Search Results (131)

Background/Objectives: Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare neuroectodermal malignancy of the nasal cavity characterized by aggressive local invasion and variable metastatic potential, with diverse clinical behavior, often presenting at advanced stages. ONB poses challenges for targeted therapeutic strategies, despite advances in surgical and multimodal treatment strategies, because of the rarity of this disease and the limited understanding of its molecular pathophysiology. Methods: A comprehensive review of genomic, multi-omic, and molecular studies was performed to integrate known targeted sites in ONB with the current understanding of its pathophysiology. Results: Recent genetic and molecular studies have identified significant epigenetic and signaling pathway alterations that are critical in pathogenesis and treatment resistance and may serve as potential therapeutic targets. Additionally, novel discovered immunohistochemical and transcriptomic markers, such as IDH2, NEUROD1, and OTX2, offer improved diagnostic specificity and prognostication. Multi-genomic platforms (i.e., multi-omics), involving the combined integration of transcriptomics, epigenetics, and proteomics findings, have led to several recent insights, including the subclassification of neural and basal genomic subtypes, the identification of key driver mutations, and new insights into disease development. This review synthesizes current knowledge on the molecular landscape of ONB, including its tumor origin, immune microenvironment, genetic alterations, and key molecular pathways involved in its pathogenesis. Conclusions: Future research may benefit from integrating these findings into precision medicine approaches, enabling earlier diagnosis and more accurate prognosis. Full article

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no reports on tumor immune microenvironment (TIME) analyses based on iCCA subclassifications. This study investigated subclassification-specific TIMEs in iCCAs for the purpose of establishing appropriate pharmacotherapy. Methods: A total of 131 resected iCCA cases were analyzed, comprising 73 tumors classified as small-duct-type and 58 as large-duct-type based on pathological evaluation. Immunohistochemical analyses targeting CD8, PD-1, PD-L1, CTLA-4, and S100 protein (a dendritic cell [DC] marker) were performed to investigate the immune-cell status in each subclassification. Results: Large-duct-type iCCA had a significantly higher CD8 expression in tumor-infiltrating cells than small-duct-type ICC. However, the expression of other molecules did not significantly differ between the two tumor types. The proportion of tumors with a high level of S100 protein expression (DC-high group) in tumor-infiltrating cells was significantly higher in small-duct-type ICCs than in large-duct-type iCCAs (30% vs. 1.7%). In small-duct-type iCCAs, the expression levels of CD8, PD-1, PD-L1, and CTLA-4 were significantly higher in the DC-high group than in the DC-low group. Conclusions: We revealed subclassification-specific TIMEs in iCCAs. A subset of small-duct-type iCCAs exhibited strong DC infiltration. In these patients, the tumors may establish an immunosuppressive TIME to evade antitumor immunity triggered by DC-mediated antigen presentation. These findings may contribute to the development of tailored pharmacotherapy for each iCCA subclassification. Full article

Objectives: In this study, the effect of positive surgical margin (PSM) length on predicting postoperative biochemical recurrence (BCR) after radical prostatectomy was evaluated, and based on the findings, an additional R subclassification to the TNM-R system was proposed. Methods: We retrospectively analyzed patients who underwent robot-assisted radical prostatectomy between 30 July 2008 and 31 December 2019. Only patients with PSM were included. Those with negative margins, those receiving neoadjuvant/adjuvant hormone therapy, or those with prior pelvic radiotherapy were excluded. A total of 353 pathology specimens were re-evaluated by a uropathologist, and the PSM length was quantitatively measured. BCR was defined as a PSA level of ≥0.2 ng/mL in two consecutive measurements. Results: The median follow-up time of the patients was 49.5 ± 33.4 months. BCR occurred in 27.1% (n = 96) of patients. A PSM cut-off length of 3.5 mm was identified for predicting BCR (p < 0.001). Among patients with PSM < 3.5 mm, 9.8% experienced BCR, while 54.3% of those with PSM ≥ 3.5 mm did. A PSM length ≥ 3.5 mm was associated with a higher risk of recurrence (OR: 1.249, 95% CI: 1.160–1.345, p < 0.001). In multivariate logistic regression analysis, PSM length remained an independent prognostic factor for BCR (p < 0.001). Conclusions: Quantitative measurement of PSM length serves as an independent predictor of BCR following radical prostatectomy. We propose subclassifying R1 margins into R1a (<3.5 mm) and R1b (≥3.5 mm), which may enhance prognostic accuracy in pathological reporting. Full article

