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Dicer, a cytoplasmic type III RNase, is essential for the maturation of microRNAs (miRNAs) and is implicated in cancer progression and chemoresistance. Our previous research demonstrated that phosphorylation of Dicer at S1016 alters miRNA maturation and glutamine metabolism, contributing to gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on the role of Dicer phosphorylation at S1728/S1852 in GEM-resistant PDAC cells. Using shRNA to knock down Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells, we examined cell viability through MTT and clonogenic assays. We also expressed phosphomimetic Dicer 2E (S1728E/S1852E) and phosphomutant Dicer 2A (S1728A/S1852A) to evaluate their effects on GEM resistance and metabolism. Our results show that phosphorylation at S1728/S1852 promotes GEM resistance by reprogramming glutamine metabolism. Specifically, phosphomimetic Dicer 2E increased intracellular glutamine, driving pyrimidine synthesis and raising dCTP levels, which compete with gemcitabine's metabolites. This metabolic shift enhanced drug resistance. In contrast, phosphomutant Dicer 2A reduced GEM resistance. These findings highlight the importance of Dicer phosphorylation in regulating metabolism and drug sensitivity, offering insights into potential therapeutic strategies for overcoming GEM resistance in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of GC, and progress in the development of effective anti-GC drugs has been insufficient. The tumor microenvironment (TME) regulates various functions of tumor cells, and interactions between the cellular and molecular components of the TME—e.g., inflammatory cells, fibroblasts, vasculature cells, and innate and adaptive immune cells—promote the aggressiveness of cancer cells and dissemination to distant organs. This review summarizes the roles of various TME cells and molecules in regulating the malignant progression and metastasis of GC. We also address the important roles of signaling pathways in mediating the interaction between cancer cells and the different components of the GC TME. Finally, we discuss the implications of these molecular mechanisms for developing novel and effective therapies targeting molecular and cellular components of the GC TME to control the malignant progression of GC. [ABSTRACT FROM AUTHOR]

Neurotensin (NT) is a peptide involved in digestion, neuromodulation, and cancer progression. NT and its receptors (NTR1 and SORT1 mainly) have been widely studied in oncology. Data show that NT expression is under the control of sex steroid hormones, in particular estradiol. We focused on its involvement in three main female hormone-sensitive cancers, breast, ovarian, and endometrial cancer, in a narrative review. NT, NTR1, and SORT1 are mostly expressed in these three cancers, and their involvement in oncologic processes such as proliferation and invasion seems to match, as does their impact on prognosis for most. The development of NT receptor-targeted therapies, including theranostics and radioligand treatments, presents a promising avenue for personalized cancer treatment. [ABSTRACT FROM AUTHOR]

The crosstalk between tumor progression and ferroptosis is largely unknown. Here, we identify malate dehydrogenase 2 (MDH2) as a key regulator of ferroptosis. MDH2 deficiency inhibits the growth of hepatocellular carcinoma (HCC) cells and enhances their sensitivity to ferroptosis induced by RAS-selective lethal 3 (RSL3), a compound known to cause ferroptosis. MDH2 knock-down enhances RSL3-induced intracellular reactive oxygen species, free iron ions and lipid per-oxides levels, leading to HCC ferroptotic cell death which is rescued by ferrostatin-1 and iron chelator deferiprone. Importantly, the inhibition of HCC cell growth caused by MDH2 deficiency is partially rescued by ferroptosis blockade. Mechanistically, MDH2 resists RSL3-induced ferroptosis sensitivity dependent on glutathione peroxidase 4 (GPX4), an enzyme responsible for scavenging lipid peroxides, which is stabilized by MDH2 in HCC. The protein expressions of MDH2 and GPX4 are positively correlated with each other in HCC cell lines. Furthermore, through our UALCAN website analysis, we found that MDH2 and GPX4 are highly expressed in HCC samples. These findings reveal a critical mechanism by which HCC evades ferroptosis via MDH2-mediated stabilization of GPX4 to promote tumor progression and underscore the potential of MDH2 inhibition in combi-nation with ferroptosis inducers for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Metastasis suppressor 1 (MTSS1) has been reported to play important roles in suppressing cancer progression. In this study, we investigated the underlying mechanism that regulates MTSS1 expression. We showed that in breast cancer cells, lncRNA-SNHG15-induced cell invasion and proliferation was accompanied with the decreased expression of MTSS1 mRNA. Further study revealed that SNHG15 mediated MTSS1 repression through blocking its promoter activity. Mechanistically, SNHG15 complexes with DDX5 and RTF1 and interacts with the core promoter of the MTSS1 gene to interfere with RNA-Pol-II-directed transcriptional initiation. Association with DDX5 stabilizes SNHG15 while binding to RTF1 allows SNHG15 to carry RTF1 to the core promoter, where RTF1 forms a complex with PNA pl II to enhance transcriptional pausing. Our findings revealed a molecular mechanism by which SNHG15 serves as a regulator to suppresses MTSS1 transcription via interaction with the gene core promoter. [ABSTRACT FROM AUTHOR]

ZKSCAN3 (also known as ZNF306) plays a pivotal role in the regulation of various cellular processes that are fundamental to the development of cancer. It has been widely acknowledged as a key contributor to cancer progression, with its overexpression consistently reported in a broad spectrum of malignancies. Importantly, clinical studies have demonstrated a significant association between elevated ZKSCAN3 levels and adverse prognosis, as well as resistance to therapeutic drugs. Specifically, ZKSCAN3 promotes tumor progression by enhancing multiple hallmark features of cancer and promoting the acquisition of cancer-specific phenotypes. These effects manifest as increased tumor cell proliferation, invasion, and metastasis, accompanied by inhibiting tumor cell apoptosis and modulating autophagy. Consequently, ZKSCAN3 emerges as a promising prognostic marker, and targeting its inhibition represents a potential strategy for anti-tumor therapy. In this review, we provide an updated perspective on the role of ZKSCAN3 in governing tumor characteristics and the underlying molecular mechanisms. Furthermore, we underscore the clinical relevance of ZKSCAN3 and its potential implications for tumor prognosis and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study aimed to analyze USP1 expression and study its roles in bladder cancer. Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1's function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic–inactive mutant) were used to overexpress USP1 in T24 cells. CCK8, colony formation, and Transwell assays were used to assess cell viability, proliferation, and migration. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Co-immunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. A xenograft mouse model was used to study the role of USP1 in bladder cancer. Results: USP1 expression was upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration, and this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1 deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could interact with c-MYC and increase c-MYC's stability depending on the catalytic activity of USP1. Conclusions: Our results suggested that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 may serve as a novel therapeutic target for treating bladder cancer. [ABSTRACT FROM AUTHOR]

