Preneoplastic Lesions Research Articles

CLINICOPATHOLOGICAL STUDY OF NEOPLASTIC LESIONS OF UTERINE CERVIX AT A TERTIARY CARE CENTRE

Background:- Cervical cancer is the second most common cancer of women in India and most common cause of death among women in developing countries. HPV infection has emerged as the important causative agent in development of carcinoma cervix. Cervical screening program has drastically reduced rates of carcinoma cervix in developed countries. Present study is being conducted to study the spectrum of neoplastic cervical lesions and its association with clinical presentation in different age groups. The present prospective Material And Methods: study was performed on all the biopsies and specimens of cervix received in the Pathology department. Total 356 cases were studied, out Results:- of which 264 cases were neoplastic, 75 cases were non neoplastic, and 17 cases were pre neoplastic lesions. Maximum number of cases seen in 5th decade, multiparous, with bleeding as most common presentation. Squamous cell carcinoma was the predominant neoplastic lesion. Conclusion:- In our study, majority of cases were multiparous commonly presented in 5th decade of life. Neoplasms of uterine cervix include a wide range of lesions, most predominant being squamous cell carcinoma, It is essential to spread awareness for strengthening of screening programmes at early age for early diagnosis and treatment.

156 Nitrogen-Doped Multi-Walled Carbon Nanotubes show Attenuated Pathogenicity in a Mouse Model of Pleural Exposure

Abstract Engineered carbon nanotubes (CNT) are currently used in many industrial products. Multi-walled carbon nanotubes (MWCNT) exhibit unique physicochemical properties and due to their low density and small size are easily aerosolized, making workplace exposure a potential risk to human health. MWCNT are similar to Asbestos in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, including sporadic pleural Mesothelioma. Mitsui-7 MWCNT (MWCNT-7) have been classified by IARC as a Group 2B carcinogen. Importantly, physicochemically-altered MWCNT synthesized with nitrogen (MWCNT-ND) have been found to elicit attenuated toxicity; however, their pathogenicity in the pleura is unknown.  Using a mouse model of direct injection into the pleural cavity, we compared the molecular changes that occur at the mesothelium over 20-months following injection with an occupationally-relevant dose of MWCNT-7, MWCNT-ND, Asbestos or carbon black. When compared to Asbestos or MWCNT-7, mice injected with MWCNT-ND did not develop respiratory symptoms. In contrast, in cell lines established from pleural effusions from MWCNT-7 or Asbestos-exposed mice with pre-neoplastic lesions or tumours, Whole-Exome-Sequencing and RNASeq revealed common molecular changes in both lesions and tumours. This identified genes involved in driving progression of pleural inflammatory lesions to Mesothelioma, whereas pre-neoplastic lesion-derived cell lines allow dissection of the hazard mechanism of pathogenic fibres at the molecular level early in disease development and thus may help predict genotoxic potency in exposed human populations. Our data demonstrate that physicochemical alteration of MWCNT (e.g. synthesis with nitrogen) attenuates pathogenicity and may offer an alternative for use in industrial applications.

96 Longitudinal Profiling of Carbon Nanotube-Induced Sporadic Mesothelioma Development: Defining the Adverse Outcome Pathway for Disease Progression

Abstract Exposure to asbestos causes pathological changes in the pleural cavity, including malignant mesothelioma (MPM). Length-dependent retention of asbestos fibres in the pleural cavity is crucial for disease development. Chronic inflammation induced by biopersistent asbestos fibres plays a key role in carcinogenesis. Engineered CarbonNanoTubes (CNT) are similar to long-fibre asbestos (LFA) in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, with evidence from our laboratory and others showing the carcinogenic potential of Long-CNT.  Asbestos-induced MPM is diagnosed most commonly at late stage; as a result, little is known about the genetic or epigenetic aberrations occurring in pre-malignant pleural lesions and whether they align with deletions/mutations commonly found in end-stage asbestos-exposed patient tumours. Using a mouse model of direct injection into the pleural cavity, we compared the molecular changes that occur at the mesothelium following injection with an occupationally-relevant dose of Long-CNT or LFA over 20-months. We show a common molecular signature induced by Long-CNT and LFA throughout disease progression eventually leading to the development of sporadic MPM. DNA methylation, gene expression profiles, as well as specific genes are similarly altered in the presence of Long-CNT and LFA, at matched longitudinal exposure times. For the first time, these data uncover the Adverse Outcome Pathway (AOP) from initial Long-CNT exposure through to induction of pre-neoplastic lesions and the development of sporadic pleural mesothelioma, replicating the pathogenesis of end-stage asbestos-induced human disease. This reinforces concerns that high aspect-ratio CNT may pose an asbestos-like hazard, including sporadic malignant mesothelioma.

