Search Results (168)

Background/Objectives: Aberrant expression of high-mobility group protein B1 (HMGB1) has been linked to cancer development and progression. Methods: To better comprehend the role of HMGB1 expression in cancer, a tissue microarray containing 14,966 samples from 134 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Results: Strong HMGB1 staining occurred in almost all normal cell types and in most cancers. Of 11,808 evaluable cancers, only 7.8% showed complete absence of HMGB1 staining (HMGB1 deficiency) while 9.9% showed 1+, 25.0% showed 2+, and 57.2% showed 3+ HMGB1 positivity. Absence of HMGB1 staining mostly occurred in pheochromocytoma (90.0%), seminoma (72.4%), gastrointestinal stromal tumor (28.6%), adrenal cortical carcinoma (25.0%), and Hodgkin’s lymphoma (25.0%). Low HMGB1 staining was linked to poor histologic grade (p < 0.0001), advanced pT stage (p < 0.0001), high UICC stage (p < 0.0001), and distant metastasis (p = 0.0413) in clear cell renal cell carcinoma, invasive tumor growth in urothelial carcinoma (pTa vs. pT2–4, p < 0.0001), mismatch repair deficiency (p = 0.0167) in colorectal cancers, and advanced pT stage in invasive breast carcinoma of no special type (p = 0.0038). Strong HMGB1 staining was linked to nodal metastases in high-grade serous ovarian carcinomas (p = 0.0213) and colorectal adenocarcinomas (p = 0.0137), as well as to poor histological grade in squamous cell carcinomas (p = 0.0010). Conclusions: HMGB1 deficiency and reduced HMGB1 expression occur in a broad range of different tumor entities. Low rather than strong HMGB1 staining is often linked to an aggressive tumor phenotype. Whether HMGB1 deficiency renders cells susceptible to specific drugs remains to be determined. Full article

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with poor prognosis, particularly in metastatic cases. The Ki-67 proliferation index is a recognized marker of tumor aggressiveness, yet its role in guiding diagnostic imaging and surgical decision-making remains underexplored. This study evaluates Ki-67’s predictive value for metastasis at diagnosis, leveraging artificial intelligence (AI) to inform personalized, minimally invasive strategies for ACC management. Methods: We retrospectively analyzed 53 patients with histologically confirmed ACC from the Adrenal-ACC-Ki67-Seg dataset in The Cancer Imaging Archive. All patients had Ki-67 indices from surgical specimens and preoperative contrast-enhanced CT scans. Descriptive statistics, t-tests, ANOVA, and multivariable logistic regression evaluated associations between Ki-67, tumor size, age, and metastasis. Random Forest classifiers—with and without the Synthetic Minority Oversampling Technique (SMOTE)—were developed to predict metastasis. A Ki-67-only model served as a baseline comparator. Model performance was assessed using the area under the curve (AUC) and DeLong’s test. Results: Patients with metastatic disease had significantly higher Ki-67 indices (mean 39.4% vs. 21.6%, p < 0.05). Logistic regression identified Ki-67 as the sole significant predictor (OR = 1.06, 95% CI: 1.01–1.12). The Ki-67-only model achieved an AUC of 0.637, while the SMOTE-enhanced Random Forest achieved an AUC of 0.994, significantly outperforming all others (p < 0.001). Conclusions: Ki-67 is significantly associated with metastasis at ACC diagnosis and demonstrates independent predictive value in regression analysis. However, integration with machine learning models incorporating tumor size and age significantly improves overall predictive accuracy, supporting AI-assisted risk stratification and precision imaging strategies in adrenal cancer care. Full article

Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug—drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation. Full article

