Risk Of Squamous Cell Carcinoma Research Articles

Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis

The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case–control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on ‘TERT rs2736100 polymorphism and LC susceptibility’ in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors.

Association of Metabolic Syndrome With Risk of Lung Cancer: A Population-Based Prospective Cohort Study

Both the incidence of lung cancer and the prevalence of metabolic syndrome (MetS) have been increasing worldwide. The relationship between MetS and lung cancer remains controversial. What is the risk of lung cancer associated with MetS and its components? Multivariable Cox regression models were used to estimate the hazard ratio (HR) of MetS-related variables on lung cancer risk, both overall and by histologic subtype, in the UK Biobank. Stratified analyses were conducted by sex, tobacco use status, and use of medication. HR curves were used to test the nonlinear associations between the metabolic markers and the risk of lung cancer. Of the 331,877 participants included in this study, a total of 77,173 participants had a diagnosis of MetS at enrollment. During a median follow-up of 10.9 years, lung cancer as the primary site developed in 2,425 participants. The HRs of MetS were 1.21 (95%CI, 1.09-1.33), 1.28 (95%CI, 1.10-1.50), and 1.16 (95%CI, 0.94-1.44) for the overall risk of lung cancer, adenocarcinoma, and squamous cell carcinoma, respectively. The HRs increased with the number of metabolic abnormalities from 1.11 to approximately 1.4 or 1.5 for those with one to five disorders. Positive association with lung cancer was observed for low high-density lipoprotein cholesterol (HDL-C), elevated waist circumference, and hyperglycemia. The relationship between MetS and lung cancer was modified by sex, with a stronger effect in female patients (P= .031). The risk of lung cancer resulting from MetS was elevated mainly among individuals who used tobacco, although the modification effect of tobacco use was not statistically significant. A nonlinear association was found between lung cancer and HDL-C, waist circumference, and glycated hemoglobin. The increased risk of lung cancer associated with MetS suggests the importance of taking metabolic status and markers into consideration for the primary prevention of lung cancer and the selection of high-risk populations for lung cancer screening.

Posaconazole and risk of cutaneous squamous cell carcinoma after lung transplantation: a single institution, retrospective cohort study.

Posaconazole and risk of cutaneous squamous cell carcinoma after lung transplantation: a single institution, retrospective cohort study.

Local recurrence risk of esophageal squamous cell carcinoma due to intralesional damage during endoscopic submucosal dissection.

It is unclear whether additional treatment should be considered given the recurrence risk after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) when the vertical margin is positive or unclear (VM1/VMX) due to intralesional damage. This study aimed to elucidate the local recurrence risk of ESCC caused by intralesional damage during ESD. Among consecutive patients with pT1a ESCCs initially treated by ESD at our institution between January 2006 and December 2018, ESCCs diagnosed as VM1/VMX were retrospectively reviewed. Exclusion criteria were piecemeal resection and any additional treatment after ESD. Intralesional damage included the following three types: a macroscopic hole inside the lesion, an incision from the lateral margin of the specimen into the lesion, and crushing injury or burn effect into the deepest area of the lesion without an obvious hole. The local recurrence rate after ESD was primarily analyzed. Of 1174 pT1a ESCCs initially treated using ESD, 22 lesions were histopathologically diagnosed as VM1/VMX due to intralesional damage (1.9%; 95% confidence interval [CI], 1.2-2.8%). At a median follow-up period of 60.0 (interquartile range, 15.0-84.0) months, no local recurrence was observed (0.0%; 95% CI, 0.0-13.3%) among 21 lesions finally evaluated. The impact of intralesional damage during ESD for ESCC on local recurrence might be negligible. Follow-up without additional treatment may be acceptable even if intralesional damage occurs and results in VM1/VMX after ESD for pT1a ESCCs.

Elafin as a Prognostic Marker in Esophageal Squamous Cell Carcinoma: A Pilot Study Using Three-Dimensional Imaging and Genomic Profiling.

Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data obtained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I-IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial-mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC.

