Search Results (114)

In the preceding and early stages of cancer progression, local drug delivery to pre-cancerous and cancerous skin lesions may be applied as an alternative or supplementary therapy. At present, 5-Fluorouracil, imiquimod, and tirbanibulin creams and ointments have established their place in practice, while several other active pharmaceutical ingredients (APIs) (e.g., calcipotriol, tretinoin, diclofenac) have been repurposed, used off-label, or are currently being investigated in mono- or combined chemotherapies of skin cancers. Apart from them, dozens to hundreds of therapeutics of natural and synthetic origin are proven to possess anti-tumor activity against melanoma, squamous cell carcinoma (SCC), and other skin cancer types in in vitro studies. Their clinical introduction is most often limited by low skin permeability, challenged targeted drug delivery, insufficient chemical stability, non-selective cytotoxicity, or insufficient safety data. A variety of prodrug and nanotechnological approaches, including vesicular systems, micro- and nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, and others, offer versatile solutions for overcoming the biophysical barrier function of the skin and the undesirable physicochemical nature of some drug molecules. This review aims to present the most significant aspects and latest achievements on the subject. Full article

Chronic atrophic gastritis and intestinal metaplasia (IM) are gastric precancerous conditions (GPCs) associated with an increased risk of gastric cancer. Early detection and accurate characterization of GPC are therefore crucial for risk stratification and the implementation of preventive strategies. In the absence of clear mucosal changes observed through white-light imaging (WLI) or virtual chromoendoscopy, endocytoscopy can help unveil the presence of GPC by enabling in vivo assessment of nuclear and cellular structures at ultra-high magnification. Endocytoscopy is typically performed using WLI following dye-based staining of the mucosa. In this case, we demonstrate that combining endocytoscopy with the texture and color enhancement imaging (TXI) mode substantially improves the assessment of the gastric mucosa. In a 61-year-old man undergoing esophagogastroduodenoscopy, WLI showed multifocal erythema in the stomach, without clearly visible lesions on either WLI or narrow-band imaging. Conventional endocytoscopy revealed multiple small spots of IM with characteristic changes in glandular structures, which were even more evident when using the TXI mode. Histological analysis of targeted biopsies confirmed small foci of IM in both the antrum and corpus. The patient was enrolled in a surveillance program because of his clinical background. The combination of endocytoscopy with the TXI mode significantly enhances the delineation of mucosal and cellular architecture, supporting a more accurate optical diagnosis. Full article

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease linked to fibrosis and hepatocellular carcinoma (HCC). Gut-derived lipopolysaccharide (LPS) promotes hepatic inflammation, fibrosis, and angiogenesis through toll-like receptor 4 (TLR4) signaling. This study examined the effects of rifaximin, a non-absorbable, gut-targeted antibiotic, on MASH-related liver fibrosis and early hepatocarcinogenesis, with a focus on the LPS–epiregulin–IL-8–angiogenesis axis.MASH was induced in Fischer 344 rats using a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD). Rifaximin (30 mg/kg/day) was orally administered for 12 weeks. Liver histology, gene expression, intestinal permeability, LPS levels, and angiogenic markers were evaluated. Rifaximin reduced hepatic inflammation, fibrosis, hydroxyproline content, and fibrogenic gene expression. The number and size of GST-P-positive preneoplastic lesions and proliferation-related genes were decreased. Portal LPS levels and Kupffer cell activation declined, with downregulation of Lbp, Cd14, Tlr4, and inflammatory cytokines. Rifaximin decreased hepatic epiregulin and IL-8 expression, attenuated CD34-positive neovascularization, and suppressed proangiogenic gene expression, accompanied by improved intestinal barrier function and reduced gut permeability. Rifaximin mitigates MASH progression by restoring gut barrier integrity, limiting LPS translocation, and inhibiting fibrogenic and angiogenic pathways. These results suggest its potential as a chemopreventive agent in MASH-related hepatocarcinogenesis. Full article

