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Laryngeal rare tumors include benign and malignant tumors of epithelial, non-epithelial, or mesenchymal origin. Chondrosarcomas are the most common mesenchymal malignant tumors of the larynx. We performed a literature review (Pubmed/Medline; PRISMA 2020) to detect the frequency of published studies from 2021 to April 2024 regarding benign and malignant epithelial, non-epithelial, or mesenchymal rare tumors of the larynx, emphasizing laryngeal chondrosarcoma (LC) cases. Articles including cases discussed before 2021 were excluded and articles without available English translations. We included 154 articles investigating rare tumors of the larynx, the majority of them discussed non-epithelial or mesenchymal entities (75â¯%). Specifically, a high proportion of studies examined benign non-epithelial or mesenchymal tumors (79.5â¯%) or mesenchymal rare malignancies (72â¯%) of the larynx concerning epithelial tumors in the last three years. Sarcomas were discussed in 74â¯% of mesenchymal laryngeal malignancies and more than 50â¯% of rare laryngeal tumor studies, and LC was discussed in â¼50â¯% of laryngeal sarcoma studies. LC studies reported 174 cases, 21â¯% of them of high-grade LC (II), including a new case of LC presented here in the supraglottic (grade II), which showed intense staining for the S100 marker. Our study highlights the awareness of rare laryngeal tumors emphasizing non-epithelial benign tumors and laryngeal sarcomas, including chondrosarcomas, as pathologic entities of the larynx. Although the majority of LC included low-grade neoplasms, a markedness proportion of LC cases was evaluated as high-grade. Future research approaches, including a range of low and high-grade tumors, would reveal prognostic markers or therapeutic targets for LC and other rare laryngeal malignancies of non-epithelial or mesenchymal origin.
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Condrosarcoma , Neoplasias Laríngeas , Humanos , Condrosarcoma/patología , Neoplasias Laríngeas/patología , Sarcoma/patologíaRESUMEN
Glioblastoma multiforme (GBM) is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation. Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression. Specifically, hypoxia is known to activate inducible factors, such as hypoxia-inducible factor 1alpha (HIF-1α), which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators, such as the vascular endothelial growth factor (VEGF). Here, we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data, as potential biomarkers of GBM prognosis and treatment efficacy. We performed a systematic review (Medline/Embase, and Pubmed database search was completed by 16th of April 2024 by two independent teams; PRISMA 2020). We evaluated methods of immunoassays, cell viability, or animal or patient survival methods of the retrieved studies to assess unbiased data. We used inclusion criteria, such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression, other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression, application of immunoassays for protein expression, and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression. We used exclusion criteria, such as data not reporting both HIF-1α and VEGF or prognosis. We included 50 studies investigating in total 1319 GBM human specimens, 18 different cell lines or GBM-derived stem cells, and 6 different animal models, to identify the association of HIF-1α/VEGF immunophenotypes, and with other prognostic factors, clinical and macroscopic data in GBM prognosis and therapeutic approaches. We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors, such as miR-210-3p, Oct4, AKT, COX-2, PDGF-C, PLDO3, M2 polarization, or ALK, leading to unfavorable survival. Reduced HIF-1α/VEGF expression correlates with FIH-1, ADNP, or STAT1 upregulation, as well as with clinical manifestations, like epileptogenicity, and a favorable prognosis of GBM. Based on our data, HIF-1α or VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression. Finally, HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy, including combined first-line treatment with histone deacetylase inhibitors, thimerosal, or an active metabolite of irinotecan, as well as STAT3 inhibitors alone, and resulting in a favorable tumor prognosis and patient survival. These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes. Data limitations may include the use of less sensitive detection methods in some cases. Overall, our data support HIF-1α/VEGF's role as biomarkers of GBM prognosis and treatment efficacy.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Glioblastoma , Subunidad alfa del Factor 1 Inducible por Hipoxia , Factor A de Crecimiento Endotelial Vascular , Glioblastoma/patología , Glioblastoma/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Pronóstico , Biomarcadores de Tumor/metabolismo , Animales , Microambiente TumoralRESUMEN
INTRODUCTION: Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post-treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone. MATERIALS AND METHODS: We performed whole-transcriptome and small non-coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC). RESULTS: We identified 12 novel saliva and serum miRNAs and a panel of unique miRNA and mRNA signatures, significantly differentially expressed in OSCC patients relative to HC (log2 fold change: 2.6-26.8; DE: 0.02-0.000001). We utilized a combined panel of the 10 top-deregulated miRNAs and mRNAs and evaluated their putative diagnostic potential (>87% sensitivity; 100% specificity), recommending seven of them for further validation. We also identified unique saliva and serum miRNAs associated with OSCC and smoking history (OSCC smokers vs. never-smokers or HC: log2 fold change: 22-23; DE: 0.00003-0.000000001). Functional and pathway analyses indicated interactions between the discovered OSCC-related non-invasive miRNAs and mRNAs and their targets, through PI3K/AKT/mTOR signaling. CONCLUSION: Our data support our hypothesis that using paired saliva and serum from the same individuals and deep sequencing analyses can provide unique combined mRNA and miRNA signatures associated with canonical pathways that may have a diagnostic advantage relative to saliva or serum alone and may be useful for clinical testing. We believe this data will contribute to effective preventive care by post-treatment monitoring of patients, as well as suggesting potential targets for therapeutic approaches.