Six polymorphisms in the lncRNA H19 gene and the risk of cancer: a systematic review and meta-analysis

BackgroundNumerous studies have demonstrated long noncoding RNA (lncRNA) play an important role in the occurrence and progression of cancer, and single nucleotide polymorphisms (SNPs) located in lncRNA are considered to affect cancer suspensibility. Herein, a meta-analysis was carried out to better assess the relationship of H19 polymorphisms and cancer susceptibility.MethodsA literature search was conducted through using PubMed, EMBASE, and Web of Science databases to obtain relevant publications before Aug 23, 2022. The reference lists of the retrieved studies were also investigated to identify additional relevant articles. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to appraise the risk of various cancers.ResultsThere appeared to be a remarkable correlation between the rs2107425 variation and decreased cancer risk among Caucasians. Nevertheless, the rs217727 polymorphism was significantly associated with an increased risk of lung cancer, hepatocellular carcinoma and oral squamous cell carcinoma. Also, we found a significant correlation between the rs2839698 polymorphism and increased cancer risk among Asians, gastric cancer, hepatocellular carcinoma, hospital-based control and larger simple size subgroups, respectively. Similarly, the rs3741219 mutation was notably related to cancer risk in higher quality score. As for rs3024270 polymorphism, the homozygous model was markedly linked to cancer risk in overall analysis and population-based controls. There was no significant association between the rs3741216 polymorphism and cancer risk.ConclusionH19 rs2839698 and rs3024270 were closely associated with overall cancer risk. H19 rs2107425 was related to lower cancer risk among Caucasians, while the rs2839698 was related to increased cancer risk among Asians. Our results supported that H19 SNPs were significantly correlated with cancer risk.

Increased risk of esophageal squamous cell carcinoma in patients with squamous dysplasia: a nationwide cohort study in the Netherlands.

Squamous dysplasia is the histological precursor of esophageal squamous cell carcinoma (ESCC). The optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. We aimed to assess the ESCC risk in patients with esophageal squamous dysplasia in a Western country. This nationwide cohort study included all patients with esophageal squamous dysplasia, diagnosed between 1991 and 2020 in the Dutch nationwide pathology databank (Palga). Squamous dysplasia was divided in mild-to-moderate dysplasia (mild, low-grade, and moderate dysplasia) and higher-grade dysplasia (high-grade dysplasia, severe dysplasia, carcinoma in situ). ESCC were identified in Palga and the Netherlands Cancer Registry. The primary endpoint was diagnosis of prevalent (≤6months) and incident (>6months after squamous dysplasia) ESCC. In total, 873 patients (55% male, aged 68years SD ± 13.2) were diagnosed with esophageal squamous dysplasia, comprising mild-to-moderate dysplasia (n = 456), higher-grade dysplasia (n = 393), and dysplasia not otherwise specified (n = 24). ESCC was diagnosed in 77 (17%) patients with mild-to-moderate dysplasia (49 prevalent, 28 incident ESCC) and in 162 (41%) patients with higher-grade dysplasia (128 prevalent, 34 incident ESCC). After excluding prevalent ESCC, the annual risk of ESCC was 4.0% (95% CI: 2.7-5.7%) in patients with mild-to-moderate dysplasia and 8.5% (95% CI: 5.9-11.7%) in patients with higher-grade dysplasia. All patients with squamous dysplasia, including those with mild-to-moderate dysplasia, have a substantial risk of developing ESCC. Consequently, endoscopic surveillance of the esophageal mucosa or endoscopic resection of dysplasia should be considered for patients with mild-to-moderate dysplasia in Western countries. KEY MESSAGES What is already known on this topic? Squamous dysplasia is the histological precursor of ESCC and is divided in distinct grades, based on the proportion of the squamous epithelium with histopathological abnormalities. In Western countries, the optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. What this study adds The ESCC risk of patients with squamous dysplasia was increased for all patients with squamous dysplasia in a Western country; 2.1% for patients with mild dysplasia, 5.1% for low-grade dysplasia, and 5.2% for moderate dysplasia. Increasing grades of squamous dysplasia were associated with an increased ESCC risk. How this study might affect research, practice, or policy We recommend that endoscopic follow-up or treatment should be considered in all patients with esophageal squamous dysplasia in Western countries: 1) for patients with mild, low-grade, and moderate dysplasia, endoscopic surveillance with careful inspection with narrow band imaging or dye-based chromoendoscopy of the esophageal mucosa is indicated; and 2) for patients with high-grade dysplasia, severe dysplasia and carcinoma in situ adequate endoscopic staging and in case of suspected neoplasia endoscopic treatment should be performed.

