Clinicopathological characteristics and outcomes of gastric-type adenocarcinoma of the cervix: a systematic review.

Background: Surgery represents the gold standard treatment for patients with stage I non-small cell lung cancer (NSCLC); however, up to 30% of those may experience recurrence. This study aims to identify prognostic factors for both early and late recurrence in this subset. Methods: We retrospectively analyzed the data of patients with stage IA-B NSCLC undergoing lung resection from 2013 to 2021 in four major lung cancer centers. Inclusion criteria were intentionally curative resections via either open or mini-invasive approaches plus lymph node dissection and a minimum follow-up of 36 months. Analyzed prognosticators included age, gender, smoking status, comorbidities, radiological appearance, surgical approach, intraoperative complications, pT stage and histologic subtypes. The overall and disease-free survivals and uni- and multivariable Cox regression for recurrence prediction were analyzed. Results: We collected data from 1132 consecutive patients (mean age 68.5 ± 8.8 years, 55.5% males and 20.1% smokers). After a mean follow-up of 57 ± 37 months, 908 (80.2%), patients were still disease-free, while the remaining 224 (19.8%) presented local (n = 86) or distant (n = 138) recurrences; 72 (32.1%) patients experienced reoccurrence within 12 months. The disease-free survival rate was significantly higher in the pT1a stage and in lepidic adenocarcinoma. The multivariable analysis and Cox regression showed that pT>1a (p = 0.001) and non-lepidic subtypes of adenocarcinoma (p < 0.001) were the best predictors of recurrence. Conclusions: Approximately one fifth of patients undergoing radical surgery for stage I NSCLC experienced recurrence within five years. Significant predictors of recurrence were a pT status greater than 1a and non-lepidic subtypes of adenocarcinoma.

Comprehensive immunological profiling across diverse clinical and pathological subtypes of lung adenocarcinoma

Harnessing retinoic acid metabolism-related genes to identify lung adenocarcinoma subtype and establish a risk model for predicting prognosis and drug therapy response.

Background. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases and remains a leading cause of cancer-related mortality worldwide. The emergence of targeted therapies, particularly epidermal growth factor receptor (EGFR) inhibitors such as erlotinib, has significantly changed treatment strategies for selected patient populations. Objective: To compare the clinical outcomes of EGFR-targeted therapy with erlotinib versus standard polychemotherapy in patients with advanced NSCLC. Materials and Methods: A retrospective cohort study was conducted including 56 patients with histologically confirmed NSCLC (adenocarcinoma subtype) treated at a specialized oncology center. Patients were divided into two groups: 28 received erlotinib, and 28 received platinum-based polychemotherapy. Treatment efficacy was assessed based on progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity profile. Survival analysis was performed using the Kaplan–Meier method, and statistical significance was determined using the log-rank test. Results: The median PFS was significantly longer in the erlotinib group compared to the polychemotherapy group (10.8 vs 6.4 months, p = 0.003). However, no statistically significant difference in overall survival was observed (20.4 vs 18.7 months, p = 0.28). The objective response rates were comparable between groups. Erlotinib demonstrated a more favorable safety profile, with significantly lower rates of hematological toxicity, while dermatologic adverse events were more common but manageable. Subgroup analysis showed improved outcomes in patients with EGFR mutations treated with erlotinib. Conclusion: Erlotinib provides a significant benefit in progression-free survival and exhibits better tolerability compared to polychemotherapy in patients with NSCLC, particularly in those with EGFR mutations. However, overall survival remains comparable between treatment strategies. These findings support the use of EGFR-targeted therapy as a preferred option in selected patient populations.

Gastroesophageal cancer presents variably across different age groups, with early-onset (EO) cases showing distinct pathological and clinical characteristics compared to late-onset (LO) disease. This study aims to delineate these differences and assess treatment outcomes in a Central European population. Data from patients diagnosed with gastroesophageal carcinoma and treated between 2010 and 2022, at a high-volume comprehensive cancer center representing approximately 5% of all national gastroesophageal cancer cases in the Czech Republic, were retrospectively analyzed. Patients were categorized into EO (< 50 years) and LO (≥ 50 years) groups. Clinicopathological characteristics were compared in the entire cohort, while treatment patterns and survival outcomes were evaluated in patients with adenocarcinoma. A total of 1,377 patients were included, with 161 (11.7%) classified as EO. EO patients are more frequently present with ECOG performance status 0 (42%), lower BMI, current smoking (44%), gastric cancer primaries (63%), and aggressive tumor characteristics such as poorly cohesive adenocarcinoma subtype (45%) and metastatic disease (55%). Hereditary cancer syndrome was confirmed in 4.3% of EO cases. Among adenocarcinoma patients, triplet chemotherapy was more frequently used in the EO group (29% vs. 11%, p < 0.001) in the first-line setting. However, no significant survival benefit was observed in inoperable or metastatic disease (median overall survival 9.1 vs. 9.6 months in EO and LO, respectively, p = 0.913). EO gastroesophageal cancer in the Central European population is associated with distinct clinicopathological characteristics, with no significant impact on survival. This study identifies distinct clinicopathological characteristics in early-onset gastroesophageal cancer in Central Europe, characterized by more aggressive attributes but without significant survival differences compared to late-onset cases.

