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It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through which dysregulated ncRNAs control resistance to the four major types of cancer therapies. We will focus on the current clinical implications of ncRNAs as biomarkers to predict treatment response (intrinsic resistance) and to detect resistance to therapy after the start of treatment (acquired resistance). Furthermore, we will present the potential of targeting ncRNA to overcome cancer treatment resistance, and we will discuss the challenges of ncRNA-targeted therapy—especially the development of delivery systems.

The combination of toripalimab (an anti-PD-1 antibody) with definitive chemoradiotherapy (CRT) demonstrated encouraging efficacy against locally advanced esophageal squamous cell carcinoma (ESCC) in the EC-CRT-001 phase II trial (NCT04005170). The primary endpoint of this trial was the clinical complete response rate (cCR), and the secondary endpoints included overall survival (OS), progression-free survival (PFS), duration of response, and quality of life. The exploratory analyses of EC-CRT-001 include exploring the role of circulating tumor DNA (ctDNA) and blood-based tumor mutational burden (bTMB) in predicting the response and survival. In total, 118 blood and 35 tissue samples from 42 enrolled patients were included in the analyses. We found that ctDNA-negative patients achieved a higher cCR compared to those with detectable ctDNA during CRT (83%, 19/23 vs. 39%, 7/18; p  = 0.008) or post-CRT (78%, 21/27 vs. 30%, 3/10; p  = 0.017). Patients with detectable ctDNA during CRT had shorter PFS ( p  = 0.014). Similarly, patients with post-CRT detectable ctDNA had a significantly shorter PFS ( p  = 0.012) and worse OS ( p  = 0.004). Moreover, patients with high bTMB levels during CRT had prolonged OS ( p  = 0.027). In conclusion, ctDNA and bTMB have the potential to predict treatment efficacy and survival in ESCC treated with CRT and immunotherapy. Toripalimab with definitive chemoradiotherapy is a promising treatment strategy for esophageal squamous cell carcinoma. Here, the authors show that ctDNA positivity and bTMB are predictive of response in patients within the EC-CRT-001 phase II trial.

Background Because of the complexity of the blood-brain barrier (BBB), brain tumors, especially the most common and aggressive primary malignant tumor type arising from the central nervous system (CNS), glioblastoma, remain an essential challenge regarding diagnostic and treatment. There are no approved circulating diagnostic or prognostic biomarkers, nor novel therapies like immune checkpoint inhibitors for glioblastoma, and chemotherapy brings only minimal survival benefits. The development of molecular biology led to the discovery of new potential diagnostic tools and therapeutic targets, offering the premise to detect patients at earlier stages and overcome the current poor prognosis. Main body One potential diagnostic and therapeutic breakthrough might come from microRNAs (miRNAs). It is well-known that miRNAs play a role in the initiation and development of various types of cancer, including glioblastoma. The review aims to answer the following questions concerning the role of RNA theranostics for brain tumors: (1) which miRNAs are the best candidates to become early diagnostic and prognostic circulating biomarkers?; (2) how to deliver the therapeutic agents in the CNS to overcome the BBB?; (3) which are the best methods to restore/inhibit miRNAs? Conclusions Because of the proven roles played by miRNAs in gliomagenesis and of their capacity to pass from the CNS tissue into the blood or cerebrospinal fluid (CSF), we propose miRNAs as ideal diagnostic and prognostic biomarkers. Moreover, recent advances in direct miRNA restoration (miRNA mimics) and miRNA inhibition therapy (antisense oligonucleotides, antagomirs, locked nucleic acid anti-miRNA, small molecule miRNA inhibitors) make miRNAs perfect candidates for entering clinical trials for glioblastoma treatment.