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Biomarcadores de Tumor , MicroARNs , Neoplasias de la Boca , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Saliva , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/sangre , Neoplasias de la Boca/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Femenino , Masculino , Biomarcadores de Tumor/genética , Saliva/metabolismo , Saliva/química , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Persona de Mediana Edad , MicroARNs/genética , MicroARNs/sangre , Transcriptoma , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica , Anciano , ARN Pequeño no Traducido/genética , ARN Pequeño no Traducido/sangre , Adulto , Estudios de Casos y Controles , Análisis de Secuencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/metabolismoRESUMEN
Tobacco use is implicated in the carcinogenesis of oral squamous cell carcinoma (OSCC), which is associated with poor survival if not diagnosed early. Identification of novel noninvasive, highly sensitive, and cost-effective diagnostic and risk assessment methods for OSCC would improve early detection. Here, we report a pilot study assessing salivary and serum miRNAs associated with OSCC and stratified by smoking status. Saliva and paired serum samples were collected from 23 patients with OSCC and 21 healthy volunteers, with an equal number of smokers and nonsmokers in each group. Twenty head and neck cancer-related miRNAs were quantified by qPCR (dual-labeled LNA probes) and analyzed by Welch t test (95% confidence interval). Four saliva miRNAs, miR-21, miR-136, miR-3928, and miR-29B, showed statistically significant overexpression in OSCC versus healthy controls (P < 0.05). miR-21 was statistically significantly overexpressed in OSCC smokers versus nonsmokers (P = 0.006). Salivary miR-21, miR-136, and miR-3928, and serum miR-21 and miR-136, showed statistically significant differential expression in early-stage tumors versus controls (P < 0.05), particularly miR-21 in smokers (P < 0.005). This pilot study provides a novel panel of saliva and serum miRNAs associated with oral cancer. Further validation as a potential useful index of oral cancer, particularly miR-21 in smokers and early-stage OSCC is warranted. PREVENTION RELEVANCE: Saliva and serum miR-21, miR-136, miR-3928, and miR-29B, are potentially associated with oral cancer even at an early stage, especially miR-21 in individuals with a smoking history, a further validation in a larger cohort of subjects with premalignant and early malignant lesions need to confirm.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , MicroARNs , Neoplasias de la Boca , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proyectos Piloto , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Neoplasias de la Boca/etiología , Neoplasias de la Boca/genética , Saliva , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias de Cabeza y Cuello/metabolismo , Fumar/efectos adversos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
OBJECTIVE: Head and neck follicular lymphoma (FL) with marginal zone (MZ) differentiation is a rare high-risk B-cell composite variant that has been reported in nodular but not extranodular sites in the parotid glands. Here we summarize the literature on FL with MZ differentiation in head and neck nodular sites and describe a rare case of extranodular FL with MZ differentiation in the parotid gland. STUDY DESIGN: We examined both the germinal center and MZ components of the parotid and bone-marrow biopsies of a 65-year-old female histologically, immunohistochemically, and molecularly to identify B-cell, germinal center, and follicular dendritic cell markers. RESULTS: The immunohistochemical and molecular analysis provided evidence that the FL and the MZ components derived from the same B-cell clone with a similar BCL2/IGH t(14;18) translocation site. The differentiated cells in the MZ did not express germinal center markers BCL6 and CD10. Both the parotid and bone-marrow proliferative B cells showed BCL6, CD2O, and CD79a positivity. CONCLUSIONS: Head and neck FL with MZ differentiation can develop in both nodular and extranodular sites and is characterized by BCL2 translocation t(14;18). Although the mechanism of MZ differentiation is unclear, the characterization of this rare histopathologic phenomenon might be clinically important.
