Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer characterized by two etiologies: the first one, observed in most cases, is attributed to Merkel cell polyomavirus (MCPyV), a DNA tumor virus, while the second one is due to ultraviolet (UV) radiation exposure. Currently, there are limited diagnostic, prognostic, and therapeutic biomarkers available for MCC. MicroRNAs (miRNAs) are small RNA molecules that do not code for proteins but regulate various cellular processes, including cell cycle progression, proliferation, differentiation, and apoptosis. The dysregulation of miRNAs has been associated with a wide range of cancers since they can act as either tumor suppressors or oncogenes. This paper aims to collect, summarize and re-organize the recent discoveries concerning miRNAs, whose dysregulation in the pathogenesis and progression of MCC is slowly emerging. Furthermore, the potential clinical applications of miRNAs as diagnostic biomarkers, possible differentiation between MCPyV-related and unrelated MCC, predictors of response to therapy and prognostics are also discussed. From this review, it emerges that miRNAs may have, in the near future, the potential to become clinically significant in improving the diagnostic accuracy, prognostic evaluation, and therapeutic options of MCCs. Finally, the new perspectives on the poorly explored field of artificial intelligence in MCC are provided.

Studies on the possible association between bacteria and oral squamous cell carcinoma (OSCC) remain inconclusive, largely due to methodological variations/limitations. The objective of this study was to characterize the species composition as well as functional attributes of the bacteriome associated with OSCC. DNA obtained from 20 fresh OSCC biopsies (cases) and 20 deep-epithelium swabs (matched control subjects) were sequenced for the V1-V3 region using Illumina’s 2x300 bp chemistry. High quality, non-chimeric merged reads were classified to species level using a prioritized BLASTN-algorithm. Downstream analyses were performed using QIIME, PICRUSt, and LEfSe. Fusobacterium nucleatum subsp. polymorphum was the most significantly overrepresented species in the tumors followed by Pseudomonas aeruginosa and Campylobacter sp. Oral taxon 44, while Streptococcus mitis, Rothia mucilaginosa and Haemophilus parainfluenzae were the most significantly abundant in the controls. Functionally, genes involved in bacterial mobility, flagellar assembly, bacterial chemotaxis and LPS synthesis were enriched in the tumors while those responsible for DNA repair and combination, purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, ribosome biogenesis and glycolysis/gluconeogenesis were significantly associated with the controls. This is the first epidemiological evidence for association of F. nucleatum and P. aeruginosa with OSCC. Functionally, an “inflammatory bacteriome” is enriched in OSSC.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

Background: The Liver Imaging Reporting and Data System (LI-RADS) combines standardized terminology with a classification system for imaging findings in patients with HCC, therefore rendering diagnostic biopsy unnecessary in many cases. This retrospective study included 23 patients with a biopsy diagnosis of HCC, performed either before or after local interventional procedures, in order to evaluate the histopathologic changes induced by previous procedures and their potential influence on the response to immune therapy. Material and Methods: The study encompassed a cohort of patients diagnosed with Hepatocellular Carcinoma (HCC). Diagnosis was established through contrast-enhanced computer tomography or magnetic resonance imaging that identified LI-RADS-5 nodules in conjunction with historical liver disease and elevated alpha-fetoprotein (AFP) levels, or through histological examination confirming positivity for glypican3, heat shock protein70, and glutamine synthetase. The study detailed the liver disease etiology, LI-RADS scores, characteristics and dimensions of HCC nodules, serum AFP concentrations, Edmondson-Steiner grading, and the expression of programmed cell death ligand 1 (PD-L1) in the tumor cells. Results: Among the study's cohort of Hepatocellular Carcinoma (HCC) patients, a portion had not received any prior treatments, while the remainder experienced local HCC recurrence following trans-arterial chemoembolization or radiofrequency ablation. Observations indicated elevated alpha-fetoprotein (AFP) levels in those who had not undergone any previous interventions, showing statistical significance. The Edmondson-Steiner classification predominantly identified grade III differentiation across patients, irrespective of their treatment history. Furthermore, an increase in intra-tumoral programmed cell death ligand 1 (PD-L1) expression was noted in patients who had not been subjected to previous therapies. Conclusion: Liver biopsy offers valuable insights for patients with Hepatocellular Carcinoma (HCC), assisting in the tailoring of immune therapy strategies, particularly in cases of recurrence following prior local interventions.

Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation; such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed cooperative effects of dual inhibition of the two pathways, in accordance with inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1-phase arrest, but not apoptosis (cleaved caspase-3, AIFM1 regulation, subG1-phase) or necroptosis (phospho-MLKL). We conclude that dual inhibition of MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block proliferation of ICC cell lines, but therapy must certainly be supplemented with standard therapies.

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox (Hox) genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Hox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Hox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

Background: Large-cell neuroendocrine carcinoma presents significant treatment challenges owing to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. Methods: In this non-randomized study, patients with metastatic LCNEC were treated with ei-ther standard chemotherapy plus atezolizumab or standard chemotherapy alone. The primary outcomes measured were progression-free survival (PFS) and overall survival (OS), with an ex-ploratory analysis of miR375 in plasma as a potential biomarker. Results: Of the 22 screened patients, 17 met the inclusion criteria and were stratified into the atezolizumab and chemotherapy (n=10) or chemotherapy alone(n=7) groups. After a median follow-up of 23.3 months, the 12-month survival rate for the atezolizumab group was 57.1% (95% CI: 32.6%-100%) and 45.7% at 24 months (95% CI: 22.4%-93.2%). In contrast, the chemotherapy group had a 14.3% survival rate at both 12 and 24 months (95% CI: 2.33%-87.7%). The log-rank test for survival showed a statistically significant difference in the atezolizumab-treated group (chi-squared = 4, df = 1, p = 0.04). A non-significant correlation was found between disease pro-gression and elevated levels of miR375. Conclusions: This pilot study suggests that atezolizumab combined with chemotherapy may be effective in treating metastatic LCNEC. The non-significant correlation between plasma miR375 levels and disease progression suggests its biomarker potential, warranting further validation research.

Background: Metastatic tumors to the oro-facial tissues are rare, with an incidence ranging between 1% and 8% of all oral malignant tumors. Generally reported with a peak of incidence in the 5th–7th decades, but possibly occurring at any age, metastases may represent the first sign of an occult cancer or manifest in patient with an already known history of a primary carcinoma, mostly from the lungs, kidney, prostate, and colon-rectum in males, or uterus, breast, lung, and ovary in females. In the oro-facial tissues the sites mostly involved are the oral mucosa, gingiva/jawbones, tongue, and the salivary glands. Methods: A systemic Review of the literature on the oro-facial metastases from Renal Cell Carcinoma has been conducted by searching the most used databases, also focusing the attention on the Clear Cell histological variant, representing the most frequent one. Results: Among the 160 analyzed studies, 211 cases of oral metastases of renal cancer were found (148 in males, 70.1%; 63 in females, 29.8%), with an average age of 59.8 years. In almost 40% of cases, metastasis represented the first clinical manifestation of the primary tumor and 122 were histologically diagnosed as ccRCCs (57.8%). The tongue was involved in most of the cases (26% - 55 cases), followed by mandible (18.9% - 40 cases), gingiva (18.4% - 39 cases), maxilla (10.9% - 23 cases), parotid gland (10.4% - 22 cases), buccal mucosa (5.2% - 11 cases), lips (3.3% - 7 cases), hard palate (2.8% - 6 cases), soft palate, masticatory space and submandibular gland (0.9% - 2 cases), lymph nodes, tonsil and oral floor (0.4% - 1 case). Among the 122 ccRCCs (84 were males, 68.8 %; 38 females, 31.1%), with an average age of 60.8 years and representing in 33.6% the first clinical manifestation, the tongue remained the most involved site (25.4% - 31 cases), followed by the gingiva (17.2% - 21 cases), parotid gland (13,1% - 16 cases), mandibular bone (12.2% - 15 cases), maxillary bone (11.4% - 14 cases), buccal mucosa and lips (4.9% - 6 cases), hard palate (4% - 5 cases), submandibular gland and soft palate (1.6% - 2 cases), lymph nodes, tonsil, oral floor and masticatory space (0.8%. 1 case). The clinical presentation in soft tissues was represented by a fast-growing exophytic mass, sometimes accompanied by pain. Instead inn bone appeared as radiolucent lesions, with ill-defined borders and cortical erosion. Conclusions: Our data focus the attention on the incidence of Renal cancer Metastases in the oro-facial tissues. Their early identification surely represents a diagnostic challenge, especially when the clinical work-up is limited to the cervico-facial region. Nevertheless, early diagnosis and recently introduced adjuvant therapies may represent the key for better outcomes. Therefore, general guidelines about clinical and radiological identification of oro-facial potentially malignant lesions should be part of the cultural background of any dentists.

A broad spectrum of lesions, including hyperplastic, metaplastic, inflammatory, infectious, and reactive, may mimic cancer all along the urinary tract. This narrative collects most of them from a clinical and pathologic perspective offering urologists and general pathologists their most salient definitory features. Together with classical, well-known, entities such as urothelial papillomas (conventional and inverted), nephrogenic adenoma, polypoid cystitis, fibroepithelial polyp, prostatic-type polyp, verumontanum cyst, xanthogranulomatous inflammation, reactive changes secondary to BCG instillations, schistosomiasis, keratinizing desquamative squamous metaplasia, post-radiation changes, vaginal-type metaplasia, endocervicosis/endometriosis (müllerianosis), malakoplakia, florid von Brunn nest proliferation, cystitis/ureteritis cystica and glandularis, among others, still other cellular proliferations with concerning histological features and poorly understood etiopathogenesis like IgG4-related disease, PEComa, and pseudosarcomatous myofibroblastic proliferations (post-operative spindle cell nodule, inflammatory myofibroblastic tumor), are reviewed. Some of these diagnoses are problematic for urologists, other for pathologists, and still others for both. Interestingly, the right identification of their definitory features will allow their correct diagnoses thus avoiding overtreatment. The literature selected for this review also focuses on the immunohistochemical and/or molecular data useful to delineate prognosis.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with complex carcinogenesis. Although there has been significant progress in the treatment of HCC over the past decades, drug resistance to chemotherapy remains a major obstacle in its successful management. In this study we were able to reduce chemoresistance in cisplatin-resistant HepG2 cells by either silencing the expression of transglutaminase type 2 (TG2) using siRNA or by pre-treatment of cells with the TG2 enzyme inhibitor cystamine. Further analysis revealed that, whereas the full-length TG2 isoform (TG2-L) was almost completely cytoplasmic in its distribution, the majority of the short TG2 isoform (TG2-S) was membrane-associated in both parental and chemoresistant HepG2 cells. Following induction of cisplatin toxicity in non-chemoresistant parental cells, TG2-S together with cisplatin quickly relocated to the cytosolic fraction. Conversely, no cytosolic relocalisation of TG2-S or nuclear accumulation cisplatin was observed following identical treatment of chemoresistant cells, where TG2-S remained predominantly membrane-associated. This suggests that deficient subcellular relocalisation of TG2-S from membranous structures into the cytoplasm may limit the apoptic response to cisplatin toxicity in chemoresistant cells. Structural analysis of TG2 revealed the presence of binding motifs for interaction of TG-S with the membrane scaffold protein LC3/LC3 homologue that could contribute to a novel mechanism of chemotherapeutic resistance in HepG2 cells.