HSD3B1 encodes an enzyme that catalyzes the conversion of adrenal precursors into potent sex steroids. A common germline variant (c.1100C) enhances this effect and is linked to breast cancer (BC) progression. As the HSD3B1 genotypes contribute to differences in local and adrenal steroid production, their transcriptional and phenotypic effects on cancers influenced by hormonal signaling such as BC and endometrial cancer (EC)—particularly in relation to menopausal status—remain unclear. We analyzed BC and EC sequenced from patients that received diagnostic tests in oncology clinics, and we determined the germline HSD3B1 c.1100 genotype (AA, AC, CC) from tumor DNA sequencing by using variant allele frequency, with inferred menopausal status assumed by age at molecular profiling. Whole-transcriptome RNA sequencing and gene set enrichment analysis showed that adrenal-permissive homozygous (CC) tumors in premenopausal ER + BC were enriched for hormone-related pathways, including Estrogen Response Early (NES ≈ +1.8). In premenopausal triple-negative BC, adrenal-restrictive homozygous (AA) tumors exhibited the elevated expression of immune and epithelial genes and the increased prevalence of MED12 alterations (AA 0.25% vs. CC 8%, p < 0.01). In endometrioid EC, CC tumors demonstrated the suppression of immune and proliferative pathways. Postmenopausal cases had higher progesterone receptor IHC positivity (AA 75% vs. CC 83%, p < 0.05) and numerically more frequent ESR1 copy number gains (AA 2.0% vs. CC 4.0%). Results highlight context-specific associations between germline HSD3B1 genotypes and tumor biology in BC and EC. Full article

Adrenal cortex carcinoma (ACC) in children is a rare tumor that is probably of multifactorial origin and is mainly associated with genetic and environmental alterations. In the south and part of the southeast of Brazil, as well as in the Paraguayan region bordering the Brazilian State of Paraná, ACC prevalence is higher than in any other country, which is associated with the high prevalence of the TP53 p.R337H variant in Paraná (0.30%), Santa Catarina (0.249%), cities around Campinas-SP (0.21%), and the Paraguayan cities on the border with Paraná (0.05%). Recent research suggests that the co-segregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone. Breast cancer may be mildly influenced by co-segregation with XAF1 p.E134*, and this variant can also confer risk for sarcoma. Objectives: The objectives of this study were to (1) estimate the prevalence of the germline TP53 p.R337H and XAF1 p.E134* variants in Paraguay (excluding cities on the border with Paraná State, Brazil) and (2) estimate whether the ethnic origin of TP53 p.R337H carriers in Paraguay is similar to that of ethnic groups in Paraná (possible Portuguese/Spanish origin). Materials and methods: DNA tests for the identification of TP53 p.R337H were carried out from 2016 to 2019 at the Bio-Materials Laboratory of Facultad Politecnica, UNA, and at the Research Center in Biotechnology and Informatics (CEBIOTEC), Asunción, Paraguay. Polymerase chain reaction followed by restriction enzyme digestion (PCR-RFLP) was used to identify TP53 p.R337H, and real-time PCR (RT-PCR) was employed for XAF1 p.E134*. Peripheral blood samples from 40,000 Paraguayan newborns (NBs) were used for the TP53 p.R337H tests. The XAF1 p.E134* tests (RT-PCR) were performed on samples from 2000 Paraguayan newborns at the Pelé Pequeno Principe Research Institute, Curitiba, PR, Brazil. Results: The TP53 p.R337H variant was not found in any of the 14 Paraguayan departments investigated. A total of 12 of the 2000 Paraguayan NBs were positive for one XAF1 p.E134* allele. Conclusions: The hypothesis of Spanish immigrants carrying p.R337H to Paraguay was disproved. TP53 p.R337H neonatal testing in Paraguay is not recommended, except when there are families with Brazilian ancestry presenting cancer cases. Additional epidemiological studies are required to determine the likelihood of the identified prevalence of the XAF1 p.E134* allele (1/153) in NBs from Paraguay without TP53 p.R337H to present cancer risk. This study complements the first national initiative for the DNA screening of newborns aimed at mapping the TP53 p.R337H and XAF1 p.E134* variants in Paraguay (based on the regions of residence of the newborns). Full article

