Everolimus 10 mg daily is approved to treat patients with advanced grade 1/2 neuroendocrine tumors (NET), although it may lead to significant toxicity. Grade 3 or higher drug-related adverse events and drug discontinuation occur in approximately one-fourth of the cases. However, phase I trials demonstrated that doses from 5 mg daily efficiently inhibit NET cell signaling. This multicenter retrospective study compared the time to treatment failure (TTF) in patients with NET who received a mean daily dose of 7 – 10mg (higher dose [HD]) or ≤ 6 mg (lower dose [LD]) of everolimus. Ninety-two patients were included: 74 (80%) in the HD group and 18 (20%) in the LD group. At a median follow-up of 4.2 years, the median time to treatment failure (TTF) was 9.2 months for HD and 7.2 months for LD (p = 0.85). TTF did not significantly differ between LD and HD (HR: 1.24, 95% CI: 0.68 - 2.25; p = 0.47), even after adjusting for age at treatment initiation, NET grade, or treatment line. Everolimus doses from 5 to 6 mg/day seem to be equally effective as higher doses, but lower doses are potentially associated with less toxicity and costs. These findings support validation through a randomized clinical trial.

Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive type of cancer primarily reported in humans, with no documented cases in animals. In this study, we present the first case of DDLPS in a wild amphibian species, Maculopaa medogensis. The tumor was discovered during a routine examination and diagnosed through a combination of advanced diagnostic methods, including micro-CT imaging, gross anatomical inspection, histological analysis, and immunohistochemistry. The tumor exhibited both well-differentiated and dedifferentiated components, characteristic of DDLPS, with evidence of tissue invasion and multiple metastases. Immunohistochemical analysis revealed strong positive expression of markers such as S100A4, CDK4, MDM2, and CD34, while Leptin expression was negative, further confirming the diagnosis. This is the first reported case of DDLPS in a non-human species, expanding our understanding of cancer in wildlife and underscoring the significance of amphibians as environmental indicators. These findings provide valuable insights for veterinary medicine and wildlife conservation, particularly regarding the role of environmental stressors in cancer development. This study highlights the need for comprehensive diagnostic approaches in wildlife pathology.

The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities in the apoptotic-regulated signaling pathways involved in apoptosis between the corpus luteum and tumors. However, the regulation of apoptosis can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis for studying novel research methods.

Breast cancer (BC) is one of the most common types of cancer in women. Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), exhibits a highly aggressive phenotype with increased metastasis and resistance to conventional treatments. Nanocarrier technology is consistently employed to overcome limitations associated with traditional breast cancer therapy. The targeted drug delivery approach using nanocarriers enhances bioavailability, prolongs circulation, and facilitates effective drug accumulation at the tumor site through active or passive targeting. Currently, the FDA has approved a few nanocarrier systems, and numerous nano formulations are undergoing preclinical and clinical development for breast cancer targeting. Common nanocarrier types include polymeric micelles, microemulsions, magnetic microemulsions, liposomes, dendrimers, carbon nanotubes, and magnetic nanoparticles (NPs). This review extensively explores the targeting potential of nanocarriers in breast cancer. This study will provide a concise summary of current advances in treatment of breast cancer and diagnostics.

There is no routine approach to identify patients with gynecologic malignancies at high risk for chemotherapy-resistance. Circulating tumor DNA (ctDNA) tumor fraction (TFx) represents a minimally-invasive approach to tumor profiling, with as yet limited data on utility in gynecologic malignancies. The objective was to investigate the use of ctDNA TFx in a cohort of patients with ovarian and endometrial cancer. Plasma samples from patients with biopsy-proven ovarian or endometrial cancer collected between 4/2018 and 4/2020 were subjected to shallow whole genome sequencing with determination of TFx via ichorCNA package. The association of TFx to continuous and categorical baseline clinicopathologic factors and progression-free survival was assessed. 210 plasma samples from 78 patients with gynecologic cancers were analyzed. Mean TFx for ovarian cancer was 5.5% and endometrial cancer 2.4% and there was no significant difference in TFx among histology either for endometrial or ovarian cancers. Grade was associated with significant difference in ‘sentinel’ TFx among ovarian cancers but not endometrial cancers. ctDNA TFx dynamics over time demonstrated rapid clearance of ctDNA in most patients with ovarian cancer, while endometrial cancer had consistently low TFx. ctDNA TFx is feasible in ovarian and endometrial cancers and may be a valuable important tool for prognostication.

Pediatric brain tumors are the leading cause of cancer-related death in children. Diagnosis cur-rently relies on surgical biopsy to obtain tumor tissue for histological analysis. There is a great need for less invasive approaches to molecularly profile tumors and monitor therapeutic response. Liquid biopsy analysis of circulating tumor biomarkers in biofluids like cerebrospinal fluid (CSF) and blood offers a promising minimally invasive strategy. This review discusses recent advances in developing liquid biopsy assays using next-generation sequencing, digital PCR, and emerging techniques to detect circulating tumor DNA (ctDNA), cells (CTCs), and exosomes in pediatric brain tumors. The ability to use these circulating biomarkers for non-invasive diagnosis, thera-peutic targeting, tracking response to therapy, and understanding resistance mechanisms is ex-amined. Technical and clinical validation challenges to translate liquid biopsies into routine clin-ical practice are also discussed.

The Wnt pathway plays an essential role in the initiation and progression of various types of cancer. ROR1 and ROR2 are Wnt receptors that are critical for β-catenin-independent (non-canonical) pathways and have been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, and therapy resistance. Both receptors have garnered interest as potential therapeutic targets since they are largely absent in adult tissue, are overexpressed in several cancers, and, as members of the receptor tyrosine kinase family, are easier to target than all other components of the pathway. Unlike ROR1 which always promotes tumorigenesis, ROR2 has a very complex role in cancer acting either to promote or inhibit tumor progression in different tumor types. In the present article, we summarize the findings on ROR2 expression in cancer patients and its impact on clinical outcome. Further, we review the biological processes and signaling pathways regulated by ROR2 that explain its dual role in cancer. Finally, we describe the ongoing strategies to target ROR2 in cancer.

Background: Esophageal cancer was hardly diagnosed in early stage, and more potential biomarkers should be found. Methods: 252 patients and normal controls which recruited in Renmin Hospital of Wuhan University, were divided into esophageal carcinoma group (105 cases), disease control group (75 cases) and the control group of healthy people (72 cases). Moreover, TISIDB and GEPIA databases were used to investigate the different expression of EC and normal tissues, and explore the roles of C1q in tumor-immune system interactions in EC. Results: The concentration of serum C1q in EC group is 196.8(180~219.4) mg/L, which is higher than the level of DC [178.10(153.70~200.85) mg/L]and HC [183.00(167.75~201.00) mg/L] (P<0.05). A higher expression level of C1q was observed in Ⅲ and Ⅳ grades [214(192~237.3) mg/ml] than grades Ⅰ and Ⅱ [180.95(172.03~193.85) mg/L] (P<0.05). C1q was positively correlated with eosinophils, active CD8 T cells, myeloid derived suppressor cells, natural killer cells, monocytes and macrophages (r = 0.373; r = 0.659; r = 0.846; r = 0.760; r = 0.499; r = 0.757; P<0.05). Conclusion: The concentrations of C1q increased in EC and related to the severity of EC, which had potential value of diagnosis of EC. There were correlations in C1q and tumor-infiltrating lymphocytes.

There is compelling evidence that the nuclear receptor TRβ, a member of the thyroid hormone receptor (TR) family, is a tumor suppressor in thyroid, breast and other solid tumors. Cell-based and animal studies reveal that the liganded TRβ induces apoptosis, reduces an aggressive phenotype, decreases stem cell populations, and slows tumor growth through modulation of a complex interplay of transcriptional networks. TRβ-driven tumor suppressive transcriptomic signatures include repression of known drivers of proliferation such as PI3K/Akt pathway and activation of novel signaling (JAK1/STAT1) and metabolic reprogramming in both thyroid and breast cancers. The presence of TRβ is also correlated with a positive prognosis and response to therapeutics in BRCA+ and triple-negative breast cancers respectively. Ligand activation of TRβ enhances sensitivity to chemotherapeutics. TRβ co-regulators and bromodomain-containing chromatin remodeling proteins are emergent therapeutic targets. This review considers TRβ as a potential biomolecular diagnostic and therapeutic target.

Gastrointestinal stromal tumors are the mostly seen mesenchymal tumors of the gastrointestinal system and mostly seen at the stomach. We report a case of giant gastrointestinal stromal tumor of the stomach in a 71-year-old woman. The physical examination and radiological findings revealed that a giant mass occupied most of the abdominal cavity. The patient underwent an en-block resection of this giant mass with partial resection of the distal stomach and transverse colon and, reconstruction with gastro-jejunostomy and end-to end colo-colic anatomoses. The histopathologic diagnosis was revealed as gastrointestinal stromal tumor of the stomach. We suggest that complete surgical resection is the only effective radical treatment approach for giant gastrointestinal stromal tumors of the stomach.

Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

Effective biomarkers are essential to the early diagnosis of non-small cell lung cancer (NSCLC). Herein, a retrospective study of 49 newly diagnosed and recurrent NSCLC patients, 31 patients with benign pulmonary disease and 24 healthy volunteers was conducted, to evaluate the diagnostic value of circulating rare cells for NSCLC. The expression of circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in peripheral blood were measured by subtraction enrichment-immunostaining-fluorescence in situ hybridization (SE-iFISH). The level of CTCs (P＜0.001) and CTECs (P＜0.001) was significantly higher in NSCLC group than that in benign pulmonary disease group. The proportion of small CTCs (P＜0.001) and CTECs (P＜0.0001) significantly increased from benign lung disease individuals to NSCLC patients. The AUC of ROC curves of total CTCs and CTECs were 0.815 (95%CI: 0.722~0.907), 0.739 (95%CI: 0.618~0.860), respectively. The cut-off values for discriminating NSCLC with benign lung disease patients were total CTCs 11.5 units/6ml and total CTECs 10.5 units/6ml, with sensitivity and specificity being 67.3% and 83.9%, 77.6% and 77.4%, respectively. When CTCs and CTECs were combined, predictive value significantly increased to 82.6% as measured by the area under the curve. Small CTCs and triploid CTCs had high positive predictive value (PPV) and positive likelihood ratio (LR+) of the diagnosis of NSCLC in early stage. CTCs and CTECs can not only be used as new biomarkers for the diagnosis of NSCLC, but can also improve diagnostic performance of the early stage NSCLC. Moreover, the combined examination of CTCs and CTECs is be superior to the single.

Skeletal metastases of unknown primary (SMUP) represent a clinical challenge dealing with patients diagnosed with bone metastases. The management have improved significantly in the past years, however fraught with lack of evidences, approach to these patients held out hope for more systematic and tailored treatment—and some patients can achieve impressive gains. Nevertheless, in real-life practice the outlook at the beginning of the take in charge of SMUP is decidedly more somber. An incomplete translational relevance of pathological and clinical data on the mortality and morbidity rate has had unsatisfactory consequences for SMUP patients and their physicians. We examined several approaches to confront the available evidences and highlighted three key points that emerge. The characterization of the SMUP biologic profile is essential to drive clinical decisions, integrating genetic and molecular profile into a multi-step diagnostic work-up. Nonetheless, pragmatic investigation plan and therapy of SMUP cannot follow a single template; it must be adapted to different pathophysiological dynamics and coordinated with efforts of a systematic algorithm and high-quality data derived from statistically powered clinical trials within. This review argues that greater efforts are required to face the unmet need dealing with SMUP patients in oncology. Finally, we provide an original functional network analysis, identifying novel therapeutic targets.