Background/Objectives: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. Although these subclassifications may help determine the appropriate treatment strategy, subclassification diagnosis currently depends on postoperative pathological examinations. This study aimed to establish a nomogram to predict ICC subclassifications. Methods: This study included 126 patients with ICC who underwent liver resection. The participants were divided into small and large duct-type ICC groups. A nomogram to predict large duct-type ICC was developed using four diagnostic imaging findings: rim-type enhancement in the early phase, an absence of tumor enhancement in the early phase, the presence of peripheral biliary dilatation due to tumor invasion, the presence of penetrating Glisson’s vessels in the tumor, and two laboratory test results: serum gamma-glutamyl transpeptidase and carbohydrate antigen 19-9 levels. Nomogram performance was also assessed. Moreover, the bootstrap method and calibration plots were used to assess nomogram validity. Results: Seventy and fifty-six patients were pathologically diagnosed with small and large duct-type ICCs, respectively. The area under the curve of the established nomogram was 0.93 and remained 0.91 after Harrell’s bias correction. The sensitivity and specificity of the nomogram developed using the Youden index were higher than those of any of the characteristic imaging findings. Calibration plots demonstrated a strong association between the nomogram and the actual data. Conclusions: We developed a novel preoperative nomogram to predict large duct-type ICC. This nomogram can be clinically useful for predicting the subclassifications of ICCs and may contribute to the establishment of a more appropriate treatment strategy for ICC. Full article

Background: Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and poor prognosis. This exploratory study aimed to identify molecular subtypes of early-stage, treatment-naive OS to guide precise therapeutic strategies. Methods: We analyzed RNA-seq data obtained from tumor tissues from 102 OS patients using a non-negative matrix factorization algorithm (NMF) to classify the tumors into three subtypes: S1, S2, and S3. Differential gene expression was evaluated using DESeq2, followed by functional enrichment analysis with clusterProfiler and CancerHallmarks. The tumor microenvironment was assessed through ESTIMATE and CIBERSORT, and drug sensitivity was predicted using OncoPredict. SAOS-2 and MG63 cells, representing the S1 subtype, were used in the viability essays to determine the effect of hesperidin, a natural phenolic compound noted for its anti-cancer potential, alone and in combination with doxorubicin and 5-fluorouracil. Results: This study revealed three OS subtypes: S1 was enriched in cell cycle regulation, vesicular transport, and RNA metabolism while S2 and S3 were enriched in pathways related to extracellular matrix organization and protein translation, respectively. S1 displayed high tumor purity, significant chemoresistance, and overexpression of KIF20 A, correlating with poor prognosis. AURKB, a hesperidin target, was implicated in S1 pathogenesis. In vitro, hesperidin significantly reduced the viability of SAOS-2 and MG63 cells and enhanced doxorubicin efficacy. Conclusions: Our findings support the molecular subclassification of OS, emphasizing subtype-specific mechanisms of tumor progression and chemoresistance, with hesperidin offering potential as a therapeutic adjunct for high-risk OS patients. Full article