Expression of ductal and acinar immunohistochemical markers in preneoplastic lesions of a pancreatic ductal adenocarcinoma mouse model

Expression of ductal and acinar immunohistochemical markers in preneoplastic lesions of a pancreatic ductal adenocarcinoma mouse model

Immunostaining of βA-Activin and Follistatin Is Decreased in HPV(+) Cervical Pre-Neoplastic and Neoplastic Lesions.

The activin-follistatin system regulates several cellular processes, including differentiation and tumorigenesis. We hypothesized that the immunostaining of βA-activin and follistatin varies in neoplastic cervical lesions. Cervical paraffin-embedded tissues from 162 patients sorted in control (n = 15), cervical intraepithelial neoplasia (CIN) grade 1 (n = 38), CIN2 (n = 37), CIN3 (n = 39), and squamous cell carcinoma (SCC; n = 33) groups were examined for βA-activin and follistatin immunostaining. Human papillomavirus (HPV) detection and genotyping were performed by PCR and immunohistochemistry. Sixteen samples were inconclusive for HPV detection. In total, 93% of the specimens exhibited HPV positivity, which increased with patient age. The most detected high-risk (HR)-HPV type was HPV16 (41.2%) followed by HPV18 (16%). The immunostaining of cytoplasmatic βA-activin and follistatin was higher than nuclear immunostaining in all cervical epithelium layers of the CIN1, CIN2, CIN3, and SCC groups. A significant decrease (p < 0.05) in the cytoplasmic and nuclear immunostaining of βA-activin was detected in all cervical epithelial layers from the control to the CIN1, CIN2, CIN3, and SCC groups. Only nuclear follistatin immunostaining exhibited a significant reduction (p < 0.05) in specific epithelial layers of cervical tissues from CIN1, CIN2, CIN3, and SCC compared to the control. Decreased immunostaining of cervical βA-activin and follistatin at specific stages of CIN progression suggests that the activin-follistatin system participates in the loss of the differentiation control of pre-neoplastic and neoplastic cervical specimens predominantly positive for HPV.

Development of Pluoronic nanoparticles of fluorocoxib A for endoscopic fluorescence imaging of colonic adenomas.

Current white light colonoscopy suffers from many limitations that allow 22% to 32% of preneoplastic lesions to remain undetected. This high number of false negatives contributes to the appearance of interval malignancies, defined as neoplasms diagnosed between screening colonoscopies at a rate of 2% to 6%. The shortcomings of today's white light-based colorectal cancer screening are addressed by colonoscopic fluorescence imaging of preneoplastic lesions using targeted fluorescent agents to enhance contrast between the lesion and the surrounding normal colonic epithelium. We describe the development of Pluronic® nanoparticles of fluorocoxib A (FA), a fluorescent cyclooxygenase-2 (COX-2) inhibitor that enables targeted imaging of inflammation and cancer in numerous animal models, for endoscopic florescence imaging of colonic adenomas. We formulated FA, a fluorescent COX-2 inhibitor, or fluorocoxib negative control (FNC), a nontargeted fluorophore and a negative control for FA, in micellar nanoparticles of FDA approved Pluronic tri-block co-polymer using a bulk solvent evaporation method. This afforded FA-loaded micellar nanoparticles (FA-NPs) or FNC-loaded micellar nanoparticles (FNC-NPs) with the hydrodynamic diameters ( ) of and and the zeta potentials ( ) of and , respectively. We intravenously injected B6;129 mice bearing colonic adenomas induced by azoxymethane and dextran-sodium sulfate with FA-loaded Pluronic nanoparticles (FA-NPs). The diffusion-mediated local FA release and its binding to COX-2 enzyme allowed for clear detection of adenomas with high signal-to-noise ratios. The COX-2 targeted delivery and tumor retention were validated by negligible tumor fluorescence detected upon colonoscopic imaging of adenoma-bearing mice injected with Pluronic nanoparticles of FNC or of animals predosed with the COX-2 inhibitor, celecoxib, followed by intravenous dosing of FA-NPs. These results demonstrate that the formulation of FA in Pluronic nanoparticles overcomes a significant hurdle to its clinical development for early detection of colorectal neoplasms by fluorescence endoscopy.