The origin of cancer remains one of the most important enigmas in modern biology. The prevailing paradigm has failed to grasp a comprehensive view of the disease. Naturally, therapies developed under the current assumptions are inadequate and cancer is practically an incurable disease. Meanwhile, descriptive studies continuously extend the molecular complexity of cancer without an equivalent advancement in its understanding. Furthermore, they tend to accumulate inconsistencies inexplicable under the classical view. This paper presents a compelling theory of the origin of carcinomas. By hypothesis, a series of generic events in epithelial tissues promoted by cellular aging and inflammation enables the reactivation of developmental programs. The origin of carcinomas in vivo is described as the time-ordered cell state transitions undergone by epithelial cells in the hyperplasia due to replicative senescence and inflammation towards a mesenchymal undifferentiated endogenous cell state with cancerous behavior. In support of the theory, the molecular, cellular, and histopathological evidence is critically reviewed. A plausible model for the origin of carcinomas is presented to explain the mechanism underlying carcinogenesis from an evolutive and developmental perspective. The implications of the hypothesis in the current strategies for cancer prevention and treatment are discussed along with rational alternatives and some predictions for possible experimental validation.

Intracranial metastases from thyroid cancer are rare. Although the prognosis of thyroid cancer patients is generally favorable, the prognosis of patients with intracranial metastases from thyroid cancer has been considered unfavorable having a lower survival rate than those without intracranial involvement. Many questions about their management remain unclear. The aim of this study was to analyze the characteristics, treatments, and outcomes of patients with brain metastases from thyroid cancer. Among 4320 patients with thyroid cancer recorded in our institutional database over a 30-year period, 20 patients with brain metastasis were retrospectively collected and analyzed. The clinical characteristics, histological type of primary cancer and metastatic brain tumor, additional previous distant metastasis, treatment modalities, locations and characteristics on radiologic findings, time interval between the first diagnosis of the primary thyroid cancer and brain metastasis, and survival were analyzed. The mean age at initial diagnosis was 59.3 ± 14.1 years, and at the manifestation of diagnosis of cerebral metastasis 64.8 ± 14.9 years. The histological types of the primary thyroid cancers were papillary in ten patients, follicular in seven, and poorly differentiated carcinoma in three. The average interval between the diagnosis of thyroid cancer and brain metastasis was 63.4 ± 58.4 months (range, 0-180 months). Ten patients had a single intracranial lesion and 10 patients had multiple lesions. Surgical resection was primarily performed in 15 patients and whole-brain radiotherapy, radiotherapy or tyrosine kinase inhibitors were applied in the other 5 patients. Overall median survival time was 15 months after diagnosis of BM from TC (range: 1-252 months). Patients with thyroid cancer can develop brain metastasis even many years after diagnosis of the primary tumor. Our study demonstrates an increased overall survival of patients younger than 60 years of age at the time of diagnosis of brain metastasis. There was no difference in survival between patients with brain metastasis from papillary or follicular thyroid carcinoma.

Renal clear cell carcinoma (ccRCC) comprises over 75% of all renal tumors and arises in the epithelial cells of the proximal convoluted tubule. Molecularly ccRCC is characterized by copy number alterations (CNAs) such as the loss of chromosome 3p and VHL inactivation. Additional driver mutations (SETD2, PBRM1, BAP1, and others) promote genomic instability and tumor cell metastasis through the dysregulation of various metabolic and immune-response pathways. Many researchers identified mutation, gene expression, and proteomic signatures for early diagnosis and prognostics for ccRCC. Despite a tremendous influx of data regarding DNA alterations, gene expression, and protein expression, the incorporation of these analyses for diagnosis and prognosis of RCC into the clinical application has not been implemented yet. In this review, we focused on the molecular changes associated with ccRCC development, along with gene expression and protein signatures, to emphasize the utilization of these molecular profiles in clinical practice. These findings, in the context of machine learning and precision medicine, may help to overcome some of the barriers encountered for implementing molecular profiles of tumors into the diagnosis and treatment of ccRCC.

Nowadays molecular and immunological research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and immune system action. An example could be renal cell carcinoma (RCC) which has deep interactions with immune mediators such as Interleukin 17 (IL-17) - an inflammatory cytokine reacting to tissue damage and external pathogens. RCC is one of the most fatal urological cancer because of its often late diagnosis and poor susceptibility to therapies. IL-17 and its relation with tumors is extremely complex and constitute a recent topic for numerous research. What is worth highlighting is IL-17 dual character in cancer development - it could be pro- as well as antitumorigenic. The aim of this review is to summarize the newest data considering multiple connections between IL-17 and RCC.

Head and neck cancer is the sixth most frequent cancer type. Drug resistance and toxicity are common challenges of the existing therapies, making the development of reliable preclinical models essential for the study of the involved molecular mechanisms as well as for eventual intervention approaches that improve the clinical outcome. Preclinical models of head and neck squamous cell carcinoma have been traditionally based in cell lines and murine models. In this review, we will go over the most frequently used preclinical models, from immortalized-cell and primary tumour cultures in monolayer or 3D, to the currently available animal models. We will scrutinize their efficiency in mimicking the molecular and cellular complexity of head and neck squamous cell carcinoma. Finally, the challenges and opportunities of other envisaged putative approaches, as well as the potential of the preclinical models to further develop customized therapies will be discussed.

(1) Background: Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study is aimed at showing the reliability of post-biopsy complete lesion removal, documented by mammogram, as additional criterion to select these patients. (2) Methods: 2173 Vacuum Assisted Breast Biopsies (VABB) documented as DCIS have been reviewed. Surgery has been performed in all cases. We retrospectively collected the reports of post-VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post-biopsy complete lesion removal and for those showing residual lesion. (3) Results: We observed 2173 cases of DCIS: 408 classified as low grade; 1262 as intermediate grade; 503 as high grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was significantly lower (8.2%) when considering patients showing mammographically documented complete removal of the lesion. (4) Conclusion: The absence of mammographically documented residual lesion following VABB is associated to a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis.

Backround: FNH is a common benign liver lesion, mostly solitary, and with no evidence of malignant transformation over time. The diagnosis can usually be made by imaging modalities with distinct features in MRI- and CT-scans. Case series: We present a case series of three patients with solitary liver tumors which were highly suspicious to be large FNH, based on radiological features. The patients were sent to our center for second opinion and probable treatment. Indication for resection was given because of nonconclusive radiologic imaging in the first, substantial growth progression in the second and elevated AFP in the third case. Histology revealed well to poor differentiated HCCs. Discussion: FNH tends to show a distinct pattern in imaging modalities, but HCC can mimic FNH. The MRI-scan using hepatotropic contrast agent is the most sensitive imaging modality to diagnose FNH. AFP is usually not elevated in FNH. Asymptomatic FNH does not require surgery but a reliable diagnosis is crucial. In case of an uncertain diagnosis surgery should be offered to patients. Conclusion: In cases with a progression in size, an elevated level of AFP should be suspicious. A second opinion at a center for hepato-biliary surgery with HCC/FNH-experienced radiologists and surgeons is reasonable. Generally, an over-therapy via surgery should be avoided and follow-ups of a newly diagnosed FNH including measurement of AFP are advisable to detect alterations.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is highly invasive and easily recurs. For HCC, chemotherapy shows a limited effect. The gold standard for HCC treatment includes curative surgical resection or liver transplantation. However, the recur-rence rate at 5 years after liver resection is estimated at approximately 70% and even at 5 years after liver transplantation, it is 20%. Therefore, improving survival outcomes after curative surgi-cal resection of liver cancer is crucial. This review highlights the importance of identifying risk factors for HCC recurrence following radical surgical resection and adjuvant therapy options that may reduce the recurrence risk and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization and radiotherapy), adjuvant systemic therapy (e.g., small molecule targeted therapy and immunotherapy), and other adjuvant therapies (e.g., chem-otherapy). However, further research is needed to refine the use of these therapies and optimize their effectiveness in preventing HCC recurrence.

This study aimed to evaluate the diagnostic and prognostic roles of GATA3 immunohistochemistry in urothelial carcinoma (UC) through a meta-analysis. We investigated GATA3 immunohistochemical expression rates and performed a subgroup analysis based on tumor site, study location, and histological subtypes. The overall survival rates of patients with GATA3-positive and negative UC were compared. The estimated GATA3 expression rate was 0.748 (95% confidence interval [CI]: 0.704–0.787). GATA3 expression rates in the urinary bladder and urinary tract were 0.775 (95% CI: 0.727–0.818) and 0.614 (95% CI: 0.426–0.774), respectively. The GATA expression rates of noninvasive and invasive UCs were 0.965 (95% CI: 0.938–0.980) and 0.644 (95% CI: 0.581–0.702), respectively. In invasive UCs, there was a significant difference in GATA3 expression between non-muscular invasion and muscular invasion subgroups (0.937, 95% CI: 0.883–0.967 vs. 0.753, 95% CI: 0.645–0.836). GATA3 expression was the highest in the microcytic subtype among the histologic subtypes (0.952, 95% CI: 0.724–0.993). There was a significant correlation between GATA3 expression and better prognosis (hazard ratio: 0.402, 95% CI: 0.311–0.521). Taken together, GATA3 expression significantly correlated with low-stage and better prognosis in UC. GATA3 expression is highly variable across histological subtypes and it is careful interpreting GATA3 expression.

Medullary thyroid carcinomas (MTCs) are rare thyroid tumors occurring in both sporadic and hereditary forms and whose pathogenesis is related to RET proto-oncogene alterations. MTCs originate from parafollicular cells, which produce calcitonin that represents the biochemical activity of MTC. Total thyroidectomy is the main treatment for MTC and often cures patients with confined diseases. In cases of metastasis, the approach depends on the rate of progression of disease. We report a case of a 54 years old female with a single, incidentally discovered, thyroid nodule of 1 cm, classified as suspicious MTC after a stimulation test with i.v. calcium. After surgery, we examined the nodule using immunohistochemistry, immunofluorescence and electron microscopy. In addition to calcitonin, we found that it expressed intracellular positivity for the RTK receptors ERBB1 and ERBB2. Consistently with MTC features, ultrastructural examination of the tumor displayed heterogeneous spindle-shaped cells containing two groups of secretory granules. Due to the significant correlation found between high ERBB1/ERBB2 levels in MTCs and extrathyroidal growth, the detection of ERBB1 and ERBB2 expression suggests that the two oncoproteins may possibly be involved in tumor proliferative responses and/or differentiation of C-cells. The biological, prognostic and therapeutic significance of these patterns would merits further investigations.

Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage (P = 0.032) and recurrence (P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136–4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC.

Urothelial cell carcinoma (UCC, bladder cancer) remains a difficult to treat malignancy with rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age, ~four times more commonly observed in men than women. The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC is highly aggressive and remains generally incurable since these cancers are associated with intrinsic and acquired drug resistance. UCC is highly lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss the novel therapies to improve the management of mUCC.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Low numbers of HCC patients being suitable for liver resection or transplantation and multidrug resistance development during pharmacotherapy leads to high death rates for HCC patients. Understanding the molecular mechanisms of HCC aetiology contributes to development of novel therapeutic strategies for prevention and treatment of HCC. UDP-glucose ceramide glycosyltransferase (UGCG), a key enzyme in glycosphingolipid metabolism, generates glucosylceramide (GlcCer), which is the precursor for all glycosphingolipids (GSLs). Since UGCG gene expression is altered in 0.8 % of HCC tumors, GSLs may play a role in cellular processes in liver cancer cells. Here, we discuss current literature about GSLs and their abundance in normal liver cells, Gaucher disease and HCC. Furthermore, we review the involvement of UGCG/GlcCer in multidrug resistance development, globosides as a potential prognostic marker for HCC, gangliosides as a potential liver cancer stem cell marker, and the role of sulfatides in tumor metastasis. Only a limited number of molecular mechanisms executed by GSLs in HCC are known, which we summarize here briefly.

