Thyroid nodules are common, affecting approximately 50% of individuals. These nodules are often discovered incidentally and exhibit benign characteristics. Following a suspicious ultrasound, a fine-needle aspiration biopsy (FNAB) is performed to assess the risk of malignancy. However, approximately 30% of cases are classified as indeterminate by cytology. In response, the development of molecular tests has refined malignancy risk assessment and reduced the need for diagnostic surgeries. To independently evaluate the real-world clinical utility and the diagnostic performance of a microRNA-based molecular test (mir-THYpe full) in improving diagnostic accuracy and avoiding unnecessary surgeries in indeterminate thyroid nodules. This is the first external, independent, prospective, real-world, observational, and non-interventional validation study of this molecular classifier. A total of 256 patients with nodules classified as Bethesda III/IV were analyzed. The test was positive for malignancy in 90 patients, 79 (90%) of whom underwent surgery. Of the 158 test-negative nodules, 7 (4.4%) underwent thyroidectomy. The test demonstrated a sensitivity of 83.0%, a specificity of 83.5%, a positive predictive value (PPV) of 62.8%, and a negative predictive value (NPV) of 93.6%. The mir-THYpe full molecular test supported 95.5% of clinical decisions when negative and 89,8% when positive, reducing surgery rates by 79.5%. Therefore, the integration of this microRNA-based classifier into clinical practice represents a valuable tool in managing indeterminate thyroid nodules, reducing unnecessary thyroidectomies, and conserving valuable healthcare resources.

The FIGO 2023 staging system of endometrial cancers (ECs) encourages integration of molecular classification with traditional histopathologic parameters for better prognostication and improved treatment decisions; however, limited availability of molecular profiling hinders its universal adoption. We aimed to assess the impact of adding molecular classification on stage migration, risk-group stratification (ESGO/ESTRO/ESP), and adjuvant treatment protocols using FIGO 2023 vs FIGO 2009 staging. A total of 234 ECs were staged using FIGO 2023 and 2009 staging by either histomorphology alone ("Molecular classification unknown group"; n = 130/234), or by complete morpho-molecular categorization ("Molecular classification known group"; n = 104/203, using Sanger sequencing for POLE mutation, with immunohistochemistry for p53 and Mismatch-repair proteins). Significant stage shifts were noted with FIGO 2023, impacting chiefly low stage (stage I and II) ECs, with stage upshifts predominating over downshifts. Without molecular categorization, tumor stage upshifted in 12.3% and downshifted in 1.5% cases. Complimenting morphology with molecular categorization increased the proportion of stage shifts by 9.3%, with 21.2% upshifts and 1.9% downshifts. Both morphology (aggressive histology, substantial LVSI, tumor location) and molecular profile (p53abn/POLE mutation) contributed to stage shifts. Molecular classification changed prognostic risk-groups in 12.5 (13/104) vs 2.3% (3/130) patients without molecular profiling, potentially impacting adjuvant treatment protocols. Majority of patients with altered risk stratification could potentially benefit from a more aggressive treatment approach, while few patients could benefit from potential treatment de-escalation. Our results indicate that integrated morpho-molecular FIGO 2023 staging significantly impacts both stage and risk group stratification, and will benefit EC patients, particularly in high-grade early stage ECs, with potential treatment implications. Further comprehensive studies are needed to fully establish the implications of molecular classification in the FIGO 2023 staging system.

Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) is characterized by solid basaloid morphology, geographic necrosis, and shadow cells, often associated with CTNNB1 mutations and aberrant β-catenin expression, exhibiting aggressive behavior. However, high-grade endometrial carcinomas with similar solid basaloid/geographic necrosis (SB-GN) features may overlap diagnostically with PiMHEC. This study aimed to investigate the clinicopathological and molecular characteristics of endometrial carcinomas with SB-GN and compare them with PiMHEC. Eighteen endometrial carcinomas with SB-GN (including 6 PiMHECs) were diagnosed in Fudan University Shanghai Cancer Center. Histopathological, immunohistochemical, and molecular features based on next-generation sequencing were reviewed. In our cohort, recurrence/metastasis occurred early (median: 5months; range: 0-21). Most cases had classic basaloid tumor cells with solid growth pattern. Spindle-shaped cells or tumor cells with more cytoplasm were occasionally observed. Twenty-eight percent of patients had squamous differentiation and 33% had shadow cells. In solid components, aberrant β-catenin expression was observed in 77.8% of cases. Eighty-three percent harbored CTNNB1 exon 3 mutations (frequent co-mutations: PTEN, ARID1A, PIK3CA). Molecular classification revealed 28% MMR-deficient, 22% POLE-mutated, 6% p53-abnormal, and 44% no specific molecular profile (NSMP). Endometrial carcinomas with SB-GN showed no significant differences compared to PiMHECs, except for higher PR positivity in solid components (58.3% vs. 0%, p = 0.046). Endometrial carcinomas with SB-GN represent a distinct and aggressive tumor group characterized by solid growth pattern, prominent necrosis, frequent basaloid morphology, high rates of CTNNB1 mutations, and aberrant β-catenin staining. Our results demonstrate that endometrial carcinomas with SB-GN and PiMHECs share similar clinicopathologic and molecular profiles, supporting a unified biological spectrum.