Microwave hyperthermia represses human papillomavirus oncoprotein activity and induces cell death due to cell stress in 3D tissue models of anogenital precancers and cancers

Hyperthermia is a well-accepted cancer therapy. Microwaves provide a very precise, targeted means of hyperthermia and are currently used to treat plantar warts caused by cutaneous-infective human papillomaviruses (HPVs). Other HPV genotypes infecting the anogenital mucosa cause genital warts or preneoplastic lesions or cervical cancer. Effective, non-ablative therapies for these morbid HPV-associated lesions are lacking. The molecular consequences of microwave treatment were investigated in invitro cultured three-dimensional HPV-positive cervical tumour tissues, and tissues formed from HPV-infected normal immortalised keratinocytes. Microwave energy delivery to tissues was quantified. Quantitative reverse transcriptase PCR was used to quantify mRNA expression. Immunohistochemistry and fluorescence immunostaining was used to assess protein expression. Microwave energy deposition induced sustained, localised cell death at the treatment site. There was a downregulation in levels of HPV oncoproteins E6 and E7 alongside a reduction in cellular growth/proliferation and induction of apoptosis/autophagy. HSP70 expression confirmed hyperthermia, concomitant with induction of translational stress. The data suggest that microwave treatment inhibits tumour cell proliferation and allows the natural apoptosis of HPV-infected cells to resume. Precision microwave delivery presents a potential new treatment for treating HPV-positive anogenital precancerous lesions and cancers. Funding was through an Innovate UK Biomedical Catalyst grant (ID# 92138-556187), a Chief Scientist Office grant (TCS/19/11) and core support from Medical Research Council (MC_ UU_12014) core funding for the MRC-University of Glasgow Centre for Virus Research.

Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon.

Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear β-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.

MiR-132-3p promotes heat stimulation-induced esophageal squamous cell carcinoma tumorigenesis by targeting KCNK2.

Epidemiological evidence supports that consumption of high-temperature food and beverages is an important risk factor for esophageal squamous cell carcinoma (ESCC);however, the underlying mechanism still remains unclear. Here, we established a series of animal models and found that drinking 65°C water can promote esophageal tumor progression from preneoplastic lesions to ESCC. RNA sequencing data showed that miR-132-3p was highly expressed in the heat stimulation group compared with controls. Further study verified that miR-132-3p were upregulated in human premalignant lesion tissues of the esophagus, ESCC tissues, and cells. Overexpression of miR-132-3p could promote ESCC cell proliferation and colony formation, whereas knockdown of miR-132-3p could inhibit ESCC progression in vitro and in vivo. Importantly, dual-luciferase reporter assays showed that miR-132-3p could bind with the 3'-untranslated regionof KCNK2 and inhibit KCNK2 gene expression. Knockdown or overexpression of KCNK2 could promote or suppress ESCC progression in vitro. These data suggest that heat stimulation can promote ESCC progression and miR-132-3p mediated this process by directly targeting KCNK2.

Abstract 6406: Radiation and STING activation limit tumor development and modulate the immune environment via distinct mechanisms