Papillary thyroid carcinoma (PTC) presents a significant health concern, particularly among Hispanic women in the United States, who exhibit a disproportionately higher chance of developing an advanced disease when compared to the non-Hispanic population. Emerging evidence suggests coagulation factor X, encoded by F10 gene, has a potential role in inhibiting cancer cell migration. However, comprehensive investigations into the differential expression patterns of F10 in Hispanic versus non-Hispanic females remain limited. RNA-sequencing data was acquired from the TCGA database for white female patients, 166 non-Hispanic and 25 Hispanic. A statistically significant (p < 0.05) 2.06-fold increase in F10 expression levels was detected in disease-free tumors compared to recurrent PTC tumors. Furthermore, an increase in F10 gene expression levels was also observed corresponding to approximately a 1.74-fold increase in non-Hispanic patients compared to Hispanic patients. The probability of tumor recurrence was 1.82 times higher in the cohort with low expression of F10 compared to the high expression cohort, correlating with the lower disease-free rates observed in Hispanic patients’ cohort when compared to non-Hispanics. This finding underscores the relevance of ethnic disparities in molecular profiles for understanding cancer susceptibility. Identifying F10 as a potential prognostic biomarker highlights avenues for targeted interventions and contributes to improving diagnostic and treatment strategies for diverse patient populations.

Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable HNSCC, DTX combined with cisplatin and 5-fluorouracil as a revolutionary treatment revealed an advantage in improvement of patient outcome. In addition. DTX plus immune check inhibitors (ICIs) showed low toxicity and increased response of patients with recurrent or metastatic HNSCC (R/M HNSCC). Accumulating data indicate that taxanes not only function as antimitotics but also impair diverse oncogenic signalings including angiogenesis, inflammatory response, ROS production, and apoptosis induction. However, despite an initial response, development of resistance remains a major obstacle to treatment response. Taxane resistance could result from intrinsic mechanisms such as enhanced DNA/RNA damage repair, increased drug efflux, and apoptosis inhibition, and extrinsic effects such as angiogenesis and interactions between tumor cells and immune cells. This review provides an overview of taxanes therapy applied in different stages of HNSCC and describe the mechanisms of taxane resistance in HNSCC. Through a detailed understanding the mechanisms of resistance may help developing the potential therapeutic methods and the effective combination strategies to overcome drug resistance.

Background – Endobronchial squamous cell carcinoma is one of the most common types of tumors with such a location. Patients often present in advanced stages of the disease, which leads to a targeted therapeutic attitude of pneumonectomy, most of the time. Practicing a lung parenchyma-preserving surgery led us to do this review. Material and Methods - We used three search platforms SCIENCE, MEDLINE and PubMed, in order to identify studies presenting case reports, studies and reviews on endobronchial squamous cell carcinoma. We identified clinical and paraclinical features of endobronchial squamous cell carcinoma. All selected articles were in English and contained clinical criteria of endobronchial squamous cell carcinoma, autofluorescence bronchoscopy in endobronchial squamous cell carcinoma, imaging features of endobronchial squamous cell carcinoma, blood tumor markers specific for lung squamous cell carcinoma, histopathological features of endobronchial squamous cell carcinoma. Results - 73 articles were analyzed, from which 47 articles were selected as bibliographic references. We have presented the criteria found for endobronchial squamous cell carcinoma in order to highlight the main characteristics and high reliability technologies for the detection of this type of cancer. Conclusions – The current literature review highlights the clinical and paraclinical characteristics of endobronchial squamous cell carcinoma. It aims to open new horizons for research and early detection, frequent practice of lung parenchymal preservation surgery.

A wide variety of renal neoplasms can have cystic areas. It happens for different reasons: some tumors have an intrinsic cystic architecture, others have a pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated to low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway and they are more frequent in patients suffering from VHL disease. The differential diagnosis with multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and it requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumors include cystic forms, a knowledge of criteria for a differential diagnosis is mandatory.

Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.

Background: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. Patients and methods: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. Results: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1>49% in combination with a negative KRAS result had a median survival of 40 months compared to patients with a positive KRAS result (9 months, p<0.05). In addition, patients diagnosed with adenocarcinoma, PDL1<49% and negative KRAS result had a median survival of 39 months compared to patients with a positive result (28 months, p<0.05). Conclusions: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.

Purpose: This study aimed to elucidate the various new classifications and the use of LDLT in this context for HCC beyond milan criteria. Methods: The clinical data of patients with HCC outside milan criteria who underwent LT at Jena University between Januar 2007 and August 2023 were retrospectively analyzed. Eligible patients were classified according to various classification systems. Clinicopathological features, overall- and disease-free survival rates were compared between the two groups (LT vs. LDLT) and in context for bridging therapy. Results: Among the 245 patients analyzed, 120 patients were outside milan criteria and 125 patients were inside milan. There was no significant difference for patients outside milan in overall survival for LT versus LDLT (OS 44,3 months vs. 28,3 months; 5y survival, 56,4% vs. 40%; p = 0.84). G3 tumor differentiation, presence of angioinvasion and lack of bridging were statistically significant risk factors predicting tumor recurrence in univariate and multivariate analysis (HR 6.34; p = 0.0002; HR 8.21; p < 0.0001; HR 7.50; p = 0.0001). Bridging therapy before transplantation provides a significant survival advantage regardless of the transplant procedure (OS: p = 0.008 ; DFS: p < 0.001). Conclusions: Patients with HCC outside milan criteria who underwent LT or LDLT had comparable outcome to patients inside milan criteria. Nevertheless, these patients remain disadvantaged on the waiting list, which is why LDLT represents a safe alternative to LT and should be considered in bridged HCC patients depending on tumor differentiation, size and tumor marker dynamics.

Background: Hepatocellular carcinoma (HCC) is one of most common cancers with a high mortality rate. HBV/HCV infection is an important risk factor to trigger HCC. Therefore, developing serum biomarkers for early diagnosis is crucial to prolong survival in HCC patients. Methods: An antibody array technology was utilized to detect serum from 20 HBV-related HCC patients, 20 chronic hepatitis B patients and 20 normal population, whose results were further validated by ELISA. Results: Both antibody array and ELISA showed that ten growth factors (SCF R, GDF-15, HGF, FGF-4, IGFBP-1, PIGF, GH, GDNF, BDNF and IGF-1) were significantly differential in HCC patients when compared to the non-HCC population. Among these growth factors, the levels of SCF R, GDF-15, HGF, GH and IGF-1 showed significant correlation with hepatitis B and its severity, indicating that these growth factors may promote HCC progression by an HBV-specific mechanism. A therapy targeting these growth factors in hepatitis B patients may help to prevent the development of HCC. FGF4 and GH were found, for the first time, to be upregulated in HCC, suggesting that these two growth factors may serve as novel serum biomarkers for the early diagnosis of HCC. Conclusion: The combined detection of all the differential growth factors may improve the diagnostic accuracy of HCC.

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

This study aimed to establish a predictive model for neoadjuvant chemoradiotherapy (nCRT) response in patients with locally advanced rectal carcinoma (LARC) using clinicopathological (CP) features along with radiomics from pretreatment Magnetic Resonance Imaging (MRI) 3D T2W contrast sequence scans. The study also assessed the impact of radiomic dimensionality on predictive performance. Seventy-five patients were prospectively enrolled with clinicopathologically confirmed LARC who underwent nCRT before surgery. Tumor properties were assessed by calculating 2142 shape, first-order, and second-order radiomics features. Least absolute shrinkage and selection operator (LASSO) and multivariate regression were used for feature selection. Two predictive models were constructed, one using 72 CP and 107 radiomics features, and the other using 72 CP and 1862 radiomics features. The models revealed moderately advantageous impact of increased dimensionality, while their predictive performance was in the range generally considered excellent, with respective AUCs of 0.86 and 0.90. A CP-only model (AUC=0.80) served as the benchmark for predictive performance without radiomics. The predictive models developed in this study using pretreatment MRI data, radiomics features, and clinicopathological parameters could potentially be used to routinely predict chemoradiotherapy responders, enabling clinicians to personalize treatment strategies for rectal carcinoma.

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer, thus it could be used as a predictive biomarker. In this review, we will dissect the gut microbiome's role as a potential predictive and diagnostic marker in HCC and evaluate the latest progress in leveraging the gut microbiome as a novel therapeutic avenue for HCC patients, with a special emphasis on immunotherapy.

Background: Despite recent advances in epithelial ovarian carcinoma (EOC) treatment, recur-rence and mortality rates have not improved significantly. DNA hypermethylation has generally been associated with ominous prognosis and chemotherapy resistance, but the role of DNMTs in EOC remains to be investigated. Methods: In the current study, we systematically retrieved gene expression data from patients with EOC and studied the immunohistochemical expression of DNMTs in 108 primary and 26 relapsed tumors. Results: Our results showed that DNMT1, DNMT3A, DNMT3B and DNMT3L RNA levels were higher and DNMT2 lower in tumors compared to non-neoplastic tissue, and DNMT3A and DNMT2 expression decreased from Stage II to Stage IV carcinomas. Proteomic data also suggested that DNMT1 and DNMT3A levels were increased in tumors. Similarly, DNMT1, DNMT3A and DNMT3L protein levels were overex-pressed and DNMT2 expression was reduced in high grade carcinomas compared to non-neoplastic tissue and low-grade tumors. Moreover, DNMT1 and DNMT3L were increased in relapsed tumors compared to their primaries. DNMT3A, DNMT1 and DNMT3B mRNA lev-els were correlated with overall survival. Conclusions: Our study demonstrates that DNMT1 and DNMT3L are upregulated in primary high grade EOC and further increase in relapses, whereas DNMT3A is upregulated only in the earlier stages of cancer progression. DNMT2 downregulation highlights a presumptive tumor-suppressor activity of this gene in ovarian car-cinoma.

No abstract available

Background: The prognostic and predictive role of stromal tumor-infiltrating lymphocytes (sTILs) is undetermined in pleomorphic invasive lobular cancer (pILC). The same applies for the expression of PD-1/PD-L1 in this rare breast cancer subtype. Here, we aimed to investigate the expression of sTILs, and analyze the PD-L1 expression levels in pILC. Methods: Archival tissues from sixty-six patients with pILC were collected. The sTIL density was scored as a percentage of tumor area, using the following cut-offs: 0%; <5%; 5-9%; and 10-50%. PD-L1 expression was analyzed using IHC on formalin-fixed, paraffin-embedded tissue sections, using the SP142 and 22C3 antibodies. Results: 82% of the sixty-six patients were hormone receptor-positive; 8% of cases were triple negative (TN), while 10% showed human epidermal growth factor receptor 2 (HER2) amplification. sTILs were present in 64% (1%) of the study population. Using the SP142 antibody, 36% of tumors demonstrated a positive PD-L1 score of 1%, and 28% had a positive PD-L1 score of 1 using the 22C3 antibody. There was no correlation of sTILs or PD-L1 expression with tumor size, tumor grade, nodal status, expression of estrogen receptor (ER) or amplification of HER2. Our data did not show any difference in survival between the three molecular subtypes of pILC with respect to sTILs and PD-L1 expression. Conclusion: This study shows that pILCs show some degree of sTILs and PD-L1 expression, however this was not associated with survival benefit. Additional large trials are needed to understand the immune infiltration in lobular cancer, even more in the pleomorphic subtype.

The survival analysis of the Cancer Genome Atlas (TCGA) dataset is a well-known method to discover the gene expression-based prognostic biomarkers of head and neck squamous cell carcinoma (HNSCC). A cutoff point is usually used in survival analysis for the patients' dichotomization in the continuous gene expression. There is some optimization software for cutoff determination. However, the software's predetermined cutoffs are usually set at the median or quantiles of gene expression value to perform the analyses. There are also few clinicopathological features available on their pre-processed data sets. We applied an in-house workflow, including data retrieving and pre-processing, feature selection, sliding-window cutoff selection, Kaplan-Meier survival analysis, and Cox proportional hazard modeling for biomarker discovery. In our approach for the TCGA HNSCC cohort, we scanned human protein-coding genes to find optimal cutoff values. After adjustment with confounders, the clinical tumor stage and the surgical margin involvement are independent risk factors for patients' prognosis. According to the resulting tables with Bonferroni-adjusted P value under the optimal cutoff and the hazard ratio, three biomarker candidates, CAMK2N1, CALML5, and FCGBP, are significantly associated with the patients' overall survival. We validated this discovery by using the other independent HNSCC dataset (GSE65858). Thus, we suggest the transcriptomic analysis could help for biomarker discovery.

