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BACKGROUND: Cutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 mutant and triple wild-type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. METHODS: This was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. A total of 254 patients with CM who had a CLIA-certified targeted sequencing assay performed on their tumor tissue were included. RESULTS: Of the 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n = 19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n = 29, 87.9%) harbor a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7-266 mutations/Mb). A total of 14 cases (9.1%) were classified as having a low TMB (≤5 mutations/Mb), 64 of 154 (41.6%) had an intermediate TMB (>5 and ≤20 mutations/Mb), 40 of 154 (26.0%) had a high TMB (>20 and ≤50 mutations/Mb) and 36 of 154 (23.4%) were classified as having a very high TMB (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13-7.69, p = 0.027, log-rank test) compared with other TCGA molecular subgroups. Of the 116 patients in our cohort with available treatment data, 36 received a combination of dual ICI with anti-CTLA4 and anti-PD1 inhibition as first-line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual-agent ICI (HR 0.26, 95% CI 0.07-0.90, p = 0.033, log-rank test). CONCLUSIONS: NRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with a combination of dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

Simple Summary: Immunotherapy is now one of the therapeutic options for the treatment of unresectable or metastatic cholangiocarcinoma. Given the poor prognosis of this cancer type and the low response rate to immunotherapy, the application of predictive biomarkers is essential for selecting suitable candidates for treatment with immune checkpoint inhibitors. The aim of this review is to document the biomarkers that have been studied, and have been associated so far, with the effectiveness of immunotherapy in cholangiocarcinoma. Further research on biomarkers from tissue or liquid biopsy, such as characteristics of tumor microenvironment, gene alterations, exosomes, miRNA, and ctDNA, will aid in identifying appropriate patients who will benefit from this treatment and in determining prognosis. Cholangiocarcinoma is a rare primary liver cancer with poor prognosis, due to the advanced stage at the time of diagnosis and limited therapeutic options, with poor response. Chemotherapy remains the standard first-line treatment, but the advent of immunotherapy has recently induced promising results. Given the fact that diagnosis frequency is increasing nowadays and the survival rate remains very low, it is crucial to recognize patients who are suitable for immunotherapy and will have the best response. Different types of biomarkers, such as interleukins, exosomes, mi-RNA, ctDNA, and gene mutations, have been studied for their feasibility, not only for the early diagnosis of biliary tract cancer but also for the determination of responsiveness in treatment. Less frequently, these studies focus on finding and observing biomarkers in patients who receive immunotherapy. This review aims to summarize current knowledge of existing/promising biomarkers in patients with unresectable or metastatic cholangiocarcinoma, treated with immunotherapy as monotherapy, or combined with chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer treatment using immune checkpoint inhibitors (ICIs) has shown great success, but not all patients respond equally. Tumour mutational burden (TMB) is a measure of genetic mutations in cancer cells and is used to predict whether ICIs will be effective. While TMB is a reliable predictor in lung cancer and melanoma, its usefulness in breast and prostate cancers remains uncertain. This study reviewed existing research to assess how well TMB pre-dicts treatment outcomes in these four cancer types. The results confirmed that high TMB is linked to better re-sponses in lung cancer and melanoma. However, findings for breast and prostate cancers were inconsistent, sug-gesting that other factors may influence treatment success. Differences in how TMB is measured also make com-parisons difficult. To improve cancer treatment, future research should focus on refining TMB assessment methods and identifying additional markers that can help personalize therapy. Background: Tumour mutational burden (TMB) is an emerging biomarker for predicting the efficacy of immune checkpoint inhibitors (ICIs) in cancer therapy. While its role is well established in lung cancer and melanoma, its predictive value for breast and prostate cancers remains unclear. Objective: This systematic review aimed to assess the predictive value of TMB for ICI therapy across four major cancer types—lung, melanoma, breast, and prostate—and to explore factors contributing to the variability in its effectiveness as a biomarker. Methods: A systematic search and a review of the literature were conducted in accordance with PRISMA guidelines. Studies examining the relationship between TMB levels and clinical outcomes following ICI therapy in the specified cancers were analyzed. The data were synthesized to evaluate TMB's predictive value and identify gaps in the current research. Results: High TMB consistently correlated with improved outcomes in lung cancer and melanoma, confirming its predictive utility in these cancers. Conversely, the findings for breast and prostate cancers were inconclusive. The variability in TMB's predictive value for these cancers suggests the need for complementary biomarkers or refined criteria to enhance its reliability. Methodological inconsistencies in TMB evaluation were also noted as a significant limitation. Conclusions: TMB serves as a robust biomarker for predicting ICI response in lung cancer and melanoma, but demonstrates limited predictive utility in breast and prostate cancers. Future research should prioritize standardizing TMB assessment protocols and investigating additional biomarkers to improve treatment personalization for these cancer types. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is a highly fatal disease, often diagnosed at advanced stages due to non-specific symptoms. This review focuses on the role of long non-coding RNAs (lncRNAs) in ovarian cancer, highlighting their dual nature as oncogenes or tumor suppressors. These molecules regulate critical cancer processes, including cell growth, survival, metastasis, and therapy resistance. By exploring their complex structures and functions, this research emphasizes the potential of lncRNAs as diagnostic markers, prognostic indicators, and therapeutic targets. Integrating insights from cutting-edge technologies like bioinformatics and single-cell sequencing, this review aims to provide a comprehensive understanding of lncRNAs in ovarian cancer. The findings could significantly advance personalized cancer medicine, offering new strategies to improve detection, treatment, and patient outcomes. Background/Objectives: Ovarian cancer is a leading cause of gynecological cancer mortality worldwide, often diagnosed at advanced stages due to vague symptoms and the lack of effective early detection methods. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer biology, influencing cellular processes such as proliferation, apoptosis, and chemoresistance. This review explores the multifaceted roles of lncRNAs in ovarian cancer pathogenesis and their potential as biomarkers and therapeutic targets. Methods: A comprehensive literature review was conducted to analyze the structural and functional characteristics of lncRNAs and their contributions to ovarian cancer biology. This includes their regulatory mechanisms, interactions with signaling pathways, and implications for therapeutic resistance. Advanced bioinformatics and omics approaches were also evaluated for their potential in lncRNA research. Results: The review highlights the dual role of lncRNAs as oncogenes and tumor suppressors, modulating processes such as cell proliferation, invasion, and angiogenesis. Specific lncRNAs, such as HOTAIR and GAS5, demonstrate significant potential as diagnostic biomarkers and therapeutic targets. Emerging technologies, such as single-cell sequencing, provide valuable insights into the tumor microenvironment and the heterogeneity of lncRNA expression. Conclusions: LncRNAs hold transformative potential in advancing ovarian cancer diagnosis, prognosis, and treatment. Targeting lncRNAs or their associated pathways offers promising strategies to overcome therapy resistance and enhance personalized medicine. Continued research integrating omics and bioinformatics will be essential to unlock the full clinical potential of lncRNAs in ovarian cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to identify markers that might help predict the likelihood of early death in patients with head and neck cancer (HNC). Researchers examined tumor samples from Swedish HNC patients, focusing on those who died within six months of diagnosis and comparing them to patients who survived for at least two years. They found that patients who died early had higher levels of two markers—Ki-67 and survivin—compared to the survivors. Ki-67 was 21% higher in early-death patients, indicating more rapid cell growth. Survivin was also more intensely present in early-death patients' cells. These findings suggest that measuring Ki-67 and survivin levels could help identify patients at a higher risk of early death, aiding in treatment planning. Background: The aim of this study was to evaluate biomarkers and biological characteristics of tumor biopsies from patients with head and neck cancer (HNC) to assess the risk of early death. Furthermore, we analyzed whether any combination of markers could be used for the prognostication of death within six months after cancer diagnosis. Materials and Methods: Patients diagnosed with HNC, receiving curative treatment decision at a multidisciplinary tumor board meeting, and who died within six months of diagnosis were included in this study. Nine patients who died within six months from diagnosis were identified and matched according to the tumor site and stage to seventeen patients who survived for at least two years. Results: The expression of markers was compared between the early-death patients and survivors. There was significantly higher Ki-67 expression in patients who died within six months than in those surviving for two years, with a mean difference of 21% (p = 0.038). A significant difference in cytoplasmic survivin expression was noted where early-death patients had increased expression compared to the survivors (p = 0.021). Furthermore, the intensity of survivin staining differed between the groups (p = 0.006). Conclusions: The results of this pilot study indicate that Ki67 and survivin could be potential prognostic biomarkers for early death in patients with HNC and possibly included in a panel of prognostic markers of value for treatment decision making. [ABSTRACT FROM AUTHOR]

Simple Summary: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). HCC incidence and mortality have increased rapidly over the past two decades in the US, with a <20% 5-year survival rate. Understanding the mechanisms of this transition and identifying biomarkers is vital for effective screening and reducing HCC-related mortality. This study evaluated genome-wide DNA methylation patterns in the buffy coats of cirrhosis patients who developed HCC and those who remained HCC-free during an average four-year follow-up. We then identified differentially methylated sites, distinguishing cirrhosis with HCC from cirrhosis without HCC. The findings support the theory that buffy coat-derived DNA methylation markers could be implementable to stratify cirrhosis patients at high risk before clinical symptoms appear. Background/Objectives: Cirrhosis is the precursor to most cases of hepatocellular carcinoma (HCC). Understanding the mechanisms leading to the transition from cirrhosis to HCC and identifying key biomarkers is crucial to developing effective screening strategies and reducing HCC-related mortality. DNA methylation is associated with gene inactivation and plays an important role in physiological and pathological processes; however, its role in cirrhosis progression to HCC is unknown. Methods: We performed genome-wide DNA methylation profiling using Illumina Infinium MethylationEPI BeadChip in pre-diagnostic samples from 22 cirrhosis patients who subsequently developed HCC and 22 cirrhosis patients who remained HCC-free during an average 4-year follow-up. In a secondary analysis, we examined a subset of patients without hepatitis C virus (HCV) infection. Results: We identified three differentially methylated positions (DMPs) located in ADAM12 (cg13674437) and PSD3 (cg06758847 and cg24595678) that show a strong association with HCC risk (lower median vs. higher median hazards ratio (HR): HR cg13674437 = 0.34, 95% CI = 0.14–0.83; HR cg06758847 = 4.89, 95% CI = 1.79–13.33; HR cg24595678 = 11.19, 95% CI = 3.27–38.35). After excluding all HCV-active patients from our analysis, the HR for the DMPs remained significant. Conclusions: In conclusion, the findings in this study support the theory that buffy coat-derived DNA methylation markers could be used to identify biomarkers among cirrhosis patients at high risk for HCC before clinical symptoms appear. A further study with a large prospective cohort is required to validate these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Telomeres play an integral role in preventing genomic instability by protecting chromosomal ends using telomeric repeats, and their dysfunction may lead to premature aging disorders and age-related diseases. During cellular division, they undergo telomere attrition, resulting in the gradual shortening of those protective caps, leading to genomic instability and cellular aging. Critically short telomeres in normal cells trigger senescence, a major contributor to age-related diseases, and opens the door for genomic instability, which promotes carcinogenesis. This review aims to provide an updated overview of telomere biology and therapeutic strategies around telomere attrition. We emphasize the importance of understanding the complex balance between preserving telomere length in aging while inhibiting telomere maintenance in cancer by proposing Optimal Therapeutic Approaches based on the most updated literature. Background/Objectives: As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. Methods: We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. Results: Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson–Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. Conclusions: The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging. [ABSTRACT FROM AUTHOR]

