ABSTRACT
Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.
Subject(s)
Antibodies, Viral , Epstein-Barr Virus Infections , Herpesvirus 4, Human , Hodgkin Disease , Humans , Hodgkin Disease/virology , Hodgkin Disease/immunology , Herpesvirus 4, Human/immunology , Antibodies, Viral/immunology , Antibodies, Viral/blood , Female , Male , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , Case-Control Studies , Middle Aged , Adult , Proteome/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Aged , Young Adult , Protein Array AnalysisABSTRACT
BACKGROUND: Immunosuppressed individuals have elevated risk of virus-related cancers. Identifying cancers with elevated risk in people with HIV (PWH) and solid organ transplant recipients (SOTRs), two immunosuppressed populations, may help identify novel etiologic relationships with infectious agents. METHODS: We utilized two linkages of population-based cancer registries with HIV and transplant registries in the United States. Cancer entities were systematically classified based on site and histology codes. Standardized incidence ratios (SIRs) were used to compare risk in PWH and SOTRs with the general population. For selected cancer entities, incidence rate ratios (IRRs) were calculated for indicators of immunosuppression within each population. FINDINGS: We identified 38,047 cancer cases in SOTRs and 53,592 in PWH, yielding overall SIRs of 1.66 (95%CI = 1.65-1.68) and 1.49 (95%CI = 1.47-1.50), respectively. Forty-three cancer entities met selection criteria, including conjunctival squamous cell carcinoma (SCC) (PWH SIR = 7.1, 95%CI = 5.5-9.2; SOTRs SIR = 9.4; 95%CI = 6.8-12.6). Sebaceous adenocarcinoma was elevated in SOTRs (SIR = 16.2; 95%CI = 14.0-18.6) and, among SOTRs, associated with greater risk in lung/heart transplant recipients compared to recipients of other organs (IRR = 2.3; 95%CI = 1.7-3.2). Salivary gland tumors, malignant fibrous histiocytoma (MFH), and intrahepatic cholangiocarcinoma showed elevated risk in SOTRs (SIR = 3.9; SIR = 4.7; and SIR = 3.2, respectively) but not in PWH. However, risks for these cancers were elevated following an AIDS diagnosis among PWH (IRR = 2.4; IRR = 4.3; and IRR = 2.0, respectively). INTERPRETATION: Elevated SIRs among SOTRs and PWH, and associations with immunosuppression within these populations, suggest novel infectious causes for several cancers including conjunctival SCC, sebaceous adenocarcinoma, salivary gland tumors, MFH, and intrahepatic cholangiocarcinoma.
ABSTRACT
Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein-Barr virus (EBV)-antibody testing have shown potential for screening of NPC; however, the long-term stability is unclear. Here, we investigated the kinetics of two EBV-antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2-marker enzyme-linked immunosorbent assay score and 13-marker multiplex serology score using the intra-class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20-year follow-up, the 2-marker score showed high stability over time, whereas the 13-marker score was more variable (p < .05). Case-control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2-marker score than the 13-marker score (p < .05). The 2-marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13-marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high-risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high-risk regions.