Bladder cancer remains a prevalent and challenging malignancy. Myeloid-derived suppressor cells (MDSCs) have emerged as key contributors to the immunosuppressive tumor microenvironment, facilitating tumor progression, immune evasion, and resistance to therapies. This review explores the role of MDSC in bladder cancer, highlighting their involvement in immune regulation; tumor progression; and resistance to therapies such as bacillus Calmette–Guérin (BCG) therapy, chemotherapy, and immune checkpoint inhibitors (ICIs). We also discuss their potential as biomarkers and therapeutic targets, with current evidence suggesting that targeting MDSCs, either alone or in combination with existing treatments such as BCG and ICIs, may enhance anti-tumor immunity and improve clinical outcomes. However,, challenges remain, particularly regarding the identification and therapeutic modulation of MDSC subpopulations. Further research is warranted to fully elucidate their role in bladder cancer and to optimize MDSC-targeted therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein has been shown to promote tumor progression, its role in the development of cervical cancer remains unclear. We find that its level is higher in cervical cancer tissues than in normal cervical tissues. And it promotes metastasis in HeLa cell lines by facilitating the epithelial-mesenchymal transition process, thereby enhancing the migration of HeLa cells in vivo. Our research might provide a new marker for predicting the development of cervical cancer. Background: Cervical cancer is the fourth most common cancer among women worldwide. The zinc finger transcription factor 281 (ZNF281)/ZBP-99 protein specifically binds to GC-rich DNA sequences and regulates gene expression, and it has been shown to promote tumor progression. In this study, we aim to investigate the function and molecular mechanism of ZNF281 in uterine cervical carcinoma. Methods: We conducted immunohistochemistry and Western blot assays to determine the expression of ZNF281 in eight human cervical cancer tissues. And, xenograft experiments involving the injection of HeLa cells into nude mice was used to determine the function of ZNF281 on proliferation. Transwell assays were used to detect the migration and invasion of HeLa cells after indicated that ZNF281 overexpression. Results: Our results indicated that ZNF281 protein levels were higher in cervical cancer tissues compared to normal cervical tissues. Additionally, ZNF281 was expressed in human cervical carcinoma cell lines, including HeLa, SiHa, C-33 A, CaSki, and HT-3, and is localized in both the cell nucleus and cytoplasm. ZNF281 overexpression did not influence HeLa cell proliferation or tumor size in situ. Moreover, nude mice injected with ZNF281-overexpressing cell lines developed more tumor lesions in the lungs compared to those injected with control cell lines. Conclusions: These findings suggest that ZNF281 is associated with tumor metastasis without affecting cell proliferation, both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Simple Summary: Small bowel cancer is considered a rare disease with limited clinical and pathological data but with a rising incidence in recent decades. The imaging, pathological diagnosis, and surgical and oncological treatment, as well as the long-term survival, are variable and related to the pathological type, tumor location, and staging. In our retrospective study, we analyzed a number of patients with primary resectable small bowel cancer who had also presented with exceptional types such as multiple bowel cancers. A total of 46 resectable (R0 resection) small bowel cancer patients were included in this study. Long-term survival depends on tumor aggressivity, invaded lymph node number, and unique or multiple locations. Introduction: Small bowel cancer is very rare; although the incidence of adenocarcinoma and other anatomopathological forms has increased recently, the diagnosis and treatment of this disease are still debatable because of the clinical heterogeneity and the absence of studies including a large number of patients. Materials and Methods: We performed a retrospective study over 10 years in which we analyzed the clinical, imaging, and anatomopathological data of 46 patients hospitalized in a surgery clinic and diagnosed with small bowel cancer (duodenum, jejunum, and ileum). Results: After clinical assessment of these patients, including complications (occlusion, bleeding, and perforation), the CT scan established the diagnosis in over 90% of the cases of the complicated form of the disease. Surgery has a curative role in localized cancers; tumor location, local invasion, the presence of locoregional lymph nodes, and the number of multiple tumors influence the type of surgery. The conventional pathological exam was completed via immunohistochemical staining. Adjuvant oncological treatment was performed after surgery (according to the guidelines); in patients with exceptional histopathological forms, the therapy was personalized. Conclusions: Most small bowel cancers were diagnosed with complications (occlusion and bleeding); the tumor type, location, and presence of multiple bowel cancers significantly influenced its management. Independently of the surgical resection (R0/R1 or R2), the prognosis of the disease depends on the tumor aggressivity, location (single/multiple), and locoregional node invasion. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the critical yet understudied role of miRNAs in areca nut-induced carcinogenesis in head and neck cancer (HNC). Through comprehensive profiling, we identified 84 miRNAs, comprising 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs) associated with areca nut-induced HNC. Further analysis of the oncogenic mechanisms revealed that 740 genes are cross-regulated by a cluster of eight hub TsmiRs. These areca nut-modulated miRNAs significantly impact key cancer-related pathways, including p53, PI3K-AKT, MAPK, and Ras signaling, and regulate critical oncogenic processes related to cell motility and survival. Moreover, miR-499a-5p was validated as a vital regulator, which mitigated areca nut-induced cancer progression, including cell migration, invasion, and chemoresistance. Our findings highlight the potential of this miRNA panel for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies, opening new avenues for future research and clinical practice. Background: While miRNAs are increasingly recognized for their role in tumorigenesis, their involvement in head and neck cancer (HNC) remains insufficiently explored. Additionally, the carcinogenic mechanisms of areca nut, a major habitual carcinogen in Southeast Asia, are not well understood. Methods and results: This study adopts a systematic approach to identify miRNA profiles associated with areca nut-induced HNC. Using miRNA microarray analysis, we identified 292 miRNAs dysregulated in areca nut-treated HNC cells, with 136 upregulated and 156 downregulated. Bioinformatic analysis of the TCGA-HNSC dataset uncovered a set of 692 miRNAs relevant to HNC development, comprising 449 overexpressed and 243 underexpressed in tumor tissues. Integrating these datasets, we defined a signature of 84 miRNAs, including 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs), highlighting their pivotal role in areca nut-induced carcinogenesis. MultiMiR analysis identified 740 genes cross-regulated by eight hub TsmiRs, significantly impacting key cancer-related pathways (p53, PI3K-AKT, MAPK, and Ras) and critical oncogenic processes. Moreover, we validated miR-499a-5p as a vital regulator, demonstrating its ability to mitigate areca nut-induced cancer progression by reducing cell migration, invasion, and chemoresistance. Conclusions: Thus, this miRNA signature addresses a crucial gap in understanding the molecular underpinnings of areca nut-induced carcinogenesis and offers a promising platform for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: This study analyzes real-world outcomes for advanced, non-oncogene addicted non-small cell lung cancer patients treated with atezolizumab monotherapy following platinum-based chemotherapy, based on data from two academic institutions in Serbia. Progression-free survival did not significantly differ between patients receiving atezolizumab as a second, third, or later line of therapy, indicating consistent efficacy across treatment lines. Additionally, the number of prior chemotherapy cycles had no significant impact on progression-free survival, suggesting that a higher prior treatment burden did not compromise atezolizumab effectiveness. Importantly, a good ECOG performance status emerged as the strongest predictor of prolonged progression-free survival, highlighting the importance of patients' health status at treatment initiation. Immune checkpoint inhibitors (ICIs) like atezolizumab have improved outcomes in advanced non-small cell lung cancer (NSCLC) patients, especially in the second-line setting after progression on platinum-based chemotherapy. However, access to ICIs remains limited in many developing nations. This study evaluated the efficacy of atezolizumab as a second-line versus later-line treatment for advanced NSCLC patients in Serbia. Methods: This retrospective study involved 147 advanced NSCLC patients treated with atezolizumab following progression on prior platinum-based chemotherapy at two academic centers in Serbia. Data on demographics and clinical, pathological, and molecular characteristics were collected. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method, and multivariable Cox proportional hazards regression identified outcome predictors. Results: The median PFS was 7.13 months, and median OS was 38.6 months. The overall response rate (ORR) was 15%, with a disease control rate (DCR) of 57.9%. No significant PFS differences were observed between patients treated with atezolizumab in the second line versus later lines. Patients with good performance status (ECOG 0–1) had significantly better PFS compared to those with poorer status (12.03 vs. 1.63 months, p < 0.0001). Conclusions: Atezolizumab is effective in both second-line and later-line settings for advanced NSCLC, particularly in patients with good performance status. This highlights the importance of patient selection based on performance status, as well as the need for wider access to ICIs in resource-limited regions. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with the head and neck region being the most common location. Perineural invasion (PNI), or the invasion of cancer into and around nerves, is a high-risk factor in cSCC associated with poor outcomes. The mechanisms of PNI in cSCC are poorly understood, but recent studies suggest that cross-communication between nerve components and cancer is a contributing factor. A better understanding of the mechanisms that promote PNI may lead to new therapies that improve outcomes in cSCC patients. Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a lifetime risk of 14–20% that is rising every year. Although prognosis for cSCC is generally good, certain high-risk features of cSCC portend increased rates of nodal and distant metastasis, recurrence, and disease-specific mortality. One such high-risk factor is perineural invasion (PNI), which is broadly defined as the invasion of cancer into and around nerves. Compared to other high-risk factors, PNI presence is associated with the highest risk for locoregional and distant metastasis. Still, the mechanisms underlying the pathogenesis of PNI remain poorly understood. Recent studies suggest the migration and invasion of tumors into nerves is a result of complex molecular crosstalk within the tumor-nerve microenvironment, wherein the milieu of signaling molecules simultaneously promote neuronal growth and tumor cell invasion. Methods: Understanding the molecular and cellular mechanisms that promote PNI will lead to future developments of targeted therapies that may improve locoregional control and survival. Results/Conclusions: In our article, we aim to provide a comprehensive review of recent findings about the pathogenesis of PNI, clinical implications of PNI-positive disease in cSCC, available treatment modalities, and potential future therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: CD59 prevents the formation of membrane attack complex, enabling tumor cells to escape complement-mediated cytotoxicity. It appears that the expression of CD59 significantly impacts survival outcomes due to its interaction with immune cells. The associations between CD59 and immune suppressive cells such as T-regulatory cells, myeloid derived suppressor cells, and macrophage create an immune suppressive environment in cervical, brain, head and neck, and stomach cancers. However, kidney cancer has less or no association, leading to better survival outcomes. Thus, assessing the levels of CD59 and its immune cell associations is crucial as it plays a predictive role in deciding prognostic outcomes. Background: CD59, a GPI-anchored membrane protein, protects cancer cells from complement-dependent cytotoxicity (CDC) by inhibiting the formation of the membrane attack complex (MAC). It has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. The role of CD59 in cancer growth and interactions between CD59 and immune cells that modulate immune evasion has not been well explored. Methods: Using cancer patient database from The Cancer Genome Atlas (TCGA) and other public databases, we analyzed CD59 expression, its prognostic significance, and its association with immune cell infiltration in the tumor microenvironment, identifying associated genomic and functional networks and validating findings with invitro cell-line experimental data. Results: This article describes the abundant expression of CD59 in multiple tumors such as cervical squamous cell carcinoma (CESC), kidney renal cell carcinoma (KIRC), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), and stomach adenocarcinoma (STAD), as well as in pan-cancer, using The Cancer Genome Atlas (TCGA) database and confirmed using multiple cancer cell lines. The expression of CD59 significantly alters the overall survival (OS) of patients with multiple malignancies such as CESC, GBM, HNSC, and STAD. Further, the correlation between CD59 and Treg and/or MDSC in the tumor microenvironment (TME) has shown to be strongly associated with poor outcomes in CESC, GBM, HNSC, and STAD as these tumors express high FOXP3 compared to KIRC. Moreover, unfavorable outcomes were strongly associated with the expression of CD59 and M2 tumor-associated macrophage infiltration in the TME via the IL10/pSTAT3 pathway in CESC and GBM but not in KIRC. In addition, TGFβ1-dominant cancers such as CESC, GBM, and HNSC showed a high correlation between CD59 and TGFβ1, leading to suppression of cytotoxic T cell activity. Conclusion: Overall, the correlation between CD59 and immune cells predicts its prognosis as unfavorable in CESC, GBM, HNSC, and STAD while being favorable in KIRC. [ABSTRACT FROM AUTHOR]