Simple Summary: Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis and has been implicated in several metabolic disorders and diseases. In particular, regucalcin is a novel suppressor in several cancer types. Regucalcin plays a potential role in suppressing carcinogenesis. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, thereby promoting dormancy in cancer patients. Notably, regucalcin is found in serum and extracellular fluids. Extracellular regucalcin has been shown to suppress the growth and bone metastatic activity of human cancer cells, suggesting that it plays an important role as a suppressor in the tumor microenvironment of cancer cells. Alteration of serum regucalcin levels under physiological and pathophysiological conditions may influence cancer activity in the microenvironment. This review discusses the potential role of extracellular regucalcin in cancer cell activity as a potential suppressor in the cancer microenvironment, proposing the role of exogenous regucalcin in cancer prevention and therapy. The regucalcin gene is located on the X chromosome, comprising seven exons and six introns. This gene and protein are expressed in various tissues and cells and is predominantly expressed in human liver, kidney, and adrenal tissues. Regucalcin gene expression is enhanced via a mechanism mediated by several signaling molecules and transcription factors. Regucalcin plays a multifunctional role in cellular regulation in maintaining cell homeostasis. In addition, regucalcin has been implicated in several metabolic disorders and diseases. In particular, regucalcin plays a role as a novel suppressor in several types of cancer patients. Increased expression of regucalcin suppresses the growth of human cancer cells, suggesting its pivotal role in suppressing tumor development. The survival time of cancer patients is prolonged with increased expression of regucalcin in the tumor tissues. The adhesion, migration, invasion, and bone metastatic activity of cancer cells are blocked by the overexpression of regucalcin, promoting dormancy in cancer patients. Interestingly, regucalcin is also found in human serum, suggesting its character as a novel biomarker in various diseases. This extracellular regucalcin has been shown to suppress human cancer cells' growth and bone metastatic activity. Thus, extracellular regucalcin may play a vital role as a suppressor of human cancer activity. Alteration of the serum regucalcin levels in physiological and pathophysiological conditions may influence the activity of cancer cells in the microenvironment. This review will discuss the potential role of extracellular regucalcin in cancer cell activity as a critical suppressor in the cancer microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: Anastomotic leakage after gastrectomy is a relatively common, but potentially lethal complication, whose morbi-mortality is greatly decreased with a prompt diagnosis and treatment. The aim of this study was to assess the performance of several serum biomarkers in reliably predicting the existence of anastomotic leakage. We confirmed the discrimination capability of C-reactive protein, procalcitonin, the neutrophil-to-lymphocyte ratio, the platelet-to-lymphocyte ratio, and fibrinogen in identifying anastomotic leakage within the first postoperative week. The use of adequate biomarkers has significant implications for optimizing clinical management strategies in these patients and may facilitate the development of future enhanced-recovery programs. Background/Objectives: Anastomotic leakage (AL) is one of the most concerning complications following gastrectomy. The aim of this study was to assess and compare the predictive accuracy of C-reactive protein (CRP), procalcitonin (PCT), the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), fibrinogen, and the mean platelet volume (MPV) in the early diagnosis of post-gastrectomy AL. Methods: A prospective bicentric observational study was conducted including all patients undergoing elective gastrectomy between August 2018 and December 2022. The performance of the selected biomarkers in predicting the existence of AL within the first 7 postoperative days (PODs) was assessed. Results: A total of 107 patients were included for analysis. The incidence of AL was 20.56%, and the median day of diagnosis was on POD5 (interquartile range 4–6). CRP, PCT, the NLR, the PLR, and fibrinogen showed significant associations with the presence of AL (from POD2 for CRP and fibrinogen and from POD3 for PCT, NLR, and PLR). CRP demonstrated a superior predictive accuracy on POD4, with a threshold value of 181.4 mg/L (NPV 99%; AUC 0.87, p < 0.001); PCT demonstrated a superior predictive accuracy on POD7, with a threshold value of 0.13 μg/L (NPV 98%; AUC 0.84, p < 0.001); the NLR showed a superior predictive accuracy on POD6, with a threshold ratio of 6.77 (NPV 95%; AUC 0.86, p < 0.001); the PLR achieved a superior predictive accuracy on POD7, with a ratio of 234 (NPV 98%; AUC 0.71; p = 0.002); and fibrinogen demonstrated a superior predictive accuracy on POD5, with a threshold of 7.344 g/L (NPV 98%; AUC 0.74; p = 0.003). In the comparison of predictive accuracy, CPR, PCT, and the NLR were found to be superior to all other biomarkers. Conclusions: CRP, PCT, and the NLR are biomarkers with a sufficient predictive ability to clinically discard the presence of AL within the first postoperative week. [ABSTRACT FROM AUTHOR]

Simple Summary: There is no evidence on the efficacy of FOLFIRI plus ramucirumab in colorectal cancer refractory to oxaliplatin plus fluoropyrimidine without bevacizumab. No predictive marker has been established for ramucirumab, either. We planned a prospective study of the efficacy and toxicity of FOLFIRI plus ramucirumab refractory to adjuvant oxaliplatin plus fluoropyrimidine, adding an exploratory analysis to estimate the association of biomarkers with ramucirumab's efficacy. A total of 48 patients were enrolled between September 2017 and September 2020. The median progression-free survival was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. The median overall survival and objective response rate were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. The incidence of adverse events was consistent with that in previous reports. FOLFIRI plus ramucirumab is one of the options for recurrent colorectal cancer refractory to adjuvant oxaliplatin plus fluoropyrimidine. Serum VEGF-D levels may not be a predictive biomarker for ramucirumab. Serum TSP-2 may be a potential prognostic biomarker. Background: FOLFIRI (5-FU + leucovorin + irinotecan) plus ramucirumab is one of the standards in second-line metastatic colorectal cancer (CRC) patients progressing after treatment with oxaliplatin/fluoropyrimidine with bevacizumab, but there is no evidence on its efficacy without prior bevacizumab. Moreover, VEGF-D has not been confirmed as a predictive biomarker for ramucirumab's efficacy, either. Methods: The RAINCLOUD study was a multicenter, single-arm, phase II trial conducted in Japan. Patients with recurrent CRC pretreated with fluoropyrimidine and oxaliplatin without bevacizumab were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints measured were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 48 patients were enrolled from 15 sites between September 2017 and September 2020. Their median age was 63.5 years (25~77), 20.1% had a right-sided tumor, and 68.8% had RAS-mutant cancer. The median PFS was 8.9 months (90% CI: 6.3–11.8), so the primary endpoint was met. Their median OS and ORR were 22.3 months (95% CI: 17.4-NA) and 41.7% (95% CI: 4.9–7.6), respectively. An incidence of grade 3/4 adverse events that reached over 5% applied to neutropenia (44%), leucopenia (10%), and hypertension (8%). In the biomarker analysis, the serum VEGF-D levels post-treatment were higher than those pre-treatment, but the PFS in those with high VEGF-D levels trended towards being worse than that in those with low VEGF-D (7.6M/5.6M (p = 0.095; HR: 0.56)). Instead, those with low TSP-2 had a better PFS than those with high TSP-2 (7.5M/4.3M (p = 0.022; HR: 0.45)). Conclusions: Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab's efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is a major global health issue, with over 1.4 million new cases and more than 330,000 deaths annually. The main challenge in treating prostate cancer is predicting and managing metastasis, which is currently incurable. This review highlights that metastasis may be driven by disruptions in the vesicular trafficking machinery that controls endosome-lysosome biology. Understanding how changes in the transport of endosomes and lysosomes contribute to cancer progression could lead to new ways to detect and treat metastatic prostate cancer, improving patient outcomes. Prostate cancer remains a significant global health concern, with over 1.4 million new cases diagnosed and more than 330,000 deaths each year. The primary clinical challenge that contributes to poor patient outcomes involves the failure to accurately predict and treat at the onset of metastasis, which remains an incurable stage of the disease. This review discusses the emerging paradigm that prostate cancer metastasis is driven by a dysregulation of critical molecular machinery that regulates endosome-lysosome homeostasis. Endosome and lysosome compartments have crucial roles in maintaining normal cellular function but are also involved in many hallmarks of cancer pathogenesis, including inflammation, immune response, nutrient sensing, metabolism, proliferation, signalling, and migration. Here we discuss new insight into how alterations in the complex network of trafficking machinery, responsible for the microtubule-based transport of endosomes and lysosomes, may be involved in prostate cancer progression. A better understanding of endosome-lysosome dynamics may facilitate the discovery of novel strategies to detect and manage prostate cancer metastasis and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) play crucial roles in the treatment of various cancers and improve overall survival (OS) and progression-free survival (PFS). However, resistance is a major problem that limits the prognosis of ICI-based therapy. Determining inflammatory markers may ameliorate the benefits of ICI-based therapies. Peripheral blood cells and biochemical markers are big candidates as inflammatory markers. Therefore, this study aimed to evaluate and compare the prognostic value of blood-based inflammatory markers in ICI-based therapy. Background: Although immune checkpoint inhibitors (ICIs) have significantly improved cancer treatment, a substantial proportion of patients do not benefit from these therapies, revealing the crucial need to identify reliable biomarkers. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), pan-immune inflammation value (PIV), systemic inflammation response index (SIRI), lactate dehydrogenase (LDH), and C-reactive protein (CRP), may provide insights into treatment outcomes. Objectives: This study aimed to evaluate the prognostic value of multiple inflammatory markers in patients with cancer receiving ICI-based therapies. Methods: A retrospective analysis was performed on 226 patients treated with ICI-based therapies at a single center between 2012 and 2023. The inflammatory markers NLR, PIV, SII, SIRI, LDH, CRP, and albumin were assessed. Cut-off values were determined using maximally selected rank statistics, and overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan–Meier method and Cox regression analysis. Results: High NLR, PIV, SII, SIRI, LDH, and CRP, as well as low albumin levels, were associated with worse OS and PFS (p < 0.001). In the multivariate analysis, high CRP, LDH, NLR, PIV, and SII independently predicted worse OS. Conclusions: Our findings confirm the prognostic utility of several inflammatory biomarkers in patients with cancer receiving ICIs, highlighting their potential for treatment stratification. Further studies are necessary to standardize cut-off values and validate these findings across broader, more diverse populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Surgical resection is the optimal treatment for early-stage lung cancer; however, recurrence rates remain high. Predicting recurrence accurately remains a significant challenge. This study aims to identify image biomarkers from preoperative chest CT scans to predict recurrence in patients undergoing lung resection. Using data from 309 patients, the study evaluates Cox proportional hazards regression analysis alongside machine learning (ML) methods for recurrence prediction. Key risk factors identified include surgical procedure, TNM staging, lymph node involvement, body composition, and tumor characteristics. Both Cox and ML models demonstrated comparable performance, achieving AUCs of 0.75–0.77, highlighting the potential of CT-based biomarkers for predicting recurrence. Background: Surgical resection remains the standard treatment for early-stage lung cancer. However, the recurrence rate after surgery is unacceptably high, ranging from 30% to 50%. Despite extensive efforts, accurately predicting the likelihood and timing of recurrence remains a significant challenge. This study aims to predict postoperative recurrence by identifying novel image biomarkers from preoperative chest CT scans. Methods: A cohort of 309 patients was selected from 512 non-small-cell lung cancer patients who underwent lung resection. Cox proportional hazards regression analysis was employed to identify risk factors associated with recurrence and was compared with machine learning (ML) methods for predictive performance. The goal is to improve the ability to predict the risk and time of recurrence in seemingly "cured" patients, enabling personalized surveillance strategies to minimize lung cancer recurrence. Results: The Cox hazards analyses identified surgical procedure, TNM staging, lymph node involvement, body composition, and tumor characteristics as significant determinants of recurrence risk, both for local/regional and distant recurrence, as well as recurrence-free survival (RFS) and overall survival (OS) (p < 0.05). ML models and Cox models exhibited comparable predictive performance, with an area under the receiver operative characteristic (ROC) curve (AUC) ranging from 0.75 to 0.77. Conclusions: These promising findings demonstrate the feasibility of predicting postoperative lung cancer recurrence and survival time using preoperative chest CT scans. However, further validation using larger, multisite cohort is necessary to ensure robustness and facilitate integration into clinical practice for improved cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: Worldwide, prostate cancer is the second most common cancer affecting men. Both the disease and treatments like surgery, radiotherapy, or drug therapy can cause unpleasant side effects, such as fatigue, muscle loss, and reduced quality of life. Exercise, particularly strength training and aerobic workouts, has been suggested to help reduce these effects. This study reviewed findings from controlled trials to evaluate how strength training, aerobic exercise, or a combination of both, affected men receiving prostate cancer treatment. The results show that combining strength and aerobic exercise significantly improves quality of life, especially in general health, mental clarity, and sexual wellbeing. Strength training alone helped by increasing muscle mass and lowering body fat. Both types of exercise improved physical strength and fitness. However, the training had no impact on laboratory results like PSA or cholesterol levels. More research is needed on long-term effects, particularly of aerobic exercise alone. Background: Prostate cancer (PC) and its treatment are often associated with side effects such as fatigue, muscle loss, and diminished quality of life (QoL). Physical exercise, particularly resistance training (RT) and aerobic training (AT), has been suggested as a strategy to mitigate these effects. However, the comparative efficacy of RT, AT, and combined RT/AT on QoL, body composition, physical fitness, and laboratory markers in PC patients is still insufficiently understood. Methods: Randomized controlled trials (RCTs) investigating structured RT, AT, or combined RT/AT programs in PC patients undergoing various treatments were included. The primary outcome was QoL, assessed using EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Secondary outcomes included body composition, fitness, and laboratory parameters. The studies were sourced from PubMed, Embase, and CENTRAL through May 2024. The effect sizes were pooled using random-effects models, and the risk of bias was systematically assessed following the GRADE approach. Results: A total of 30 RCTs, encompassing 2216 PC patients, were analyzed. Combined RT/AT significantly improved QoL subdomains, including global health, and cognitive and sexual function, while reducing fatigue and urinary symptoms. RT alone improved body composition by increasing lean body mass and reducing body fat percentage. Both RT and combined RT/AT enhanced strength (chest and leg press) and VO2peak. No significant changes were observed in laboratory markers, such as PSA or lipid levels. The effects of isolated AT remain unclear due to limited data. Conclusions: RT and combined RT/AT significantly improve QoL, fitness, and body composition in PC patients, with no detectable effect on PSA or lipid levels. Further research is needed to elucidate the specific effects of AT and to investigate long-term outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer treatments, while improving survival rates, can have serious side effects on the heart. This study looks at how certain cancer therapies, such as chemotherapy and targeted treatments, can cause heart problems. By closely monitoring patients' heart function and using specific biomarkers to detect early signs of heart damage, we aim to identify which patients are most at risk and when these problems might occur. Our goal is to improve the way cancer patients are treated by finding better ways to protect their heart health during treatment. The findings from this research could help doctors develop more personalized approaches to cancer care, ensuring that patients receive effective cancer therapies while minimizing the risk of long-term heart complications. Background/Objectives: Cardio-oncology has become essential in addressing cardiovascular complications from cancer therapies. While advancements in treatments have improved survival rates, they also increase cardiovascular risks. This study evaluates the cardiotoxic effects of cytostatic treatments, examining the relationship between tumor characteristics, such as histopathology and TNM classification, and cardiovascular complications, aiming to improve cardiotoxicity prevention and management in oncology patients. Methods: We conducted a retrospective analysis of cancer patients treated with anthracyclines, HER2-targeted therapies, and radiotherapy. Cardiac function was monitored via echocardiography, focusing on global longitudinal strain and left ventricular ejection fraction (LVEF). Cardiac troponins and natriuretic peptides were measured to detect subclinical cardiotoxicity, with patients stratified by TNM cancer stage and histopathology. Results: Our analysis identified a significant association between certain cytostatic treatments, such as anthracyclines and HER2-targeted therapies, and a reduction in LVEF, particularly in patients with advanced-stage cancer. Biomarker assessments indicated early signs of cardiotoxicity in patients before clinical symptoms emerged. The findings also demonstrated a higher prevalence of cardiovascular complications in patients with pre-existing risk factors. Conclusions: This study highlights the importance of personalized treatment protocols in minimizing cardiotoxicity and improving the quality of life for oncology patients. Regular cardiac monitoring, combined with the use of biomarkers, can help identify high-risk patients early, allowing for timely interventions. Future research should focus on optimizing cardioprotective strategies to mitigate the cardiovascular risks associated with modern cancer therapies. Clinical Trial Registration: N/A (retrospective study). [ABSTRACT FROM AUTHOR]

