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Simple Summary: Cholesterol and cholesterol derivatives accumulate in prostate cancer cells. Epidemiologic studies about diet and/or treatment with cholesterol-lowering drugs indicate that this metabolite plays a role in cancer progression, but they do not discriminate its possible role in cancer incidence. The goal of this study is so to determine whether cholesterol availability impacts tumor formation itself. Using a drosophila model specifically dedicated to the study of early epithelial tumorigenesis, we find that basal extrusion, a critical step of tumor formation, directly depends on cholesterol availability through dietary intake, and on cholesterol metabolization by the tumor cells. As we find that many genes related to cholesterol homeostasis and metabolism are ill-expressed in primary prostate cancer samples, this work indicates that cholesterol levels and metabolism could play a crucial role in the early phases of prostate cancer as well. Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in the Drosophila melanogaster accessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammation is one of the major risk factors for colorectal cancer development. This study aims to determine the effect of genetic mutations on inflammation-induced colon tumor cell heterogeneity and differentiation. Using single-cell approaches, we found that the addition of BRAFV600E to Apc mutant mice (BLM) increased colon epithelial tumor differentiation. Additionally, we found that BLM epithelial tumors had increased expression of revival colon stem cell (RevCSC) markers and reduced WNT signaling compared to Apc mutant epithelial tumors (Min). In contrast, the loss of Msh2 in Min mice (MSH2KO) increased epithelial tumor stem cell populations with increased WNT signaling compared to Min epithelial tumor. We also identified additional potential regulators of BLM epithelial tumor differentiation such as CDX2 and NDRG1. Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (MinApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAFV600E mutation (BRAFF-V600ELgr5tm1(Cre/ERT2)CleMinApcΔ716/+, BLM) or knocking out Msh2 (Msh2LoxP/LoxPVil1-creMinApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Nowadays, tumor tests to analyze DNA in tumor cells from epithelial tubal/ovarian cancers (EOCs) are performed in many centers to detect tumor pathogenic variants (TPVs) in the BRCA1/2 genes. Information on the presence of these TPVs guides treatment options and further genetic testing in patients and relatives. However, there is no standardization of testing procedures, and information about how testing is performed is limited. Therefore, we described how BRCA1/2 tumor testing is performed in 999 EOC patients in the Netherlands in 2019 using real-world clinical data. Tumor tests were performed for 502 patients (50.2%) and TPVs were detected in 14.7% of the tests. This study shows that there is variability in the execution of BRCA1/2 tumor tests, but there were no indications for quality differences. Adequate reporting and quality monitors are essential to ensure that all centers perform reliable tumor tests to ultimately identify all patients with BRCA1/2 TPVs. Analyzing BRCA1/2 tumor pathogenic variants (TPVs) in epithelial tubal/ovarian cancers (EOCs) has become an essential part of the diagnostic workflow in many centers to guide treatment options and genetic cascade testing. However, there is no standardization of testing procedures, including techniques, gene assays, or sequencers used, and data on the execution of tumor tests remains scarce. Therefore, we evaluated characteristics of BRCA1/2 tumor testing in advanced-stage EOC with real-world national data. Pathology reports of patients diagnosed with EOC in 2019 in the Netherlands were obtained from the Dutch Pathology Registry (PALGA), and data regarding histological subtype and BRCA1/2 tumor tests were extracted. A total of 999 patients with advanced-stage EOC were included. Tumor tests were performed for 502 patients (50.2%) and BRCA1/2 TPVs were detected in 14.7%. Of all tests, 48.6% used hybrid capture techniques and 26.5% used PCR-based techniques. More than half of the tests (55.0%) analyzed other genes in addition to BRCA1/2. Overall, this study highlights the heterogeneity in the execution of BRCA1/2 tumor tests. Despite a lack of evidence of quality differences, we emphasize that adequate reporting and internal and external quality monitors are essential for the high-quality implementation and execution of reliable BRCA1/2 tumor testing, which is crucial for identifying all patients with BRCA1/2 TPVs. [ABSTRACT FROM AUTHOR]

Simple Summary: Thymic epithelial tumors are a rare and mostly indolent type of solid tumors. Histology, tumor staging, and resection status are important indicators of prognosis. Preoperative therapy is utilized in patients with advanced thymic tumors when primary surgery is unlikely to achieve R0 resection. By administering preoperative therapy, clinicians hope to have a better chance of resecting the tumor completely so that the patient may have a better prognosis. Many retrospective and a few prospective studies have been conducted in the past two decades on preoperative therapy. Also, many novel agents have recently entered the field of thymic tumor treatment. This review is a re-examination of the current evidence. For most patients with advanced thymic epithelial tumors (TETs), a complete resection is a strong indicator of a better prognosis. But sometimes, primary surgery is unsatisfactory, and preoperative therapy is needed to facilitate complete resection. Neoadjuvant chemotherapy is the most used form of preoperative therapy. But studies on neoadjuvant chemotherapy have included mainly patients with thymoma; its efficacy in patients with thymic carcinoma is less known. Neoadjuvant chemoradiation has also been explored in a few studies. Novel therapies such as immunotherapy and targeted therapy have shown efficacy in patients with recurrent/metastatic TETs as a second-line option; their role as preoperative therapy is still under investigation. In this review, we discuss the existing evidence on preoperative therapy and the insight it provides for current clinical practice and future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: The triage of glandular cell abnormalities of the uterine cervix poses many challenges due to high interobserver variability. p16/Ki67 dual staining has been proposed as an objective test that could decrease interobserver variability in diagnosing atypical glandular cells. Our results indicate the possible role of p17/Ki67 dual staining in triaging glandular cell abnormalities. Very limited information exists about the role of p16/Ki67 dual staining on glandular cells in detecting glandular precancerous lesions and cervical adenocarcinoma. In this study, we investigated the diagnostic accuracy of p16/Ki67 dual staining for the detection of glandular and squamous lesions on the uterine cervix and for cancer of the upper reproductive tract. We performed a retrospective analysis of prospectively collected data on 96 patients with glandular cell abnormalities. We analyzed the diagnostic accuracy of p16/Ki67 dual staining for atypical glandular cells, not otherwise specified (AGC-NOS); atypical glandular cells, favor neoplastic (AGC-FN); adenocarcinoma in situ (AIS); and A-CA (cervical adenocarcinoma). A separate analysis for the detection of squamous precancerous lesions and squamous-cell carcinoma (CIN3+) and for cancer of the upper reproductive tract (EC/OC) was performed. Among patients who had normal histology or a low-grade lesion on final analysis, only 8.5% had positive dual staining. On the other hand, 85.7% of patients with AIS+ on final histology had positive dual staining. The respective specificities of p16/Ki67 dual staining on AGC-NOS for the detection of AIS+ (adenocarcinoma in situ or cervical adenocarcinoma), CIN3+ and EC/OC were 91.5%, 88.7% and 86.4%. High specificity values of p16/Ki67 dual staining on cervical smears labelled as AGC-NOS for the detection of CIN3+ and AIS+ suggest that this method might be a useful addition in cervical cancer screening. [ABSTRACT FROM AUTHOR]

The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors have revolutionized cancer therapy and improved clinical outcomes. Immunotherapy is now increasingly combined with chemotherapy and other conventional treatments, such as radiation therapy, as part of the multimodal treatment of earlier-stage cancers. Although generally well tolerated and capable of inducing long-lasting responses, immunotherapy for thymic epithelial tumors can be challenging due to defects in immune self-tolerance, which increase the risk of immune-mediated toxicity. In order to improve the safety of immunotherapy and maximize clinical benefit in patients with thymic cancers, there is a pressing need to identify potential biomarkers of response and toxicity for this patient population. In this paper, we review the current role of immunotherapy for thymic cancers and discuss future applications across the spectrum of stage and histology of these diseases. Thymic epithelial tumors are a histologically diverse group of cancers arising from the epithelial compartment of the thymus. These tumors are characterized by a low tumor mutation burden, a lack of actionable genomic changes, and, especially with thymomas, defects in immune tolerance. Surgery is the mainstay of the management of resectable disease, whereas advanced, unresectable tumors are treated with platinum-based chemotherapy. Disease recurrence can occur months to years after frontline treatment. Although several options are available for conventional treatment of recurrent thymic tumors, response rates are generally low, and treatment-related toxicity can affect quality of life. A subset of patients benefit from biologic therapies, but there remains an unmet need for the development of new treatments. Immune checkpoint inhibitors are safe, clinically active, and have contributed to an improvement in survival for patients with a wide variety of cancers. However, the application of these revolutionary treatments for thymic cancers is limited to their use for the management of recurrent thymic carcinoma because of the risk of immune toxicity. In this paper, we review the current uses of immunotherapy for the management of thymic epithelial tumors and highlight potential strategies to improve safety and broaden the application of these treatments for patients with thymic cancers. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) expression in neoplastic and immune cells of the tumor microenvironment determines the efficacy of antitumor immunity, while it can be regulated at the epigenetic level by various factors, including HDACs. In this study, we aim to evaluate the expression patterns of PD-L1 in thymic epithelial tumors (TETs), while we attempt the first correlation analysis between PD-L1 and histone deacetylases (HDACs) expression. Methods: Immunohistochemistry was used to evaluate the expression of PD-L1 in tumor and immune cells of 91 TETs with SP263 and SP142 antibody clones, as well as the expressions of HDCA1, -2, -3, -4, -5, and -6. Results: The PD-L1 tumor proportion score (TPS) was higher, while the immune cell score (IC-score) was lower in the more aggressive TET subtypes and in more advanced Masaoka–Koga stages. A positive correlation between PD-L1 and HDAC-3, -4, and -5 cytoplasmic expression was identified. Conclusions: Higher PD-L1 expression in neoplastic cells and lower PD-L1 expression in immune cells of TETs characterizes more aggressive and advanced neoplasms. Correlations between PD-L1 and HDAC expression unravel the impact of epigenetic regulation on the expression of immune checkpoint molecules in TETs, with possible future applications in combined therapeutic targeting. [ABSTRACT FROM AUTHOR]