Heart allograft rejection: molecular diagnosis using intra-graft targeted gene expression profiling.

CPX-351 is a standard front-line induction regimen for newly diagnosed acute myeloid leukaemia (AML) with myelodysplasia-related changes (AML-MRC). The 2022 International Consensus Classification (ICC) and World Health Organization (WHO) classifications redefine AML with myelodysplasia-related (AML-MR) to include myelodysplasia-related mutations as well as cytogenetic abnormalities. Clinical outcomes of patients treated with CPX-351 within these refined AML-MR classifications remain unclear. We conducted a retrospective, multicentre study of 235 adults with newly diagnosed AML-MR treated with CPX-351 across seven US academic centres. Patients were stratified by age (younger: <60 vs. older: ≥60 years) and AML-MR subgroup: cytogenetics (AML-MRc), molecular (AML-MRm) and antecedent haematological disorder (AML-AHD). Outcomes included complete remission (CR) and CR with incomplete recovery (CR/CRi), rates of allogeneic haematopoietic stem cell transplant (alloHSCT) and overall survival (OS). The overall CR/CRi rate of CPX-351 was 52%, with no difference by age. AML-MRm had the highest CR/CRi rate (57%). Among CR/CRi responders, 55% underwent alloHSCT (<60 years: 53% vs. ≥60 years: 57%). Median OS was 13.8 months with no significant difference by age. Younger AML-MRm patients had longer median OS compared with older AML-MRm patients (38.0 vs. 19.5 months; p = 0.05). Favourable outcomes in AML-MRm, particularly in younger patients, support molecular classification in guiding therapy and selectively extending CPX-351 use beyond older adults.

Endometrial cancer is the sixth most common cancer in women worldwide and the fourth most common cancer in women in the United States. In the United States, its incidence and mortality rates have continued to increase since the late 1990s. Endometrial cancer comprises most uterine corpus carcinomas and represents a heterogeneous group of cancers varying in pathology, histology, molecular biology, immunogenicity, and prognosis. Recently, the advancement of molecular classification and subsequent clinical trials have led to new FDA approvals for the use of immune checkpoint inhibitors in endometrial cancer. However, recurrent and advanced-stage endometrial cancer continues to demonstrate high morbidity and mortality, denoting an unmet need for innovative immunotherapeutic strategies. This review explores current concepts in the endometrial cancer tumor immune microenvironment, comparing antigenicity, immunosurveillance, and immunoregulation among molecular and histologic subtypes and providing insight into which subtypes may be particularly responsive to immunotherapy. Novel immunotherapeutic strategies targeting cancer antigens, emerging immune checkpoints, immunomodulatory cytokines, and tumor-infiltrating immune cells are described, and corresponding clinical trials are presented. Integrated approaches such as immunogenic modulation, which enhances tumor susceptibility to immune attack, and immune subset conditioning, which modifies suppressive immune components within the tumor immune microenvironment, are presented as promising avenues to render "cold" tumors responsive. Together, the immunotherapies reviewed here offer potential strategies for treating patients with advanced or refractory endometrial cancer.

A comprehensive analysis of optimizers in message passing neural networks for molecular property prediction task.

An enhancement of multi-scope topological graph pooling and representation learning with attention for molecular graph classification.

Recent advances in radionuclide drug conjugates (RDCs) for cancer theranostics: From targeted design to clinical translation.