It has been suggested that particle size plays an important role in determining the genotoxicity of gold nanoparticles (GNPs). The purpose of this study was to compare the potential radio-sensitization effects of two different sized GNPs (3.9 and 37.4 nm) fabricated and examined in vitro in Lewis Lung carcinoma (LLC) as a model of non-small cell lung cancer through use of comet and clonogenic assays. After the treatment of 2Gy X-ray irradiation, both particle sizes demonstrated increased DNA damage when compared to treatment with particles only and radiation alone. This radio-sensitization was further translated into a reduction in cell survival demonstrated by clonogenicity. This work indicates that GNPs of both sizes induce DNA damage in LLC cells at the tested concentrations, whereas the 37.4 nm particle size treatment group demonstrated greater significance in vitro. The presented data aids in the evaluation of the radiobiological response of Lewis Lung carcinoma cells treated with gold nanoparticles.

Background: We aimed to create a model of radiological and pathological criteria able to predict the upgrade rate of low-grade ductal carcinoma in situ (DCIS) to invasive carcinoma, in patients undergoing vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. Methods: 3100 VABBs were retrospectively reviewed among which we reported 295 low-grade DCIS who subsequently underwent surgery. The association between patients’ features and the upgrade rate to invasive breast cancer (IBC) was evaluated by univariate analysis. Finally, we developed a predictive multivariable model based on the features which were significantly associated with the univariate analysis outcome. Results: the upgrade rate to invasive carcinoma was 10.8 %. At univariate analysis, the risk of upgrade was significantly lower in the absence of post- biopsy residual lesion (p<0.001), age > 50 (p=0.029), and in presence of low-grade DCIS only in specimens with microcalcifications (p=0.002). According to the final multivariable model, the predicted probability of diagnostic underestimation for a patient with all the three favourable features selected at univariate analysis was 1% (95% CI: 0.3%-4%). Conclusions: An easy to use predictive model of radiological and pathological criteria is able to identify patients with low-grade carcinoma in situ with low risk of upstaging to infiltrating carcinomas.

Collision tumors, even uncommon, characterized by two distinctive (morphological, as well immunohistochemical) and spatially independent tumor components in the same location, are always puzzling for clinicians, pathologists and patients because they don’t fit in usual approaching schemes, neither diagnostic, nor therapeutic. Reviewing the specialized literature, until now, collision tumors have been reported in multiple locations such as the skin, esophagus, stomach, liver, kidney, bladder, adrenal gland or thyroid. We report a case of coexistence on the same site of a malignant tumor of ascending colon and a benign one emerging from peritoneal lining, thought initially by the surgeon to be right sided serosal carcinomatosis. But the histopatological examination reveals that those multiple serosal nodules were benign granular cell tumors collided with highly aggressive transparietal signet-ring colon carcinoma. These results put the patient's prognosis and therapeutic strategy in a different light than the clinical-imaging and intraoperative assessment.

β₂-m, β₂-microglobulin; CAF, cancer associated fibroblast; CSC, cancer stem cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; ECM, extracellular matrix; EGF-R, epidermal growth factor receptor; ER, endoplasmic reticulum; FDA, Food and Drug Administration; HLA, human leukocyte antigen; HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; ICP immune checkpoint; ICPi, immune checkpoint inhibitor; IFN, interferon; LMP, low molecular weight protein; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; mTOR, mammalian target of rapamycin; MSI, multispectral imaging; NK, natural killer; OS, overall survival; PBL, peripheral blood lymphocytes; PBMNC, peripheral blood mononuclear cells; PD1, programmed death receptor 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; PI3K, phosphatidyl-linositol-3-kinase; R/M, recurrence and or metastatic; STAT, signal transducer and activator of transcription; TAA, tumor-associated antigen; TAM, tumor associated macrophages; TAP, transporter associated with antigen processing; TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte; TLS, tertiary lymphoid structure; TME, tumor microenvironment; Treg, regulatory T cell; TSA, tumor-specific antigen; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor.

Approximately half of head and neck squamous cell carcinoma (HNSCC) cases recur, and most of them recur within the first two years after treatment. Although it has been suggested that the interval to recurrence after radical treatment and prognosis in patients with HNSCC are associated, investigations are insufficient. In this study, patients diagnosed with HNSCC at Kyushu University Hospital were retrospectively analyzed (n = 500). A total of 234 patients experienced recurrence, with 110 and 124 patients experiencing early recurrence (ER) (recurrence within 2–6 months) and late recurrence (LR) (recurrence after 7 months), respectively. There were two independent risk factors for poor prognosis in the multivariate analyses: ER (hazard ratio [HR] = 3.200, 95% confidence interval [CI] = 1.570–6.521, p = 0.001) and no radiotherapy (HR = 0.374, 95% CI = 0.191–0.733, p = 0.004). In patients with recurrent HNSCC, a short interval to recurrence is a risk factor for poor prognosis and survival. This study demonstrated the prognostic value of ER in patients. During the selection of treatment for patients with recurrence, the recurrent area, initial treatment content, and strategy of changing salvage therapy depending on the recurrence status should be considered.

Over the few decades, cancer-associated mortalities and morbidities were continuously increased worldwide despite sophisticated technological advancements. Pharmaceutical interventions associated with drugs exhibit a high degree of side effects and toxicities in addition to very high costs. Subsequently, to reduce or to vanish the side effects and high costs, researchers are now exploring natural bioactive compounds such as quercetin in its nanoformulations along with biologics as cargo delivery vehicles. Quercetin along with mesenchymal stromal lineage-derived extracellular vesicles (EVs) possesses an anti-cancer potential that can be explored to treat hepatocellular carcinoma (HCC). Exerting enhanced effect, nano quercetin synergistically with EVs triggers the anti-cancer mechanisms by regulating and dysregulating several signalling mechanisms including NF-κB, p53, JAK/STAT, MAPK, Wnt/β-catenin and PI3K/AKT, in addition to PBX3/ERK1/2/CDK2, and miRNAs modulation. In addition, findings regarding the potential checkpoints of anti-cancer signalling pathways were investigated that offer opportunities to develop engineered EVs incorporated with nano quercetin for the development of novel therapeutics to treat HCC in future. In this present mechanistic review, we abridged the regulation of such signalling mechanisms synergetic approach of nano quercetin and EVs. The regulatory role of EVs in the manifestation of innumerable miRNAs has also been tailed with special context to HCC.

The Cancer Genome Atlas (TCGA) has classified papillary thyroid carcinoma (PTC) into indolent RAS-like and aggressive BRAF-like based on its distinct driver gene mutations. This study aimed to assess clinicopathology and pERK1/2 expression variations between BRAF-like and RAS-like PTCs and establish predictive models for BRAFV600E and RAS-mutated PTCs. A total of 222 PTCs underwent immunohistochemistry staining to assess pERK1/2 expression and Sanger sequencing to analyze the BRAF and RAS genes. Multivariate logistic regression was employed to develop prediction model. Independent predictors for the BRAFV600E mutation include a nuclear score of 3, the absence of capsules, an aggressive histology variant, and pERK1/2 levels exceeding 10% (X2=0.128, P&gt;0.05, AUC=0.734, P&lt;0.001). RAS mutation predictive model includes follicular histology variant and pERK1/2 expression &gt;10% (X2=0.174, P&gt;0.05, AUC=0.8, P&lt;0.001). We proposed using the prediction model concurrently with four potential combination group outcomes. PTC cases included in combination of low BRAFV600E-scoring group and high RAS-scoring group are categorized as RAS-like (adjOR=4.857, P=0.01, 95% CI=1.470-16.049). PTCs included in combination of high BRAFV600E-scoring group and low RAS-scoring group are categorized as BRAF-like PTCs (adjOR=3.091, P=0.001, 95% CI=1.594-5.995). The different prediction models indicate variations in biological behaviour between BRAF-like and RAS-like PTCs, necessitating adjustments in treatment approaches.

(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.

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

In the last decade a group of Ca2+ channels called Piezo were discovered, demonstrating a decisive role in the cellular response to mechanical stimuli and being essential in the biological behaviour of cells regarding the extracellular compartment. Several investigations have suggested a potential role in carcinogenesis with a tumor supressor role in some cases, but increased expression in several high grade neoplasms. Regarding Piezo2 expression in mammary gland neoplasms, early results suggested a protective role of Piezo2, but posterior works resulted in a relationship between Piezo2 expression and the highly-aggressive triple negative phenotype of breast carcinoma. A cohort of 125 patients with clinical follow up was chosen to study Piezo2 expression and clarify its clinical implications, using the same immunohistochemical valuation performed for other breast carcinoma parameters. Fisher exact was chosen to identify potential relationships between the different variables. A significant association was found with the Ki67 proliferation index, but not with mitoses. The tendency of most proliferative tumors was to have a diminished score for Piezo2. A similar association was found between Piezo2 expression and perineurial invasion.

Hepatocellular carcinoma (HCC) poses a significant global health concern, with its incidence steadily increasing. The development of HCC is a multifaceted, multi-step process involving alterations in various signaling cascades. In recent years, significant progress has been made in understanding the molecular signaling pathways that play central roles in hepatocarcinogenesis. In particular, the EGFR/PI3K/Akt/mTOR signaling pathway in HCC has garnered renewed attention from both basic and clinical researchers. Preclinical studies in vitro and in vivo have shown the effectiveness of targeting the key components of this signaling pathway in human HCC cells. Thus, targeting these signaling pathways with small molecule inhibitors holds promise as a potential therapeutic option for patients with HCC. In this review, we will explore recent advancements in understanding the role of the EGFR/PI3K/Akt/mTOR signaling pathway in HCC and assess the effectiveness of targeting this signaling cascade as a potential strategy for HCC therapy based on preclinical studies

(1) Background: This case presents a rare and challenging clinical scenario involving a 50-year-old female patient diagnosed with Inflammatory Carcinoma, a particularly aggressive and rapidly growing form of breast cancer. The disease is characterized by heat, redness, swelling and noticeable changes in the breast's skin texture, resembling the skin of an orange (peau d'orange). This case is important because it contributes to the limited clinical literature on such aggressive forms of breast cancer.; (2) Methods: The multidisciplinary approach was employed. Diagnostic procedures such as imaging tests, biopsy, and histopathological examination were performed to confirm the diagnosis of Inflammatory Carcinoma and assess the extent of the disease. The presence of the HER2 protein on the tumor cells supported the selection of a combination therapy involving systemic chemotherapy and targeted biological therapy.; (3) Results: The patient responded positively to the combination therapy consisting of systemic chemotherapy and targeted biological therapy. The aggressive nature of Inflammatory Carcinoma, characterized by rapid growth and distinct skin changes, was effectively addressed. The presence of the HER2 protein on the tumor cells indicated the potential efficacy of the combination therapy in aggressive forms of breast cancer.; (4) Conclusions: This case highlights the critical importance of a multidisciplinary approach in managing complex cases of breast cancer, especially rare and aggressive subtypes like Inflammatory Carcinoma. The positive response of the patient to the combination therapy involving systemic chemotherapy and targeted biological therapy demonstrates the potential for favorable outcomes in aggressive disease presentations.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is reasonable epidemiological cohort data to recommend surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommend that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) should consider HCC surveillance. NITs include fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US or if US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II), can help to identify high risk of incident HCC in NAFLD patients. Innovative parameters including Mac-2 binding protein glycated isomer , type IV collagen 7S, free apoptosis inhibitor of macrophage, combination of single nucleoside polymorphisms are expected to be established. Considering a large number of NAFLD population, optimal screening tests must meet several criteria including high sensitivity, cost effectiveness and availability.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib has been the standard of care for almost a decade until 2018 when FDA approved an alternative first-line agent namely lenvatinib. Whereas FOLFOX4 results an alternative first-line treatment for the chinese clinical oncology guidelines. In addition to cabozantinib, regorafenib, and ramucirumab, two therapeutics against the PD-L1/PD1 axis have been recently approved for subsequent-line therapy, as nivolumab and pembrolizumab. However, similar to other solid tumors, the response rate of single-agent targeting PD-L1/PD1 axis is low. Therefore a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors, the addition of immune checkpoint inhibitors after resection or during locoregional therapy, immune checkpoint inhibitors in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with an attent evaluation of new ICIs based combinatory approaches.