Simple Summary: Saliva is a vital fluid with diverse roles in oral and systemic health, including digestion, oral protection, and microbiome balance and support wound healing. It also serves as a non-invasive diagnostic tool, reflecting overall health and cancer. While saliva can protect against oral cancer, it may promote tumor progression and metastasis through exosomes and microRNA components. This review explores saliva's biological functions, its role in head and neck cancer progression/metastasis, and the potential therapeutic tool. Saliva plays a multifaceted role in oral health and systemic well-being. It supports digestion, protects oral tissues, maintains a healthy oral microbiome, and facilitates wound healing. Additionally, saliva serves as a diagnostic tool that reflects systemic health and disease/therapeutic states. Furthermore, although saliva shows a protective effect against oral cancer development, once tumor formation occurs, it may be involved in tumor progression and metastasis via exosomes and microRNAs. This review discusses the essential role of saliva; its relationship with the development, progression, and metastasis of head and neck squamous cell carcinoma (HNSCC); liquid biopsy tools for early diagnosis and monitoring of HNSCC; and the potential of exosomes as therapeutic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides a comprehensive overview of advancements in melanoma biomarkers, emphasizing the potential of serologic biomarkers for early diagnosis, prognosis, and personalized treatment of melanoma. Notable markers include S100B and lactate dehydrogenase (LDH), already partially integrated into clinical practice, and new candidates like melanoma-inhibiting activity (MIA), osteopontin, and tumor-associated antigen 90 immune complex (TA90-IC), which offer predictive capabilities for treatment outcomes. New biomarkers, including genetic, proteomic, and cellular markers, are emerging as crucial tools. These biomarkers, such as circulating tumor DNA (ctDNA) and RNA, can offer real-time insights into tumor dynamics, enabling non-invasive monitoring through liquid biopsies. Additionally, tumor-educated platelets and circulating immune cells show promise in understanding melanoma's aggressive behavior. Lastly, the review discusses the integration of these biomarkers into clinical protocols and the need for continued research to establish these tools' accuracy, improving patient-specific treatment strategies. Melanoma is one of the most malignant cancers, and the global incidence of cutaneous melanoma is increasing. While melanomas are highly prone to metastasize if diagnosed late, early detection and treatment significantly reduce the risk of mortality. Identifying patients at higher risk of metastasis, who might benefit from early adjuvant therapies, is particularly important, especially with the advent of new melanoma treatments. Therefore, there is a pressing need to develop additional prognostic biomarkers for melanoma to improve early stratification of patients and accurately identify high-risk subgroups, ultimately enabling more effective personalized treatments. Recent advances in melanoma therapy, including targeted treatments and immunotherapy, have underscored the importance of biomarkers in determining prognosis and predicting treatment response. The clinical application of these markers holds the potential for significant advancements in melanoma management. Various tumor-derived genetic, proteomic, and cellular components are continuously released into the bloodstream of cancer patients. These molecules, including circulating tumor DNA and RNA, proteins, tumor cells, and immune cells, are emerging as practical and precise liquid biomarkers for cancer. In the current era of effective molecular-targeted therapies and immunotherapies, there is an urgent need to integrate these circulating biomarkers into clinical practice to facilitate personalized treatment. This review highlights recent discoveries in circulating melanoma biomarkers, explores the challenges and potentials of emerging technologies for liquid biomarker discovery, and discusses future directions in melanoma biomarker research. [ABSTRACT FROM AUTHOR]