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Linfoma Folicular , Femenino , Humanos , Anciano , Linfoma Folicular/genética , Linfoma Folicular/química , Linfoma Folicular/patología , Médula Ósea , Translocación Genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Diferenciación CelularRESUMEN
According to population-based studies, lung cancer is the prominent reason for cancer-related mortality worldwide in males and is also rising in females at an alarming rate. Sorafenib (SOR), which is approved for the treatment of hepatocellular carcinoma and renal cell carcinoma, is a multitargeted protein kinase inhibitor. Additionally, SOR is the subject of interest for preclinical and clinical trials in lung cancer. This study was designed to assess in vivo the possible effects of sorafenib (SOR) in diethylnitrosamine (DEN)-induced lung carcinogenesis and examine its probable mechanisms of action. A total of 30 adult male rats were divided into three groups (1) control, (2) DEN, and (3) DEN + SOR. The chemical induction of lung carcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg once a week for two weeks. The DEN-administered rats were co-treated with SOR of 10 mg/kg by oral gavage for 42 alternate days. Serum and lung tissue samples were analyzed to determine SRY-box transcription factor 2 (SOX-2) levels. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) levels were measured in lung tissue supernatants. Lung sections were analyzed for cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) histopathologically. In addition, cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) were analyzed by immunohistochemistry and immunofluorescence methods, respectively. SOR reduced the level of SOX-2 that maintenance of cancer stemness and tumorigenicity, and TNF-α and IL-1ß levels. Histopathological analysis demonstrated widespread inflammatory cell infiltration, disorganized alveolar structure, hyperemia in the vessels, and thickened alveolar walls in DEN-induced rats. The damage was markedly reduced upon SOR treatment. Further, immunohistochemical and immunofluorescence analysis also revealed increased expression of COX-2 and JNK expression in DEN-intoxicated rats. However, SOR treatment alleviated the expression of these inflammatory markers in DEN-induced lung carcinogenesis. These findings suggested that SOR inhibits DEN-induced lung precancerous lesions through decreased inflammation with concomitant in reduced SOX-2 levels, which enables the maintenance of cancer stem cell properties.
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Laryngeal squamous cell carcinoma (LSCC) is one of the most aggressive cancers, and its early diagnosis is urgent. Exosomes are believed to have diagnostic significance in cancer. However, the role of serum exosomal microRNAs, miR-223, miR-146, and miR-21, and phosphatase and tensin homologue (PTEN) and hemoglobin subunit delta (HBD) mRNAs in LSCC is unclear. Exosomes were isolated from the blood serum of 10 LSCC patients and 10 healthy controls to perform scanning electron microscopy and liquid chromatography quadrupole time-of-flight mass spectrometry analyses to characterize them and to undergo reverse transcription polymerase chain reaction to identify miR-223, miR-146, miR-21, and PTEN and HBD mRNA expression phenotypes. Biochemical parameters, including serum C-reactive protein (CRP) and vitamin B12, were also obtained. Serum exosomes of 10-140 nm were isolated from LSCC and controls. Serum exosomal miR-223, miR-146, and PTEN were found to be significantly decreased (p < 0.05), in contrast to serum exosomal miRNA-21 (p < 0.01), and serum vitamin B12 and CRP (p < 0.05) were found to be significantly increased, in LSCC vs controls. Our novel data show that the combination of reduced serum exosomal miR-223, miR-146, and miR-21 profiles and biochemical alterations in CRP and vitamin B12 levels may be useful indicators of LSCC that could be validated by large studies. Our findings also suggest a possible negative regulatory effect of miR-21 on PTEN in LSCC, encouraging a more extensive investigation of its role.
