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Objective: Oral cancer examinations seek to clinically identify early oral cancers and discover premalignancies prior to their progression to invasive cancer. Method and materials: A cross-sectional study was conducted between April and August 2017 to explore and quantify the diagnostic approach used by United States (US) general dental practitioners following discovery of an oral lesion suspicious for malignancy/premalignancy. US licensed general dental practitioners who were clinically active members of the US National Dental Practice-Based Research Network were eligible to participate. Data for analysis were obtained via two questionnaires. Results: The majority of participants were males, practiced full-time, had a suburban primary practice, were born during the 1950s, and graduated dental school in the 1980s or 2000s. After identifying an oral lesion suspicious for premalignancy/malignancy, the next action of most general dental practitioner respondents (65.4%) was to refer the patient for consultation/biopsy. Most general dental practitioners (87.2%) referred to an oral and maxillofacial surgeon; 22% of general dental practitioners reported personally biopsying suspicious lesions. There was a relatively weak association between completing an Advanced Education in General Dentistry or General Practice Residency and subsequently personally performing biopsies on patients with oral lesions suspicious for malignancy/premalignancy (OR 1.33, P = .06). Most written referrals took place electronically and often included information, including lesion location (87.0%), lesion sign/symptoms (85.3%), lesion history (83.9%), radiographs (59.3%), medical history (50.6%), dental history (48.8%), and photographs (42.4%). When a referral biopsy was performed, referring clinicians were most frequently informed of the findings via a written report (96.7%, when positive for malignancy/premalignancy, and 95.4% when negative). Conclusion: A snapshot is presented of current actions taken by US general dental practitioners following the discovery of oral abnormalities suspicious for premalignancy/malignancy. [ABSTRACT FROM AUTHOR]

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re‐irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re‐radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow‐up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV‐based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA‐positive samples were identified by tracking patient‐specific CNVs found in earlier sequential plasma samples. ctDNA‐positivity after 5 and 10 radiation fractions (both: log‐rank, p =.050) as well as at the end of irradiation correlated with short progression‐free survival (log‐rank, p =.006). Moreover, a pronounced decrease of ctDNA toward re‐radiotherapy termination was associated with worse treatment outcome (log‐rank, p =.005). Dynamic ctDNA tracking in serial plasma beyond re‐radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re‐radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow‐up intervals, and dose prescription. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CHOL) is the second most common primary liver malignancy, characterized by high aggressiveness and heterogeneity. It is typically diagnosed at an advanced stage, leading to a poor prognosis. Although Peptidyl Proline Isomerase H (PPIH) has been implicated in various tumors, its role in CHOL remains unexplored. This study aims to investigate the diagnostic value and potential function of PPIH in CHOL. Methods: We analyzed the expression levels, prognostic significance, and diagnostic efficiency of PPIH in CHOL using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, coupled with gene enrichment analyses. The CIBERSORT database was employed to assess the correlation between PPIH expression and immune cell infiltration in CHOL. Additionally, immunohistochemical experiments were conducted to validate PPIH expression levels in CHOL tissues and to explore its correlation with TP53 gene mutations. Results: Our findings indicate that overexpression of PPIH mRNA in CHOL is associated with poor prognosis, with increased PPIH protein levels observed in CHOL tissues. Furthermore, PPIH expression showed a positive correlation with TP53 mutations. PPIH demonstrated strong diagnostic value for CHOL. Moreover, PPIH may influence tumor progression through its involvement in cell cycle regulation and spliceosome pathways, and is associated with immune cell infiltration levels. Conclusion: The results of this study suggest that PPIH is a potential novel biomarker with significant diagnostic value for patients with CHOL. PPIH may also play a role in modulating the immune microenvironment, contributing to poor prognosis. [ABSTRACT FROM AUTHOR]

The development of metastasis is a leading cause of cancer-related death that involves specific changes in the plasma membrane (PM) and nucleus of cancer cells. Elevated levels of membrane lipids, including sphingomyelin, cholesterol, and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), in the PM, contribute to changes in membrane rigidity, lipid raft formation, and actin polymerisation dynamics, processes that drive cell invasion. This review discusses the relationship between well-studied cytoplasmic phosphoinositides and their lesser-known nuclear counterparts, highlighting their functional role in metastatic progression. Nuclear phosphoinositides, particularly PI(4,5)P2, are essential for regulating transcription factors and chromatin organisation, thereby shaping gene expression patterns. We also explore the role of PI(4,5)P2 and its metabolism in cancer cell invasiveness and metastasis, proposing a model in which the dysregulation of cytosolic and/or nuclear PI(4,5)P2 pool triggers malignant transformation. Understanding the PI(4,5)P2-related mechanisms underlying metastasis may provide insights into potential therapeutic targets, paving the way for more effective therapies and improved patient outcomes. [ABSTRACT FROM AUTHOR]

Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics. Dysregulation of mitochondrial reactive oxygen species (mtROS) contributes to intestinal tumorigenesis. Here the authors report that excessive mtROS induces the release of mitochondrial PGAM5 into cytoplasm and subsequent dephosphorylation of MST3 kinase, promoting colorectal cancer progression. [ABSTRACT FROM AUTHOR]

Despite the current diagnostic and therapeutic approaches to bladder cancer being widely accepted, there have been few significant advancements in this field over the past decades. This underscores the necessity for a paradigm shift in the approach to bladder cancer. The role of amyloids in cancer remains unclear despite their identification in several other pathologies. In this study, we present evidence of amyloids in bladder cancer, both in vitro and in vivo. In a murine model of bladder cancer, a positive correlation was observed between amyloids and tumor stage, indicating an association between amyloids and bladder cancer progression. Subsequently, the amyloid proteome of the RT4 non-invasive and HT1197 invasive bladder cancer cell lines was identified and included oncogenes, tumor suppressors, and highly expressed cancer-related proteins. It is proposed that amyloids function as structures that sequester key proteins. Therefore, amyloids should be considered in the study and diagnosis of bladder cancer. [ABSTRACT FROM AUTHOR]

Background: Radiofrequency ablation (RFA) is considered a promising alternative to surgical excision for patients with small, unifocal early-stage breast cancer. A significant concern with the application of RFA in patients diagnosed with ductal carcinoma in situ (DCIS) via needle biopsy is the underdiagnosis of invasive cancer. The extent of this underdiagnosis in DCIS patients eligible for RFA has not been clearly defined. Methods: This retrospective study assessed lesions diagnosed as DCIS via needle biopsy and eligible for RFA at our institution from April 2009 to March 2024. The eligibility criteria for RFA included a lesion size of ≤ 1.5 cm, unifocality, and clinical node negativity. Underdiagnosis was defined as the presence of invasive cancer in surgical specimens. We evaluated the frequency and risk factors associated with underdiagnosis. Results: During the study period, 606 lesions were diagnosed as DCIS via needle biopsy. Of these, 209 lesions met the criteria for RFA, with underdiagnosis determined in 40 lesions (19.1%). The distribution of pathological T (pT) stages among these lesions was as follows: DCIS in 169 lesions (80.9%), pT1mi in 20 lesions (9.6%), pT1a in 5 lesions (2.4%), pT1b in 9 lesions (4.3%), pT1c in 5 lesions (2.4%), and pT2 in 1 lesion (0.5%). Multivariate logistic regression analysis identified lesion size ≥ 10 mm as a significant risk factor for underdiagnosis (p = 0.016). Adjuvant endocrine therapy and chemotherapy were administered to 26 (65.0%) and 6 (15.0%) of the underdiagnosed lesions, respectively. Conclusions: Our findings highlight the risk of underdiagnosing invasive breast cancer in patients undergoing RFA for needle biopsy-diagnosed DCIS. It is crucial to acknowledge the potential for undertreatment when considering RFA as a treatment option. [ABSTRACT FROM AUTHOR]

AbstractA growing body of research on extracellular vesicles (EVs) in cancer has revealed their novel and crucial activities in the progression of tumors while also paving the way for potential therapeutic interventions. It is now known that EVs are natural delivery vehicles for particular payloads of source cells, enabling them to influence diverse functions of cells both in healthy and malignant cells. In this review, we comprehensively summarize mechanistic insights into sEV roles in RB, the most frequent intraocular malignancy that affects the retina of young children. We also explore the therapeutic potential of sEVs as an emerging area as biomarkers and vehicles for targeted therapy. Additionally, we address the potential challenges and limitations of translating sEVs-based technologies into clinical practice. [ABSTRACT FROM AUTHOR]