Simple Summary: The 5-year survival rate of Classical Hodgkin's lymphoma (cHL) exceeds 90%; however, adolescents between 15 and 18 years old show a higher disease-related mortality, and their overall prognosis is worse than that of both children and adults. We investigated the immune checkpoint inhibitors (ICPIs) therapeutic targets and specific T-regulatory and cytotoxic T-cell subsets in the subgroup of adolescent cHL patients, and we challenged their prognostic power. We showed that microenvironment of cHL in adolescent patients is enriched of ICPI targets that may be considered for therapeutic applications. Remarkably, LAG-3 is more consistently expressed than in pediatric and adult cHL, strengthening the state of immune anergy and reinforcing the rationale behind therapeutic approaches based on the use of new anti-LAG-3 antibodies. Furthermore, the presence of PD-1+ T-cells strongly relates to advanced stage disease, and a low density of CD8+ T lymphocytes is associated with recurrence and progression of disease. Background. Classical Hodgkin's lymphoma (cHL) in adolescents between 15 and 18 years old shows a higher disease-related mortality, and the overall prognosis is worse than in both children and adults. Objectives. We investigated the immune checkpoint inhibitors (ICPIs) therapeutic targets and specific T-regulatory and cytotoxic T-cell subsets in the subgroup of adolescent cHL patients, and we challenged their prognostic power. Methods. We retrieved formalin-fixed paraffin-embedded (FFPE) tissue of adolescent patients diagnosed with cHL and tested by immunohistochemistry the immune checkpoint molecules CTLA-4, LAG-3, PD-1, and PDL1 as well as the biological markers FOXP3 and CD8. Results. All the cases of our cohort expressed the immune checkpoint molecules CTLA-4, LAG-3, and PD-1 in microenvironment (ME), and the number of PD1+ cells was strongly associated with advanced disease, being higher in stage III/IV, indicating a possible role in the progression of cHL. A higher risk of recurrence and progression occurred in patients with lower amount of CD8+ microenvironmental T-cells at diagnosis (67.14 ± 27.23 vs. 42.86 ± 17.33 p = 0.032 and 65.59 ± 26.68 vs. 37 ± 17.45 p = 0.046, respectively). Conclusions. We showed that microenvironment of cHL in adolescent patients is enriched with potential therapeutic targets of ICPI that may be considered for therapeutic applications. Furthermore, the presence of PD-1 expressing T-cells strongly relates to advanced stage disease and a low density of CD8+ T lymphocytes is associated with recurrence and progression of disease. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates four blood-based biomarkers, mSEPT9, IGFBP2, DKK3, and PKM2, for colorectal cancer (CRC) detection. Current CRC screening methods are often invasive, leading to low compliance. We evaluated the diagnostic accuracy of these plasma biomarkers individually and their combinations in 124 CRC patients and 124 healthy controls. Our results showed that the combination of plasma biomarkers improved accuracy; the combined model outperformed individual biomarkers in detecting CRC. These findings suggest that a multi-biomarker blood test could offer a less invasive, effective alternative for CRC detection, potentially improving early detection rates and patient adherence to screening guidelines. Further research is needed to validate these findings in larger, diverse populations and explore their integration into routine clinical practice. Background: Colorectal cancer (CRC) is a leading cause of death worldwide. Despite its preventability through screening, compliance still needs to improve due to the invasiveness of current tools. There is a growing demand for validated molecular biomarker panels for minimally invasive blood-based CRC screening. This study assessed the diagnostic accuracy of four promising blood-based CRC biomarkers, individually and in combination. Methods: This case–control study involved plasma samples from 124 CRC cases and 124 age- and sex-matched controls. Biomarkers tested included methylated DNA encoding the Septin-9 gene (mSEPT9) using Epi proColon® 2.0 CE, insulin-like growth factor binding protein 2 (IGFBP2), dickkopf-3 (DKK3), and pyruvate kinase M2 (PKM2) by ELISA. Diagnostic accuracy was measured using the receiver operating characteristic (ROC), area under the curve (AUC), as well as sensitivity and specificity. Results: Diagnostic accuracy for mSEPT9, IGFBP2, DKK3, and PKM2 was 62.9% (95% CI: 56.8–62.9%), 69.7% (95% CI: 63.1–69.7%), 61.6% (95% CI: 54.6–61.6%), and 50.8% (95% CI: 43.4–50.8%), respectively. The combined biomarkers yielded an AUC of 74.4% (95% CI: 68.1–80.6%), outperforming all biomarkers except IGFBP2. Conclusions: These biomarkers show potential for developing a minimally invasive CRC detection tool as an alternative to existing approaches, potentially increasing adherence, early detection, and survivorship. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer (LC) is the leading cause of cancer-related mortality in Thailand, particularly in the Chiang Mai province. Beyond cigarette smoking, long-term exposure to indoor radon is a significant risk factor for the development of LC. In Kong Khaek, a subdistrict of the Mae Chaem district in Chiang Mai, the average indoor radon activity concentration exceeds both global and national averages. Understanding the impact of chronic low-dose radiation exposure on human populations living in high-background radiation areas is crucial. However, no specific biomarkers are currently available to detect LC resulting from prolonged exposure to indoor radon. Background: Indoor radon is a significant risk factor for the development of LC. This study aimed to identify potential biomarkers for LC risk in high background radiation areas using a metabolomics approach (UHPLC-HRMS). Methods: Based on the indoor radon activity concentration measurements in the Kong Khaek subdistrict, serum samples were collected from 45 nonsmoker or former smoker participants, comprising 15 LC patients and 30 matched healthy controls (low- and high-radon groups, respectively). Results: A total of 90 and 111 differential metabolites were identified in the LC group compared with the low- and high-radon groups, respectively, using criteria such as a variable importance in projection (VIP) of >1, a fold change (FC) of >1 or <0.5, and a p value of <0.05. Receiver operating characteristic (ROC) curves (an AUC of ≥ 0.9) indicated that 30 and 21 of these metabolites had the potential to serve as biomarkers of LC development in the low- and high-radon groups, respectively. The KEGG pathway enrichment analysis suggested that D-sphingosine may have been a candidate biomarker associated with LC in both groups. Conclusions: Overall, this study provides new insights into metabolic biomarkers for screening LC development in high-risk individuals with prolonged exposure to indoor radon. Further large-scale studies are needed to validate our results. [ABSTRACT FROM AUTHOR]

Simple Summary: Research increasingly shows that bacteria, the largest part of the gut microbiome, may play a significant role in cancer. These microorganisms produce metabolites that can travel through the body and interact with host cells via microbial metabolite receptors, potentially affecting cancer development. This study investigates the involvement of these receptors in human cells across twenty-three types of cancer. By analyzing data from both cancer cell lines and human tumor samples, we examined how these interactions may impact key cancer-related processes, such as immune response, tumor growth, and spread. Notably, we identified several receptors that are consistently altered in cancer, which might serve as helpful biomarkers for diagnosis or treatment. This research highlights the potential of targeting the gut microbiome in cancer therapy and provides valuable insights for developing new cancer treatments based on microbiome interactions. Background/Objectives: The role of the gut microbiome in cancer biology has become an increasingly prominent area of research, particularly regarding the role of microbial metabolites and their receptors (MMRs). These metabolites, through the various gut–organ axes, have been proven to influence several pathogenetic mechanisms. This study conducted a comprehensive pan-cancer analysis of MMR transcriptomic profiles across twenty-three cancer types, exploring the mechanisms through which they can influence cancer development and progression. Methods: Utilizing both cancer cell lines from CCLE (Cancer Cell Line Encyclopedia) and human tumor samples from TCGA (The Cancer Gene Atlas), we analyzed 107 MMRs interacting with microbial metabolites such as short-chain fatty acids, bile acids, indole derivatives, and others while studying their interactions with key known cancer genes. Results: Our results revealed that certain MMRs, such as GPR84 and serotonin receptors, are consistently upregulated in various malignancies, while others, like ADRA1A, are frequently downregulated, suggesting diverse roles in cancer pathophysiology. Furthermore, we identified significant correlations between MMR expression and cancer hallmark genes and pathways, including immune evasion, proliferation, and metastasis. Conclusions: These findings suggest that the interactions between microbial metabolites and MMRs may serve as potential biomarkers for cancer diagnosis, prognosis, and therapy, highlighting their therapeutic potential. This study underscores the significance of the microbiota–cancer axis and provides novel insights into microbiome-based strategies for cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Hybrid epithelial/mesenchymal (E/M) cells are the most metastatic of carcinoma cell types. Hybrid E/M cells have both epithelial and mesenchymal properties reminiscent of chimeras, mythical creatures composed of different animals. The co-expression of epithelial and mesenchymal proteins is a defining feature of hybrid E/M cancer cells. In this review, we discuss the use of cytokeratin (epithelial) and vimentin (mesenchymal) intermediate filaments as markers in hybrid E/M cells. We describe the structures and functions of these filaments that are uniquely expressed in hybrid E/M cells and speculate on potential hybrid structures formed between vimentin and cytokeratin. We also describe cell-surface cytokeratin and vimentin and their functions and discuss their potential as predictive biomarkers and as targets for anti-cancer therapy. The epithelial–mesenchymal transition (EMT) program is critical to metastatic cancer progression. EMT results in the expression of mesenchymal proteins and enhances migratory and invasive capabilities. In a small percentage of cells, EMT results in the expression of stemness-associated genes that provide a metastatic advantage. Although EMT had been viewed as a binary event, it has recently become clear that the program leads to a spectrum of phenotypes, including hybrid epithelial/mesenchymal (E/M) cells that have significantly greater metastatic capability than cells on the epithelial or mesenchymal ends of the spectrum. As hybrid E/M cells are rarely observed in physiological, non-diseased states in the adult human body, these cells are potential biomarkers and drug targets. Hybrid E/M cells are distinguished by the co-expression of epithelial and mesenchymal proteins, such as the intermediate filament proteins cytokeratin (CK; epithelial) and vimentin (VIM; mesenchymal). Although these intermediate filaments have been extensively used for pathological characterization and detection of aggressive carcinomas, little is known regarding the interactions between CK and VIM when co-expressed in hybrid E/M cells. This review describes the characteristics of hybrid E/M cells with a focus on the unique co-expression of VIM and CK. We will discuss the structures and functions of these two intermediate filament proteins and how they may interact when co-expressed in hybrid E/M cells. Additionally, we review what is known about cell-surface expression of these intermediate filament proteins and discuss their potential as predictive biomarkers and therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Exosomes are small extracellular vesicles released by all cells that play a crucial role in cell-to-cell communication. Exosomes derived from cancer cells carry tumorigenic properties, transmitting these signals to surrounding cells within the tumor microenvironment or to distant sites. However, the complexity of exosome cargo remains poorly understood. In this study, we isolated exosomes from human lung adenocarcinoma A549 cell cultures, characterized their physicochemical and morphological properties, and analyzed their proteomic and miRNA cargo through high-throughput profiling and bioinformatics. Key molecules within the exosomal cargo were identified, and network analysis revealed their potential effects on the physiology of potential recipient cells. Furthermore, we compared the miRNA profiles of malignant A549 exosomes with those from normal lung fibroblast MRC-5 cells, identifying tumor-associated miRNAs for potential biomarker exploration in clinical samples. This study advances our understanding of exosomal molecular components and their interactions, opening avenues for further research into their roles in cancer. Background/Objectives: Exosomes, nano-sized extracellular vesicles released by all cells, play a key role in intercellular communication and carry tumorigenic properties that impact surrounding or distant cells. The complexity of the exosomal molecular interactome and its effects on recipient cells still remain unclear. This study aims to decipher the molecular profile and interactome of lung adenocarcinoma A549 cell-derived exosomes using multi-omics and bioinformatics approaches. Methods: We performed comprehensive morphological and physicochemical characterization of exosomes isolated from cell culture supernatant of A549 cells in vitro, using DLS, cryo-TEM, Western blot, and flow cytometry. Proteomic and miRNA high-throughput profiling, coupled with bioinformatics network analysis, were applied to elucidate the exosome molecular cargo. A comparative miRNA analysis was also conducted with exosomes derived from normal lung fibroblast MRC-5 cells. Results: Exosomes exhibited an average size of ~40 nm and disk-shaped lipid bilayer structures, with tetraspanins CD9 and CD63 validated as exosomal markers. Proteomic analysis identified 68 proteins, primarily linked to the extracellular matrix organization and metabolic processes. miRNA sequencing revealed 72 miRNAs, notably hsa-miR-619-5p, hsa-miR-122-5p, hsa-miR-9901, hsa-miR-7704, and hsa-miR-151a-3p, which are involved in regulating metabolic processes, gene expression, and tumorigenic pathways. Th integration of proteomic and miRNA data through a proteogenomics approach identified dually affected genes including ERBB2, CD44, and APOE, impacted by both exosomal miRNA targeting and protein interactions through synergistic or antagonistic interactions. Differential analysis revealed a distinct miRNA profile in A549 exosomes, associated with cancer-related biological processes, compared to MRC-5 exosomes; notably, hsa-miR-619-5p emerged as a promising candidate for future clinical biomarker studies. The network analysis also revealed genes targeted by multiple upregulated tumor-associated miRNAs in potential exosome-recipient cells. Conclusions: This integrative study provides insights into the molecular interactome of lung adenocarcinoma A549 cell-derived exosomes, providing a foundation for future research on exosomal cargo and its role in tumor cell communication, growth, and progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous studies using a metabolomics approach in relation to prostate cancer (PCa) risk assessment have focused on endogenous metabolism. As far as we know, the associations between circulating metabolites derived from exogenous sources, such as diet or lifestyle, and PCa risk have not been widely studied. In our work, we examined the associations between endogenous and exogenous plasma metabolites and PCa risk in a case–control study conducted in the frame of the EPIC study. The main findings of our study include novel negative and positive associations of food metabolites, such as cyclamate and biomarkers of plant-based foods, respectively, with PCa cancer risk. Furthermore, a few microbial metabolites were associated with PCa risk, suggesting the potential role of microbiota in prostate cancer development. Our results reinforce the use of nutritional metabolomics to deepen the understanding of the complex role of diet and its potential mechanisms of action in prostate carcinogenesis. Background and Objective: Nutrimetabolomics may reveal novel insights into early metabolic alterations and the role of dietary exposures on prostate cancer (PCa) risk. We aimed to prospectively investigate the associations between plasma metabolite concentrations and PCa risk, including clinically relevant tumor subtypes. Methods: We used a targeted and large-scale metabolomics approach to analyze plasma samples of 851 matched PCa case–control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Associations between metabolite concentrations and PCa risk were estimated by multivariate conditional logistic regression analysis. False discovery rate (FDR) was used to control for multiple testing correction. Results: Thirty-one metabolites (predominately derivatives of food intake and microbial metabolism) were associated with overall PCa risk and its clinical subtypes (p < 0.05), but none of the associations exceeded the FDR threshold. The strongest positive and negative associations were for dimethylglycine (OR = 2.13; 95% CI 1.16–3.91) with advanced PCa risk (n = 157) and indole-3-lactic acid (OR = 0.28; 95% CI 0.09–0.87) with fatal PCa risk (n = 57), respectively; however, these associations did not survive correction for multiple testing. Conclusions: The results from the current nutrimetabolomics study suggest that apart from early metabolic deregulations, some biomarkers of food intake might be related to PCa risk, especially advanced and fatal PCa. Further independent and larger studies are needed to validate our results. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug resistance remains a significant challenge in melanoma treatment. This study identifies laminB1, a nuclear structural protein, as a key regulator of melanoma cell response to target therapy. LaminB1 expression tightly relates to melanoma progression and prognosis. Interfering laminB1 amplifies the drug response of melanoma cells by a cooperative effect of enhanced apoptosis and suppressed protective autophagy. These findings highlight the potential of laminB1 as a diagnostic marker and therapeutic target for melanoma treatment. Background/Objectives: Drug resistance poses a substantial clinical challenge in melanoma treatment, yet the underlying mechanism remains elusive. Here, we report the novel role of laminB1, a nuclear structure protein, in regulating the response of BRAF-mutated melanoma cells to vemurafenib. Results: Our analysis of clinical samples and existing databases highlights the tight correlation between the laminB1 expression level and melanoma progression and prognosis. Notably, we observe that laminB1 expression is upregulated when BRAF-mutated melanoma cells develop resistance to vemurafenib. The knockdown of laminB1 substantially increases the sensitivity of melanoma cells to vemurafenib. Furthermore, we found laminB1 suppression increases cell apoptosis via the escalation of DNA damage in a vemurafenib-dose-dependent manner. Conversely, protective cell autophagy is negatively regulated by laminB1 suppression. Interestingly, this distinct regulation pattern of apoptosis and autophagy by laminB1 cooperatively promotes the response of BRAF-mutated melanoma cells to vemurafenib. Conclusions: Our findings unveil the potential of laminB1 as both a diagnosis marker and a therapeutic target of melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, pembrolizumab has become applicable for recurrent and metastatic head and neck cancer (RMHNC), but only a limited number of patients can benefit from it. In this study, we explored predictive markers for the therapeutic effect and prognosis of pembrolizumab for RMHNC. The results showed that the immune-modified Glasgow Prognostic Score (imGPS), which we previously proposed, is a better predictive marker than the previously known neutrophil-to-lymphocyte ratio (NLR) and mGPS. The imGPS can be easily evaluated with just a blood test, so we hope that it will become more widely used in the clinical environment. Background: Previously, we proposed that the immune-modified Glasgow Prognostic Score (imGPS), which adds the lymphocyte count to the mGPS, is helpful as a prognostic marker for patients with head and neck squamous cell carcinoma. In this study, we investigated the imGPS as a marker for the therapeutic effect of pembrolizumab in treating recurrent and metastatic head and neck cancer (RMHNC). Methods: This study included RMHNC patients who were treated with pembrolizumab from December 2019 to April 2024. ALB, CRP, lymphocyte counts, neutrophil-to-lymphocyte ratios (NLRs), mGPSs, and imGPSs were extracted as biomarkers, and the response rate and prognosis were analyzed for each. Results: A total of 54 patients were enrolled. Lymphocyte counts were correlated with the overall response rates (ORRs) (p = 0.0082). Although the mGPS did not show significant differences in ORRs, imGPSs revealed a significant difference (p = 0.013). CRP, ALB, and lymphocyte counts were correlated with overall survival (OS) and/or progression-free survival (PFS). NLRs, mGPSs, and imGPSs were also correlated with OS and/or PFS, with imGPSs showing the greatest area under the curve (OS; AUC = 0.795, PFS; AUC = 0.754). Conclusions: This study demonstrates that the imGPS is an excellent predictive marker for the therapeutic effect and prognosis of pembrolizumab for RMHNC. The imGPS can be employed with daily blood tests, highlighting the potential to forecast the impact of the ICI with high reliability. [ABSTRACT FROM AUTHOR]