Background: Periprosthetic joint infections (PJIs) remain a major challenge in arthroplasty. This study tries to evaluate the PJI-TNM classification as predictor for the revision-free implant survival in patients with PJI of the hip or knee joint. Methods: To this end, we perform a retrospective study of all consecutive patients with PJI of an inlying hip or knee arthroplasty between January 2015 and December 2019. Results: A total of 443 cases (hip: n = 247; knee n = 196) were identified. In total, 439 patients underwent surgery (DAIR: n = 138 cases (31%), explantation: n = 272 (61%), irrigation with debridement without exchange of implant components: n = 29 (6.5%)). Four patients refused surgical treatment and 39.5% were lost to follow-up. In total, 78 patients died during follow-up and 27 deaths were directly related to PJI/complications during treatment. Patients with inlying “standard”-implants (p < 0.001) and without previous history of PJI (p = 0.002) displayed a significantly higher postoperative revision-free implant survival. In terms of the PJI-TNM subclassification, patients with loosened implants but without soft-tissue defects (T1) displayed the highest revision-free implant survival. In contrast, patients classified as M3 (no surgical treatment possible) displayed an inferior outcome compared to M0, M1, or M2. Patients with different N-subclassifications (“non-human cells”/causative pathogen) did not display differences in revision-free implant survival. Conclusions: The PJI-TNM classification is well suited to classify PJIs. Its complexity allows for more than 500 different combinations of classifications. Further validation data are needed, but to us, the PJI-TNM classification seems to offer the possibility of comparing patients with PJIs. It may, therefore, be a very valuable tool in order to compare cohorts with PJIs and provide individual data for patient specific outcomes. Full article

Diffuse large B-cell lymphoma (DLBCL), recognized as the most prevalent variant of adult non-Hodgkin lymphoma, presents considerable challenges in diagnosis owing to its diverse morphological features and frequent extranodal involvement, which may frequently mimic nonhematopoietic neoplasms. The 2022 WHO Classification of Lymphoid and Hematopoietic Tissues provides essential updates, highlighting the necessity of combining morphology, immunohistochemistry, cytogenetics, and molecular testing for precise subclassification. This review presents a practical method for differentiating DLBCL from other aggressive B-cell neoplasms, such as Burkitt lymphoma, B-lymphoblastic lymphoma, and mantle cell lymphoma. It highlights vital diagnostic tools, including CD45, B/T-cell markers, germinal center markers, and the Hans algorithm, as well as the role of FISH in identifying rearrangements of key genes MYC, BCL2, and BCL6, which are significant for recognizing double-hit and triple-hit lymphomas. Special focus is given to EBV-associated DLBCL and uncommon subtypes featuring plasmablastic or ALK-positive traits. This review aims to enhance diagnostic accuracy and ensure appropriate treatment strategies for patients with large B-cell lymphomas by emphasizing thorough morphological evaluation, specific adjunct testing, and adherence to the most recent classification standards. Full article

Background/Objectives: The 2022 European LeukemiaNet (ELN 2022) is a widely used genotypic risk classification tool for the treatment and prognostication of acute myeloid leukemia (AML) patients. Our study evaluates its effectiveness in categorizing adverse-risk AML patients on standard therapy based on their overall survival (OS). Methods: We conducted a retrospective study involving 256 AML patients. Results: Those in the ELN 2022 adverse-risk group had the shortest OS (p < 0.0001) and were predominantly characterized by myelodysplasia-related (MR) mutations, complex karyotype (CK), monosomal karyotype (MK), and TP53 mutation (TP53 Mut). Subclassification and analysis of this adverse-risk group based on the TP53 Mut status revealed a significantly shorter OS compared to the adverse TP53 wild-type (TP53 WT) counterparts (p = 0.0036). We propose refining the ELN 2022 adverse-risk group into two categories, adverse TP53 Mut and adverse TP53 WT groups, to represent adverse- and ultra-adverse-risk groups, respectively. We used an external validation dataset to confirm our findings. Conclusions: This refinement allows for a more accurate classification of these adverse-risk patients based on their clinical outcomes. Full article