Simple Summary: Sinonasal cancers (SNCs) are rare tumours of the nasal cavity and paranasal sinuses with recognised or suspected associations with some occupational carcinogens, including wood and leather dusts and nickel and chromium compounds. In Italy, a population-based SNC registry organised as a network of regional registries was officially established in 2008 to monitor SNC occurrence and evaluate occupational exposure. In this study, we analysed survival of SNC patients based on the SNC registry of the Lombardy region, north-west Italy (10 million people, one-sixth of the Italian population). In 2008–2020, we recorded more than 800 cases. Vital status was determined until mid-2023. About 50% of patients died within 5 years of diagnosis. Survival was strongly dependent on patients' age (worst prognosis in the elderly), tumour location (worst prognosis for paranasal sinuses), and for some histological types. Survival has not improved in recent years. Women and men had a similar prognosis. Sinonasal cancers (SNCs) are rare malignancies associated with occupational exposures. The aim of this study was to analyse the survival of SNC patients using data from the population-based SNC registry of the Lombardy region (10 million people), Italy. We included epithelial SNC cases registered in 2008–2020 and followed-up for vital status until 31 July 2023. Multivariate flexible parametric models with time-dependent covariates were fitted to calculate excess hazard ratios (EHRs) and 95% confidence intervals (CIs) of death. Based on 827 cases (553 males, 274 females) and 514 deaths (345 males, 169 females), the 5-year observed survival was 49% and the net survival was 57%. Age had a substantial impact on survival, particularly within the first year (EHR, 1.35; 95% CI, 1.12–1.51 per 10 years). Compared with the nasal cavity, the EHR for paranasal sinuses was 4.70 (95% CI, 2.96–7.47) soon after diagnosis. Compared with squamous cell carcinomas, the EHR was 0.69 (95% CI, 0.52–0.91) for adenocarcinomas, 1.68 (95% CI, 1.20–2.35) for undifferentiated and unspecified carcinomas, and 1.78 (95% CI, 1.07–2.95) for neuroendocrine carcinomas. Age and cancer site showed time-dependent effects on prognosis, especially within the first month after diagnosis. Prognosis was also markedly affected by cancer morphology. No associations were found for gender and period of diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Romania ranks second in Europe in both mortality and incidence rates for cervical cancer, and the majority of cases are diagnosed in locally advanced stages. Therapeutic guidelines indicate concomitant chemoradiotherapy as the proper treatment (total dose 85–90 Gy at point A). Yet, in Romania, as a result of poor radiotherapy infrastructure, deficient patient access to radiotherapy, and specific socio-psychologic factors, concurrent chemoradiotherapy is usually suboptimal (total dose 60–65 Gy at point A) and often followed by radical surgery aimed at better local control. Our retrospective cohort study of 351 patients with histopathological confirmed locally advanced cervical cancer proved that complete pathologic response is present in less than half of patients previously treated by concurrent chemoradiotherapy, thus demonstrating the rationale behind radical surgery—better local control, especially in unfavorable aggressive histological types like adenocarcinoma and adenosquamous carcinoma or tumors that have progressed under concurrent chemoradiotherapy. We discuss several possible causes for the over-usage of surgery in Romania for treating locally advanced cervical cancer. The incidence and mortality of cervical cancer are high in Romania compared to other European countries, particularly for locally advanced cervical cancer cases, which are predominant at the time of diagnosis. Widely accepted therapeutic guidelines indicate that the treatment for locally advanced cervical cancer consists of concurrent chemoradiotherapy (total dose 85–90 Gy at point A), with surgery not being necessary as it does not lead to improved survival and results in significant additional morbidity. In Romania, the treatment for locally advanced cervical cancer differs, involving lower-dose chemoradiotherapy (total dose 60–65 Gy at point A), followed by surgery, which, under these circumstances, ensures better local control. In this regard, we attempted to evaluate the role and necessity of surgery in Romania, considering that in our study, residual lesions were found in 55.84% of cases on resected specimens, especially in cases with unfavorable histology (adenocarcinoma and adenosquamous carcinoma). This type of surgery was associated with significant morbidity (28.22%) in our study. The recurrence rate was 24.21% for operated-on patients compared to 62% for non-operated-on patients receiving suboptimal concurrent chemotherapy alone. In conclusion, in Romania, surgery will continue to play a predominant role until radiotherapy achieves the desired effectiveness for local control. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic or inoperable thymic carcinoma (TC) has a very poor prognosis. Since this tumor is rare, few clinical trials have been conducted to date, and thus, the development of new drugs is slow. The aberrant pathways involved in TC need to be examined in more detail in order to identify novel target molecules for TC therapy. Next-generation sequencing has been used to comprehensively investigate genetic alterations in thymic epithelial tumors (TET). However, limited information is currently available on epigenetic alterations. In the present study, genome-wide screening was conducted on aberrantly methylated CpG islands in TET, and 92 genes were identified. We then focused on the DNA methylation and mRNA and protein expression of NPTX2 in TET. The DNA methylation level of NPTX2 was higher, while its mRNA and protein expression levels were lower in TC than in the normal thymus and thymoma. Furthermore, relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. Collectively, the present results indicate the potential use of NPTX2 as a tumor suppressor in TC. Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in TET, and this identified neuronal pentraxin 2 (NTPX2) as a significantly hypermethylated CpG island in TC relative to thymomas. NPTX2 is released from pre-synaptic cells in response to neuronal activity/seizure, and plays a role in host immunity and acute inflammation. TET samples were obtained from 38 thymomas, 25 TC, and 6 NECTT. The DNA methylation, mRNA, and protein expression levels of NPTX2 were examined. The DNA methylation rate of the NPTX2 gene was significantly higher in TC than in the normal thymus and thymomas, except B3. The mRNA expression level of NPTX2 was lower in TC than in the normal thymus. An inverse relationship was observed between mRNA expression levels and methylation levels. Relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. NECTT showed very high mRNA and protein expression levels and low DNA methylation levels of NPTX2. NPTX2 may function as a tumor suppressor in TC, and have an oncogenic function in NECTT. [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal adenocarcinoma is a type of cancer that originates in cells lining the lower part of the esophagus, the tube that connects the throat to the stomach. This cancer specifically arises from glandular cells, which produce mucus to help lubricate the lining of the esophagus. In this work, we investigated whether and to what extent truncated O-glycans, called Tn and STn antigens, are expressed under pathophysiological conditions and whether these correlate with clinicopathological data and overall survival. This investigation is particularly significant in the context of targeted therapies, since Tn and STn antigens are tumor-specific target structures. Differential glycosylation, marked by the presence of truncated O-glycans, is a distinctive feature of epithelial-derived cancers. However, there is a notable gap in research regarding the expression of Tn and STn antigens in esophageal adenocarcinoma (EAC). To address this, we employed commercially available antibodies, previously validated for Tn and STn antigens, to analyze two cohorts of EAC tissues. Initially, large-area tissue sections from formalin-fixed paraffin-embedded (FFPE) EAC and corresponding healthy tissues were subjected to immunohistochemistry (IHC) staining and scoring. Subsequently, we evaluated the RNA expression levels of crucial O-glycosylation related genes—C1GALT1 and C1GALT1C1—using a quantitative real-time polymerase chain reaction (qRT-PCR). In a comprehensive analysis, a substantial cohort of EAC tissues (n = 311 for Tn antigen, n = 351 for STn antigen) was investigated and correlated with clinicopathological data. Our findings revealed that Tn and STn antigens are highly expressed (approximately 71% for both) in EAC, with this expression being tumor-specific. Notably, Tn antigen expression correlates significantly with the depth of tumor cell infiltration (p = 0.026). These antigens emerge as valuable markers and potential therapeutic targets for esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Thymic carcinomas are the most aggressive thymic epithelial tumors. While thymic carcinomas do not have a single specific cause, various aspects of their growth have been evaluated at the molecular level. In this review, we organize the recent findings according to what have been defined as the hallmarks of cancer. The identification of the molecular alterations that drive the growth of these tumors is crucial for the development of effective target therapies. Inactivation of CDKN2A, TP53, and CDKN2B by somatic mutation or deletion is most common in thymic carcinomas. In advanced tumors, mutations in genes that regulate epigenetic and chromatin remodeling can occur. On the contrary, mutations in tyrosine kinase receptors and other oncogenes are only occasional, with those of KIT being the most common and present in only 10% of thymic carcinomas. Thymic carcinomas present an enhanced and aberrant vasculature that has been targeted in clinical trials with promising results. Additionally, thymic carcinomas evade the control of the immune system, with some tumors showing a response to immune checkpoint inhibitors. Thymic epithelial tumors, comprising thymic carcinomas and thymomas, are rare neoplasms. They differ in histology, prognosis, and association with autoimmune diseases such as myasthenia gravis. Thymomas, but not thymic carcinomas, often harbor GTF2I mutations. Mutations of CDKN2A, TP53, and CDKN2B are the most common thymic carcinomas. The acquisition of mutations in genes that control chromatin modifications and epigenetic regulation occurs in the advanced stages of thymic carcinomas. Anti-angiogenic drugs and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown promising results for the treatment of unresectable tumors. Since thymic carcinomas are frankly aggressive tumors, this report presents insights into their oncogenic drivers, categorized under the established hallmarks of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver tumours in children are definitely "surgical tumours", and their complete resection is essential for cure. Compared to adults, the extent of resection in children can be much greater; up to 75–85% of the liver parenchyma can be safely resected. However, parenchymal preservation resection (segmentectomy, bisegmentectomy) seems to be a good option in carefully selected patients. There are very few publications regarding minor liver resections in children. From the available literature and data presented here, we propose that (bi)segmentectomy can become a viable surgical option in patients with favourable tumour locations and the absence of portal invasion in imaging. But, when qualifying a child for minor resection, it is important to remember that meeting oncological goals remains the primary objective of liver surgery. Further studies evaluating the impact of parenchymal preservation surgery on surgical and oncological outcome after liver resection in children should be conducted with a larger dataset. Purpose: To present a single-centre experience in bi- and uni-segmentectomies for primary liver tumours in children. Methods: This study included 23 patients that underwent (bi)segmentectomy. There were 15 malignant tumours (hepatoblastoma—13 patients), 7 benign tumours, and 1 calcifying nested stromal epithelial tumour. Results: The median tumour diameter was 52 mm (range 15–170 mm). Bisegmentectomy 2–3 was most frequently performed (seven patients), followed by bisegmentectomy 5–6 (four patients). The median operative time was 225 min (range 95–643 min). Intraoperative complications occurred in two patients—small bowel perforation in one and an injury of the small peripheral bile duct resulting in biloma in the other. The median resection margin in patients with hepatoblastoma was 3 mm (range 1–15 mm). Microscopically negative margin status was achieved in 12 out of 13 patients. There were two recurrences. After a median follow-up time of 38 months (range 12–144 months), all 13 patients with HB were alive with no evidence of disease. Two relapsed patients were alive with no evidence of disease. Conclusions: From the available literature and data presented here, we propose that (bi)segmentectomy can become a viable surgical option in carefully selected paediatric patients and is sufficient to achieve a cure. Further studies evaluating the impact of parenchymal preservation surgery on surgical and oncological outcome should be conducted with a larger dataset. [ABSTRACT FROM AUTHOR]