Simple Summary: This article explores the molecular pathways involved in lung cancer, alongside genomic alterations and genetic syndromes associated with the disease. It also reviews testing methods and their role in advancing personalized treatment approaches, offering insights into current therapeutic strategies. This article provides a comprehensive overview of lung cancer from a genetic perspective, emphasizing the molecular pathways involved in its pathogenesis. This review presents the genetic syndromes and key genomic variations, including alterations and instabilities, contributing to tumor development and progression. Furthermore, advancements in genomic testing, such as liquid biopsy, are explored, highlighting their utility in early diagnosis, prognostic evaluation, and personalized treatment strategies. The role of biomarkers in informing therapeutic decisions and optimizing patient outcomes is also examined, offering insights into their potential to refine clinical interventions. This review aims to enrich the understanding of the genetic landscape of lung cancer, providing insights that may lead to improved diagnostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript aims to provide a comprehensive update on biomarkers in rectal cancer, focusing on both established and emerging markers. It highlights the most significant advancements in recent years, particularly those that align with the evolution of neoadjuvant treatment in this disease. Furthermore, it explores the relationship between biomarkers and pathological response, emphasizing their potential to serve as prognostic factors. Despite promising findings, many of these biomarkers have not yet been validated for routine clinical application. This review seeks to consolidate current knowledge, identify existing challenges, and propose future directions for research in this critical area of rectal cancer management. Colorectal cancer (CRC) is a neoplasm with a high prevalence worldwide, with a multimodal treatment that includes a combination of chemotherapy, radiotherapy, and surgery in locally advanced stages with acceptable pathological complete response (pCR) rates, this has improved with the introduction of total neoadjuvant therapy (TNT) reaching pCR rates up to 37% in compare with classic neoadjuvant treatment (NAT) where pCR rates of around 20–25% are achieved. However, the patient population that benefits most from this therapy has not been determined, and there is a lack of biomarkers that can predict the course of the disease. Multiple biomarkers have been studied, ranging from hematological and molecular markers by imaging technique and combinations of them, with contradictory results that prevent their use in routine clinical practice. In this review, we evaluate the most robust prognostic biomarkers to be used in clinical practice, highlighting their advantages and disadvantages and emphasizing biomarker combinations and their predictive value. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer and stroke are leading causes of global disability and mortality. With improvements in cancer-associated mortality and advancements in treatment of active malignancy, it is more common to encounter patients with ischemic stroke and active malignancy. In this paper, we first review the epidemiology regarding cancer-associated ischemic stroke and management challenges. We then highlight the pathophysiological contributors to the development of hypercoagulability, as well as tumor-associated and treatment-associated contributors to stroke in patients with cancer. The final section addresses acute treatment, secondary prevention, recovery, and future directions regarding management of cancer-associated stroke. Cancer and stroke are leading causes of global disability and mortality. With improvements in cancer-associated mortality and advancements in treatment of active malignancy, it is more common to encounter patients with ischemic stroke and active malignancy. Evidence suggests that cancer-associated ischemic stroke is a unique subtype of stroke; however, there is limited guidance when considering diagnostic workup, secondary prevention, rehabilitation, and future directions within this population. In this narrative review, we aim to describe the epidemiology, pathophysiological mechanisms, management, and future directions regarding understanding of cancer-associated ischemic stroke. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to address an urgent issue: about 20% of cancer patients undergoing treatment do not respond adequately to the standard two-dose COVID-19 vaccination. This highlights the need to identify factors influencing vaccine efficacy in this vulnerable group, including psychological conditions such as distress, anxiety, and depression. The primary objectives were to determine whether these psychological factors, along with clinical variables such as metastatic stage and smoking, influenced antibody response and vaccine activation six months post-vaccination. This study also examined changes in psychological distress over time in relation to gender and education. The results showed that 14.2% of patients did not achieve an antibody response at six months, with high distress and metastatic cancer as significant predictors of non-response (OR = 2.46, p = 0.04). These findings suggest that integrating distress management strategies into oncology care could enhance vaccine response, supporting improved health outcomes for cancer patients. Background/Objectives: Our previous study of 291 cancer patients, we showed that 20% did not respond to two doses of COVID-19 vaccine administered six weeks apart. Methods: Here, we investigated if psychological factors (distress, anxiety, and depressive symptoms) affected antibody response and markers of vaccine activation (D-dimer) after 6 months from initial vaccination. Results: Overall, 31 subjects (14.2%) had no antibody response at 6 months. Our analysis revealed significant predictors of vaccine failure, including the stage of metastatic disease and high-stress levels (OR = 2.46, 95% CI, 1.05–5.77, p = 0.04). Notably, nonresponders showed twice the prevalence of distress than responders (21% vs. 10%, p = 0.04). Longitudinal measurements of IgG levels indicated that participants with high depressive symptoms at baseline maintained lower antibody levels over six months (p = 0.003). In addition, women with high anxiety showed reduced levels of D-dimer at 6 months (p = 0.03). These data also showed that smokers and former smokers had significantly lower antibody levels than their nonsmoking counterparts (p = 0.0004). At baseline, the high discomfort rate (≥5) was 34.4% in women and 23.8% in men; only men experienced an increase in median discomfort during the observation period. Moreover, a higher educational level was related to increased distress among women (p = 0.046). Conclusions: These findings underscore a critical association between elevated psychological distress and reduced immune responses to the COVID-19 vaccine, emphasizing the urgent need for targeted psychological and behavioral support within this vulnerable population. [ABSTRACT FROM AUTHOR]

Simple Summary: Children with aggressive acute lymphoblastic leukemia (ALL) currently undergo frequent, invasive bone marrow biopsies to monitor their treatment response. This research explores a less invasive alternative using circulating tumor DNA (ctDNA) in blood plasma. We used a mouse model of ALL to study how ctDNA levels change during leukemia progression and treatment. Our findings show that ctDNA can accurately reflect the spread of leukemia and may be better at detecting the presence of residual cancer cells in organs compared to traditional blood tests. This research could lead to less invasive and more effective ways of monitoring treatment response in young leukemia patients, potentially improving their care and outcomes. Background: In infant KMT2A (MLL1)-rearranged (MLL-r) acute lymphoblastic leukemia (ALL), early relapse and treatment response are currently monitored through invasive repeated bone marrow (BM) biopsies. Circulating tumor DNA (ctDNA) in peripheral blood (PB) provides a minimally invasive alternative, allowing for more frequent disease monitoring. However, a poor understanding of ctDNA dynamics has hampered its clinical translation. We explored the predictive value of ctDNA for detecting minimal/measurable residual disease (MRD) and drug response in a patient-derived xenograft (PDX) model of infant MLL-r ALL. Methods: Immune-deficient mice engrafted with three MLL-r ALL PDXs were monitored for ctDNA levels before and after treatment with the menin inhibitor SNDX-50469. Results: The amount of ctDNA detected strongly correlated with leukemia burden during initial engraftment prior to drug treatment. However, following SNDX-50469 treatment, the leukemic burden assessed by either PB leukemia cells through flow cytometry or ctDNA levels through droplet digital polymerase chain reaction (ddPCR) was discrepant. This divergence could be attributed to the persistence of leukemia cells in the spleen and BM, highlighting the ability of ctDNA to reflect disease dynamics in key leukemia infiltration sites. Conclusions: Notably, ctDNA analysis proved to be a superior predictor of MRD compared to PB assessment alone, especially in instances of low disease burden. These findings highlight the potential of ctDNA as a sensitive biomarker for monitoring treatment response and detecting MRD in infant MLL-r ALL. [ABSTRACT FROM AUTHOR]