BackgroundThe Cancer Genome Atlas (TCGA) molecular classification has advanced risk stratification for endometrial carcinoma but has demonstrated comparable survival outcomes between the microsatellite instability (MSI) and copy-number low (CN-L) subtypes. In this study, we aimed to identify potential autophagy-related molecular signatures to increase the precision of TCGA-based prognostic stratification in early-stage endometrial carcinoma.MethodsUnivariate Cox regression analysis of the TCGA-Uterine Corpus Endometrial Carcinoma cohort was used to identify autophagy-related genes associated with survival outcomes in patients with endometrial carcinoma. The candidates were analyzed by the Kaplan-Meier method. Multivariate Cox regression was used to assess whether PEA15 served as an independent prognostic factor, especially for the MSI and CN-L subtypes. We examined the correlation between PEA15 protein expression and patient survival through immunohistochemical analysis of tissue microarrays from our institutional cohort of stage I endometrial cancer patients.ResultsUnivariate analysis revealed that NRG3, PEA15, DNAJB1, BAK1, DRAM1, KLHL24, ATF6, CDKN2A, MBTPS2, and UVRAG were significantly associated with survival outcomes in early-stage endometrial carcinoma patients. Multivariate analysis established PEA15 as an independent prognostic factor. Immunohistochemical analysis of tissue microarrays revealed that elevated PEA15 expression was significantly correlated with poorer overall survival and disease-free survival. Both univariate and multivariate Cox regression confirmed high PEA15 expression as an independent prognostic factor for recurrence in patients with stage I endometrioid adenocarcinoma.ConclusionsThe autophagy-related gene PEA15 is an independent prognostic biomarker in early-stage endometrial carcinoma, improving risk stratification between the MSI and CN-L subtypes. Immunohistochemical detection has clinical potential for molecular classification, offering opportunities for personalized postoperative management strategies.

A tumor microenvironment-based classification of gastric cancer for more effective diagnosis and treatment.

A systematic framework enhancing molecular screening efficiency in drug discovery via scaffold-driven fuzzy similarity and adaptive spectral clustering.

ChiralCat: Molecular chirality classification with enhanced spatial representation using learnable queries

The molecular classification of endometrial cancer has revolutionized risk stratification, with POLE-mutated tumors recognized for their excellent prognosis. However, the optimal management of patients with nodal involvement remains unclear. This multi-center retrospective study evaluates the outcomes of patients with stage IIIC endometrial cancer with positive sentinel lymph nodes harboring POLE mutations. Of 164 POLE-mutated cases undergoing sentinel node mapping, 11 (6.7%) had nodal metastases (classified as isolated tumor cells [n = 6; 54.5%], micro-metastases [n = 3; 27.3%], or macro-metastases [n = 2; 18.2%]). All patients except 1 received adjuvant therapy, tailored according to molecular and pathologic risk factors. After a median follow-up of 7.6 months, no recurrences were observed. These findings suggest excellent short-term outcomes, even in node-positive POLE-mutated endometrial cancer. Nevertheless, the study does not support omitting adjuvant therapy in this setting. Larger studies and long-term data, such as those expected from the ongoing Refining Adjuvant treatment IN endometrial cancer Based On molecular features (RAINBO)/ Blue trial are needed to guide safe de-escalation strategies.

Gastrointestinal stromal tumors (GISTs) originate from mesenchymal precursor cells of the gastrointestinal wall and account for approximately 3% of all gastrointestinal malignancies. In adults, these tumors most commonly harbor mutually exclusive activating mutations in KIT, PDGFRA, BRAF, or SDH-family genes. KIT and PDGFRA mutations are well-established predictive biomarkers for response to tyrosine kinase inhibitors (TKIs). The advent of Next Generation Sequencing (NGS) has accelerated the identification of novel genetic alterations, improving disease characterization, providing prognostic and predictive information, and enabling detection of rare germline variants. We conducted a retrospective analysis of 31 patients with GIST to evaluate the implementation of NGS testing and the interpretation of pathogenicity in real-life clinical practice. Identified mutations were compared with publicly available databases, and rare KIT exon 11 variants underwent computational modeling to assess their impact on protein conformation and imatinib interaction. Germline testing was performed when indicated. In addition to common primary and secondary mutations in KIT and PDGFRA, three patients carried rare KIT exon 11 variants not previously classified in public databases: p.Gln556del (upstream of codons 557/559) and p.Asn566_Pro573del and p.Val569_Leu576_del (downstream), all located within the juxtamembrane (JM) domain. One patient harbored an SDHB c.287-1G⟩C alteration resulting in aberrant splicing, also detected in the germline. The structural modeling predicted that all rare KIT exon 11 variants affected protein conformation and influenced imatinib interaction. Clinically, all three variants were associated with response to imatinib and met ACMG-AMP criteria for pathogenicity as well as ASCO-CAP tier 1 classification. Our findings highlight the clinical relevance of integrating NGS into routine GIST management, particularly for the identification and interpretation of rare genetic variants. The study underscores the importance of data sharing and collective variant annotation to support accurate molecular classification, prognostic assessment, and therapeutic decision-making for individual patients.