Background: For obstructive colon cancer, many studies have been conducted on the use of self-expandable metallic stents (SEMS) as a bridge to surgery (BTS). However, there are currently no available prospective data on the impact of bridging period and there is a lack of research on the effects of neoadjuvant chemotherapy during the bridging period. Objectives: Patients who undergo successful SEMS placement for obstructive left-sided colon adenocarcinoma without metastases will be eligible for this study. Design: This study is a multicenter, non-inferiority, randomized (1:1), open-label, controlled trial. Methods & analysis: The patients assigned to the control group will undergo curative surgery within two weeks after successful SEMS placement. The patients assigned to the experimental group will undergo three cycles of neoadjuvant FOLFOX chemotherapy within two weeks after successful SEMS placement. Curative surgery will be performed within four weeks of the last administration of neoadjuvant FOLFOX. Circulating tumor DNA (ctDNA) will be collected at specific time points. Discussion: The optimal time interval for SEMS placement as a BTS can significantly impact long-term oncologic outcomes. In this study, our goal is to identify the optimal time interval for SEMS placement as a BTS. Recently, there has been interest in applying neoadjuvant chemotherapy for locally advanced colon cancer. In the context of early treatment for tumor dissemination following SEMS placement, neoadjuvant chemotherapy may be beneficial for delayed surgery after SEMS placement as a BTS. The results of this trial will be an important reference for the application of neoadjuvant chemotherapy in locally advanced colon cancer. Additionally, researchers will investigate whether ctDNA can serve as a reliable indicator to guide decisions about the timing and type of subsequent treatment. Based on the results of this trial, a patient-tailored treatment strategy can be developed for obstructive colon cancer. Registration: This study is registered on ClinicalTrials.gov Identifier: NCT04889820, registered on May 17, 2021 in clinicaltrials.gov; Protocol ID: XC21MIDI0004. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to investigate the nuanced relationship between spiritual well-being and fear of cancer progression among individuals diagnosed with cancer. Methods: The study was conducted in 2023 and utilized a predictive cross-sectional survey. A total of 398 cancer patients were recruited using convenience sampling. The Spiritual Well-Being Scale (SWBS) and the Fear of Progression (FOP) scale were used for data collection. Data analysis was performed using SPSS version 26, AMOS, and JASP to assess the reliability of the constructs and the potential relationship between the two main variables. Results: The mean age of the participants was 49.14 years (SD = 16.16, 95% CI: 47.55 50.74). All constructs demonstrated strong factorial validity and reliability. Simple linear regression analysis revealed that spiritual well-being significantly predicted fear of cancer progression (R 2 = 0.064, F = 27, p < 0.001). Discussion: The findings indicated a significant relationship between spiritual well-being and fear of cancer progression. These results highlighted the interconnectedness of spiritual well-being and fear of cancer progression among cancer patients. [ABSTRACT FROM AUTHOR]

Persistent infection with oncogenic human papillomavirus (HPV) types, such as HPV 16 or 18, is a major factor in cervical cancer development. However, only a small percentage of infected women develop cancer, indicating that other factors are involved. Emerging evidence links vaginal microbiota with HPV persistence and cancer progression. Alterations in microbial composition, function, and metabolic pathways may contribute to this process. Despite the potential of metagenomics to explore these interactions, studies on the vaginal microbiota's role in cervical cancer are limited. This review systematically examines the relationship between cervical microbiota, HPV, and cervical cancer by analyzing studies from PubMed, EBSCO, and Scopus. We highlight how microbial diversity influences HPV persistence and cancer progression, noting that healthy women typically have lower microbiota diversity and higher Lactobacillus abundance compared to HPV-infected women, who exhibit increased Gardenella, Prevotella, Sneathia, Megasphaera, Streptococcus, and Fusobacterium spp., associated with dysbiosis. We discuss how microbial diversity is associated with HPV persistence and cancer progression, noting that studies suggest healthy women typically have lower microbiota diversity and higher Lactobacillus abundance, while HPV-infected women exhibit increased Gardnerella , Prevotella , Sneathia , Megasphaera , Streptococcus , and Fusobacterium spp., indicative of dysbiosis. Potential markers such as Gardnerella and Prevotella have been identified as potential microbiome biomarkers associated with HPV infection and cervical cancer progression. The review also discusses microbiome-related gene expression changes in cervical cancer patients. However, further research is needed to validate these findings and explore additional microbiome alterations in cancer progression. [ABSTRACT FROM AUTHOR]

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy. Typically, oncogenes show higher expression in tumors and are linked to poor prognoses. However, some highly expressed genes in tumors are associated with better outcomes and act as tumor suppressors, termed paradoxical genes. We explored these genes using bioinformatics, revealing their significant roles in regulating tumor metabolism and immune microenvironments, offering new insights for targeted cancer therapy. Created in BioRender. ZHAO, X. (2025) https://BioRender.com/b00e214. [ABSTRACT FROM AUTHOR]

Histone deacetylation represents a significant epigenetic mechanism that involves the removal of acetyl groups from histones, subsequently influencing gene transcription. Overexpression of histone deacetylases (HDACs) is prevalent across various cancer types, positioning HDAC inhibitors as broadly applicable therapeutic agents. These inhibitors are known to enhance tumor immune antigenicity, potentially slowing tumor progression. Furthermore, the tumor microenvironment, which is intricately linked to cancer development, acts as a mediator in the proliferation of numerous cancers and presents a viable target for oncological therapies. This paper primarily explores how HDAC inhibitors can regulate cancer progression via the tumor microenvironment and suppress tumor growth through multiple pathways, in addition to examining the synergistic effects of combined drug therapies involving HDAC inhibitors. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates a correlation between inflammation and the development and progression of cancer. Among the various inflammatory signals, interleukin-17 (IL-17) family cytokines serve as a critical link between inflammation and cancer. IL-17 is a highly versatile pro-inflammatory cytokine that plays a pivotal role in host defense, tissue repair, the pathogenesis of inflammatory diseases, and cancer progression. During the early stages of tumorigenesis, IL-17 signaling directly promotes the proliferation of tumor cells. Conversely, IL-17 has been shown to exhibit antitumor immunity in several models of grafted subcutaneous tumors. Additionally, dynamic changes in the microbiome can influence the secretion of IL-17, thereby affecting tumor development. The specific role of IL-17 is contingent upon its functional classification, spatiotemporal characteristics, and the stage of tumor development. In this review, we introduce the fundamental biology of IL-17 and the expression profile of its receptors in cancer, while also reviewing and discussing recent advancements regarding the pleiotropic effects and mechanisms of IL-17 in inflammation-related cancers. Furthermore, we supplement our discussion with insights into the mechanisms by which IL-17 impacts cancer progression through interactions with the microbiota, and we explore the implications of IL-17 in cancer therapy. This comprehensive analysis aims to enhance our understanding of IL-17 and its potential role in cancer treatment. [ABSTRACT FROM AUTHOR]

Background and aims: Small gastric subepithelial tumors (SETs) in the stomach can be managed through surveillance or resection. However, it is still controversial how often the lesion would progress if left untreated. This study aimed to evaluate the progression rate of small SETs and identify risk factors influencing tumor growth. Methods: PubMed, Cochrane Library, Web of Science, and Scopus were searched for relevant studies until March 2023. Patient information, endoscopic features of SETs, and surveillance information were extracted from each included study. A random-effects model was applied along with subgroup and sensitivity analyses. Results: Based on 14 studies with 5405 SETs smaller than 3.5 cm, the annual incidence of size increase was 4.0 (95%CI 2.2–5.8) per 100 person-years, and the overall incidence was 12.8% (95%CI 8.3%–17.3%) across a surveillance duration of 51.3 ± 16.9 months. The predicted risk factors for tumor growth included ≥ 1 cm lesion size (1–2 cm vs. < 1 cm, OR 2.61, 95%CI 1.80–3.79; and > 2 cm vs. 1–2 cm, OR 1.25, 95%CI 0.87–1.81), origin in the muscularis propria (OR 2.09, 95%CI 1.41–3.10), mucosal change (OR 3.27, 95%CI 1.95–5.50), irregular margin (OR 3.16, 95%CI 1.15–8.69), and hypoechoic pattern (OR 3.06, 95%CI 1.34–7.00). Conclusions: Most small gastric SETs, particularly those smaller than 1 cm, did not increase in size during surveillance. Special attention should be given to lesions larger than 1 cm, originating from the muscularis propria, or exhibiting mucosal change, irregular margin, and hypoechoic pattern. [ABSTRACT FROM AUTHOR]