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis thereby supports tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To ask the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic area with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

Deep learning (DL) algorithms used for DOTATATE PET lesion detection typically require large, well-annotated training datasets. These are difficult to obtain due to low incidence of gastroenteopancreatic neuroendocrine tumors (GEP-NETs), and the high cost of manual annotation. Furthermore, networks trained and tested with data acquired from site specific PET/CT instrumentation, acquisition and processing protocols have reduced performance when tested with offsite data. This lack of generalizability requires even larger, more diverse training datasets. The objective of this study is to investigate the feasibility of improving DL algorithm performance by better matching the background noise in training datasets to higher noise, out-of-domain testing datasets. 68Ga-DOTATATE PET/CT datasets were obtained from two scanners: Scanner1, a state-of-the-art digital PET/CT (GE DMI PET/CT; n=83 subjects), and Scanner2, an older-generation analog PET/CT (GE STE; n=123 subjects). Set1, the data set from Scanner1 was reconstructed with standard clinical parameters (5 minutes; Q.Clear) and list-mode reconstructions (VPFXS 2, 3, 4, and 5-minutes). Set2, data from Scanner2, representing out-of-domain clinical scans, used standard iterative reconstruction (5 minutes; OSEM). Reconstructed datasets were divided into training, validation, and testing datasets in a 60%, 20%, 20% proportion, and a deep neural network was trained with each: Network1 for Scanner1 and Network2 for Scanner2. DL performance (Network1) was tested with out-of-domain test data (Set2). To evaluate the effect of training sample size, we tested DL model performance using a fraction (25%, 50%, and 75%) of Set1 for training. Scanner1, list-mode 2-minute reconstructed data demonstrated the most similar noise level compared that of Set2, resulting in the best performance (F1=0.713). This was not significantly different compared to the highest performance, upper-bound limit using in-domain training for Network2 (F1=0.755; p-value=0.103). Regarding sample size, the F1 score significantly increased from 25% training data (F1=0.478) to 100% training data (F1=0.713; p&lt;0.001). List-mode data from modern PET scanners can be reconstructed to better match the noise properties of older scanners. Using existing data and their associated annotations dramatically reduces the cost and effort in generating these datasets, and significantly improves the performance of existing DL algorithms. List-mode reconstructions can provide an efficient, low-cost method to improve DL algorithm generalizability.

Major depressive disorder (MDD) and substance use disorder (SUD) are of immense medical and social concerns. Although significant progress on neuronal involvement in mood and reward circuitries has been achieved, only relatively recently the role of glia in these disorders have attracted attention. Detail understanding of the glial function in these devastating diseases could offer novel interventions. Here, following a brief review of circuitries involved in mood regulation and reward perception, specific contribution of the neurotrophic factors, neuroinflammation and gut microbiota to these diseases are highlighted. In this context, the role of specific glial cells (e.g., microglia, astroglia, oligodendrocytes and synantocytes) on phenotypic manifestation of MDD or SUD are emphasized. In addition, potential use of this knowledge in developing novel therapeutics is touched upon.

Carcinoid syndrome (CS) is a rare condition associated with neuroendocrine tumors (NETs), particularly those originating in the gastrointestinal tract, which secrete bioactive substances like serotonin. The management of CS requires a multidisciplinary approach due to its complex clinical manifestations, including flushing, diarrhea, bronchospasm, and carcinoid heart disease. Optimal care involves collaboration between several professional figures like oncologists, endocrinolo-gists, gastroenterologists, surgeons, and dietitians. Currently, a wide range of treatments are available focused on both symptom control and tumor burden reduction. Somatostatin analogs (SSAs) are the first-line therapy for symptom relief. Still, in patients with progressive disease or refractory CS, other options include targeted therapies, peptide receptor radionuclide therapy (PRRT), liver-directed therapies, and surgical resection when feasible. Furthermore, management of complications related to prolonged serotonin release and malnutrition as a result of exocrine pancreatic insufficiency, post-surgical conditions, vitamin deficit, and chronic diarrhea often re-quires early detection to mitigate symptoms and improve the quality of life in these patients. The complexity of CS necessitates individualized care and continuous coordination among specialists to optimize outcomes and enhance patient well-being.

Neurofibroma is a type of benign tumor that affects the peripheral nerves. It can be classified into three subtypes: localized, diffuse, and plexiform, with localized being the most prevalent. Although uncommon, neurofibromas can appear as diffuse tumors that impact the skin and underlying tissues of the head, neck, and body in young individuals and children. Diffuse neurofibromas are characterized by thickened, indurated, and ill-defined skin lesions that often invade underlying tissues. We present a unique case of a 45-year-old Caucasian woman who developed debilitating headaches caused by a gradually enlarging diffuse neurofibroma on her scalp and a comprehensive review of diffuse neurofibroma and its differential diagnosis. Although diffuse neurofibromas are less common in middle-aged individuals, they should still be considered a possible diagnosis in infiltrative and indurated skin lesions. Identifying its characteristic histopathological findings to diagnose diffuse neurofibroma accurately is crucial since its clinical presentations can vary.

CTC numbers in the blood of cancer patients can indicate the progression and invasiveness of tumors and their prognostic and predictive value has been repeatedly demonstrated. However, the standard baseline CTC count at the beginning of treatment, while informative, is not completely reliable and may not adequately reflect the state of the disease. The growing number of studies indicate that long-term monitoring of CTC numbers in the same patient provides more comprehensive prognostic data and should be incorporated into clinical practice, as a factor that contributes to therapeutic decisions. This Review describes the current status of CTC enumeration as a prognostic and predictive factor, highlights the shortcomings of current solutions and advocates for longitudinal CTC analysis as a more effective method of the evaluation of developing disease, treatment efficacy, and long term-monitoring of the minimal residual disease.

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and the most common form of head and neck cancer, posing significant challenges for disease management. Single-cell RNA sequencing (sc-RNAseq) has emerged as a valuable tool for addressing these challenges by enabling detailed characterization of the tumor microenvironment (TME) at the cellular level. This review assesses the utility of sc-RNAseq in HNSCC research, compiling current strategies employing single-cell technologies. For HNSCC etiology, sc-RNAseq allows for the construction of cellular atlases, characterization of different cell types, and investigation of key genes and processes involved in cancer initiation, development, and progression within the TME. In terms of HNSCC diagnosis and prognosis, the high resolution offered by sc-RNAseq enables the identification of cell type-specific signatures, enhancing prognostic models and disease stratifiers for more accurate patient outcome assessments. Regarding HNSCC treatment, sc-RNAseq provides insights into cellular responses to various treatments, including radiotherapy, chemotherapy, and immunotherapy, contributing to improved patient stratification and personalized treatment strategies. This review highlights the unique contributions of sc-RNAseq to HNSCC research, addressing its cellular and biological complexity, and emphasizes its potential for advancing research and clinical practice in other cancer types.

The use of chimeric antigen receptor (CAR) in natural killer (NK) cells for cancer therapy is gaining momentum, marking a significant shift in cancer treatment. This review aims to explore the potential of CAR-NK cell therapy in cancer immunotherapy, providing a fresh perspective. It discusses the innovative approaches in CAR-NK cell design and engineering, particularly targeting refractory or recurrent cancers. By comparing CAR-NK cells with traditional therapies, the review highlights their unique ability to tackle tumor heterogeneity and immune system suppression. Additionally, it explains how novel cytokines and receptors can enhance CAR-NK cell efficacy, specificity, and functionality. The review underscores the advantages of CAR-NK cells, including reduced toxicity, lower cost, and broader accessibility compared to CAR-T cells, along with their potential in treating both blood cancers and solid tumors.

GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Lactococcus lactis subsp. cremoris C60 is a probiotic strain of lactic acid bacteria (LAB) which induces various immune modifications in myeloid lineage cells. These modifications subsequently reg-ulate T cell function, resulting in enhanced immunity both locally and systemically. Here, we report that C60 suppresses tumor growth by enhancing macrophage function via metabolic al-terations, thereby increasing adenosine triphosphate (ATP) production in a murine melanoma model. Intragastric (i.g.) administration of C60 significantly reduced tumor volume compared to saline administration in mice. The anti-tumor function of intratumor (IT) macrophage was up-regulated in mice administered with C60, as evidenced by an increased inflammatory phenotype (M1) rather than an anti-inflammatory/reparative (M2) phenotype, along with enhanced anti-gen-presenting ability, resulting in increased tumor antigen-specific CD8+ T cells. Through this functional modification, we identified that C60 establishes a glycolysis-dominant metabolism, rather than fatty acid oxidation (FAO), in IT macrophages, leading to increased intracellular ATP levels. To address the question of why orally supplemented C60 exhibits functions in distal places, we found a possibility that bacterial cell wall components, which could be distributed throughout the body from the gut, may induce stimulatory signals in peripheral macrophages via Toll-like receptors (TLRs) signaling activation. Thus, C60 strengthens macrophage anti-tumor immunity by promoting a predominant metabolic shift towards glycolysis upon TLR-mediated stimulation, thereby increasing substantial energy production.

Abstract Epithelial ovarian carcinoma (EOC) is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. EOC is poorly responsive to immune check-point inhibitors due to immunologic features including limited tumor mutational burden (TMB), poor infiltration by immune cells and active immunosuppression. Thus, novel strategies are needed to overcome the frequent lack of preexisting immunity in patients with EOC. We developed and tested an autologous dendritic cell (DC)-based vaccine (DCVAC) which has recently been shown to be safe and to significantly improve progression-free survival (PFS) in two independent randomized phase II clinical trials enrolling patients with EOC (SOV01, NCT02107937; SOV02, NCT02107950). In addition, our exploratory data analyses suggest that the clinical benefits of DCVAC were more pronounced in patients with EOC with lower than-median TMB and scant CD8+ T cells infiltration. Thus, DC-based vaccine stands out as a promising clinical tool to jumpstart anticancer immunity in patients with immunologically „cold“ EOC. Our findings underscore the need for personalized immunotherapy and clinical relevance of potential tumor-related biomarkers within immunotherapy field. Additional clinical trials are needed to address these strategies as well as the potential value of TMB and immune infiltrate at baseline as biomarkers to guide the clinical management of EOC.