BackgroundUpper tract urothelial carcinoma (UTUC), including renal pelvic urothelial carcinoma and ureter urothelial carcinoma, accounts for 10% of urothelial carcinoma (UC). Poorer outcomes and different genetic characteristics of UTUC were reported compared to urothelial carcinoma of the bladder (UCB), which accounts for most cases of UC. Therefore, there is an urgent need for the development of molecular characterization and precision therapies tailored specifically for UTUC.MethodsTo elucidate the genetic landscape of UTUC, we included 4 UTUC samples in this study and also perform next-generation sequencing (NGS) of whole exome sequencing. After that, long-read sequencing (LRS) was employed to conduct Whole genome sequencing (WGS) analyses on tumor samples obtained from the four UTUC patients, utilizing the Pacific Biosciences (PacBio) REVIO platform.ResultsThe clinical phenotypes of four UTUC patients including tumor stage, location and response to treatment, etc. were collected. NGS of four patients yielded negative results. The WGS mapped the mutation landscape in the tumor tissues of four UTUC patients, and screened the sequencing results according to UTUC and solid tumor related genes. Seven pathogenic or likely pathogenic single nucleotide variant (SNV) were obtained. Among the detected structural variations (SVs), four patients shared multiple segments of SVs with close positions. The 12q24.31-p11.1 inversion was shared by four patients. In the detection of STR and DNA methylation, comparing the results of patients and normal controls, many different fragments were obtained. It shows that LRS has important advantages over NGS for accurate tumor detection and treatment.ConclusionThe analysis revealed multiple genetic variants potentially associated with UTUC carcinogenesis or development, and indicated advantages of TGS over next-generation sequencing (NGS) in cancer genetic variant detection, especially in SV and Short Tandem Repeats (STRs). This study may lay the groundwork for molecular classification and offer valuable insights into the development of precision therapies for UTUC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-15254-x.

Geographical differentiation of onions (Allium cepa) cultivated in South Korea revealed by untargeted metabolomics and chemometric analysis.

This study aimed to evaluate the correlations between programmed death-ligand 1 (PD-L1) expression, the mismatch repair system, and p53 status in endometrial cancer, considering tumor stage. A retrospective analysis of clinicopathological and immunohistochemical data was conducted on 254 patients treated at Holy Cross Cancer Centre (Poland). The majority of patients had endometrioid adenocarcinoma (89.8%) and FIGO stage I disease (69.7%). Positive PD-L1 expression (threshold ≥ 1%) was observed in only 3.9% of cases, while mismatch repair system deficiency and aberrant p53 expression were present in 18.1% and 17.3%, respectively. No significant correlations were found between PD-L1 expression and clinicopathological parameters, repair system status, or p53 (p = 0.328 and p = 0.359, respectively). However, a significant association (p = 0.046) was noted between PD-L1 positivity and the microsatellite-unstable/hypermutated molecular subtype, with 30% of PD-L1 positive tumors exhibiting this subtype compared to 10.2% of PD-L1 negative tumors. No molecular marker demonstrated a significant association with recurrence risk (p > 0.05), in contrast to the FIGO stage, which showed a significant correlation (p < 0.001). Although PD-L1 expression was rare, it was significantly associated with microsatellite instability, highlighting the potential of molecular classification to identify candidates for immunotherapy. However, the low frequency of PD-L1 positivity and the small sample size warrant caution in interpreting these findings, and further research is needed to confirm the clinical relevance of PD-L1 in endometrial cancer.

Ultrasensitive multifunctional biosensor integrating ECL quenching and DPV enhancement for early classification of thyroid cancer via BRAF V600E and microRNA-221 detection.

Development of a lactylation-related molecular classification and machine learning-based gene signature to predict survival, response to immunotherapy for ovarian cancer