Simple Summary: Bladder cancer (BC) is one of the most common urological cancers affecting more men than women. The absence of biomarkers for early detection and prognostication add to the burden of the disease. The SPP1 protein is differentially expressed in many malignancies and could serve as a potential prognostic biomarker. However, its expression profile, clinical significance and prognostic value, as well as its relationship with immune infiltration, have not been comprehensively studied in bladder cancer. Herewith, we aimed to investigate the prognostic value of SPP1 expression and its association with other cancer-promoting factors in bladder cancer. Our data indicated that SPP1 is differentially expressed at an early stage of BC development and is associated with an unfavorable prognosis. Interaction between SPP1 and other proteins/genes and immune cell infiltrates may play an important role in the pathogenesis and could as a potential therapeutic target for bladder cancer. Secreted phosphoprotein-1 (SPP1) expression is differentially altered in many malignancies and could serve as a potential prognostic biomarker. Recent findings indicated that SPP1 possesses a broader role in bladder cancer (BC) pathogenesis than previously envisioned; however, the underlying mechanisms governing its expression, cellular localization, prognostic value and immune-related role in bladder cancer remain poorly understood. The expression and the prognosis value of SPP1 were assessed using immunohistochemistry (IHC) staining on a tissue microarray. SPP1 expression was correlated with the clinicopathological parameters, and survival analysis was calculated using a Kaplan–Meier plotter. Bioinformatics analysis of TCGA data was queried using UALCAN, CIBERSORT and TIMER datasets to decipher the biological processes enrichment pattern, protein–protein interactions and characterize tumor-infiltrating immune cells, respectively. IHC revealed that SPP1 expression is significantly associated with tumor type, stage, grade and smoking status. The Kaplan–Meier survival curve showed that low SPP1 expression is an unfavorable prognostic indicator in bladder cancer patients (p = 0.02, log-rank). The significant increased expression of the SPP1 level is associated with evident hypomethylation of the gene promoter in cancer compared to normal tissues in the TCGA-bladder dataset. Missense mutation is the most frequent genetic alteration of the SPP1 gene. Protein–protein interactions demonstrated that SPP1 shares the same network with many important genes and is involved in many signaling pathways and biological processes. TIMER reported a significant correlation between SPP1 expression and multiple immune cells infiltration. Furthermore, the expression of SPP1 was found to be positively correlated with a number of immune checkpoint genes such as PD-1 and CTLA4. The current investigation indicates that the SPP1 protein could serve as a prognostic biomarker and merit further investigation to validate its clinical usefulness in patients with bladder cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: We investigated the prevalence of genetic alterations and their association with epidermal growth factor receptor (EGFR) mutations and prognosis in early-stage non-small cell lung cancer (NSCLC) after curative resection. The results showed that the prevalence of EGFR mutations, anaplastic lymphoma kinase (ALK) rearrangements, and ROS proto-oncogene 1 (ROS1) fusion were 43.0%, 5.7%, and 1.6%, respectively. Patients with EGFR-mutant NSCLC had a higher risk of recurrence than those without EGFR mutations. Additionally, EGFR mutations were related to a high proportion of distant metastases and a higher risk of central nervous system recurrence. A definitive surgical resection is the preferred treatment for early-stage non-small cell lung cancer (NSCLC). Research on genetic alterations, including epidermal growth factor receptor (EGFR) mutations, in early-stage NSCLC remains insufficient. We investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutations and recurrence after a complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resections at a single regional cancer center in Korea were recruited. We retrospectively compared the clinical and pathological data between the recurrence and non-recurrence groups. Among the 659 enrolled cases, the median age was 65.86 years old and the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutations was 43% (194/451). Among them, L858R point mutations and exon 19 deletions were 52.3% and 42%, respectively. Anaplastic lymphoma kinase (ALK) rearrangement was found in 5.7% of patients (26/453) and ROS proto-oncogene 1 (ROS1) fusion was found in 1.6% (7/441). The recurrence rate for the entire population was 19.7%. In the multivariate analysis, the presence of EGFR mutations (hazard ratio (HR): 2.698; 95% CI: 1.458–4.993; p = 0.002), stage II (HR: 2.614; 95% CI: 1.29–5.295; p = 0.008) or III disease (HR: 9.537; 95% CI: 4.825–18.852; p < 0.001) (vs. stage I disease), and the presence of a pathologic solid type (HR: 2.598; 95% CI: 1.405–4.803; p = 0.002) were associated with recurrence. Among the recurrence group, 86.5% of the patients with EGFR mutations experienced distant metastases compared with only 66.7% of the wild type (p = 0.016), with no significant difference in median disease-free survival (52.21 months vs. not reached; p = 0.983). In conclusion, adjuvant or neoadjuvant targeted therapy could be considered more actively because EGFR mutations were identified as an independent risk factor for recurrence and were associated with systemic recurrence. Further studies on perioperative therapy for other genetic alterations are necessary. [ABSTRACT FROM AUTHOR]

Simple Summary: Thymic epithelial tumors (TET) are rare. Therefore, large studies, specifically concerning genetic alterations, are difficult in these tumors and require multi-institutional effort. However, such studies are important because alterations in certain genes of these tumors could be useful in the diagnosis of difficult cases, provide a better understanding of the nature of these tumors, or may even be therapeutically targetable. A few genetic alterations have already been identified in TET. This review will focus on gene fusions that have been reported in a subset of TET. The histopathologic features and clinical characteristics of these subtypes of TET and the potential clinical implications of the gene fusions for outcome of the patient and therapeutic options will be discussed. Thymic epithelial tumors (TET) are rare and large molecular studies are therefore difficult to perform. However, institutional case series and rare multi-institutional studies have identified a number of interesting molecular aberrations in TET, including gene fusions in a subset of these tumors. These gene fusions can aid in the diagnosis, shed light on the pathogenesis of a subset of tumors, and potentially may provide patients with the opportunity to undergo targeted therapy or participation in clinical trials. Gene fusions that have been identified in TET include MAML2 rearrangements in 50% to 56% of mucoepidermoid carcinomas (MAML2::CRTC1), 77% to 100% of metaplastic thymomas (YAP1::MAML2), and 6% of B2 and B3 thymomas (MAML2::KMT2A); NUTM1 rearrangements in NUT carcinomas (most commonly BRD4::NUTM1); EWSR1 rearrangement in hyalinizing clear cell carcinoma (EWSR1::ATF1); and NTRK rearrangement in a thymoma (EIF4B::NTRK3). This review focuses on TET in which these fusion genes have been identified, their morphologic, immunophenotypic, and clinical characteristics and potential clinical implications of the fusion genes. Larger, multi-institutional, global studies are needed to further elucidate the molecular characteristics of these rare but sometimes very aggressive tumors in order to optimize patient management, provide patients with the opportunity to undergo targeted therapy and participate in clinical trials, and to elucidate the pathogenesis of these tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Similarly to other solid malignancies, there is a growing interest in testing immune checkpoint inhibitors (ICIs) for thymic epithelial tumors (TETs). However, the thymus has unique biological features that can increase the risk of immune-related adverse events. In this article, the relationships among the thymus, immune system, and autoimmune diseases (ADs) usually associated with TETs, and their impact on the potential benefits and risks of immunotherapy, are reviewed. The results of completed clinical trials of immunotherapy for refractory/relapsed thymomas and thymic carcinomas are presented. Thymic epithelial tumors (TETs) comprise a rare group of thoracic cancers, classified as thymomas and thymic carcinomas (TC). To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory tumors. Unlike other solid cancers, the development of targeted biologic and/or immunologic therapies in TETs remains in its nascent stages. Moreover, since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology, which can confer susceptibility to autoimmune diseases and ultimately influence the risk–benefit balance of immunotherapy, especially for patients with thymoma. Indeed, early results from single-arm studies have shown interesting clinical activity, albeit at a cost of a higher incidence of immune-related side effects. The lack of knowledge of the immune mechanisms associated with TETs and the absence of biomarkers predictive of response or toxicity to immunotherapy risk limiting the evolution of immunotherapeutic strategies for managing these rare tumors. The aim of this review is to summarize the existing literature about the thymus's immune biology and its association with autoimmune paraneoplastic diseases, as well as the results of the available studies with immune checkpoint inhibitors and cancer vaccines. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced ovarian cancer (Stages III-IV) continues to be one of the gynecological tumors with the highest mortality. Standard treatment consists of debulking surgery and subsequent adjuvant chemotherapy. Recently, some authors have postulated that the administration of hyperthermic chemotherapy during surgery could increase the survival of patients, especially in cases in which chemotherapy had already been administered before surgery to reduce tumor volume. Our study is important because it collects data from 11 tertiary hospitals in Spain, and the data are subjected to a statistical technique that reproduces the data that we would find in a prospective study but using retrospective data (propensity score matching). It also offers a current view of the status of ovarian cancer treatment in our country. Introduction: Epithelial ovarian cancer (EOC) is primarily confined to the peritoneal cavity. When primary complete surgery is not possible, neoadjuvant chemotherapy (NACT) is provided; however, the peritoneum-plasma barrier hinders the drug effect. The intraperitoneal administration of chemotherapy could eliminate residual microscopic peritoneal tumor cells and increase this effect by hyperthermia. Intraperitoneal hyperthermic chemotherapy (HIPEC) after interval cytoreductive surgery could improve outcomes in terms of disease-free survival (DFS) and overall survival (OS). Materials and Methods: A multicenter, retrospective observational study of advanced EOC patients who underwent interval cytoreductive surgery alone (CRSnoH) or interval cytoreductive surgery plus HIPEC (CRSH) was carried out in Spain between 07/2012 and 12/2021. A total of 515 patients were selected. Progression-free survival (PFS) and OS analyses were performed. The series of patients who underwent CRSH or CRSnoH was balanced regarding the risk factors using a statistical analysis technique called propensity score matching. Results: A total of 170 patients were included in each subgroup. The complete surgery rate was similar in both groups (79.4% vs. 84.7%). The median PFS times were 16 and 13 months in the CRSH and CRSnoH groups, respectively (Hazard ratio (HR) 0.74; 95% CI, 0.58–0.94; p = 0.031). The median OS times were 56 and 50 months in the CRSH and CRSnoH groups, respectively (HR, 0.88; 95% CI, 0.64–1.20; p = 0.44). There was no increase in complications in the CRSH group. Conclusion: The addition of HIPEC after interval cytoreductive surgery is safe and increases DFS in advanced EOC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell cancer (SCC) of the vulva is one of the rare gynecological malignancies, and surgery is the initial treatment of choice for early-stage vulvar cancer. International guidelines offer conflicting recommendations regarding surgical and pathological tumor-free resection margins for SCC of the vulva. The aim of this study was therefore to analyze the node-negative patients with SCC of the vulva treated with surgery alone at the Department of Women's Health, University Clinic, Tuebingen, Germany with regard to the achieved marginal distance and its impact on prognosis. The present study observed no significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva on disease-free and overall survival. Background: The aim of this study was to evaluate the impact of pathological tumor-free margin distance on survival in SCC patients treated with surgery alone. Methods: This retrospective study included 128 patients with node-negative disease that received no adjuvant treatment. Disease-free and overall survival were analyzed according to pathological tumor-free margin distance. Results: The patients were subclassified into three resection margin category groups: "1 to 3 mm" (n = 42), ">3 to 8 mm" (n = 47) or ">8 mm" (n = 39). Thirty-nine of the 128 patients (30.5%) developed recurrent disease. Median follow-up for disease-free survival (DFS) was 6.49 years (95% CI 5.16 years; 7.62 years), and median follow-up for overall survival (OS) was 6.29 years (95% CI 5.45 years; 7.33 years). The 5-year DFS rate was 0.70 (95% CI: 0.62–0.79), and the 5-year OS rate was 0.79 (95% CI: 0.71–0.87). Regarding the survival outcome, there were no independent significant differences in either disease-free survival (DFS) (p = 0.300) or overall survival (p = 1.000) among patients within the three tumor-free resection margin categories. Multivariate analyses did not show any statistically significant association between tumor-free resection margin distance and recurrent disease or death, either when analyzed as a categorical variable or when analyzed as a continuous variable. Conclusion: The present study did not show a significant impact of pathological tumor-free resection margin distance following surgery in patients with node-negative SCC of the vulva (that did not receive adjuvant treatment) on disease-free and overall survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Pulmonary sarcomatoid carcinoma (PSC) is an aggressive subtype of non-small-cell lung cancer (NSCLC). It does not respond favorably to standard chemotherapy, and the response to PD-1/PD-L1 inhibitors remains modest. The introduction of new therapeutic approaches for this subtype is crucial. Our study demonstrates that PD-L1 expression was significantly higher in the epithelial component than in the sarcomatoid component. Expression of PD-L1 in both components was only seen in 32.1% of patients. However, the majority of PSC patients had at least one immune checkpoint expression in both components. Thus, combination immune checkpoint inhibition based on expression profiles may prove as a personalized and effective treatment strategy. This study also reveals a high rate of MET exon 14 skipping mutation (METex14) in PSC. METex14 selectively induced PD-L1 expression through MAPK or PI3K/Akt pathways. A combination of targeted therapies with immunotherapy in this population also warrants further investigation as a novel treatment approach. Immunotherapy has transformed lung cancer management, but PSC remains an aggressive subtype with a poor prognosis. This study investigates the differential expression of PD-L1 and alternative immune checkpoints (ICs; B7x, B7-H3, and HHLA2), and genetic alterations in PSCs. Tumor specimens of 41 PSC patients were evaluated. PD-L1, B7x, B7-H3, and HHLA2 were positive in 75.0%, 67.6%, 73.0%, and 91.9% of tumors, respectively. PD-L1 expression was significantly higher in the epithelial compared to the sarcomatoid component (median TPS: 50% vs. 0%, p = 0.010). Expression of PD-L1 in both components was only seen in 32.1% of patients. However, at least one IC was expressed in 92.9% of epithelial and 100% of sarcomatoid components. Furthermore, METex14 was detected in 19.5% of patients and was associated with a higher sarcomatoid percentage. Our preclinical studies revealed that METex14 induced PD-L1 expression via MAPK or PI3K/Akt pathways, and MET inhibitors decreased PD-L1 expression. Our findings demonstrate distinct expressions of ICs in PSC subcomponents. Thus, combination IC inhibition as a therapeutic strategy in PSC warrants further exploration. A high percentage of METex14 in PSC and its role in regulating PD-L1 expression reveal different therapeutic targets in this aggressive NSCLC subtype. [ABSTRACT FROM AUTHOR]

In recent years, natural polysaccharides have been widely used in the preparation of drug delivery systems. In this paper, novel polysaccharide-based nanoparticles were prepared by layer-by-layer assembly technology using silica as a template. The layers of nanoparticles were constructed based on the electrostatic interaction between a new pectin named NPGP and chitosan (CS). The targeting ability of nanoparticles was formed by grafting the RGD peptide, a tri-peptide motif containing arginine, glycine, and aspartic acid with high affinity to integrin receptors. The layer-by-layer assembly nanoparticles (RGD-(NPGP/CS)3NPGP) exhibited a high encapsulation efficiency (83.23 ± 6.12%), loading capacity (76.51 ± 1.24%), and pH-sensitive release property for doxorubicin. The RGD-(NPGP/CS)3NPGP nanoparticles showed better targeting to HCT-116 cells, the integrin αvβ3 high expression human colonic epithelial tumor cell line with higher uptake efficiency than MCF7 cells, the human breast carcinoma cell line with normal integrin expression. In vitro antitumor activity tests showed that the doxorubicin-loaded nanoparticles could effectively inhibit the proliferation of the HCT-116 cells. In conclusion, RGD-(NPGP/CS)3NPGP nanoparticles have potential as novel anticancer drug carriers because of their good targeting and drug-carrying activity. [ABSTRACT FROM AUTHOR]

Simple Summary: The impact of human papillomavirus (HPV) status on cervical glandular lesions is a debated topic. In general, non-HPV-related adenocarcinomas would appear to have a worse prognosis. Assessing this question in early stage or in situ adenocarcinomas may be interesting, as conservative surgery is feasible in these cases. Moreover, this population group accounts for 80% of the cases of high-grade glandular lesions in clinical practice. This research aims to evaluate the outcomes of long-term follow-up in HPV-positive and -negative women. Evaluating these findings may be of interest to know whether HPV status may impact management planning in the early and in situ stages of adenocarcinomas. Our results showed that the recurrence rate was not significantly different between the two groups. However, an analysis limited to only a portion of our sample showed a type-specific association with disease relapse. It is unknown whether human papillomavirus (HPV) status impacts the prognosis of early stage cervical glandular lesions. This study assessed the recurrence and survival rates of in situ/microinvasive adenocarcinomas (AC) according to HPV status during a 5-year follow-up. The data were retrospectively analyzed in women with available HPV testing before treatment. One hundred and forty-eight consecutive women were analyzed. The number of HPV-negative cases was 24 (16.2%). The survival rate was 100% in all participants. The recurrence rate was 7.4% (11 cases, including four invasive lesions (2.7%)). Cox proportional hazards regression showed no difference in recurrence rate between HPV-positive and HPV-negative cases (p = 0.148). HPV genotyping, available for 76 women and including 9/11 recurrences, showed a higher relapse rate for HPV-18 than HPV-45 and HPV-16 (28.5%, 16.6%, and 9.52%, p = 0.046). In addition, 60% and 75% of in situ and invasive recurrences, respectively, were HPV-18 related. The present study showed that most ACs were positive for high-risk HPV, and the recurrence rate was unaffected by HPV status. More extensive studies could help evaluate whether HPV genotyping may be considered for recurrence risk stratification in HPV-positive cases. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we developed a generic framework to analyze the Surveillance, Epidemiology, and End Results (SEER) database to generate reliable machine learning (ML) prediction models for cancer recurrence. As a proof-of-concept, using 130,979 oral tongue squamous cell carcinoma patients, we generated ML models to predict 5- and 10-year recurrence with high accuracy, recall, and precision. Thus, we demonstrate an effective framework for guiding future ML efforts in predicting cancer recurrence using the SEER database, with implications for the guidance of patient management and follow-up care. Despite diagnostic advancements, the development of reliable prognostic systems for assessing the risk of cancer recurrence still remains a challenge. In this study, we developed a novel framework to generate highly representative machine-learning prediction models for oral tongue squamous cell carcinoma (OTSCC) cancer recurrence. We identified cases of 5- and 10-year OTSCC recurrence from the SEER database. Four classification models were trained using the H2O ai platform, whose performances were assessed according to their accuracy, recall, precision, and the area under the curve (AUC) of their receiver operating characteristic (ROC) curves. By evaluating Shapley additive explanation contribution plots, feature importance was studied. Of the 130,979 patients studied, 36,042 (27.5%) were female, and the mean (SD) age was 58.2 (13.7) years. The Gradient Boosting Machine model performed the best, achieving 81.8% accuracy and 97.7% precision for 5-year prediction. Moreover, 10-year predictions demonstrated 80.0% accuracy and 94.0% precision. The number of prior tumors, patient age, the site of cancer recurrence, and tumor histology were the most significant predictors. The implementation of our novel SEER framework enabled the successful identification of patients with OTSCC recurrence, with which highly accurate and sensitive prediction models were generated. Thus, we demonstrate our framework's potential for application in various cancers to build generalizable screening tools to predict tumor recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor-infiltrating lymphocytes (TILs) have long been used to predict the prognosis of solid tumors. TIL levels have been reported to be closely associated with the prognosis of patients with squamous cell carcinoma. In contrast, major histocompatibility complex (MHC) class I chain-related molecule A (MICA), which acts as a ligand for NKG2D in natural killer (NK) cells and CD8+ T cells, is related to a higher survival rate in patients with oral squamous cell carcinoma (OSCC). In this study, we investigated the association of OSCC with TILs and MICA in patients with OSCC and its potential as a biomarker. Background: Tumor-infiltrating lymphocytes (TILs) have been used to predict the prognosis of solid tumors. In this study, we investigated which molecules in TILs play a role in the prognosis of patients with oral squamous cell carcinoma (OSCC). Methods: In a retrospective case-control study, we immunohistochemically evaluated the expression of CD3, CD8, CD45RO, Granzyme B, and the major histocompatibility complex class I chain-related molecule A (MICA) of the histocompatibility complex as predictors of prognosis in 33 patients with OSCC. The patients were classified as TILsHigh or TILsLow according to the number of TILs for each molecule in the central tumor (CT) and invasive margin (IM). Furthermore, MICA expression scores were determined based on the intensity of the staining. Results: CD45RO+/TIL in the nonrecurrent group were significantly higher than those in the recurrent group in the CT and IM areas (p < 0.05). The disease-free survival/overall survival rate of the CD45RO+/TILsLow group in the CT and IM areas and the Granzyme B+/TILsLow group in the IM area was significantly lower than that of the CD45RO+/TILsHigh group and the Granzyme B+/TILsHigh group, respectively (p < 0.05). Furthermore, the MICA expression score of tumors around the CD45RO+/TILsHigh group was significantly higher than that of the CD45RO+/TILsLow group (p < 0.05). Conclusions: A high ratio of CD45RO-expressing TILs was associated with a disease-free/overall survival improvement in OSCC patients. Furthermore, the number of TILs that express CD45RO was associated with the expression of MICA in tumors. These results suggest that CD45RO-expressing TILs are useful biomarkers for OSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the most common cancers worldwide and improved treatments are needed. The present research focused on the use of a DNA vaccine targeted at one of the commonly found tumor-associated antigens, human MUC1. MUC1 transgenic mice were vaccinated with MUC1 DNA mixed with bone-marrow-derived dendritic cells (BMDCs). Then, inflammation-driven colon cancer was induced by injection of a carcinogen, azoxymethane, and administration of dextran-sulfate-sodium-containing drinking water. This mouse model of colon cancer resembles the colon cancer found in humans. The number and size of colonic tumors were compared to mice vaccinated with MUC1 DNA alone or BMDCs alone. The combination of MUC1 DNA and BMDCs reduced the tumor burden more than in the controls, showing an additive preventive effect. These findings demonstrate that in this human MUC1 transgenic mouse model, MUC1-expressing colonic tumors can be partially prevented by a vaccine containing MUC1 DNA and BMDCs. The preventive efficacy of MUC1-specific DNA immunization on inflammation-driven colon carcinogenesis in human MUC1 transgenic (MUC1.Tg) mice was investigated. Mice were vaccinated with MUC1 DNA mixed with autologous bone-marrow-derived dendritic cells (BMDCs), and then colonic tumors were induced by azoxymethane (AOM) injection and oral administration of dextran sulfate sodium (DSS). Two types of tumors, squamous metaplasia and tubular adenoma, were observed. Both expressed high levels of MUC1 as indicated by the binding of anti-MUC1 antibodies with different specificities, whereas MUC1 expression was not detected in normal colonic mucosa. When mice were immunized with MUC1 DNA + BMDCs, tumor incidence, tumor number, and tumor size were significantly reduced. In contrast, vaccination with MUC1 DNA alone or BMDCs alone was ineffective in reducing tumor burden. Inflammation caused by DSS was not suppressed by the MUC1 DNA + BMDCs vaccination. Furthermore, MUC1 protein expression levels, as judged by anti-MUC1 antibody binding in tumors grown after vaccination, did not significantly differ from the control. In conclusion, an inflammation-driven carcinogenesis model was established in MUC1.Tg mice, closely resembling human colon carcinogenesis. In this model, vaccination with MUC1 DNA + BMDCs was effective in overriding MUC1 tolerance and reducing the tumor burden by a mechanism not affecting the level of colonic inflammation. [ABSTRACT FROM AUTHOR]

Simple Summary: While anti-PD1 antibodies have demonstrated efficacy in some patients with metastatic anal cancer, these agents have no proven benefit for those with localized disease treated with chemoradiation. Difficulty procuring fresh tumor tissue required for RNA and protein expression analysis has limited extensive molecular profiling for this rare cancer. Our team utilized a novel digital spatial profiling technology on pretreatment anal cancer specimens to identify biomarkers associated with recurrence after chemoradiation. We observed that recurrent tumors had higher baseline expression of immune checkpoint biomarkers, higher MAPK signaling activation and higher PI3K/Akt signaling activation. These findings provide a rationale that supports future clinical trials with immunotherapy that seek to improve survival beyond chemoradiation for patients with localized squamous cell cancer of the anus. The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancers have a poor prognosis mainly attributed to late diagnosis when a cure is not possible. Markers that are capable of predicting cancerous changes at an early stage are needed. Here, we quantified the soluble isoform of CTLA-4 (sCTLA-4), a molecule usually described for its immune function, in normal, potentially malignant and malignant oral and oropharyngeal epithelial samples. We report a distinct sCTLA-4 staning pattern and distribution in normal samples indicative of a new role for this molecule in epithelial cell growth and development. We also describe significant changes in sCTLA-4 staining in potentially malignant and malignant samples, suggestiong the potential of sCTLA-4 as a predictor of disease progression. Background: Head and neck cancer (HNC) has a high mortality rate, with late diagnosis remaining the most important factor affecting patient survival. Therefore, it is imperative to identify markers that aid in early detection and prediction of disease progression. HNCs evade the immune system by different mechanisms, including immune checkpoints. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is an immune checkpoint receptor that downregulates anti-tumour immune responses, with evidence of involvement in HNC. The less studied, alternatively spliced, soluble isoform (sCTLA-4) also plays an immunosuppressive role that contributes to immune escape. We quantified sCTLA-4 in normal, potentially malignant, and malignant oral and oropharyngeal tissues to elucidate any role in tumourigenesis and identify its potential as a biomarker for diagnosis and patient stratification. Methods: Normal, low- and high-grade epithelial dysplasia, and squamous cell carcinoma oral and oropharyngeal biopsies were selectively stained for sCTLA-4 and quantified using the image analysis software QuPath. Results: Distinct sCTLA-4 staining patterns were observed, in which normal epithelial sCTLA-4 expression correlated with keratinocyte differentiation, while disrupted expression, both in intensity and localisation, was observed in dysplastic and neoplastic tissues. Conclusions: Our data indicate an additional, previously unknown role for sCTLA-4 in epithelial cell differentiation and proliferation. Furthermore, our findings suggest the potential of sCTLA-4 as a biomarker for predicting disease progression and patient stratification for targeted HNC therapies. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused major changes in the healthcare sector due to adaptations required to hospitalize and treat an impressive number of patients. This retrospective study intended to collect reliable information on urothelial cancer patients in Romania. The primary objective was to compare the pre-pandemic and pandemic periods to observe the differences that occurred in the management of patients with urothelial carcinoma. The secondary objective was to determine the risk factors for urothelial cancer progression in the study cohort correlated with the COVID-19 pandemic. All patients that were diagnosed and treated at our clinic with a diagnosis of urothelial carcinoma (transitional cell carcinoma) during 2019–2021 were included in the current study. A total of 1122 eligible unique cases were identified during the study period. The number of patients who underwent intervention in the pre-pandemic year was 421, followed by a 22.6% decrease in 2020 to 326 cases and a 13.1% increase in 2021 to 375 cases. The proportion of muscle-invasive bladder cancer (MIBC) cases was significantly higher during the pandemic years, from 30.5% MIBC cases in 2019 to 37.4% in 2020 and 39.4% in 2021, suggesting a delay in presentations during the pandemic. Stage III and IV (TNM) cases were significantly more frequent, even though approximately 40% of all patients were operated on in stage I. The number of cystectomies increased significantly, from 5.2% in 2019 and 4.3% in 2020 to 10.1% in 2021, while the number of elective surgeries decreased, although no significant difference was observed regarding the in-hospital mortality and disease progression at six months. Patients with stage III and IV at presentation had the highest likelihood of disease progression at six months (HR = 5.61). Distant invasion was the second highest risk factor (HR = 5.13), followed by MIBC type (HR = 2.49). Nevertheless, the duration of hospitalization and year of diagnosis during the COVID-19 pandemic were not significant risk factors for cancer progression at six months. It can be concluded that there was a significant delay in patient presentations in 2020, and we advocate for increased public health awareness for urothelial cancer and increased attention toward the screening and management of these patients in the following years. [ABSTRACT FROM AUTHOR]