Simple Summary: This systematic review explores prognostic and predictive factors in colorectal cancer, aiming to identify key determinants that influence patient outcomes and treatment responses. By synthesizing evidence from relevant studies, the review assesses the impact of various factors such as tumor characteristics, biomarker expression, and treatment modalities on disease prognosis and therapeutic efficacy. Through a comprehensive analysis, this review provides valuable insights into the factors that can help clinicians tailor treatment strategies and improve patient outcomes in colorectal cancer management. Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes. This systematic review aims to comprehensively evaluate prognostic and predictive determinants in CRC, encompassing both traditional and emerging biomarkers. A systematic search of major electronic databases was conducted to identify relevant studies published from 1995 up to 2024. Eligible articles were critically appraised, and data extraction was performed according to predefined criteria. The prognostic determinants examined included clinicopathological features such as tumor stage, grade, and lymph node involvement, as well as molecular biomarkers including RAS, BRAF, and MSI status. Predictive determinants encompassed biomarkers influencing response to targeted therapies and immunotherapy, such as HER2 and Immunoscore. The review also explores novel prognostic and predictive markers, including tumor microenvironment characteristics and liquid biopsy-based biomarkers. Synthesizing evidence from diverse studies, this review provides insights into the prognostic and predictive landscape of CRC, highlighting the potential clinical implications of identified determinants. Understanding the multifaceted nature of prognostic and predictive factors in CRC is imperative for the advancement of personalized treatment strategies and improvement of patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript describes an innovative biomarker for cancer. Cancer cells often exhibit altered metabolism, known as the Warburg effect, where they preferentially use anaerobic glycolysis even in the presence of oxygen. This leads to increased production of methylglyoxal, a side-product of glycolysis. We demonstrate here for the first time that human tumor cells can produce and release free methylglyoxal at high levels, whereas normal cells do not. Consequently, it appears that, in spite of some limitations, free methylglyoxal can be used as a metabolic new clinically useful biomarker in cancers, including cases for which there is still no available biomarker. Our findings open the way to further bio-clinical developments. Background: A fundamental property of cancer cells is their metabolic reprogramming, allowing them to increase glucose uptake and glycolysis. Using a rat colon adenocarcinoma model, we previously showed that blood levels of free methylglyoxal (MG), a side-product of glycolysis, remained normal in animals grafted with a non-growing tumor cell clone, while MG levels were significantly increased and positively correlated with tumor growth in animals grafted with a tumorigenic cell clone issued from the same tumor. Methods: We measured free MG in the blood of cancerous non-diabetic patients and compared the results to healthy subjects and non-cancerous diabetic patients. We also measured free MG in tumors and in the corresponding non-cancer tissues, and the peripheral blood. Results: We show that free MG levels in the peripheral blood of cancer patients are significantly increased in comparison with free MG levels in the peripheral blood of healthy controls (p < 0.0001), and similar to those in the peripheral blood of hyperglycemic diabetic patients (p = 0.965). In addition, we show that repeated free MG level measurement could be used for the therapeutic monitoring of cancer patients. Moreover, we confirmed that free MG is produced by tumor cells at significantly higher levels than cells from their corresponding tissues (p < 0.0001), and is subsequently released in the peripheral blood. Conclusions: Free MG measured in the blood could be a new metabolic biomarker useful for the diagnostic, prognostic and follow-up of non-diabetic patients with cancers, such as bronchus carcinoma, pancreatic carcinoma and glioblastoma, for which there are presently no available useful biomarkers. [ABSTRACT FROM AUTHOR]

As part of a symposium, current and former directors of Immune Monitoring cores and investigative oncologists presented insights into the past, present and future of immune assessment. Dr. Gnjatic presented a classification of immune monitoring technologies ranging from universally applicable to experimental protocols, while emphasizing the need for assay harmonization. Dr. Obeng discussed physiologic differences among CD8 T cells that align with anti-tumor responses. Dr. Lyerly presented the Soldano Ferrone lecture, commemorating the passionate tumor immunologist who inspired many, and covered a timeline of monitoring technology development and its importance to immuno-oncology. Dr. Sonabend presented recent achievements in glioblastoma treatment, accentuating the range of monitoring techniques that allowed him to refine patient selection for clinical trials. Dr. Guevara-Patiño focused on hypoxia within the tumor environment and stressed that T cell viability is not to be confused with functionality. Dr. Butterfield accentuated monitoring of dendritic cell metabolic (dys)function as a determinant for tumor vaccine success. Lectures were interspersed with select abstract presentations. To summarize the concepts, Dr. Maecker from Stanford led an informative forum discussion, pointing towards the future of immune monitoring. Immune monitoring continues to be a guiding light towards effective immunotherapeutic strategies.

MicroRNAs, short non-protein coding RNAs, are overexpressed in GCTs. Circulating levels of germ cell tumor (GCT)-associated miRNAs, such as miR-371a-3p, can be utilized as efficient and cost-effective alternatives in diagnosing and managing patients presenting with GCTs. This quality of miRNAs has demonstrated favorable performance characteristics as a reliable blood-based biomarker with high diagnostic accuracy compared to current serum tumor markers (STMs), including α-fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH). The conventional STMs exhibit limited specificity and sensitivity. Potential clinical implications of miRNAs include impact on de-escalating or intensifying treatment, detecting recurrence at earlier stages, and lessening the necessity of cross-sectional imaging or invasive tissue biopsy for non-teratomatous GCTs. Here, we also highlight the outstanding issues that must be addressed prior to clinical implementation. Standards for measuring circulating miRNAs and determining ideal cutoff values are essential for integration into current clinical guidelines.