Background: With the increasing importance of thermal ablation (TA) in hepatocellular carcinoma (HCC) treatment, local tumor progression (LTP) has become a nonignorable recurrence type after ablation. Purposes: To analyze the influence of peritumoral liver parenchyma on LTP and to explore the possible reasons for this influence. Methods: Ablated HCCs with peritumoral parenchymal biopsy and ablation margins greater than 5 mm were included from two hospitals. The grade of necroinflammatory activity (G) and stage of fibrosis (S) of the parenchyma were evaluated by Scheuer staging system. Univariate/multivariate Cox model was used to analyze the possible factors influencing LTP. Peritumoral satellite focus rate, ablation energy, ablation volume after treatment, ablation volume after one-month, and volume reduction rate were collected and analyzed to explore the possible reasons for influence. Propensity score matching (PSM) was used to balance baselines across different groups. Results: 346 HCCs (64 with LTP, 282 without LTP) were enrolled from January 2013 to June 2022, with a median follow-up of 27 months. Univariate/multivariate analysis showed fibrosis was a protective factor in LTP (OR = 0.70, 95%CI: 0.55–0.89). The low-fibrosis group exhibited higher satellite focus rate (15.6% vs. 8.4%, p = 0.048), lower ablation energy (22637 ± 9424 J vs. 33352 ± 13779 J, p < 0.001) and higher volume reduction rate (0.33 ± 0.06 vs. 0.25 ± 0.06, p < 0.001) than the high-fibrosis group. Therefore, we speculated that the protective effect of fibrosis was due to its blocking of tumor invasion and reduction of sublethal zones. Conclusion: Fibrosis of the peritumoral liver parenchyma is a stable protective factor in LTP occurrence. Key results: (1) Fibrosis of the peritumoral parenchyma was a protective factor for local tumor progression (OR = 0.70, 95% CI: 0.55–0.89). (2) The low fibrosis group had a higher peritumoral satellite focus rate (15.6% vs. 8.4%, p = 0.048) than the high fibrosis group, possibly due to the dense parenchyma impeding tumor invasiveness. (3) The low fibrosis group had a higher volume reduction rate (0.33 ± 0.06 vs. 0.25 ± 0.06, p < 0.001) than the high fibrosis group, possibly due to the dense parenchyma reducing the area of the sublethal zone. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the diagnostic performance of combining diffusion-weighted imaging (DWI) with T2-weighted imaging (T2WI) for detecting muscularis propria invasion in rectal cancer. Methods: We conducted a retrospective analysis of MR images from 76 patients with pathologically confirmed rectal cancer between January 2018 and June 2022. Patients were categorized into invasion and non-invasion groups. the present of muscularis propria invasion. The examination regimen included T2WI, dynamic enhanced scanning and DWI.The apparent diffusion coefficient (ADC) values from DWI were compared between the groups, and the diagnostic performance of combining ADC with T2WI was assessed. Results: There were differences in ADCmean, ADCmsi, and ADCmin values between the non-invasion group and theinvasion group, and the t values were 3.949, 2.221 and 2.978, respectively. The P values were 0.000, 0.029 and 0.004, respectively. Using an ADCmean threshold of 1.07 × 10− 3 mm²/s, the sensitivity and specificity for detecting muscularis propria invasion were 82.22% and 61.29%, respectively, with an overall diagnostic accuracy of 89.5%. For ADCmsi, with a threshold of 0.996 × 10− 3 mm²/s, the sensitivity and specificity were 62.75% and 73.33%, respectively, yielding a diagnostic accuracy of 82.9%. The ADCmin, with a threshold of 0.854 × 10− 3 mm²/s, demonstrated sensitivity and specificity of 78.43% and 66.67%, respectively, with a diagnostic accuracy of 85.5%. Conclusion: T2WI combined ADC value has a good predictive value for judging the degree of musculature invasion of medium-to-high rectal cancer, while ADC mean has a higher comprehensive diagnostic efficiency. Our finding may provide reference for increasing accuracy in mid-to-high rectal cancer diagnosis. [ABSTRACT FROM AUTHOR]

Background and study aims: Diffuse infiltrative gastric cancer can be difficult to diagnose owing to a lack of endoscopic features in the superficial mucosa. Moreover, a forceps biopsy may not reveal a pathological diagnosis. We aimed to evaluate the diagnostic yield and safety of endoscopic mucosal resection (EMR) and 'open-lid submucosal biopsy', a technique wherein EMR followed by biopsy of the ulcer floor is performed for a pathological diagnosis. Patients and methods: This retrospective observational study involved patients with suspected diffuse invasive gastric cancer on endoscopy and cross-sectional imaging in whom endoscopic forceps biopsy did not lead to a pathological diagnosis. Patients who underwent EMR and open-lid submucosal biopsy were included. The primary outcome was the total diagnostic yield. The secondary outcomes were the diagnostic yields of EMR and open-lid submucosal biopsy and incidence of complications. Results: Between June 2011 and February 2022, EMR and open-lid submucosal biopsy for diagnostic purposes were performed on seven patients without complications. EMR was diagnostic in four (57%) cases of diffuse infiltrative gastric cancer. Open-lid submucosal biopsy was diagnostic in five (71%) cases. As the primary endpoint, the combination of EMR and open-lid submucosal biopsy led to a pathological diagnosis in six cases (86%). Secondary analysis revealed gastric adenocarcinoma in 9 of 22 (41%) EMR specimens, while open-lid submucosal biopsies were positive for adenocarcinoma in 14 of 60 specimens (23%). Conclusions: The combination of EMR and open-lid submucosal biopsy was safe and showed good accuracy for the diagnosis of diffuse infiltrative gastric cancer. [ABSTRACT FROM AUTHOR]

Secretory autophagy is a classical form of unconventional secretion that integrates autophagy with the secretory process, relying on highly conserved autophagy-related molecules and playing a critical role in tumor progression and treatment resistance. Traditional autophagy is responsible for degrading intracellular substances by fusing autophagosomes with lysosomes. However, secretory autophagy uses autophagy signaling to mediate the secretion of specific substances and regulate the tumor microenvironment (TME). Cytoplasmic substances are preferentially secreted rather than directed toward lysosomal degradation, involving various selective mechanisms. Moreover, substances released by secretory autophagy convey biological signals to the TME, inducing immune dysregulation and contributing to drug resistance. Therefore, elucidating the mechanisms underlying secretory autophagy is essential for improving clinical treatments. This review systematically summarizes current knowledge of secretory autophagy, from initiation to secretion, considering inter-tumor heterogeneity, explores its role across different tumor types. Furthermore, it proposes future research directions and highlights unresolved clinical challenges. [ABSTRACT FROM AUTHOR]

Assessing the response to oncological treatments is paramount for determining the prognosis and defining the best treatment for each patient. Several biomarkers, including imaging, can be used, but standardization is fundamental for consistency and reliability. Tumor response evaluation criteria have been defined by international groups for application in pharmaceutical clinical trials evaluating new drugs or therapeutic strategies. RECIST 1.1 criteria are exclusively based on unidimensional lesion measurements; changes in tumor size are used as surrogate imaging biomarkers to correlate with patient outcomes. However, increased tumor size does not always reflect tumor progression. The introduction of immunotherapy has led to the development of new criteria (iRECIST, Level of Evidence (LoE) Ib) that consider the possibility that an increase in disease burden is secondary to the immune response instead of progression, with the new concept of Unconfirmed Progressive Disease (a first progression event which must be confirmed on follow-up). Specific criteria were devised for HCC (mRECIST, LoE IV), which measure only enhancing HCC portions to account for changes after local therapy. For GIST treated with imatinib, criteria were developed to account for the possible increase in size reflecting a response rather than a progression by assessing both tumor size and density on CT (Choi, LoE II). This article provides concise and relevant practice recommendations aimed at general radiologists to help choose and apply the most appropriate criteria for assessing response to treatment in different oncologic scenarios. Though these criteria were developed for clinical trials, they may be applied in clinical practice as a guide for day-to-day interpretation. Key Points: Response evaluation criteria, designed for use in clinical trials, might serve as a surrogate biomarker for overall survival. RECIST 1.1 defines measurable and non-measurable disease among which target lesions and non-target lesions are selected at baseline as reference for follow-ups. Some therapies and/or cancers require the use of different criteria, such as iRECIST, mRECIST, and Choi criteria. [ABSTRACT FROM AUTHOR]