Prognostic model based on telomere-related genes predicts the risk of oral squamous cell carcinoma

BackgroundThis study investigated a potential prognostic model based on telomere-related genes (TRGs) for the clinical prediction of oral squamous cell carcinoma (OSCC).MethodsGene expression data and associated clinical phenotypes were obtained from online databases. Differentially expressed (DE)-TRGs were identified between OSCC and normal samples, followed by protein-protein interaction and enrichment analyses. Subsequently, the prognostic genes explored based on the DE-TRGs and survival data were applied in the establishment of the current prognostic model, and an integrated analysis was performed between high- and low-risk groups using a prognostic model. The expression of certain prognostic genes identified in the present study was validated using qPCR analysis and/or western blot in OSCC cell lines and clinical samples.Results169 DE-TRGs were identified between the OSCC samples and controls. DE-TRGs are mainly involved in functions such as hypoxia response and pathways such as the cell cycle. Eight TRGs (CCNB1, PDK4, PLOD2, RACGAP1, MET, PLK1, KPNA2, and CCNA2) associated with OSCC survival and prognosis were used to construct a prognostic model. qPCR analysis and western blot showed that most of the eight prognostic genes were consistent with the current bioinformatics results. Analysis of the high- and low-risk groups for OSCC determined by the prognostic model showed that the current prognostic model was reliable.ConclusionsA novel prognostic model for OSCC was constructed by TRGs. PLOD2 and APLK1 may participate in the progression of OSCC via responses to hypoxia and cell cycle pathways, respectively. TRGs, including KPNA2 and CCNA2, may serve as novel prognostic biomarkers for OSCC.

Impact of Alcohol Dehydrogenase 7 Polymorphism and Alcohol Consumption on Risk of Head and Neck Squamous Cell Carcinoma: A Korean Case-Control Study.

Head and neck squamous cell carcinoma (HNSCC) is closely associated with alcohol consumption and individual genetic susceptibility, such as single nucleotide polymorphism (SNP) of alcohol dehydrogenase (ADH). This study aimed to investigate the association of ADH7 SNPs with the risk of HNSCC. We analyzed ADH7 rs1573496C>G, rs3737482T>C, rs1154460G>A, and rs284787T>C SNPs in 250 patients with HNSCC and 322 controls in the Korean populations. Genotyping was conducted using the TaqMan assay. Linkage disequilibrium and haplotypes were analyzed. The odds ratios (OR) and 95% confidence intervals (CI) of the CT and CC genotypes of ADH7 rs3737482T>C were 0.48 (0.29-0.78) and 0.69 (0.49-0.96), indicating a significantly decreased risk. In SNP of rs1154460G>A, the OR and 95% CI of the AA genotype was 1.63 (1.11-2.40), showing a significant increase in the risk. Furthermore, SNPs of ADH7 rs3737482T>C and ADH7 rs1154460G>A exhibit synergistic interactions with alcohol composition on the risk of HNSCC. None of the haplotypes were associated with the risk of HNSCC. ADH7 rs3737482T>C and rs1154460G>A SNPs are associated with the risk of development of HNSCC in Koreans. They could serve as molecular biological markers to screen high-risk groups for HNSCC.

Adiposity and risk of oesophageal cancer subtypes in the Million Women Study.

The strong association of body mass index (BMI) with increased oesophageal adenocarcinoma risk is established, but its relationship with oesophageal squamous cell carcinoma is less clear. There is little evidence regarding the association of abdominal adiposity with either subtype. In a large prospective cohort of women in the UK, mean age 56.2 [standard deviation (SD) = 4.9] years, we investigated the risk of oesophageal adenocarcinoma and squamous cell carcinoma in relation to self-reported BMI, waist circumference (WC) and waist-hip ratio (WHR), using Cox regression to estimate adjusted relative risks (RR) and 95% confidence intervals (CIs), taking account of potential reverse causation bias. During mean follow-up of 17.7 (SD = 4.9) years, 1386 adenocarcinomas and 1799 squamous cell carcinomas of the oesophagus were registered among 1 255 529 women. Compared with women of BMI 22.5 to <25 kg/m2, those with BMI ≥35 kg/m2 had a 2.5-fold risk of adenocarcinoma (adjusted RR = 2.46, 95% CI = 1.99-3.05) and an almost 70% reduction in risk of squamous cell carcinoma (RR = 0.32, 95% CI = 0.22-0.46). These associations were broadly similar in each 5-year follow-up period, and were evident in both never and ever smokers, although somewhat stronger for squamous cell carcinoma among current and past smokers than in never smokers (Pheterogeneity = 0.007). After controlling for BMI, WC and WHR were associated with risk of squamous cell carcinoma but not adenocarcinoma. In this population of middle-aged women, there was robust evidence that greater BMI is associated with an increased risk of oesophageal adenocarcinoma and a reduced risk of squamous cell carcinoma.