Oncogene-induced senescence (OIS) is regarded a tumor suppressive mechanism in normal cells. Accumulated evidences, however, demonstrate that OIS would play a role in cancer promotion through the secretion of senescence associated secretory phenotypes (SASP). The underlying mechanisms remain to be addressed. In this study, we found that c-Myc oncogene could induce senescence in human diploid lung fibroblasts and non-small cell lung cancer cells (NSCLC) without concomitant emergence of apoptosis. c-Myc-induced senescence (cMIS) caused morphological enlargement, increased F-actin and nuclear G-actin that generally detected in senescent cells. These events were found to be associated with increased expression of cofilin-1, an actin-binding protein required for actin dynamics. Transfection of c-Myc could induce cofilin-1, but transfection of truncated Myc-Nick mutant and inhibition of c-Myc reduced cofilin-1 expression. Additionally, knockdown of cofilin-1 could suppress cMIS. The chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assay showed that the endogenous c-Myc mainly bound to two out of three predicted E-boxes located in middle and proximity to the transcription initiation site of the CFL1 promoter. Interestingly, ectopic expression of c-Myc bound to all E-boxes, especially the distal one. Furthermore, the conditioned medium (CM) collected from cells with cMIS could enhance the proliferation and migration of other NSCLC cells, whereas that obtained from cofilin-1 silencing cells with forced expression of c-Myc diminished these capacities. The c-Myc transactivated cofilin-1 could also be triggered by H2O2 through the middle E-box. Surprisingly, a physical interaction between c-Myc and cofilin-1 was detected, and H2O2 increased this effect. Clinically, high expression of both c-Myc and CFL1 genes correlated to worse survival rates among NSCLC patients, especially those with the adenocarcinoma subtype. Taken together, the c-Myc-cofilin-1 regulatory axis would explain the mechanism of OIS promoted cancer progression, and it may be a potent target for design of treatments.

Lung adenocarcinoma is classified into subtypes based on pathological features; however, the clinical and biological characteristics of each subtype, including driver mutations and programmed death-ligand 1 (PD-L1) expression, remain unclear. We aimed to clarify these characteristics. We retrospectively analyzed 1412 cases of stage I–III lung adenocarcinoma that underwent complete resection between 2004 and 2023. Clinical and biological characteristics were compared by predominant subtypes. Among the 1412 cases, the predominant subtypes were papillary (n = 686, 48.6%), lepidic (n = 317, 22.5%), acinar (n = 234, 16.6%), solid (n = 166, 11.8%), and micropapillary (n = 9, 0.6%). The lepidic subtype was more common in females (58.0% vs. 43.5%; p < 0.001), had a lower smoking rate (47.3% vs. 60.9%; p < 0.001), smaller invasive size (8 mm vs. 18 mm; p < 0.001), higher frequency of epidermal growth factor receptor (EGFR) mutation (63.4% vs. 45.2%; p < 0.001), and lower PD-L1 expression (15.5% vs. 45.2%; p < 0.001). The solid subtype was more prevalent in males (76.5% vs. 50.2%) and smokers (83.1% vs. 54.5%), with a larger invasive size (20.1 mm vs. 15.0 mm), fewer EGFR mutations (12.6% vs. 54.2%; p < 0.001), and higher PD-L1 expression (66.6% vs. 35.2%; p < 0.001). The 5-year Recurrence-free survival rates for the lepidic, acinar, papillary, and solid subtypes were 88.2, 72.9, 65.1, and 58.2%, respectively (p < 0.001). Lung adenocarcinoma subtypes present distinct clinical and pathological profiles, which may affect treatment strategies and prognostic evaluation.