Purpose: To assess the association between minimal ablative margin (MAM) and local tumor progression (LTP) following CT-guided thermal ablation of colorectal liver metastases (CRLM) in a multicenter cohort and across two confirmation software. Materials and methods: This multicenter retrospective study included patients who underwent CT-guided radiofrequency or microwave ablation for CRLM between 2009 and 2021 in three institutions. Three-dimensional (3D) MAM was retrospectively assessed using dedicated ablation confirmation software by automatic non-rigid (Ablation-fit) or semi-automatic rigid co-registration (SAFIR) of intraprocedural pre- and post-ablation contrast-enhanced CT scans by two independent reader teams blinded to patient outcomes. LTP was assessed on a per-tumor basis. Factors associated with LTP-free survival were assessed using multivariable Cox regression analysis. Results: Overall, 113 patients (mean age: 67 ± 10 years; 78 men) who underwent thermal ablation for 189 CRLM (mean diameter: 1.9 ± 1.1 cm) met the inclusion criteria. 173/189 (92%) CRLM could be successfully analyzed using both software. Over a median follow-up of 31 months (IQR: 22–47), 21 of 173 CRLM (12.1%) developed LTP. On multivariable analysis, 3D MAM was independently associated with LTP in both software (Ablation-fit: HR 0.47, 95% CI: 0.36–0.61, p < 0.001; SAFIR: HR 0.42, 95% CI: 0.32–0.55, p < 0.001). No LTP was observed in CRLM ablated with MAM ≥ 4 mm (Ablation-fit) and ≥ 5 mm (SAFIR). The per-tumor median absolute difference in MAM quantification between both software was 2 mm (IQR: 1–3). Conclusion: MAM was independently associated with LTP after thermal ablation of CRLM across multicenter data and two confirmation software. Ablations achieving a MAM ≥ 5 mm were associated with local control in both software. Clinical relevance statement: MAMs from intraprocedural contrast-enhanced CT were independently associated with LTP after thermal ablation of CRLM across multicenter data and two confirmation software, with a margin ≥ 5 mm associated with local control in both software. Key Points: Sufficient ablative margins are critical for local control following thermal ablation of CRLM. Intraprocedural CT-derived MAM was the only independent factor associated with LTP across two confirmation software. No LTP was observed in CRLM ablated with a MAM ≥ 5 mm. [ABSTRACT FROM AUTHOR]

• Lung parenchyma is composed of numerous microvessels and epithelial cells in an architecture organized in a network maintained by basement membranes. • The composition of lung basement membranes regulates metastases growth and development. • Basement membranes and ECM regulate all the steps of the metastatic cascade: from the acquisition of invasiveness of the primary tumor cells to the metastatic growth of distant metastases. • Targeting basement membranes is a very interesting approach to target metastatic growth and metastatic vascularization. The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components—collagens, fibronectin, and laminin—and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases. [ABSTRACT FROM AUTHOR]

• Cogelation with hyaluronic acid (HA) softens collagen matrices and reduces pore sizes. • HA modulates cell traction force generation and transmission. • CD44 is required for cell traction force generation in hyaluronic acid (HA)-rich environments. • RhoA-mediated contractility is involved in cell-ECM interactions in HA-rich environments. • HA attenuates tumor invasiveness in a CD44-dependent manner. Mechanical properties of the extracellular matrix (ECM) critically regulate a number of important cell functions including growth, differentiation and migration. Type I collagen and glycosaminoglycans (GAGs) are two primary components of ECMs that contribute to mammalian tissue mechanics, with the collagen fiber network sustaining tension, and GAGs withstanding compression. The architecture and stiffness of the collagen network are known to be important for cell-ECM mechanical interactions via cell surface adhesion receptor integrin. In contrast, studies of GAGs in modulating cell-ECM interactions are limited. Here, we present experimental studies on the roles of hyaluronic acid (HA) in single tumor cell traction force generation using a recently developed 3D cell traction force microscopy method. Our work reveals that CD44, a cell surface receptor to HA, is engaged in cell traction force generation in conjunction with β1-integrin. We find that HA significantly modifies the architecture and mechanics of the collagen fiber network, decreasing tumor cells' propensity to remodel the collagen network, attenuating traction force generation, transmission distance, and tumor invasion. Our findings point to a novel role for CD44 in traction force generation, which can be a potential therapeutic target for diseases involving HA rich ECMs such as breast cancer and glioblastoma. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH)-mutant gliomas, comprising both astrocytomas and oligodendrogliomas, represent a distinct group of tumors that pose an interdisciplinary challenge. Addressing the needs of affected patients requires close collaboration among various disciplines, including neuropathology, neuroradiology, neurosurgery, radiation oncology, neurology, medical oncology, and other relevant specialties when necessary. Interdisciplinary tumor boards are central in determining the ideal diagnostic and therapeutic strategies for these patients. The key tasks of a tumor board include the evaluation of imaging findings, selecting the appropriate surgical approach, discussing additional treatment options, and identification/determination of tumor recurrence and progression. In addition to established treatments such as radiotherapy and alkylating chemotherapy, patients with an isocitrate dehydrogenase (IDH)-mutant glioma for whom additional treatment is indicated may now also have the option of receiving treatment with an mutant isocitrate dehydrogenase inhibitor such as vorasidenib or ivosidenib. In this regard, the collaborative nature of tumor boards becomes even more crucial for evaluating comprehensively the needs of these patients. Through interdisciplinary discussions, tumor boards aim to develop personalized treatment strategies that maximize therapeutic efficacy while minimizing potential side effects and preserving patients' quality of life. [ABSTRACT FROM AUTHOR]

[Display omitted] • Reprogramming of lipid metabolism in TAM is closely related to its biological functions, especially polarization. • The complicated crosstalk of lipid metabolism exists between TAMs and tumor cells in TME. • Targeting TAM lipid metabolism is a promising strategy for clinical tumor therapy. Lipid metabolism has been implicated in a variety of normal cellular processes and strongly related to the development of multiple diseases, including tumor. Tumor-associated macrophage (TAM) has emerged as a crucial regulator in tumorigenesis and promising target for tumor treatment. Aim of review: A thorough understanding of TAM lipid metabolism and its value in tumorigenesis may provide new ideas for TAM-based anti-tumor therapy. Key scientific concepts of review: TAMs can be divided into two main types, M1-like TAMs and M2-like TAMs, which play anti-tumor and pro-tumor functions in tumor occurrence and development, respectively. Accumulating evidence has shown that lipid metabolic reprogramming, including fatty acid uptake and utilization, cholesterol expulsion, controls the polarization of TAMs and affects the tumorgenesis. These advances in uncovering the intricacies of lipid metabolism and TAMs have yielded new insights on tumor development and treatment. In this review, we aim to provide an update on the current understanding of the lipid metabolic reprogramming made by TAMs to adapt to the harsh tumor microenvironment (TME). In particular, we emphasize that there is complex lipid metabolism connections between TAMs and distinct tumors, which influences TAM to bias from M1 to M2 phenotype in tumor progression, and ultimately promotes tumor occurrence and development. Finally, we discuss the existing issues on therapeutic strategies by reprogramming TAMs based on lipid metabolism regulation (or increasing the ratio of M1/M2-like TAMs) that could be applied in the future to clinical tumor treatment. [ABSTRACT FROM AUTHOR]

The literature on skull base chondrosarcoma (CHS) is scarce. We report outcomes for pediatric and young patients ≤22 years with base of skull CHSs treated with proton-based radiation therapy (PBRT). We retrospectively reviewed all patients treated with PBRT between 1981 and 2023. Primary endpoints were overall survival (OS), chondrosarcoma-specific survival (CSS), progression-free survival (PFS), local control, and distal control. Eighty-four patients were identified. Median age at diagnosis was 19 years (range, 6-22). Most patients (n = 79, 94%) had conventional CHS, whereas 5 (6%) had mesenchymal CHS. Nine patients (11%) underwent gross total resection, 64 (76%) subtotal resection, and 11 patients (13%) underwent biopsy. Twenty-four (29%) patients progressed before radiation therapy. The median prescription dose was 70 Gy (relative biological equivalent) (range, 50-79.7). At a median follow-up of 18.0 years (IQR, 9.2-26.2) from diagnosis, 11 patients recurred (7 local, 4 distant). Six patients died of disease. Five patients died of other causes. Ten-year OS, CSS, and PFS rates for all patients were 93.3%, 94.7%, and 88%, respectively. Twenty-year OS, CSS, and PFS rates for conventional CHS (n = 79) were 93.1%, 97.1%, and 89.2%, respectively. Mesenchymal histology was significantly associated with worse OS and PFS. Preradiation therapy tumor progression portended worse OS and CSS. Eight patients (9.9 %) experienced a late toxicity grade 3 or greater. This is the largest cohort of pediatric base of skull CHSs in literature to date. High-dose PBRT after surgical resection achieves excellent disease control with minimal toxicity. [ABSTRACT FROM AUTHOR]