Background: Intracranial atherosclerotic stenosis (ICAS) is a leading cause of ischemic stroke, particularly in the anterior circulation. Understanding the underlying stroke mechanisms is essential for guiding personalized treatment strategies. This study proposes an integrated framework that combines CT perfusion imaging, vascular anatomical features, computational fluid dynamics (CFD), and machine learning to classify stroke mechanisms based on the Chinese Ischemic Stroke Subclassification (CISS) system. Methods: A retrospective analysis was conducted on 118 patients with intracranial atherosclerotic stenosis. Key indicators were selected using one-way ANOVA with nested cross-validation and visualized through correlation heatmaps. Optimal thresholds were identified using decision trees. The classification performance of six machine learning models was evaluated using ROC and PR curves. Results: Time to Maximum (Tmax) > 4.0 s, wall shear stress ratio (WSSR), pressure ratio, and percent area stenosis were identified as the most predictive indicators. Thresholds such as Tmax > 4.0 s = 134.0 mL and WSSR = 86.51 effectively distinguished stroke subtypes. The Logistic Regression model demonstrated the best performance (AUC = 0.91, AP = 0.85), followed by Naive Bayes models. Conclusions: This multimodal approach effectively differentiates stroke mechanisms in anterior circulation ICAS and holds promise for supporting more precise diagnosis and personalized treatment in clinical practice. Full article

Monteggia fractures represent complex injuries requiring careful assessment and surgical intervention. This case report presents a rare variation of a Bado type I Monteggia fracture–dislocation that resembles features from the Jupiter subclassification type IID. A 39-year-old male sustained a high-energy injury while riding an all-terrain vehicle, resulting in a proximal segmental ulnar shaft fracture with anterior radial head dislocation. Open reduction and internal fixation (ORIF) of the ulna using a pre-contoured proximal ulna low-contact dynamic compression plate (LC-DCP) successfully restored alignment, leading to spontaneous reduction of the radial head. The postoperative course was uneventful, with satisfactory healing and functional recovery. This case underscores the importance of meticulous ulnar reconstruction in Monteggia fracture–dislocations and contributes to the limited literature on anterior radial head dislocation patterns. Full article

While major advances in the subclassification of Bantu languages have been made thanks to comprehensive, lexicon-based classifications, there are still several important uncertainties obscuring not only the diachronic linguistic processes that gave rise to Bantu diversification, but also the population dynamics of ancestral Bantu speakers underlying them. In this paper, we address one of these persisting mysteries of Bantu genealogy, i.e., the unclassified Yeyi (R41) language of southern Africa. While the Bantu origin of Yeyi is straightforward and undisputed, its closest relatives are unknown, as is the major Bantu branch to which it belongs. We use a lexicon-based, Bayesian phylogenetic approach, comparing Yeyi to languages of the wider geographic region, including even more far-flung languages that have previously been hypothesized to bear a close relationship to Yeyi. The resultant linguistic phylogeny shows that Yeyi is part of the Wider Eastern Bantu branch as its own clade with Narrow Eastern Bantu languages as its closest relatives and none of its nearest neighbors. We argue that this relatively isolated position of Yeyi within Eastern Bantu suggests an early migration into southern Africa from the putative Wider Eastern Bantu homeland, which was followed by the loss of Yeyi’s putative earlier sister languages, presumably through a shift to Bantu languages spoken by more recent migrants. Full article

Background: Usher syndrome (USH), the most common cause of combined deaf-blindness, is a genetically and phenotypically heterogeneous disorder characterized by congenital hearing impairment and progressive vision loss due to rod-cone dystrophy. Although the original classification in three subtypes (USH I, USH II, and USH III) is still valid, recent findings have changed and widened perspectives in its classification, genotype–phenotype correlations, and management strategies: Objective: This study aims to provide new insights into the classification of Usher syndrome, explore the genotype-phenotype correlations, and review current and emerging management strategies. Methods: A comprehensive literature review has been conducted, incorporating data from clinical studies, genetic databases, and patient registries. Results: Recent studies have led to the identification of several novel pathogenic variants in the USH genes, leading to refined subclassifications of Usher syndrome. Interactions between different genes being part of the network of this ciliopathy have been investigated and new mechanisms unveiled. Significant correlations were found between certain genotypes and the presentation of both auditory and visual phenotypes. For instance, pathogenic variants in the MYO7A gene (USH1B) were generally associated with more severe hearing impairment and earlier onset of retinal dystrophy, if compared to other USH genes-related forms. Other genes, such as USH1G, traditionally considered as causing a specific subtype, can display phenotypic heterogeneity in some patients. Conclusions: This review provides insights into a better understanding of Usher syndrome that considers recent findings regarding its genetic causes and clinical features. Precise genotype–phenotype correlations can lead to better genetic counselling, more precise characterization of the natural history of the condition, and a personalized and effective management approach. Recent progress has been made in research into gene-specific therapies that appear promising for improving the quality of life for individuals affected by Usher syndrome. Full article