The early and accurate detection of cancer remains a critical challenge in biomedical diagnostics. In this work, we propose and investigate a novel surface plasmon resonance (SPR) biosensor platform based on a multilayer configuration incorporating copper (Cu), silicon nitride (Si₃N₄), and molybdenum disulfide (MoS₂) for the optical detection of various cancer types. Four distinct sensor architectures (Sys₁–Sys₄) were optimized through the systematic tuning of Cu thickness, Si₃N₄ dielectric layer thickness, and the number of MoS₂ monolayers to enhance sensitivity, angular shift, and spectral sharpness. The optimized systems were evaluated using refractive index data corresponding to six cancer types (skin, cervical, blood, adrenal, breast T1, and breast T2), with performance metrics including sensitivity, detection accuracy, quality factor, figure of merit, limit of detection, and comprehensive sensitivity factor. Among the configurations, Sys₃ (BK7–Cu–Si₃N₄–MoS₂) demonstrated the highest sensitivity, reaching 254.64 °/RIU for adrenal cancer, while maintaining a low detection limit and competitive figures of merit. Comparative analysis revealed that the MoS₂-based designs, particularly Sys₃, outperform conventional noble-metal architectures in terms of sensitivity while using earth-abundant, scalable materials. These results confirm the potential of Cu/Si₃N₄/MoS₂-based SPR biosensors as practical and effective tools for label-free cancer diagnosis across multiple malignancy types. Full article

Objectives: Differentiation of adrenal incidentalomas (AIs) remains a challenge in the oncological setting. The aim of the study was to explore the diagnostic efficacy of [18F]Fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET/CT)-based radiomics in identifying adrenal metastases and to compare it with that of conventional PET/CT parameters. Materials: Retrospective analysis was performed on 195 AIs for model construction, nomogram drawing, and internal validation. An additional 30 AIs were collected for external validation of the radiomics model and nomogram. Logistic regression analysis was employed to build models based on clinical and PET/CT routine parameters. The open-source software Python (version 3.7.11) was utilized to process the regions of interest (ROI) delineated by ITK-SNAP, extracting radiomic features. Least absolute shrinkage and selection operator (LASSO) regression analysis was applied for feature selection. Based on the selected features, the optimal model was chosen from ten machine learning algorithms, and the nomogram was constructed. Results: The area under the curve (AUC), sensitivity, specificity, and accuracy of conventional parameters of PET/CT were 0.919, 0.849, 0.892, and 0.844, respectively. XGBoost demonstrated superior diagnostic efficiency among the radiomics models, outperforming those constructed using independent predictors. The AUC, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of XGBoost’s internal and external validation were 0.945, 0.932, 0.930, 0.960, 0.970, 0.890 and 0.910, 0.900, 0.860, 1, 1, 0.750. The accuracy, sensitivity, specificity, PPV, and NPV of the nomogram in external validation were 0.870, 0.952, 0.667, 0.870, and 0.857. Conclusions: The radiomics model and conventional PET/CT parameters both showed high diagnostic performance (AUC p > 0.05) in discriminating adrenal metastases from benign lesions, offering a practical, non-invasive approach for clinical assessment. Full article

Background and Objectives: The comparative efficacy and safety of nivolumab plus ipilimumab (Nivo-Ipi) combination therapy between patients with either postoperative recurrent non-small cell lung cancer (NSCLC) or inoperable stage III/IV NSCLC have yet to be conclusively determined. Materials and Methods: This retrospective study reviewed the medical records of consecutive patients diagnosed with either postoperative recurrent NSCLC or inoperable stage III/IV NSCLC. Both groups, referred to as the postoperative and inoperable cohorts respectively, underwent Nivo-Ipi therapy at four Japanese medical institutions between December 2020 and November 2022. The study’s primary aim was to evaluate and compare the efficacy and safety outcomes across these two groups. Results: A total of 161 patients received Nivo-Ipi therapy (postoperative group, n = 30; inoperable group, n = 131). The objective response rate was comparable between the postoperative and inoperable groups (36.7% vs. 32.1%, p = 0.67). Median progression-free survival did not differ significantly between groups (8.9 months vs. 6.5 months, p = 0.14). However, median overall survival was significantly longer in the postoperative group (not reached vs. 13.0 months, p = 0.012). The incidence of grade ≥ 3 adverse events in the postoperative group included lung injury (13.3%), liver dysfunction (10.0%), adrenal insufficiency (6.7%), and colitis (6.7%). No significant difference was observed in the frequency of grade ≥ 3 treatment-related adverse events between the groups, and no treatment-related deaths occurred in the postoperative group. Conclusions: Patients with postoperative recurrent NSCLC treated with Nivo-Ipi demonstrated significantly longer overall survival compared to those with inoperable NSCLC. Given its favorable efficacy and acceptable toxicity profile, postoperative recurrent disease may warrant consideration as a stratification factor in clinical trials for advanced NSCLC. Nivo-Ipi therapy could serve as a preferred first-line treatment option for patients with postoperative recurrent NSCLC. Full article