Simple Summary: In this study, we evaluated the expression of Toll-like receptors (TLRs) on NK and NKT-like cells in patients with gastric cancer (GC) in comparison to its two subtypes: intestinal and diffuse, and in healthy volunteers. We showed that TLR expression increases with disease progression, which may be related to the adaptive immune response to tumor progression. Furthermore, we identified differences in TLR expression depending on the gastric cancer subtype. RT-qPCR analysis revealed significantly higher expression of TLR2, TLR3, TLR4, and TLR9 genes in patients with GC. The results suggest that TLR expression levels may represent a valuable diagnostic and prognostic biomarker and potentially support the personalization of treatment and the development of new immunotherapy strategies in the future. Background/Objectives: The aim of this study was to determine the assessment of the percentage of NK and NKT-like cells expressing Toll-like receptors (TLR-2, TLR-3, TLR-4, and TLR-9) in patients with gastric cancer (GC) compared with healthy volunteers (HV) and to investigate differences according to cancer subtype. We also assessed TLR gene expression by RT-qPCR to assess whether TLRs could be diagnostic and prognostic biomarkers. Methods: The study included 86 patients with histologically confirmed gastric cancer and 30 healthy volunteers. Peripheral blood samples were collected from the participants, and TLR expression on NK and NKT-like cells was assessed by flow cytometry and RT-qPCR. The expression of TLR2, TLR3, TLR4, and TLR9 genes was assessed using genetic material derived from NK and NKT-like cells sourced from PBMC. The obtained results were statistically analyzed using Mann–Whitney U and Kruskal–Wallis tests, and the predictive ability of variables was assessed using ROC curve analysis. Results: A significantly higher expression of TLR receptors (TLR-2, TLR-3, TLR-4, and TLR-9) was found in patients with gastric cancer compared to healthy volunteers (p < 0.05). TLR expression also differed depending on the cancer subtype, and higher expression was observed in more advanced GC subtypes. RT-qPCR analysis showed significantly increased expression of TLR genes in the group of GC patients. ROC curves indicate a high ability of TLRs to differentiate between GC patients and healthy individuals. Conclusions: The expression of TLRs on NK and NKT-like cells is clearly increased in patients with gastric cancer, especially in more advanced subtypes of the tumor. The results suggest that TLRs could potentially be used as diagnostic and prognostic biomarkers and represent potential targets for immune therapies in GC. However, further studies are needed to determine the functional role of TLRs in disease progression and the possibility of their use in personalized treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: This review specifically examines the advancing comprehension and management of intraductal papillary mucinous neoplasms (IPMNs) by integrating various diagnostic approaches, encompassing genomic and molecular biomarkers, alongside clinical and radiographic information. This review highlights the difficulty in differentiating low-risk from high-risk IPMNs and underscores the significance of biomarkers such as KRAS and GNAS mutations, which are directly linked to IPMN progression. Furthermore, it examines the efficacy of advanced imaging modalities, including MRI with MRCP and contrast-enhanced endoscopic ultrasound (EUS), for enhanced malignancy detection. This review also emphasizes novel models that integrate cystic fluid markers, clinical nomograms, and radiomics to enhance risk stratification. This review is unique in that it provides a thorough analysis of new molecular insights and emphasizes customized patient care while providing useful suggestions based on current international guidelines. This review helps clinicians improve IPMN treatment strategies and outcomes. Currently, there is no reliable method of discerning between low-risk and high-risk intraductal papillary mucinous neoplasms (IPMNs). Operative resection is utilized in an effort to resect those lesions with high-grade dysplasia (HGD) prior to the development of invasive disease. The current guidelines recommend resection for IPMN that involve the main pancreatic duct. Resecting lesions with HGD before their progression to invasive disease and the avoidance of resection in those patients with low-grade dysplasia is the optimal clinical scenario. Therefore, the importance of developing preoperative models able to discern HGD in IPMN patients cannot be overstated. Low-risk patients should be managed with nonsurgical treatment options (typically MRI surveillance), while high-risk patients would undergo resection, hopefully prior to the formation of invasive disease. Current research is evolving in multiple directions. First, there is an ongoing effort to identify reliable markers for predicting malignant transformation of IPMN, mainly focusing on genomic and transcriptomic data from blood, tissue, and cystic fluid. Also, multimodal models of combining biomarkers with clinical and radiographic data seem promising for providing robust and accurate answers of risk levels for IPMN patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This study looked at different ways to predict the risk of colorectal cancer using blood tests. Sixteen studies from 2015 to 2024 were reviewed, focusing on people with an average risk of cancer who were undergoing a colonoscopy for screening. The most common test was a complete blood count, which showed good accuracy. Other tests included tests of proteins, metabolites, enzymes, and markers related to insulin and anemia. The best results came from a test using a group of plasma metabolites. While these tests could make cancer screening more accurate, many studies did not show how these models could be used in real-life settings. More research is needed to understand how these models can be effectively used in current screening programs. Background/Objectives: Risk prediction models (RPMs) for colorectal cancer (CRC) could facilitate risk-based screening. Models incorporating biomarkers may improve the utility of current RPMs. We performed a systematic review of studies reporting RPMs for CRC that evaluated the impact of blood-based biomarkers on clinical outcome prediction at the time of screening colonoscopy in average-risk populations. Methods: We conducted a search of MEDLINE, Web of Science, and PubMed databases from inception through April 2024. Studies that developed or validated a model to predict risk of CRC or its precursors were included. Studies were limited to those including patients undergoing average-risk CRC screening. Results: Sixteen studies published between 2015 and 2024 were included. Outcomes included CRC (16 studies) and high-risk adenomas (1 study). Using a complete blood count was the most common biomarker and was able to achieve an AUC of 0.82 and a specificity of 0.88. Other blood-based biomarkers included were various serum proteins/metabolites/enzymes, plasma metabolites, insulin-related factors, and anemia markers. The highest-performing model, with an AUC of 0.99, involved the use of a plasma metabolite panel. Conclusions: The evidence base of RPMs for CRC screening is expanding and incorporating biomarkers, which remain a prominent aspect of model discovery. Most RPMs included a lack of internal/external validation or discussion as to how the model could be implemented clinically. As biomarkers improve the discriminatory potential of RPMs, more research is needed for the evaluation and implementation of RPMs within existing CRC screening frameworks. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer (PC) is one of the most common causes of cancer-related deaths. Unfortunately, the number of deaths caused by this cancer is expected to increase in the future. Early diagnosis of pancreatic cancer is essential for improving treatment efficacy. MicroRNAs are endogenous non-coding RNAs and play a role in the post-transcriptional regulation of expression of many genes—they can also be useful as diagnostic and prognostic biomarkers in various cancers, including pancreatic cancer. Using microRNA detection in patients' blood is becoming more and more popular. We review the clinical value of microRNAs in the screening, diagnosis, prognosis, and monitoring of pancreatic cancer therapy. Pancreatic cancer (PC) is a serious malignant tumor with a high mortality rate, mainly due to late diagnosis and a lack of effective therapeutic interventions. The possibility of recognizing this cancer with reliable biomarkers using minimally invasive methods is of great importance for improving early detection, prognostic assessment, and targeted treatment methods. In recent years, small non-coding RNAs, especially microRNAs, have emerged as promising candidates for biomarkers of pancreatic cancer. Despite the methodological and analytical limitations of microRNA determination and a lack of available automated and standardized tests, a prospective systematic assessment of this new parameter's use in the detection of pancreatic cancer is warranted. This review provides general information on the diagnostic and prognostic utility of microRNAs, which appear to be well-established in many studies. In summary, microRNAs are promising non-invasive biomarkers of pancreatic cancer, offering potential opportunities for early detection, prognosis, and treatment monitoring. As research in this field progresses, microRNAs should become valuable tools in the fight against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) consists of a group of heterogeneous tumors that are diagnosed comparatively late and often have a poor prognosis. Current head and neck research is motivated to find biomarkers for early detection, diagnosis, and therapy monitoring. Extravesicular (EV)-microRNA obtained by liquid biopsy of blood offers a promising approach here since the respective target mRNAs and their function in tumor neogenesis are partly already known. In this study, blood sera from 50 HNSCC patients and 16 controls treated between 2020–2023 at the Department of Otorhinolaryngology, Head and Neck Surgery of the University Hospital of Münster, were obtained by liquid biopsy. A specific EV-miRNA panel consisting of EV-miR-21, -1246, -200c, -let-7a, -11a, and -26a was determined. The expression of the analyzed EV-microRNA of the patients was then examined for correlation with clinical parameters regarding the diagnostic and prognostic value and suitability for therapy monitoring. Background: Biomarkers for HNSCC are still lacking. Biomolecules obtained via liquid biopsy are being investigated for diagnosis, prognosis, and therapy monitoring, including extracellular vesicles (EVs) and EV-cargo, e.g., proteins, RNA, and microRNA. This study aims to understand localization-dependent EV-microRNA expression in blood sera, their dynamics over time (12 months FU), and insights into their potential in diagnostics and therapy monitoring. Methods: Via liquid biopsy, blood serum was taken from 50 patients with HNSCC and 16 controls. Extracellular vesicles were isolated from serum by precipitation, and the contained microRNA-21, -1246, -200c, -let-7a, -181a, and -26a were amplified by reverse transcription and determined with real-time PCR. Expression ratios (HNSCC to healthy controls) were collated with the patients' clinical parameters. A second liquid biopsy was carried out avg. 12 months later in the tumor aftercare. A sub-analysis with the Oropharynx subsite was implemented. Results: EV-mir-21, -let-7a, and -181a were 2.5–3-fold higher expressed in HPV/p16+ than in HPV/p16- HNSCC. Different expressions of EV-mir-181a and -26a could be demonstrated depending on the therapy modality. Conclusions: EV-microRNA could be a promising biomarker in the diagnosis and therapy monitoring of HNSCC. A systematic comparison of EV- and tissue microRNA expression in different HNSCC-subsites is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is a highly aggressive brain cancer with limited treatment options. This research aims to improve our understanding of GBM progression by focusing on extracellular vesicles released by tumor cells that carry important biological information. The authors developed a laboratory model that closely mimics the tumor microenvironment, allowing for the study of extracellular vesicles released from various cell types within the tumor. This model enabled the identification of specific surface markers on extracellular vesicles that could serve as potential noninvasive diagnostic tools for GBM. The findings suggest that these markers may help improve extracellular vesicle isolation and provide insights into the molecular characteristics of the tumor. This study has the potential to significantly impact the research community by offering new approaches to GBM diagnosis and advancing our knowledge of tumor biology, which could ultimately inform future therapeutic strategies. Background/Objectives: Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options. Extracellular vesicles (EVs) derived from GBM cells contain important biomarkers, such as microRNAs, proteins, and DNA mutations, which are involved in tumor progression, invasion, and resistance to treatment. Identifying surface markers on these EVs is crucial for their isolation and potential use in noninvasive diagnosis. This study aimed to use tumor-derived explants to investigate the surface markers of EVs and explore their role as diagnostic biomarkers for GBM. Methods: Tumor explants from nine GBM patients without IDH1/IDH2 mutations or 1p-19q co-deletion were cultured to preserve both tumor viability and cytoarchitecture. EVs were collected from the tumor microenvironment using differential centrifugation, filtration, and membrane affinity binding. Their surface protein composition was analyzed through multiplex protein assays. RNA-Seq data from TCGA and GTEx datasets, along with in silico single-cell RNA-seq data, were used to assess EV surface biomarker expression across large GBM patient cohorts. Results: The in vitro model successfully replicated the tumor microenvironment and produced EVs with distinct surface markers. Biomarker analysis in large datasets revealed specific expression patterns unique to GBM patients compared with healthy controls. These markers demonstrated potential as a GBM-specific signature and were correlated with clinical data. Furthermore, in silico single-cell RNA-seq provided detailed insights into biomarker distribution across different cell types within the tumor. Conclusions: This study underscores the efficacy of the tumor-derived explant model and its potential to advance the understanding of GBM biology and EV production. A key innovation is the isolation of EVs from a model that faithfully mimics the tumor's original cytoarchitecture, offering a deeper understanding of the cells involved in EV release. The identified EV surface markers represent promising targets for enhancing EV isolation and optimizing their use as diagnostic tools. Moreover, further investigation into their molecular cargo may provide crucial insights into tumor characteristics and evolution. [ABSTRACT FROM AUTHOR]

Simple Summary: Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at identifying the molecular factors associated with disease relapse and investigating them as therapeutically exploitable targets. Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance. Background: Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at the identification of the molecular factors associated with disease relapse and their further investigation as therapeutically exploitable targets. Methods: Analyses were conducted on formalin-fixed paraffin-embedded tissues of the primary tumors of relapsed (cases) and not relapsed (controls) HER2+ BC patients treated with adjuvant trastuzumab. The nCounter Human Breast Cancer Panel 360 was used. Logistic regression and partitioning around medoids were employed to identify the genes associated with disease recurrence. Cytotoxicity experiments using trastuzumab-resistant cell lines and a network pharmacology approach were carried out to investigate drug efficacy. Results: A total of 52 patients (26 relapsed and 26 not relapsed) were analyzed. We found that a higher expression of HDAC6 was significantly associated with an increased risk of recurrence, with an adjusted OR of 3.20 (95% CI 1.38–9.91, p = 0.016). Then, we investigated the cytotoxic activity of the selective HDAC6 inhibitor Nexturastat A (NextA) on HER2+ cell lines, which were both sensitive and trastuzumab-resistant. A sub-cytotoxic concentration of NextA, combined with trastuzumab, showed a synergistic effect on BC cell lines. Finally, using a network pharmacology approach, we identified HSP90AA1 as the putative molecular candidate responsible for the synergism observed in vitro. Conclusions: Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is often linked to changes in the regulation of genes, with DNA methylation playing a key role in controlling gene expression and maintaining stability. Many cancers show widespread loss of DNA methylation, particularly in repetitive elements like LINE-1, which can serve as an indicator of overall genomic health. Cell-free DNA (cfDNA), which is present in bodily fluids, offers a non-invasive way to track these changes and could be useful in diagnosing and monitoring cancer. Recent studies suggest that analyzing the methylation of LINE-1 in cfDNA could help predict disease outcomes and evaluate treatments like immunotherapy. This review aims to explore the current research on using LINE-1 methylation in cfDNA as a potential biomarker for cancer detection and therapy monitoring, addressing the need for further investigation into this promising approach. Epigenetic dysregulation is a hallmark of many human malignancies, with DNA methylation being a primary mechanism influencing gene expression and maintaining genomic stability. Genome-wide hypomethylation, characteristic of many cancers, is partly attributed to the demethylation of repetitive elements, including LINE-1, a prevalent non-LTR retrotransposon. The methylation status of LINE-1 is closely associated with overall genomic methylation levels in tumors. cfDNA comprises extracellular DNA fragments found in bodily fluids such as plasma, serum, and urine, offering a dynamic snapshot of the genetic and epigenetic landscape of tumors. This real-time sampling provides a minimally invasive avenue for cancer diagnostics, prognostics, and monitoring. The methylation status of LINE-1 in cfDNA has emerged as a promising biomarker, with several studies highlighting its potential in diagnosing and predicting outcomes in cancer patients. Recent research also suggests that cfDNA-based LINE-1 methylation analysis could serve as a valuable tool in evaluating the efficacy of cancer therapies, including immunotherapy. The growing clinical significance of cfDNA calls for a closer examination of its components, particularly repetitive elements like LINE-1. Despite their importance, the role of LINE-1 elements in cfDNA has not been thoroughly gauged. We aim to address this gap by reviewing the current literature on LINE-1 cfDNA assays, focusing on their potential applications in diagnostics and disease monitoring. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) is a deadly form of cancer, affecting areas like the mouth, throat, and larynx. This review explores the complex molecular pathways involved in HNSCC development and progression, focusing on the role of microRNAs (miRNAs)—small molecules that regulate gene expression. We aim to provide a comprehensive overview of how miRNAs influence HNSCC, their potential as diagnostic and prognostic markers, and their use in developing new targeted therapies. We also discuss promising nanotechnology-based approaches for delivering miRNA therapies more effectively. By synthesizing the current knowledge on miRNAs in HNSCC, this research may help identify new biomarkers for early detection and prognosis, as well as novel therapeutic targets. Ultimately, these insights could lead to improved personalized treatments and better outcomes for HNSCC patients. This paper presents a comprehensive comparative analysis of biomarkers for head and neck cancer (HNC), a prevalent but molecularly diverse malignancy. We detail the roles of key proteins and genes in tumourigenesis and progression, emphasizing their diagnostic, prognostic, and therapeutic relevance. Our bioinformatic validation reveals crucial genes such as AURKA, HMGA2, MMP1, PLAU, and SERPINE1, along with microRNAs (miRNA), linked to HNC progression. OncomiRs, including hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-196a-5p, and hsa-miR-200c-3p, drive tumourigenesis, while tumour-suppressive miRNAs like hsa-miR-375 and hsa-miR-145-5p inhibit it. Notably, hsa-miR-155-3p correlates with survival outcomes in addition to the genes RAI14, S1PR5, OSBPL10, and METTL6, highlighting its prognostic potential. Future directions should focus on leveraging precision medicine, novel therapeutics, and AI integration to advance personalized treatment strategies to optimize patient outcomes in HNC care. [ABSTRACT FROM AUTHOR]