Statin use and its association with decreased risk of esophageal squamous cell carcinoma in betel nut chewers.

Betel nut chewing involves the chewing of areca nuts or betel quid (areca nuts wrapped in betel leaves), which is associated with an increased risk of esophageal squamous cell carcinoma (ESCC). Statins have anticancer properties. We investigated the association between statin use and ESCC risk in betel nut chewers. The study included 105 387 betel nut chewers matched statin users and nonusers. Statin use was defined as the use of ≥28 cumulative defined daily doses (cDDDs) of statin. The primary outcome was incidence of ESCC. The incidence rate of ESCC was significantly lower in statin users than in nonusers (2.03 vs. 3.02 per 100 000 person-years). Statin users had a lower incidence rate ratio of 0.66 for ESCC (95% confidence interval [CI]: 0.43-0.85) relative to nonusers. After potential confounders were adjusted for, statin use was determined to be associated with a reduced risk of ESCC (adjusted hazard ratio [aHR], 0.68; 95% CI: 0.51-0.91). A dose-response relationship was observed between statin use and ESCC risk; the aHRs for statin use at 28-182 cDDDs, 183-488 cDDDs, 489-1043 cDDDs, and > 1043 cDDDs were 0.92, 0.89, 0.66, and 0.64, respectively. Statin use was revealed to be associated with a reduced risk of ESCC in betel nut chewers.

BI06 Short sharp shock or slow burn: clinician perspectives on treatment of actinic keratoses with 5-fluorouracil 5% cream monotherapy vs. 5-fluorouracil/calcipotriol ointment combination therapy

Abstract Actinic keratoses (AK) are common in immunocompromised patients and associated with increased risk of cutaneous squamous cell carcinoma (cSCC). The current standard of care is 5-fluorouracil cream 5% (5-FU) monotherapy for 4 weeks. In recent years, 5-FU cream and calcipotriol ointment (5-FU-Cal) combination AK therapy for 4–6 days has emerged as potentially more effective and better tolerated, although the original randomized controlled trial (RCT) excluded immunosuppressed patients. Previously, we shared immunosuppressed patients’ real-world perspectives of using 5-FU monotherapy vs. 5-FU-Cal combination therapy (Junejo MH, Demirel S, Matin R et al. Short shock or slow burn? Patient perspectives on treatment of actinic keratoses with 5-fluorouracil 5% cream monotherapy versus 5-fluorouracil plus calcipotriol combination therapy. Clin Exp Dermatol 2023; 48:31–2). The majority (81%) found 5-FU-Cal to be more effective than 5-FU monotherapy. Despite 47% reporting worse local skin reactions (LSRs), most preferred the 5-FU-Cal combination. We now report results from a clinician survey on the use of 5-FU monotherapy vs. 5-FU-Cal combination therapy for the treatment of AK. An online survey was sent to 200 UK consultant dermatologists. Fifty-seven (28.5%) completed the survey, all of whom reported using 5-FU monotherapy for treating AK in patients with prior cSCC; 43 (75%) reported this to be their preferred treatment. Most clinicians (n = 40; 70%) were aware of 5-FU-Cal combination therapy, although only 24 (42%) reported using it to treat AK in patients with prior cSCC. Of these, 18 (75%) used combination treatment for AK as part of field change, 14 (58%) used it for the treatment of patches of more than five AK and 13 (54%) used it for grouped AK. Very few (n = 4; 17%) used combination therapy for treatment of cSCC in situ (n = 4), single AK (n = 3) or superficial basal cell carcinoma (n = 1). Of 24 clinicians using 5-FU-Cal, the majority felt that patients developed LSRs often (n = 11; 46%) or always (n = 7; 29%); fewer felt that LSRs occurred sometimes (n = 5; 21%) or rarely (n = 1; 4%). Clinicians using combination therapy primarily felt the LSRs were moderate but not severe enough to require supplementary treatment or discontinuation (n = 17; 71%). Half (n = 12; 50%) of those using combination therapy felt patients did not signal a preference between 5-FU monotherapy vs. 5-FU-Cal combination therapy. Two-thirds (n = 38/57; 67%) of clinicians reported an interest in participating in a RCT comparing 5-FU vs. 5-FU-Cal vs. sunscreen alone for the treatment of AK in patients with prior cSCC. This is the first evaluation of clinician perspectives on the use of the newly emerging 5-FU-Cal therapy for AK. These data provide a rationale for the inclusion of combination 5-FU-Cal therapy in future studies using topical AK treatments for cSCC prevention in the UK.