Liquid biopsy, based on the circulating tumor cells (CTCs) and cell-free nucleic acids has potential applications at multiple points throughout the natural course of cancer, from diagnosis to follow-up. The advantages of doing ctDNA assessment vs. tissue-based genomic profile are the minimal procedural risk, the possibility to serial testing in order to monitor disease-relapse and response to therapy over time and to reduce hospitalization costs during the entire process. However some critical issues related to ctDNA assays should be taken in consideration. The sensitivity of ctDNA assays depends on the assessment technique and genetic platforms used, on tumor-organ, stage, tumor heterogeneity, tumor clonality. The specificity is usually very high, whereas the concordance with tumor-based biopsy is generally low. In patients with renal cell carcinoma (RCC) qualitative analyses of ctDNA have been performed with interesting results regarding selective pressure from therapy, therapeutic resistance, exceptional treatment response to everolimus and mutations associated with aggressive behavior. Quantitative analyses showed variations of cfDNA levels at different tumor stage. Compared to CTC assay, ctDNA is more stable than cells and easier to isolate. Splice variants, information at single-cell level and functional assays along with proteomics, transcriptomics and metabolomics studies can be performed only in CTCs.

Aim: This analytical cross-sectional study aimed to examine whether there is a correlation between tumor differentiation and certain biomarkers in patients with hepatocellular carcinoma (HCC). Methods: Poorly differentiated (n=443), moderately differentiated (n=379), and well-differentiated (n=272) tumors were separated from the research population, along with a control group (n=364). Biopsies were used to establish the presence of HCC, and biomarker levels were analyzed using chemiluminescence immunoassays in both infected and uninfected individuals. Results: The correlation between age and tumor size was shown to be statistically significant (p0.05) across all subgroups using both descriptive and inferential statistics. Patients with hepatitis C virus and non-A, non-B hepatitis had more advanced tumors than those with other types of poorly differentiated liver cancer. Similarly, individuals with HBsAg and moderate differentiation had bigger tumors, although there was no correlation between hepatitis C and non-A, non-B. Patients with HBsAg or hepatitis C had bigger tumors in the well-differentiated group, albeit the hepatitis C connection was not statistically significant. In addition, the study stressed that tumor size increases with age and that farmers were the most commonly diagnosed profession category. Conclusions: It is clear that early detection in infected populations is crucial for improving HCC outcomes and that chemiluminescence immunoassay has the potential to be a helpful platform for biomarker research. However, the study is limited by its small sample size and its emphasis on only three tumor markers, indicating that more biomarker research is required to improve the accuracy of HCC diagnosis and prognosis.

Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Because of their expression pattern, they have historically been attractive targets for immunotherapies. The investigation of mechanistic roles of CT antigens in promoting oncogenesis has historically been a prominent research question, and a growing number of studies implicate CT antigens in promoting almost all the hallmarks of cancer. This suggests that CT antigens may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas, although their role in the pathogenesis, prognostication, and treatment for this family of cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and therapeutic response and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.

The incidence of human papillomavirus-related head and neck squamous cell carcinoma (HPV+HNSCC) has reached epidemic levels in the last decade. While prophylactic vaccines will prevent future HPV infections, there are currently no HPV-specific antiviral drugs to treat current HPV infections or HPV+HNSCC. HPV replication and transcription are promising targets for anti-HPV therapeutics, as modulation of these processes can alter expression levels of HPV E6 and E7, which are required for maintenance of the transformed phenotype. This is a particularly attractive target in in HPV+HNSCC where the majority of tumors have episomal genomes replicating in an E1-E2 dependent manner. Here, we describe a model system to study HPV16 E1-E2 mediated DNA replication and HPV16 E2-mediated transcriptional activation and repression in multiple HNSCC cell lines. Our results demonstrate that low levels of IFIT1 are required for HPV16 replication in HNSCC cell lines and HPV16 E1 interacts with IFIT1. Restoration of IFIT1 expression in HNSCC cell lines partially inhibits HPV16 E1-E2 mediated replication. This system can be used to study replication and transcription by HPV16 E1 and E2 in HNSCC as well as be utilized to screen potential anti-HPV therapeutics that target HPV16 replication and transcription.

Renal cell carcinoma (RCC), alternative term for kidney cancer, is becoming more common worldwide each year, and there are many different contributing factors. Among all cancers, RCC is the 14th most prevalent; and it ranks as the 14th and 9th most prevalent cancer overall for women and men respectively. RCC cases increased by more than 430,000 in 2020. While disease burdens are highest in Eastern Europe (Belarus and Russia) and North America (Canada and the United States), Africa, Asia, and Latin America are predicted to report increase in prevalence as these regions embrace change in lifestyle. The majority of RCC cases are accidentally found on imaging, and survival is greatly impacted by the disease stage at diagnosis, with a metastatic cancer having a 5-year survival rate of 12%. As a consequence of early discovery and more improved treatments, RCC mortality has declined. The key epidemiologic variables of RCC include vast regional and geographical heterogeneity in prevalence rates, and the cause is largely unclear. Recognized risk factors include smoking, being overweight, having previous episodes of hypertension, and suffering chronic renal illness. Unexpectedly swift, RCC diagnosis and therapy have advanced. RCC prevalence continues to rise although survival rates have sharply improved. Cancer survival and treatment have improved, and more gains are projected as a result of clinical and translational research. In this review, kidney cancer statistics and recent literatures are examined on a global scale. It covered aspects of kidney cancer, including its epidemiology, causes, risk factors, current immunotherapy, chances for prevention, and future planning.

A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab was 21.1 months (range, 18.8 months-not reached) and 10.5 months (range, 8.2‒12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.3 months-not reached) and 4.0 months (range, 2.5‒6.4 months), respectively. The objective response rates based on response evaluation criteria in solid tumors (RECIST) criteria version 1.1 and modified RECIST were 33.3% and 54.2%, respectively. On multivariate analysis, Child-Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02‒0.76, p = 0.02) and intrahepatic tumor occupancy rate &lt;50% (hazard ratio &lt;0.01, 95% CI 0.003‒0.35, p &lt;0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers in humans, characterised by high resistance to conventional chemotherapy, late diagnosis, and high mortality rate. It is necessary to elucidate the molecular mechanisms involved in hepatocarcinogenesis to improve diagnosis and treatment outcomes. The Runt-related (RUNX) family of transcription factors (RUNX1, RUNX2, and RUNX3) participates in cardinal biological processes and play paramount roles in the pathogenesis of numerous human malignancies. Their role is often controversial as they can act as oncogenes or tumour suppressors, dependent on cellular context. Evidence shows that deregulated RUNX genes may be involved in hepatocarcinogenesis from the earliest to the latest stages. In this review, we summarise the topical evidence on the roles of RUNX gene family members in HCC. We discuss their possible application as non-invasive molecular markers for early diagnosis, prognosis, and development of novel treatment strategies in HCC patients.

Currently, large cell neuroendocrine carcinoma of the lung (LCNEC) is classified as a rare lung cancer subtype, but given the high incidence of lung cancer, the overall number of cases is considerable. The pathologic diagnosis is based on the microscopic appearance of the tumor cells, the amount of intra-tumoral necrosis, the mitotic rate, and the presence of positive neuroendocrine markers identified by immunohistochemistry. Recently, a subdivision into two main categories was proposed based on mutation signatures involving the RB1, TP53, KRAS, and STK11/LKB1 genes, into SCLC-like (small cell lung cancer-like) and NSCLC-like (non-small cell lung cancer-like) LCNEC. In terms of treatment, surgery remains the best option for resectable, stage I–IIIA cases. Chemotherapy and radiotherapy have conflicting evidence. Etoposide/platinum remains the standard chemotherapy regimen. However, based on the newly proposed LCNEC subtypes, some retrospective series report better outcomes using a pathology-driven chemotherapy approach. Encouraging outcomes have also been reported for immunotherapy and targeted therapy, but the real impact of these strategies is still being determined in the absence of adequate prospective clinical trials. The current paper scrutinizes the epidemiology, reviews the reliability of pathologic diagnosis, discusses the need for molecular subtyping, and reviews the heterogeneity of treatment algorithms in LCNEC.

The burden of hepatocellular carcinoma (HCC) continues to pose a significant global health problem. Several systemic therapies have recently been shown to improve survival for patients with unresectable disease. However, evidence is limited to support the use of neoadjuvant or adjuvant systemic therapies in patients with resectable disease, despite the high risk of recurrence. Neoadjuvant and adjuvant systemic therapies are being investigated for their potential to reduce recurrence after resection and improve overall survival. Our review identified various early-phase clinical trials showing impressive preliminary signals of pathologic complete response in resectable disease and others suggesting neoadjuvant therapies, particularly when combined with adjuvant strategies, may convert unresectable disease to resectable and cause significant tumor necrosis, potentially decreasing recurrence rates. The role of adjuvant therapies alone may also have a role in the management of these patients, particularly in reducing recurrence rates. Heterogeneity in trial design, therapies used, patient selection, and a scarcity of randomized phase III trials necessitate the cautious implementation of these treatment strategies. Future research is required to identify predictive biomarkers, optimize the timing and type of therapeutic combinations, and minimize treatment-related adverse effects, thereby personalizing and enhancing treatment strategies for patients with resectable and borderline resectable HCC.

Background and Aims: Dyslipidemia and cardiovascular diseases (CAD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 cluster, has been associated CAD, but its impact on metabolic traits and liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 have HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC) and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n=125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p<0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The G allele was associated with higher risk of HCC and advanced tumor stage (p<0.05) in the Overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p<0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p<0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p<0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p<0.05). Conclusions: In sum, the rs599839 A>G variant improves dyslipidemia thus protecting against CAD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively

Mitochondrial production of 2-hydroxyglutarate (R-2HG) can be catalyzed by wild-type isocitrate dehydrogenase 2 (IDH2) and alcohol dehydrogenase, iron-containing 1 (ADHFE1). We investigated whether biochemical background and substrate concentration in breast cancer cells promote 2HG production. To estimate its role in 2HG production, we analyzed 2HG levels and its enantiomers in breast cancer cells using analytical approaches for metabolomics. By manipulation of mitochondrial substrate fluxes, including glutaminolysis, using genetic and pharmacological approaches we demonstrated the existence of an active competition between 2HG producing enzymes, i.e. IDH2 and ADHFE1. Moreover, we show that distinct fractions of IDH2 enzyme molecules operate in distinct oxido-reductive modes, providing NADPH and producing 2HG simultaneously. We have also detected 2HG release into breast cancer patient´s urine undergoing adjuvant therapy and detected a correlation with stages of breast carcinoma development. In summary, we provide a background for vital mitochondrial production of 2HG in breast cancer cells with outcomes towards cancer biology and possible future diagnosis of breast carcinoma.