Proteomics analysis of circulating exosomes derived from cancer cells represents a promising approach to the elucidation of cell–cell communication and the discovery of putative biomarker candidates for cancer diagnosis and treatment. Nonetheless, the proteome of exosomes derived from cell lines with different metastatic capabilities still warrants further investigation. Here, we present a comprehensive quantitative proteomics investigation of exosomes isolated from immortalized mammary epithelial cells and matched tumor lines with different metastatic potentials in an attempt to discover exosome markers specific to breast cancer (BC) metastasis. A total of 2135 unique proteins were quantified with a high confidence level from 20 isolated exosome samples, including 94 of the TOP 100 exosome markers archived by ExoCarta. Moreover, 348 altered proteins were observed, among which several metastasis-specific markers, including cathepsin W (CATW), magnesium transporter MRS2 (MRS2), syntenin-2 (SDCB2), reticulon-4 (RTN), and UV excision repair protein RAD23 homolog (RAD23B), were also identified. Notably, the abundance of these metastasis-specific markers corresponds well with the overall survival of BC patients in clinical settings. Together, these data provide a valuable dataset for BC exosome proteomics investigation and prominently facilitate the elucidation of the molecular mechanisms underlying primary tumor development and progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma (ccRCC) progression, which is the most common form of kidney cancer, is associated with the loss of the Von Hippel-Lindau (VHL) gene in renal epithelium. VHL promotes proteasomal degradation of Hypoxia Inducible Factor alpha (HIF-α) thereby inhibiting the transcription of genes that are required for cell growth and proliferation during hypoxia (lack of oxygen). Accumulation of HIF-α consequent to VHL loss results in the activation of HIF target genes irrespective of oxygen availability which initiates tumorigenesis in the kidney. In this review, we discuss which signaling networks and genes are upregulated in response to HIF-α activation and how they drive ccRCC progression. We also highlight the potential therapies available to treat ccRCC patients as well as several medical and scientific challenges that impede the scientific investigation in this field. The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. [ABSTRACT FROM AUTHOR]

Simple Summary: Malignant salivary gland tumors are rare, accounting for 0.05–2 per 100,000 inhabitants worldwide. The parotid gland represents the most frequent cancer site, and both primary and secondary malignant tumors can affect it. Primary cancer includes many histological types, while intraparotid metastases have usually a cutaneous origin. Because of the rarity and heterogeneity of parotid tumors, the prognosis is difficult to assess. The literature focused on specific primary tumors or secondary cancer. The aim of this retrospective observational study was to evaluate the clinical features and prognosis of malignant epithelial tumors of the parotid gland. In particular, a comparison between primary and secondary cancer and survival analyses were performed. Moreover, complications were recorded. Primary and secondary malignant tumors can affect the parotid gland. The aim of this retrospective study was to evaluate the clinical features and prognosis of malignant epithelial tumors of the parotid gland. In particular, a comparison between primary and secondary cancer and survival analyses were performed. Eighteen patients with primary cancer and fifteen with intraparotid metastasis from cutaneous squamous cell carcinoma were included. A chart review was performed to collect clinical data (age, sex, smoking, alcohol consumption, tumor stage, type of surgical procedure, complications, recurrence and death). The majority of primary tumors were early (T1-2 N0, 83%) with mucoepidermoid carcinoma being the most common (33%). Secondary tumors were mostly staged P2 (53%) and N0 (67%). Subjects with secondary tumors were older than those with primary cancer. Post-operative permanent facial palsy was observed in 5 patients (17%) with primary cancer and 9 (60%) with secondary tumors (p = 0.010). Two-year overall survival for primary and secondary parotid cancer was 76.58% and 43.51%, respectively (p = 0.048), while 2-year disease-free survival was 76.05% and 38.50%, respectively (p = 0.152). In conclusion, secondary cancer of the parotid gland has worse survival than primary tumors. In the future, the implementation of multimodality treatment of intraparotid metastases is necessary to improve oncologic outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Endoscopic ultrasound is now regarded as a valuable technique for assessing subepithelial lesions and determining their potential malignancy. The objective of this article is to thoroughly review the most recent advancements in the endoscopic field that can provide an accurate diagnosis and, as a result, establish the best treatment and outcomes for these types of lesions. Gastrointestinal Stromal Tumors (GISTs) are subepithelial lesions (SELs) that commonly develop in the gastrointestinal tract. GISTs, unlike other SELs, can exhibit malignant behavior, so differential diagnosis is critical to the decision-making process. Endoscopic ultrasound (EUS) is considered the most accurate imaging method for diagnosing and differentiating SELs in the gastrointestinal tract by assessing the lesions precisely and evaluating their malignant risk. Due to their overlapping imaging characteristics, endosonographers may have difficulty distinguishing GISTs from other SELs using conventional EUS alone, and the collection of tissue samples from these lesions may be technically challenging. Even though it appears to be less effective in the case of smaller lesions, histology is now the gold standard for achieving a final diagnosis and avoiding unnecessary and invasive treatment for benign SELs. The use of enhanced EUS modalities and elastography has improved the diagnostic ability of EUS. Furthermore, recent advancements in artificial intelligence systems that use EUS images have allowed them to distinguish GISTs from other SELs, thereby improving their diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioneuronal and neuronal tumours are rare and mostly found in young adults and children, representing less than 5% of primary central nervous system (CNS) tumours. Accurate diagnosis is often difficult, requiring a significant body of evidence (clinical, radiological, pathology and molecular). The aim of this paper is to describe the main entities reported in the 2021 World Health Organization (WHO) classification, including, on the one hand, their histomolecular and imaging features and, on the other hand, their therapeutic management. Gross total resection is the cornerstone of the treatment of these tumours when achievable. MAPK pathway abnormalities could represent an interesting target for novel drugs. Rare glial, neuronal and glioneuronal tumours in adults form a heterogeneous group of rare, primary central nervous system tumours. These tumours, with a glial and/or neuronal component, are challenging in terms of diagnosis and therapeutic management. The novel classification of primary brain tumours published by the WHO in 2021 has significantly improved the diagnostic criteria of these entities. Indeed, diagnostic criteria are nowadays multimodal, including histological, immunohistochemical and molecular (i.e., genetic and methylomic). These integrated parameters have allowed the specification of already known tumours but also the identification of novel tumours for a better diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: How to treat patients with synchronous head and neck cancer and superficial esophageal squamous cell neoplasm (SHNSESCN) has not been studied. This study found that endoscopic resection (ER) of superficial esophageal squamous cell neoplasm (SESCN) significantly improved overall survival in patients with SHNSESCN compared with no treatment (NT) of SESCN. Furthermore, treatment-related mortality and morbidity were not significantly different between ER and NT of SESCN. Multivariate analysis showed that Eastern Cooperative Oncology Group performance status score and head and neck cancer disease progression were the two independent indicators of overall survival. Endoscopic resection of SESCN is the recommended treatment for patients with SHNSESCN, but further prospective randomized studies are needed to confirm this. There are no studies on treating synchronous head and neck cancer (HNC) and superficial esophageal squamous cell neoplasm (SESCN). We aimed to report the outcomes of endoscopic resection (ER) and no treatment (NT) of SESCN in patients with synchronous HNC and SESCN (SHNSESCN). This retrospective study included 47 patients with SHNSESCN. Treatment for SESCN was ER (n = 30) or NT (n = 17). The ER group had significantly lower Charlson comorbidity index scores and a higher proportion of Eastern Cooperative Oncology Group performance status (ECOG PS) scores ≤1. The location and stage of the two tumors did not differ significantly between the groups. The 1-year, 3-year, and 5-year OS rates of the ER group were significantly better than those in the NT group. Treatment-related morbidity and mortality were not significantly different between the two groups. In the subgroup analysis of synchronous advanced HNC and SESCN, ER for SESCN also had a higher OS rate. Multivariate analysis showed that ECOG PS score and HNC disease progression were the two independent indicators of OS. In conclusion, treatment of SESCN with ER is the recommended approach for patients with SHNSESCN, but further randomized controlled trials are needed to confirm this. [ABSTRACT FROM AUTHOR]

Simple Summary: Residual glandular tissue (RGT) after risk-reducing mastectomy in patients with a familial predisposition (high-risk collective) is associated with a risk of breast cancer that cannot be precisely determined. The residual risk should be as assessable as possible. For this purpose, a monocentric retrospective analysis of measurable factors influencing the postoperative residual glandular tissue was performed. Analyzed were 117 breasts, 63 left and 54 right, from a cohort of 81 patients (carriers of a pathogenic mutation) with unilateral (36 patients) or bilateral (45 patients) risk-reducing mastectomy. Consultation and possible testing were performed with the patient's consent at the FBREK (Familial Breast and Ovarian Cancer) Center of the University Hospital Düsseldorf (UKD), or in advance at another site of the German Consortium for Familial Breast and Ovarian Cancer. MRI-assisted detection of residual skin flap thickness and volumetry of each breast were performed. Residual glandular tissue was recorded volumetrically. In addition, patient-related covariates were recorded, and their influence on postoperative residual glandular tissue and skin flap thickness was analyzed using univariate and multivariate regression. Purpose: This study seeks to evaluate MR imaging morphological factors and other covariates that influence the presence of residual glandular tissue after risk-reducing mastectomy in patients with a familial predisposition. Methods: We analyzed women of a high-risk collective with pathogenic mutation (BRCA1 (n = 49), BRCA2 (n = 24), or further mutation (n = 9)). A total of 117 breasts were analyzed, 63 left and 54 right, from a cohort of 81 patients, who were on average 40 years old. The mean follow-up was 63 months (range 12–180 months, SD = 39.67). Retrospective analysis of MR imaging data from 2006–2022 of patients of a high-risk collective (all carriers of a pathogenic mutation) with contralateral (RRCM) or bilateral risk-reducing mastectomy (RRBM) was performed. In the image data the remaining skin flap thickness by distance measurements at eight equally distributed, clockwise points and the retromamillary area, as well as by volumetry of each breast, was elected. Residual glandular tissue was also volumetrized. In addition, patient-related covariates were recorded and their influence on postoperative residual glandular tissue and skin flap thickness was analyzed by uni- and multivariate regressions. Results: A significant association with postoperative residual glandular tissue was shown in multivariate analysis for the independent variables breast density, skin flap mean, and surgical method (all p-values < 0.01). A negatively significant association could be seen for the variables preoperative breast volume (p-values < 0.01) and surgeon experience (most p-values < 0.05–<0.1). Conclusion: Postoperative residual glandular tissue is an important tool for quantifying the risk of developing breast cancer after risk-reducing mastectomy. Different effects on residual glandular tissue were shown for the independent variables breast density, skin flap, surgical method, preoperative breast volume, and surgeon experience, so these should be considered in future surgical procedures preoperatively as well as postoperatively. Breast MRI has proven to be a suitable method to analyze the skin flap as well as the RGT. [ABSTRACT FROM AUTHOR]