Background: Actinic keratoses (AKs) are common pre-neoplastic lesions that may progress to cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) is an effective field-directed treatment for AK, but its impact on key biomarkers remains unclear. This study evaluates the clinical, dermatoscopic, and immunohistochemical effects of PDT on AK, with a focus on proliferation (Ki67, p53) and inflammation (COX-2) markers, to assess its efficacy in delaying carcinogenesis. Methods: In our prospective one-center study, we enrolled 31 patients with AK, with no history of previous AK treatment. They underwent three PDT sessions at four-week intervals, with follow-up eight weeks after the final session. Clinical, dermatoscopic, and immunohistochemical analyses of Ki67, p53, and COX-2 expression were performed before and after treatment. Results: Clinically, 54.8% of patients achieved complete lesion clearance, with no residual severe AK lesions. Ki67 and p53 immunoexpression significantly decreased post-PDT (p < 0.05), confirming its antiproliferative effect. COX-2 expression also declined significantly (p < 0.05), supporting PDT’s anti-inflammatory role. However, COX-2 remained stable or increased in 35.48% of cases, possibly due to inflammation-induced regeneration. There is a positive correlation between the reduction in Ki67, p53, and COX-2 immunoexpression and the decrease in AK severity (both according to Olsen grade and dermatoscopic grade). Conclusions: PDT effectively reduces AK severity, proliferation, and inflammation markers, potentially delaying carcinogenesis. However, residual biomarker expression suggests that additional treatment sessions or combination therapies may be necessary for complete lesion clearance. Further studies are required to optimize PDT protocols. Full article

Hepatocarcinogenesis is linked to environmental factors, with microplastics (MPs) emerging as a global environmental concern that may contribute to liver injury. However, the impact of MPs on the early stages of hepatocarcinogenesis has been largely ignored. Here we investigated the impact of long-term MP exposure on the formation of preneoplastic lesions during hepatocarcinogenesis induced by diethylnitrosamine (DEN) in rats. Rats were injected with DEN to induce preneoplastic lesions, and then they were orally administered with 1 µm MPs 0.5 mg/kg body weight per day for 20 weeks. The results revealed that long-term exposure to MPs did not induce the formation of glutathione S-transferase placental form (GST-P)-positive foci as preneoplastic lesions during hepatocarcinogenesis in these animals, thereby indicating non-carcinogenicity. However, MP exposure resulted in a 1-fold increase in both the number and size of GST-P-positive foci in rats initiated with DEN compared to those treated with DEN alone. Accordingly, MP exposure led to a 0.61-fold increase in the index of proliferating cell nuclear antigen (PCNA)-positive cells in DEN-initiated rats when compared to DEN treatment alone. In addition, the composition of the gut microbiota was significantly altered, accompanied by various levels of short-chain fatty acids. Our results suggest that long-term MP exposure can promote pre-neoplastic lesion formation in DEN-induced rats by increased cell proliferation as well as alterations in the gut microbiota and short-chain fatty acid levels. This highlights the potential health risks associated with hepatocarcinogenesis linked to long-term exposure to MPs. Full article

Gallbladder carcinoma (GBC) is one of the most aggressive malignancies of the biliary tract, often originating from chronic inflammation associated with gallstones and cholecystitis. Persistent inflammation plays a pivotal role in the development of preneoplastic changes, such as metaplasia, which may progress to malignancy. Despite its relatively low incidence, GBC is characterized by a poor prognosis due to late-stage diagnosis, highlighting the urgent need for improved early detection strategies. This study aimed to assess the diagnostic and prognostic significance of CA 19-9 and CEA levels in patients with gallbladder lesions, while also evaluating systemic inflammation and hemostatic dysregulation. A retrospective analysis was conducted on patients diagnosed with gallbladder lesions, with histopathological confirmation of adenocarcinoma and metaplasia. Laboratory assessments included serum levels of tumour markers, inflammatory markers such as CRP, and key hemostatic parameters, including thrombocyte count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels. A predictive scoring model was developed using the cutoff values of CA 19-9 and CEA to assess their combined diagnostic potential. Among the patients studied, 48.9% had an initial diagnosis of chronic cholecystitis, while 32.2% presented with acute cholecystitis. Adenocarcinoma was identified in 6.7% of cases after histopathological examination, predominantly in females over 65 years old with acute cholecystitis. Metaplasia was detected in 7.8% of cases, primarily in elderly females with chronic cholecystitis. Laboratory findings revealed significantly elevated levels of CA 19-9, CEA, AFP, and CA-125 in patients with adenocarcinoma. Additionally, abnormalities in hemostatic parameters, including increased fibrinogen levels and alterations in thrombocyte count, were observed in patients with malignancy. A combined predictive score using CA 19-9 and CEA demonstrated strong potential for detecting adenocarcinoma and metaplasia, improving diagnostic accuracy. Our findings emphasize the clinical importance of integrating tumour markers, inflammatory biomarkers, and hemostatic parameters in the evaluation of gallbladder lesions associated with chronic inflammation. The combined assessment of these factors enhances early detection, facilitates malignancy risk stratification, and improves prognostic evaluation, particularly in patients with metabolic and cardiovascular comorbidities. Full article