The optimal approach for partial breast irradiation (PBI) is unknown. We investigated a novel de-intensified 3-fraction PBI regimen for photons, protons, and brachytherapy. A multicenter nonrandomized controlled trial with the primary outcome of adverse cosmesis at 3 years versus before PBI. Eligibility criteria were age ≥50 years treated with breast-conserving surgery for node-negative estrogen receptor–positive (ER+) invasive breast cancer or any ductal carcinoma in situ (DCIS) measuring ≤2.5 cm. Photon and proton PBI were prescribed 21.9 Gy (relative biological effectiveness) and brachytherapy 21 Gy in 3 fractions. Radiation therapy technique and adjuvant endocrine therapy were selected at physician and patient discretion. Between June 17, 2015, and July 13, 2017, 161 eligible patients were treated with photons (56), protons (49), or brachytherapy (56). Median patient age was 66.8 years. One hundred twenty-six (78.3%) had invasive breast cancer (all ER+) and 35 (21.7%) had DCIS (88.6% ER+). Fifty-four percent of patients with invasive breast cancer and 25.8% of patients with ER+ DCIS initiated and adhered to the prescribed endocrine therapy. The proportion of patients with adverse cosmesis (by trained nurse assessment) was 14.5% at baseline and 2.3% at 3 years (difference, −12.2%; 95% CI, −100% to −6.4%). Adverse cosmesis at the last follow-up, with a median follow-up of 5 years, was 5.7% by nurse assessment, 5.6% by panel assessment of digital photographs, and 5.2% by patient self-report. There were no observed clinically meaningful changes in other patient-reported outcomes, and just 2 grade 2 or higher adverse events, both grade 2, in the brachytherapy cohort. Five-year local recurrence–free survival and progression-free survival were 98.0% and 95.5%, respectively. There were no local recurrences among 60 patients with invasive breast cancer and Ki67 ≤13.25%. Deintensified 3-day PBI provided favorable disease control, tolerability, and cosmetic outcomes, meeting the prespecified criteria for acceptability. This approach is an attractive option for patients with small node-negative ER+ breast cancer and DCIS. [ABSTRACT FROM AUTHOR]

To compare the oncologic outcomes of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) undergoing complete versus incomplete transurethral tumor resection (TURBT) before radiation therapy. Patients with nonmetastatic MIBC who underwent curative-intent radiation therapy between 2002 and 2018 at 10 Canadian institutions were retrospectively evaluated. Inverse probability of treatment weighting was performed using baseline characteristics. Differences in survival outcomes by complete and incomplete TURBT were analyzed. Of the 757 patients included, 66% (498) had documentation of a complete and 34% (259) an incomplete TURBT. Before adjustment, 121 (47%) and 45 (9%) patients who underwent incomplete and complete TURBT, respectively, were diagnosed with cT3-4 tumor (P <.001). After weight-adjustment, all baseline cohort characteristics were balanced (absolute standardized differences < 0.1). The adjusted median follow-up was 27 months. Adjusted survival analyses showed no significant difference in 5-year overall survival (48% vs 52%, 1.03 [0.82-1.29]; P =.8), cancer-specific survival (64% vs 61%, 0.93 [0.70-1.25]; P =.7), metastasis-free survival (43% vs 46%, 0.97 [0.79-1.19]; P =.8), and disease-free survival (32% vs 35%, 0.95 [0.79-1.15]; P =.7) between the 2 groups. Complete TURBT may be associated with clinical organ-confined disease. Extent of TURBT was not independently associated with oncologic outcomes in patients with MIBC treated with radiation therapy. [ABSTRACT FROM AUTHOR]

14‐3‐3σ functions as an oncogene in colorectal cancer and is associated with therapy resistance. However, the mechanisms underlying these observations are not clear. The results in this report demonstrate that loss of 14‐3‐3σ in colorectal cancer cells leads to a decrease in tumor formation and increased sensitivity to chemotherapy. The increased sensitivity to chemotherapy is due to a decrease in the expression of UPR pathway genes in the absence of 14‐3‐3σ. 14‐3‐3σ promotes expression of the UPR pathway genes by binding to the transcription factor YY1 and preventing the nuclear localization of YY1. YY1, in the absence of 14‐3‐3σ, shows increased nuclear localization and binds to the promoter of the UPR pathway genes, resulting in decreased gene expression. Similarly, a YY1 mutant that cannot bind to 14‐3‐3σ also shows increased nuclear localization and is enriched on the promoter of the UPR pathway genes. Finally, inhibition of the UPR pathway with genetic or pharmacological approaches sensitizes colon cancer cells to chemotherapy. Our results identify a novel mechanism by which 14‐3‐3σ promotes tumor progression and therapy resistance in colorectal cancer by maintaining UPR gene expression. [ABSTRACT FROM AUTHOR]

Platinum-based neoadjuvant chemotherapy prior to radical cystectomy is the preferred treatment for muscle-invasive bladder cancer despite modest survival benefit and significant associated toxicities. Here, we profile the global proteome of muscle-invasive bladder cancers pre- and post-neoadjuvant chemotherapy treatment using archival formalin-fixed paraffin-embedded tissue. We identify four pre-neoadjuvant chemotherapy proteomic clusters with distinct biology and response to therapy and integrate these with transcriptomic subtypes and immunohistochemistry. We observe proteomic plasticity post-neoadjuvant chemotherapy that is associated with increased extracellular matrix and reduced keratinisation compared to pre-neoadjuvant chemotherapy. Post-neoadjuvant chemotherapy clusters appear to be differentially enriched for druggable proteins. For example, MTOR and PARP are over-expressed at the protein level in tumours identified as neuronal-like. In addition, we determine that high intra-tumoural proteome heterogeneity in pre-neoadjuvant chemotherapy tissue is associated with worse prognosis. Our work highlights aspects of muscle-invasive bladder cancer biology associated with clinical outcomes and suggests biomarkers and therapeutic targets based on proteomic clusters. The proteomic landscape of muscle-invasive bladder cancer (MIBC) in the context of platinum-based neoadjuvant chemotherapy (NAC) remains to be explored. Here, proteomic analysis of MIBC tumours pre- and matched post-NAC treatment identifies proteomic clusters with distinct biological and clinical features. [ABSTRACT FROM AUTHOR]

Precise neoepitope discovery is crucial for effective cancer therapeutic vaccines. Conventional approaches struggle to build a repertoire with sufficient immunogenic epitopes. We developed a workflow leveraging full-length ribosome-nascent chain complex-bound mRNA sequencing (FL-RNC seq) and artificial intelligence-based predictive models to accurately identify the neoepitope landscape, especially large-scale transcript variants (LSTVs) missed by short-read sequencing. In the MC38 mouse model, we identified 22 LSTV-derived neoepitopes encoded by a synthesized mRNA lipid nanoparticle vaccine. As a standalone therapy and combined with anti-PD-1 immunotherapy, the vaccine curbed tumor progression, induced robust T cell-specific immunity, and modulated the tumor microenvironment. This underscores the multifaceted potentials of LSTV-derived vaccines. Our approach expands the neoepitope source repertoire, offering a method for discovering personalized cancer vaccines applicable to a broader tumor range. The results highlight the importance of comprehensive neoepitope identification and the promise of LSTV-based vaccines for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acid (LPA) exerts its physiological roles through the endothelialdifferentiation gene (EDG) family LPA receptors (LPAR1-3) or the non-EDG family LPA receptors (LPAR4-6). LPAR6 plays crucial roles in hair loss and cancer progression, yet its structural information is very limited. Here, we report the cryoelectron microscopy structure of LPA-bound human LPAR6 in complex with a mini G13 or Gq protein. These structures reveal a distinct ligand binding and recognition mode that differs significantly from that of LPAR1. Specifically, LPA uses its charged head to form an extensive polar interaction network with key polar residues on the extracellular side of transmembrane helix 5-6 and the extracellular loop 2. Structural comparisons and homology analysis suggest that the EDG and non-EDG families use two distinct modes for LPA binding. The structural observations are validated through functional mutagenesis studies. We further uncover the mechanisms of LPAR6 activation and principles of G-protein coupling. The structural information revealed by our study lays the groundwork for understanding LPAR6 signaling and provides a rational basis for designing compounds targeting LPAR6. [ABSTRACT FROM AUTHOR]