Glioblastoma (GB), even though not frequent, is an extremely aggressive brain tumor, with a strong impact on patient outcomes, in terms of both length and quality of life. The protocol estab-lished by Stupp and coworkers in 2005, based on radiotherapy and temozolomide chemotherapy, after maximum safe surgical resection, remains the gold standard for GB treatment. However, it is evident nowadays that the extreme GB intratumoral and intertumoral heterogeneity, invasive-ness and recurrence are not compatible with a routinary and unfortunately uneffective treatment. In this review article, we summarize the principal challenging issues in finding new valuable therapies for GB and focus on the impact that extracellular vesicle (EV) research and exploitation can have in the field. EVs are natural particles delimited by a lipidic bilayer and full of functional cellular content, released and uptaken by cells as key means of cell communications. Moreover, being stable in body fluids, well-immunotolerated, able to cross physiological, inter-species, and inter-kingdom barriers, and to target specific cells, releasing inherent or externally loaded functionally active molecules, EVs can be potentially ideal allies in fighting GB and assuring to GB patients a better prognosis. Here we report the main results obtained until now, focusing on both EV sources and molecular cargo used in the different functional studies, mainly in vivo. Finally, we perform a SWOT analysis reporting both the main advantages and the pitfalls of developing EV-based GB therapeutic strategies to highlight the main directions to explore for realizing the promise of EV exploitation for GB treatment.

CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin super family, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MCTs play an important role in glycolysis, the enzymatic conversion of glucose to pyruvate and adenosine triphosphate (ATP). Pyruvate is further converted to lactic acid which is exported from the cytoplasm by MTC-1 and MCT-4 to maintain intracellular pH and a stable metabolic state. Under physiological conditions, cellular energy production is induced by mitochondrial oxidative phosphorylation. Glycolysis usually occurs under anaerobic conditions, whereas cancer cells depend on glycolysis under aerobic conditions. T cells also require glycolysis for differentiation, proliferation, and activation. Human malignant melanoma cells expressed higher levels of MCT-1 and MCT-4, co-localized with CD147 on the plasma membrane and showed an increased glycolysis rate compared to normal human melanocytes. Silencing of CD147 by siRNA abrogated the membrane expression of MCT-1 and MCT-4 and disrupted glycolysis, inhibiting cancer cell activity. The differentiation of CD4+ T cells into Th17 cells is a pivotal process in the development of various immune disorders, including psoriasis. Studies using CD147-deficient mice demonstrated the involvement of CD147 in psoriasis. MCT-1 was absent on CD4+ T cells in CD147-deficient mice. Naïve CD4+ T-cells from CD147-deficient mice show low potential for differentiation into Th17 cells. Imiquimod-induced skin inflammation was significantly milder in CD147-deficient mice than in wild-type mice. These findings indicate that CD147/Basigin is involved in the development of malignant tumors and T cell mediated immunological disorders via regulation of glycolysis.

Mesenchymal stromal cells (MSCs) are a subset of heterogeneous non-hematopoietic fibro-blast-like cells which play important roles in tissue repair, inflammation, and immune modula-tion. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in the last years as key regulator of tumor microenvironment. Indeed, they are now con-sidered as active players in the pathophysiology of hematologic malignancies rather than passive by-standers in hematopoietic microenvironment. Once the malignant event occurs, the BMME acquires cellular, molecular, and epigenetic abnormalities affecting tumor growth and progres-sion. In this context, MSC behavior is affected by signals coming from cancer cells. Furthermore, it has been showed that stromal cells themselves play a major role in several hematological malig-nancies’ pathogenesis. This bidirectional crosstalk creates a functional tumor niche unit wherein tumor cells acquire a selective advantage over their normal counterpart and are protected from drug treatment. It is therefore of critical importance to unveil the underlying mechanisms which activate a protumor phenotype of MSCs for defining unmasked vulnerabilities of hematological cancer cells which could be pharmacologically exploited to disrupt the tumor/MSCs coupling. The present review will focus on the current knowledge about MSC dysfunction mechanisms in the BMME of hematological cancers, sustaining tumor growth, immune escape, and cancer pro-gression.

Prostate cancer is a highly heterogeneous disease, and mortality is mainly due to metastases, but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3,929 primary tumors and 2,721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and find that mutations in EYA1 and CSMD3 are associated with poor outcome in prostate cancer.

MicroRNA (miRNA) is small non-coding RNAs that play vital roles in post-transcriptional gene regulation by inhibiting mRNA translation or promoting mRNA degradation. Dysregulation of miRNA has been implicated in numerous human diseases, including cancers. The family members of miR-34 (miR-34s), composed of miR-34a, miR-34b, and miR-34c, have emerged as the most extensively studied tumor-suppressive miRNAs. In this comprehensive review, we aim to provide an overview of the major signaling pathways and gene networks regulated by the miR-34s in various cancers and highlight the critical tumor suppressor role of miR-34s. Furthermore, we will discuss the potential of using miR-34 mimics as a novel therapeutic approach against cancer, while also addressing the challenges associated with their development and delivery. It is anticipated that gaining a deeper understanding of the functions and mechanisms of miR-34s in cancer will greatly contribute to the development of effective miR-34-based cancer therapeutics.

Pancreatic cancer (PC) is the seventh leading cause of cancer-related death. PC incidence has con-tinued to increase by about 1% each year in both men and women. Although the 5‐year relative survival rate of PC has increased from 3% to 12%, it is still the lowest among cancers. Hence, novel therapeutic strategies are urgently needed. Challenges in PC-targeted therapeutic strate-gies stem from the high PC heterogeneity and from the poorly understood interplay between cancer cells and the surrounding microenvironment. Signaling pathways that drive PC cell growth have been the subject of intense scrutiny and interest has been attracted by necroptosis, a distinct type of programmed cell death. In this review, we provide a historical background on necroptosis and a detailed analysis of the ongoing debate on the role of necroptosis in PC malignant progression.

Neuroendocrine tumors (NETs) of duodenal origin are an unusual subset among all NETs, comprising only about 3% of this neoplasm class. In general, NETs are characterized by overexpression of somatostatin receptors and carry an excellent prognosis with early diagnosis and intervention. Chromogranin A (CgA), a protein originating in secretory vesicles of neurons and endocrine cells, has gained wide usage in NET diagnosis and surveillance. Lanreotide is a synthetic octapeptide somatostatin analog with potent anti-proliferative action which has been approved by the FDA (U.S.) and EMA (E.U.) for NET treatment. It is known for its inhibitory effects on growth hormone, serotonin, CgA, and other markers. Here we describe a 56yr-old female with functional NET of duodenal origin, where serum CgA was successfully reduced from 3636 to <100 ng/mL after multidose lanreotide within five months. Of note, no metastatic spread was identified on positron emission tomography/computed tomography with 64Cu-labeled somatostatin analog tracer. Surgical resection of distal antrum, pylorus, and proximal duodenum followed without complication. Histology revealed several foci of well-differentiated tumor cells with characteristic neuroendocrine features and clear surgical margins; low proliferation index (2%) was noted on Ki-67 staining. While select laboratory and imaging modalities are available for diagnosis and monitoring of duodenal NET, this is the first reported therapeutic use of lanreotide in this NET setting. The observed serum CgA attenuation, even before surgery, supports its effectiveness in management of primary nonmetastatic duodenal NET.

Cancer diseases lead to the second-highest death rate all over the world. The dynamics of invasion of cancer cells into the human body tissues and metastasis are the main causes of death in patients with cancer. This study deals with theoretical investigation of the dynamics of invasion of cancer cells for tumour growths in human body tissues using discretized Cahn-Hilliard, concentration and reaction-diffusion equations which were solved by Finite Difference Method with the aid of MATLAB computer software. A Crank-Nicolson numerical scheme was developed for the discretized model equations. The numerical result obtained was used to describe the dynamics of cancer invasion of tissues with respect to cancer cells density on tumour growth, turbulence and mobility and equilibrium between charge and discharge of cancer cells. The results of the study provide new insights into combating cancer disease by providing mitigating and intervention measures to this major health problem.

Chronic inflammation may have a detrimental impact on human health as it tends to result in cancer. In addition, it is often linked to different steps that participate in tumorigenesis, including cellular transformation, survival, promotion, invasion, proliferation, angiogenesis, and metastasis. Hence, inflammation predisposes cancer development and plays a vital role in promoting all tumorigenesis stages. Inflammation is caused by many factors, such as bacterial and viral infections, tobacco smoking, autoimmune diseases, obesity, asbestos exposure, and many others, increasing cancer risk. Moreover, cancer can be enhanced by mutations that proceed to cancer progression. Consequently, it leads to immunosuppression and provides a favorable background for tumor development. Although many studies address the question of relationships between inflammation and cancer development, little attention is paid to the link between inflammation and blood cancer. Therefore, the current study reviews the role of inflammation in cancer development, particularly in blood cancer. A meta-analysis research approach meets the research objective and answers the research question. The review results indicate that chronic inflammation directly relates to the development of many cancer types, blood cancer in particular.

(1) Background: The present study was carried out to provide new information about the relation between angiogenesis, tumor stage Oral squamous cell carcinoma (OSCC); (2) Materials and methods: Thirty formalin-fixed paraffin embedded blocks were used, 10 of them were previously diagnosed as well differentiated OSCC, 10 moderate differentiated OSCC and 10 poorly differentiated OSCC. To determine the expression of CD31 and D2-40 proteins, streptavidin-biotin immunoperoxidase staining technique was used. The areas with the most vascular density (hot spots) were determined. The stained vessels were counted independently in intratumoral and peritumoral stroma in five areas of hot spot at ×400 magnification; (3) Results: Immunohistochemical staining using CD 31 protein showed that CD31-positive vessels in the peritumoral and intratumoral stroma subjacent to the malignant invading nests which was recorded highest values in poor differentiated OSSC followed by moderate differentiated OSSC then well differentiated OSSC. D2-40 expression was positive in lymphatic vessel in the peritumoral and intratumoral stroma subjacent to the malignant invading nests. Poorly differentiated OSSC tissue sections recorded the highest vessels count followed by moderate differentiated OSSC then well differentiated OSSC. There was statistically significant difference found between the three studied groups regarding CD31 and D2-40 levels. Also there was statistically significant positive correlation found between CD31 level and D2-40 level and vice versa; (4) Conclusion: CD31 and D2-40 are related to stage of OSCC and are consistent with angiogenesis in tumor progression.

Neuroendocrine tumors develop from systemic endocrine and nerve cells, and their occurrence has increased recently. Since these tumors are heterogeneous, pathological classification has been based on the affected organ. In 2019, the World Health Organization introduced a change that is expected to influence neuroendocrine tumor research, as gastroenteropancreatic neuroendocrine tumors are now included within a unified classification. In this retrospective study, we aimed to investigate the characteristics (e.g., lymph node metastases, all other metastases) of gastroenteropancreatic neuroendocrine tumors using this new classification in 50 cases. Tumor size, depth, MIB-1 index, lymphatic invasion, venous invasion, and neuroendocrine tumor grade were significantly correlated with lymph node metastasis and all other metastases. Venous invasion was more strongly correlated with lymph node metastasis and all other types of metastasis than with lymphatic invasion. Identification rates for lymphatic invasion were considered lower because of structural problems such as lymphatic vessels being much thinner than veins. However, venous invasion was considered effective in compensating for the low rate of identification in cases of lymphatic invasion. In future research, a unified classification and standardized framework for assessment will be important when analyzing the characteristics of neuroendocrine tumors, and large-scale studies are required.