Abstract Carcinogen-induced lung cancer in A/J mice is an established model of tumor initiation and development. The impact of radiation, immune response, and STING pathway activation on tumor development in this model is not well understood. In this study, we examined the effect of radiation and the STING agonist, DMXAA (Vadimezan), on the development of urethane-induced lung cancer. A/J mice were treated with urethane (i.p.) to induce the development of lung tumors. Three days after urethane treatment, mice received 13 Gy thorax radiation treatment (RT)/mock RT, DMXAA (20 mg/kg i.p.)/vehicle, or a combination treatment (n = 5). Mice were euthanized after 6 hours to 7 days after treatment to assess early events in the lung with RNA-sequencing and flow cytometry, or 5 months after treatment to assess tumor growth and long-term changes to the immune microenvironment with multiplex immunofluorescence. Mice treated with urethane followed by RT had fewer lung surface tumors (p &amp;lt; 0.01) and reduced tumor area (p = 0.0732) compared to their mock RT controls. In parallel, mice that received urethane pre-treatment and RT had high numbers of tertiary lymphoid structures (TLSs; these contained T-cells, B-cells, MHCII+ APCs and CXCL13) compared to the mock RT control mice (p &amp;lt; 0.001). Analysis of immune cell contents of the TLS revealed a notable increase in CD4, CD8 and regulatory T-cells in the RT condition (with urethane pretreatment). Important early events in the lung following RT of urethane pre-treated mice included a transient increase in type I and type II interferons, CD4 and CD8 T-cell infiltration (p &amp;lt; 0.001) and a strong downregulation of cell cycle events. In contrast to these findings, DMXAA treatment after urethane resulted in fewer tumors (p &amp;lt; 0.05), but larger tumors compared to the vehicle-treated group. An increase in immune cells was observed in the lung, however, without clear structures that resembled TLSs. Early events following DMXAA treatment with urethane pre-treatment included dampened levels of type I IFN and TNF-α in circulation and a decrease in T-cell infiltration into the lungs. Interestingly, RT and DMXAA combination treatment (with urethane pre-treatment) drove a synergistic anti-tumor effect, further reducing tumor numbers compared to the RT or DMXAA controls 5 months after treatment. RT and STING agonist treatment of pre-neoplastic lesions have differential impacts on tumor growth in the A/J mouse model, and work synergistically when combined. The different outcomes of RT and DMXAA on tumor growth may be driven by their distinctive mechanism of action on immune responses and capacities to form TLSs. These findings may have future implications for strategies for the early treatment of lung and other cancers, and they suggest that immune responses, including modulation of the STING pathway, may be an important aspect of early tumor development that could be targeted therapeutically. Citation Format: Kay Shigemori, Yanyan Jiang, Bruno Beernaert, Anderson J. Ryan, Eileen E. Parkes. Radiation and STING activation limit tumor development and modulate the immune environment via distinct mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6406.

Artificial intelligence as a noninvasive tool for pancreatic cancer prediction and diagnosis.

Pancreatic cancer (PC) has a low incidence rate but a high mortality, with patients often in the advanced stage of the disease at the time of the first diagnosis. If detected, early neoplastic lesions are ideal for surgery, offering the best prognosis. Preneoplastic lesions of the pancreas include pancreatic intraepithelial neoplasia and mucinous cystic neoplasms, with intraductal papillary mucinous neoplasms being the most commonly diagnosed. Our study focused on predicting PC by identifying early signs using noninvasive techniques and artificial intelligence (AI). A systematic English literature search was conducted on the PubMed electronic database and other sources. We obtained a total of 97 studies on the subject of pancreatic neoplasms. The final number of articles included in our study was 44, 34 of which focused on the use of AI algorithms in the early diagnosis and prediction of pancreatic lesions. AI algorithms can facilitate diagnosis by analyzing massive amounts of data in a short period of time. Correlations can be made through AI algorithms by expanding image and electronic medical records databases, which can later be used as part of a screening program for the general population. AI-based screening models should involve a combination of biomarkers and medical and imaging data from different sources. This requires large numbers of resources, collaboration between medical practitioners, and investment in medical infrastructures.

Insights Obtained from the Nontumorous Glandular Tissue in Patients with Endocrine Tumors.

The pathology of neoplasia tends to focus on the tumor that requires characterization, grading, and staging. However, nontumorous tissue surrounding the lesion can also provide information, particularly about pathogenetic mechanisms. In endocrine tissues, this takes the form of precursor lesions that characterize several genetic predisposition syndromes. In addition, because of the unique functional aspects of endocrine neoplasia, the nontumorous tissue provides evidence of hormone excess, with hyperplasia and/or atrophy and other involutional changes allowing the pathologist to confirm both hormone function by the tumor and the effects of medical therapies. In this article, we review the various clinically relevant features that should be assessed and reported to enhance clinical management of patients with endocrine neoplasms. For example, in thyroid there may be inflammatory thyroiditis or goiter of various etiologies; there may be C-cell hyperplasia either as a preneoplastic lesion in patients with genetic predisposition to medullary thyroid carcinoma or as a reactive phenomenon. Drug-induced changes can be seen in thyroid and adrenal cortex. In neuroendocrine tissues, the nontumorous tissues may show precursor lesions such as endocrine cell hyperplasia/dysplasia; there may be related or unrelated hyperplastic or neoplastic lesions. Some tissues, such as pituitary corticotrophs and adrenal cortex, develop changes that reflect feedback suppression by hormone excess that can serve as biomarkers of tumor functionality and provide enhanced clinicopathologic correlates.