Simple Summary: A CRISPR knockout screen was performed targeting all genes of the human genome with about 12 knockout sgRNAs each. By comparing pancreatic cancer cells with high or low metastatic capacity, genes were identified that affect the viability of metastatic cells while not affecting cell viability of non-metastatic cells. Further functional studies looked at some of the identified candidate genes. For one of the metastasis-related genes—MYBL2—a change in its interaction with another regulator gene was found to be implicated in metastasis. Background/Objectives: Early and aggressive metastasis is a major feature of pancreatic ductal adenocarcinoma. Understanding the processes underlying metastasis is crucial for making a difference to disease outcome. Towards these ends, we looked in a comprehensive manner for genes that are metastasis-specific. Methods: A genome-wide CRISPR-Cas9 gene knockout screen with 259,900 single guide RNA constructs was performed on pancreatic cancer cell lines with very high or very low metastatic capacity, respectively. Functional aspects of some of the identified genes were analysed in vitro. The injection of tumour cells with or without a gene knockout into mice was used to confirm the effect on metastasis. Results: The knockout of 590 genes—and, with higher analysis stringency, 67 genes—affected the viability of metastatic cells substantially, while these genes were not vital to non-metastasizing cells. Further evaluations identified different molecular processes related to this observation. One of the genes was MYBL2, encoding for a well-known transcription factor involved in the regulation of cell survival, proliferation, and differentiation in cancer tissues. In our metastasis-focussed study, no novel functional activity was detected for MYBL2, however. Instead, a metastasis-specific transformation of its genetic interaction with FOXM1 was observed. The interaction was synergistic in cells of low metastatic capacity, while there was a strong switch to a buffering mode in metastatic cells. In vivo analyses confirmed the strong effect of MYBL2 on metastasis. Conclusions: The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved. [ABSTRACT FROM AUTHOR]

Simple Summary: Integrin α6β4 makes triple-negative breast cancer (TNBC) more aggressive by controlling genes that drive tumor invasion and metastasis. PTPRZ1 is linked to cancer relapse, but its role in TNBC is not well understood. We discovered that PTPRZ1 expression is significantly increased by integrin α6β4 in TNBC. We also found that integrin β4 gene expression correlates with PTPRZ1 in breast cancer patient samples. Importantly, we found that integrin α6β4 controls PTPRZ1 through UCHL1, which in turn stabilized Hif-1α. When UCHL1 or PTPRZ1 are blocked, the aggressiveness driven by integrin β4 signaling decreased substantially. Data analysis showed that high levels of these genes (ITGB4, UCHL1, Hif1α, PTPRZ1) are linked to worse survival rates, especially in patients who received chemotherapy treatment. Our findings suggest that integrin α6β4 helps TNBC become invasive through UCHL1-Hif-1α regulation of PTPRZ1, pointing to a new approach to targeting integrin α6β4 signaling using PTPRZ1 and UCHL1 inhibitors. Integrin α6β4 drives triple-negative breast cancer (TNBC) aggressiveness through the transcriptional regulation of key genes. Here, we investigated how integrin α6β4 regulates protein tyrosine phosphatase receptor type Z1 (PTPRZ1). Using stable re-expression of integrin β4 (ITGB4) in cells naturally devoid of integrin α6β4 or knockdown or knockout (KO) of ITGB4, we found that integrin α6β4 regulates PTPRZ1 expression. To gain mechanistic insight, we focused on Hif-1α due to the impact of integrin α6β4 on a hypoxia-associated signature. We found that nuclear localization of Hif-1α, but not Hif-2α, was substantially enhanced with integrin α6β4 signaling. Hif-1α knockdown by shRNA or chemical inhibition decreased PTPRZ1 expression, while chemical activation of Hif-1α increased it. Upstream of Hif-1α, integrin α6β4 upregulates UCHL1 to stabilize Hif-1α and ultimately regulate PTPRZ1. Inhibition of UCHL1 and PTPRZ1 dramatically decreases integrin α6β4-mediated cell migration and three-dimensional invasive growth. Finally, public breast cancer database analyses demonstrated that ITGB4 correlates with PTPRZ1 and that high expression of ITGB4, UCHL1, HIF1A, and PTPRZ1 associated with decreased overall survival, distant metastasis free survival, post progression survival, and relapse-free survival. In summary, these findings provide a novel function of integrin α6β4 in promoting tumor invasive phenotypes through UCHL1-Hif-1α-mediated regulation of PTPRZ1. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer type and the leading cause of mortality for women worldwide. The microbiome influences various cancer therapies, including radiotherapy. Thus, radiotherapy-derived metabolites and microbiome composition may affect cancer progression and treatment response, and vice versa. This review explores this bidirectional relationship as well as providing current evidence and future perspectives in this field. The gut microbiome has emerged as a crucial player in modulating cancer therapies, including radiotherapy. In the case of breast cancer, the interplay between the microbiome and radiotherapy-derived metabolites may enhance therapeutic outcomes and minimize adverse effects. In this review, we explore the bidirectional relationship between the gut microbiome and breast cancer. We explain how gut microbiome composition influences cancer progression and treatment response, and how breast cancer and its treatments influence microbiome composition. A dual role for radiotherapy-derived metabolites is explored in this article, highlighting both their therapeutic benefits and potential hazards. By integrating genomics, metabolomics, and bioinformatics tools, we present a comprehensive overview of these interactions. The study provides real-world insight through case studies and clinical trials, while therapeutic innovations such as probiotics, and dietary interventions are examined for their potential to modulate the microbiome and enhance treatment effectiveness. Moreover, ethical considerations and patient perspectives are discussed, ensuring a comprehensive understanding of the subject. Towards revolutionizing treatment strategies and improving patient outcomes, the review concludes with future research directions. It also envisions integrating microbiome and metabolite research into personalized breast cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: While tumor cell invasion beyond the surgically resectable "margin" of glioblastoma is thought to be associated with nearly 100% of recurrences and poor survival, no reliable methods exist for mapping the location of invading tumor cells within the human brain. Building on prior work demonstrating the ability of Q-space magnetic resonance imaging (QSI) to highlight structural alterations in tissue architecture, we hypothesized that using this imaging method to construct tumor-associated tractography might identify tumor-specific structures that underlie cellular invasion. Our results demonstrate that such tractography patterns can be observed in a tumor-specific manner, and provide preliminary evidence that those patterns may colocalize with invading tumor cells, and metrics derived from them may be associated with patient survival time. Background: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent. Methods: Patients from a single center with newly diagnosed glioblastoma (n = 7) underwent preoperative Q-space magnetic resonance imaging (QSI; 3T, 64 gradient directions, b = 1000 s/mm2) between 2018 and 2019. Tumors were manually segmented, and patterns of inter-voxel coherence spatially intersecting each segmentation were generated to represent tumor-associated tractography. One patient additionally underwent regional biopsy of diffusion tract- versus non-tract-associated tissue during tumor resection for RNA sequencing. Imaging data from this cohort were compared with a historical cohort of n = 66 glioblastoma patients who underwent similar QSI scans. Associations of tractography-derived metrics with survival were assessed using t-tests, linear regression, and Kaplan–Meier statistics. Patient-derived glioblastoma xenograft (PDX) mice generated with the sub-hippocampal injection of human-derived glioblastoma stem cells (GSCs) were scanned under high-field conditions (QSI, 7T, 512 gradient directions), and tumor-associated tractography was compared with the 3D microscopic reconstruction of immunostained GSCs. Results: In the principal enrollment cohort of patients with glioblastoma, all cases displayed tractography patterns with tumor-intersecting tract bundles extending into brain parenchyma, a phenotype which was reproduced in PDX mice as well as in a larger comparison cohort of glioblastoma patients (n = 66), when applying similar methods. Reconstructed spatial patterns of GSCs in PDX mice closely mirrored tumor-associated tractography. On a Kaplan–Meier survival analysis of n = 66 patients, the calculated intra-tumoral mean diffusivity predicted the overall survival (p = 0.037), as did tractography-associated features including mean tract length (p = 0.039) and mean projecting tract length (p = 0.022). The RNA sequencing of human tissue samples (n = 13 tumor samples from a single patient) revealed the overexpression of transcripts which regulate cell motility in tract-associated samples. Conclusions: QSI discriminates tumor-specific patterns of inter-voxel coherence believed to represent white matter pathways which may be susceptible to glioblastoma invasion. These findings may lay the groundwork for future work on therapeutic targeting, patient stratification, and prognosis in glioblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: The prognostic value of lymphovascular or perineural invasion in prostate cancer specimens regarding oncological outcomes after radical prostatectomy is unclear. Within a contemporary study cohort of 822 prostate cancer patients, 78 (9%) exhibited lymphovascular invasion and 633 (77%) exhibited perineural invasion in RP specimens. In univariable Cox regression models, lymphovascular invasion and perineural invasion were both associated with higher rates of biochemical recurrence (BCR). However, after multivariable adjustment for standard pathologic tumor characteristics, lymphovascular or perineural invasion was not found to be an independent predictor for BCR. These phenomes may be explained by the strong association between the Gleason Grade Group and pathologic tumor stage with lymphovascular as well as perineural invasion. Objective: The aim of this study was to test for the association between lymphovascular invasion or perineural invasion in radical prostatectomy (RP) specimens and biochemical recurrence (BCR). Methods: Relying on a tertiary-care database, we identified prostate cancer patients treated with RP between January 2014 and June 2023. Of these, the majority underwent robotic-assisted RP (81%). Kaplan–Meier survival analyses and Cox regression models addressed BCR according to either lymphovascular invasion or perineural invasion in RP specimens. Additionally, the linear trend test assessed the association between the Gleason Grade Group or pathologic tumor stage and lymphovascular or perineural invasion. Results: Of 822 patients, 78 (9%) exhibited lymphovascular invasion and 633 (77%) exhibited perineural invasion in RP specimens. In survival analyses, the five-year BCR-free survival rates were 62% in patients with lymphovascular invasion vs. 70% in patients without lymphovascular invasion (p = 0.04) and 64% in patients with perineural invasion vs. 82% in patients without perineural invasion (p = 0.01). In univariable Cox regression models, lymphovascular invasion (hazard ratio 1.58, 95% confidence interval 1.01–2.47; p = 0.045) and perineural invasion (hazard ratio 1.77, 95% confidence interval 1.13–2.77; p = 0.013) were both associated with a higher BCR rate. After accounting for age at surgery, PSA value, pathologic tumor stage, Gleason Grade Group, lymph node invasion, positive surgical margin, surgical approach, and adjuvant radiation therapy, lymphovascular (p = 0.740) or perineural invasion (p = 0.341) were not significantly associated with a higher BCR since the Gleason Grade Group and pathologic tumor stage highly correlated with lymphovascular as well as perineural invasion. Conclusions: In univariable models, lymphovascular or perineural invasion is associated with BCR. After adjustment for standard pathologic tumor characteristics, lymphovascular or perineural invasion is not an independent predictor for BCR. [ABSTRACT FROM AUTHOR]