Ependymoma (EPN) is a common form of brain tumor in children, often resistant to available cytotoxic therapies. Molecular profiling studies have led to a better understanding of EPN subtypes and revealed a critical role of oncogenes ZFTA-RELA fusion and EPHB2 in supratentorial ependymoma (ST-EPN). However, the immune system's role in tumor progression and response to therapy remains poorly understood. New treatments for various molecular subtypes of EPN are desperately needed. Using ST-EPN-ZFTA subtype-specific syngeneic mouse models, we found an increased frequency of M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. Transcriptomic profiling of ST-EPN-ZFTA and analysis of a human EPN dataset revealed multiple protein kinases as potential druggable targets. By matching transcriptomic signatures with the target spectrum of FDA-approved drugs, we found that the multikinase inhibitor dasatinib potently inhibited the growth of EPN both in vitro and in vivo, mainly through blocking EPHB2 and ABL1. Treatment with dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an M1-like phenotype and increasing CD8 T cell activation. Furthermore, dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 cells compromised the durability of EPN responses and reduced overall survival. These data indicate that dasatinib has the potential to be an effective therapy for ST-EPN-ZFTA molecular subgroup of EPN and support further investigation of dasatinib in clinical trials. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a commonly observed malignant tumor in orthopedics that has a very poor prognosis. The endosomal sorting complex required for transport (ESCRT) is important for the development and progression of cancer and may be a significant target for cancer therapy. First, we built a prognostic signature using 7 ESCRT-related genes (ERGs) to predict OS patient prognosis. Analysis of internal and external datasets revealed that the ERG signature has good predictive ability and reproducibility. Immune analysis demonstrated a significant correlation between OS patient immune status and ERG signature score. Moreover, ERG signature score was found to be associated with the response of OS patients to immunotherapy and anticancer drugs. Additionally, we constructed a prognostic signature consisting of 10 ESCRT-related long noncoding RNAs (ERLs) that effectively predicted the prognosis of OS patients. Furthermore, two subgroups of OS patients with distinct prognoses (clusters 1 and 2) were identified. Finally, LMO7-AS1 was chosen for functional experimental validation. The knockdown of LMO7-AS1 suppressed the malignant progression of OS cells. Furthermore, transcriptome sequencing was performed on OS cells and revealed a correlation between LMO7-AS1 and the PI3K-Akt signaling pathway. In conclusion, our ESCRT transcriptome-associated signatures can act as prognostic biomarkers for OS, and LMO7-AS1 is a novel therapeutic target for the treatment of OS. [ABSTRACT FROM AUTHOR]

Abstract\nHighlightsEndoplasmic Reticulum (ER) stress is intricately involved in cancer development, progression and response to chemotherapy. ER stress related genes might play an important role in predicting the prognosis in lung adenocarcinoma patients and may be manipulated to improve the treatment outcome and overall survival rate. In this review, we analyzed the contribution of the three major ER stress pathways—IRE1, ATF6, and PERK—in lung cancer pathogenesis via modulation of tumor microenvironment (TME) and processes as metastasis, angiogenesis, apoptosis and N-glycosylation. Furthermore, we discuss the regulatory role of microRNAs in fine-tuning ER stress pathways in Non-Small Cell Lung Cancer (NSCLC). Our review also highlights various promising strategies to overcome chemoresistance by targeting ER stress pathways, offering new therapeutic opportunities.Endoplasmic reticulum (ER) stress manifests as loss of protein homeostasis leading to accumulation of misfolded/unfolded proteins in the ER lumenIt is triggered by stimuli as hypoxia, metabolic stress, mutations and various pathological conditions as cancer.ER stress has various repercussions in lung cancer including tumor growth progression, metastasis and chemoresistance.Various miRNAs are implicated in modulation of ER stress response in lung cancer, which may be explored further for finding the new treatment approaches. [ABSTRACT FROM AUTHOR]

Growing evidence implicates that intratumoral microbiota are closely linked to cancer progression; however, research on the role of these microbiota in the development of gastric cancer remains limited. Here, using 16 S rRNA sequencing, tumor tissue proteomics and serum cytokines analysis, we identified enrichment of specific microbial communities within tumors of gastric cancer patients, possibly affecting the tumor microenvironment by immune modulation, metabolic processes, and inflammatory responses. Based on the results of in vivo experiments and intratumoral microbiota analysis, we found that Streptococcus mitis can inhibit gastric cancer progression via suppressing M2 macrophage polarization and infiltration, as well as altering the intratumoral microbial community. In summary, our findings suggest that the intratumoral microbiota, exemplified by Streptococcus mites, may be involved in regulating the progression of gastric cancer, thereby emerging as potential therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) are key components of the pancreatic adenocarcinoma (PAAD) tumor microenvironment (TME), where they promote tumor progression and metastasis through immunosuppressive functions. Although significant progress has been made in understanding the crosstalk between cancer cells and CAFs, many underlying mechanisms remain unclear. Recent studies have highlighted the importance of calcium signaling in enhancing interactions between tumor cells and the surrounding stroma, with the S100 family of proteins serving as important regulators. While the roles of some S100 proteins have been extensively studied, others, such as S100A13, remain less well understood. Methods: Bioinformatic analysis was employed to predict the pathogenic potential of CAFs and S100A13. Stable S100A13 knockdown CAFs were generated using a short hairpin RNA system. Cellular viability and apoptosis rates were evaluated through CCK-8 and flow cytometry tests, respectively. Additionally, the wound healing and migration assays were conducted to assess the invasive and metastatic capabilities. Transcriptome analysis was conducted to identify differential gene expression and associated signaling pathways in PAAD cells derived from an indirect culture system. Furthermore, the protumoral role of S100A13 in PAAD was further verified using both 3D bioprinting and cell line-based xenograft tumor models. Results: In this study, we identified a strong association between S100A13, a calcium-binding protein, and CAFs in PAAD. Gene expression analysis revealed that S100A13 was highly expressed in CAFs and correlated with poor prognosis. Knockdown of S100A13 in CAFs reduced the metastatic potential of PAAD cells. In addition, S100A13 depletion impaired cell motility and calcium signaling pathways within the TME. Furthermore, silencing S100A13 in CAFs markedly slowed PAAD progression in both tumor spheroids and Balb/c nude mice. Conclusions: Together, our findings underscore the critical role of CAFs-derived S100A13 in PAAD progression and suggest that targeting S100A13 may offer a promising therapeutic strategy for PAAD. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) is a vital biological process that is essential for regulating cell progression and tumor microenvironment. This study aimed to explore the relationship between PCD-related genes expression and prognosis in thyroid cancer (THCA), especially IL20RA, as a potential prognostic marker for THCA. Data from The Cancer Genome Atlas (TCGA) database was utilized to develop a PCD-related risk prediction model based on LASSO regression along with univariate Cox regression. The correlation between PCD-related genes and immune cell infiltration was also assessed. The prognostic value of the key PCD-related gene for THCA was investigated by immunohistochemistry. The immune regulatory function and biological function of the key PCD related molecules were detected by cellular experiments. We identified four PCD-related genes (NPC2, E2F1, IL20RA, and TREM2) and constructed a risk model that exhibited excellent accuracy in predicting the prognosis of THCA. Moreover, we confirmed that high expression of IL20RA related to the poor prognosis of THCA. IL20RA promoted cell proliferation and IL20RA knockdown increased apoptosis and ferroptosis. Analysis of the immune microenvironment and detection of macrophages polarization showed that IL20RA promoted the polarization of M2 macrophages while reducing the polarization of M1. We constructed a prognostic prediction model and identified several PCD-related genes. The function of IL20RA which could potentially provide a foundation for additional investigations into diagnostic markers and treatment targets for THCA. [ABSTRACT FROM AUTHOR]

