Search Results (1,431)

Background and Objectives: Stratifying thyroid nodules according to malignancy risk is a crucial step in early diagnosis and patient care. Recently, deep learning techniques have emerged as powerful tools for medical diagnostics, particularly with convolutional neural networks (CNNs) applied to medical image classification. This study aimed to develop a new hybrid CNN model for classifying thyroid nodules using the TN5000 ultrasound image dataset. Materials and Methods: The TN5000 dataset includes 5000 ultrasound images, with 3572 malignant and 1428 benign nodules. To address the issue of class imbalance, the researchers applied an R-based anomaly data augmentation method and a GAN-based technique (G-RAN) to generate synthetic benign images, resulting in a balanced dataset for training. The model architecture was built on a pre-trained EfficientNet-B3 backbone, further enhanced with squeeze-and-excitation (SE) blocks and residual refinement modules to improve feature extraction. The task was to classify malignant nodules (labeled 1) and benign nodules (labeled 0). Results: The proposed hybrid CNN achieved strong performance, with an accuracy of 89.73%, sensitivity of 90.01%, precision of 88.23%, and an F1-score of 88.85%. The total training time was 42 min. Conclusions: The findings demonstrate that the proposed hybrid CNN model is a promising tool for thyroid nodule classification on ultrasound images. Its high diagnostic accuracy suggests that it could serve as a reliable decision-support system for clinicians, improving consistency in diagnosis and reducing human error. Future work will focus on clinical validation, explainability of the model’s decision-making process, and strategies for integration into routine hospital workflows. Full article

Background: Both clinical and research data support the contribution of IL6-mediated local immunosuppression coupled with IL6-initiated protumorigenic processes, e.g., sustained proliferation and angiogenesis in the development of many cancers, including lung cancer. By virtue of their pharmacologic advantage, controlled release, local delivery formulations can provide immunochemopreventive relevant agent levels at the target site with negligible systemic agent-related effects. Bioavailability is a major challenge with chemopreventive agents. Methods: Janus nanoparticles (JNPs), however, are a versatile drug delivery platform that addresses several major cancer preventive challenges including bioavailability and retention of bioactivity, with elimination of potential deleterious effects with systemic administration. Furthermore, JNPs feature two discrete compartments that enable concurrent delivery of two chemically distinct agents with complementary mechanisms of action. Results: Our data show that the synthetic vitamin A derivative, fenretinide (4HPR), and the IL6R inhibitor, tocilizumab (TCZ), inhibit pathways integral for the development of lung cancer. Initial molecular modeling and kinase activity assays confirmed that 4HPR serves as a competitive inhibitor for active-site ATP binding of two key IL6 downstream kinases (JAK1, CK2). Concurrent RNA-seq analyses that employed Qiagen Ingenuity Pathway Analysis showed significant inhibition of canonical pathways associated with DNA replication and division in conjunction with significant activation of immunogeneic cell death and TREM 1 signaling pathways and showed the immune-augmenting, cancer-preventive impact of 4HPR-TCZ treatment on gene expression in premalignant lung epithelial cells. Subsequent qRT-PCR analyses corroborated the RNA seq findings and demonstrated 3- to 6-fold increased expression of TREM 1 and immunogenic cell death genes, such as TREM1 and NLRC4 and HSPA6 and DDTT3, respectively. These data collectively guided the development of human serum albumin–chitosan JNPs for the co-delivery of 4HPR and TCZ, respectively. 4HPR-TCZ JNP characterization studies demonstrated high circularities and stability in suspension, as shown by consistency in diameter and minimal changes to the polydispersity index, while confocal microscopy confirmed their biocompartmental nature. Subsequent tertiary chemoprevention in vivo studies that employed a highly aggressive human lung cancer cell line showed that JNPs releasing 4HPR and 4HPR-TCZ significantly reduced tumor volume, as assessed by vital tumor tissue, suppressed proliferation, increased apoptosis, and promoted intratumor vascular instability. Conclusions: Collectively, these studies elucidate 4HPR-TCZ in vitro chemopreventive mechanisms of action and demonstrate proof of concept for JNP-4HPR-TCZ in vivo efficacy. Full article