Simple Summary: Inter-alpha-trypsin inhibitor-5 (ITIH5), a class II tumor suppressor gene, encodes a protein that is lost during tumor progression in many solid cancers. Unexpectedly, however, ITIH5 is significantly upregulated in cholangiocarcinoma (CCA), making it a potential liquid biopsy marker for early CCA detection, as recently shown. Indeed, CCA is the first tumor entity described in which ITIH5 is upregulated rather than downregulated in the tumor compared to normal tissue. In our study, we demonstrate that CCAs with abundant ITIH5 protein expression have favorable survival, a low UICC stage and the absence of perineural invasion. The re-expression of ITIH5 impairs the colony growth of cholangiocarcinoma cell lines. Although ITIH5 is upregulated in the tumor, it retains its tumor-suppressive function in CCA, similar to other tumor entities such as breast cancer and pancreatic cancer, where it is downregulated. Thus, ITIH5 may have both diagnostic and prognostic biomarker potential in CCA. The mechanisms of ITIH5 upregulation, particularly in intrahepatic CCAs, during oncogenic transformation remain unclear, but their elucidation could improve future CCA therapies. Background: Cholangiocarcinoma (CCA) are aggressive bile duct cancers with a poor prognosis for which there are only few established prognostic biomarkers and molecular targets available. The gene ITIH5, a known class II tumor suppressor gene (C2TSG), encodes a secreted protein of the extracellular matrix mediating tumor suppressive properties. Recently, it was surprisingly found that the ITIH5 protein is specifically upregulated in CCAs and that ITIH5 detection in blood could be an excellent liquid biopsy marker for indicating the presence of a CCA tumor in a patient. We therefore investigated whether patients with CCAs with abundant versus low ITIH5 protein expression also differ in their prognosis. Methods: To clarify this question, a large CCA cohort (n = 175) was examined using immunohistochemistry on a tissue microarray (TMA). Results: Abundant ITIH5 expression in CCA was associated with favorable survival, a low UICC stage and the absence of perineural invasion (PNI). Conclusions: ITIH5 has biomarker potential not only for the early detection of CCA from blood-based liquid biopsies but also as a prognostic tissue biomarker for risk stratification. Our results suggest that the upregulation of ITIH5 is particularly abundant in intrahepatic CCAs (iCCA). The mechanisms mediating the strong initial upregulation of ITIH5 during the oncogenic transformation of bile duct cells are still unclear. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study examined PD-L1 expression in advanced Thyroid Cancer (TC) and its relationship with histological subtypes, molecular mutations, and progression-free survival (PFS). Analyzing data from 176 patients with advanced TC, our study found significant variability in PD-L1 expression with Oncocytic Thyroid Cancer (OTC) and Anaplastic Thyroid Cancer (ATC) exhibiting the highest frequencies of PD-L1 expression, while Medullary TC (MTC) and Papillary TC Follicular Variant (PTCFV) did not show any PD-L1 expression. Notably, PD-L1 positivity correlated with shorter progression-free survival (PFS) in ATC and was associated with TP53 mutation. These findings suggest that PD-L1 expression, combined with genetic profiling could inform personalized immunotherapy strategies for aggressive forms of TC, emphasizing the need for further research to validate these biomarkers and enhance treatment efficacy. Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the deadliest form of primary brain cancer, and the survival of patients is only about 15 months after diagnosis, even with aggressive treatment. Many cellular factors that are used by GBM cells to divide abnormally and invade brain tissue to result in patient death are unknown. Here, we investigated the potential role of the cellular enzyme QSOX1, which creates specific bonds within proteins, in GBM cell proliferation, migration in a dish, and invasion into brain tissue in our chick embryo brain tumor model system. By experimentally reducing QSOX1 protein production in GBM cells, we found that this reduction resulted in less proliferation, slower migration, and less invasion into brain tissue. These results show the importance of the QSOX1 enzyme in GBM cells in order for them to exhibit their abnormal aggressive behavior that drives this incurable cancer. Background: Quiescin Sulfhydryl Oxidase 1 (QSOX1) is an enzyme that catalyzes the oxidation of free thiols to generate disulfide bonds in a variety of proteins, including the cell surface and extracellular matrix. QSOX1 has been reported to be upregulated in a number of cancers, and the overexpression of QSOX1 has been correlated with aggressive cancers and poor patient prognosis. Glioblastoma (GBM) brain cancer has been practically impossible to treat effectively, with cells that rapidly invade normal brain tissue and escape surgery and other treatment. Thus, there is a crucial need to understand the multiple mechanisms that facilitate GBM cell invasion and to determine if QSOX1 is involved. Methods and Results: Here, we investigated the function of QSOX1 in human glioblastoma cells using two cell lines derived from T98G cells, whose proliferation, motility, and invasiveness has been shown by us to be dependent on disulfide bond-containing adhesion and receptor proteins, such as L1CAM and the FGFR. We lentivirally introduced shRNA to attenuate the QSOX1 protein expression in one cell line, and a Western blot analysis confirmed the decreased QSOX1 expression. A DNA content/cell cycle analysis using flow cytometry revealed 27% fewer knockdown cells in the S-phase of the cell cycle, indicating a reduced proliferation. A cell motility analysis utilizing our highly quantitative SuperScratch time-lapse microscopy assay revealed that knockdown cells migrated more slowly, with a 45% decrease in migration velocity. Motility was partly rescued by the co-culture of knockdown cells with control cells, indicating a paracrine effect. Surprisingly, knockdown cells exhibited increased motility when assayed using a Transwell migration assay. Our novel chick embryo orthotopic xenograft model was used to assess the in vivo invasiveness of knockdown vs. control cells, and tumors developed from both cell types. However, fewer invasive knockdown cells were observed after about a week. Conclusions: Our results indicate that an experimental reduction in QSOX1 expression in GBM cells leads to decreased cell proliferation, altered in vitro migration, and decreased in vivo invasion. [ABSTRACT FROM AUTHOR]

Simple Summary: Serous ovarian carcinoma (SOC) is the most common type of ovarian cancer, but predicting its behaviour and patient outcomes has been challenging. This research is the first to comprehensively assess histopathological features such as lymphovascular space invasion, tumour budding, the tumour–stroma ratio, the stromal type, microvessel density, tumour-infiltrating lymphocytes, and tertiary lymphoid structures in the same cohort of both primary and metastatic SOC cases. By simultaneously evaluating these features, our study provides new insights into the tumour microenvironment and its role in disease progression. This comprehensive approach highlights the prognostic value of these features and offers a straightforward method for assessing tumour aggressiveness in routine clinical practice. These findings could lead to better risk stratification and personalised treatment strategies for SOC patients, particularly in settings where access to advanced molecular testing is limited. Background/Objectives: Serous ovarian carcinoma (SOC) is the most common subtype of epithelial ovarian cancer, with high-grade (HGSOC) and low-grade (LGSOC) subtypes presenting distinct clinical behaviours. This study aimed to evaluate histopathologic features in SOC, correlating these with prognostic outcomes, and explore the potential clinical implications. Methods: We analysed 51 SOC cases for lymphovascular space invasion (LVSI), tumour border configuration (TBC), microvessel density (MVD), tumour budding (TB), the tumour–stroma ratio (TSR), the stromal type, tumour-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs). A validation cohort of 54 SOC cases from The Cancer Genome Atlas (TCGA) was used for comparison. Results: In the discovery set, significant predictors of aggressive behaviour included LVSI, high MVD, high TB, and low TILs. These findings were validated in the validation set where the absence of TLSs, lower peritumoural TILs, immature stromal type, and low TSR were associated with worse survival outcomes. The stromal type was identified as an independent prognostic predictor in SOC across both datasets. Inter-observer variability analysis demonstrated substantial to almost perfect agreement for these features, ensuring the reproducibility of the findings. Conclusions: The histopathological evaluation of immune and stromal features, such as TILs, TLSs, TB, TSR, and stromal type, provides critical prognostic information for SOC. Incorporating these markers into routine pathological assessments could enhance risk stratification and guide treatment, offering practical utility, particularly in low-resource settings when molecular testing is not feasible. [ABSTRACT FROM AUTHOR]