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development, and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in-depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

Although pancreatic neuroendocrine neoplasms (PNENs) are relatively rare tumors, their number is increasing with advances in diagnostic imaging modalities. Even small lesions that are difficult to detect using computed tomography or magnetic resonance imaging can be detected with endoscopic ultrasound (EUS). Contrast-enhanced EUS is useful, and not only diagnosis but also malignancy detection have become possible by evaluating the vascularity of tumors. Pathological diagnosis using EUS with fine-needle aspiration (EUS-FNA) is useful when diagnostic imaging is difficult. EUS-FNA can also evaluate the grade of malignancy. Pooling the data of the studies which compared the PNENs grading between EUS-FNA samples and surgical specimen, the concordance rate was 77.5% (κ-statistic: 0.65, 95% confidence interval = 0.59 - 0.71, P< 0.01). EUS is a particularly important modality for the treatment of PNENs.

Glioma tumors are one of the most devastating cancer types. Of the different glioma tumors, glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an effective cure. Recent advantages in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OV) in cancer treatment is one of those immune-therapeutic alternatives. OV have a double oncolytic action by both, directly destroying the cancer cells, sparing the patient’s life, and stimulating a tumor specific immune response to revert the ability of tumors to escape the control of the immune system. OV are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility to use some viruses to specifically infect tumors eluding undesired toxic effects in the patient. Here we have revisited the literature in order to describe the main OV proposed so far as therapeutic alternatives to destroy glioma cells in vitro and trigger tumor destruction in vivo. Some clinical trials are exploring the use of this therapy as an alternative were other approaches provide limited hope.

The use of circulating cell-free (cf) DNA to monitor cancer progression and response to therapy has significant potential but there is only limited data on whether this technique can detect the presence of low frequency subclones that may ultimately confer therapy resistance. In this study, we sought to evaluate whether whole-exome sequencing of cfDNA can accurately profile the mutation landscape of metastatic melanoma. We used whole-exome sequencing (WES) to identify variants in matched tumor-derived genomic (g) DNA and plasma-derived cfDNA isolated from a cohort of 10 metastatic cutaneous melanoma patients. WES parameters such as sequencing coverage and total sequencing reads were comparable between gDNA and cfDNA. There was significant concordance between gDNA and cfDNA based on the total number of variants identified and the degree of overlap in variants which was independent of the site of tumor biopsy. The mutant allele frequency of common single nucleotide variants was lower in cfDNA reflecting lower read depth and dilution of circulating tumor DNA in the circulation by other cfDNA species. In addition to known melanoma driver mutations, several other melanoma-associated mutations were found to be concordant between matched gDNA and cfDNA. This study highlights that WES of cfDNA can capture clinically-relevant mutations present in melanoma metastases, but does not appear to provide any additional unique information on tumor heterogeneity. Targeted deep sequencing may be required to detect low frequency genomic aberrations known for predicting therapy resistance.

Endothelial cells form a powerful interface between tissues and immune cells. In fact, one of the underappreciated roles of endothelial cells is to orchestrate immune attention to specific sites. Tumor endothelial cells have a unique ability to dampen the immune responses and thereby maintain an immunosuppressive microenvironment. Recent approaches to trigger immune responses in cancers have focused on activating nucleic acid sensors such as cGAS/STING in combination with immunotherapies. In this review, we present a case for targeting nucleic acid sensing pathways within the tumor vasculature to invigorate tumor immune responses. We introduce two specific nucleic acid sensors, the DNA sensor TREX1 and the RNA sensor RIG-I and discuss their functional roles in the vasculature. Finally, we present perspectives on how these nucleic acid sensors in the tumor endothelium can be targeted in an antiangiogenic and immune activation context. We believe understanding the role of nucleic acid sensing in the tumor vasculature can enhance our ability to design more effective therapies targeting the tumor microenvironment.

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

Caribbean sponges of the genus Smenospongia are a prolific source of chlorinated secondary metabolites. The use of molecular networking as a powerful dereplication tool revealed the presence in the metabolome of S. aurea of two new members of the smenamide family, namely smenamide F (1) and G (2). The structure of smenamide F (1) and G (2) was determined by spectroscopic analysis (NMR, MS, ECD). The relative and the absolute configuration at C-13, C-15, and C-16 was determined on the basis of the conformational rigidity of a 1,3-disubstituted alkyl chain system (i.e. the C-12/C-18 segment of compound 1). Smenamide F (1) and G (2) were shown to exert a selective moderate antiproliferative activity against cancer cell lines MCF-7 and MDA-MB-231, while being inactive against MG-63.

Macrophages and dendritic cells (DCs) acquire functionally distinct properties in response to various environmental stimuli; the interaction of these cells with myeloid-derived suppressor cells (MDSCs) in tumor microenvironments regulates cancer progression. Immunodeficient mice lacking T cells are less likely to reject human cancer cells because of major histocompatibility complex (MHC) mismatches. The xenograft tumor microenvironment, comprising human cancer and mouse host cells, exhibits more complex bidirectional signaling and function than a syngeneic tumor microenvironment. Here human and mouse colorectal cancer cells were transplanted into nude mice to elucidate differences in macrophage, DC, and MDSC functions in human xenograft and mouse allograft tumor models. Plasma interferon-γ and interleukin-18 concentrations in the former model after intraperitoneal lipopolysaccharide (LPS) administration were significantly higher than those in the latter model and non-transplanted control group. Splenic MHC class I, II, and CD80 expression increased in CD11b+ and MDSC populations after LPS administration in only the xenograft tumor model. The number of CD80- and MRC1-expressing cells decreased upon LPS administration in only the xenograft tumor. These results suggxest that macrophages and DCs function normally in xenograft tumor models, whereas their functions in response to LPS administration vary in allograft tumor models.

It has been proposed that tumourigenicity was an intrinsic feature of embryonic/germ cell developmental axis as well as embryonic/germ cell-related genes play a crucial role in tumourigenicity. Our previous studies indicated that primordial germ cell (PGC)-like potential could be reactivated in tumourigenesis. In this study, 4T1, 168FARN and 67NR cells which originated from the same mouse breast cancer were studied and the results indicated that the acquisition of embryonic/germ cell-like state is essential for tumourigenicity. We further demonstrated that somatic to PGC-like transformation (SPLT) was activated in 4T1 cells and that inhibition of PGC-like cell formation by depleting pluripotency and/or PGC specification-related genes markedly repressed SPLT and the tumourigenicity. Collectively, our findings reveal that tumourigenicity is linked to the acquisition of PGC-like state through SPLT in 4T1 cells, provide new insight into deeper understanding the biological nature of tumours and novel therapeutical strategies for cancer targeting.

The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/ or marks ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors.

This review systematically examines the multifaceted relationship between the tumor microenvironment, stromal interactions, and colorectal cancer (CRC) progression and metastasis. The analysis begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. In summary, this review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.

Neutrophils are the most abundant immune cells and make up about 70% of white blood cells in human blood and play a critical role as the first line of defense in the innate immune response. They also help regulate the inflammatory environment to promote tissue repair. However, in cancer, neutrophils can be manipulated by tumors to either promote or hinder tumor growth depending on the cytokine pool. Studies have shown that tumor-bearing mice have increased levels of neutrophils in peripheral circulation, and that neutrophil-derived exosomes can deliver various cargos, including lncRNA and miRNA, which contribute to tumor growth and degradation of extracellular matrix. Exosomes derived from immune cells generally possess anti-tumor activities and induce tumor-cell apoptosis by delivering cytotoxic proteins, ROS generation, H2O2 or activation of Fas-mediated apoptosis in target cells. Engineered exosome-like nanovesicles have been developed to deliver chemotherapeutic drugs precisely to tumor cells. However, tumor-derived exosomes can aggravate cancer-associated thrombosis through the formation of neutrophil extracellular traps. Despite the advancements in neutrophil-related research, a detailed understanding of tumor-neutrophil crosstalk is still lacking and remains a major barrier in developing neutrophil-based or targeted therapy. This review will focus on the communication pathways between tumors and neutrophils, and the role of neutrophil-derived exosomes (NDEs) in tumor growth. Additionally, potential strategies to manipulate NDEs for therapeutic purposes will be discussed.

Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. This paper provides deep insight into immune related adverse events (irAEs) posing a major challenge and drawback to ICIT, and presents right management strategies for very complex complications. Moreover, for the first time in literature, a non-linear mathematical model is introduced to measure the ICIT success rate and to decide about the optimum ICIT duration. Furthermore, a strategy is presented to overcome or to delay the progression after initial good response in a subset of patients.

Astrocytes are essential for normal brain development and functioning. They respond to brain injury and disease through a process referred to as reactive astrogliosis, where the reactivity is highly heterogenous and context dependent. Reactive astrocytes are active contributors to brain pathology and can exert beneficial, detrimental, or mixed effects following brain insults. Transforming growth factor-β (TGF-β) has been identified as one of the key factors regulating astrocyte reactivity. Genetic and pharmacological manipulation of TGF-β signaling pathway in animal models of CNS injury and disease alters pathological and functional outcomes. This review aims to provide recent understanding regarding astrocyte reactivity and TGF-β signaling in brain injury, aging, and neurodegeneration. Further, it explores how TGF-β signaling modulates astrocyte reactivity and function.

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

This review article explores the significance and prospects of using diverse T-cell variants in the context of combined therapy for lung cancer treatment. Recently, there has been an increase in research focused on understanding the critical role of tumor-specific T-lymphocytes and the potential benefits of autologous T-cell-based treatments for individuals with lung cancer. One promising approach involves intravenous administration of ex vivo-activated autologous lymphocytes to improve the immune status of patients with cancer. Investigations are also exploring the factors that influence the success of T-cell therapy and the methods used to stimulate them. Achieving a comprehensive understanding of the characteristics of activated lymphocytes and deciphering the mechanisms underlying their activation of innate anti-tumor immunity will pave the way for numerous clinical trials and the development of innovative strategies for cancer therapy.

Papillary tumors of the pineal region (PTPR) are extremely rare malignancies usually treated with surgery and adjuvant tumor bed radiotherapy (RT). We present the case of a 69-year-old man diagnosed with PTPR after presenting with two weeks of confusion and ataxia. Imaging the head with computed tomography (CT) and magnetic resonance imaging (MRI) showed hydrocephalus and a 2 cm pineal region mass. We review the presenting symptoms, investigations, and differential diagnosis for patients with pineal region masses. The pathological features, including immunohistochemistry, are described with exemplative images. We report how the patient’s hydrocephalus was managed with medications and neurosurgical interventions, as well as the curative treatment of his tumor with surgery and postoperative tumor bed RT with 54 Gray (Gy) in 30 fractions. We also review the PTPR literature, including prognostic features and the evidence for treatment modalities. Few publications outline adjuvant radiotherapy planning treatment volumes, which are reported here. The patient was followed with a brain MRI every three months and is asymptomatic with no evidence of recurrent disease 18 months after surgery. PTPR has very high local recurrence rates following treatment and further research is needed to find more effective interventions and improve patient outcomes.