Objectives: The current standard of care for endocrine tumors includes a personalized diagnostic and therapeutic approach aimed at the early detection of tumor recurrence after radical surgery. Assessment of tumor-associated biological factors in serum may be useful in patient management. The aim of this study is to determine whether any of the selected growth factors (VEGF, FGF), lectins (Galectin-1, Galectin-3), proteins (Fascin), or TNF-α measured in serum may serve as a potential marker of recurrence. Methods: A total of 68 cases, including 43 patients with disseminated endocrine neoplasm (neuroendocrine tumor (NET) 30 cases, medullary thyroid cancer (MTC) 6 cases, adrenal neoplasm 7 cases) and 25 healthy participants, were included in the analysis. Serum concentrations of TNF-α, Fascin, VEGF, Galectin-1, Galectin-3, and FGF were determined in all cases. The results were compared between groups. Results: A comparison between all patients and controls revealed differences in TNF-α concentrations (2.88 vs. 0.93 (ng/mL), p = 0.008). When comparing the concentrations of the measured factors between the subgroups (classified by tumor type) and the control group, differences were found for TNF-α (p = 0.007) and Fascin (p = 0.035). In the case of Fascin, differences were found for MTC and adrenal neoplasm patients (0.52 vs. 5.28 (ng/mL), p = 0.048), as well as MTC and NET patients (0.52 vs. 5.59 (ng/mL), p = 0.007), while the differences between NET patients and controls were close to significance (5.59 vs. 3.67 (ng/mL), p = 0.076). For TNF-α, significant differences were found between NET patients and controls (2.88 vs. 0.03 (ng/mL), p = 0.005) as well as between MTC patients and controls (2.77 vs. 0.93 (ng/mL), p = 0.004). Conclusions: Serum concentrations of selected proteins and growth factors (Fascin, TNF-α) are significantly higher in those with disseminated endocrine tumors compared to healthy controls. More studies are needed to determine the role of these selected proteins and growth factors in the early detection of NET/MTC recurrence. Full article

This article profiles 27 innovative advancements in small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) in 2024. These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann–Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra^®, Voydeya^®, Iqirvo^®, Voranigo^®, Livdelzi^®, Miplyffa^®, Revuforj^®, and Crenessity^®) are classified as “first-in-class” and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development. Full article

Inhibitors of cytosolic phospholipase A₂ (GIVA cPLA₂) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA₂ inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA₂ may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography–high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA₂ inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA₂, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA₂ inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer. Full article

Objective: Chronic stress affects the immune system via the hypothalamic–pituitary–adrenal (HPA) axis and autonomic system. Chronic inflammation is a risk factor for cardiovascular diseases, cancer onset and progression, susceptibility to infection, and cognitive impairment. Mind–body interventions (MBIs) could affect the immune and neuroendocrine systems, and we aimed to assess the correlations among these systems through a meta-analysis. Methods: RCTs were identified by searching three databases: PubMed, Embase, and Scopus. Of the 1697 studies identified, 89 were included in this study. Risk of bias was examined using the Cochrane risk-of-bias assessment tool. Data were pooled using a random-effects model, and SMDs were calculated. I² statistics and Egger’s test were used to assess the significance of the asymmetry. Influence diagnostics were used to assess whether pooled effects were disproportionately dependent on any single study. The trim-and-fill method was applied to all identified asymmetric instances. Meta-regression was used to examine the moderating effect of MBI efficacy on biomarkers. Results: MBIs generally decreased the levels of inflammatory factors, such as the CRP, IL-6, TNF-α, IL-1, IL-8, IL-17, ESR, and cortisol, and increased IL-10, IFN-γ, IL-1ra, BDNF, and secretory IgA. In a subgroup analysis of the CNS and cancer, qigong and yoga showed increased BDNF and IL-6, respectively. Notably, IL-10 was increased in inflammatory diseases, and IFN-γ was increased in viral infections. Conclusions: This study revealed MBIs decrease inflammatory cytokine and increase anti-inflammatory, antiviral, and immune-activating factors. These results suggest the MBIs including gentle physical exercise may be beneficial for neuropsychiatric disorders or tumors. Prospero registration number: CRD42024507646. Full article