Simple Summary: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan receptor involved in various functions, including in breast cancer. Chemoresistance in breast cancer is a major clinical issue, and the role of RHAMM and hyaluronan in this process is not well understood. Our study found that RHAMM and hyaluronan are linked to increased aggressiveness and recurrence in breast cancer after chemotherapy. In lab experiments, epirubicin-resistant breast cancer cells had higher RHAMM levels than non-resistant cells. Knockdown of RHAMM decreased the growth and migration of both cell types. It also lowered CD44 levels, a marker of cancer stem cells, and changed N-cadherin and E-cadherin, resulting in more typical epithelial cell behavior. These findings suggest that abnormal RHAMM activity contributes to chemoresistance by enhancing cancer stem cell properties and altering cell characteristics, promoting cancer growth and spread. This research could lead to new ways to combat breast cancer chemoresistance. Background/Objectives: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan (HA) receptor, which exerts diverse biological functions in not only physiological but also pathological conditions in human malignancies, including breast cancer. Although chemoresistance is a significant clinical challenge in breast cancer, a possible contribution of RHAMM and hyaluronan to breast cancer chemoresistance has remained unclear. Methods: We immunolocalized RHAMM and HA in breast carcinoma tissues. Also, we utilized epirubicin-sensitive (parental) and rpirubicin-resistant (EPIR) breast cancer cell lines to explore the role of RHAMMM in breast cancer progression. Results: We found out that RHAMM and HA were cooperatively correlated with breast cancer aggressiveness and recurrence after chemotherapy. In vitro studies demonstrated that RHAMM was overexpressed in EPIR cells compared to parental cells. In addition, the knockdown of RHAMM significantly suppressed proliferation and migration of both parental and EPIR cells. On the other hand, the expression level of cancer stem cell marker CD44, which was overexpressed in M-EPIR (epirubicin-resistant MCF-7 subline) compared to MCF-7, was significantly suppressed by knockdown of RHAMM. In addition, the knockdown of RHAMM significantly altered the expression of N-cadherin and E-cadherin, leading to an epithelial phenotype. Conclusions: Aberrant RHAMM signaling were considered to cause chemoresistance related to cancer stemness and epithelial to mesenchymal transition, and increased cell proliferation and migration of both chemo-sensitive and chemo-resistant breast cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Rectal cancer (RC) is the third most common gastrointestinal malignancy, with a rising incidence, particularly among the population under 50 years old. Extramural venous invasion (EMVI) is defined as the presence of malignant cells in veins beyond the muscularis propria near the primary colorectal tumor. The aim of our retrospective study was to assess the prognostic value of separate pathological EMVI reporting in operative RC samples and to determine its relationship with standard pathohistological and surgical parameters among a selected cohort of RC patients from our institution. Finally, EMVI is proved not only to be a feature of aggressive tumor behavior, but also as a separate and independent parameter in patients with rectal cancer. The results we obtained strongly suggest the importance of separately reporting extramural vascular invasion (EMVI) from lymphovascular invasion (LVI) in daily practice, as well as that EMVI could be a good addition to TNM staging. Background/Objectives: Vascular invasion, especially extramural vascular invasion (EMVI), has emerged as a prognostic parameter for rectal cancer (RC) in recent years. Prediction of recurrence and metastasis development poses a significant challenge for oncologists, who need markers for prediction of adverse outcome. The aim of this study was to examine the prognostic significance of pathohistologically detected EMVI in untreated rectal cancer and its implications in separate reporting. Methods: We examined 100 untreated RC patients who underwent curative resection from January 2016 to June 2018 with a follow-up of 5 years. Patients were divided into equal EMVI− and EMVI+ groups based on histological re-examination of H&E-stained postoperative surgical samples. Results: The presence of EMVI within the selected cohort was significantly associated with female gender, T3/T4 and N1/N2 post-operative stages, positive lymph nodes, lymph node ratio LNR2 and LNR3 groups, abundant tumor-infiltrating lymphocytes, positive lympho-vascular invasion (LVI), perineural (PNI), and circumferential resection margin (CRM) (p < 0.05 in all tests). Within EMVI+ patients, local recurrences and/or metastases and death outcomes were more frequent events (p = 0.029 and p = 0.035, respectively), while survival analyses revealed that EMVI+ patients had significantly shorter overall survival (OS, p = 0.040) and disease-free survival (DFS, p = 0.028). Concerning LVI, differences in OS between LVI+ and LVI− patients were not statistically significant (p = 0.068), while LVI+ patients had significantly shorter DFS (p = 0.024). Moreover, univariate COX regression analysis demonstrated the negative impact of EMVI on OS (HR: 2.053, 95% CI: 1.015–4.152; p = 0.045) and DFS (HR: 2.106, 95% CI: 1.066–4.870; p = 0.038), which was not the case for LVI + RC patients. Conclusions: The obtained results strongly suggest the significance of separate reporting of EMVI from lympho-vascular invasion, as it is potentially a surrogate marker for adverse prognosis and outcome. [ABSTRACT FROM AUTHOR]

Purpose: Craniopharyngioma is a tumor derived from the squamous epithelium of Rathke's pouch. Despite successful excision, recurrence is common, typically occurring at the original tumor site. More rarely, recurrences can manifest at distant locations. This article reports on three distinct types of ectopic recurrence and reviews the existing literature. Methods: We reviewed clinical records and neuroimaging data of craniopharyngioma patients at our institution, identifying three cases of ectopic recurrence. Additionally, we conducted a literature review of similar cases published between 1975 and 2023, focusing on historical background, pathophysiology, clinical and radiological features, and treatment options. Results: We identified nineteen articles detailing ectopic recurrence of craniopharyngiomas in pediatric patients. The right frontal lobe was the most frequently reported site of recurrence. The shortest interval to recurrence was 11 months, while the longest was 14 years. Most cases were managed with surgical resection, yielding positive outcomes. In our cases, the recurrence sites were temporal intraparenchymal, intraosseous orbital, and occipital intraventricular. All were successfully treated with surgery, with no subsequent recurrences. Conclusion: Although craniopharyngiomas are histologically benign, they can recur locally and, more rarely, at distant sites. Surgical intervention is generally well-tolerated. Further research into tumor cell dissemination mechanisms is essential to develop strategies for preventing ectopic recurrence. [ABSTRACT FROM AUTHOR]

To examine whether the endometrial cancer (EC) survival disadvantage among Black populations is US-specific, a comparison between African-descent populations from different countries with a high development index is warranted. We analyzed 28 213 EC cases from cancer registries in Florida (2005-2018) and the French Caribbean islands of Martinique (2005-2018) and Guadeloupe (2008-2018) combined. Kaplan-Meier and all-cause Cox proportional hazards models were used to compare survival. Models were stratified by EC histology type and the main predictor examined was race/ethnicity (non-Hispanic White [NHW] and no-Hispanic Black [NHB] women in the United States versus Black women residing in the Caribbean). For endometrioid and nonendometrioid EC, after adjusting for age, histology, stage at diagnosis, receipt of surgery, period of diagnosis, and poverty level, US NHB women and Caribbean Black women had a higher risk of death relative to US NHW women. There was no difference between US NHB and Caribbean Black women (hazard ratio [HR] = 1.07; 95% CI, 0.88-1.30) with endometrioid EC. However, Caribbean Black women with nonendometrioid carcinomas had a 40% higher risk of death (HR = 1.40; 95% CI, 1.13-1.74) than US NHB women. The low EC survival among US Black women extends to foreign populations of African descent. For the aggressive nonendometrioid ECs, survival among Caribbean Black women outside of the United States is considerably worse. This article is part of a Special Collection on Gynecological Cancers. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Prostatic carcinosarcoma comprises <1% of all prostate neoplasms. The literature on this disease is limited to a few case studies, primarily due to the rarity of this malignancy. We aimed to investigate the demographic, clinical, and histologic factors, prognosis, and survival of prostatic carcinosarcoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with prostatic carcinosarcoma from 2000-2018. Demographic and clinical data, including age, race, sex, tumor grade, stage, tumor size, lymph node status, metastasis, and treatment modalities, were recorded. RESULTS: Patients with prostatic carcinosarcoma had a median age of 72 years at diagnosis, most cases among White individuals (93%). When reported, the histologic grade comprised moderately differentiated (3.3%), poorly differentiated (56.7%), and undifferentiated/anaplastic (40%) subtypes. In patients with reported data, tumor size varied between 2-5 cm (15.8%) and >5 cm (84.2%). Distant metastasis most commonly occurred in the liver (12.5%) and lung (12.5%), followed by the bone (8.3%). The most common treatment performed was surgery with radiation (32.4%). The five-year overall survival was 11.9%. CONCLUSIONS: Prostatic carcinosarcoma affects men in the seventh decade of life. Regional and distant tumor stage is considered an indicator of survival. Prostate carcinosarcoma is rare; due to its aggressive nature, a deeper understanding, and an improved personalized therapeutic approach are necessary for improving patient outcomes in this challenging arena of oncology. [ABSTRACT FROM AUTHOR]