Cervical cancer (CC) remains a significant global health challenge, characterized by its genetic heterogeneity and complex molecular landscape. The current study investigates the germline variants in proto-oncogenes and tumor suppressor genes among patients diagnosed with cervical cancer. Utilizing a custom NGS panel targeting 48 genes implicated in oncogenesis, we identified 148 nucleotide sequence alterations across the cohort. Of these, 35 variants (23.6%) were classified as benign, while 105 (70.9%) were categorized as variants of uncertain significance (VUS), whose clinical relevance remains to be elucidated. Moreover, we discovered seven pathogenic or likely pathogenic mutations, as well as a polymorphic variant rs1042522 in the TP53 gene, which has been previously associated with an increased risk of CC. Our findings contribute to the understanding of the molecular-genetic landscape of cervical cancer, highlighting the potential impact of rare germline mutations on the disease's pathogenesis and progression. This study underscores the importance of comprehensive genetic screening in improving the diagnostic and therapeutic strategies for cervical cancer patients.

Human Papillomavirus (HPV) related cancers account for a large percentage of cancers. The tumor microenvironment (TME) is a complex structure and contributes significantly to tumor development, progression, and invasion. The TME is particularly pronounced in HPV-related cancers and HPV is known to influence the TME. In cancer research, there is an urgent need for new models to deepen our understanding of the pathophysiology of the disease and to facilitate the development of innovative therapies. In this context, 3D cell culture has emerged as a promising method in cancer research, that offers significant potential compared to conventional approaches. 3D modelling can produce results that are more consistent with clinical outcomes without the ethical concerns and problems of animal models. In this review, our aim is to discuss the tumor microenvironment in HPV-related cancers and demonstrate the importance of advancing 3D cell culture models for this purpose.

Aim: Ovarian cancer is the leading cause of gynecological cancer deaths worldwide. Treatment methods are listed as surgery, chemotherapy and radiotherapy depending on the stage of the cancer, but developing resistance to chemotherapy increases the need for alternative agents that act on the same pathways. In this study, the effects of rosmarinic acid (RA) and doxorubicin (DX) on the activation of FOXP3, an important tumor suppressor gene, in OVCAR3 cells were examined. Material Method: In the study, human ovarian adenocarcinoma cell line was used. MTT test was applied to determine the effect of rosmarinic acid and doxorubicin on the proliferation of OVCAR3 cells. Expression levels of FOXP3 for cell proliferation and Capase-3 for Apoptosis were determined by qRT-PCR and Western blot analysis. Wound healing model was applied to determine metastasis. The results were evaluated with one-way ANOVA in SPSS 20.0 program as p≤0.05. Results: It was determined that rosmarinic acid alone and in combination with doxorubicin inhibited the proliferation of OVCAR3 cells in a time- and dose-dependent manner for 24, 48 and 72 hours, and caused the cells to die by causing them to undergo apoptosis. It was observed that Caspase-3 expression increased approximately tenfold in OVCAR3 cells, while FOXP3 expression increased only in RA treatment and was downregulated in DX and RA+DX treatments. Coclusion According to the results of our study, it was observed that many steps of the signaling pathways related to proliferation, migration and apoptosis were affected by the combination of RA and DX in OVCAR3 cells. This shows that RA will gain an important place in cancer treatment with more comprehensive studies.

Inflammatory myofibroblastic tumor (IMT) is a rare soft tissue tumor of mesenchymal origin that most commonly presents in children. IMTs hold non-specific symptoms and radiological features, rendering diagnosis challenging. Presentation: We report a case of a 26-year-old man who was diagnosed at a different center with IMT of the right lower lobe. He underwent lobectomy with a positive gross margin, after which he was referred to our institution for further management, where we performed redo surgery with removal of residual tumor from the bronchial stump. The case presented here shows that interdisciplinary surgical planning is vital to ensure proper detection and successful tumor resection, while highlighting a unique case of recurrence necessitating a redo surgery.Conclusion: IMT is a rare entity in adults presenting with diverse, non-specific symptoms. IMT’s usually follow a favorable prognosis, but behavior may be unpredictable. While uncommon in adults, strong clinical suspicion is warranted. Complete surgical resection is the treatment of choice and follow up is crucial given the potential for recurrence.

Background: Glioblastoma (GBM) is a highly aggressive, invasive, and growth-factor-independent grade IV glioma. Survival following the diagnosis is generally poor, with a median survival of approximately 15 months, and it is considered the most aggressive and lethal central nervous system tumor. Conventional treatments based on surgery, chemotherapy, and radiation therapy only delay progression, and death is inevitable. Malignant glioma cells are resistant to traditional therapies, potentially due to a subpopulation of glioma stem cells that are invasive and capable of rapid regrowth. Methods: Systematic retrieval of information was performed on PubMed. Specified keywords were used in PubMed and the articles published in peer-reviewed scientific journals were associated with brain GBM cancer, sodium iodide symporter (NIS). Additionally, the words 'radionuclide therapy', 'radioiodine', 'iodine-131', 'molecular imaging', 'gene therapy', and 'translational imaging' were used. Other keywords such as ‘glioblastoma', 'targeted', 'theranostic', 'symporter', 'virus', 'solid tumor', 'combined therapy', 'pituitary', or 'plasmid' were also used in appropriate literature databases and search engines. 19 articles were found in this search on Mesenchymal Stem Cell Sodium Iodide Symporter and GBM. \ These articles were from the years 2000 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. Results: For as long as they express functional NIS, mesenchymal stem cells systemically repress T and B cells; however, after that, they are largely replaced by mesenchymal stem cells generated from embryonic stem cells that are functionally competent. As a result of their natural capacity to identify malignancies, MSC are employed as tumor therapy vehicles. Because MSCs may be transplanted in several methods, they have been proposed as ideal vehicles for NIS gene transfer. Conclusion: Non-invasive imaging-based detection of glioma stem cells presents an alternate means to monitor the tumor and diagnose and evaluate recurrence. The sodium iodine symporter gene is a specific gene in a variety of human thyroid disease that functions to move iodine into the cell. In recent years, an increasing number of studies related to the sodium iodide symporter gene have been reported in a variety of tumors and as therapeutic vectors for imaging and therapy. Gene therapy and nuclear medicine therapy for GBM provide a new direction.

Spinal cord tumors, though rare, present formidable challenges in clinical management due to their intricate nature. Traditional treatment modalities like surgery, radiation therapy, and chemotherapy have been the mainstay for managing these tumors. However, despite significant advancements, challenges persist, including the limitations of surgical resection and the potential side effects associated with radiation therapy. In response to these limitations, a wave of innovative approaches is reshaping the treatment landscape for spinal cord tumors. Advancements in gene therapy, immunotherapy, and targeted therapy are offering groundbreaking possibilities. Gene therapy holds the potential to modify the genes responsible for tumor growth, while immunotherapy harnesses the body's own immune system to fight cancer cells. Targeted therapy aims to strike a specific vulnerability within the tumor cells, offering a more precise and potentially less toxic approach. Additionally, novel surgical adjuncts are being explored to improve visualization and minimize damage to surrounding healthy tissue during tumor removal. These developments pave the way for a future of personalized medicine for spinal cord tumors. By delving deeper into the molecular makeup of individual tumors, doctors can tailor treatment strategies to target specific mutations and vulnerabilities. This personalized approach offers the potential for more effective interventions with fewer side effects, ultimately leading to improved patient outcomes and a better quality of life. This evolving landscape of spinal cord tumor management signifies the crucial integration of established and innovative strategies to create a brighter future for patients battling this complex condition.

Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, a generative contrastive learning based on deep learning model. MetGen generates synthetic metastatic cancer expression profiles using primary cancer and normal tissue expression data. Our results demonstrate that MetGen generates comparable samples to actual metastatic cancer samples, and we discuss the learning mechanism of MetGen. Additionally, we demonstrate MetGen's interpretability using metastatic prostate cancer and metastatic breast cancer. MetGen has learned highly relevant signatures in cancer, tissue, and tumor microenvironment, such as immune response and the metastasis process, which potentially fosters a more comprehensive understanding of metastatic cancer biology. The development of MetGen represents a significant step toward the study of metastatic cancer biology by providing a generative model that identifies candidate therapeutic targets for the treatment of metastatic cancer.

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.

52 years have passed since President Nixon launched the "War on Cancer". The goals outlined by the President were not achieved because cancer treatment applied such as chemotherapy, radiotherapy, and targeted therapy have not fully met expectations. We suggest a new chemotherapeutic strategy: disrupting the communication between cancer cells and their microenvironment by chemical means. Immunological synapses that form between cancer cells and immune or other stromal cells provide an attractive target for this approach. Synapses form ligand-receptor clusters within interface of the interacting cells. Despite their differences, synapses share common properties: intercellular protein clusters; the proximity of these proteins; and their cooperative interaction making a synapse an unified functional unit. Synapses provide the limited space for the focused intercellular exchange of signaling molecules and particles. Therefore, destruction of synapses is expected to cause collapse of various tumor types. Additionally, the clustered arrangement of synapse components offers opportunities to increase treatment safety by reducing the concentration of cell impermeable agents used, to enhance its specificity applying cross-linking reagents, thus restricting modifications of surface-exposed molecules. By attaching a cleavable cell permeable toxic agent to a crosslinker should further enhance a killing potential in treating cancer. The proposed approach promises to be simple, universal, and less expensive than existing cancer therapy methods.

Background: Peripheral Ossifying Fibroma (POF) is a benign gingival tumor generally presenting as a slow-growing mass, usually not ulcerated, and without bleeding. Histopathological exam shows fibrous connective tissue with spots or extensive areas of intralesional calcifications, which can also be detectable on radiograms. Methods and case presentation: We present the case of a 4-year-old male with a retro-incisive swelling of the hard palate, associated with speaking and feeding difficulties. On CT scans, a small intralesional calcification was detected. After conscious sedation, the patient was subjected to diode laser excision (910 nm, 2W, CW, 300 m fiber) with-out post-operative complications. A review was conducted by searching the words “peripheral ossifying fibroma” AND “children” OR “infant” and including manuscripts of the last 15 years. Results: POF is an uncommon lesion of the oral mucosa and may sporadically affect the palatal mucosa in children. Considering its epidemiology and conventional clinical presentation as epu-lis, the pre-operative diagnosis may be relatively difficult. Risk factors could be represented by plaque, calculus, or trauma, all supporting a possible reactive pathogenesis, but a certain etiology is still missing. The main problem of POF is the recurrence rate, which is particularly high (8-20%), thus suggesting that a deep excision is recommended with full extension to the hard tis-sue of bone and to the adjacent periodontal ligament. Diode laser surgery may be recommended for such treatments, especially in pediatric patients, associated with intraoperative conscious se-dation. Data emerging from the relevant literature on POF management in children have been collected and discussed. Conclusions: The authors suggest the use of diode laser for the complete excision of POF, especially in less-compliant patients as children, with a low grade of comorbidi-ties and good outcomes, giving the surgeon a viable alternative to conventional surgery.