Phenobarbital, a hepatic metabolic enzyme inducer, inhibits preneoplastic hepatic lesions with expression of selective autophagy receptor p62 and ER-phagy receptor FAM134B in high-fat diet-fed rats through the inhibition of ER stress.

We investigated the role of endoplasmic reticulum (ER)-phagy in NAFLD-related hepatocarcinogenesis in high-fat diet (HFD)-fed and/or phenobarbital (PB)-treated rats by clustering the expression levels of the selective autophagy receptor p62 and the ER-phagy-specific receptor FAM134B in preneoplastic hepatic lesions. We obtained four clusters with variable expression levels of p62 and FAM134B in preneoplastic lesions, and a variable population of clusters in each group. PB administration increased the clusters with high expression levels of p62 while HFD feeding increased the clusters with high expression levels of both p62 and FAM134B. The areas of preneoplastic lesions of these clusters were significantly increased than those of other clusters with low expression levels of p62 and FAM134B. The combination of HFD feeding with PB counteracted the effects of each other, and the cluster composition was similar to that in the control group. The results were associated with decreased gene expression of ER stress, inflammatory cytokine, autophagy, and increased expression of antioxidant enzyme. The present study demonstrated that clustering analysis is useful for understanding the role of autophagy in each preneoplastic lesion, and that HFD feeding increased preneoplastic lesions through the inhibition of ER-phagy, which was cancelled with PB administration through the induction of ER-phagy.

Potential use of TG68 -A novel thyromimetic - for the treatment of non-alcoholic fatty liver (NAFLD)-associated hepatocarcinogenesis.

Several lines of evidence suggest that the thyroid hormone signaling pathway is altered in patients with NAFLD and that pharmacological strategies to target the thyroid hormone/thyroid hormone nuclear receptor axis (TH/THR) in the liver may exert beneficial effects. In this study, we investigated the effect of TG68, a novel THRβ agonist, on rat hepatic fat accumulation and NAFLD-associated hepatocarcinogenesis. Male rats given a single dose of diethylnitrosamine (DEN) and fed a high fat diet (HFD) were co-treated with different doses of TG68. Systemic and hepatic metabolic parameters, immunohistochemistry and hepatic gene expression were determined to assess the effect of TG68 on THRβ activation. Irrespectively of the dose, treatment with TG68 led to a significant reduction in liver weight, hepatic steatosis, circulating triglycerides, cholesterol and blood glucose. Importantly, a short exposure to TG68 caused regression of DEN-induced preneoplastic lesions associated with a differentiation program, as evidenced by a loss of neoplastic markers and reacquisition of markers of differentiated hepatocytes. Finally, while an equimolar dose of the THRβ agonist Resmetirom reduced hepatic fat accumulation, it did not exert any antitumorigenic effect. The use of this novel thyromimetic represents a promising therapeutic strategy for the treatment of NAFLD-associated hepatocarcinogenesis.

The Role of Artificial Intelligence in Monitoring Inflammatory Bowel Disease—The Future Is Now

Crohn's disease and ulcerative colitis remain debilitating disorders, characterized by progressive bowel damage and possible lethal complications. The growing number of applications for artificial intelligence in gastrointestinal endoscopy has already shown great potential, especially in the field of neoplastic and pre-neoplastic lesion detection and characterization, and is currently under evaluation in the field of inflammatory bowel disease management. The application of artificial intelligence in inflammatory bowel diseases can range from genomic dataset analysis and risk prediction model construction to the disease grading severity and assessment of the response to treatment using machine learning. We aimed to assess the current and future role of artificial intelligence in assessing the key outcomes in inflammatory bowel disease patients: endoscopic activity, mucosal healing, response to treatment, and neoplasia surveillance.

High sensitivity and specificity rates of cobas® HPV test as a primary screening test for cervical intraepithelial lesions in a real-world setting.