Background Bladder cancer (BC) has the highest per-patient cost of all cancer types. Hence, we aim to develop a non-invasive, point-of-care tool for the diagnostic and molecular stratification of patients with BC based on combined microRNAs (miRNAs) and surface-enhanced Raman spectroscopy (SERS) profiling of urine. Methods Next-generation sequencing of the whole miRNome and SERS profiling were performed on urine samples collected from 15 patients with BC and 16 control subjects (CTRLs). A retrospective cohort (BC = 66 and CTRL = 50) and RT-qPCR were used to confirm the selected differently expressed miRNAs. Diagnostic accuracy was assessed using machine learning algorithms (logistic regression, naïve Bayes, and random forest), which were trained to discriminate between BC and CTRL, using as input either miRNAs, SERS, or both. The molecular stratification of BC based on miRNA and SERS profiling was performed to discriminate between high-grade and low-grade tumors and between luminal and basal types. Results Combining SERS data with three differentially expressed miRNAs (miR-34a-5p, miR-205-3p, miR-210-3p) yielded an Area Under the Curve (AUC) of 0.92 ± 0.06 in discriminating between BC and CTRL, an accuracy which was superior either to miRNAs (AUC = 0.84 ± 0.03) or SERS data (AUC = 0.84 ± 0.05) individually. When evaluating the classification accuracy for luminal and basal BC, the combination of miRNAs and SERS profiling averaged an AUC of 0.95 ± 0.03 across the three machine learning algorithms, again better than miRNA (AUC = 0.89 ± 0.04) or SERS (AUC = 0.92 ± 0.05) individually, although SERS alone performed better in terms of classification accuracy. Conclusion miRNA profiling synergizes with SERS profiling for point-of-care diagnostic and molecular stratification of BC. By combining the two liquid biopsy methods, a clinically relevant tool that can aid BC patients is envisaged.

Background Only few studies, with small patient cohorts, have evaluated the effect of radiotherapy (RT) for metaplastic breast cancer (MBC). Hence, it is important to investigate the role of RT in MBC survival using a large population-database. Methods A retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) from 1973 to 2015 was performed. We compared MBC patients with or without RT for overall survival (OS) and breast cancer-specific survival (BCSS) using univariate and multivariate Cox proportional hazard regressions before and after propensity score matching (PSM). Results From a total of 2267 patients diagnosed with MBC between 1998 and 2015, 1086 (47.9%) received RT. In the multivariate analysis before PSM, RT provided a better OS (HR 0.73; 95% CI 0.61–0.88; p = 0.001) and BCSS (HR 0.71; 95% CI 0.58–0.88; p = 0.002). Multivariate analyses after PSM (n = 1066) confirmed that patients receiving RT (n = 506) survived longer than those without RT (OS, HR 0.64; 95% CI 0.51–0.80; p < 0.001 and BCSS, HR 0.64; 95% CI 0.50–0.83; p = 0.001). A longer OS was observed when RT was given to older patients (p = 0.001) and in case of large tumor size (p = 0.002). Intriguingly, patients with N0 stage showed better OS after RT (HR 0.69, P = 0.012). Conclusions Our findings support the beneficial effect of RT for MBC patients. In particular, older patients or with large tumor size have a greater survival benefit from RT. In conclusion, we have assessed the importance of the use of RT in MBC as survival factor and this could lead to the development of guidelines for this rare sub-type of tumors.

Non-coding RNAs (ncRNAs) are essential players in many cellular processes, from normal development to oncogenic transformation. Initially, ncRNAs were defined as transcripts that lacked an open reading frame (ORF). However, multiple lines of evidence suggest that certain ncRNAs encode small peptides of less than 100 amino acids. The sequences encoding these peptides are known as small open reading frames (smORFs), many initiating with the traditional AUG start codon but terminating with atypical stop codons, suggesting a different biogenesis. The ncRNA-encoded peptides (ncPEPs) are gradually becoming appreciated as a new class of functional molecules that contribute to diverse cellular processes, and are deregulated in different diseases contributing to pathogenesis. As multiple publications have identified unique ncPEPs, we appreciated the need for assembling a new web resource that could gather information about these functional ncPEPs. We developed FuncPEP, a new database of functional ncRNA encoded peptides, containing all experimentally validated and functionally characterized ncPEPs. Currently, FuncPEP includes a comprehensive annotation of 112 functional ncPEPs and specific details regarding the ncRNA transcripts that encode these peptides. We believe that FuncPEP will serve as a platform for further deciphering the biologic significance and medical use of ncPEPs. The link for FuncPEP database can be found at the end of the Introduction Section.

Immune checkpoint therapy (ICT) has shown promising potential in the treatment of multiple solid tumors. However, the role of ICT in pancreatic ductal adenocarcinoma (PDAC) remains limited. Patterns of immune checkpoints (ICs) in PDAC represent the basis for establishing a potent ICT. The aim of this study is to create a profile of IC expression and its prognostic relevance in cancer cells of PDAC. Therefore, tumor cells from peripheral and central tissue microarray (TMA) spots from histologically confirmed PDAC of 68 patients after tumor resection were investigated in terms of expressions of TIM3, IDO, B7H4, LAG3, VISTA, and PD-L1 using immunohistochemistry. The presence of the respective ICs was compared to overall survival (OS). The presence of VISTA and PD-L1 significantly correlates with shorter OS (median OS: 22 months vs. 7 months and 22 months vs. 11 months, respectively, p < 0.05). For the presence of TIM3, IDO, B7H4, and LAG3, no difference in OS was observed (p > 0.05). The analysis of OS of combined subgroups for VISTA and PD-L1 (VISTA and PD-L1 neg., VISTA pos. and PD-L1 neg., VISTA neg. and PD-L1 pos., and VISTA and PD-L1 pos.) yielded overall statistical significance difference (p = 0.02). These results suggest that the presence of VISTA and PD-L1 is of prognostic relevance and potentially qualifies them as targets for ICT.