Publically available (own) transcriptomic data were re-analyzed to quantify the alteration of functional pathways in the thyroid cancer, establish the gene hierarchy, identify potential gene targets and predict the effects of their manipulation. The expression data were generated from one case of papillary thyroid carcinoma (PTC) and from genetically manipulated BCPAP (papillary) and 8505C (anaplastic) human thyroid cancer cell lines. The study used the genomic fabric perspective that considers the transcriptome as a multi-dimensional mathematical object based on the three independent characteristics that can be derived for each gene from the expression data. We found remarkable remodeling of the thyroid hormone synthesis, cell cycle, oxidative phosphorylation and apoptosis pathways. Serine peptidase inhibitor, Kunitz type, 2 (SPINT2) was identified as the Gene Master Regulator of the investigated PTC. The substantial increase of the expression synergism of SPINT2 with apoptosis genes in the cancer nodule with respect to the surrounding normal tissue (NOR) suggests that its experimental overexpression may force the PTC cells into apoptosis with negligible effect on the NOR cells. The predictive value of the expression coordination for the expression regulation was validated with data from 8505C and BCPAP cells before and after lentiviral transfection with DDX19B.

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintained and reinforced their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

Tertiary lymphoid structures (TLSs) have become the focus of antitumor immunity. However, the prognostic significance of TLSs in epithelial ovarian cancer (EOC) treated with primary debulking surgery (PDS) or interval debulking surgery (IDS) remains unelucidated. This retrospective study examined the prognostic value of TLSs in tumor tissues obtained during PDS and IDS. Pathological specimens were collected from patients with EOC who underwent PDS or IDS between 2017 and 2020 at the National Cancer Center Hospital East. The correlation of tumor-infiltrating lymphocyte frequency, TLS presence, and PD-L1 expression with progression-free survival (PFS) and overall survival (OS) and the correlation between TLS and PD-L1 expression were analyzed. Overall, 25 specimens (15 from PDS and 10 from IDS) were analyzed. The presence of TLS was associated with a significantly longer OS in patients who underwent PDS but not in patients who underwent IDS. No correlation was identified between TLS and PFS in patients with PDS or with IDS. However, TLS was positively correlated with PD-L1 positivity. The prognostic impact of TLS, specifically in pre-chemotherapy specimens, and a positive correlation between TLS and PD-L1 indicate the potential of TLS as a meaningful biomarker for understanding antitumor immunity and developing immunotherapy for EOC.

This report elucidates a case of papillary carcinoma of the Thyroglossal Duct Cyst in a 19-year-old female. The swelling at presentation was suprahyoid, fixed and non-mobile with deglutition or tongue protrusion. Papillary carcinoma was diagnosed post-op through histopathological examination and a follow-up total thyroidectomy was planned. As the origin of TGDC papillary carcinoma is highly debated, no evidence-based guidelines yet exist as to the best line of treatment, however, Sistrunk’s procedure followed by total/near total thyroidectomy is widely considered the standard management practice in such cases.

This study aims to explore the utilization of deep learning models, specifically the innovative Multi-Modal Contextual Fusion Convolutional Neural Network (MSHA), for the detection and diagnosis of Adrenocortical Carcinoma (ACC) using computed tomography (CT) images. The objective is to develop an accurate and reliable model that can assist in the effective detection and classification of ACC. The study utilizes a dataset comprising contrast-enhanced CT images from 53 confirmed ACC patients. The MSHA model is employed, which incorporates a combination of mixed-scale dense convolution, self-attention mechanism, hierarchical feature fusion, and attention-based contextual information techniques. Evaluation metrics are used to assess the performance of the MSHA model, and a comparison is made with other established models, including ResNet50, VGG16, VGG19, and InceptionV3. The evaluation of the MSHA model demonstrates high performance, with an accuracy of 96.65% and precision, sensitivity, specificity, and F1 score of 96.0%. These results highlight the MSHA model's capability in accurately detecting and classifying ACC. Furthermore, compared to other models, the MSHA model outperforms ResNet50, VGG16, VGG19, and InceptionV3, indicating its superior performance in ACC detection and diagnosis. The findings of this study suggest that the MSHA model holds significant potential in assisting healthcare professionals with the detection and diagnosis of ACC. With its advanced features and contextual fusion techniques, the MSHA model achieves high accuracy and performance. The results highlight the clinical significance of this novel model and its potential to improve patient management and outcomes in the detection and diagnosis of ACC using CT images.

Simple summary: The noninvasive differentiation of hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC) remains challenging. In recent years, the number of studies on the application of radiomics in liver cancer has grown dramatically. However, there have been very few studies on the differentiation of HCC from ICC based on multisequence magnetic resonance imaging (MRI) radiomics. This study aimed to investigate the efficacy of a radiomic model based on preoperative fat suppression T2-weighted imaging (FS-T2WI) and dynamic contrast-enhanced MRI features in the arterial phase (A) and portal venous phase (P) for the differentiation of HCC from ICC. Abstract: The purpose of this study was to investigate the efficacy of magnetic resonance imaging (MRI) radiomics in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC). The clinical and MRI data of 129 pathologically confirmed HCC cases and 48 ICC cases from April 2016 to December 2021 at the Affiliated Hospital of North Sichuan Medical College were retrospectively analyzed. Included cases were randomly divided at a ratio of 7:3 into a training group of 124 cases (90 HCC cases and 34 ICC cases) and a validation group of 53 cases (39 HCC cases and 14 ICC cases). Radiomic features were extracted from axial fat-suppression T2-weighted imaging (FS-T2WI) and axial arterial-phase (A) and portal-venous-phase (P) dynamic contrast-enhanced MRI sequences, and the corresponding datasets were generated. The least absolute shrinkage and selection operator (LASSO) method was used to select the best radiomic features. Logistic regression was used to establish a radiomic model for each sequence (FS-T2WI, A, and P models) and a joint model (M model) integrating the radiomic features of all the sequences. The performance of each model was evaluated using the area under the receiver operating characteristic curve (AUC). The AUC of the FS-T2WI, A, P, and M models for distinguishing HCC from ICC was 0.693, 0.863, 0.818, and 0.914 in the training group and 0.690, 0.784, 0.727, and 0.802 in the validation group, respectively. The results of this study suggest that MRI-based radiomics may help noninvasively differentiate HCC from ICC. The model integrating the radiomic features of multiple sequences showed further improvement in performance.

The influence of preoperative examination of oral squamous cell carcinoma (OSCC) mucosal surrounding by VELscope (Visually Enhanced Lesion Scope) on the radicality of surgical treatment of OSCC was the goal of this study.It is the first analysis of its kind with a total number of 122 patients suffering from OSCC with homogenous distribution of different tumor stages randomized into a study and a control group and enrolled in our study after meeting the inclusion criteria. The preoperative checkup by VELscope accompanied by the marking of the range of a loss of fluorescence in the study group was performed before the surgery. We have developed a unique mucosal tattoo marking technique for this purpose. The pathohistological results after surgical treatment, i.e. the margin status, were then compared. We achieved the pathological free margin (pFM) in 55 patients, the pathological close margin (pCM) in 6 cases and we encountered no case of the pathological positive margin (pPM) in the mucosal layer in the study group. In comparison, the control group results revealed pPM in 7 cases, pCM in 14 cases and pFM in 40 of all cases in the mucosal layer. This study proved that the preoperative autofluorescence evaluation of a tumor mucosal surrounding can enhance the ability to reach the pFM resection.

Background: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. The pathogenesis of chronic liver disease varies according to the underlying etiological factor, although in most cases it develops from a liver cirrhosis. The worsening progression of liver disease is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. The aim of this study is to evaluate the clinical utility of circulating angiogenic markers VEGF, Ang-1, Ang-2, the Angiopoietin receptor (Tie1/2), HGF and PECAM-1 to screen early onset patients and to follow the evolution of HCC. Materials and Methods: We enrolled 62 patients; 33 out of 62 subjects were diagnosed for HCC and 29/62 for liver cirrhosis of different etiology without signs of neoplasia. Patients underwent venous blood sampling before and after treatments for VEGF, Ang-1, Ang-2, Tie1, Tie2, HGF and PECAM-1 measurement. Results: Ang-1 and Ang-2 are detectable not only in patients already suffering from HCC but also in cirrhotic patients without signs of cancer. Patients with HCC show higher HGF concentrations than patients with cirrhosis. A significant reduction in serum levels of Ang-2, Ang-2/Ang-1 and Ca 19-9 after DAAs therapy was observed. Moreover, VEGF levels were increased after treatment of HCC. Conclusion: The preliminary study here presented confirms that the mechanism of tumor angiogenesis is very complex and involves a very large number of factors. The integration of different methodologies and multi-marker algorithms is likely to emerge for the early diagnosis of HCC and the monitoring of the risk of relapse.

Keywords: free radicals; oxidative stress; hepatocellular carcinoma; anti-oxidants; kaempferol

This study was to designed to develop sorafenib-loaded polymeric nanoparticles, surface-modified with pluronic F-127 for the effective treatment of hepatocellular (HCC) and renal cell carcinomas (RCC). Poly lactic coglycolic acid (PLGA) was used to encapsulate different concentrations of sorafenib by a simple modified solvent evaporation method applying pluronic F-127 as a surfactant and coating agent. The preformulation and characterization studies were conducted to evaluate the incompatibilities among sorafenib, PLGA and pluronic F-127, and physicochemical properties of the formulations, respectively. The sizes of the coated and plain PLGA nanoparticles were ~140 ± 14.7 nm and ~ 120 ± 10.1 nm, respectively. It has been confirmed from the in vitro release studies that PLGA sustained the release of sorafenib, avoiding the initial burst release, while the in vivo studies demonstared that surface-modified nanoparticles have greater affinity in the target aorgans than plain PLGA nanoparticles and free drug keeping the dose constant (20 mg/kg body weight). The delivery of sorafenib-loaded polymeric PLGA nanoparticles into the target tissues and their pharmacokinetic parameters have been improved significantly compared to the reported formulations.

Renal cell carcinoma (RCC) accounts for approximately 90-95% of all kidney cancers in adults, with the clear cell RCC (ccRCC) the most frequently identified subtype. RCC is known for its responsiveness to immunotherapy, making it an area of significant research interest. Immune checkpoint (IC) molecules, which regulate immune surveillance, are established therapeutic targets in RCC. The aim of this study was to analyze the influence of polymorphisms in genes HVEM and CD160 on susceptibility to ccRCC and patient overall survival (OS) with over a ten-year period of observation. We genotyped three HVEM single nucleotide polymorphisms (SNPs): rs1886730, rs2234167, and rs8725, and two CD160 SNPs: rs744877 and rs2231375, in 238 ccRCC patients and 521 controls. Our findings indicated that heterozygosity within rs2231375 and/or rs2234167 increases ccRCC risk. Furthermore, in women, heterozygosity within additional HVEM SNPs, rs8725 and rs1886730, is associated with an increased ccRCC risk. The presence of a minor allele for rs1886730, rs2234167, rs8725, and rs2231375 was also correlated with certain clinical features of the disease. Moreover, the rs1886730 SNP was found to be associated with patients' OS. In conclusion, our study highlights an association between HVEM and CD160 polymorphisms and the risk of developing ccRCC as well as patient’s OS.