Oral cancer, the most common head and neck malignancy, has a high recurrence rate and poor prognosis largely owing to chemotherapy resistance. The adverse effects of conventional therapies have prompted investigations into safer and more effective alternative therapies. Chloroquine (CQ) and hydroxychloroquine (HCQ) have shown potential owing to their roles in autophagy modulation and immune regulation. This study clarifies the selective efficacy of hydroxychloroquine (HCQ) and chloroquine (CQ) in oral squamous cell carcinoma models, emphasizing distinct responses in gingival (Ca9-22) and tongue (SCC-9) carcinoma cells. Non-oncogenic oral epithelial cells (GMSM-K) and oral carcinoma cell lines from the tongue (SCC-9, Cal-27) and gingiva (Ca9-22) were used. Cell viability, cytotoxicity, and colony formation were assessed via MTT, LDH, and crystal violet assays. Flow cytometry was used to measure apoptosis, autophagy, oxidative stress, mitochondrial membrane potential, and DNA damage. The transcriptomic profiles of apoptosis and autophagy-related genes were assessed by qPCR arrays. Bioinformatics analysis allowed estimation of the main gene interaction networks. Pre-screening showed that GMSM-K and Cal-27 cells were non-responsive or exhibited non-specific toxicity at high doses; therefore, subsequent analyses focused on Ca9-22 (GC) and SCC-9 (TC). HCQ significantly reduced viability and colony formation in Ca9-22 cells while moderately affecting SCC-9 cells. Autophagy inhibition was accompanied by compensatory up-regulation of autophagy-related genes, consistent with feedback activation of TFEB and FOXO3a pathways. Gene expression profiling and flow-cytometry analyses revealed cell-type-specific differences in apoptosis, mitochondrial potential, and DNA damage, suggesting HCQ’s selective anti-tumor potential in gingival carcinoma. These findings highlight HCQ as a repurposed adjuvant therapy that modulates autophagy and apoptosis to enhance chemosensitivity in oral cancer. Full article

Background: Accumulating evidence suggests that cannabidiol (CBD) exerts variable effects on cancer cells that influence cellular activity, including growth. While anecdotal evidence abounds, mechanistic studies have lagged. Methods: Malme-3M cells derived from melanoma and less-aggressive BJ fibroblast cells were incubated with CBD. CE-MS mass spectroscopy was used to measure metabolite changes resulting from CBD treatment. Results: Data indicate a differential response between malignant Malme-3M cells and BJ fibroblasts with respect to metabolites critical for primary metabolic function. A significant reduction in TCA metabolites is seen with a corresponding increase in glycolytic output in the Malme-3M cell line. A similar reduction in TCA activity in BJ fibroblasts appears to differentially activate fatty acid oxidation. ATP is significantly reduced in the Malme-3M cells with a corresponding decrease in metabolites associated with redox maintenance. Conclusions: This is the first metabolomics analyses of malignant Malme-3M cells and less-aggressive BJ fibroblasts after pre-treatment with CBD. The data suggest that the CBD-induced metabolic perturbation could reprogram cellular metabolism and affect ATP production and redox maintenance of the more-aggressive Malme-3M cells. Full article

Background: Artificial intelligence (AI) has shown significant promise in augmenting diagnostic capabilities across medical specialties. Recent advancements in generative AI allow for synthesis and interpretation of complex clinical data including imaging and patient history to assess disease risk. Objective: To evaluate the diagnostic performance of a dermatology-trained multimodal large language model (DermFlow, Delaware, USA) in assessing malignancy risk of pigmented skin lesions. Methods: This retrospective study utilized data from 59 patients with 68 biopsy-proven pigmented skin lesions seen at Indiana University clinics from February 2023 to May 2025. De-identified patient histories and clinical images were input into DermFlow, and clinical images only were input into Claude Sonnet 4 (Claude) to generate differential diagnoses. Clinician pre-operative diagnoses were extracted from the clinical note. Assessments were compared to histopathologic diagnoses (gold standard). Results: Among 68 clinically concerning pigmented lesions, DermFlow achieved 47.1% top diagnosis accuracy and 92.6% any-diagnosis accuracy, with F1 = 0.948, sensitivity 93.9%, and specificity 89.5% (balanced accuracy 91.7%). Claude had 8.8% top diagnosis and 73.5% any-diagnosis accuracy, F1 = 0.816, sensitivity 81.6%, specificity 52.6% (balanced accuracy 67.1%). Clinicians achieved 38.2% top diagnosis and 72.1% any-diagnosis accuracy, F1 = 0.776, sensitivity 67.3%, specificity 84.2% (balanced accuracy 75.8%). DermFlow recommended biopsy in 95.6% of cases vs. 82.4% for Claude, with multiple pairwise differences favoring DermFlow (p < 0.05). Conclusions: DermFlow demonstrated comparable or superior diagnostic performance to clinicians and superior performance to Claude in evaluating pigmented skin lesions. Although additional data must be gathered to further validate the model in real clinical settings, these initial findings suggest potential utility for dermatology-trained AI models in clinical practice, particularly in settings with limited dermatologist availability. Full article