Dedifferentiated liposarcoma (DDLPS) with inflammatory myofibroblastic tumor (IMT)-like features is a rare and diagnostically challenging variant of soft tissue sarcoma. We report the case of a 74-year-old man who presented with a mesenteric mass in 2022 and recurrent tumors in 2024. Tissue from both primary and recurrent tumors were submitted to our reference center for pathological reevaluation, with a suspicion of IMT being suspected. Although the tumors exhibited morphological characteristics consistent with those observed in IMT, they displayed distinctive histological, immunohistochemical and molecular features suggestive of DDLPS with IMT-like features, including amplification of the MDM2 gene. This report highlights the morphological spectrum of DDLPS, the diagnostic role of molecular pathology, and the importance of differentiating this aggressive neoplasm from benign entities such as IMT.

Background Mechanisms of development and progression of high-grade serous ovarian cancer (HGSOC) are poorly understood. EVI1 and PARP1, part of TGF-ß pathway, are upregulated in cancers with DNA repair deficiencies with DNA repair deficiencies and may influce disease progression and survival. Therefore we questioned the prognostic significance of protein expression of EVI1 alone and in combination with PARP1 and analyzed them in a cohort of patients with HGSOC. Methods For 562 HGSOC patients, we evaluated EVI1 and PARP1 expression by immunohistochemical staining on tissue microarrays with QuPath digital semi-automatic positive cell detection. Results High EVI1 expressing (> 30% positive tumor cells) HGSOC were associated with improved progression-free survival (PFS) (HR = 0.66, 95% CI: 0.504–0.852, p  = 0.002) and overall survival (OS) (HR = 0.45, 95% CI: 0.352–0.563, p  < 0.001), including multivariate analysis. Most interestingly, mutual high expression of both proteins identifies a group with particularly good prognosis. Our findings were proven technically and clinically using bioinformatical data sets for single-cell sequencing, copy number variation and gene as well as protein expression. Conclusions EVI1 and PARP1 are robust prognostic biomarkers for favorable prognosis in HGSOC and imply further research with respect to their reciprocity.

Background: Proton pump inhibitors (PPIs) have been shown to regulate the gut microbiome and affect the response to immune checkpoint inhibitors (ICIs). Contradictory results on survival have been observed in patients concomitantly treated with ICIs and PPIs. We performed a systematic review and meta-analysis to determine the association between PPI use and survival outcomes in ICI-treated cancer patients. Methods: EMBASE, MEDLINE/PubMed, Cochrane Library databases, and major oncology conference proceedings were searched. Studies comparing overall survival (OS) and progression-free survival (PFS) between PPI-treated and PPI-free groups of ICI-treated cancer patients were included. Data regarding study and patient characteristics, ICI and PPI treatments, and survival outcomes were extracted. Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using random effects models. Subgroup meta-analyses and meta-regressions were performed to explore possible factors of heterogeneity among the studies. Results: A total of 33 studies were included, comprising 7383 ICI- and PPI-treated patients and 8574 ICI-treated and PPI-free patients. The pooled HR was 1.31 (95% CI, 1.19–1.44; p < 0.001) for OS and 1.30 (95% CI, 1.17–1.46; p < 0.001) for PFS, indicating a significant negative association between PPI use and survival in ICI-treated patients. Subgroup meta-analyses by factors including cancer type, ICI type, and time window of PPI use revealed that ICI and PPI use impacted survival in patients with non-small cell lung or urothelial cancer, patients treated with anti-PD-1/PD-L1 antibodies, and patients receiving PPI as baseline treatment or 60 days before ICI treatment initiation. Conclusions: PPI use in patients treated with ICIs was associated with shorter OS and PFS, especially in several specific subgroups of cancer patients. PPIs should be strictly controlled and appear to not impact survival if given temporarily after ICI initiation. These observations could provide the basis for clinical guidelines for concomitant PPI and ICI use.