Background/Objetives: This study standardized a chemically induced colorectal cancer (CRC) model using azoxymethane (AOM) and dextran sodium sulfate (DSS) in BALB/c mice, replicating the progression from preneoplastic lesions to adenocarcinoma observed in human colorectal carcinogenesis. Methods: The CCR-AOM/DSS model was standardized in male and female BALB/c mice. Two protocols were tested. Subsequently, the positive control group was established with nine evaluation points. Tumor progression was characterized histopathologically and corroborated by methylene blue staining and scanning electron microscopy. Results: Two cycles of 2% DSS combined with a single injection of AOM (10 mg/kg) were necessary to induce adenocarcinoma in 100% of the mice, with no significant sex-based differences in tumor development. Females showed earlier tumor susceptibility under certain protocols. Inflammatory processes played a critical role in tumorigenesis, with neutrophil infiltration and fibrosis observed. Conclusions: The findings align with previous reports, emphasizing the influence of DSS cycles, molecular weight, and mouse strain on model outcomes. This standardized model provides a reliable platform for the preclinical evaluation of novel preventive and therapeutic strategies for CRC. Full article

Flutamide (FL), a non-steroidal drug used for its antiandrogenic, anticancer, and disrupting endocrine properties, induces mitochondrial toxicity and drug metabolism enzymes and promotes hepatocarcinogenesis. The inhibition of mitophagy, leading to the accumulation of damaged mitochondria, is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of FL in high-fat diet (HFD)-induced non-obese steatosis rats, categorized into four groups: basal diet (BD), BD + FL, HFD, and HFD + FL. The FL exacerbated HFD-induced steatosis and marginally increased preneoplastic lesions. To analyze hepatic preneoplastic lesions, we divided them into clusters based on the expression ratios of the mitophagy regulators LC3 and AMBRA1. The expression rates of LC3 and AMBRA1 in these precancerous lesions were classified into three clusters using k-means clustering. The HFD group exhibited an increased ratio of mitophagy inhibition clusters, as indicated by decreased LC3 and increased AMBRA1 levels in background hepatocytes and preneoplastic lesions. FL counteracted HFD-mediated mitophagy inhibition, as indicated by increased LC3 and decreased AMBRA1 levels in background hepatocytes. Our clustering analysis revealed that FL-induced mitophagy induction relied on Parkin expression. The present study underscores the significance of cluster analysis in understanding the role of mitophagy within small preneoplastic lesions and suggests that FL may potentially exacerbate NAFLD-associated hepatocarcinogenesis by affecting mitophagy. Full article

Background/Objectives: Gastric intestinal metaplasia (GIM) is considered an irreversible preneoplastic precursor for gastric adenocarcinoma in adults. However, its significance in children and the long-term outcome remain poorly understood. Methods: All children diagnosed with GIM between 2000 and 2020 were identified at a large tertiary referral centre. Upon reaching adulthood (≥18 years), the patients were invited to undergo follow-up esophagogastroduodenoscopy (using narrow-band imaging additionally to high-definition white light endoscopy), with gastric biopsies obtained according to the updated Sydney protocol. Childhood and adulthood gastric biopsies were re-evaluated by two experienced gastrointestinal pathologists using Kreyberg staining. Results: Paediatric GIM was diagnosed in 178/14,409 (1.2%) esophagogastroduodenoscopies performed during the study period. Fifty adult patients with childhood GIM agreed to participate in the study. The mean age at childhood and adulthood endoscopies were 14.3 years (median 15) and 25.2 years (median 24), respectively. The mean follow-up interval was 10.5 years. All childhood GIM cases were classified as complete-type. Notably, GIM completely resolved in 41/50 of patients (82%) by the time of adulthood follow-up. No dysplasia or carcinoma was detected in any patient. Childhood Helicobacter pylori infection, similar to other evaluated host-related factors, was not significantly associated with the persistence of GIM into adulthood (11.2% vs. 29.3%, p = 0.41). Conclusions: Childhood GIM was a rare finding but demonstrated a high rate of reversibility by adulthood regardless of Helicobacter pylori status, with no cases of dysplasia or carcinoma observed during long-term follow-up. Full article