This study investigates the immunomodulatory effects of a well-characterized cannabidiol (CBD)-rich cannabis extract, CAN296, on T lymphocytes (T cells), particularly Cluster of Differentiation 4 (CD4⁺) helper and Cluster of Differentiation 8 (CD8⁺) cytotoxic subsets, by examining T-cell activation, cytokine secretion, and cytotoxic molecule expression in comparison with the conventional treatments dexamethasone (DEX) and tacrolimus (TAC). It addresses key processes involved in the formation of premalignant immune-mediated lesions, such as those seen in oral lichen planus (OLP) and oral manifestations of graft-versus-host disease (oGVHD). CD4⁺ and CD8⁺ T cells were isolated from healthy donors and assessed in vitro for T cell activation via CD69 expression, secreted tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels according to enzyme-linked immunosorbent assay (ELISA), and cytotoxic molecule expression Granzyme B, Perforin, Fas Ligand (Fas-L) quantified by flow cytometry. Cells were treated with different doses of CAN296 (2, 4, 8 µg/mL), DEX (0.4, 4, 40 µg/mL), or TAC (0.1, 1, 10 ng/mL), and all parameters were compared to untreated controls. CAN296 significantly inhibited T cell activation, reducing CD69 expression in CD4⁺ T cells to 2–11% and in CD8⁺ T cells to 5–17%. It also markedly suppressed TNF-α secretion in CD4⁺ T cells at all concentrations (p < 0.0001). In CD8⁺ T cells, CAN296 led to a near-complete reduction in TNF-α and IFN-γ, leaving both cytokines barely detectable at all tested doses (p < 0.0001). The effect of cell inhibition was significantly more pronounced than that observed with DEX or TAC, displaying dose-dependent reductions. TAC inconsistently lowered TNF-α while paradoxically increasing IFN-γ at lower concentrations. Additionally, CAN296 consistently suppressed cytotoxic molecule expression, reducing Granzyme B by 81–82%, Perforin by 40–53%, and Fas-L by 40–44%. DEX showed variable effects on cytotoxic molecule expression. At the same time, TAC demonstrated inconsistent modulation of Perforin and Granzyme B. Overall, CAN296 outperformed DEX and TAC, demonstrating more potent and consistent immunomodulatory effects. CBD-rich cannabis extract, CAN296, exhibits potent immunomodulatory properties by effectively inhibiting T cell activation, lowering pro-inflammatory cytokines, and suppressing cytotoxic molecule expression. Its efficacy surpasses conventional therapies like DEX and TAC, offering a promising novel treatment modality for T cell-mediated disorders, including OLP and oGVHD. These findings support further development of CAN296 formulations to optimize dosing and delivery, followed by clinical trials to validate its therapeutic potential. Full article

High-intensity focused ultrasound (HIFU) has recently emerged as a novel non-invasive treatment modality in dermatology, offering precise ablation of cutaneous lesions with minimal damage to surrounding tissue. Originally developed for deep-seated tumors, dermatological HIFU platforms operating at ~20 MHz enable submillimeter-scale treatment of thermal or mechanical injuries localized to the epidermis and superficial dermis, making them suitable for managing benign, premalignant, and malignant skin conditions. This review outlines the mechanistic basis of HIFU—including thermal coagulation, acoustic cavitation, and immunomodulatory effects—and presents the current evidence for its efficacy in treating actinic keratoses and basal cell carcinomas (BCCs), where early studies report clearance rates of 70–97% and excellent cosmetic outcomes. Compared to conventional therapies such as surgery, photodynamic therapy, or cryotherapy, HIFU offers reduced procedural pain, faster healing, and the ability to treat multiple lesions in a single session. Its role in field cancerization and potential utility in prophylaxis for high-risk skin areas are also explored. While promising, long-term oncologic outcomes and standardized treatment protocols remain under investigation. HIFU represents a significant advancement in non-invasive skin cancer management, aligning oncologic efficacy with patient-centered care. Full article