010 Enhanced outcome prediction in cutaneous squamous cell carcinoma using deep-learning and computational histopathology (cSCCnet)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer and leads to a significant disease burden. Although metastases occur in &amp;lt; 5% of patients, effective treatments are limited and 5-year survival is poor, with mortality rates equivalent to those of melanoma in some regions of the world. Despite recent advances in understanding the molecular pathogenesis of cSCC, patient risk stratification is limited and based on clinicopathological staging, with few validated prognostic biomarkers available to guide management [de Jong E, Lammerts MUPA, Genders RE, Bowes Bavinck JN. Update of advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol 2022; 36(Suppl. 1):6–10]. In this study, we aimed to use artificial intelligence technology to develop a deep learning model using digitized whole-slide images of cSCC to quantify the risk of metastasis. Routine haematoxylin and eosin-stained slides of 256 primary cSCCs from immunocompetent patients at four collaborating centres were scanned. The area of interest encompassing tumour and peritumoral stroma was annotated, and 512 × 512 pixel tiles were generated from each slide. High-quality tiles (containing sufficient tumour content) were pooled together, with patient-level labels inherited by tiles. We trained multiple models using an 80:10:10 split for training, validation and testing, and the model achieving the highest tile- and slide-level validation accuracy was identified (ResNet50). The final model, namely, cSCCnet, achieved 88% sensitivity, 73% specificity, 64% positive predictive value and 92% negative predictive values on the independent test set. Blinded review of the top predictive tiles by three histopathologists suggested that the predictive features identified by cSCCnet were distinct from histopathological features commonly used by clinicians to estimate metastatic risk. We have demonstrated that it is possible to train a deep learning model using digital pathology to predict the risk of metastasis. cSCCnet surpassed the published performance of currently used staging systems, as well as commercially available gene panel testing (de Jong et al.; Wysong A, Newman JG, Covington KR et al. Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2021; 84:361–9). The morphological features and patterns identified by cSCCnet are different from established histopathological high-risk criteria, indicating that this technology can enhance current practice. Although further validation in a prospective cohort is pending, this is an important step toward creating a risk stratification tool that can be incorporated into routine pathology workflows, significantly improving patient outcomes for this common cancer.

Causal relationship between gastro-esophageal reflux disease and risk of lung cancer: insights from multivariable Mendelian randomization and mediation analysis.