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Bariatric bypass surgery has been an effective treatment for morbid obesity. However, there is an increasing number of reported cases of gastric cancer after bypass surgery. Our systematic review showed an increasing trend of gastric cancer cases after bariatric bypass surgery in the last decade, mostly located in the excluded stomach (77%) and diagnosed in an advanced stage. In addition to known risk factors such as tobacco smoking (17%), H. pylori infection (6%), and family history of gastric cancer (3%), bile reflux, a recently proposed cancer-promoting factor, was also estimated in 18% of the cases. Our data suggest that gastric cancer risk assessment should be considered before gastric bypass surgery, and further investigations are needed to determine the value of post-operative gastric cancer surveillance.
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Cirugía Bariátrica , Derivación Gástrica , Laparoscopía , Obesidad Mórbida , Neoplasias Gástricas , Humanos , Obesidad Mórbida/cirugía , Derivación Gástrica/efectos adversos , Neoplasias Gástricas/etiología , Neoplasias Gástricas/cirugía , Laparoscopía/efectos adversosRESUMEN
OBJECTIVES/HYPOTHESIS: We recently documented that acidic bile, a gastroesophageal reflux content, can cause invasive hypopharyngeal squamous cell carcinoma, by inducing widespread DNA damage and promoting nuclear factor kappa B (NF-κB)-related oncogenic molecular events. Poly or adenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), a sensitive sensor of DNA damage, may interact with NF-κB. We hypothesized that PARP-1 is activated in hypopharyngeal cells (HCs) with marked DNA damage caused by acidic bile, hence there is an association between PARP-1 and NF-κB activation or its related oncogenic profile, in this process. STUDY DESIGN: In vitro study. METHODS: We targeted PARP-1 and NF-κB(p65), using pharmacologic inhibitors, 1.0 µM Rucaparib (AG014699) and 10 µM BAY 11-7082 {3-[4=methylphenyl)sulfonyl]-(2E)-propenenitrile}, respectively, or silencing their gene expression (siRNAs) and used immunofluorescence, luciferase, cell viability, direct enzyme-linked immunosorbent assays, and qPCR analysis to detect the effect of targeting PARP-1 or NF-κB in acidic bile-induced DNA damage, PARP-1, p-NF-κB, and B-cell lymphoma 2 (Bcl-2) expression, as well as NF-κB transcriptional activity, cell survival, and mRNA oncogenic phenotype in HCs. RESULTS: We showed that (i) PARP-1 is overexpressed by acidic bile, (ii) targeting NF-κB adequately prevents the acidic bile-induced DNA double-strand breaks (DSBs) by gamma H2A histone family member X (γH2AX), oxidative DNA/RNA damage, PARP-1 overexpression, anti-apoptotic mRNA phenotype, and cell survival, whereas (iii) targeting PARP-1 preserves elevated DNA damage, NF-κB activation, and anti-apoptotic phenotype. CONCLUSION: We document for the first time that the activation of PARP-1 is an early event during bile reflux-related head and neck carcinogenesis and that NF-κB can mediate DNA damage and PARP-1 activation. Our data encourage further investigation into how acidic bile-induced activated NF-κB mediates DNA damage in hypopharyngeal carcinogenesis. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1146-1155, 2023.
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Bilis , FN-kappa B , Humanos , FN-kappa B/metabolismo , Bilis/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Ácidos y Sales Biliares , Carcinogénesis , ARN Mensajero/metabolismo , Daño del ADN , ADN/metabolismoRESUMEN
Deregulation of the DNA mismatch repair (MMR) mechanism has been linked to poor prognosis of upper aerodigestive tract cancers. Our recent in vitro data have provided evidence of crosstalk between deregulated miRNAs and MMR genes, caused by tobacco smoke (TS) N-Nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in hypopharyngeal cells. Here, we explored whether chronic exposure to TS components can affect MMR mechanism and miRNA profiles in hypopharyngeal mucosa. Using a mouse model (C57Bl/6J wild type) of in vivo 14-week exposure to NNK (0.2 mmol/L) and N-Nitrosodiethylamine (NDEA; 0.004 mmol/L), with or without nicotine (0.02 µmol/L), we provide direct evidence that TS components can promote dysplasia, significant downregulation of Msh2 and Mlh1 genes and deregulation of miR-21, miR-155, miR-34a, and miR-451a. By analyzing eight human specimens from tobacco smokers and eight controls, we provide clinical evidence of a significant reduction in hMSH2 and hMLH1 mRNAs in hypopharyngeal squamous cell carcinoma (HSCC). In summary, deregulation of the MMR mechanism and miRNAs is caused by chronic exposure to TS-related N-Nitrosamines, with or without nicotine, in the early stages of upper aerodigestive tract carcinogenesis, and can also be detected in human HSCC. Thus, we encourage future studies to further elucidate a possible in vivo dose-dependent effect of individual or combined N-Nitrosamines, NNK and/or NDEA, and nicotine, on the MMR mechanism and their clinical testing to elaborate prognosis and risk assessment.