The risk of Helicobacter pylori (H. pylori)-related gastric tumorigenesis is closely associated with the degree of chronic gastritis, although other gastric mucosa microbes may be relevant in this process. The morphological identification of the gastric mucosa associated with the cancer-promoting microbiome may have important implications for gastric cancer prevention. This study characterized gastric mucosa microbiome communities in relation to their mucosal morphologies. A total of 94 biopsies from non-neoplastic gastric bodies underwent 16S rRNA sequencing. Microbiome structures were characterized in relation to their mucosal morphologies, which were obtained using narrow-band imaging with magnifying endoscopy. H. pylori infection- and inflammatory mucosa-associated gastric mucosal morphologies exhibited decreased bacterial alpha diversity measures and an increase in the abundance of the Helicobacter genus, while the mucosal morphology associated with severely atrophic mucosa exhibited increased bacterial alpha diversity measures and a decrease in the abundance of the Helicobacter genus. This type of mucosal morphology was also associated with increased levels of well-known gastric cancer-related bacteria, e.g., Streptococcus. The microbial dysbiosis associated with gastric mucosa morphology also correlated well with the occurrence of gastric cancer and the DNA methylation status. Our results suggest that gastric microbiome communities correlate well with their premalignant condition-associated mucosal morphologies. Full article

Pre-B-cell leukemia factor 1 (PBX1) is a transcription factor that plays a significant role in various physiological, developmental, and oncogenic processes in humans. The mechanisms and interactions of PBX1 in both solid and hematologic malignancies remain significant areas of study. It was initially found in pre-B-cell acute lymphoblastic leukemia as a result of the chromosomal translocation t(1;19). Over the years, its role in other blood neoplasms has been studied. PBX1 and its variant E2A::PBX1 regulate gene expression that influences cell proliferation and differentiation in hematopoietic lineages. Their interaction with oncogenic partners results in abnormal gene regulation and tumorigenesis. Research has predominantly focused on the role of these factors in leukemias and plasma cell neoplasms, whereas other hematologic neoplasms have been largely overlooked. The potential application of PBX1 as a prognostic and predictive biomarker has recently gained attention. However, further research is needed to fully understand its complex role and how it can be targeted for therapeutic purposes. This review summarizes current knowledge on PBX1’s role in the growth of both mature and immature hematologic neoplasms. Moreover, it focuses on its prospective use as a therapeutic target and to predict prognosis, especially for aggressive neoplasms that do not respond to current therapeutic approaches. Full article

Background: Line-field confocal optical coherence tomography (LC-OCT) is a non-invasive imaging technique providing high-resolution en-face and cross-sectional views of the epidermis and superficial dermis for in vivo characterisation of actinic keratosis (AK), Bowen’s disease (BD) and squamous cell carcinoma (SCC). Despite its promise, standardised imaging protocols are lacking. Objective: This systematic review aims to assess the utility of LC-OCT for diagnosing AK, BD and SCC, with particular emphasis on workflow optimisation and protocol standardisation. Methods: A systematic literature search was performed using PubMed, Embase, and Scopus databases (January 2018–October 2024). Two reviewers independently screened the records, extracted data and applied the Confidence in the Evidence from Reviews of Qualitative research (CERQual) framework to assess confidence in key findings. Results: Eleven studies met the inclusion criteria. LC-OCT reliably identified key histopathological correlates. Across studies, LC-OCT consistently visualised hyperkeratosis, keratinocytic atypia, parakeratosis, and acanthosis, as well as characteristic vascular alterations and dermal remodeling. LC-OCT also demonstrated its capacity to detect invasive features by revealing disruptions in the dermo-epidermal junction and the presence of tumour strands infiltrating the dermis. Multimodal imaging combined with technical optimisations such as minimal probe pressure, paraffin oil coupling, and dermoscopy-guided localisation, substantially improved image resolution and interobserver concordance. Conclusions: This systematic review provides a basis for establishing standardised LC-OCT imaging protocols in keratinocytic tumours. While LC-OCT shows promise as a non-invasive diagnostic tool, further multicenter studies are needed to refine imaging workflows and evaluate the integration of artificial intelligence-based analysis to improve diagnostic accuracy and reproducibility. Full article