Hepatocellular carcinoma (HCC) is characterized by uncontrolled cellular proliferation driven by aberrant signal transduction. Cells respond to potential carcinogenic signals by inducing cellular senescence (CS) as a defense mechanism. However, assessing CS levels in various tumors is challenging due to heterogeneity and the lack of universal CS markers. This study integrates single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from HCC samples to analyze gene expression profiles. HCC-specific senescence-related pathways are identified, and genes from these pathways distinguish molecular subtypes associated with senescence in HCC. These subtypes exhibit significant variations in biological and clinical attributes. A specific CS risk model is developed, revealing associations between CS scores and prognosis, clinical staging, immune infiltration, immunotherapy response, and drug sensitivity. The key gene G6PD is identified as a potential senescence-related target in liver cancer. Molecular experiments confirm the effective suppression of HepG2 cell proliferation, invasion, and migration upon G6PD knockdown. In summary, this analysis enhances our understanding of HCC-specific senescence molecular features and introduces a novel senescence-related biomarker, offering promising implications for future research.

Hepatocellular Carcinoma (HCC) continues to pose a substantial global health challenge due to its high incidence and limited therapeutic options. In recent years, the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has emerged as a critical signaling cascade in HCC pathogenesis. The review commences with an overview of the JAK/STAT pathway, delving into the dynamic interplay between the JAK/STAT pathway and its numerous upstream activators, such as cytokines and growth factors enriched in pathogenic livers afflicted with chronic inflammation and cirrhosis. This paper also elucidates how the persistent activation of JAK/STAT signaling leads to diverse oncogenic processes during hepatocarcinogenesis, including uncontrolled cell proliferation, evasion of apoptosis, and immune escape. In the context of therapeutic implications, this review summarizes recent advancements in targeting the JAK/STAT pathway for HCC treatment. Preclinical and clinical studies investigating inhibitors and modulators of JAK/STAT signaling are discussed, highlighting their potential in suppressing the deadly disease. The insights presented herein underscore the necessity for continued research into targeting the JAK/STAT signaling pathway as a promising avenue for HCC therapy.

LOXL2, a copper-dependent amine oxidase, has emerged as a promising therapeutic target in hepatocellular carcinoma (HCC). Increased LOXL2 expression in HCC has been linked with aggressive phenotype and represents a poor prognostic factor. Here, we focus on mechanisms by which LOXL2 orchestrates multiple oncogenic functions in HCC development. We are reviewing current knowledge about the roles of LOXL2 in the modulation of the HCC tumor microenvironment, formation of premetastatic niches, and epithelial-mesenchymal transition. Also, we are highlighting the complex interplay between LOXL2 and hypoxia, angiogenesis, and vasculogenic mimicry in HCC. At the end of the review, we summarize current LOXL2 inhibitors and discuss their potential in HCC precision treatment.

Keywords: head-and-neck cancer; chemoradiation; cisplatin; carboplatin; loco-regional control; metastases-free survival; overall survival; toxicity.

CRCMSS/pMMR contain a significantly increased fraction of TREM2+ macrophages (TAMs) and CD66+ neutrophils (TANs) together with decrease of CD4-CD8-CD3+ double negative T lymphocytes (DNTs); no differences were revealed by the analysis of myeloid and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells display an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCMSS/pMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCMSS/pMMR.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN- signaling and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells was found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN- signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Purpose: Recently introduced molecules namely long non-coding RNAs (lncRNAs) are associated with various diseases, including breast cancer, and they may have the potential to act as biomarkers. Invasive ductal carcinoma (IDC) is a frequently observed type of breast cancer that diagnosis through immunohistochemical methods. However, no reliable non-invasive markers such as circulating markers have been introduced for it, so far. Materials and methods: The relative quantitation (RQ) of two lncRNAs, RP11-445H22.4 and TINCR, was measured in tumoral tissues and paired adjacent non-tumoral tissues (PANTs) as well as in plasma samples using real-time polymerase chain reaction (RT-PCR). Furthermore, promoter methylation of the two lncRNAs genes was assessed using methylation-specific PCR (MSP). In order to compare the diagnostic values, plasma levels of CA 15-3 were measured as a conventional circulating biomarker using ELISA. The receiver operating characteristic (ROC) curve was used to illustrate the sensitivity and specificity of the potential biomarkers. Results: The RP11-445H22.4 and TINCR genes were upregulated in tumor tissues compared to PANTs (RQ_{RP11-445H22.4} = 2.7, RQ_TINCR = 4.4). Furthermore, the presence of RP11-445H22.4 and TINCR in the plasma of patients was significantly more than healthy controls (RQ_{c.RP11-445H22.4} = 4.12, RQ_c.TINCR = 4.16, P<0.001). The promoters of RP11-445H22.4 and TINCR genes were hypomethylated in the tumoral tissues with a negative correlation with their gene expression. Conclusion: Based on the findings, it can be speculated that the expression levels of these two lncRNAs as well as their promoter methylation can be considered as a therapeutic target and potential biomarker for breast carcinoma.

Background and Aim: Zinc plays a pivotal role in various zinc enzymes, resulting in the maintenance of liver function. Patients with chronic liver diseases (CLDs) usually have lower concentrations of zinc, which decrease further as liver fibrosis progresses. It remains unknown whether long-term zinc supplementation improves liver function and reduces the risk of hepatocellular carcinoma (HCC) development. Patients and Methods: Two hundred sixty-seven patients with CLDs who received a zinc preparation (Zn-group; 196 patients), or who did not receive zinc (no Zn-treatment group; 71 patients) were retrospectively analyzed in this study. The Zn-group was divided into 4 groups according to their serum Zn concentrations at 6 months after the start of Zn treatment. Results: Liver function significantly deteriorated in the no Zn-treatment group, while no notable change was observed in the Zn-group. The cumulative incidence rates of events and HCC at 3 years were lower in the Zn-group (9.5%, 7.6%) than in the no Zn-treatment group (24.9%, 19.2%) (p<0.001). According to the serum Zn concentrations, the cumulative incidence rates of events and HCC were significantly decreased in patients with Zn concentrations ≥ 70 µg/dl (p<0.001). Conclusion: Zinc supplementation appears to be effective at maintaining liver function and suppressing events and HCC development, especially among patients whose Zn concentration is greater than 70 µg/dl.

MicroRNAs are small non-coding RNAs that are implicated in several physiological processes such as cell development, proliferation, differentiation, apoptosis, immune response and angiogenesis. In the last couple of decades, several studies on miRNA profiling in OSCC have tried to associate miRNAs with clinical characteristics such as relapse, metastasis, and survival, however, the results have been found to vary considerably, sometimes even being contradictory. The main objective of our study was to analyse and verify miRNA expression in oral squamous cell carcinoma in a Spanish population. Second, we attempted to associate the identified deregulated miRNAs with molecular pathways. 8 Oral Squamous Cell Carcinoma patients and 8 healthy control samples were analysed by a microarray Affymetrix® miRNA 4.1 array plate and validated with 8 more cases using RT-qPCR. Deregulated miRNAs were studied using Diana Tools miRPath 3.0 to associate miRNA targets with molecular pathways. Microarray analysis identified 80 deregulated miRNAs (35 over-expressed and 45 under-expressed). Only miR-497-5p and miR-4417 maintained its deregulated expression after validation with qPCR. Among the molecular pathways in which deregulated miRNAs could be implicated, the most statistically significant pathway was ‘proteoglycans in cancer’. No relationship was found between miR-497-5p or miR-4417 expression and clinical or pathological parameters except of nodular affectation (high miR-4417 expression in patients with nodular affectation, p = 0.035) and radiotherapy (diminished miR-497-5p expression in patients who needed radiotherapy, p = 0.05). We have verified the altered expression of miR-497-5p and miR-4417 in Oral Squamous Cell Carcinoma samples and related the deregulated miRNAs with the ‘proteoglycans in cancer’ pathway.

In the last two decades, the discovery of various pathways involved in renal cell carcinoma (RCC) have led to the development of biologically-driven targeted therapies. Hypoxia inducible factors (HIFs), angiogenic growth factors, von Hippel-Lindau (VHL) gene mutations and oncogenic miRNAs play essential roles in the pathogenesis and drug resistance of clear cell renal cell carcinoma. These insights have led to the development of VEGF inhibitors, mTOR inhibitors and immunotherapeutic agents which have significantly improved outcomes of patients with advanced RCC. HIF inhibitors will be a valuable asset in the growing therapeutic armamentarium of RCC. Various histone deacetylase (HDAC)inhibitors, including selenium and agents such as PT2385 and PT2977, are being explored in various clinical trials as potential HIF inhibitors to ameliorate the outcomes of RCC patients. In this article, we will review the current treatment options and highlight the potential role of selenium in the modulation of drug resistance biomarkers expressed in ccRCC tumors.

Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer compared to normal tissues. The downregulation of NGAL was strongly correlated with the degree of differentiation and stage (I-IV), and can serve as a prognostic biomarker for oral cancer. Tobacco carcinogens were also found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration, and also induced resistance against cisplatin. Silencing of NGAL activated mTOR signaling and reduced autophagy by the LKB1-AMPK-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and MMP-9 were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer.

The crosstalk between tumor progression and ferroptosis is largely unknown. Here, we identify malate dehydrogenase 2 (MDH2) as a key regulator of ferroptosis. MDH2 deficiency inhibits hepatocellular carcinoma (HCC) cell growth and promotes sensitivity of HCC cells to RSL3-induced ferroptosis. MDH2 knockdown enhances RSL3-induced intracellular reactive oxygen species (ROS), free iron ions and lipid peroxides levels, leading to HCC ferroptotic cell death which is rescued by Ferrostatin-1 and iron chelator Deferiprone. Importantly, inhibition of HCC cell growth caused by MDH2 deficiency is partially rescued by ferroptosis blockade. Mechanistically, MDH2 resists RSL3-induced ferroptosis sensitivity by dependence on GPX4, which is stabilized by MDH2 in HCC. The protein expression of MDH2 and GPX4 is positively correlated with each other in HCC cell lines. Furthermore, through UALCAN website analysis, we find that MDH2 and GPX4 are highly expressed in HCC samples. These findings reveal a critical mechanism by which HCC evades ferroptosis via MDH2-mediated stabilization of GPX4 to promote tumor progression and underscore the potential of MDH2 inhibition in combination with ferroptosis inducers for the treatment of HCC.

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR=0.45; P=0.002). At multivariable analysis, microvascular infiltration (HR=1.22; P<0.04) and a higher tumor grading (HR=1.27; P<0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR=0.56; P<0.001), a successful pre-transplant downstaging (HR=0.63; P=0.01) and use of everolimus (HR=0.46; P<0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (30 days; P<0.001), longer treatment duration (P<0.001), and higher drug exposure (5.9ng/mL; P<0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction of the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.

(1) Background: China holds the highest esophageal squamous cell carcinoma (ESCC) incidence areas in the world, with some areas of incidence over 100 per 100,000. Despite extensive public health efforts, its etiology is still poorly understood. This study aims to review and summarize past research into potential etiologic factors for ESCC in China. (2) Methods: Relevant observational and intervention studies were systematically extracted from four databases using key terms, reviewed using Rayyan software, and summarized into Excel tables. (3) Results: Among the 207 studies included in this review, 130 studies were focused on genetic etiologic factors, followed by 22 studies focused on dietary-related factors, 18 studies focused on HPV-related factors, and 37 studies focused on other factors. (4) Conclusions: ESCC in China involves a variety of factors including genetic variations, gene-environment interactions, dietary factors like alcohol, tobacco use, pickled vegetables, and salted meat, dietary behavior such as hot food/drink consumption, infections like HPV, poor oral health, gastric atrophy, and socioeconomic factors. Public health measures should prioritize genetic screening for relevant polymorphisms, conduct comprehensive investigations into environmental, dietary, and HPV influences, enhance oral health education, and consider socioeconomic factors overall as integral strategies to reduce ESCC in high-risk areas of China.