Cervical carcinoma (CC) is the fourth most common malignancy among women. Screening with Papanicolau smear is linked to a reduction in CC incidence rates when screening programs have been developed. However, this technique has several limitations, including moderate sensitivity rates for detection of cervical preneoplastic HPV-related lesions. In this real-world study, we proposed to evaluate the sensitivity and specificity rates of cobas® test, which amplifies target DNA fragments by polymerase chain reaction and hybridization of nucleic acids for the detection of 14 HR-HPV types in a single analysis) used as primary screening test for CC and preneoplastic lesions in women aged 25-65 years in a large University Hospital in Buenos Aires. A total of 1044 patients were included in the sample (median age: 46 years); sensitivity and specificity rates for the HR-HPV test used as primary screening test were 98.66% (95% confidence interval [95CI]: 97.67-99.3%) and 87.15% (95CI: 84.93-89.15%), respectively. The positive predictive value was 88.47% (95CI: 86.54%-90.42%) and the negative predictive value was 98.48% (95CI: 97.75%-99.23%). The cobas® HR-HPV testing was highly sensitive and specific for the detection of CC and preneoplastic lesions in real practice.

Targeted Next-Generation Sequencing of Flat Urothelial Lesions Reveals Putative Pathobiological Pathways, Potential Biomarkers, and Rational Therapeutic Targets

Flat urothelial lesions are controversial diagnostic and prognostic urologic entities whose importance relies mainly on their ability to progress to muscle-invasive tumors via urothelial carcinoma in situ (CIS). However, the carcinogenetic progression of preneoplastic flat urothelial lesions is not well established. Moreover, predictive biomarkers and therapeutic targets of the highly recurrent and aggressive urothelial CIS lesion are lacking. Using a targeted next-generation sequencing (NGS) panel of 17 genes directly involved in bladder cancer pathogenesis, we investigated alterations of genes and pathways with clinical and carcinogenic implications on 119 samples of flat urothelium, including normal urothelium (n = 7), reactive atypia (n = 10), atypia of unknown significance ( n = 34), dysplasia ( n = 23), and CIS (n = 45). The majority of the flat lesions were tumor-associated but grossly/microscopically or temporally separated from the main tumor. Mutations were compared across flat lesions and concerning the concomitant urothelial tumor. Associations between genomic mutations and recurrence after intravesical bacillus Calmette–Guerin treatment were estimated with Cox regression analysis. TERT promoter mutations were highly prevalent in intraurothelial lesions but not in the normal or reactive urothelium, suggesting that it is a critical driver mutation in urothelial tumorigenesis. We found that synchronous atypia of unknown significance-dysplasia-CIS lesions without concomitant papillary urothelial carcinomas had a similar genomic profile that differed from atypia of unknown significance-dysplasia lesions associated with papillary urothelial carcinomas, which harbored significantly more FGFR3, ARID1A, and PIK3CA mutations. KRAS G12C and ERBB2 S310F/Y mutations were exclusively detected in CIS and were associated with recurrence after bacillus Calmette–Guerin treatment (P = .0006 and P = .01, respectively). This targeted NGS study revealed critical mutations involved in the carcinogenetic progression of flat lesions with putative pathobiological pathways. Importantly, KRAS G12C and ERBB2 S310F/Y mutations were identified as potential prognostic and therapeutic biomarkers for urothelial carcinoma.

An evaluation of an innovative screening program based on risk criteria for early diagnosis of head and neck cancers.

Head and neck cancer represents 3% of all cancers and is the cause of 5% of the deaths caused by cancer. The purpose of this study is to evaluate the implementation of a screening program to diagnose the early phase of the head and neck oncological processes. We have studied 324 asymptomatic patients who had at least one major risk factor (habitual consumption of tobacco or alcohol) or two minor risk factors: family history of head and neck cancer of the upper aerodigestive tract, occupational exposure, poor oral hygiene and history of Human Papillomavirus or chronic inflammatory processes of the aerodigestive tract. Family and personal head and neck oncological medical history, ENT exploration, performance of CT scans or biopsies and program procedures were analyzed. The most usual referral criteria for being sent to a specialist was being a smoker (98.1%). 10.5% reported family histories of head and neck cancer, 9.9% reported occupational exposure, 7.1% were referred due to poor oral hygiene and 5.9% were referred for gastroesophageal reflux disease. Although being asymptomatic was a requirement for inclusion, we verified that, after the anamnesis, 9.6% of the patients had some symptom to which they did not give importance to 119 patients (36.7%) presented a lesion that potentially could become malignant, located in the larynx and hypopharynx (25%) and in the oral cavity and oropharynx (10.8%). Eighteen patients (5.56%) presented more than one lesion. The detection rate of neoplasia was 1.2% and the detection rate of pre-neoplastic lesions was 4.6%. There did exist a statistically significant ratio between the detection of pre-neoplastic lesions and occupational exposure to carcinogenic agents (p = 0.006), poor oral hygiene (p = 0.01) and gastroesophageal reflux disease (p = 0.007). Samples were taken for a pathological anatomy study in 30 patients (9.25%). In order to follow up the patients, 22.8% were controlled at hospital medical consultations, 11.1% were examined at outpatient consultation and 66% were given appointments for follow-up visits. The use of this screening program could be a tool for the early diagnosis of malignant head and neck tumors and to foster healthy habits for cancer prevention.