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Neoplasias de Cabeza y Cuello , MicroARNs , Nitrosaminas , Contaminación por Humo de Tabaco , Carcinógenos/análisis , Carcinógenos/toxicidad , Reparación de la Incompatibilidad de ADN , Humanos , MicroARNs/genética , Nicotina , Nitrosaminas/análisis , Nitrosaminas/toxicidad , Humo , Carcinoma de Células Escamosas de Cabeza y Cuello , Nicotiana , Contaminación por Humo de Tabaco/análisisRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) constitutes a life-threatening inflammatory syndrome. Postmortem histological findings of bone marrow (BM) from COVID-19 patients showed histiocytosis and hemophagocytosis and supported the hypothesis that secondary HLH (sHLH) may be triggered by SARS-CoV-2 infection. However, there are a limited number of sHLH cases in which trephine has been performed in living post-COVID-19 patients. Here we present a recent case and a mini-review of sHLH diagnosed by trephine biopsy in living patients after COVID-19. An 81-year-old man with a past medical history of hypertension, diabetes, ischemic stroke, was referred to the hospital to evaluate leukocytosis, pyuria, and elevation of inflammatory markers four weeks after recovering from COVID-19. Computed tomography of the abdomen did not reveal focal signs of infection or hepatosplenomegaly. The patient received intravenous meropenem and two packed red blood cell units. Leukocytes and C-reactive protein were gradually decreased. A BM biopsy was performed and the patient was discharged on cefixime. BM smear revealed severe anemia, lymphopenia, and dysplastic morphologic findings of erythroblasts, neutrophils, and megakaryocytes. Trephine biopsy revealed hypercellular marrow dyserythropoiesis, plasmacytosis, lymphocytosis, histiocytosis, hemophagocytosis, and the absence of granulomas or carcinoma. Immunohistochemistry documented a mixed population of T lymphocytes (CD3+) and B lymphocytes (CD20+). Strong positivity for CD68 confirmed histiocytosis. CD138 κ, λ staining proved polyclonal plasmacytosis. Perl's staining showed excess hemosiderin deposits. Based on our findings, we document sHLH in trephine BM biopsy of a living post-COVID-19 patient and persistent leukocytosis, underscoring the diagnostic value of trephine biopsy in preventing life-threatening conditions such as COVID-19.
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COVID-19 , Linfohistiocitosis Hemofagocítica , Anciano de 80 o más Años , Biopsia/efectos adversos , Médula Ósea/patología , COVID-19/complicaciones , Humanos , Leucocitosis/complicaciones , Leucocitosis/patología , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/etiología , Masculino , SARS-CoV-2RESUMEN
Tobacco smoking is the most known risk factor for hypopharyngeal cancer. Bile reflux has recently been documented as an independent risk factor for NFκB-mediated hypopharyngeal squamous cell carcinoma. However, the carcinogenic effect of tobacco smoke on the hypopharynx and its combination with bile has not yet been proven by direct evidence. We investigated whether in vivo chronic exposure (12-14 weeks) of murine (C57Bl/6J) hypopharyngeal epithelium to tobacco smoke components (TSC) [N-nitrosamines; 4-(N-Methyl-N-Nitrosamino)-1-(3-pyridyl)-1-butanone (0.2 mmol/L), N-nitrosodiethylamine (0.004 mmol/L)], as the sole drinking fluid 5 days per week, along with topically applied (two times/day) bile [deoxycholic acid (0.28 mmol/L)], can accelerate a possible TSC-induced neoplastic process, by enhancing NFκB activation and the associated oncogenic profile, using histologic, IHC, and qPCR analyses. We provide direct evidence of TSC-induced premalignant lesions, which can be exacerbated by the presence of bile, causing invasive carcinoma. The combined chronic exposure of the hypopharynx to TSC with bile causes advanced NFκB activation and profound overexpression of Il6, Tnf, Stat3, Egfr, Wnt5a, composing an aggressive phenotype. We document for the first time the noxious combination of bile with a known risk factor, such as tobacco smoke nitrosamines, in the development and progression of hypopharyngeal cancer, via NFκB, in vivo. The data presented here encourage further investigation into the incidence of upper aerodigestive tract cancers in smokers with bile reflux and the early identification of high-risk individuals in clinical practice. This in vivo model is also suitable for large-scale studies to reveal the nature of inflammatory-associated aerodigestive tract carcinogenesis and its targeted therapy. PREVENTION RELEVANCE: Early assessment of bile components in refluxate of tobacco users can prevent the chronic silent progression of upper aerodigestive tract carcinogenesis. This in vivo model indicates that bile reflux might have an additive effect on the tobacco-smoke N-nitrosamines effect and could be suitable for large-scale studies of diagnostic and therapeutic interventions.