A number of agents, including immune checkpoint inhibitors, have become available for the treatment of hepatocellular carcinoma (HCC). However, the objective response rate of these drugs is currently only 30% to 40%, with a high incidence of side effects. There are also no prac-tical biomarkers to predict their therapeutic effects. Most of the systemic therapies for HCC are performed in general hospitals without research facilities. Such hospitals can perform imaging tests, like CT and MRI, as well as pathological diagnosis using tumor tissue sampling and im-munohistochemical staining. However, analyzing tumor genomic or transcriptomic profiles is difficult because of limitations in facilities, personnel, and cost. Therefore, in this review, we provide an overview of the wide range of research that has been conducted on HCC biomarkers from blood, tissue, or imaging information that can be used practically in general hospitals for predicting the therapeutic effect of systemic therapies before treatment begins. For general hos-pitals that treat HCC patients, we recommend conducting treatment after assessing the state within the tumor tissue as much as possible by collecting blood and tissue samples and per-forming pre- treatment MRI image evaluations.

Efficient management of basal cell carcinoma (BCC) requires reliable assessments of both tumors and post-treatment scars. We aimed to estimate image similarity metrics that account for BCC's perceptual color and texture deviation from perilesional skin. 176 clinical photographs of BCC were assessed by six physicians using a visual deviation scale. Internal consistency and inter-rater agreement were estimated using Cronbach's α, weighted Gwet's AC2, and quadratic Cohen's Kappa. The mean visual scores were used to validate a range of similarity metrics employing different color spaces, distances, and image embeddings from pre-trained VGG16 neural network. The calculated similarities were transformed into discrete values using ordinal logistic regression models. The Bray-Curtis distance in the YIQ color model and rectified embeddings from the 'fc6' layer minimized the mean squared error and demonstrated strong performance in representing perceptual similarities. Box plot analysis and Wilcoxon rank-sum test were used to visualize and compare the levels of agreement, conducted on a random validation round between the two groups: ‘Human-System’ and ‘Human-Human’. The proposed metrics were comparable in terms of internal consistency and agreement with human raters. The findings suggest that the proposed metrics offer a robust, and cost-effective approach to monitoring BCC treatment outcomes in clinical settings.

Non-alcoholic fatty liver disease (NAFLD) affects up to a quarter of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The incidence of NASH is projected to increase by up to 56% over the next 10 years. There is growing epidemiological evidence that NAFLD has become the fastest growing cause of hepatocellular carcinoma (HCC) in industrialized countries. The annual incidence of HCC varies between patients with NASH cirrhosis and patients with noncirrhotic NAFLD. In this review, NAFLD/NASH-associated HCC will be described, including its epidemiology, risk factors promoting hepatocarcinogenesis, and management of HCC in patients with obesity and associated metabolic comorbidities, including preventive strategies and therapeutic approaches to address this growing problem.

Radiotherapy is the primary treatment modality for non-metastatic nasopharyngeal carcinoma (NPC) across all TNM-stages. Locoregional control rates have been impressive even from the 2D-radiotherapy (RT) era, except when the ability to deliver optimal dose coverage to the tumor is compromised. However, short- and long-term complications following head and neck RT are potentially debilitating, and thus, there had been much research investigating technological advances in RT delivery over the past decades, with the primary goal of limiting normal tissue damage. On this note, with a plateau in gains of therapeutic ratio by modern RT techniques, future advances have to be focused on individualization of RT, both in terms of dose prescription and delineation of target volumes. In this review, we analyzed the guidelines and evidence related to contouring methods, and dose prescription for early and locoregionally-advanced (LA-) NPC. Next, with the preference for induction chemotherapy (IC) in patients with LA-NPC, we assessed the evidence concerning radiotherapy adaptations guided by IC response, as well as functional imaging and contour changes during treatment. Finally, we discussed on RT individualization that is guided by EBV DNA assessment, and its importance in the era of combinatorial immune checkpoint blockade therapy with RT.

Oral cancer ranks sixth among Taiwan's top 10 cancers, and most patients with poor prognosis acquire metastases. The essential fatty acid alpha-linolenic acid (ALA) has been found to diminish many cancer properties. However, the anti-cancer activity of ALA in oral cancer has yet to be determined. Migration and invasion assays confirmed OSCC cells' EMT capabilities, whereas flow cytometry and Western blotting identified the molecular pathways. ALA dramatically reduced cell growth in a concentration dependent manner, according to the findings. Low concentrations of ALA (100 or 200 μM) inhibit colony formation, expression of Twist and EMT-related proteins, expression of MMP2/-9 proteins and enzyme activity, as well as cell migration and invasion. Treatment with high concentrations of ALA (200 or 400 μM) greatly increases JNK phosphorylation and c-jun nuclear accumulation, then upregulates the FasL/caspase8/caspase3 and Bid/cytochrome c/caspase9/caspase3 pathways, leading to cell death. Low concentrations of ALA inhibit SAS and GNM cell migration and invasion by suppressing Twist and downregulating EMT-related proteins, or by decreasing the protein expression and enzyme activity of MMP-2/-9, whereas high concentrations of ALA promote apoptosis by activating the JNK/FasL/caspase 8/caspase 3-extrinsic pathway and the Bid/cytochrome c/caspase 9 pathway. ALA demonstrates potential as a treatment for OSCC patients.

Non-alcoholic fatty liver disease (NAFLD) has gained attention in the last few years due to its increasing prevalence worldwide becoming a global epidemic. This review aims to discuss the latest recommendations regarding diagnosis and treatment of NAFLD-associated HCC and the remaining challenges. Thus, there is a high amount of data derived from basic and clinical studies that revealed the molecular pathways which drive NAFLD-associated hepatocellular carcinoma (HCC). Based on these findings, new prevention, surveillance and treatment strategies are emerging. However, current data on treatment modalities in NAFLD-associated HCC are still scarce, but based on subgroup analysis results from non-NAFLD HCC studies are promising and could provide a basis for future research agenda to address NAFLD/NASH patients. Conclusion: Due to the pandemic proportions that NAFLD gained in the last few years, there is a high amount of data derived from basic and clinical studies that revealed the molecular path-ways which drive NAFLD-associated HCC. Based on these findings, new prevention, surveillance and treatment strategies could be developed at an individual level.

Papillary thyroid cancer (PTC) is commonly characterized by multifocality, which is associated with aggressive features and a less favorable prognosis. The current study aimed to compare the clinicopathologic characteristics and long-term oncological outcomes of bilateral and unilateral multifocal PTC. The medical records of 1745 patients with multifocal PTC who underwent thyroid surgery at Seoul St. Mary’s Hospital were retrospectively reviewed. The clinicopathological characteristics and recurrence rates were compared based on cancer laterality. Further, 357 patients who underwent total thyroidectomy were matched to investigate the recurrence risk and disease-free survival (DFS). Before propensity score matching (PSM), there was no significant difference in the recurrence rate between the bilateral and unilateral multifocal PTC groups. Cancer laterality was not a predictor of DFS based on the Cox regression analyses. However, after PSM, unilateral multifocality was associated with a significantly high risk of recurrence. Similarly, unilateral multifocality was associated with a significantly poor DFS based on the Kaplan–Meier analysis. Compared with bilateral PTC, unilateral multifocal PTC was associated with a poor DFS. A comprehensive preoperative examination should be performed to detect multifocality before the initial surgical intervention for optimal treatment. Postoperative short-term follow-up is recommended for unilateral multifocal PTC for recurrence surveillance.

Renal cell carcinoma (RCC) is the second most common cancer of the urinary system. The current therapeutic strategies are based on partial or total nephrectomy and/or targeted therapies based on immune checkpoint inhibitors to which patients are often refractory. Preventive and screening strategies are not existing and the few available biomarkers for RCC are characterized by the lack of sensitivity, outlining the need of novel noninvasive and sensitive biomarkers for an early diag-nosis and a better disease monitoring. Blood liquid biopsy (LB) is a non- or minimally invasive procedure for a more representative view of tumor heterogeneity than the tissue biopsy, poten-tially allowing real-time monitoring of cancer evolution. Growing interest is focused on the extra-cellular vesicles (EVs) secreted by either healthy or tumoral cells and recovered in a variety of bio-logical matrices, blood included. EVs are involved in cell-to-cell crosstalk transferring their mRNAs, miRNAs, and proteins content. In particular, transferred miRNAs may regulate the tu-morigenesis and proliferation also impacting on resistance to apoptosis, thus representing poten-tial useful biomarkers. Here we present the latest efforts in the identification of circulating miR-NAs in blood samples, focusing on the potential use of EV derived miRNAs as RCC diagnostic, prognostic markers.

Mesothelin is a protein that is expressed in the mesothelial cell lining in the pleura, peritoneum, and pericardium. The gene of mesothelin encodes a precursor protein that is processed to yield mesothelin, which is attached to the cell membrane by a glycophosphatidylinositol linkage and a shred fragment named the megakaryocytic-potentiating factor. The biological functions of this substance in normal cells are still unknown. Experimental studies on knockout mice suggest that this substance does not play an important role in development and reproduction. In contrast, it has been observed that mesothelin is produced in abnormal amounts in several malignant neoplasms, such as mesotheliomas and pancreatic adenocarcinomas. Given that mesothelin is overexpressed in many solid tumours and has antigenic properties, this molecule could be considered a tumour marker or an antigenic target for many malignancies. Many molecular studies also have demonstrated that mesothelin is overexpressed in serous ovarian carcinomas and may bind to ovarian cancer antigen Ca-125, favouring the spread of the tumour in the abdominal cavity. 3 Here, we discuss the current knowledge of mesothelin and focus on its role in clinical and pathological diagnoses as well as its impact on the prognosis in serous ovarian carcinomas. We also briefly discuss the latest progress of mesothelin-targeting therapies for this aggressive and lethal neoplasm.

: Plant-derived terpenes have aroused considerable interest as chemotherapeutic agents for a variety of diseases. This study aimed at the isolation and purification of the scarce terpenes psiadin, plectranthone and saudinolide from their respective plants, followed by the determination of antiproliferative activity, against hepatic cancer cell lines (HepG2, Hep3B), and the potential molecular mechanisms. Time- and dose-dependent cytotoxicity, evaluated using MTT and colony-forming assays, were exhibited by psiadin and plectranthone against the cancer cells. Flow cytometry showed that these two terpenes blocked cell cycle progression and induced mitochondrial-mediated apoptosis, particularly through increased cytochrome c and disruption of mitochondrial membrane potential. Additionally, they initiated the generation of reactive oxygen species as well as inhibiting NF-B. Psiadin lowered several essential cyclins and cyclin-dependent kinases and reduced RB activation. It was concluded that psiadin, in particular, has a significant therapeutic potential with the biggest advantage of differentiating between cancer and normal cells which is acutely lacking in current cytotoxic drugs. Its precise mode of action needs further investigation but appears predominantly to cause cell cycle arrest by interfering with cyclin production. It will be important to determine, in future studies, whether these terpenes will similarly inhibit other cancer cell lines and retain its activity against tumors in vivo.

Programmed cell death protein 1 (PD-1) is a biomarker on the surface of cells that has a role in promoting self-tolerance by suppressing the inflammatory activity of T cells. In this work, one peptide of PD-1 was used as the template in molecular imprinting. The magnetic peptide-imprinted poly(ethylene-co-vinyl alcohol) composite nanoparticles (MPIP NPs) were characterized by dynamic light scattering (DLS), high-performance liquid chromatography (HPLC), Brunauer-Emmett-Teller (BET) analysis and superconducting quantum interference device (SQUID) analysis. Natural killer-92 (NK-92) cells were added to these composite nanoparticles and then incubated with human hepatoma (HepG2) cells. The viability and apoptosis pathway of HepG2 were then studied using cell counting kit-8 (CCK8) and the quantitative real-time polymerase chain reaction (qRT-PCR), respectively. These nanoparticles were found significantly enhance the activity of natural killer cells toward HepG2 cells by increasing expression of NK-kB, caspase 8 and especially caspase 3.