The PIM kinase family, consisting of PIM1, PIM2, and PIM3, is a group of serine/threonine protein kinases crucial for cellular growth, immunoregulation, and oncogenesis. PIM1 kinase is often overexpressed in solid and hematopoietic malignancies, promoting cell survival, proliferation, migration, and senescence by activating key genes. In vitro and in vivo studies have established the oncogenic potential of PIM1 kinases. These kinases have been implicated in tumor progression, metastasis, and resistance to chemotherapy, underscoring their potential as a therapeutic target for cancer therapy. This review delves into the intricate molecular mechanisms through which PIM1 interacts with specific substrates in different tumor tissues, leading to diverse outcomes in various human cancers. Over the past decade, the inhibition of PIM1 in cancers has garnered significant attention as a potential standalone treatment. Various in vitro, in vivo, and early clinical trial data have provided support for this approach to varying extents. Novel compounds that inhibit PIM1 kinase have shown effectiveness and a favorable toxicity profile in preclinical studies. Several of these substances are now being studied in clinical trials due to their promising outcomes. This article provides a thorough examination of the PIM1 kinase pathways and the recent advancements in producing PIM1 kinase inhibitors for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa. [ABSTRACT FROM AUTHOR]

Background: A multicenter database was utilized to examine the current treatment landscape and clinical outcomes among patients with metastatic hormone‐sensitive prostate cancer (mHSPC) following approval of upfront androgen receptor signaling inhibitors (ARSIs). Methods: We retrospectively analyzed patients with mHSPC who commenced treatment between February 2018 and June 2023. The Kaplan–Meier method was used to assess oncological outcomes, including time to castration‐resistant prostate cancer (CRPC), progression‐free survival 2 (PFS2, duration from initial treatment to tumor progression during second‐line treatment), cancer‐specific survival (CSS), and overall survival (OS). Cox regression analyses were performed to determine the impact of treatment choices on oncological outcomes. In addition, the incidence rate of adverse events was assessed. Results: In total, 829 patients were analyzed; 42.5% received ARSIs with androgen deprivation therapy (ADT), 44.0% received combined androgen blockade (CAB), and 13.5% received ADT alone. Kaplan–Meier curves and multivariate Cox regression analyses indicated higher rates of CRPC and shorter PFS2 in patients treated with CAB versus ARSIs with ADT. By contrast, CSS and OS were not significantly different between the ARSI with ADT group and the CAB group. Grades 3–4 adverse events occurred in 1.9% of patients receiving CAB and 6.0% of those receiving ARSIs with ADT. Conclusions: Initial treatment with ARSIs in combination with ADT resulted in a longer time to CRPC and longer PFS2 compared to CAB. Although CAB and ADT alone were associated with fewer adverse events, ARSIs with ADT should be considered a first‐line treatment option given its superior oncological outcomes. [ABSTRACT FROM AUTHOR]

This study develops a prognostic model to predict metastasis and prognosis in colorectal cancer liver metastases by identifying distinct macrophage subsets. Using scRNA-seq data from primary colorectal cancer and liver metastases, we dissected the cellular landscape to find unique macrophage subpopulations, particularly EEF1G + macrophages, which were prevalent in liver metastases. The study leveraged data from GSE231559, TCGA, and GEO databases to construct an 8-gene risk model named EMGS, based on the EEF1G + macrophage gene signature. Patients were divided into high-risk and low-risk groups using the median EMGS score, with the high-risk group showing significantly worse survival. This group also demonstrated upregulated pathways associated with tumor progression, such as epithelial-mesenchymal transition and angiogenesis, and downregulated metabolic pathways. Moreover, the high-risk group presented an immunosuppressive microenvironment, with a higher TIDE score indicating lower effectiveness of immunotherapy. The study identifies potential drugs targeting the high-risk group, suggesting therapeutic avenues to improve survival. Conclusively, the EMGS score identifies colorectal cancer patients at high risk of liver metastases, highlighting the role of specific macrophage subsets in tumor progression and providing a basis for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Gastric foveolar type neoplasia is a rare histological variant of gastric tumors. It is very difficult to differentiate between benign and malignant intraepithelial foveolar neoplasia (IFN). Although limited molecular alterations have been identified in IFNs, somatic copy number alterations (SCNAs), which are linked to tumor progression, have not been systematically evaluated in IFN. Methods: The aim of the present study was to comprehensively examine SCNAs using a SNP array in 37 cases of IFN, compared with intestinal type dysplasia, including 39 low grade (LGD) and 32 high grade dysplasia (HGD) cases. In addition, gene mutations were evaluated using a gene panel. Finally, we attempted to determine molecular profiles using a hierarchical clustering analysis. Results: Two patterns could be categorized according to the SCNAs in 108 tumors examined: high (subgroup 1) and low (subgroup 2) frequencies of SCNAs. Although IFN and LGD were associated with subgroup 2, HGD was found in both subgroups. The median numbers of total SCNAs and copy number gains were higher in IFN or HGD than in LGD. In addition, the IFN genotype was characterized by altered genes located at 4p13–4q35.2, including RAP1GDS1 and LEF1, which may be associated with IFN development. Finally, no significant mutations were found in IFNs using a gene panel. Conclusions: The current molecular profiles of IFN may help elucidate the mechanisms of IFN development. [ABSTRACT FROM AUTHOR]

Most melanomas progress from radial to vertical growth phase before spreading locoregionally and distally. Much is still unknown about the metabolic changes in the tumor cells and their microenvironment during this metastatic progression. We aimed to gain new insight into the molecular characteristics of melanoma in regard to spatial lipidomics to deliver new knowledge regarding tumor metastatic progression. We included 10 fresh tumor samples from 10 patients including two in situ melanomas, two invasive primary melanomas, and six metastatic melanomas (four in‐transit metastases and two distant metastases). In addition, we analyzed four healthy skin controls from the same patients. Time‐of‐flight imaging secondary ion mass spectrometry (ToF‐SIMS) enabled detailed spatial‐lipidomics that could be directly correlated with conventional histopathological analysis of consecutive H&E‐stained tissue sections. Significant differences in the lipid profiles were found in primary compared to metastatic melanomas, notably an increase in phosphatidylethanolamine lipids relative to phosphatidylinositol lipids and an increase in GM3 gangliosides in the metastatic samples. Furthermore, analysis of the data from in transit versus distant metastases samples highlighted that specific phospholipids, and a difference in the long versus shorter chain GM3 gangliosides, discriminated the metastatic routes. Further studies are warranted to verify these preliminary findings. Lipidomic changes could serve as a novel biomarker for tumor progression and even serve as a target for novel treatments. Furthermore, analyzing the lipid profiles could help to differentiate between primary and metastatic melanomas in challenging cases. [ABSTRACT FROM AUTHOR]

The Hallmark of Cancers consists of various biological capabilities of the tumor cell which help the medical experts to understand the development and identification of these cells during various stages of the cancer disease. The hallmark of cancer classification is a widely accepted framework that characterizes the fundamental biological capabilities of cancer cells. This classification is based on the work of Hanahan and Weinberg, who identified 10 hallmark capabilities that collectively enable the development and progression of cancer. The hallmark of cancer classification provides a comprehensive framework for understanding the biological basis of cancer development and progression. It helps researchers to identify the key molecular and cellular pathways that are involved in the disease, which can inform the development of new diagnostic tools and therapies. Multi-label classification aims to assign a set of labels to the samples under study. This paper focuses on creating an improved model by hybridizing the biomedical domain-specific embeddings for all the extracted biomedical features on the machine learning model. The use of domain-specific embeddings adds semantics to the vector-represented text. More specifically the study has tried to improve the efficacy of the multi-label classification as compared with other state-of-art methods using BioWordVec and the MeSH embeddings. The experimental work showed a significant improvement in the performance of our model which is being trained on the machine learning algorithm Support Vector Machine (SVM). The paper also focuses on understanding the label correlation which is studied by conducting a case study with medical domain experts and is also analyzed with the proposed model. [ABSTRACT FROM AUTHOR]

Objective: This study reports the surgical management and outcomes of patients with malignancies affecting the IVC. Methods: This was a retrospective study that considered patients undergoing surgery for IVC thrombectomy in Calgary, Canada, from 1 January 2010 to 31 December 2021. Parameters of interest included primary malignancy, the extent of IVC involvement, surgical strategy, and medium-term outcomes. Results: Six patients underwent surgical intervention for malignancies that affected the IVC. One patient had a retroperitoneal leiomyosarcoma, 1 had hepatocellular carcinoma with thrombus extending into the IVC and right atrium, 1 had adrenocortical carcinoma with IVC thrombus extending into the right atrium, and 3 had clear cell renal cell carcinoma with thrombus extending into the IVC. Surgical strategy for the IVC thrombectomy varied where 5 patients required the institution of cardiopulmonary bypass and underwent deep hypothermic circulatory arrest. No patient died perioperatively. One patient died 15-months post-operatively from aggressive malignancy. Conclusion: Different types of malignancy can affect the IVC and surgical intervention is usually indicated for these patients. Herein, we have reported the outcomes of IVC thrombectomy at our center. [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is a rare and highly aggressive form of skin cancer. However, there is limited research on the clinicopathological features of early‐onset MCC (EOMCC) and the differences between EOMCC and late‐onset MCC (LOMCC). Our objective was to evaluate the clinicopathological features and cancer‐specific survival (CSS) of EOMCC. Methods: Our cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2018, to December 31, 2020. Data from 1941 patients who were diagnosed with primary cutaneous MCC were included. We then divided the patients with MCC into two groups: those with EOMCC (526 patients) and those with LOMCC (1415 patients). CSS is used as the primary outcome. Results: The EOMCC group exhibited trends toward advanced tumor progression, an expanded surgical scope, increased lymph node retrieval, intensified radiotherapy, greater utilization of systemic therapy, and a better prognosis. Multivariate analysis revealed that LOMCC (HR 3.305 [2.002–5.456], P < 0.001), advanced T stage (HR 1.430 [1.139–1.797], P = 0.002), advanced N stage (HR 1.522 [1.221–1.897], P < 0.001), M1 stage (HR 2.587 [1.480–4.521], P < 0.001), and radiation (HR 0.586 [0.410–0.837], P = 0.003) were significantly associated with CSS. Among these factors, EOMCC/LOMCC was most strongly associated with CSS, indicating that LOMCC is an independent risk factor for CSS. Interestingly, we found that regional EOMCC and localized or in situ LOMCC had almost completely overlapping survival curves (Plog‐rank = 0.620). Additionally, we observed that the TNM staging + age model was a more accurate predictor of CSS among MCC patients than using TNM staging alone. Conclusions: We found that EOMCC has distinct clinicopathological features compared to LOMCC. EOMCC is associated with better CSS. The combination of TNM staging and age was more accurate for predicting patient outcomes than TNM staging alone. [ABSTRACT FROM AUTHOR]