Papillomaviruses (PVs) frequently infect humans as well as non-human species. While most PV infections are asymptomatic, PVs can also cause hyperplastic papillomas (warts) as well as pre-neoplastic and neoplastic lesions. In this review, the life cycle of PVs is discussed, along with the mechanisms by which PVs cause hyperplastic and neoplastic diseases. The humoral and cell-mediated immune responses to PVs are reviewed, giving context to the later discussion on the use of vaccines to reduce canine and feline PV-associated disease. Both dogs and cats are infected by numerous different PV types classified into multiple different PV genera. The taxonomic classification of PVs is reviewed, along with the significance of this classification. The PV-associated diseases of dogs and cats are then described. These descriptions include the clinical presentation of the disease, the causative PV types, the histological features that allow diagnosis, and, where appropriate, possible treatment options. The review is comprehensive and contains the latest information about PVs and the diseases they cause in dogs and cats. Full article

Anal Squamous Cell Carcinoma (SCCA) is a rare Human Papillomavirus type 16 (HPV16)-associated carcinoma whose pathogenesis is still poorly understood. Recent studies based on biopsy and Next Generation Sequencing (NGS) approaches have linked the viral episomal status to aggressive SCCA phenotypes, suggesting a potential role of the 16E5 oncoprotein in tumor development. Our previous findings indicated that 16E5 induces Fibroblast Growth Factor Receptor 2 (FGFR2) isoform switching, aberrant mesenchymal FGFR2c expression, Epithelial Mesenchymal Transition (EMT), and cell invasion in various in vitro human keratinocyte models, as well as in the in vivo context of cervical Low-grade Squamous Intraepithelial Lesions (LSILs). To further explore the role of 16E5 in epithelial carcinogenesis, this study aims to investigate the molecular profile in HPV-related anal lesions. The results showed a significant positive correlation between 16E5 and FGFR2c, as well as 16E5 or FGFR2c and key EMT-related transcription factors, particularly in the group of HPV16 positive anal samples not containing without high grade lesions. Additionally, by coupling the molecular analysis with an interactome investigation, we hypothesized a potential functional interplay between the Ca²⁺ channel Transient Receptor Potential Ankyrin 1 (TRPA1) and FGFR2c, mediated by 16E5 during the establishment of the oncogenic signaling. These findings will help to elucidate the actual relevance of 16E5 in the early progression of anal lesions and contribute to determine its potential as target for future preventive approaches for HPV16-positive SCCA. Full article

Background: Thua-nao is a traditional fermented soybean product widely consumed in the northern areas of Thailand. There has been little research on the biological activity of Thua-nao, particularly its anticancer properties. Objectives: The objective of this study was to examine the cancer chemopreventive effects of dried Thua-nao on liver and colorectal carcinogenesis induced by carcinogens in rats. Methods: Rats were injected with diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH) to induce preneoplastic lesions. Rats orally received dried Thua-nao for 13 weeks. The preneoplastic lesions, including glutathione S-transferase placental form (GST-P)-positive foci and aberrant crypt foci (ACF), were evaluated in the liver and colon, respectively. The cancer chemopreventive mechanisms of dried Thua-nao on liver and colorectal carcinogenesis were examined. Results: Dried Thua-nao administration suppressed colorectal aberrant crypt foci. Moreover, dried Thua-nao reduced proliferation cell nuclear antigen (PCNA)-positive cells in the colon. Interestingly, dried Thua-nao modulated the gut microbiota in DEN- and DMH-induced rats. Isoflavones, including genistein and daidzein, represent promising chemopreventive agents in dried Thua-nao. Conclusions: In conclusion, these results highlight the cancer chemopreventive effect of dried Thua-nao in DEN and DMH-induced colorectal carcinogenesis through cell proliferation reduction and gut microbiota modulation. Full article