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Reflujo Biliar , Neoplasias de Cabeza y Cuello , Neoplasias Hipofaríngeas , Nitrosaminas , Contaminación por Humo de Tabaco , Animales , Bilis/química , Carcinogénesis/inducido químicamente , Ácido Desoxicólico/efectos adversos , Ratones , FN-kappa B , Nitrosaminas/toxicidad , Humo/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello , Nicotiana/efectos adversosRESUMEN
Prostate cancer is one of the most commonly diagnosed malignancies in men. Most of these tumors are adenocarcinomas. Plasmacytoid is a rare variant of adenocarcinoma described by previous studies in the genitourinary system and is characterized by the plasmacytoid appearance of tumor cells with abundant cytoplasm and abnormally placed hyperchromatic nuclei. However, to the best of our knowledge, plasmacytoid adenocarcinoma has rarely been described in the prostate. This report describes a new case of plasmacytoid adenocarcinoma of the prostate diagnosed by biopsy and summarizes the known literature on plasmacytoid features in the genitourinary system. A 62-year-old male patient presented to the hospital with urinary retention, hematuria, weakness and weight loss. The digital rectal examination revealed an irregular enlargement. Laboratory findings showed elevated levels of prostate specific antigen (PSA; 43.6 ng/ml). Transrectal ultrasound showed invasion of the right seminal vesicle. Prostate tumor core biopsies were collected and sent for diagnosis. Histological examination revealed a high-grade prostatic adenocarcinoma Gleason score of 5+5 (total score 10). The tumor cells had a plasmacytoid appearance with abundant cytoplasm and abnormally placed hyperchromatic nuclei. The immunohistochemical phenotype was characterized by abundant positivity for cytokeratin (CK)AE1/AE3 and PSA. By contrast, tumor cells were negative for p63, CK 34BE12 and GATA binding protein 3 (urothelial markers), synaptophysin (neuroendocrine marker). Tumor cells were also negative for E-cadherin, which is particularly indicative of CDH1 alterations. To the best of our knowledge, this is the first description of a plasmacytoid adenocarcinoma of the prostate diagnosed by biopsy, showing an irregular immunophenotype that may indicate somatic CDH1 alterations. The presentation of a novel rare variant of prostatic carcinoma that differs from other neoplasms of the genitourinary system may contribute to an improved understanding of this uncommonly found histological pattern that may also be mandatory due to the clinical and prognostic implications of this diagnosis.
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The signal transducer and activator of transcription 3 (STAT3) oncogene is a transcription factor with a central role in head and neck cancer. Hypopharyngeal cells (HCs) exposed to acidic bile present aberrant activation of STAT3, possibly contributing to its oncogenic effect. We hypothesized that STAT3 contributes substantially to the bile reflux-induced molecular oncogenic profile, which can be suppressed by STAT3 silencing or pharmacological inhibition. To explore our hypothesis, we targeted the STAT3 pathway, by knocking down STAT3 (STAT3 siRNA), and inhibiting STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3-201; STA-21), in acidic bile (pH 4.0)-exposed human HCs. Immunofluorescence, luciferase assay, Western blot, enzyme-linked immunosorbent assay and qPCR analyses revealed that STAT3 knockdown or pharmacologic inhibition significantly suppressed acidic bile-induced STAT3 activation and its transcriptional activity, Bcl-2 overexpression, transcriptional activation of IL6, TNF-α, BCL2, EGFR, STAT3, RELA(p65), REL and WNT5A, and cell survival. Our novel findings document the important role of STAT3 in bile reflux-related molecular oncogenic events, which can be dramatically prevented by STAT3 silencing. STA-21, SI3-201 or Nifuroxazide effectively inhibited STAT3 and cancer-related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux-related hypopharyngeal carcinogenesis.