Background/Objectives: The germline polymorphism in the HSD3B1 gene (c.1100 C) results in adrenal-permissive (CC) or adrenal-restrictive (AA) functions of the protein product by regulating the production of high-affinity ligands that activate androgen signaling. Prior studies have indicated that the CC genotype is associated with worse response to hormonal therapies in prostate cancer (PC) patients. Methods: To characterize the impact of germline HSD3B1 variants on somatic tumor features, we examined 6550 primary and metastatic PCs from the Caris Life Sciences database, in which the genomic and transcriptomic landscapes were acquired via paired whole-exome/whole-transcriptome sequencing. Results: The overall prevalence of the HSD3B1 AA genotype (restrictive–homozygous) was 48.8%, AC (permissive–heterozygous) was 32.8%, and CC (permissive–homozygous) was 14.9%. There was enrichment of the CC genotype in these PC patients as compared to prior reports that examined non-cancerous populations. However, the rates of the CC genotype varied between metastatic site and by race. Compared to the AA genotype, tumors harboring the CC genotype did not demonstrate increased AR alterations, nor higher expression of AR, FOXA1, HOXB13, or AR signaling signatures. We instead found significant changes in immune-associated hallmark pathways, immune cell fractions, and biomarkers that inform the use of immune therapies (TMB-high, MSI-high). Further, the CC and AA genotypes exhibited notable differences in the expression of immunoglobulins, MHC class I/II molecules, and cell surface targets. The differences in expression by HSD3B1 genotype were especially notable in lung and liver metastases. Conclusions: Our study indicates that in prostate cancers, HSD3B1 germline c.1100 allele status may not directly influence tumor-intrinsic genomics but is associated with novel functions beyond androgen signaling. Full article

Background and Clinical Significance: Renal cell carcinoma (RCC) is the third most common cancer that metastasizes to the oral and maxillofacial region following breast and lung cancers. Metastatic involvement in the oral cavity is rare and can present as a diagnostic challenge due to non-specific clinical features that mimic other benign or malignant conditions. The limited information available regarding oral metastasis of RCC highlights the importance of recognizing this uncommon presentation. Case Presentation: A 50-year-old female presented with a painful swelling in the buccal and palatal mucosa of the right maxilla that progressively enlarged over several months. Initially, this lesion was diagnosed clinically as a pyogenic granuloma. However, given the lesion’s continued growth and unusual presentation, a biopsy was performed. Histopathological examination confirmed the lesion as metastatic renal clear-cell carcinoma (ccRCC), with immunohistochemical analysis verifying the renal origin. Further diagnostic tests, including a computed tomography (CT) urogram, chest CT, and bone scintigraphy, revealed additional metastases in the left adrenal gland, lungs, and bone. Conclusions: This case is notable because the oral lesion was the first visible sign of RCC, making it a rare presentation of metastatic RCC. This underscores the importance of thorough history taking, detailed clinical evaluations, and considering rare metastatic conditions in the differential diagnosis of oral swellings. Additionally, this case reinforces the significance of routine cancer screenings for early detection of undiagnosed cancer. We also updated a previous literature review of metastatic RCC to the head and neck region, covering cases until 2023. Full article

This case report presents a rare occurrence of adrenal insufficiency induced by Zytiga (abiraterone acetate) in a patient with high-risk localized prostatic adenocarcinoma. Abiraterone acetate is a potent, selective and irreversible CYP17A1 inhibitor and is commonly used in the treatment of prostate cancer, but it can cause various endocrine side effects, especially if not used concurrently with the appropriate treatment. The clinical implications of this adverse event and management strategies are discussed here in this case report to raise awareness about this potential risk in patients with prostate cancer undergoing treatment with abiraterone acetate, especially when used in an erroneous manner without monitoring. Full article