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Introduction: Metastatic prostate cancer (PCa) presents a significant challenge in oncology due to its high mortality rate and the absence of effective biomarkers for predicting patient outcomes. Building on previous research that highlighted the critical role of the long noncoding RNA (lncRNA) H19 and cell adhesion molecules in promoting tumor progression under hypoxia and estrogen stimulation, this study aimed to assess the potential of these components as prognostic biomarkers for PCa at the biopsy stage. Methods: This research utilized immunohistochemistry and droplet digital PCR to analyze formalin-fixed paraffin-embedded (FFPE) biopsies, focusing on specific markers within the H19/cell adhesion molecules pathway. Results: A novel multivariate analysis led to a “BioScore”, a composite biomarker score to predict disease progression. This score is based on evaluating five key markers: the expression levels of Hypoxia-Inducible Factor 2 Alpha (HIF-2α), endothelial Nitric Oxide Synthase (eNOS), β4 integrin, E-cadherin transcript (CDH1), and lncRNA H19. The criteria for the “BioScore” involve identifying three out of these five markers, combining elevated levels of HIF-2α, eNOS, β4 integrin, and CDH1 with reduced H19 expression. Conclusions: This finding suggests the possibility of identifying, at the time of biopsy, PCa patients at higher risk of metastasis based on dysregulation in the H19/cell adhesion molecules circuitry. This study provides a valuable opportunity for early intervention in managing PCa, potentially contributing to personalized treatment strategies.

Background: Perinephric fluid is commonly identified in patients with renal colic and urolithiasis, especially in cases associated with hydronephrosis. However, its clinical relevance, particularly its impact on treatment decisions and prognosis, is not well established. Methods: This retrospective, single-center study included adult patients who presented to the emergency department (ED) with suspected renal colic between January 2021 and October 2023. Patients underwent ultrasound evaluations, which were analyzed for perinephric fluid, hydronephrosis, stone size, and stone location. Data on patient demographics, laboratory results, and clinical outcomes, including the need for urological interventions, were also collected and analyzed. Multivariate logistic regression was used to assess factors associated with perinephric fluid presence. Results: Of the 509 patients included, 200 (39.3%) had perinephric fluid. Hydronephrosis was significantly associated with perinephric fluid (OR: 4.14, p = 0.007), as were stones located in the proximal (OR: 3.06, p = 0.003) and distal ureter (OR: 2.31, p = 0.018). However, sonographic perinephric fluid did not significantly affect the likelihood of urological intervention, in-hospital complications, sepsis, acute kidney injury (AKI), acute kidney disease (AKD), and prolonged hospital stay. Conclusions: Perinephric fluid is a common finding in patients with renal colic and urolithiasis, particularly in cases involving hydronephrosis and ureteral stones. However, despite its prevalence, sonographic perinephric fluid was not significantly associated with the need for urological intervention, longer hospital stays, or worse clinical outcomes. Further prospective studies are required to clarify its clinical implications fully. [ABSTRACT FROM AUTHOR]

Introduction: Metastatic prostate cancer (PCa) presents a significant challenge in oncology due to its high mortality rate and the absence of effective biomarkers for predicting patient outcomes. Building on previous research that highlighted the critical role of the long noncoding RNA (lncRNA) H19 and cell adhesion molecules in promoting tumor progression under hypoxia and estrogen stimulation, this study aimed to assess the potential of these components as prognostic biomarkers for PCa at the biopsy stage. Methods: This research utilized immunohistochemistry and droplet digital PCR to analyze formalin-fixed paraffin-embedded (FFPE) biopsies, focusing on specific markers within the H19/cell adhesion molecules pathway. Results: A novel multivariate analysis led to a "BioScore", a composite biomarker score to predict disease progression. This score is based on evaluating five key markers: the expression levels of Hypoxia-Inducible Factor 2 Alpha (HIF-2α), endothelial Nitric Oxide Synthase (eNOS), β4 integrin, E-cadherin transcript (CDH1), and lncRNA H19. The criteria for the "BioScore" involve identifying three out of these five markers, combining elevated levels of HIF-2α, eNOS, β4 integrin, and CDH1 with reduced H19 expression. Conclusions: This finding suggests the possibility of identifying, at the time of biopsy, PCa patients at higher risk of metastasis based on dysregulation in the H19/cell adhesion molecules circuitry. This study provides a valuable opportunity for early intervention in managing PCa, potentially contributing to personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: A large amount of evidence from clinical studies has demonstrated that circulating tumor cells are strong predictors of outcomes in many cancers. However, the clinical significance of CTC enumeration in metastatic colorectal cancer is still questioned. The aim of this study was to evaluate the clinical value of CTC dynamics in mCRC patients receiving first-line treatments. Materials and methods: Serial CTC data from 218 patients were used to identify CTC trajectory patterns during the course of treatment. CTCs were evaluated at baseline, at a first-time point check and at the radiological progression of the disease. CTC dynamics were correlated with clinical endpoints. Results: Using a cut-off of ≥1 CTC/7.5 mL, four prognostic trajectories were outlined. The best prognosis was obtained for patients with no evidence of CTCs at any timepoints, with a significant difference compared to all other groups. Lower PFS and OS were recognized in group 4 (CTCs always positive) at 7 and 16 months, respectively. Conclusions: We confirmed the clinical value of CTC positivity, even with only one cell detected. CTC trajectories are better prognostic indicators than CTC enumeration at baseline. The reported prognostic groups might help to improve risk stratification, providing potential biomarkers to monitor first-line treatments.

Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the rarity of the illnesses, the development of treatment measures for malignancies of the gastrointestinal system is far behind. The number of patients eligible for curative treatment is limited due to cancer's aggressive nature and the difficulties of early identification. Furthermore, surgery is frequently intrusive and linked with a significant level of risk. The therapy result of hepatobiliary cancers is unsatisfactory due to these complicated variables, leaving significant space for improvement.

Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.

It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5′-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study’s findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.

Therapy failure and metastasis-associated mortality are stumbling blocks in the management of PDAC in patients. Failure of therapy is associated to intense hypoxic conditions of tumors. To develop effective therapies, a complete understanding of hypoxia-associated changes in genetic landscape of tumors during disease progression is needed. Because artificially immortalized cell lines do not rightly represent the disease progression, studying genetics of tumors in spontaneous models is warranted. In the current study, we generated a spectrum of spontaneous human (UM-PDC1; UM-PDC2) and murine (HI-PanL, HI-PancI, HI-PanM) models representing localized, invasive, and metastatic PDAC from a patient and transgenic mice (K-rasG12D/Pdxcre/Ink4a/p16-/). These spontaneous models grow vigorously under hypoxia and exhibit activated K-ras signaling, progressive loss of PTEN, and tumorigenicity in vivo. Whereas UM-PDC1 form localized tumors, the UM-PDC2 metastasize to lungs in mice. In an order of progression, these models exhibit genomic instability marked by gross chromosomal rearrangements, centrosome-number variations, Aurora-kinase/H2AX colocalization, loss of primary cilia, and α-tubulin acetylation. The RNA sequencing of hypoxic models followed by qRT-PCR validation and gene-set enrichment identified Intestine-Specific Homeobox factor (ISX)–driven molecular pathway as an indicator PDAC aggressivness. TCGA-PAAD clinical data analysis showed high ISX expression correlation to poor survival of PDAC patients, particularly women. The functional studies showed ISX as a regulator of i) invasiveness and migratory potential and ii) VEGF, MMP2, and NFκB activation in PDAC cells. We suggest that ISX is a potential druggable target and newly developed spontaneous cell models are valuable tools for studying mechanism and testing therapies for PDAC.

Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases.

Cholangiocarcinoma (CCA) is one of the most lethal cancers, and its rate of occurrence is increasing annually. The diagnoses of CCA patients remain elusive due to the lack of early symptoms and is misdiagnosed as HCC in a considerable percentage of patients. It is crucial to explore the underlying mechanisms of CCA carcinogenesis and development to find out specific biomarkers for early diagnosis of CCA and new promising therapeutic targets. In recent times, the reprogramming of tumor cells metabolism has been recognized as a hallmark of cancer. The modification from the oxidative phosphorylation metabolic pathway to the glycolysis pathway in CCA meets the demands of cancer cell proliferation and provides a favorable environment for tumor development. The alteration of metabolic programming in cancer cells is complex and may occur via mutations and epigenetic modifications within oncogenes, tumor suppressor genes, signaling pathways, and glycolytic enzymes. Herein we review the altered metabolism in cancer and the signaling pathways involved in this phenomena as they may affect CCA development. Understanding the regulatory pathways of glucose metabolism such as Akt/mTOR, HIF1α, and cMyc in CCA may further develop our knowledge of this devastating disease and may offer relevant information in the exploration of new diagnostic biomarkers and targeted therapeutic approaches for CCA.