Osteosarcoma (OS) are the most prevalent malignant bone tumors in adolescents and young adults.. OS cells grow in a permissive local microenvironment which modulates their behavior and facilitates all steps in tumor development (e.g., proliferation/quiescence, invasion/migration, drug resistance) and contributes to their intrinsic heterogeneity. The lung parenchyma is the most common metastatic site in OS, and metastatic foci are frequently associated with a poor clinical outcome. Although multiple factors may be responsible for the disease, including genetic mutations (e.g., Rb, p53), the molecular mechanism of development of OS remains unclear and the conventional treatment for OS is still based on a sequential approach that combines chemotherapy and surgery. Also, despite the increase in clinical trials, the survival rates for OS have not improved. Non-specific targeting therapies thus show poor therapeutic effects with side effects at high doses. For these reasons, many efforts have been done to characterize the complex genome of osteosarcoma thanks to the whole exome analysis with the aim to identify predictive biomarkers to give to these patients a better therapeutic option. This review aims to summarize and discuss the main recent advances in OS molecular research for precision medicine.

Tumor infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, and total TILs (CD4+, CD8+, Treg, B cells) within chemotherapy-treated tumors compared to chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic response with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherpy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

Lung cancer accounts for the majority of cancer cases. In recent years, checkpoint inhibitor immunotherapy (ICI) has emerged as a new treatment. A better understanding of the tumor microenvironment, or TMJ, or the immune system surrounding the tumor is needed. Cytokines are small proteins that carry messages between cells and are known to play an important role in the body's response to inflammation and infection. Cytokines are important for immunity in lung cancer. It promotes tumor growth (oncogenic cytokines) or inhibits tumor growth (anti-tumor cytokines) by controlling signaling pathways for growth, proliferation, metastasis, and apoptosis. The immune system relies heavily on cytokines. They can also be produced in the laboratory for therapeutic use. Cytokine therapy helps the immune system stop the growth or kill cancer cells. Interleukins and interferons are two types of cytokines used to treat cancer. This article begins by addressing the role of the tumor microenvironment (TMJ) and its components in lung cancer. This review also highlights the functions of various cytokines such as IL, TGF and TNF.

The role of upfront primary tumor resection (PTR) in patients with unresectable metastatic col-orectal cancer (CRC) without severe symptoms remains controversial. We retrospectively ana-lyzed the role of PTR in overall survival (OS) in different subgroups. Among 331 patients diag-nosed with synchronous metastatic CRC between 2010 and 2020, 223 were analyzed. The PTR group (n = 42) showed better performance (p = 0.038); higher frequencies of right-sided origin (p = 0.014), T4 stage (p = 0.005), M1a stage (p = 0.015), and <2 organ metastases (p = 0.002); and re-ceived fewer targeted agents (p < 0.001) than the chemotherapy group (n = 181). The PTR group showed longer OS (20.5 versus 14.0 months, p = 0.016), but PTR was marginally related to OS in multivariate analysis (p = 0.060). Male sex (p = 0.022), good performance status (p = 0.07), left-sided tumor (p = 0.069), low serum carcinoembryonic antigen level (p = 0.092), T3 stage (p = 0.029), M1a stage (p = 0.025), <2 organ metastases (p = 0.017), and administration of targeted agents, especially bevacizumab (p = 0.024), were related to survival benefit after PTR. Upfront PTR should be considered when selecting patients with favorable prognoses for bevacizumab administration.

Brain metastasis (BrM), involving the spread of cells from a primary tumor through the blood circulation system to the brain microvasculature, eventually progresses despite multiple treatments and remains a substantial contributor to major mortality in patients with advanced- stage cancer. Molecular signatures and immune cellular components of the tumor microenvironment (TME) are emerging as essential regulators involved in establishing an organ-specific metastasis (colonization) and therapeutic response. A comprehensive understanding of detailed characterization and the immune landscape in context of process of BrM formation will greatly expand the horizon of treatments available to target these deadly diseases. In this review, we provide a comprehensive picture of the complex interactions between tumor cells and immune cellular components participated in the BrM process. Based on this knowledge, we will discuss opportunities and challenges for therapeutic strategies against BrM.

MicroRNAs (miRNAs) are single-stranded, noncoding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and dog diseases. Most cancers tested, to date, have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we have comprehensively summarized the importance of miRNA in human and dog cancer research. We have discussed the current state of development and potential for miRNA as both a diagnostic marker and a therapeutic target.

Liquid biopsy has been developed to diagnose and monitor cancer. Despite the recent advances in investigating early cancer detection and diagnosis strategies, there is still a lack of improvements in capturing (CTCs). To archive this, we developed an efficient CTC detection system by integrating gold nanoparticles and a microfluidic platform, which can achieve CTC capture within 120 min. The microdevice was functionalized by immobilizing antibodies specific to the target cells. The method was tested with spiked tumor cells in whole human blood with three pancreatic cancer cell lines and compared with purified cancer cells suspended in a phosphate buffer solution. Our results captured pancreatic cancer cells spiked in blood samples with efficiency (90±3.2)% and were used to isolate CTCs from patients with metastatic pancreatic cancer. This methodology will enable the production of functionalized, patterned surfaces that interact with tumor cells, enhancing the selective capture of CTCs from biological assays.

The tumor microenvironment (TME) plays a critical role in cancer progression and treatment outcomes. Despite advances in cancer research, many therapeutic strategies have failed to provide the desired clinical outcomes. In this integrated review, aimed to explore the role of TME in cancer biology and develop novel therapeutic strategies that target not only cancer cells but also the surrounding microenvironment. Study conducted a comprehensive literature search using PubMed, Embase, and Web of Science databases for articles published between 2016 and 2022. Inclusion of articles that discussed the impact of TME on cancer development and progression, as well as articles that proposed novel therapeutic strategies targeting the TME. The analysis of the literature revealed that the TME plays a crucial role in cancer development and progression by promoting cancer cell survival, angiogenesis, invasion, and metastasis, and by interfering with the efficacy of cancer therapies. The TME is composed of a complex network of non-cancerous cells, extracellular matrix components, and signaling molecules that interact with cancer cells. Several novel therapeutic strategies have been proposed based on the modulation of TME components. One of the most promising approaches is the use of immunotherapy, which aims to enhance the immune system's ability to recognize and attack cancer cells. Immunotherapy drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and immune-stimulatory monoclonal antibodies have been approved for the treatment of different cancer types. These approaches have shown promising results in preclinical studies and clinical trials. The TME plays a critical role in cancer development and progression, and targeting its components represents a promising avenue for cancer therapy. Novel therapeutic strategies such as immunotherapy, extracellular matrix-targeting drugs, and nanoparticle-based therapies have shown promising results in preclinical studies and clinical trials. However, further research is needed to identify the most effective strategies and to overcome the challenges associated with TME targeting.

Brain tumors are abnormal cells growth in the brain tissues that can be cancerous, or not. In any case, they could be a very aggressive disease that should be detected as early as possible. Usually, magnetic resonance imaging (MRI) is the main tool commonly adopted by neurologists and radiologists to identify and classify any possible anomalies present in the brain anatomy. In the present work, an automatic unsupervised method called Z2-$\gamma$, based on the use of adaptive finite-elements and suitable pre-processing and post-processing techniques, is introduced. In particular, the proposed methodology is able to automatically classify whether a given MR image represents a healthy or a diseased brain and in this latter case, is able to locate the tumor area.

Extensive growth in the volume of irregular brain cells is known as brain tumor. Human brain is surrounded by stiff skull. There are various issues that occur due to the growth of any tumor inside this restricted space. The malignant and benign are two main categories of the brain tumor. The skull is pressurized to enlarge from inside in case of growth of any benign or malignant tumor. This tumor leads to harm in brain and it may be dangerous to life also. The brain tumor is divided into two kinds - primary or secondary. The brain tumor detection techniques have various phases. In this paper, comparative study of CNN with GLCM approach and superpixel based spectral clustering is done tumor. This work takes into account metrics like accuracy, sensitivity and specificity for drawing the comparison between both the techniques.

Segmentation of brain tumor images is a major research topic in medical imaging to have a refined detection and understanding of abnormal masses in the brain. This paper proposes a new segmentation method, consisting of three main steps, to detect brain lesions using magnetic resonance imaging (MRI). In the first step, the parts of the image delineating the skull bone are removed to exclude insignificant data. In the second step, which is the main contribution of this study, the particle swarm optimization (PSO) technique is applied to detect the block that contains the brain lesions. The fitness function, used to determine the best block among all candidate blocks, is based on a two-way fixed-effects analysis of variance (ANOVA). In the last step of the algorithm, the K-means segmentation method is used in the lesion block to classify it as tumor or not. A thorough evaluation of the proposed algorithm is performed using the MRI database provided by the Kouba imaging center in Algiers, Algeria. Estimates of the selected fitness function are first compared to those based on the sum-of-absolute-differences (SAD) dissimilarity criterion and demonstrate the efficiency and robustness of the ANOVA. The performance of the optimized brain tumor segmentation algorithm is then compared to the results of several state-of-the-art techniques, including fuzzy C-means, K-means, Otsu thresholding, local thresholding, and watershed segmentation. The results obtained using Dice coefficient, Jaccard distance, correlation coefficient, and root mean square error (RMSE) measurements demonstrate the superiority of the proposed optimized segmentation algorithm over equivalent techniques.

The development of a fast and accurate intraoperative method that enables the differentiation and stratification of cancerous lesions is still a challenging problem in laboratory medicine. Therefore, it is important to find and optimize a simple and effective analytical method that enables the selection of distinctive metabolites. This study aims to assess the usefulness of solid-phase microextraction (SPME) probes as a sampling method for the lipidomic analysis of brain tumors. To this end, SPME was applied to sample brain tumors immediately after excision, followed by lipidomic analysis via liquid chromatography-high resolution mass spectrometry (LC-HRMS). The results showed that long fibers were a good option for extracting analytes from an entire lesion to obtain an average lipidomic profile. Moreover, significant differences between tumors of different histological origin were observed. In-depth investigation of the glioma samples revealed that malignancy grade and isocitrate dehydrogenase (IDH) mutation status impact the lipidomic composition of the tumor, whereas 1p/19q co-deletion did not appear to alter the lipid profile. This first on-site lipidomic analysis of intact tumors proved that chemical biopsy with SPME is a promising tool for the simple and fast extraction of lipid markers in neurooncology.

Liquid biopsy via isolation of circulating tumour cells (CTCs) represents a promising diagnostic tool capable of supplementing state-of-the-art for prostate cancer (PC) prognosis. Unfortunately, most of CTC technologies, such as AdnaTest or Cellsearch, critically rely on the Epithelial-Cell-Adhesion-Molecule (EpCAM) marker, limiting the possibility of detecting stem-like cells (CSCs) and mesenchymal-like cells (EMT-CTCs) that are present during PC progression. In this tontext, dielectrophoresis (DEP) is an epCAM independent, label-free, enrichment system, separating rare cells simply on the basis of their specific electrical properties. As compared to other technollgies, DEP represents a superior technique in terms of running costs, cells yield and specificity, but due to its higher complexity, requires still further technical as well as clinical development. Interestingly, DEP can be improved by the use of microfluid, nanostructured materials and fluoroimaging in order to increase its potential applications. In the context of PC, the utility of DEP can be translated in its capacity to detect CTC in the bloodstream in their epithelial, mesenchymal, or epithelial-mesenchymal phenotypes, which should be taken into account when choosing CTC enrichment and analysis methods for PC prognosis and early diagnosis.

Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.

Background/Aim: Uterine leiomyoma, also known as fibroids, is the most common benign neoplasm of the female genital tract. Leiomyoma, including its subtypes, is the most common uterine tumor. The subtypes account for approximately 10% of leiomyomas. Intravenous leiomyomatosis, a uterine leiomyoma subtype, is an intravascular growth of benign smooth muscle cells, occasionally with pelvic or extrapelvic extension. Uterine leiomyosarcoma, a malignant tumor, tends to metastasize hematogenously, and distant metastasis to the lungs and liver is common. Therefore, this intravenous leiomyomatosis’ oncological features resemble those of the malignant tumor uterine leiomyosarcoma. Cancer stem cells migrate to distant organs via intravascular infiltration, leading to micrometastases. Materials and Methods: We examined the oncological properties of intravenous leiomyomatosis using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: CD44-positive mesenchymal tumor stem-like cells were detected in both intravenous leiomyomatosis and uterine leiomyosarcoma. The oncological nature of intravenous leiomyomatosis was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in intravenous leiomyomatosis, Cyclin E and Ki-67-positive cells were rare, and no pathological findings suspected to be malignant were observed. Conclusion: It is expected that establishing a treatment method targeting cancer stem cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis.

: Increased glucose and choline uptake are hallmarks of cancer. We investigated if the uptake and conversion of [2H9]choline alone and together with that of [6,6’ 2H2]glucose can be assessed in subcutaneous tumors by deuterium metabolic imaging (DMI) after bolus administration of these compounds. Therefore tumors with human renal carcinoma cells were grown subcutaneously in mice up to ~0.5 cm3. Mice were anesthetized with isoflurane and IV infused in the MR magnet for ~20 sec with ~0.2 ml solutions containing either [2H9]choline (0.05g/kg) alone or together with [6,6’ 2H2]glucose (1.3g/kg). 2H MR was performed on a 11.7T MR system with a home-built 2H/1H coil using a 900 excitation pulse and 400ms repetition time. 3D DMI was recorded at high resolution (2x2x2mm) in 37 min or at low resolution (3.7x3.7x3.7mm) in 2:24 min. Absolute tissue concentrations were calculate assuming initial [HOD]=13.7mM. Within 5 minutes after [2H9]choline infusion its signal appeared in tumor spectra representing concentration increasing up to 0.3–1.2 mM and then slowly decreased or remained constant over 100 minutes. In plasma [2H9]choline disappeared within 15 minutes post-infusion implying that its tumor signal arises from tissue and not blood. After infusing a mixture of [2H9]choline and [6,6’ 2H2]glucose their signals were observed separately in tumor 2H spectra. Over time the [2H9]choline signal broadened, possibly due to conversion to other choline compounds, [[6,6’ 2H2]glucose] declined, [HOD] increased and a lactate signal appeared, reflecting glycolysis. Metabolic maps of all 2H compounds were reconstructed from high resolution DMIs. As choline infusion and glucose DMI is feasible in patients, their simultaneous detection has clinical potential for tumor characterization.

Breast cancer, although the most frequently diagnosed malignant tumour in humans, has a less clear aetiology compared to other frequent cancer types. Mouse-mammary tumour virus (MMTV) is involved in breast cancer in mice and dogs and might play a role in the aetiology of some breast cancers in humans, since it has been identified in 20-40% of breast cancer samples in Western Europe, USA, Australia and some other parts of the world population. The purpose of our study was to identify MMTV DNA sequences in breast tissue samples from breast cancer patients operated in our regional centre from Romania. We have selected 75 patients with non-metastatic breast cancer treated with curative intent and searched with PCR the MMTV-like DNA sequence in the breast cancer tissue and normal breast tissue obtained from the same patients. Since none of the examined samples was positive for MMTV-like target sequences on PCR we could not prove that MMTV plays a role in the aetiology of breast cancer in our patient group. This finding is similar to publications of other geographically related research groups and might be due to the fact that only the Mus musculus domesticus mouse species was proven to carry infectious MMTV, but not the Mus musculus musculus species, which is specific to South-Eastern Europe (including Romania) and some parts of Asia.

Tumor microenvironment (TME) represents a complex network between tumor cells and a variety of components including immune, stromal and vascular endothelial cells as well as extracellular matrix. A wide panel of signals and interactions here take place, resulting in a bi-directional modulation of cellular functions. Many stimuli, on one hand, induce tumor growth and spread of metastatic cells and, on the other hand, contribute to the establishment of an immunosuppressive environment. The latter feature is achieved by soothing immune effector cells, mainly cytotoxic T lymphocytes, B and NK cells, and/or through expansion of regulatory cell populations, including regulatory T and B cells, tumor-associated macrophages and myeloid-derived suppressor cells. In this context, immune checkpoints (IC) are key players in the control of T cell activation and anti-cancer activities, leading to the inhibition of tumor cell lysis and of pro-inflammatory cytokine production. Thus, these pathways represent promising targets for the development of effective and innovative therapies both in adults and childhood. Here we address the role of different cell populations homing the TME and of well-known and recently characterized IC in the context of pediatric solid tumors. We also discuss preclinical and clinical data available using IC inhibitors alone, in combination each other or administered with standard therapies.

Proper and timely segregation of cellular genome is an important and a prime requirement of all cell division programmes. Mis-segregation of chromosomes and resulting aneuploidy leads to several clinical consequences. Over the years, shugoshin emerges as a key protein factor involved in the segregation of genetic material in dividing cells. Deletion or altered level of shugoshin is reported in several human malignancies, as a result, shugoshin now emerges as an important tumour associated gene and a possible target for cancer therapy. Apart from the role in cancer, recent studies also showed the involvement of shugoshin in several other clinical disorders. Through this review, we tried to highlight the clinical relevance of shugoshin.

In the last few decades, the dynamics of tumor cells and their growths are presented via clinical, experimental, and theoretical approaches, which leads to the development of the new idea of multiple cancer therapies to control and reduce the death rate for earlier detection. In this paper, we discussed the dynamics of tumor cell growth and its treatment process. We analyzed some simple mathematical models and generalized the study to understand the growth of tumor cells. The main proposed model is a system of ordinary differential equations which combines interactions among natural killer cells, dendritic cells and cytotoxic CD8+ T cells. The model is solved numerically to explain how the tumor cells spread and become more dangerous as well as the treatment process of cancer. It is also studied that how the cell behaves in the presence of different therapy and drugs. The optimal control of chemotherapy has been discussed. It has also been explained how much the model is effective in reducing tumor cells over time. Finally, a couple of spatially distributed models are discussed for tumor cell growth.

The lymphocyte function–associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA’s role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

Protein 53 (P53) shows different functions either to support or to contrast malignant growth. P53 history tells that discoveries of molecular features have contributed to the emergence of P53 functions. Conversely, the shift of paradigms demonstrates that P53 functions coexist even if are in conflict with one another. Since 1979, five paradigms have been assembled then deconstructed by taking into account P53 functions of viral protein, oncogene, tumor suppressor gene, transcription factor, apoptotic factor. By summarizing the past five disassembled P53 paradigms, in this investigation the current paradigm involving P53 in the modulation of a composite bio-morphological entity namely, tumor immune microenvironment (TIME) is analyzed. The aims of this investigation were to provide an overview of solid and validated knowledge occurring in all P53 paradigms and to determine P53 abilities to modify TIME through manipulation of viruses. As a result, definitive P53 evidence concerns its genetic localization, amino acids composition, its isoforms and subcellular expression in organelles. P53 “mutome” assembles all mutations affecting this complex protein. Lastly, both categories of tumor promoting and non-oncogenic viruses related to P53 were scrutinized. In conclusion, paradigms teach that P53 is undruggable because its drugs inevitably target all P53 functions.

Background: Glioblastoma remains a challenging brain tumor to treat due to its infiltrative nature. Accurately identifying tumor boundaries during surgery is crucial for successful tumor resection. This study introduces an innovative intraoperative visualization method utilizing a surgical fluorescence microscope to precisely locate tumor cells. The focus of the study is on IR-Glint, a novel preparation comprising Cy7.5-labeled aptamers Gli-233nt and Gli-55_3L specific to human glioblastoma. Methods: The aptamers were modified using molecular modeling and quantum chemical techniques. The effectiveness of the preparation was assessed using flow cytometry and microscopy on primary cultures of human glioblastoma. In vivo studies were conducted on mouse and rabbit models, employing orthotopic xenotransplantation of human brain glioblastoma with various imaging techniques, including PET/CT, in vivo fluorescence visualization, confocal laser scanning, and surgical microscopy. Results: The experiments validated the potential of IR-Glint for intraoperative visualization of glioblastoma using infrared imaging. Surface application of the aptamer-based formulation on the brain allowed clear visualization of the tumor, aiding surgeons in tumor resection. This approach also reduces the dosage required and mitigates potential toxic effects on the patient. Conclusions: This study demonstrates the promising potential of using in-frared dye-labeled aptamers for intraoperative visualization of glioblastoma. By improving surgical treatment outcomes in neurosurgery, this novel approach may pave the way for future advancements in the field.

The precise molecular basis of anti-tumor immunity is not yet fully understood, although commensal Bifidobacterium (c-BIF) is expected to be one of the key players in cancer control via antigenic mimicry. We investigated the sequence similarity between c-BIF and cytotoxic T lymphocyte (CTL) epitope peptides against human tumor-associated antigens to better understand the molecular basis of antigenic mimicry. We used two different similarity analyses for this purpose, a linear sequence analysis and a similarity analysis of T cell receptor (TCR)-mediated recognition of CTL epitope peptides on antigen-presenting cells. The linear sequence analysis revealed 3,900 positive numbers of similarity sites between them with 126 mean per peptide and 107 median per peptide, while the TCR-mediated recognition analysis revealed 5,018 positive numbers with a mean of 162 and median of 132 per peptide. These results demonstrated the existence of durable and abundant sequence similarities between c-BIF and CTL epitope peptides, suggesting that the former play a pivotal in inducing cellular and humoral immunity against the latter in the absence of cancer cells via antigenic mimicry.

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

The pathophysiology of Nonketotic Hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neuronal model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance and protein analyses. The study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology and offer new perspectives for therapeutic options.

Early detection and precise characterization of brain tumors play a crucial role in improving patient outcomes and extending survival rates. Among neuroimaging modalities, magnetic resonance imaging (MRI) is the gold standard for brain tumor diagnostics due to its ability to produce high-contrast images across a variety of sequences, each highlighting distinct tissue characteristics. This study focuses on enabling multimodal MRI sequences to advance the automatic segmentation of low-grade astrocytomas, a challenging task due to their diffuse and irregular growth patterns. A novel mutual-attention deep learning framework is proposed, which integrates complementary information from multiple MRI sequences, including T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, to enhance the segmentation accuracy. Unlike conventional segmentation models, which treat each modality independently or simply concatenate them, our model introduces mutual attention mechanisms. This allows the network to dynamically focus on salient features across modalities by jointly learning interdependencies between imaging sequences, leading to more precise boundary delineations even in regions with subtle tumor signals. The proposed method is validated using the UCSF-PDGM dataset, which consists of 35 astrocytoma cases, presenting a realistic and clinically challenging dataset. The results demonstrate that T2w/FLAIR modalities contribute most significantly to the segmentation performance. The mutual-attention model achieves an average Dice coefficient of 0.87, outperforming traditional approaches. This study provides an innovative pathway toward improving segmentation of low-grade tumors by enabling context-aware fusion across imaging sequences. Furthermore, the study showcases the clinical relevance of integrating AI with multimodal MRI, potentially improving non-invasive tumor characterization and guiding future research in radiological diagnostics.