Deep learning for invasive lung adenocarcinoma subtyping remains vulnerable to real-world imaging perturbations. We present a margin consistency framework evaluating 203,226 patches from 143 whole-slide images across five adenocarcinoma subtypes from the BMIRDS-LUAD dataset. Our approach integrates attention-weighted aggregation with margin-aware training, achieving strong feature-logit space alignment with Kendall correlations of 0.88 during training and 0.64 during validation. To address feature over-clustering from contrastive regularization, we introduce Perturbation Fidelity scoring that applies structured perturbations through Bayesian-optimized parameters. Vision Transformer-Large achieves 95.20±4.65 percent accuracy, representing 40% error reduction from 92.00±5.36% baseline. ResNet101 with attention mechanism reaches 95.89±5.37% from 91.73±9.23% baseline, a 50% error reduction. All five subtypes exceed 0.99 area under receiver operating characteristic curves. Cross-institutional validation on WSSS4LUAD achieves 80.1% accuracy with ResNet50 with attention mechanism, demonstrating method robustness despite approximately 15-20% performance degradation from domain shift, indicating opportunities for future domain adaptation research.

Network biology traditionally identifies gene correlations that reflect biological pathways. While LIONESS enables individualized gene networks, the influence of replication timing on these correlations remains unexplored. Replication timing reflects the temporal order of DNA synthesis and is tightly linked to chromatin state, methylation, and transcriptional stability, all of which affect tumor behavior. Integrating replication-timing proxies derived from methylation data therefore offers a bridge between epigenetic state and functional gene coordination, while morphology provides an additional route for inferring gene expression.This is the first study to integrate replication-timing proxies and morphological embeddings into individualized LIONESS gene networks. The aim is to determine how replication timing and morphology derived from bulk methylation and image embeddings influence gene coexpression in pancreatic cancer. Patient-specific networks were generated for basal and classical pancreatic ductal adenocarcinoma subtypes using TCGA data.Results show an 80% AUC for RNA-replication-timing–based subtype prediction modules and a 75% AUC for morphology-based networks. Incorporating replication timing and morphology increased network robustness while maintaining classification performance. Notably, the 80% AUC was achieved using only 17 of the 50 Moffitt genes, with 16 overlapping the PURIST gene set, indicating that replication timing captures clinically relevant regulatory structure. These findings suggest that replication-timing proxies can act as epigenetic indicators of mechanistic gene coordination and may help identify patients with distinct replication stress or chromatin accessibility profiles relevant to therapeutic response.

The exon 19 deletion (19 Del) and the exon 21 L858R point mutation (21 L858R) are two main subtypes of EGFR-mutant lung adenocarcinoma (LUAD) with distinct response to targeted treatment and immunotherapy. Understanding the intratumor heterogeneity (ITH) of EGFR-mutant LUAD may explain the reason. 157 multi-region tumor samples and matched distant normal lung tissues from 29 treatment-naïve operable EGFR-mutant LUAD patients were collected to perform whole genome sequencing, panel sequencing and whole transcriptome sequencing. We aimed to comprehensively assess genomic and transcriptomic ITH between 19 Del and 21 L858R. The 21 L858R LUAD exhibited significantly higher copy number variation (CNV) ITH index (ITHi) compared to the 19 Del LUAD, but there was no significant difference in somatic single-nucleotide variant (SNV) ITHi between them. Meanwhile, 19 Del LUAD owned more clonal genetic alterations, while 21 L858R LUAD had more subclonal events. Both linear and branch evolution models existed in 19 Del and 21 L858R LUAD. Besides, 19 Del seemed to be more dominant for driving tumor development, while other driver mutations participated jointly with 21 L858R in tumor evolution. Moreover, 19 Del LUAD exhibited significantly higher immune score and checkpoint inhibition signature than 21 L858R. Additionally, it indicated that high-level TMB might be a favorable prognostic factor for EGFR-mutant LUAD. Our study demonstrated diverse genomic heterogeneity and tumor immune microenvironment in EGFR-mutant LUAD, which might elaborate on potential explanations for different efficacy between 19 Del and 21 L858R and provide valuable hints to treatment strategy.

The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is highly lethal and therapy resistant. A better understanding of the underlying molecular mechanisms driving this aggressive tumor subtype is necessary for the development of effective therapies. Notably, upregulation of keratin 17 (K17) in cancer is associated with poor patient outcome and the basal-like PDAC subtype. Here, we identified a critical dependency of basal-like PDACs on de novo pyrimidine biosynthesis, driven by intra-mitochondrial K17. Mechanistically, K17 translocated into the mitochondrial intermembrane space via a mitochondrial localization sequence (MLS) recognized by the translocase of the outer mitochondrial membrane 20 (TOM20). In the mitochondria, K17 bound to and stabilized dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of de novo pyrimidine biosynthesis, by preventing its ubiquitination-mediated degradation. Blocking the entry of K17 into the mitochondria sensitized cancer cells to gemcitabine, a pyrimidine analog and standard chemotherapeutic agent. In animal studies, pharmacologic inhibition of DHODH combined with gemcitabine treatment decreased tumor growth and doubled survival in mice bearing K17⁺ but not K17⁻ PDAC. These findings define a mitochondrial role for K17 in driving pyrimidine biosynthesis and uncover a metabolic vulnerability in K17⁺ basal-like PDACs that can be therapeutically targeted.