[Display omitted] • RNA binding proteins (RBPs) impact tumor development and play a role in sorting noncoding RNAs (ncRNAs) into exosomes. • The RBP-ncRNA-exosome mechanism is crucial in tumor regulation and provides insights for innovative treatment strategies. • This mechanism influences tumor metastasis, multidrug resistance, angiogenesis, the immunosuppressive microenvironment, and tumor progression. • Potential therapeutic strategies include targeted drug discovery and genetic engineering of therapeutic exosomes. RNA binding proteins (RBPs) play a role in sorting non-coding RNAs (ncRNAs) into exosomes. These ncRNAs, carried by exosomes, are involved in regulating various aspects of tumor progression, including metastasis, angiogenesis, control of the tumor microenvironment, and drug resistance. Recent studies have emphasized the importance of the RBP-ncRNA-exosome mechanism in tumor regulation. This comprehensive review aims to explore the RBP-ncRNA-exosome mechanism and its influence on tumor development. By understanding this intricate mechanism provides novel insights into tumor regulation and may lead to innovative treatment strategies in the future. The review discusses the formation of exosomes and the complex relationships among RBPs, ncRNAs, and exosomes. The RBP-ncRNA-exosome mechanism is shown to affect various aspects of tumor biology, including metastasis, multidrug resistance, angiogenesis, the immunosuppressive microenvironment, and tumor progression. Tumor development relies on the transmission of information between cells, with RBPs selectively mediating sorting of ncRNAs into exosomes through various mechanisms, which in turn carry ncRNAs to regulate RBPs. The review also provides an overview of potential therapeutic strategies, such as targeted drug discovery and genetic engineering for modifying therapeutic exosomes, which hold great promise for improving cancer treatment. [ABSTRACT FROM AUTHOR]

Background: There is interest in using bladder-preserving therapy as an alternative definitive therapy for muscle invasive bladder cancer in certain high-risk groups such as the elderly. Objective: To determine if bladder-preserving therapy represents a safer alternative to surgical intervention in elderly patients with muscle invasive bladder cancer. Methods: We surveyed the Surveillance, Epidemiology and End Results database (SEER) for cases of non-metastasized malignant bladder cancer in patients aged 80+. Survival outcomes with radical cystectomy (RC) with or without chemotherapy were compared to those after chemotherapy and radiation without cystectomy. We performed log-rank tests and Kaplan-Meier and cox regression and hazard analyses before and after propensity score matching. Results: A total of 2995 patients were identified, with 49.98% treated with RC only, 8.65% treated with RC/chemotherapy, and 41.37% treated with chemotherapy and radiation without RC. Median overall survival for the RC only, RC/chemotherapy and chemotherapy/radiation groups were 31.4, 44.1, and 24.6 months, respectively. On multivariate analysis, hazard ratios (reference: RC/chemotherapy group) were RC Only (HR = 1.408 (95% CI 1.188–1.669), p < 0.0001) and chemotherapy/radiation (HR = 1.650 (95% CI 1.390–1.959), p < 0.0001). After matching the chemotherapy/radiation and RC/chemotherapy groups, the former continued to show survival hazard (HR = 1.744 (95% CI 1.414–2.155), p < 0.0001). Conclusions: Octogenarians should be offered definitive local therapy for their localized bladder cancer including RC and chemotherapy. Bladder-sparing alternatives should be reserved for patients unfit for surgery. [ABSTRACT FROM AUTHOR]

Objectives: Bladder-Sparing Approach was presented in patients who are not willing or not suitable for Radical Cystectomy (RC). There have been inconsistencies in the literature regarding the comparison of survival rates of these two methods. Our objective is to evaluate the survival rate of patients with muscle-invasive bladder cancer (MIBC) undergoing different treatment methods. Design: Retrospective cross-sectional study. Setting: A secondary care, multicenter study in Kerman, Iran 2008 to 2016. Participants: All 200 patients who were diagnosed with Muscle Invasive Bladder Cancer and were admitted to our hospitals. Patients with inaccessible medical files and patients with pathologies other than TCC were excluded. Main outcome measures: Radical cystectomy and different methods of bladder preservation were compared based on their survival rate. Interventions: Radical cystectomy or bladder preservation Results: Overall survival of the patients was 2 years [95% CI: 1.37–2.63]. The overall 5-year survival rate of patients with MIBC was 32%. Having a 6.4 years overall survival, the RC group showed the highest survival compared with others (p = 0.01); the overall survival of patients undergoing TMT, TURT, chemotherapy, or radiotherapy monotherapy was 3.15 years [95% CI: 2.242–4.061], 4.06 [95% CI: 3.207–4.931], 2.58 [95% CI: 1.767–3.399], and 3.14 [95% CI: 1.614–4.672] years, respectively. Patients younger than 65 undergoing RC had an overall survival of 7 years, compared with 2 years for the TMT group. (p = 0.0001). Conclusions: The Bladder-Preservation method, as a replacement for RC, showed a lower overall survival rate in our study. A prospective randomized clinical trial may declare the best treatment. [ABSTRACT FROM AUTHOR]

The mutual regulation between hydrogen sulfide (H 2 S) and microRNA (miRNA) is involved in the development of many diseases, including cancer, cardiovascular disease, inflammatory disease, and high-risk pregnancy. Abnormal expressions of endogenous H 2 S-producing enzyme and miRNA in tissues and cells often indicate the occurrence of diseases, so the maintenance of their normal levels in the body can mitigate damages caused by various factors. Many studies have found that H 2 S can promote the migration, invasion, and proliferation of cancer cells by regulating the expression of miRNA, while many H 2 S donors can inhibit cancer progression by interfering with the proliferation, apoptosis, cell cycle, metastasis, and angiogenesis of cancer cells. Furthermore, the mutual regulation between H 2 S and miRNA can also prevent cell injury in cardiovascular disease and inflammatory disease through anti-inflammation, anti-oxidation, anti-apoptosis, and pro-autophagy. In addition, H 2 S can promote angiogenesis and relieve vasoconstriction by regulating the expression of miRNA, thereby improving fetal growth in high-risk pregnancy. In this review, we discuss the mechanism of mutual regulation between H 2 S and miRNA in various diseases, which may provide reliable therapeutic targets for these diseases. • H 2 S promotes the progression of cancer cells by regulating the miRNA expression. • H 2 S donors inhibit cancer growth via the mutual regulation between H 2 S and miRNA. • The mutual regulation between H 2 S and miRNA plays a protective role in diseases. • H 2 S plays a double-edged sword role in inflammation via interaction with miRNA. [ABSTRACT FROM AUTHOR]

Purpose: To assess the accuracy of preoperative sonographic staging in patients with primary invasive breast cancer. Methods: We retrospectively analyzed a prospectively kept service database of patients with newly diagnosed, unifocal, cT1-3, invasive breast cancer. All patients were diagnosed at a single center institution between January 2013 and December 2021. Clinical T stage was assessed preoperatively by ultrasound and correlated with the definite postoperative pathologic T stage. Demographics, clinical and pathological characteristics were collected. Factors influencing accuracy, over- and underdiagnosis of sonographic staging were analyzed with multivariable regression analysis. Results: A total of 2478 patients were included in the analysis. Median patients' age was 65 years. 1577 patients (63.6%) had clinical T1 stage, 864 (34.9%) T2 and 37 (1.5%) T3 stage. The overall accuracy of sonography and histology was 76.5% (n = 1896), overestimation was observed in 9.1% (n = 225) of all cases, while underestimation occurred in 14.4% (n = 357) of all cases. Accuracy increased when clinical tumor stage cT was higher (OR 1.23; 95% CI 1.10–1.38, p ≤ 0.001). The highest accuracy was seen for patients with T2 stage (82.8%). The accuracy was lower in Luminal B tumors compared to Luminal A tumors (OR 0.71; 95% CI 0.59–0.87, p ≤ 0.001). We could not find any association between sonographic accuracy in HER2 positive patients, and demographic characteristics, or tumor-related factors. Conclusion: Our unicentric study showed a high accuracy of sonography in predicting T stage, especially for tumors with clinical T2 stage. Tumor stage and biological tumor factors do affect the accuracy of sonographic staging. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate differences between HPV‐16 mono‐ and HPV‐16/18 co‐infections in terms of cervical dysplasia and invasive cancer. Methods: This multicentre, retrospective study spanned from December 2017 to December 2020, involving women who visited gynaecological oncology clinics for colposcopy with either HPV‐16 or HPV‐16/18 positivity. A total of 736 patients, 670 in Group 1 (HPV‐16 positivity) and 66 in Group 2 (HPV‐16/18 positivity), were compared for the presence of CIN2+ lesions detected by colposcopic biopsy or endocervical curettage (ECC). Exclusions included hysterectomized patients, those with prior gynaecological cancers, and patients with HPV positivity other than types 16 and 18. Results: Among the included patients, 42.4% had a diagnosis of CIN2+ lesions. The cytology results demonstrated abnormal findings in 45.3% in Group 1 and 42.2% in Group 2, with no significant difference between the groups. ECC revealed CIN2+ lesion in 49 (8.7%) patients in group 1, while only 1 (1.7%) patient had CIN2+ lesion in group 2. There was no difference between 2 groups in terms of ECC result (p = 0.052). In group 1, 289 (43.1%) patients had CIN2+ lesion, while 23 (34.8%) patients had CIN2+ lesions in group 2. There was no difference between group 1 and 2 in terms of diagnosis of CIN2+ lesions (p = 0.19). Conclusion: This multicentre retrospective study found no significant differences between HPV‐16 mono‐ and HPV‐16/18 co‐infections regarding cervical pathologies. Larger studies are needed to validate and further explore these findings. [ABSTRACT FROM AUTHOR]