A recent study has reported that anti-reflux surgery reduced the risk of lung cancer. However, the exact causal association between gastro-esophageal reflux disease (GORD) and lung cancer remains obscure. Therefore, we conducted a multivariable and network Mendelian randomization (MR) study to explore this potential association and mediation effect. Independent single nucleotide polymorphisms (SNPs) strongly associated with GORD were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). The summary statistics were obtained from the largest GORD GWAS meta-analysis of 367 441 (78 707 cases) European individuals, and the summary statistics of lung cancer and pathological subtypes came from International Lung Cancer Consortium (ILCCO) and FinnGen databases. Univariable and multivariable MR analyses were performed to investigate and verify the causal relationship between genetically predicted GORD and lung cancer. Network MR analysis was conducted to reveal the mediating role of GORD between smoking initiation and lung cancer. The univariable MR analysis demonstrated that GORD was associated with an increased risk of total lung cancer in both ILCCO [inverse variance weighted (IVW): odds ratio (OR) = 1.37, 95% confidence interval (CI) 1.16-1.62, P = 1.70E-04] and FinnGen database (IVW: OR = 1.25, 95% confidence interval CI 1.03-1.52, P = 2.27E-02). The consistent results were observed after adjusting the potential confounders [smoking traits, body mass index (BMI) and type 2 diabetes] in multivariable MR analyses. In subtype analyses, GORD was associated with lung adenocarcinoma (IVW: OR = 1.27, 95% CI 1.02-1.59, P = 3.48E-02) and lung squamous cell carcinomas (IVW: OR = 1.50, 95% CI 1.22-1.86, P = 1.52E-04). Moreover, GORD mediated 32.43% (95% CI 14.18-49.82%) and 25.00% (95% CI 3.13-50.00%) of the smoking initiation effects on lung cancer risk in the ILCCO and FinnGen databases, respectively. This study provides credible evidence that genetically predicted GORD was significantly associated with an increased risk of total lung cancer, lung adenocarcinoma and lung squamous cell carcinomas. Furthermore, our results suggest GORD is involved in the mechanism of smoking initiation-induced lung cancer.

Skin and gut microbial associations with squamous cell carcinoma in solid organ transplant recipients.

Solid organ transplant recipients (SOTRs) are burdened with a significantly higher risk of squamous cell carcinoma (SCC) compared to the general population. Accumulating evidence suggests the potential influence of microbial dysbiosis on transplant outcomes. Based on these observations, we sought to identify differences in the cutaneous and gut microbiomes of SOTRs with and without a history of SCC. This case-control study collected and analyzed non-lesional skin and fecal samples of 20 SOTRs > 18years old with either ≥ 4 diagnoses of SCC since most recent transplant (n = 10) or 0 diagnoses of SCC (n = 10). The skin and gut microbiomes were investigated with Next-Generation Sequencing, and analysis of variance (ANOVA) followed by Tukey pairwise comparison procedure was used to test for differences in taxonomic relative abundances and microbial diversity indices between the two cohorts. Analyses of the skin microbiome showed increased bacterial and reduced fungal diversity in SOTRs with a history of SCC compared to SOTRs without a history of SCC (bacterial median Shannon diversity index (SDI) = 3.636 and 3.154, p < 0.05; fungal SDI = 4.474 and 6.174, p < 0.05, respectively). Analyses of the gut microbiome showed reduced bacterial and fungal diversity in the SCC history cohort compared to the SCC history-negative cohort (bacterial SDI = 2.620 and 3.300, p < 0.05; fungal SDI = 3.490 and 3.812, p < 0.05, respectively). The results of this pilot study thus show a trend toward the bacterial and fungal communities of the gut and skin being distinct in SOTRs with a history of SCC compared to SOTRs without a history of SCC. It furthermore demonstrates the potential for microbial markers to be used in the prognostication of squamous cell carcinoma risk in solid organ transplant recipients.

Oral cavity and oropharyngeal carcinoma disparities in age and survival in Indigenous and non-Indigenous populations of Queensland

ObjectivesTo investigate the risk and prognosis of oral squamous cell carcinoma (SCC) between Indigenous and non-Indigenous populations of Queensland.Materials and methodsRetrospective analysis of data from the Queensland Cancer Registry (QCR) between the years 1982–2018. Main outcome measures were age at diagnosis and cumulative survival to compare the risk and prognosis of oral SCC between the populations.Results9424 patients with self-declared ethnicity were identified with oral SCC from the QCR, with a male to female ratio of 2.56:1. Of these patients, 9132 were non-Indigenous (96.9%) and 292 Indigenous (3.1%). Indigenous people were significantly younger at diagnosis (mean (SD) age 54.3 (10.1) years), compared to 62.0 (12.1) years in non-Indigenous people. Mean survival in the full cohort was 4.3 years (SD: 5.6), with Indigenous people presenting a significant shorter mean survival of 2.0 years (SD: 3.5) when compared with 4.4 years (SD: 5.7) in non-Indigenous people (p < 0.001).ConclusionsIndigenous Australians are diagnosed at a significantly younger age and present with worse survival and poorer prognosis. Due to missing variables in the Queensland Cancer Registry, it is not possible in the current study to ascertain the scientific or social reasons behind these disparities.Clinical relevanceResults from this study can inform public policy and raise awareness in Queensland regarding disparity in oral cancer prognosis.