Simple Summary: To provide insights into the role of the extracellular matrix (ECM) in health and pathological conditions, it is important to identify tissue-specific proteins, their interacting networks and functions. Latest discoveries suggest that multiple tumors express, and use to their advantage, atypical ECM components that are not found in the cancer tissue of origin. The aim of this review was to summarize and critically assess available information on the expression and function of atypical carcinoma-, bone- and cartilage-specific components of the extracellular matrix. To the best of our knowledge, this topic has not previously been covered by any published review, and thus provides a novel perspective for devising strategies to target tumor stroma as anti-cancer therapeutic options. The extracellular matrix (ECM) is the complex three-dimensional network of fibrous proteins and proteoglycans that constitutes an essential part of every tissue to provide support for normal tissue homeostasis. Tissue specificity of the ECM in its topology and structure supports unique biochemical and mechanical properties of each organ. Cancers, like normal tissues, require the ECM to maintain multiple processes governing tumor development, progression and spread. A large body of experimental and clinical evidence has now accumulated to demonstrate essential roles of numerous ECM components in all cancer types. Latest findings also suggest that multiple tumor types express, and use to their advantage, atypical ECM components that are not found in the cancer tissue of origin. However, the understanding of cancer-specific expression patterns of these ECM proteins and their exact roles in selected tumor types is still sketchy. In this review, we summarize the latest data on the aberrant expression of bone and cartilage ECM proteins in epithelial cancers and their specific functions in the pathogenesis of carcinomas and discuss future directions in exploring the utility of this selective group of ECM components as future drug targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 15% of patients diagnosed with high-grade non-mucinous epithelial ovarian cancer (EOC) have a germline BRCA1/2 mutation, although all patients are often able to access germline testing. Importantly, the risk of familial ovarian cancer reduces with advancing age at diagnosis. The aim of our study was to determine the prevalence of germline and somatic BRCA1/2 mutations in women diagnosed with non-mucinous high-grade EOC aged ≥80. We found that somatic BRCA1/2 mutations occurred nine times more frequently than germline BRCA1/2 mutations in women aged ≥80. The only germline BRCA1/2 mutation reported in a patient aged ≥80 was detected in both germline and tumour DNA. These data suggest that germline BRCA1/2 testing in women diagnosed with high-grade non-mucinous EOC aged ≥80 can be reserved for those with a detectable tumour BRCA1/2 mutation. Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour BRCA1/2 variants. The value of germline BRCA1/2 testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour BRCA1/2 testing by the North West of England Genomic Laboratory Hub. A subgroup of women also underwent germline testing using a panel of homologous recombination repair (HRR) genes and/or tumour testing for homologous recombination deficiency (HRD) using Myriad's myChoice® companion diagnostic. Seven-hundred-two patients successfully underwent both germline and tumour BRCA1/2 testing. Of these, 48 were diagnosed with non-mucinous high-grade EOC aged ≥80. In this age group, somatic BRCA1/2 pathogenic/likely pathogenic variants (PV/LPVs) were detected nine times more often than germline BRCA1/2 PV/LPVs. The only germline PV reported in a patient aged ≥80 was detected in germline and tumour DNA (BRCA2 c.4478_4481del). No patient aged ≥80 had a germline PV/LPVs in a non-BRCA1/2 HRR gene. Thirty-eight percent of patients aged ≥80 had a tumour positive for HRD. Our data suggest that tumour BRCA1/2 and HRD testing is adequate for patients diagnosed with non-mucinous high-grade EOC aged ≥80, with germline BRCA1/2 testing reserved for women with a tumour BRCA1/2 PV/LPVs. [ABSTRACT FROM AUTHOR]

Simple Summary: Compared with other head and neck cancer types, the prognosis of recurrent early glottic cancer (rEGC) may be less dependent on the presence of regional (N) and/or distant metastases (M). The latter two are clinically infrequent due to rEGC's peculiar biology, but the currently available staging systems still rely upon these parameters. Thus, we developed a new staging system (SUD) centered on the comparison between the T stages of the recurrence and the primary tumor. Then, in our cohort of 258 patients with rEGC treated at our Institution in Florence, Italy, we verified how the SUD system performs in the prediction of the overall and disease-specific survival, compared to the other classifications already in use. (1) Background: The treatment of recurrent early glottic cancer (rEGC) remains challenging. We wanted to investigate how the oncological outcomes are affected by the initial and recurrent stages, in order to propose our newly developed Same–Up–Down (SUD) staging system. (2) Methods: In our cohort of 258 rEGC patients, we retrospectively assessed the prognostic performances of the rTNM (the TNM staging system for recurrence), CLRSS, CLRSS-2, and SUD staging systems by univariate and multivariate Cox analysis, comparing their predictive capability using Harrell's C-index. (3) Results: The SUD classification satisfactorily predicted both overall survival (p = 0.022) and second-recurrence-free survival (p = 0.024, as same + down vs. upstage) in our cohort. It also outperformed the other three systems in terms of prediction of survival, with an improvement of 1.52%, 1.18%, and 3.96% in the predictive capacity of overall survival, disease-specific survival, and second-recurrence-free survival, respectively. (4) Conclusions: The SUD staging system can efficiently predict survival in rEGC patients, whose prognosis heavily depends on both the initial and recurrent locoregional extension. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing (WGS), we identified copy number variations (CNVs). In addition, we quantified chromosomal instability using genome-wide instability and found that it could detect newly diagnosed EOC. In addition, the data showed RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. Our data demonstrated that cfDNA, detected by shallow WGS, represents a potential tool for diagnosing EOC and predicting its prognosis. Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing of plasma cell-free DNA (cfDNA), we investigated biomarkers that could detect EOC and predict survival. Plasma cfDNA from 40 EOC patients and 20 healthy subjects were analyzed by shallow whole-genome sequencing (WGS) to identify copy number variations (CNVs) and determine the Z-scores of genes. In addition, we also calculated the genome-wide scores (Gi scores) to quantify chromosomal instability. We found that the Gi scores could distinguish EOC patients from healthy subjects and identify various EOC histological subtypes (e.g., high-grade serous carcinoma). In addition, we characterized EOC CNVs and demonstrated a relationship between RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. This study identified RAB25 amplification as a predictor of EOC patient survival. Moreover, we showed that Gi scores could detect EOC. These data demonstrated that cfDNA, detected by shallow WGS, represented a potential tool for diagnosing EOC and predicting its prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: We have recently reported that the cytosolic C-terminal domain (CTD) of the tumour suppressor PTCH1, the Hedgehog proteins receptor, interacts with the autophagy-related protein ATG101 and impairs autophagic flux. In this study, we identified the interaction region and found that it is absent in a subset of colorectal, stomach and endometrial cancers. We demonstrated that truncation mutants lack the ability to constraint autophagy, resulting in a proliferative advantage and reduced sensitivity to autophagy inducers or glycolysis inhibitors in cell lines harbouring endogenous PTCH1 CTD mutations compared to isogenic cells expressing wild-type PTCH1. In summary, this study highlights the importance of the PTCH1-ATG101 interaction in the regulation of basal and stimulated autophagy and the metabolic flexibility in cancer cells. The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor's activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli pathway, its C-terminal domain (CTD) was reported to have additional non-canonical functions. One of them is the reduction of autophagic flux through direct interaction with the Unc-51, like the autophagy activating kinase (ULK) complex subunit autophagy-related protein-101 (ATG101). With the aim of investigating whether this function of PTCH1 is important in cancer cell fitness, we first identified frameshift mutations in the CTD of PTCH1 in cancer databases. We demonstrated that those mutations disrupt PTCH1 interaction with ATG101 and increase autophagic flux. Using deletion mutants of the PTCH1 CTD in co-immunoprecipitation studies, we established that the 1309–1447 region is necessary and sufficient for interaction with ATG101. We next showed that the three most common PTCH1 CTD mutations in endometrial, stomach and colon adenocarcinomas that cause frameshifts at S1203, R1308 and Y1316 lack the ability to interact with ATG101 and limit autophagic flux, determined by bafilomycin A1-sensitive accumulation of the autophagy markers LC3BII and p62. We next engineered PTCH1 indel mutations at S1223 by CRISPR/Cas9 in SW620 colon cancer cells. Comparison of two independent clones harbouring PTCH1 S1223fs mutations to their isogenic parental cell lines expressing wild-type PTCH1 showed a significant increase in basal and rapamycin-stimulated autophagic flux, as predicted by loss of ATG101 interaction. Furthermore, the PTCH1 CTD mutant cells displayed increased proliferation in the presence of rapamycin and reduced sensitivity to glycolysis inhibitors. Our findings suggest that loss of the PTCH1-ATG101 interaction by mutations in the CTD of PTCH1 in cancer might confer a selective advantage by stimulating autophagy and facilitating adaptation to nutrient deprivation conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Thymic epithelial tumors (TETs) are rare malignancies that arise from the epithelial cells of the thymus. In most cases, TETs are characterized by a good prognosis, and their aggressiveness reflects the histopathological subtypes defined in the guidelines of the World Health Organization. Over the years, the challenge has been to characterize TETs at both genetic and epigenetic levels, revealing a deep deregulation of key cellular pathways linked to cancer onset and development or autoimmunity. The present work collects the main research concerning the epigenetic deregulation of TETs, with a special focus on DNA methylation, histone tail modifications, and non-coding RNAs dysregulation potentially useful for clinical practice. Thymic epithelial tumors (TETs) arise from the epithelial cells of the thymus and consist in the 1% of all adult malignancies, despite the fact that they are the most common lesions of the anterior mediastinum. TETs can be divided mainly into thymomas, thymic carcinomas, and the rarest ad aggressive neuroendocrine forms. Despite the surgical resection is quite resolving, the diagnosis of TETs is complicated by the absence of symptoms and the clinical presentation aggravated by several paraneoplastic disorders, including myasthenia gravis. Thus, the heterogeneity of TETs prompts the search for molecular biomarkers that could be helpful for tumor characterization and clinical outcomes prediction. With these aims, several researchers investigated the epigenetic profiles of TETs. In this manuscript, we narratively review the works investigating the deregulation of epigenetic mechanisms in TETs, highlighting the need for further studies combining genetic, epigenetic, and expression data to better characterize the different molecular subtypes and identify, for each of them, the most relevant epigenetic biomarkers of clinical utility. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase receptor type J (PTPRJ), also known as DEP-1, HPTPη, or CD148, belongs to the R3 subfamily of receptor protein tyrosine phosphatases (RPTPs). It was first identified as an antioncogene due to its protein level being significantly downregulated in most epithelial tumors and cancer cell lines (e.g., colon, lung, thyroid, breast, and pancreas). PTPRJ regulates mouse optic nerve projection by inhibiting the phosphorylation of the erythropoietin-producing hepatocellular carcinoma (Eph) receptor and abelson murine leukemia viral oncogene homolog 1 (c-Abl). PTPRJ is crucial for metabolism. Recent studies have demonstrated that PTPRJ dephosphorylates JAK2 at positions Y813 and Y868 to inhibit leptin signaling. Akt is more phosphorylated at the Ser473 and Thr308 sites in Ptprj−/− mice, suggesting that PTPRJ may be a novel negative regulator of insulin signaling. PTPRJ also plays an important role in balancing the pro- and anti-osteoclastogenic activity of the M-CSF receptor (M-CSFR), and in maintaining NFATc1 expression during the late stages of osteoclastogenesis to promote bone-resorbing osteoclast (OCL) maturation. Furthermore, multiple receptor tyrosine kinases (RTKs) as substrates of PTPRJ are probably a potential therapeutic target for many types of diseases, such as cancer, neurodegenerative diseases, and metabolic diseases, by inhibiting their phosphorylation activity. In light of the important roles that PTPRJ plays in many diseases, this review summarizes the structural features of the protein, its expression pattern, and the physiological and pathological functions of PTPRJ, to provide new ideas for treating PTPRJ as a potential therapeutic target for related metabolic diseases and cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment options for advanced thymic malignancies are limited. Immune checkpoint inhibitors are effective against advanced thymic epithelial tumors, but the treatment is associated with an elevated risk for adverse events. In this article, we aim to highlight new insights regarding predictive markers for treatment efficacy and risk of adverse events that would allow for safe and precise clinical indications for immunotherapy in thymic malignancies. Thymic epithelial tumors (TETs) are rare thoracic malignancies with a favorable prognosis when complete surgical resection can be achieved. Therapeutic options for advanced, irresectable, or recurrent disease are limited and currently, a therapeutic standard treatment beyond platinum-based chemotherapy is undefined. Immune checkpoint inhibitors are effective against TETs, however their use is associated with a serious risk of immune-mediated toxicity. In this article, we highlight new insights regarding markers of predictive value for both treatment efficacy and risk of adverse effects in immune checkpoint inhibitor treatment for thymic epithelial tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Endoscopic submucosal dissection (ESD) facilitates a successful en bloc resection regardless of tumor size. In this review, we summarize up-to-date reports with long-term observation after ESD for colorectal epithelial neoplasms. The strategy of ESD and additional surgery depending on the curative status showed an excellent five-year disease-specific survival rate. Incomplete resection is a risk factor for local recurrence, and endoscopists must improve their skill level. In non-curative ESD, optimization of additional surgery could reduce disease-specific death without additional surgery. In this review, we summarize up-to-date reports with five-year observation after colorectal endoscopic submucosal dissection (ESD). Five-year cause-specific survival rates ranged from 98.6 to 100%. The local recurrence rates ranged from 1.1 to 2.2% in complete resection and 7.5 to 25.0% in incomplete resection. Incomplete resection was a risk factor for local recurrence. In non-curative ESD, five-year cause-specific survival rates ranged from 93.8 to 100% with additional surgery, and 92.7 to 99.1% without surgery. The choice of additional surgery should be based on the individual patient's age, concomitant diseases, wishes, life expectancy, and the risk of lymph node metastasis. The metachronous cancer rates ranged from 0.22 to 1.1%. Both local recurrence and metachronous tumors should be checked with a follow-up colonoscopy after ESD. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the potential role of imaging-based parameters or pathological factors as useful cancer biomarkers has been reported in several studies, only a few investigations have been conducted to assess the associations between them. We hypothesized that the imaging features of OSCC, derived from perfusion- and diffusion-weighted techniques, may reflect not only the characteristics of cancer but also the microenvironment composition. We found that a number of pathological factors affected the imaging parameters, i.e., the inflammatory infiltrate, tumor grading and desmoplastic reaction. Evident relationships emerged between the DKI parameters and tumor-infiltrating lymphocytes. Significant differences in a few DCE-MRI parameters were also found according to the tumor grading. These findings may be helpful for a more comprehensive biological characterization of OSCC and could be used in future investigations for diagnostic and prognostic purposes. Background: In this prospective study, we hypothesized that magnetic resonance imaging (MRI) may represent not only the tumor but also the microenvironment, reflecting the heterogeneity and microstructural complexity of neoplasms. We investigated the correlation between both diffusion kurtosis imaging (DKI) and dynamic contrast-enhanced (DCE)-MRI with the pathological factors in oral cavity squamous cell carcinomas (OSCCs). Methods: A total of 37 patients with newly diagnosed OSCCs underwent an MR examination on a 3T system. The diffusion coefficient (D), the kurtosis parameter (K), the transfer constants Ktrans and Kep and the volume of extravascular extracellular space ve were quantified. A histogram-based approach was proposed to investigate the associations between the imaging and the pathological factors based on the histology and immunochemistry. Results: Significant differences in the DCE-MRI and DKI parameters were found in relation to the inflammatory infiltrate, tumor grading, keratinization and desmoplastic reaction. Relevant relationships emerged between tumor-infiltrating lymphocytes (TILs) and DKI, with lower D and higher K values being associated with increased TILs. Conclusion: Although a further investigation is needed, these findings provide a more comprehensive biological characterization of OSCCs and may contribute to a better understanding of DKI-derived parameters, whose biophysical meaning is still not well-defined. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is an uncommon type of malignancy/cancer worldwide. However, NPC is an endemic disease in southeast Asia and southern China and the reasons behind the underlying for such changes are unclear. Even though the Epstein–Barr infection (EBV) has been suggested as an important reason for undistinguishable NPC, the EBV itself is not adequate to source this type of cancer. The risk factors, for example, genetic susceptibility, and environmental factors might be associated with EBV to undertake a part in the NPC carcinogenesis. Normal healthy people have a memory B cell pool where the EBV persists, and any disturbance of this connection leads to virus-associated B cell malignancies. Less is known about the relationship between EBV and epithelial cell tumors, especially the EBV-associated nasopharyngeal carcinoma (EBVaNPC) and EBV-associated gastric carcinoma (EBVaGC). Currently, it is believed that premalignant genetic changes in epithelial cells contribute to the aberrant establishment of viral latency in these tumors. The early and late phases of NPC patients' survival rates vary significantly. The presence of EBV in all tumor cells presents prospects for the development of innovative therapeutic and diagnostic techniques, despite the fact that the virus's exact involvement in the carcinogenic process is presently not very well known. EBV research continues to shed light on the carcinogenic process, which is important for a more comprehensive knowledge of tumor etiology and the development of targeted cancer therapeutics. In order to screen for NPC, EBV-related biomarkers have been widely used in a few high-incidence locations because of their close associations with the risks of NPC. The current review highlights the scientific importance of EBV and its possible association with NPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial cancers, such as lung, breast, and colon cancers, have high mortality rates because of their ability to spread across multiple organs in the body. Besides the standard of care which includes chemotherapy and radiotherapy, approaches directed to use patient's own immune responses against the disease called immunotherapies have emerged as a powerful treatment option. In the past 10 years, immune checkpoint blockade, a form of immunotherapy which either stimulates or removes the breaks of the immune response against cancer, is having the largest impact in the clinic. However epithelial cancers are commonly either naturally resistant or develop resistance to these types of treatments. Hence, there is an urgent need to boost the effectiveness of immune checkpoint blockers. Small molecule inhibitors are chemical molecules which are specifically designed to target important cancer proteins and unlike chemotherapy, typically have manageable toxicity. These inhibitors have shown good efficacy in reducing tumour growth but more recently, they have been shown to enhance the performance of immune cells in eliminating cancers. In this review, we have focused on tactical usage of small molecule inhibitors to boost the efficacy of immune checkpoint blockers. We believe our review will pave the way for novel research combining the two therapeutic modalities. Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy of ICB therapies. Addition of receptor tyrosine kinase inhibitors (RTKi) as potential modulators of an unfavorable local immune environment has resulted in moderate life expectancy improvement. Though the combination strategy of ICB and RTKi has shown significantly better results compared to individual treatment, the benefits and adverse events are additive whereas synergy of benefit would be preferable. There is therefore a need to investigate the potential of inhibitors other than RTKs to reduce malignant cell survival while enhancing anti-tumor immunity. In the last five years, preclinical studies have focused on using small molecule inhibitors targeting cell cycle and DNA damage regulators such as CDK4/6, CHK1 and poly ADP ribosyl polymerase (PARP) to selectively kill tumor cells and enhance cytotoxic immune responses. This review provides a comprehensive overview of the available drugs that attenuate immunosuppression and overcome hostile TME that could be used to boost FDA-approved ICB efficacy in the near future. [ABSTRACT FROM AUTHOR]