Extranodal extension in metastatic lymph nodes (LNs) is a poor prognostic factor in bladder cancer (BC). Furthermore, cancer invasion levels in sentinel LNs are associated with prognosis in melanoma. The present study aimed to evaluate the LN invasion level, defined as the extent of cancer invasion in anatomical and immunological LN substructures, and compare it with the pathological node (pN) stage of the tumor-node-metastasis staging system in BC. A total of 98 patients with BC who underwent radical cystectomy and pelvic lymphadenectomy were retrospectively assessed. The LN invasion level was classified as follows: Level 0, no cancer cell within the resected LNs; Level 1, cancer cells confined to intracapsular lymph vessels and subcapsular or transverse sinuses; Level 2, cancer cells infiltrating the cortex, paracortex or medulla; and Level 3, cancer cells infiltrating or beyond the LN capsule. The proportion of patients with Levels 0, 1, 2 and 3 was 70.4% (69/98), 8.2% (8/98), 14.3% (14/98) and 7.1% (7/98), respectively. Kaplan-Meier survival curves of recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) with LN invasion levels better strati- fied outcome patient when using Levels 1-3 compared with pN1-3. In addition, LN invasion levels better predicted RFS, CSS and OS, in comparison with the pN stage (c-index of 0.672 vs. 0.646, 0.688 vs. 0.665, and 0.702 vs. 0.661, respectively). Finally, multivariate analysis revealed that the predictive accuracy of the model integrating pathological tumor (pT) stage and LN invasion levels in RFS, CSS and OS was greater than that of the conventional model that included pT and pN stage (c-index of 0.723 vs. 0.703, 0.710 vs. 0.694, and 0.725 vs. 0.692, respectively). In conclusion, the model with LN invasion levels accurately predicted the prognosis of patients with BC after radical cystectomy and pelvic lymphadenectomy. [ABSTRACT FROM AUTHOR]

Breast cancer typically arises from the terminal duct-lobular unit of the mammary gland and rarely from the ducts inside the nipple. The present paper reports a rare case of primary invasive ductal carcinoma of the papilla, which was a locally advanced triple-negative breast cancer that was treated with 6 cycles of neoadjuvant chemotherapy with a nab-paclitaxel, epirubicin and cyclophosphamide regimen. Surgical pathology confirmed that a pathological complete response was achieved and adjuvant radiotherapy was performed postoperatively. No recurrence or metastasis occurred as of April 2024. A review of previous similar cases revealed that primary invasive breast cancer of the nipple has several manifestations. Changes in the nipple should be treated cautiously and a pathological biopsy should be performed in a timely manner. Breast cancer occurring in the nipple can be treated with reference to the same type of common breast cancer, and neoadjuvant chemotherapy can also be performed first if neoadjuvant chemotherapy is indicated. [ABSTRACT FROM AUTHOR]

Secukinumab is a monoclonal antibody directed against interleukin-17 approved for the treatment of psoriasis and spondyloarthritis. The favorable oncological profile of secukinumab in patients with a history of malignancy has been shown in patients with psoriasis. However, systematic data to this regard have not been published yet for patients with spondyloarthritis. The objective of the present study was to evaluate the oncological safety of secukinumab in patients affected by this group of diseases. We performed a retrospective study in which we identified from our cohort patients with spondyloarthritis treated with secukinumab and with a history of malignancy. These patients' baseline demographic, treatment, rheumatological, and oncological data were collected. The neoplastic outcome (i.e., cancer recurrence or progression) after secukinumab start was then analyzed. Our study included 22 patients with spondyloarthritis. The most frequently reported oncological diagnosis was breast cancer (9 [41%] patients). Secukinumab was started after a median of 24 months following cancer diagnosis. At this time point, all but three patients were in oncological remission. No case of cancer relapse or progression was recorded over a median follow-up of 30 months. In the largest cohort reported to date to this regard, secukinumab was not associated with oncological recurrence or progression in patients with spondyloarthritis with a history of malignancy. Secukinumab may, therefore, represent a safe option in this clinical scenario. [ABSTRACT FROM AUTHOR]

Recent studies have explored the prognostic role of the C-reactive protein to albumin ratio (CAR) in patients with bile duct cancer (BTC), but the results have been inconsistent. This study aimed to provide insight into the prognostic significance of the CAR in BTC prior to treatment using a meta-analysis. Summarized hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for prognosis and clinicopathological features using fixed or random effects models. Fourteen studies with a total of 1,543 subjects were included in this meta-analysis. Elevated CAR was significantly associated with poor overall survival (HR = 2.17, 95% CI = 1.81–2.60, P < 0.001) and decreased disease-free survival or recurrence-free survival (HR = 2.53, 95% CI = 1.98–3.25, P < 0.001) in BTC. In addition, high CAR was significantly associated with the presence of lymph node metastasis (OR = 1.54, 95% CI = 1.12– 2.13, P = 0.008), bile duct invasion (OR = 2.64, 95% CI = 1.54–4.54, P < 0.001), and tumor stages III–IV (OR = 3.11, 95% CI = 1.05–9.20, P = 0.040). However, there was no significant association between CAR and sex, microvascular invasion, or resection. An elevated CAR was significantly related to worse long-term and short-term survival and advanced clinicopathological features of BTC. CAR could serve as a valuable, noninvasive prognostic marker in patients with BTC. [ABSTRACT FROM AUTHOR]

• ECM synthesis poses significant demands for biomass generation with requirements different from cell proliferation. • With its high glycine and proline content, collagen synthesis imposes unique biosynthetic demands. • Pro-fibrotic signaling cascades mediate metabolic rewiring in activated fibroblasts. • Targeting the metabolic pathways supporting collagen synthesis provides opportunities for treating fibrotic conditions. • Nutrient availability influences metabolic pathways regulating collagen synthesis and creates new vulnerabilities. The extracellular matrix (ECM) is present in all tissues and crucial in maintaining normal tissue homeostasis and function. Defects in ECM synthesis and remodeling can lead to various diseases, while overproduction of ECM components can cause severe conditions like organ fibrosis and influence cancer progression and therapy resistance. Collagens are the most abundant core ECM proteins in physiological and pathological conditions and are predominantly synthesized by fibroblasts. Previous efforts to target aberrant collagen synthesis in fibroblasts by inhibiting pro-fibrotic signaling cascades have been ineffective. More recently, metabolic rewiring downstream of pro-fibrotic signaling has emerged as a critical regulator of collagen synthesis in fibroblasts. Here, we propose that targeting the metabolic pathways involved in ECM biomass generation provides a novel avenue for treating conditions characterized by excessive collagen accumulation. This review summarizes the unique metabolic challenges collagen synthesis imposes on fibroblasts and discusses how underlying metabolic networks could be exploited to create therapeutic opportunities in cancer and fibrotic disease. Finally, we provide a perspective on open questions in the field and how conceptual and technical advances will help address them to unlock novel metabolic vulnerabilities of collagen synthesis in fibroblasts and beyond. [ABSTRACT FROM AUTHOR]

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The aim of this study was to characterize the clinicopathological features and prognostic factors of T1/2 size (<4 cm) gingival squamous cell carcinoma (SCC) and to verify the impact of bone invasion. This was a single-centre, retrospective cohort study involving 206 patients with gingival SCC (maxilla or mandible), treated between 2000 and 2020. The patients were divided into three subgroups based on tumour size and bone invasion. The 5-year overall survival (OS) and disease-free survival (DFS) were 80.6% and 67.6%, respectively. Histological differentiation, advanced T stage, positive resection margin, bone invasion, and postoperative adjuvant therapy were associated with a poor prognosis (P < 0.05). Multivariate Cox analysis indicated that only histological differentiation (hazard ratio (HR) 2.68, P = 0.007) and bone invasion (HR 2.08, P = 0.036) were significantly associated with DFS. Bone invasion was observed in 145 (70.4%) patients, of whom 43 (20.9%) had a T1/2 size tumour. The subgroup with bone invasion and T1/2 size showed significantly worse OS and DFS when compared to the subgroup without bone invasion and similar or worse survival when compared to the subgroup with bone invasion and T3/T4 size. Histological differentiation and bone invasion were poor prognostic factors for gingival SCC, even in cases with small-sized tumours. For suspected bone invasion in small-sized tumours, an adequate bone margin is necessary and postoperative adjunctive therapy needs to be considered. [ABSTRACT FROM AUTHOR]