Examining ultrafine particle pollution and lung cancer risk in a large, diverse cohort.

8532 Background: Health effects associated with particles less than 2.5 μm in diameter (PM2.5) have been well studied, leading to the establishment of air quality standards and routine monitoring. Additionally, there is growing experimental evidence that ultrafine particles (UFPs), defined as particles less than 0.1µm in diameter, may adversely affect lung health, eliciting greater injury than larger particles due to deeper penetration into airways and longer retention in the lung parenchyma. Only two epidemiological studies have investigated this topic, finding no associations between ambient UFPs and respiratory mortality or overall lung cancer incidence respectively. Given the limited epidemiologic investigation of UFPs and lung cancer, we examined the association between airport-related UFPs and lung cancer incidence in a large, racially and ethnically diverse cohort. Methods: We estimated airport-related UFP exposure for 71,387 participants of the Multiethnic Cohort, who lived within a 53 km×43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993-1996) through December 31, 2013. Cox proportional hazards regression was used, with calendar month/year as the time variable, to examine associations between UFP exposure and lung cancer risk adjusting for demographics, lifetime smoking, neighborhood socioeconomic status, occupation and lifestyle factors. Subgroup analyses were conducted by racial and ethnic groups, lung cancer histology, and smoking status. Co-pollutant models were run to mutually adjust for other traffic-related air pollutants. Results: A per unit increase in the interquartile range (IQR) of airport-related UFP exposure was not associated with lung cancer risk overall [HR = 1.01, 95% CI: 0.97-1.05] or by race and ethnicity. UFP exposure was suggestive of a positive association with risk of lung squamous cell carcinoma (SCC) [HR per IQR = 1.08, 95% CI: 1.00-1.17]. No associations were observed for other histologies [Phet for histology = .05]. UFP exposure was associated with an increased SCC risk among current smokers [HR = 1.11, 95% CI: 1.01-1.22] but not among never or past smokers [Phet for smoking = 0.51]. Conclusions: This study suggests a possible association between airport-related UFP exposure and risk of SCC. These results may be explained by previous studies finding that UFPs activate genes involved in oxidative damage, TNF-α signaling via NF-κB, and secretion of inflammatory and cardiopulmonary disease biomarkers. These findings warrant further investigation in large epidemiologic cohorts.

Risk of Oral Squamous Cell Carcinoma in One Hundred Patients with Oral Lichen Planus: A Follow-Up Study of Umberto I University Hospital of Rome.

This study aims to retrospectively assess the potential risk of malignant transformation in patients with diagnosed oral lichen planus (OLP) between 2015 and 2022, and to evaluate the influence of different risk factors. The department's database and medical records from 2015 to 2022 were searched for patients with a confirmed diagnosis of OLP based on both clinical and histological parameters. A total of 100 patients (59 females and 41 males) were found with a mean age of 64.03 years. In the considered period, the percentage of diagnosed OLP patients was 1.6%, while the percentage of diagnosed OLP patients with transformation to oral squamous cell carcinoma (OSCC) was 0.18%. A statistically significant difference was found with age (p = 0.038), tobacco status (p = 0.022), and radiotherapy (p = 0.041). The analysis revealed the presence of significant risk in ex-smokers (>20 pack-years), with an odds ratio (OR) of 10.0000 (95% confidence interval (95% CI) 1.5793-63.3186); in alcohol-drinker patients, with an OR of 4.0519 (95% CI 1.0182-16.1253); in ex-smoker and alcohol-drinker patients, with OR of 17.6250 (95% CI 2.2464-138.2808); and in patients who had undergone radiotherapy, with OR of 6.3000 (95% CI 1.2661-31.3484). The malignant transformation of oral lichen planus was slightly higher than thought, and the results revealed a possible association with age, tobacco and alcohol status, and history of radiotherapy. An elevated risk of malignant transformation was observed in heavy ex-smoker patients, alcohol-drinker patients, and alcohol-drinker patients with a history of smoking (ex-smokers). Persuading the patient to quit tobacco and alcohol consumption and periodic follow-ups are recommended in general, but particularly in the presence of these risk factors.