Boron neutron capture therapy (BNCT) is an emerging binary targeted radiotherapy modality. This study evaluates the therapeutic potential of boronophenylalanine (BPA)-mediated BNCT in cervical cancer and to elucidate its underlying molecular mechanisms. A comprehensive set of in vitro and invivo approaches was employed using cervical cancer cell lines (HeLa, SiHa) and normal cervical epithelial cells (H8). The experimental techniques included clonogenic assays, flow cytometry, Western blotting, immunohistochemistry, and xenograft mouse models to assess cytotoxicity, boron uptake, DNA damage response, apoptosis, and therapeutic efficacy. Cervical cancer cells exhibited significantly higher L-type amino acid transporter 1 (LAT1) expression compared with normal controls, which correlated with enhanced BPA uptake. BPA-BNCT induced profound, dose-dependent cell death and reversed the conventional radiotherapeutic sensitivity profiles between cancer and normal cells. Notably, BNCT demonstrated selective cytotoxicity across different pathological subtypes of cervical cancer, with enhanced therapeutic efficacy observed in adenocarcinoma-a subtype typically resistant to conventional radiotherapy. Mechanistically, BNCT triggered complex DNA double-strand breaks that overwhelmed cellular repair mechanisms, despite robust activation of both homologous recombination (via RAD51) and nonhomologous end joining (via KU70/80). This irreparable DNA damage resulted in G2/M phase arrest and activation of the mitochondrial apoptosis pathway. In xenograft models, BPA-BNCT achieved significant tumor growth suppression and substantially prolonged survival, while maintaining a wide therapeutic window and showing no evidence of systemic toxicity. BPA-BNCT exerts potent and selective antitumor effects against cervical cancer through a dual mechanism: LAT1-mediated boron delivery ensures tumor specificity, while the resulting high-linear energy transfer radiation induces DNA damage that capitalizes on the inherent limitations of the tumor cells' DNA repair capacity, leading to catastrophic cell death. The therapy demonstrates a distinct advantage in treating adenocarcinoma subtypes, which are typically less responsive to conventional radiotherapy. These findings provide robust preclinical evidence supporting BNCT as a promising therapeutic approach, particularly for radiotherapy-resistant cervical adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a complex tumor microenvironment. Although the class-3 semaphorin (SEMA3) gene family has been implicated in tumor progression and immune regulation, its specific role and clinical relevance in PDAC are not yet fully understood. Multi-omics data from public cohorts (TCGA and GEO) were integrated to perform unsupervised clustering based on SEMA3 family expression.A prognostic risk model was constructed using univariate Cox and LASSO regression, and validated in an independent cohort. Immune infiltration, mutation profiling, and drug sensitivity analyses were conducted. Single-cell and spatial transcriptomic data were used to characterize the expression and spatial distribution of SEMA3 genes at cellular resolution. Two molecular subtypes with distinct survival outcomes were identified. A nine-gene prognostic signature was established, effectively stratifying patients into high- and low-risk groups with significant survival differences. High-risk patients exhibited an immunosuppressive microenvironment, higher tumor mutational burden, and increased KRAS mutation frequency. Drug sensitivity analysis revealed subtype-specific therapeutic vulnerabilities. Single-cell and spatial transcriptomic analyses revealed that SEMA3 family genes modulate immune cell infiltration and spatial immune heterogeneity within the tumor microenvironment. Single-cell and spatial transcriptomics highlighted SEMA3C as a key mediator highly expressed in malignant and stromal cells, with spatially restricted patterns suggesting its role in modulating cell-cell communication and immune evasion. This study underscores the prognostic and immunological significance of SEMA3 family genes in PDAC. The developed risk model and nomogram demonstrate robust predictive ability, while SEMA3C emerges as a promising therapeutic target. Our findings provide insights into the heterogeneity of PDAC and support the development of personalized treatment strategies.