Simple Summary: Conjunctival melanoma (CM) is an aggressive cancer with an unmet need for prognostic biomarkers and more effective treatments. In recent years, a rapid increase in available epigenetic technologies and epigenetic modulation-based treatment options has led to the development/implementation of various epi-drugs in the cancer field. Like other cancers, CM occurrence and prognosis are also believed to be influenced by multiple genetic and epigenetic factors. While the genetic understanding of CM has been significantly improved in recent decades, the epigenetic understanding of CM remains limited. A relatively small number of CM epigenetics studies published to date have revealed some potential biomarkers and/or therapeutic targets; however, their results warrant replication in independent and larger studies/samples. Furthermore, not all epigenetic aspects of CM have been investigated in published studies; hence, an in-depth understanding of CM epigenetics remains largely incomplete. Additional studies are therefore urgently needed to advance our epigenetic understanding of CM and improve clinical outcomes by taking advantage of new therapy options driven by epigenetic knowledge. The purpose of this article is to provide a literature review of the epigenetic understanding of conjunctival melanoma (CM), with a primary focus on current gaps in knowledge and future directions in research. CM is a rare aggressive cancer that predominantly affects older adults. Local recurrences and distant metastases commonly occur in CM patients; however, their prediction and management remain challenging. Hence, there is currently an unmet need for useful biomarkers and more effective treatments to improve the clinical outcomes of these patients. Like other cancers, CM occurrence and prognosis are believed to be influenced by multiple genetic and epigenetic factors that contribute to tumor development/progression/recurrence/spread, immune evasion, and primary/acquired resistance to therapies. Epigenetic alterations may involve changes in chromatin conformation/accessibility, post-translational histone modifications or the use of histone variants, changes in DNA methylation, alterations in levels/functions of short (small) or long non-coding RNAs (ncRNAs), or RNA modifications. While recent years have witnessed a rapid increase in available epigenetic technologies and epigenetic modulation-based treatment options, which has enabled the development/implementation of various epi-drugs in the cancer field, the epigenetic understanding of CM remains limited due to a relatively small number of epigenetic studies published to date. These studies primarily investigated DNA methylation, ncRNA (e.g., miRNA or circRNA) expression, or RNA methylation. While these initial epigenetic investigations have revealed some potential biomarkers and/or therapeutic targets, they had various limitations, and their findings warrant replication in independent and larger studies/samples. In summary, an in-depth understanding of CM epigenetics remains largely incomplete but essential for advancing our molecular knowledge and improving clinical management/outcomes of this aggressive disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular testing is becoming the standard of care across multiple tumor types in oncology. In non-small cell lung cancer (NSCLC), the uptake of molecular testing with next-generation sequencing (NGS) has been earlier than in other fields due to the clinical relevance of the molecular results. There are multiple approaches to NGS, ranging from sending testing internally, often reflexively, to referring externally to limited or comprehensive panels. This study aims to identify the differences in time to results, time to treatment, molecular alterations, and clinical outcomes for different molecular workflows in NSCLC. The results may impact the workflows for testing in a variety of cancers. Purpose: Broad-based molecular testing with next-generation sequencing (NGS) is now the standard of care in advanced non-small cell lung cancer (NSCLC). Two approaches to molecular testing are (1) reflexive testing at pathologic NSCLC confirmation, often using an in-house molecular panel, and (2) send-out testing to private vendors, ordered by a clinician. This study explored the outcomes with reflex versus send-out testing. Methods: A retrospective chart review was conducted of patients diagnosed with de novo stage IV NSCLC in 2019 and 2020 at three hospitals in the same system, one academic hospital (Northwestern Memorial Hospital, or NMH) utilizing reflex, in-house NGS, and two community-based hospitals (Central DuPage Hospital, or CDH, and Delnor, or D) sending out tissue samples for testing. The outcomes assessed were the time from biopsy to results, biopsy to treatment, the incidence of first-line targetable mutations and the use of first-line targeted therapies, and overall survival. Results: In total, 191 patients met the inclusion criteria, 85 at NMH, 106 at CDH + D, and in total, 131 in 2019 and 60 in 2020. The time to results was significantly shorter with reflexive NGS when compared with send-out testing; the time to treatment was also shorter but not statistically significant. At CDH + D, the time to results was significantly shorter with a limited panel than with comprehensive testing, but the time to treatment was similar. NGS testing rates were 95% at NMH and 84.5% at CDH + D (p = 0.009), with 31.0% at NMH receiving 1L targeted therapies versus 20.8% at CDH + D (p = 0.08). In 2019, the median time from biopsy to treatment was 35 days at NMH and 38 days at CDH and Delnor; in 2020, time to treatment was 26 days and 37 days, respectively. Overall survival trended longer in 2020 relative to 2019 independent of site. Conclusion: Reflexive NGS testing is associated with a shorter time to actionable results and higher rates of first-line targetable mutations than send-out testing. In practices with send-out testing, limited panels had slightly faster turnaround times but no difference in time to treatment. If resources allow, reflexive NGS should be considered in healthcare systems for patients with NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the fecal and tumor microbiome as potential biomarkers of tumor response to neoadjuvant immunotherapy in combination with chemoradiation. We performed 16S rRNA amplicon sequencing on fecal and tumor samples, as well as fecal metabolomics, on biosamples collected from patients with resectable esophageal or gastroesophageal junction carcinoma before and during treatment. The fecal microbiome of patients whose tumors achieved a pathologic complete response revealed enrichment in sphingolipid and primary bile acids, with corresponding elevated abundance of several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. While these results provide initial insight, further study is necessary to validate these data and determine how microbes alter the immune response with neoadjuvant immunotherapy. Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II–III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray–Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers to diagnose and treat. Despite over 4,300 clinical trials for pancreatic cancer exploring various treatments, progress in developing effective options for PDAC remains slow. This review seeks to offer a detailed and insightful analysis of the current landscape of PDAC-related clinical trials, with the primary goal of identifying ways to expedite drug development and enhance patient outcomes in the battle against this aggressive disease. Despite many decades of research, pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to diagnose and treat effectively. Although there have been improvements in the 5-year overall survival rate, it is still very low at 12.5%. The limited efficacy of current therapies, even when PDAC is detected early, underscores the aggressive nature of the disease and the urgent need for more effective treatments. Clinical management of PDAC still relies heavily on a limited repertoire of therapeutic interventions, highlighting a significant gap between research efforts and available treatments. Over 4300 clinical trials have been or are currently investigating different treatment modalities and diagnostic strategies for PDAC, including targeted therapies, immunotherapies, and precision medicine approaches. These trials aim to develop more effective treatments and improve early detection methods through advanced imaging techniques and blood-based biomarkers. This review seeks to categorize and analyze PDAC-related clinical trials across various dimensions to understand why so few chemotherapeutic options are available to patients despite the numerous trials being conducted. This review aims to provide a comprehensive and nuanced understanding of the landscape of PDAC-related clinical trials, with the overarching goal of identifying opportunities to accelerate progress in drug development and improve patient outcomes in the fight against this devastating disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to a shortage of reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) following treatment with atezolizumab plus bevacizumab (Ate/Bev), we assessed the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. We prospectively enrolled 32 patients, analyzing changes in IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels from blood samples collected before the first and second Ate/Bev treatments. Patients with increased IL-10, IL-17, and TNF-α levels demonstrated significantly better survival and marginally improved progression-free survival compared to those with decreased cytokine levels. Additionally, a positive correlation was found between changes in IL-10 and TNF-α levels. Multivariable analysis confirmed that increases in these cytokines are significant predictors of improved survival (p = 0.005). Early increases in IL-10 and TNF-α levels post-Ate/Bev treatment may thus serve as effective biomarkers for clinical outcomes in advanced HCC patients. Background/Objectives: Reliable biomarkers for predicting outcomes in hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev) are still lacking. Cytokines, which play a crucial role in immune regulation and HCC progression, have potential as predictive markers, but data supporting their use are limited. This study aimed to evaluate the impact of early changes in cytokine levels on the clinical outcomes of advanced HCC patients. Methods: We prospectively enrolled 32 advanced HCC patients, collecting blood samples before the first and second Ate/Bev treatments. These samples were analyzed for IL-2, IL-6, IL-10, IL-12, IL-17, IFN-γ, and TNF-α levels to assess changes post-treatment. The primary outcome was overall survival, with a secondary focus on progression-free survival (PFS) at 6 months. Results: The mean age of the participants was 64.2 years, with the majority being male (93.8%). Patients showing increased IL-10, IL-17, and TNF-α levels had significantly better survival (p < 0.05) and marginally improved PFS compared to those with decreased cytokine levels. Interestingly, a positive correlation was noted between changes in IL-10 and TNF-α levels (p = 0.009). Furthermore, a multivariable analysis revealed that increased levels of IL-10 and TNF-α were significant predictors of enhanced survival (hazard ratio, 0.07; 95% confidence interval, 0.01–0.46; p = 0.005). Conclusions: An early increases in IL-10 and TNF-α after Ate/Bev treatment may serve as effective biomarkers for clinical outcomes in advanced HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In tumorigenesis, aberrant DNA methylation may be an earlier and stronger modifier of gene expression than mutations. Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Global, genome-wide hypomethylation positively correlated with the increasing aggressiveness of tumors, being the strongest in hgOvCa. Remarkably, the ten most significant differentially methylated regions (DMRs) in the genome, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs potentially useful as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. By identifying potential biomarkers, this study might improve ovarian tumor outcome. Background: Changes in DNA methylation patterns are a pivotal mechanism of carcinogenesis. In some tumors, aberrant methylation precedes genetic changes, while gene expression may be more frequently modified due to methylation alterations than by mutations. Methods: Herein, 128 serous ovarian tumors were analyzed, including borderline ovarian tumors (BOTS) with (BOT.V600E) and without (BOT) the BRAF V600E mutation, low-grade (lg), and high-grade (hg) ovarian cancers (OvCa). The methylome of the samples was profiled with Infinium MethylationEPIC microarrays. Results: The biggest number of differentially methylated (DM) CpGs and regions (DMRs) was found between lgOvCa and hgOvCa. By contrast, the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups and, in relation to BOT, their genome was strongly downmethylated. Remarkably, the ten most significant DMRs, discriminating BOT from lgOvCa, encompassed the MHC region on chromosome 6. We also identified hundreds of DMRs, being of potential use as predictive biomarkers in BOTS and hgOvCa. DMRs with the best discriminative capabilities overlapped the following genes: BAIAP3, IL34, WNT10A, NEU1, SLC44A4, and HMOX1, TCN2, PES1, RP1-56J10.8, ABR, NCAM1, RP11-629G13.1, AC006372.4, NPTXR in BOTS and hgOvCa, respectively. Conclusions: The global genome-wide hypomethylation positively correlates with the increasing aggressiveness of ovarian tumors. We also assume that the immune system may play a pivotal role in the transition from BOTS to lgOvCa. Given that the BOT.V600E tumors had the lowest number of DM CpGs and DMRs compared to all other groups, when methylome is considered, such tumors might be placed in-between BOT and OvCa. [ABSTRACT FROM AUTHOR]