Joint effect of human papillomavirus exposure, smoking and alcohol on risk of oral squamous cell carcinoma

BackgroundSmoking, alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for oral squamous cell carcinoma (OSCC) including SCC of oropharynx (SCCOP) and SCC of oral cavity (SCCOC). Researchers have examined each of these risk factors independently, but few have observed the potential risk of their interaction. This study investigated the interactions among these risk factors and risk of OSCC.MethodsTotally 377 patients with newly diagnosed SCCOP and SCCOC and 433 frequency-matched cancer-free controls by age and sex were included. Multivariable logistic regression was performed to calculate ORs and 95% CIs.ResultsWe found that overall OSCC risk was independently associated with smoking (adjusted OR(aOR), 1.4; 95%CI, 1.0–2.0), alcohol consumption (aOR, 1.6; 95%CI, 1.1–2.2), and HPV16 seropositivity (aOR, 3.3; 95%CI, 2.2–4.9), respectively. Additionally, we found that HPV16 seropositivity increased the risk of overall OSCC in ever-smokers (aOR, 6.8; 95%CI, 3.4–13.4) and ever-drinkers (aOR, 4.8; 95%CI, 2.9–8.0), while HPV16-seronegative ever-smokers and ever-drinkers had less than a twofold increase in risk of overall OSCC (aORs, 1.2; 95%CI, 0.8–1.7 and 1.8; 95%CI, 1.2–2.7, respectively). Furthermore, the increased risk was particularly high for SCCOP in HPV16-seropositive ever-smokers (aOR, 13.0; 95%CI, 6.0–27.7) and in HPV16-seropositive ever-drinkers (aOR, 10.8; 95%CI, 5.8–20.1), while the similar increased risk was not found in SCCOC.ConclusionThese results suggest a strong combined effect of HPV16 exposure, smoking, and alcohol on overall OSCC, which may indicate a strong interaction between HPV16 infection and smoking and alcohol consumption, particularly for SCCOP.

Direct and indirect effects of alcohol and its toxic metabolite acetaldehyde on human esophageal myofibroblasts and epithelial cells.

Mechanisms by which alcohol increases the risk of esophageal squamous cell carcinoma remain undefined. Human esophageal myofibroblasts (HEMFs) subjacent to the squamous epithelium are exposed directly to these agents via epithelial barrier defects and indirectly via factors derived from the exposed epithelium. Our aim was to investigate the cellular biology of HEMFs and HEMF-esophageal epithelial cell interactions in response to alcohol and its toxic metabolite acetaldehyde. An immortalized HEMF and a human esophageal epithelial cell line (Epi) were treated with alcohol (0 to 200 mM) or acetaldehyde (0 to 100 μM) in a cyclic fashion or incubated with supernatants collected from treated cells. Healthy cell %, reactive oxygen species (ROS), and proliferation were assessed via flow cytometry, luminescence, scratch wound, and colorimetric assays, respectively. A 15-plex multiplex assay was performed on cell supernatants, followed by IL-6 and IL-8 qRT-PCR and ELISA. Healthy HEMF decreased to less than 80% at 30 mM alcohol and 70 μM acetaldehyde, with microscopic changes at 40 μM acetaldehyde. HEMF ROS was detected at 100 mM alcohol and 80 μM acetaldehyde. Supernatants from 30 mM alcohol- or 40 μM acetaldehyde-treated HEMFs increased Epi proliferation more than two-fold that of lower doses. In the complementary studies, healthy Epi cells decreased to less than 80% at 50 mM and 70 μM acetaldehyde, with microscopic changes at 40 μM. Supernatants from Epi treated with 50 mM alcohol or 40 μM acetaldehyde increased HEMF proliferation more than two-fold that of lower doses. A multiplex assay of supernatants showed the greatest increase in concentrations of IL-6 and IL-8 in HEMFs and in Epi treated with higher doses of alcohol or acetaldehyde. Neutralization of IL-6 and IL-8 in supernatants of HEMFS and esophageal epithelial cells inhibited the proliferation of Epi and HEMFs, respectively. Alcohol and acetaldehyde doses in which the majority of HEMFs and epithelial cells are healthy, elicit the production of paracrine mediators with pro-proliferative effects on neighboring cells. Understanding the effect of alcohol and acetaldehyde on HEMFs and HEMF-epithelial interactions could help to identify the molecular basis by which alcohol increases the risk for esophageal cancer.