Immunotherapy is becoming a promising strategy for treating diverse cancers. However, it benefits only a selected group of gastric cancer (GC) patients since they have highly heterogeneous immunosuppressive microenvironments. Thus, a more sophisticated immunological subclassification and characterization of GC patients is of great practical significance for mRNA vaccine therapy. This study aimed to find a new immunological subclassification for GC and further identify specific tumor antigens for mRNA vaccine development. First, deep autoencoder (AE)-based clustering was utilized to construct the immunological profile and to uncover four distinct immune subtypes of GC, labeled as Subtypes 1, 2, 3, and 4. Then, in silico prediction using machine learning methods was performed for accurate discrimination of new classifications with an average accuracy of 97.6%. Our results suggested significant clinicopathology, molecular, and immune differences across the four subtypes. Notably, Subtype 4 was characterized by poor prognosis, reduced tumor purity, and enhanced immune cell infiltration and activity; thus, tumor-specific antigens associated with Subtype 4 were identified, and a customized mRNA vaccine was developed using immunoinformatic tools. Finally, the influence of the tumor microenvironment (TME) on treatment efficacy was assessed, emphasizing that specific patients may benefit more from this therapeutic approach. Overall, our findings could help to provide new insights into improving the prognosis and immunotherapy of GC patients. Full article

Purpose: Existing T3 subclassifications for upper tract urothelial cancer (UTUC) are limited by heterogeneity and a primary focus on renal pelvis tumors. Our study aimed to propose a novel pT3 subclassification system specifically tailored to pT3 UTUC patients. Materials and Methods: This study analyzed 120 pT3 UTUC cases from a Taiwanese multicenter registry, using a standardized pathology report and a single pathologist for evaluation. Results: Univariate analysis revealed survival differences based on existing subclassifications. Multivariate analysis identified concurrent fat and parenchyma invasion as an independent predictor of worse overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Conclusions: This study proposes a novel pT3 subclassification incorporating fat and parenchyma invasion, applicable to all UTUC sites. This subclassification may improve risk stratification, guide treatment decisions, and ultimately enhance patient outcomes. Full article

Vulvar carcinoma is a rare disease, meeting the criteria for a “rare cancer”, but its incidence is increasing, especially in women <60 years of age. Squamous cell carcinoma (VSCC) accounts for the overwhelming majority of vulvar carcinomas and is the focus of this review. As with many cancers, the increased understanding of molecular events during tumorigenesis has led to the emergence of the molecular subclassification of VSCC, which is subclassified into tumors that arise secondary to high-risk human papillomavirus infection (HPV-associated, or HPVa) and those that arise independently of HPV (HPVi), most commonly in the setting of a chronic inflammatory condition of the vulvar skin. This latter group of HPVi VSCC arises in most cases secondary to mutations in TP53, but recently, attention has focused on the uncommon TP53 wild-type HPVi VSCC. These three molecular subtypes of VSCC (HPVa, HPVi p53 abnormal, and HPVi p53 wild type), as well as their precursor lesions, cannot be diagnosed based on a routine histopathological examination or immunostaining for p53 and p16 as surrogate markers for TP53 mutation and high-risk HPV infection, respectively, are required. The molecular subtyping of VSCC shows high reproducibility and provides important prognostic information. HPVa VSCC has the most favorable prognosis, while HPVi VSCC with TP53 mutations (p53abn) has the worst prognosis, and HPVi VSCC with wild-type TP53 (p53wt) has an intermediate prognosis. In this review, we discuss the evidence supporting this molecular subclassification and its implications for the diagnosis and treatment of VSCC and its precursors. Full article