Inhibition of the protein neddylation pathway has emerged as an attractive anticancer strategy in pre-clinical studies. MLN4924, as a small molecule inhibitor of neddylation, has been found to effectively inhibit the growth of a variety of cancer cells. However, its clinical application still faces some major challenges in terms of poor water solubility, biological stability, poor targeting, and rapid clearance from the body. Herein, we developed a biomimetic nanovesicle platform (named P-PAM/MLN) by ultrasonically storing the MLN4924-loaded polyamidoamine (PAMAM) dendrimer inside platelet membrane vesicles (PMVs) for tumor therapy. Benefiting from PMV-based camouflage, P-PAM/MLN exhibited enhanced tumor affinity, avoiding the off-target toxicity of MLN4924. Moreover, P-PAM/MLN could selectively release MLN4924 in response to the acidic microenvironment of lysosomal compartments via the "proton sponge" effect. Consequently, the biomimetic nanovesicles could remarkably inhibit tumor progression with negligible toxicity. In terms of significance, the nanovesicles provide a precisely targeted delivery platform for delivering small molecule drugs to the tumor tissue as well as an effective reference for the combined application of nanocarriers and clinical drugs. [ABSTRACT FROM AUTHOR]

Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy. [ABSTRACT FROM AUTHOR]

Background: HER2 expression has been confirmed to be associated with bladder cancer aggressiveness. Anti-HER2 RC48-ADC is approved in China for the treatment of patients with advanced urothelial carcinoma with failed chemotherapy who are HER2 positive (IHC 2 + or 3 +). The discovery of HER2 positivity in urothelial carcinoma and the development of anti-HER2 drugs have brought new hope for bladder preservation treatment in MIBC. Objective: To investigate HER2 expression in MIBC patients and its correlations with clinical characteristics, to analyze the impact of HER2 expression on the prognosis of MIBC patients administered bladder-preservation comprehensive therapy, and to explore the efficacy and safety of RC48-ADC in MIBC patients administered bladder-preservation comprehensive therapy. Methods: We retrospectively collected information on MIBC patients. All 217 patients underwent cTURBT, of whom 175 received GC chemotherapy, while the remaining 42, due to intolerance to GC chemotherapy and HER2 positivity (IHC 2 + or 3 +), received RC48-ADC treatment. Of the 175 patients administered cTURBT combined with GC chemotherapy, 92 and 83 were HER2-negative and HER2-positive, respectively. Recurrence-free survival (RFS) and overall survival (OS) in HER2-negative and HER2-positive patients were compared to analyze the correlation between HER2 expression and prognosis. RFS and OS in the 83 HER2-positive patients administered cTURBT combined with GC chemotherapy and the 42 HER2-positive patients administered cTURBT combined with RC48-ADC were compared to analyze the differences in prognosis between the two treatment methods. The adverse reactions of GC and RC48-ADC were also compared. Results: Among the 217 included patients, 125 (57.6%) were HER2 positive (IHC 2 + or 3 +). HER2 positivity was significantly associated with tumor size, multifocality, pathological grade, tumor stage, and pelvic lymph node metastasis (P < 0.05). Totally 175 patients underwent cTURBT combined with GC chemotherapy, including 92 HER2-negative and 83 HER2-positive cases. There were no significant differences in gender, age, smoking status, tumor location, and ECOG score between the two groups (P > 0.05), but the proportions of patients with tumors > 3 cm, multifocal tumors, T3 stage, high-grade tumors, and pelvic lymph node metastasis were higher in the HER2-positive group versus the HER2-negative group (P < 0.05). Tumor recurrence rate in the 83 HER2-positive patients was 67.5%, with a median RFS of 19.0 months (95% CI: 10.3–27.7). Totally 22 deaths occurred during the follow-up period, with a median OS of 56.0 months (95% CI: 45.7–66.3). In the 92 HER2-negative patients, the tumor recurrence rate was 56.5%, with a median RFS of 36.0 months (95% CI: 26.1–45.9); 4 deaths occurred during the follow-up period, with the median OS not reached. After cTURBT, of the 125 HER2-positive patients examined, 83 were included in the GC treatment group versus 42 in the RC48-ADC group. There were no differences in gender, age, smoking status, tumor location, tumor size, multifocality, clinical T stage, pathological grade, pelvic lymph node metastasis, and ECOG score between the two groups (P > 0.05). In the GC group, 56 recurrences (67.5%) were detected during the follow-up period, with a median RFS of 19.0 months (95% CI: 10.3–27.7); meanwhile, 22 deaths (52.4%) occurred, with a median OS of 56.0 months (95% CI: 45.7–66.3). In the RC48-ADC group, 15 recurrences (35.7%) were recorded during the follow-up period, with the median RFS not reached; there were 2 deaths (4.8%), with the median OS not reached. The incidence rates of any-grade and grade ≥ 3 adverse reactions were both lower in the RC48-ADC group than in the GC treatment group. Conclusions: This study confirms that cTURBT combined with RC48-ADC treatment for HER2-positive MIBC is superior to combined GC treatment in terms of RFS and OS, representing an effective treatment regimen for bladder preservation in MIBC patients. [ABSTRACT FROM AUTHOR]

Background: Lymphatic leakage is a common complication after radical cystectomy and pelvic lymph node dissection (PLND) for muscle-invasive bladder cancer (MIBC).This study aimed to investigate the risk factors contributing to postoperative lymphatic leakage in patients with MIBC. Materials and methods: A total of 534 patients undergoing radical cystectomy and PLND were enrolled in the retrospective study at Peking University Third Hospital from January 2010 to July 2023. Patients were categorized into lymphatic leakage(n = 254)and non-leakage groups (n = 280) and compared demographic, perioperativ and pathologic factors. Multivariate logistic regression was applied to identify risk factors for lymphatic leakage. Spearman correlation was used to analyze the relationship between lymph leakage ratio and risk factors. Results: Patients with lymphatic leakage had significantly higher rates of receiving extended PLND (19.7% vs. 11.4%, p = 0.008), higher total number of dissected lymph nodes (median 11 vs. 8, p < 0.001), longer hospital stays (median 13 vs. 11 days, p < 0.001), higher postoperative hypoalbuminemia rate (56.7% vs. 36.4%, p < 0.001) and higher fever rate (14.2% vs. 8.6%, p = 0.04) compared to the non-leakage group. On multivariate analysis, higher number of dissected lymph nodes (OR 3.278, 95% CI 1.135–9.471, p = 0.028) was found to be a independent risk factor for lymphatic leakage. Additionally, a positive correlation was observed between the numbers of dissected lymph nodes and lymphatic leakage rate (R = 0.456, p = 0.013). Conclusions: The increased number of dissected lymph nodes is associated with a heightened risk of lymphatic leakage following radical cystectomy for MIBC. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment (TME) of peritoneal metastasis (PM), where they contribute to tumor progression and metastasis via secretion of interleukin-6 (IL-6). Here, we investigated the role of IL-6 in PM of gastric cancer (GC) and assessed whether anti-IL-6 receptor antibody (anti-IL-6R Ab) could inhibit PM of GC. We conducted immunohistochemical analysis of IL-6 and α-smooth muscle (α-SMA) expressions in clinical samples of GC and PM, and investigated the interactions between CAFs and GC cells in vitro. Anti-tumor effects of anti-IL-6R Ab on PM of GC were investigated in an orthotopic murine PM model. IL-6 expression was significantly correlated with α-SMA expression in clinical samples of GC, and higher IL-6 expression in the primary tumor was associated with poor prognosis of GC. Higher IL-6 and α-SMA expressions were also observed in PM of GC. In vitro, differentiation of fibroblasts into CAFs and chemoresistance were observed in GC cells cocultured with fibroblasts. Anti-IL-6R Ab inhibited the progression of PM in GC cells cocultured with fibroblasts in the orthotopic mouse model but could not inhibit the progression of PM consisting of GC cells alone. IL-6 expression in the TME was associated with poor prognosis of GC, and CAFs were associated with establishment and progression of PM via IL-6. Anti-IL-6R Ab could inhibit PM of GC by the blockade of IL-6 secreted by CAFs, which suggests its therapeutic potential for PM of GC. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role of myosteatosis, sarcopenia, and perioperative serum biomarkers as independent predictors of major complications within 180 days following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). We retrospectively analyzed of 127 MIBC patients who underwent RC between 2013 and 2023 at a single institution. Preoperative body composition was assessed using CT scans at the L3 vertebral level to measure psoas muscle density (PMD), skeletal muscle density (SMD), axial muscle density (AMD), and muscle indices. Novel inflammatory and nutritional markers, including serum chloride levels within 24 h post-surgery, were also evaluated. Major complications were defined as Clavien-Dindo grade ≥ 3. Multivariate analysis was performed to identify independent predictors of postoperative complications. Among the cohort, 30.7% of patients experienced major complications within 90 days, and 36.2% within 180 days. Sepsis was the most common major complication (19 of 241 complications, 7.9%). Ten patients died during the observation period. Myosteatosis (p = 0.002) and postoperative serum chloride levels (p < 0.001) were significant independent predictors of 180-day major complications. Patients with low PMD had an adjusted odds ratio (OR) of 3.959 for developing major complications, while increased serum chloride levels were associated with a reduced risk of complications (OR = 0.985). Multivariate analysis reveals associations between myosteatosis, aging, and anemia. Myosteatosis and perioperative serum chloride levels are significant predictors of major complications after RC for MIBC. Incorporating body composition analysis and early serum chloride monitoring into perioperative care may improve risk stratification and patient outcomes following RC. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma is a prevalent urological malignancy, imposing substantial burdens on both patients and society. In our study, we used bioinformatics methods to select four putative target genes associated with EMT and prognosis and developed a nomogram model which could accurately predicting 5-year patient survival rates. We further analyzed proteome and single-cell data and selected PLCG2 and TMEM38A for the following experiments. Overexpression models of PLCG2 and TMEM38A were generated in Caki-1 and 786-O cell lines using plasmids. The in vitro experiments demonstrated that both of them exerted pro-apoptotic effects on Caki-1 and 786-O cells, inducing G2/M phase arrest, inhibiting proliferation, and suppressing EMT. In summary, we identified potential tumor suppressor factors and stratified ccRCC patients into high-risk and low-risk groups based on these factors. Furthermore, we elucidated the impact of PLCG2 and TMEM38A in Caki-1 and 786-O cell lines, offering novel avenues for therapeutic target exploration. [ABSTRACT FROM AUTHOR]