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Reflujo Biliar , Factor de Transcripción STAT3 , Carcinogénesis/genética , Línea Celular Tumoral , Humanos , FN-kappa B/metabolismo , Oncogenes , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Laryngopharyngeal reflux, a variant of gastroesophageal reflux disease, has been considered a risk factor in the development of hypopharyngeal cancer. Bile acids are frequently present in the gastroesophageal refluxate and their effect has been associated with inflammatory and neoplastic changes in the upper aerodigestive tract. Recent in vitro and in vivo studies have provided direct evidence of the role of acidic bile refluxate in hypopharyngeal carcinogenesis and documented the crucial role of NFκB as a key mediator of early oncogenic molecular events in this process and also suggested a contribution of STAT3. Acidic bile can cause premalignant changes and invasive squamous cell cancer in the affected hypopharynx accompanied by DNA damage, elevated p53 expression and oncogenic mRNA and microRNA alterations, previously linked to head and neck cancer. Weakly acidic bile can also increase the risk for hypopharyngeal carcinogenesis by inducing DNA damage, exerting antiapoptotic effects and causing precancerous lesions. The most important findings that strongly support bile reflux as an independent risk factor for hypopharyngeal cancer are presented in the current review and the underlying mechanisms are provided.
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Reflujo Biliar/complicaciones , Reflujo Biliar/patología , Neoplasias Hipofaríngeas/etiología , Neoplasias Hipofaríngeas/patología , Ácidos y Sales Biliares/metabolismo , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/patología , Daño del ADN , Humanos , FN-kappa B/metabolismo , ARN Mensajero/metabolismo , Factores de Riesgo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Renal Cell Carcinoma (RCC) is the most common type of cancer in the kidney and is mostly asymptomatic. Previous studies have supported the important role of sex hormones in RCC pathophysiology and that targeted hormone receptor therapy, such as estrogen receptor targeting, is a promising treatment strategy. However, to the best of our knowledge, it remains unknown whether hormonal therapy, such as controlled ovarian stimulation for in vitro fertilization, serves a role in the development and progression of RCC. The present report describes a case of RCC developed after a fertility stimulation therapy and provides a summary of the known literature on the role of hormone receptors in the development and progression of RCC. A 35-year-old woman received fertility stimulation treatment with follitropin alfa 900 units, human chorionic gonadotropic hormone 5,000 units, injectable leuprolide 1 mg/0.2 ml and cetrotide 0.25 mg. The patient presented to the hospital with shortness of breath and weight loss. The patient had no known genetic predisposition or family history of malignancies and no exposure to chemicals. The patient never used tobacco, alcohol or recreational drugs. Imaging revealed a 17x19 mm, heterogeneously enhancing, and partially exophytic mass in the right kidney. After partial nephrectomy, the pathological evaluation confirmed the diagnosis of clear cell RCC. To the best of our knowledge, this was the first time that a case of ovarian stimulation therapy was associated with the development of RCC. This case raises concerns about the potential oncogenic effect of controlled ovarian stimulation therapy in RCC promotion, suggesting a need for systematic research to clarify the clinical significance of existing pre-clinical data.
RESUMEN
Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1ß, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Receptores ErbB/metabolismo , Concentración de Iones de Hidrógeno , Pepsina A/metabolismo , Transducción de Señal , Supervivencia Celular , Transformación Celular Neoplásica/genética , Células Cultivadas , Receptores ErbB/agonistas , Receptores ErbB/genética , Humanos , Hipofaringe/citología , Hipofaringe/metabolismo , FN-kappa B/metabolismo , Pepsina A/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. METHODS: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. RESULTS: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the "oncomirs", miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of "tumor suppressor" miR-451a. CONCLUSION: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD.
RESUMEN
Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.