Background: Patients undergoing brain tumor resection experience neurological and cognitive (i.e., neurocognitive) changes reflected in altered performance on neuropsychological tests. These changes can be difficult to explain or predict. Brain connectivity, measured with neuroimaging, offers one potential model for examining these changes. In this study, we evaluated whether longitudinal changes in brain connectivity correlated with changes in neurocognitive abilities in patients before and after brain tumor resection.

Methods: Patients underwent functional and diffusion MR scanning and neuropsychological evaluation before tumor resection followed by repeat scanning and evaluation two weeks post-resection. Using this functional and diffusion imaging data, we measured changes in the topology of the functional and structural networks. From the neuropsychological testing scores, we derived a composite score that described a patient’s overall level of neurocognitive functioning. We then used a multiple linear regression model to test whether structural and functional connectivity measures were correlated with changes in composite scores.

Results: Multiple linear regression on 21 subjects showed that connectivity changes were highly correlated with changes in neuropsychological evaluation scores (R² adjusted = 0.79, p<0.001). Changes in functional local efficiency (p<0.001) and global efficiency (p<0.05) were inversely correlated with changes in composite score, while changes in modularity (p<0.01) as well as the patient’s age (p<0.05) were directly correlated with changes in composite score.

Conclusion: Short interval changes in brain connectivity markers were strongly correlated with changes in the composite neuropsychological test scores in brain tumor resection patients. Our findings support the need for further exploration of brain connectivity as a biomarker relevant to brain tumor patients.

Recognizing the need to enhance immune cells' ability to target and eliminate tumor cells by focusing on tumor-associated antigens is crucial for the success of immunotherapy. Numerous cell-based therapies, such as CAR-T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, CAR-NK cell therapy, and T-cell receptor (TCR)-based therapies, are currently undergoing clinical and pre-clinical evaluation across various cancer types. However, a significant challenge lies in managing the inflammatory responses that are harmful to cancer patients. To overcome this, developing advanced strategies to target tumor cells precisely while preserving immune balance in cancer patients is imperative. One promising approach involves using modified tumor-associated macrophages (TAMs), which constitute approximately 50% of the tumor microenvironment (TME) and play a pivotal role in tumor progression. CAR-Macrophage (CAR-M) therapy is an emerging potential asset of immunotherapy for a wide range of tumors.

Cumulative evidence attests to the essential roles of commensal microbes in the physiology of the hosts. Although microbiome has been a major research subject since the time of Luis Pasteur and William Russell over 140 years ago, recent findings that certain intracellular bacteria contribute to the pathophysiology of healthy or diseased tissues have brought the field of microbiome to a new era of investigation. In particular, in the field of breast cancer research, breast-tumor resident bacteria are deemed to be the essential players of tumor initiation and progression. This is a resurrection of Russel’s bacterial cause of cancer theory abandoned over 100 years ago. This review will introduce some of the recent findings that exemplify the roles of breast tumor-resident microbes in breast carcinogenesis and metastasis and provide mechanistic explanations of these phenomena. Such information would be able to justify the utility of breast-tumor resident microbes as biomarkers for disease progression and therapeutic targets.

The abstract should be a total of about 250 words and structured to contain the following headings: Background/Objectives, Methods, Results, Conclusions. Background/Objectives: Place the question addressed in a broad context and highlight the purpose of the study; Methods: Describe briefly the main methods or treatments applied. Include any relevant preregistration numbers, and species and strains of any animals used; Results: Summarize the article’s main findings; Conclusions: Indicate the main conclusions or interpretations. The abstract should be an objective representation of the article: it must not contain results which are not presented and substantiated in the main text and should not exaggerate the main conclusions. Clinical trial abstracts should include items that the CONSORT group has identified as essential.

Background: Interleukins play dual roles in breast cancer, acting as both promoters and 11 inhibitors of tumorigenesis within the tumor microenvironment, which is shaped by their 12 inflammatory functions. This study analyzed the subtype-specific prognostic significance 13 of anti-inflammatory and pro-inflammatory signatures using microarray-based gene ex- 14 pression analysis. Correlations between these interleukin signatures and immune cell 15 markers (CD8, IgKC, CD20) and immune checkpoints (PD-1) were also evaluated. 16 Materials and Methods: The study investigated the prognostic significance of an anti- 17 inflammatory interleukin signature (IL-12, IL-21, IFN-γ) and a pro-inflammatory interleu- 18 kin signature (IL-4, IL-5, IL-10, IL-13, IL-17, CXCL1) for metastasis-free survival (MFS) 19 using Kaplan-Meier curves and Cox regression analyses in a cohort of 461 patients with 20 early breast cancer. Correlations were analyzed using the Spearman-Rho correlation coef- 21 ficient. 22 Results: Kaplan-Meier curves revealed that the prognostic significance of the anti-inflam- 23 matory signature was specifically pronounced in the basal-like subtype (p=0.004, Log 24 Rank). This signature retained independent prognostic significance in multivariate Cox 25 regression analysis (HR 0.463, 95% CI 0.290-0.741; p=0.001). Higher expression of the anti- 26 inflammatory interleukin signature was associated with longer MFS. The pro-inflamma- 27 tory interleukin signature showed a significant prognostic effect in the whole cohort, with 28 higher expression associated with shorter MFS (p=0.034). Strong correlations were found 29 between the anti-inflammatory signature and CD8 expression (ρ=0.391; p<0.001) and be- 30 tween the pro-inflammatory signature and PD-1 expression (ρ=0.627; p<0.001).

Approximately 20% of patients with colorectal cancer (CRC) are diagnosed with a mucinous subtype of this tumor, have a worse prognosis, and often show resistance to available therapies. Molecules from the mucin family are involved in the regulation of epithelial-mesenchymal transition (EMT), which significantly determines the cancer aggressiveness. This study aimed to examine the diagnostic and prognostic significance of mucinous histology and EMT markers in patients with early-onset CRC and their association with disease severity and tumor characteristics. The study included tumor tissue samples from 106 patients diagnosed with CRC before the age of 45, 53 with mucinous and 53 with non-mucinous tumors. The EMT status was determined by immunohistochemical analysis of E-cadherin and Vimentin in tissue sections. Mucinous tumors had a significantly higher cytoplasmic E-cadherin score (P=0.043), they were significantly less differentiated (P=0.007), more advanced (P=0.005), and predominately affected right colon (P=0.030) in comparison to non-mucinous tumors. Epithelial tumors were significantly better differentiated (P=0.034) and with less prominent tumor budding (P < 0.001) than mesenchymal tumors. The process of EMT appears to be more prominent in tumors of younger patients regardless of mucinous histology. EMT status may represent a useful prognostic tool in early-onset CRC.

Von Hippel-Lindau disease (VHL) is a multiple organ neoplastic syndrome with autosomal dominant transmission, complete penetrance, and variable expression caused by mutations in the VHL gene. Although VHL disease is hereditary in many cases, new mutations cause up to 20 % of the incidence. Mutations in VHL may cause the development of cysts and tumors in many organs, including brain and spinal cord hemangioblastoma, renal cell carcinoma (RCC), retinal heman-gioblastoma (RH), pheochromocytoma, epididymal and broad ligament cystadenomas, endo-lymphatic sac tumor, pancreatic neuroendocrine tumors, and renal and pancreatic cysts. VHL is a syndrome associated with functional inactivation of the Von Hippel–Lindau protein (pVHL). pVHL is a tumor suppressor mainly known for its role as a regulator of hypoxia-inducible factor (HIF) activity. The prevalence of VHL disease is between 1 in 39 000 and 1 in 91 000 individuals in different regional populations. Here, we review the etiology, epidemiology, pathophysiology, genetics, clinical manifestations, diagnosis, and current treatments, as well as the molecular aspects of this disease. We also discuss the animal models used to study this disease, VHL biomarkers, and current VHL clinical trials for VHL according to NIH.

Background: Pancreatic neuroendocrine tumors (pNETs) represents a rare subset of pancreatic cancer. Functional tumors caused hormonal changes and clinical syndromes, while non-functional ones are often diagnosed late. Surgical management need a multidisciplinary planning, involving enucleation, distal pancreatectomy with or without spleen preserving, cen-tral pancreatectomy, pancreaticoduodectomy or total pancreatectomy. Minimally invasive ap-proach increased in the last decade compared to the open technique. The aim of this study is to analyze current diagnostic and surgical trends for pNETs, to identify better interventions and their outcomes. Methods: The study adhered to PRISMA guidelines, conducting a systematic review of literature from May 2008 to March 2022 across multiple databases. Several combinations of keywords was used ("NET", "pancreatic", "surgery", "laparoscopic", "minimally invasive", "robotic”, “enuclea-tion”,“parenchima sparing”) and relevant article references was manually checked. Manuscript quality was evaluated. Results: The study screened 3867 manuscripts, twelve studies were selected, primarily from Ita-ly, the United States, and China. A total of 7767 surgical treated patients was collected from 160 included centers. The mean age was 56,3 y.o. Enucleations (EN) and distal pancreatectomy (DP) was the most common performed surgery and represents 43.4% and 38.6% of the total interven-tions, respectively. Pancreatic fistula, post operative bleeding, re-operation and follow up was recorded and analyzed. Conclusions: Enucleation show better postoperative outcomes and lower mortality rates com-pared to pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), despite similar risks of postoperative pancreatic fistula (POPF). DP was preferred over enucleation for pancreas body-tail, while laparoscopic enucleation is better for head pNETs.

CD44 is a type I transmembrane glycoprotein, which is associated with poor prognosis in various solid tumors. Since CD44 plays critical roles in tumor development by regulating cell adhesion, survival, proliferation, and stemness, it has been considered a target for tumor therapy. Anti-CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody-drug conjugates and chimeric antigen receptor-T cell therapy. We previously developed anti‐pan-CD44 mAbs, C₄₄Mab-5 and C₄₄Mab-46, which can recognize both CD44 standard (CD44s) and variant isoforms. In the present study, a defucosylated mouse IgG_2a version of the anti-pan-CD44 mAbs (5-mG_2a-f and C₄₄Mab-46-mG_2a-f) was generated to evaluate the antitumor activities against CD44-positive cells. Both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f recognized CD44s-overexpressed CHO-K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could activate effector cells in the presence of CHO/CD44s cells and exhibited the complement‐dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5-mG_2a-f and C₄₄Mab-46-mG_2a-f significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control defucosylated mouse IgG_2a. These results indicate that 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could exert antitumor activities against CD44-positive cancers and could be a promising therapeutic regimen for tumors.