out rejection, whereas Prospera appears better suited for early detection. Dd-cfDNA interpretation in MOT recipients warrants cautious consideration. Overall, tailoring assay selection and optimizing diagnostic thresholds to clinical context may enhance transplant surveillance and patient management strategies. Full article

Introduction: Skin aging is influenced both by intrinsic factors and environmental exposures, such as UV radiation, which accelerate structural changes within the skin’s extracellular matrix (ECM). Understanding these changes is crucial for developing effective anti-aging treatments. Materials and Methods: This pilot cross-sectional study examined skin biopsy samples from three Caucasian male subjects with different levels of UV exposure, aiming to evaluate the effectiveness of two-photon microscopy (2PM) and Second Harmonic Generation (SHG) in visualizing and quantifying structural changes associated with skin aging. The samples were analyzed using 2PM to assess the structure and density of collagen and elastin fibers within the ECM. Integrated optical density (IOD) and the SHG-to-Autofluorescence Aging Index of the Dermis (SAAID) were used for quantitative analysis. Results: This study revealed a significant decrease in collagen density and increased disorganization in the ECM with age. Photo-exposed skin showed a more pronounced degradation of collagen and a higher increase in elastin content compared to non-photo-exposed skin. The average IOD for collagen was notably lower in elderly subjects compared to younger subjects, with a marked decrease in chronically photo-exposed skin. Discussion: The SAAID values indicated a substantial impact of photoaging, with lower scores in photo-exposed elderly skin compared to non-exposed skin. Conclusions: In conclusion, 2PM and SHG microscopy were effective in visualizing and quantifying age- and UV-induced skin remodeling, providing valuable insights into the distinct mechanisms driving intrinsic and extrinsic aging. Full article

Background and Objectives: Lumbar disc herniation (LDH) is influenced by genetic, mechanical, and behavioral factors, with genetic predisposition playing a key role. Vitamin D receptor (VDR) polymorphisms have been implicated in LDH susceptibility, warranting further investigation. This study aimed to assess the association between VDR polymorphisms (FokI, ApaI, and TaqI) and LDH risk through a systematic review, meta-analysis, and trial sequential analysis (TSA). Materials and Methods: A systematic literature search was conducted across PubMed, Web of Science, Scopus, Cochrane Library, and CNKI, up until 30 January 2025. A meta-analysis was performed using Review Manager 5.3, with odds ratios (ORs) and 95% confidence intervals (CIs), and heterogeneity assessed via the I² statistic. The publication bias and TSA were evaluated using CMA 3.0 and TSA software to ensure the reliability of the results. The FATHMM-XF method was applied to predict the functional effect of coding and non-coding polymorphisms. Results: From 79 records, 10 studies were entered into the meta-analysis. The meta-analysis results showed no significant association of FokI and ApaI polymorphisms with LDH, while TaqI exhibited a protective effect, particularly in Asian populations and larger studies. The subgroup analysis revealed significant ethnicity-specific associations for TaqI, with stronger effects observed in Asian compared to Caucasian individuals. The trial sequential analysis indicated that additional studies are required to confirm the findings for FokI, while the recessive model of TaqI polymorphism showed a near-sufficient sample size for reliable conclusions. Conclusions: The TaqI polymorphism, particularly the tt genotype, appears to have a protective effect against LDH, especially in Asian populations and larger studies. However, further large-scale, multi-ethnic research is needed to confirm these findings and explore underlying biological mechanisms. Full article