Background/Objectives: Gastric intestinal metaplasia (GIM) is a recognized premalignant condition for gastric cancer (GC), but long-term outcomes and predictors of progression remain incompletely understood. This study aimed to evaluate the progression of GIM and identify factors associated with malignant transformation. Methods: In this retrospective single-center study, 1204 adult patients with histologically confirmed GIM and at least 12 months of follow-up after esophagogastroduodenoscopy (EGD) were analyzed. Clinical and pathological variables, including GIM extent, Helicobacter pylori status, family history of GC, demographic factors, and residence in endemic regions, were assessed. Patients were stratified into high- and low-risk groups according to established criteria, and progression to GC or other neoplasms was recorded. Results: During a mean follow-up of 38.6 months, 49.1% of patients had no detectable GIM at the end of follow-up, 48.7% remained unchanged, and 2.2% showed disease progression. Among progressed cases, adenocarcinoma accounted for 66.7%, dysplasia for 29.6%, and SCC for 3.7%. Progression was significantly more common among males, older patients, and those with antrum + corpus involvement. The overall progression rate from GIM to adenocarcinoma was 1.5% (approximately 0.45% per patient-year). No significant difference in progression or survival was observed between high- and low-risk groups. Conclusions: The long-term malignant transformation rate of GIM is low. Male sex and extensive gastric involvement were associated with higher progression rates, while H. pylori was not predictive of malignant transformation. These findings support individualized surveillance strategies for patients with GIM, while routine surveillance of antrum-limited GIM may provide minimal benefit but increase healthcare burden. Full article

Background/Objectives: A knowledge gap persists regarding anticoagulation therapy after endovascular stent insertion for malignant superior vena cava obstruction (mSVCO). Guidelines are supported by retrospective studies with a radiological focus and lack specific drug recommendations. No studies to date have captured the multi-disciplinary nature of decision-making over time. Methods: This single-center retrospective service evaluation includes patients with solid organ malignancy who received a stent for mSVCO between July 2016 and May 2022. Patient and treatment characteristics, clinical outcomes and prescribing decisions were collected from medical records and analyzed. Results: Of 49 patients (55% female, mean age 59), 73% had metastatic extra-thoracic disease at stent insertion. Technical success was achieved in 98% of cases and 92% survived to discharge. Forty-eight patients were followed until death. Median survival was 2.4 months. Post-procedure imaging (performed in 55% of patients) revealed 10 (21%) cases of systemic venous thromboembolism and 7 cases of stent thrombosis. Forty-four (91%) patients received anticoagulation therapy (62% therapeutic dose low molecular weight heparin). Those with thrombotic complications were fitter pre-procedurally than the rest of the cohort. There was one case of major bleeding. Twenty-two instances of therapy modification occurred following the initial plan, including nine changes due to a patient preference for oral therapy. Conclusion: Patients undergoing stenting for mSVCO demonstrate high thrombotic risk and a poor prognosis. Anticoagulation plans are frequently modified post discharge due to changing risk profiles and patient preferences. Multi-disciplinary collaboration is essential to support patient-centered and individualized management. Future research should investigate direct oral anticoagulants and anti-platelet therapy and develop risk assessment tools for this population. Full article

Acute leukemias are highly aggressive hematologic malignancies that demand intensive chemotherapy regimens. However, drug toxicity remains a major barrier to treatment success and patient survival. In this context, pharmacogenomics offers a promising strategy by identifying single-nucleotide variants (SNVs) that influence drug metabolism, efficacy, and toxicity, ultimately impacting treatment outcomes. This study analyzed data from the ClinPGx/PharmGKB database to identify clinically annotated variants related to chemotherapy response in Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). A total of 24 variants were curated for AML and 57 for ALL. Among these, nonsynonymous variants were most frequent in ALL (31.6%), while synonymous variants predominated in AML (33.3%). Although traditionally considered neutral, synonymous and intronic variants may influence gene expression through regulatory or splicing mechanisms. The analysis revealed clinically significant variants associated with chemotherapy response, particularly in the ABCB1 gene, observed in 12.5% of AML and 10.5% of ALL cases. Several variants, particularly TPMT, NUDT15, ABCC1, SLC28A3, and RARG, were associated with severe adverse effects such as myelotoxicity, mucositis, cardiotoxicity, and hepatotoxicity. This study reinforces the importance of genetic variants in modulating the therapeutic response and toxicity to chemotherapy drugs in acute leukemias. Analysis of ClinPGx/PharmGKB data emphasizes ABCB1 as a potential resistance marker and supports pre-treatment genotyping of genes like TPMT and NUDT15 to prevent severe toxicities. Future advances should include the expansion of pharmacogenetic studies in underrepresented populations and the clinical validation of new markers in prospective trials, aiming to consolidate precision medicine as a routine part of the therapeutic management of acute leukemias. Full article