Objectives: Positive resection margins after breast-conserving surgery (BCS) most often demands a repeat surgery. To preoperatively identify patients at risk of positive margins, a multivariable model has been developed that predicts positive margins after BCS with a high accuracy. This study aimed to externally validate this prediction model to explore its generalizability and assess if additional preoperatively available variables can further improve its predictive accuracy. The validation cohort included 225 patients with invasive breast cancer who underwent BCS at Aarhus University Hospital, Aarhus, Denmark during 2020–2022. Receiver operating characteristic (ROC) and calibration analysis were used to validate the prediction model. Univariable logistic regression was used to evaluate if additional variables available in the validation cohort were associated with positive margins and backward elimination to explore if these variables could further improve the model´s predictive accuracy. Results: The AUC of the model was 0.60 (95% CI: 0.50–0.70) indicating a lower discriminative capacity in the external cohort. We found weak evidence for an association between increased preoperative breast density on mammography and positive resection margins after BCS (p = 0.027), but the AUC of the model did not improve, when mammographic breast density was included as an additional variable in the model. [ABSTRACT FROM AUTHOR]

Background: Damage-associated molecular patterns (DAMPs) induced by immunogenic cell death (ICD) may be useful for the immunotherapy to patients undergoing pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to predict the prognosis and immunotherapy responsiveness of PDAC patients using DAMPs-related genes. Methods: K-means analysis was used to identify the DAMPs-related subtypes of 175 PDAC cases. The significance of gene mutation and immune status in different subtypes was detected. LASSO regression was used to construct a DAMPs-related prognostic signature to predict the immunotherapy responsiveness of PDAC. Subsequently, in vivo and in vitro experiments and Bulk-RNA seq were used to verify the effect of hub gene pannexin 1 (PANX1) on PDAC. Results: Two subtypes were clustered based on the expression levels of DAMPs genes from 175 PDAC patients. Besides, the prognosis and immune landscape in up-regulated DAMPs expression subtypes was poor. In addition, we constructed a DAMPs-related prognostic signature that correlated with immune cell infiltration and predicted immunotherapy or chemotherapy responsiveness of patients with PDAC. Mechanically, through Bulk-RNA sequencing and experiments, we found that PANX1 promoted tumor progression and immune regulation via the ATP release to active NOD1/NFκB signaling pathway in PDAC. Conclusion: Our in silico analyses established a classification system based on ICD-related DAMPs genes in PDAC, and constructed a DAMPs-related prognostic model to predict the efficacy of immunotherapy. This study will provide a new perspective for targeting the DAMPs-related molecule PANX1 in the treatment of PDAC. [ABSTRACT FROM AUTHOR]

Marked by iron buildup and lipid peroxidation, ferroptosis is a relatively new regulatory cell death (RCD) pathway. Many diseases like cancer, myocardial ischemia-reperfusion injury (MIRI), neurological disorders and acute renal failure (AKI) are corelated with ferroptosis. The main molecular processes of ferroptosis discovered yet will be presented here, along with the approaches in which it interacts with tumour-associated signaling pathways and its uses in systemic therapy, radiation therapy, and immunotherapy managing tumors. [ABSTRACT FROM AUTHOR]

Novel strategies to disrupt tumor progression have emerged from studying the interactions between tumor cells and tumor-associated macrophages (TAMs). However, the molecular mechanisms of interactions between tumor cells and TAMs underlying oral squamous cell carcinoma (OSCC) progression have not been fully elucidated. This study explored the molecular mechanism of the HSP27/IL-6 axis in OSCC chemoresistance, invasion, and migration. Here, we demonstrated the higher expression of HSP27 in OSCC cells. Paracrine HSP27 from OSCC cells enhanced chemoresistance, invasion, migration, and EMT in OSCC by inducing M2 polarization and IL-6 secretion in TAMs. HSP27 and IL-6 established a positive feedback loop between OSCC cells and M2 TAMs. TAMs-derived IL-6 orchestrated OSCC stemness and chemoresistance through upregulating β-catenin and CD44, and enhanced OSCC invasion, migration, and EMT via autocrine HSP27/TLR4 signaling. Collectively, HSP27/IL-6 axis facilitates OSCC chemoresistance, invasion, and migration by orchestrating macrophages through a positive feedback loop. We identify the regulatory mechanism underlying the interaction and crosstalk between OSCC cells and TAMs mediated by the HSP27/IL-6 axis. Targeting the HSP27/IL-6 axis could be a promising treatment strategy for OSCC patients, potentially controlling disease progression and improving prognosis and recurrence outcomes. Graphical Headlights 1. HSP27/IL-6 axis promotes OSCC chemoresistance, invasion, and migration by promoting M2 polarization and IL-6 secretion of TAMs. 2. HSP27/IL-6 mediates a positive feedback loop between OSCC cells and M2 TAMs. 3. Targeting HSP27/IL-6 axis might be a promising treatment strategy for OSCC. [ABSTRACT FROM AUTHOR]

Introduction: Pemetrexed is a first line drug for brain metastases from lung cancer, either as monotherapy or combined with other drugs. The frequent occurrence of initial and acquired resistance to pemetrexed results in limited treatment effectiveness in brain metastases. CD146 was recently found to play important roles in chemoresistance and tumor progression. However, the underlying mechanisms of CD146's effects in pemetrexed resistance remain undefined. Method and results: Sensitivity to pemetrexed was assessed with a preclinical brain metastasis (BM) model based on lung adenocarcinoma PC9 cells. The role and mechanism of CD146 in pemetrexed resistance in non-small cell lung cancer (NSCLC) brain metastasis were explored in vitro and in vivo. A subpopulation of brain metastatic cells derived from progenitor PC9 cells (PC9-BrMS) was significantly resistant to pemetrexed. CD146 levels were significantly increased in pemetrexed resistant brain metastases, while CD146 inhibition suppressed pemetrexed resistance in BM cells. Mechanistically, CD146 mediated pemetrexed resistance in brain metastatic cells by promoting DNA damage repair, maintaining normal cell cycle progression, and regulating the NF-KB pathway to counter apoptosis, and these effects was based on increased DNA damage, cell cycle arrest, and occurrence of apoptosis after CD146 inhibition as well as the reemergence of pemetrexed resistance after CD146 restoration. Discussion: In summary, this study revealed that the resistance of NSCLC brain metastatic cells to PEM was dependent on CD146.Thus CD146 might be targeted in clinic to overcome pemetrexed resistance in brain metastases from NSCLC. [ABSTRACT FROM AUTHOR]