This study explores the change in inflammatory markers over the course of neoadjuvant chemoradiation and adjuvant chemotherapy for LARC and assesses the association with clinicopathological factors at pre-specified time-points. We examined the trends of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP), carcinoembryonic antigen (CEA), fibrinogen, and albumin through multilevel modelling of 29 prospective LARC patients across six time-points: before neoadjuvant chemoradiation (T1), week 3 of chemoradiation (T2), post-chemoradiation (T3), post-surgery (T4), midpoint of adjuvant chemotherapy (T5), and chemotherapy completion (T6). Variables collected included ethnic background, body mass index (BMI), smoking status, and pathological responses graded by Ryan tumour regression grade and pathological tumour and nodal status. NLR and PLR demonstrated an increasing trend during chemoradiation. Median CEA was highest at baseline and lowest at T4. The highest median values for NLR, PLR, CRP, and fibrinogen were at T4. Smokers demonstrated a trend towards a higher NLR compared to non-smokers. NLR was significantly higher in Caucasians compared to Asians at T2. Patients with pathological node-negative status had a higher NLR at T5 and T6 and a higher PLR at T1, T3, T5 and T6. Overall, inflammatory indices change dynamically throughout treatment and vary with clinicopathological factors. Full article

Purpose: We investigated care disparities and associated factors along the segments of adult musculoskeletal tumor (MST) care prior to initiation of treatment. Patients and Methods: This cohort included newly diagnosed MST patients who were referred to Stanford Medical Center for establishing care from July 2020 to April 2024. We investigated the interval from the onset of symptoms to the first appointment with a primary care provider (PCP wait-time), and the interval from first PCP appointment to obtaining the first imaging study (imaging wait-time) and to obtaining biopsy results (biopsy wait-time). Sarcoma consult wait-time was defined as the interval between referral date and consult date. We performed a survey among sarcoma physicians and non-physician staff on the perception of wait-time. Results: Among 402 eligible patients, approximately 38.5% had PCP a wait-time longer than 5 weeks, with young adults and Hispanic patients having the highest rate of such long wait-times. Approximately 20.6% of patients had an imaging wait-time longer than 5 weeks, with young adults having the highest proportion of such long wait-times. In addition, Hispanic (p = 0.02), Black (p = 0.05) and Caucasian (p = 0.02) patients had significantly higher percentages of patients with an imaging wait-time of more than 5 weeks compared to Asians. Approximately 79.3% of patients had a biopsy wait-time longer than 5 weeks, with Black and Hispanic patients having the highest percent of such long wait-times. In addition, compared to public insurance, private insurance was associated with a higher proportion of patients with PCP wait-times, imaging wait-times, sarcoma consult wait-times and biopsy wait-times longer than 5 weeks. The survey responses overwhelmingly indicated that a wait-time of more than 5 weeks was not acceptable. Conclusions: Substantial disparities in MST care related to age group, ethnicity and insurance type existed in multiple segments of the care journey prior to the initiation of treatment. Our study provides insights for practice, research and policy considerations for narrowing sarcoma care disparities. Full article

Epidermal growth factor receptor (EGFR) mutations are described in 10–15% of Caucasian patients and in 50% of Asian patients with non-squamous non-small cell lung cancer (NSCLC). The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapeutic scenario and has changed the natural history of the disease. Despite the results obtained with osimertinib, a third-generation TKI, most patients experience disease progression. The search for new therapeutic strategies both to enhance first-line treatment and to ensure adequate second-line therapies represents an unmet medical need, towards which all efforts are being concentrated. In this review, we describe the main strategies identified to improve the prognosis of patients with EGFR-mutated NSCLC. Full article

Introduction: Social sustainability is deeply connected to the well-being of marginalized groups, and it is important to highlight how mental health impacts the social inclusion of homeless individuals, particularly veterans. Homelessness is a growing global issue, disproportionately affecting U.S. veterans, with mental health challenges playing a significant role in its onset and perpetuation. Purpose: This study aims to compare the sociodemographic and clinical characteristics of homeless veterans and non-veterans in the U.S. Method: Using public data (N = 6295), this quantitative study applies descriptive and inferential statistical analyses. Results: Homeless veterans are more likely than non-veterans to be older, male, and identify as Caucasian or African American. They are more frequently high school graduates or have higher education, and report being divorced, widowed, married, or in varied employment statuses (full-time, part-time, or unemployed). Veterans exhibit higher rates of severe mental illnesses, schizophrenia, trauma- and stressor-related disorders, ADHD, bipolar disorder, personality disorders, depression, anxiety, and substance or alcohol use disorders. However, they are less likely than non-veterans to report substance-induced disorders, intoxication, dependence, or abuse involving cocaine, cannabis, opioids, and other substances. Conclusions: Psychosocial interventions for homeless veterans should prioritize mental health-related concerns, whereas efforts for homeless non-veterans should focus on addressing substance use. Future research should develop tailored interventions, explore the sociodemographic factors influencing homelessness, and investigate the interplay between trauma, mental health, and substance use. Addressing these issues can contribute to a more resilient, inclusive, and sustainable society by providing long-term support and integration opportunities for those most affected. The novelty of this study lies in distinguishing between mental health issues prevalent in veterans and substance use disorders more common in non-veterans, offering insights for tailored interventions. It also connects these findings to social sustainability, suggesting that addressing these issues can promote a more inclusive and resilient society. Full article