Background/Objectives: Bloodstream infections (BSIs) caused by carbapenem-resistant Enterobacterales (CREs) are a growing public health threat due to limited therapeutic options and high mortality. In Turkey, oxacillinase-48 (OXA-48) producers predominate, while OXA-48/New Delhi metallo-β-lactamase (NDM) co-producers are increasingly detected. Although ceftazidime–avibactam (CAZ-AVI) is effective against OXA-48, treating NDM-positive isolates remains challenging. Cefiderocol, a novel siderophore cephalosporin active against both serine- and metallo-β-lactamases, is not yet available in Turkey. Establishing baseline susceptibility rates and identifying clinical predictors of resistance are, therefore, crucial before its introduction. Methods: This retrospective study included adult patients with CRE-BSIs diagnosed at a tertiary university hospital in Istanbul between January and December 2023. Demographic, clinical, and microbiological data were collected from electronic medical records. Susceptibility to cefiderocol, CAZ-AVI, and colistin was determined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2023 criteria. Risk factors for cefiderocol resistance were analyzed. Results: Among 202 isolates, cefiderocol showed the highest susceptibility (94%, n = 190), followed by CAZ-AVI (82%, n = 166) and colistin (70%, n = 141), with all pairwise differences being statistically significant (p < 0.001). Cefiderocol resistance (6%, n = 12) was significantly associated with hematologic malignancy, hematopoietic stem cell transplantation, prior CAZ-AVI or polymyxin exposure, prolonged hospitalization, and repeated admissions. Conclusions: Cefiderocol demonstrated potent in vitro activity against CRE-BSI isolates, with resistance confined to distinct high-risk clinical settings. This pre-implementation study provides baseline microbiological and epidemiological data from an OXA-48 endemic region with rising NDM prevalence, underscoring the importance of early surveillance and stewardship strategies before cefiderocol becomes clinically available. Full article

Background: Diagnosing facial melanoma, specifically lentigo maligna (LM) and lentigo maligna melanoma (LMM), is a daily clinical challenge, particularly for small or traumatized lesions. LM and LMM are part of the broader group of atypical pigmented facial lesions (aPFLs), which also includes benign look-alikes such as solar lentigo (SL), atypical nevi (AN), seborrheic keratosis (SK), and seborrheic-lichenoid keratosis (SLK), as well as pigmented actinic keratosis (PAK), a potentially premalignant keratinocytic lesion. Standard dermoscopy with handheld devices is the most widely used diagnostic tool in dermatology, but its accuracy heavily depends on the clinician’s experience and the perceived difficulty of the case. As a result, many benign aPFLs are excised for histological analysis, often leading to aesthetic concerns. Reflectance confocal microscopy (RCM) can reduce the need for biopsies, but it is limited to specialized centers and requires skilled operators. Aims: This study aimed to assess the impact of personal skill, diagnostic confidence, and perceived difficulty on the diagnostic accuracy and management in the differential dermoscopic diagnosis of aPFLs. Methods: A total of 1197 aPFLs dermoscopic images were examined on a teledermoscopic web platform by 155 dermatologists and residents with 4 skill levels (<1, 1–4, 5–8, >8 years). They were asked to give a diagnosis, to estimate their confidence and rate the case, and choose a management strategy: “follow-up”, “RCM” or “biopsy”. Diagnostic accuracy was examined according to the personal skill level, confidence level, and rating in three settings: (I) all seven diagnoses, (II) LM vs. PAK vs. fully benign aPFLs, (III) malignant vs benign aPFLs. The same analyses were performed for management decisions. Results: The diagnostic confidence has a certain impact on the diagnostic accuracy, both in terms of multi-class diagnosis of six aPFLs in diagnostic (setting 1) and in benign vs malignant (setting 3) or benign vs. malignant/premalignant discrimination (setting 2). The perceived difficulty influences the management of benign lesions, with easy ratings predominantly matching with “follow-up” decision in benign cases, but not that of malignant lesions assigned to “biopsy”. The experience level had an impact on the perception of the number of real easy cases and had no to minimal impact on the average diagnostic accuracy of aPFLs. It, however, has an impact on the management strategy and specifically in terms of error reduction, namely the lowest rates of missed malignant cases after 8 years of experience and the lowest rates of inappropriate biopsies of benign lesions after 1 year of experience. Conclusions: The noninvasive diagnosis and management of aPFLs rest on a daily challenge. Highlighting which specific subgroups of lesions need attention and second-level examination (RCM) or biopsy can help detect early malignant cases, and, in parallel, reduce the rate of unnecessary removal of benign lesions. Full article