Effective diagnosis and treatment of lung adenocarcinoma depends on accurate typing, subtyping, and grading. Herein, we present the CLWD dataset, a valuable resource for the lung cancer pathology community, comprising 408 whole-slide images (WSIs) from 210 patients specifically curated for the study of lung adenocarcinoma subtypes. Scanned at 80 × magnification, it is one of the largest datasets in Asia, with a particular emphasis on Chinese patient demographics. Notably, the dataset includes comprehensive clinical information, such as age, sex, and diagnosis, providing a robust foundation for diverse research needs. Publicly accessible, it supports a range of applications, including machine learning model development and validation. An initial evaluation of lung adenocarcinoma subtype classification using a multi-instance learning framework demonstrated that this dataset can substantially advance global research and improve the accuracy of subtype diagnosis.

Primary pulmonary enteric adenocarcinoma: A single-institute retrospective study on its imaging classification and survival outcomes.

Pancreatic Acinar Cell Carcinoma (PACC) are a uncommon histological subtype (around 1-2%) of pancreatic adenocarcinoma. These tumors derive from acinar cells and may be associated with mixed histologies such as neuro-endocrine or ductal excreto-pancreatic contingents. The histological diagnosis of acinar differentiation relies on morphology and immunohistochemistry using anti-BCL10 immunohistochemical staining. Due to the low prevalence of PACC, dedicated studies are difficult to conduct and PACC management is similar to that of ductal adenocarcinoma (PDAC) in international guidelines. Retrospective studies appear to show larger but less aggressive tumors, with fewer lymph node involvement and a more favorable prognosis than PDAC. Recent research also highlighted a different carcinogenesis. Unlike PDAC, KRAS mutations are unfrequent, but Homologous Recombination Deficiencies (HRD) are commonly found (30% of cases). In most cases, they are associated with germline mutations, notably BRCA2, which may offer an opportunity for genetic counselling. Other molecular alterations, such as BRAF (approximately 3%) or MMR deficiency (2-4%), have also been reported. Thus, the identification of pancreatic acinar cell carcinoma should trigger theranostic molecular analyses for treatment personalization.

We report a case of GALT-associated carcinoma, a rare morphological variant of colorectal adenocarcinoma characterised by cystic glands containing eosinophilic material, set within dense lymphoid stroma with germinal centres. Since its first description in 1999, only 26 cases have been documented. Its association with lymphoid tissue, the presence of intraepithelial lymphocytes, and the absence of goblet cells led to the hypothesis that it may originate from M-cells located in the dome epithelium of gut-associated lymphoid tissue, hence the alternative term "dome-type carcinoma". Through detailed histological, immunohistochemical, ultrastructural and molecular analyses of our case, supported by a comprehensive literature review, we found no evidence supporting M-cell differentiation: intraepithelial B lymphocytes were absent, GP2 immunostaining was negative and ultrastructural features were inconsistent with M-cell morphology. Nevertheless, the lesion's pushing growth pattern, lack of high-risk histopathological features and indolent behaviour justify its recognition as a distinct morphological subtype of colorectal cancer.

A multicenter external validation of Lung-PNet: Classification of pure ground-glass nodules into invasive adenocarcinoma and non-invasive subtypes on chest CT images

ABSTRACT Background Pancreatic ductal adenocarcinoma (PDAC) lacks a reliable diagnostic biomarker, largely due to its asymptomatic onset and frequent late-stage detection, resulting in a poor 5-year survival rate. Identifying biomarkers for timely diagnosis is critical. Cancer cells display distinct protein regulation changes that drive disease hallmarks, and characterizing these across PDAC subtypes may provide insights into disease progression. Research design and methods In this study, a label-free quantitative (LFQ) proteomics approach using mass spectrometry (MS) was employed to profile circadian rhythm-regulated proteins in the secretome of PDAC cell lines. Results LFQ analysis revealed rhythmic protein regulation patterns, reflecting temporal control of biological processes in PDAC. Upregulated pathways included signal transduction, glycolysis, angiogenesis, and protein synthesis, indicating enhanced metabolic and proliferative activity. Downregulated immune pathways suggested potential immune modulation. Comparative analysis revealed subtype-specific patterns: the quasi-mesenchymal subtype exhibited higher levels of metabolic and extracellular matrix (ECM) remodeling proteins, while the classical subtype showed higher levels of ECM-degrading proteins, consistent with known phenotypic differences. Conclusion These findings highlight rhythmically regulated proteins as potential subtype-specific markers in PDAC and provide a basis for future validation studies. Mass spectrometry proteomics data are available via the ProteomeXchange Consortium (PRIDE: PXD054693).