Background Genetic testing for BRCA1/2 germline mutations in hereditary breast/ovarian cancer patients requires screening for single nucleotide variants, small insertions/deletions and large genomic rearrangements (LGRs). These studies have long been run by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The recent introduction of next-generation sequencing (NGS) platforms dramatically improved the speed and the efficiency of DNA testing for nucleotide variants, while the possibility to correctly detect LGRs by this mean is still debated. The purpose of this study was to establish whether and to which extent the development of an analytical algorithm could help us translating NGS sequencing via an Ion Torrent PGM platform into a tool suitable to identify LGRs in hereditary breast-ovarian cancer patients. Methods We first used NGS data of a group of three patients (training set), previously screened in our laboratory by conventional methods, to develop an algorithm for the calculation of the dosage quotient (DQ) to be compared with the Ion Reporter (IR) analysis. Then, we tested the optimized pipeline with a consecutive cohort of 85 uncharacterized probands (validation set) also subjected to MLPA analysis. Characterization of the breakpoints of three novel BRCA1 LGRs was obtained via long-range PCR and direct sequencing of the DNA products. Results In our cohort, the newly defined DQ-based algorithm detected 3/3 BRCA1 LGRs, demonstrating 100% sensitivity and 100% negative predictive value (NPV) (95% CI [87.6–99.9]) compared to 2/3 cases detected by IR (66.7% sensitivity and 98.2% NPV (95% CI [85.6–99.9])). Interestingly, DQ and IR shared 12 positive results, but exons deletion calls matched only in five cases, two of which confirmed by MLPA. The breakpoints of the 3 novel BRCA1 deletions, involving exons 16–17, 21–22 and 20, have been characterized. Conclusions Our study defined a DQ-based algorithm to identify BRCA1 LGRs using NGS data. Whether confirmed on larger data sets, this tool could guide the selection of samples to be subjected to MLPA analysis, leading to significant savings in time and money.

Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA.

Hemangiopericytoma (HPT) is a rare mesenchymal tumor of fibroblastic type and for its rarity is poorly studied. The most common sites of metastatic disease in patients with intracranial HPT are the bone, liver, and lung, suggestive for an hematogenous dissemination; for this reason, we investigated, for the first time, the presence of circulating tumor cells (CTCs) in hemangiopericytoma patient by CellSearch® and SceenCell® devices. Peripheral blood samples were drawn and processed by CellSearch, an EpCAM-dependent device, and ScreenCell®, a device size based. We found nontypical CTCs by CellSearch system and the immunofluorescence analysis performed on CTCs isolate by ScreenCell demonstrated the presence of single CTCs and CTC clusters. The molecular characterization of single CTCs and CTC clusters, using antibodies directed against EpCAM, CD34, cytokeratins (8, 18, and 19), and CD45, showed a great heterogeneity in CTC clusters. We believe that the present study may open a new scenario in the rare tumors: the introduction of the liquid biopsy and the molecular characterization of circulating tumor cells could lead to personalized targeted treatments and also for rare tumors.

The programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) pathway has emerged as a critical inhibitory pathway regulating T-cell response in non-small-cell lung cancer (NSCLC), and the development of PD-1/PD-L1 inhibitors has changed the landscape of NSCLC therapy. Nevertheless, the high degree of non-responders demonstrates that we are still far from completely understanding the events underlying tumor immune resistance. Although the expression of PD-L1 in tumor tissue has been correlated with clinical response to anti PD-1 inhibitors, the ability of this marker to discriminate the subgroup of patients who derive benefit from immunotherapy is suboptimal. Circulating tumor cells (CTCs), as an accessible source of tumor for biologic characterization that can be serially obtained with minimally invasive procedure, hold significant promise to facilitate treatment-specific biomarkers discovery. We recently demonstrated that the presence of PD-L1 on CTCs apparently predicts resistance to the anti-PD-1 Nivolumab in metastatic NSCLC patients and that PD-L1 positive CTCs usually have an elongated morphology that can be ascribed to epithelial–mesenchymal transition (EMT). We here demonstrate for the first time that PD-L1 positive CTCs isolated from NSCLC patients are characterized by partial EMT phenotype, and hypothesize that the co-expression of PD-L1 and EMT markers might represent for these cells a possible molecular background for immune escape.

The article focuses on a study which evaluates how cilia guard the kidneys in ischemia-reperfusion (IR) injury which caused acute kidney injury. It notes that primary cilia are sensory organelles involved in sensing mechanical and chemical changes in the tubular environment. Study findings demonstrate that pretreatment with the AT2R agonist C21 signiicantly reduces tubular cell deciliation and maintains ciliary length in both cortical and medullary tubules during IR.