Background/Objectives: Brazilian red propolis has attracted attention for its pharmacological properties. However, signs of toxicity were recently observed in long-term studies using the hydroalcoholic extract of red propolis (RPHE), likely due to polyprenylated benzophenones. This study aimed to develop a benzophenone-free red propolis extract (BFRP) and validate an HPLC-PDA method to quantify its main constituents: isoliquiritigenin, vestitol, neovestitol, medicarpine, and 7-O-methylvestitol. Methods: BFRP’s toxicity was assessed in zebrafish larvae through a vibrational startle response assay (VSRA) and morphological analysis. Genotoxicity was evaluated using the micronucleus test in rodents, and the extract’s effects on chemically induced preneoplastic lesions in rat colon were studied. An HPLC-PDA method was used to quantify BFRP’s main compounds. Results: BFRP primarily contained vestitol (128.24 ± 1.01 μg/mL) along with isoliquiritigenin, medicarpin, neovestitol, and 7-O-methylvestitol. Zebrafish larvae exposed to 40 µg/mL of BFRP exhibited toxicity, higher than the 10 µg/mL for RPHE, though no morphological differences were found. Fluorescent staining in the notochord, branchial arches, and mouth was observed in larvae treated with both BFRP and RPHE. No genotoxic or cytotoxic effects were observed up to 2000 mg/kg in rodents, with no impact on hepatotoxicity or nephrotoxicity markers. Chemoprevention studies showed a 41.6% reduction in preneoplastic lesions in rats treated with 6 mg/kg of BFRP. Conclusions: These findings indicate that BFRP is a safe, effective propolis-based extract with potential applications for human health, demonstrating reduced toxicity and chemopreventive properties. Full article

The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett’s esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to BE are endoscopic and screening cytologic programs with endoscopic ablation of various forms. The former have not been proven to be cost-effective and there are mixed results for eradication. A fresh approach is sorely needed. We prospectively followed 2229 mostly male veterans at high risk for colorectal cancer in a 27-year longitudinal long-term study, collecting data on colorectal neoplasia development and other preneoplastic lesions, including BE and spontaneous regression (SR). Another cross-sectional BE study at a similar time period investigated antigenic changes at the GEJ in both BE glandular and squamous mucosa immunohistochemistry and the role of inflammation. Ten of the prospective cohort (21.7%) experienced SR out of a total of forty-six BE patients. Significant differences between SR and stable BE were younger age (p < 0.007); lower platelet levels (p < 0.02); rectal p87 elevation in SR (p < 0.049); a reduced innate immune system (InImS) FEREFF ratio (ferritin: p87 colonic washings) (p < 0.04). Ancillary testing showed a broad range of neoplasia biomarkers. InImS markers may be susceptible to intervention using commonplace and safe medical interventions and encourage SR. Full article

2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC) is a major compound in Cleistocalyx nervosum seed extract (CSE), which has been reported to have various biological activities, including anti-cancer activity. Therefore, this study attempted to evaluate whether DMC is a chemopreventive compound in CSE. Moreover, the preventive mechanisms of CSE and DMC in the DEN-induced early stages of hepatocarcinogenesis in rats were investigated. Male Wistar rats were intraperitoneally injected with DEN 50 mg/kg bw once a week for 8 weeks. Rats received CSE and DMC orally throughout the experiment. The number of glutathione S-transferase placental form (GST-P)-positive foci in the liver was measured. Furthermore, the preventive mechanisms of CSE and DMC on DEN-induced HCC, including cell proliferation and apoptosis, were investigated. Administering CSE at a dosage of 400 mg/kg bw and DMC at a dosage of 10 mg/kg bw significantly decreased the number and size of GST-P-positive foci and GST-P expression. In addition, DMC inhibited the development of preneoplastic lesions by decreasing cell proliferation and causing cell apoptosis; however, CSE inhibited the development of preneoplastic lesions by inducing cell apoptosis. In conclusion, DMC exhibited a cancer chemopreventive effect on the early stages of hepatocarcinogenesis by increasing cell apoptosis and reducing cell proliferation. Full article