Introduction: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients with ALK or ROS1 gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but there is no direct comparison of their efficacy in homogeneous Caucasian populations in real-world practice. In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease. Materials and Methods: One hundred four NSCLC patients with ALK or ROS1 gene rearrangement were enrolled for first-line therapy with ALK inhibitors (crizotinib in 25 patients, brigatinib in 22 patients, and alectinib in 41 patients) or the ROS1 inhibitor (crizotinib in 16 patients) as part of daily clinical practice in two Polish cancer centers. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to treatment methods and clinical data. Results: In ALK-rearranged patients, ORR was insignificantly higher in patients treated with second-generation ALK inhibitors than in patients receiving crizotinib (68.25% vs. 48% of patients, p = 0.0547). Median PFS in the crizotinib group was 8 months, and in the group that received second-generation ALK inhibitors this was not reached (HR = 5.2182, 95% CI: 2.6163–10.4079, p < 0.0001). Similarly, median OS was significantly lower in patients treated with crizotinib than in patients receiving second-generation ALK inhibitors (26 vs. not reached, HR = 3.529, 95% CI: 1.5559–7.2258, p = 0.002). The efficacy of crizotinib in patients with ROS1 and ALK gene rearrangement did not differ significantly (ORR—37.5 vs. 48%, median PFS—6 vs. 7 months, median OS—8 vs. 26 months, respectively). In ALK-rearranged patients, multivariate analysis showed that the only factor significantly increasing the risk of progression was liver metastases (HR = 2.1917, p = 0.0418). The risk of death was significantly higher in patients treated with crizotinib (HR = 2.4823, p = 0.0359) and in patients with liver metastases (HR = 3.1266, p = 0.0104). Conclusions: Second-generation ALK inhibitors are more effective than crizotinib in ALK-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors. Full article

Background: Varicella zoster virus (VZV) infection can be life-threatening for fragile and immunosuppressed patients. Recombinant VZ vaccination (RVZV) has been recommended for vulnerable patients to reduce the risk of reactivation. Hemodialysis (HD) patients often have weakened immune systems and a high prevalence of comorbidities, which may justify the use of RVZV. This study examines the difference in VZ antibody levels following RVZV and its significance in HD patients. Methods: We measured the levels of immunoglobulin G antibodies against VZ (VZ-IgG) in the HD population. We also collected demographic and clinical data for each patient, including their age, length of time on dialysis, Charlson Comorbidity Index (CCI), and markers of nutritional and inflammatory status. Results: A total of 160 patients were evaluated, with 111 (69.4%) male and 143 (89.3%) Caucasian. The mean VZ-IgG levels after one year were significantly higher in patients who received RVZV than those who did not (2177 ± 834 versus 1494 ± 882, p < 0.001). Additionally, among all other risk factors, only CCI harmed the VZ-IgG levels in non-vaccinated HD patients (B −403 with 95%CI −778 −27.9, p = 0.039). Overall, 98.8% of patients were found to be seropositive for VZ, with only one patient in each group (RVZV and non-RVZV) testing negative. Conclusions: Patients who received RVZV showed higher VZ IgG levels after one year compared to those who did not. Moreover, unvaccinated patients with more comorbidities had lower anti-VZ IgG titers. Full article