T-type Ca2+ channels and their relationship with pre-neoplastic and neoplastic lesions in the human breast.

The expression of T-type voltage-dependent Ca2+ channels (Cav3) has been previously observed in breast cancer, but their expression and subcellular localization were not evaluated in pre-neoplastic lesions. Therefore, this work aimed to evaluate protein expression and subcellular localization of T-type channel isoforms in human breast tissue samples. Protein expressions of CaV3.1, CaV3.2, and CaV3.3 were evaluated by immunohistochemistry in breast without alteration, in proliferative non-neoplastic lesions, and in neoplastic ductal epithelial lesions of the human breast. CaV3.1, CaV3.2, and CaV3.3 nuclear expressions were decreased in advanced stages of neoplastic transformation, whereas CaV3.1 and CaV3.2 cytoplasmic expression increased. Also, the decrease in nuclear expression was correlated with an increase in cytoplasmic expression for CaV3.1 isoform. The change in CaV3 protein expression and subcellular localization are consistent with the neoplastic transformation stages of mammary epithelial cells, evident in early neoplastic lesions, such as ductal carcinomas in situ. These results suggest a possible involvement of CaV3 in the carcinogenic processes and could be considered as a potential pharmacological target in new therapies for breast cancer treatment.

Frequency of Preneoplastic and Neoplastic Lesions in Cholecystectomy Specimen from a Tertiary Care Hospital in Uttar Pradesh, India: A Cross-sectional Study

Introduction: Cholelithiasis is known to cause a spectrum of changes, including inflammation in the gallbladder wall, cholesterolosis, atrophy, metaplasia, dysplasia, polyps, and eventually cancer. Gallbladder Carcinoma (GBC) is a rare and highly fatal malignancy. Aim: To determine the frequency of preneoplastic and neoplastic lesions, along with demographic and clinical aspects of different gallbladder lesions. Materials and Methods: This cross-sectional study was performed on 788 patients who underwent elective cholecystectomy for gallbladder disease at Hind Medical College, Sitapur, Uttar Pradesh, India, from August 2017 to October 2021. All patients underwent a history and physical examination, followed by routine laboratory tests and other investigations, including full abdominal ultrasound. Histopathologic evaluation of the gallbladder specimen was also performed after surgical resection. Categorical variables were presented as numbers and percentages (%), while continuous variables were presented as mean ± Standard Deviation (SD). Results: A total of 788 cholecystectomy specimens were analysed. The mean age of the patients was 42.49±1.39 years with female predominance 640 (82.05%). The majority of cases were between 40-49 269 (34.13%) and 60-69 399 (50.63) years of age. Preneoplastic changes were found in 764 (96.96%) cases, while neoplastic pathology was evident in 24 (3.04%) cholecystectomy specimens. The most commonly observed preneoplastic change was chronic cholecystitis in 532 (67.54%) cases. Other lesions associated with chronic cholecystitis were cholesterolosis in 76 cases (9.64%), xanthogranulomatous cholecystitis in 34 cases (4.31%), follicular cholecystitis in 30 cases (3.80%), and GBC in 24 cases (3.04%). Conclusion: This study observed that chronic cholecystitis and cholesterolosis, followed by xanthogranulomatous cholecystitis, were associated with metaplastic changes in gallbladder pathologies. It is believed that metaplasia-dysplasia could be linked to GBC. Therefore, routine microscopic examination is required for all cholecystectomies. However, further studies on gallbladder carcinogenesis are needed.