Subject(s)
Antibodies, Viral , Epstein-Barr Virus Infections , Herpesvirus 4, Human , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , Taiwan/epidemiology , Herpesvirus 4, Human/immunology , Antibodies, Viral/blood , Male , Female , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/epidemiology , Epstein-Barr Virus Infections/virology , Adult , Middle Aged , Nasopharyngeal Neoplasms/virology , Nasopharyngeal Neoplasms/immunology , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/blood , Nasopharyngeal Neoplasms/epidemiology , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Carcinoma/immunology , Nasopharyngeal Carcinoma/diagnosis , Nasopharyngeal Carcinoma/blood , Nasopharyngeal Carcinoma/epidemiology , Kinetics , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Young Adult , Risk Factors , AgedABSTRACT
For deep learning-based machine learning, not only are large and sufficiently diverse data crucial but their good qualities are equally important. However, in real-world applications, it is very common that raw source data may contain incorrect, noisy, inconsistent, improperly formatted and sometimes missing elements, particularly, when the datasets are large and sourced from many sites. In this paper, we present our work towards preparing and making image data ready for the development of AI-driven approaches for studying various aspects of the natural history of oral cancer. Specifically, we focus on two aspects: 1) cleaning the image data; and 2) extracting the annotation information. Data cleaning includes removing duplicates, identifying missing data, correcting errors, standardizing data sets, and removing personal sensitive information, toward combining data sourced from different study sites. These steps are often collectively referred to as data harmonization. Annotation information extraction includes identifying crucial or valuable texts that are manually entered by clinical providers related to the image paths/names and standardizing of the texts of labels. Both are important for the successful deep learning algorithm development and data analyses. Specifically, we provide details on the data under consideration, describe the challenges and issues we observed that motivated our work, present specific approaches and methods that we used to clean and standardize the image data and extract labelling information. Further, we discuss the ways to increase efficiency of the process and the lessons learned. Research ideas on automating the process with ML-driven techniques are also presented and discussed. Our intent in reporting and discussing such work in detail is to help provide insights in automating or, minimally, increasing the efficiency of these critical yet often under-reported processes.
ABSTRACT
BACKGROUND: Screening with anti-Epstein-Barr virus (EBV) serology and endoscopy decreased nasopharyngeal carcinoma (NPC) mortality in Guangdong in a randomized trial. We conducted a secondary analysis of this trial using local incidence and cost data to optimize screening programs, hypothesizing that screening could be cost-effective in southern China. METHODS: Screening costs and life-years after NPC diagnosis were obtained from the Guangdong trial's intent-to-screen population (men and women aged 30-69). Seropositive subjects were rescreened annually for 5 years. Thereafter, we evaluated 12 screening strategies in Guangdong and Guangxi using a validated model. Strategies used combinations of serology, nasopharyngeal swab PCR (NP PCR), endoscopy, and MRI from trial subcohorts. Incidence data and costs were obtained from local cancer registries and the provincial healthcare system. RESULTS: In the intent-to-screen population, screening with serology and endoscopy was cost-effective (¥42,366/life-year, 0.52 GDP per capita). Screening for 5 to 15 years between ages 35 and 59 years met a willingness-to-pay threshold of 1.5 GDP/quality-adjusted life-years in all modeled populations. Despite doubling costs, adding MRI could be cost-effective via improved sensitivity. NP PCR triage reduced endoscopy/MRI referrals by 37%. One-lifetime screen could reduce NPC mortality by approximately 20%. CONCLUSIONS: EBV-based serologic screening for NPC is likely to be cost-effective in southern China. Among seropositive subjects, the preferred strategies use endoscopy alone or selective endoscopy triaged by MRI with or without NP PCR. These data may aid the design of screening programs in this region. IMPACT: These findings support population-based screening in southern China by defining the target population, cost-effectiveness, and optimized screening approach.
Subject(s)
Cost-Benefit Analysis , Early Detection of Cancer , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , Female , Middle Aged , China/epidemiology , Male , Nasopharyngeal Carcinoma/diagnosis , Nasopharyngeal Carcinoma/virology , Nasopharyngeal Carcinoma/economics , Adult , Nasopharyngeal Neoplasms/diagnosis , Nasopharyngeal Neoplasms/economics , Nasopharyngeal Neoplasms/virology , Early Detection of Cancer/economics , Early Detection of Cancer/methods , Aged , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/complications , Mass Screening/economics , Mass Screening/methodsABSTRACT
Melanoma causes significant morbidity in solid organ transplant recipients (SOTRs). Melanomas diagnosed before transplantation can recur with intensive immunosuppression, but outcomes have not been well studied. We evaluated 901 non-Hispanic White SOTRs with a pretransplant melanoma identified using linked transplant and cancer registry data in the United States. Most pretransplant melanomas were invasive (60.7%), and the median time from diagnosis to transplantation was 5.1 years. After transplantation, 41 SOTRs developed a new invasive melanoma, corresponding to 9-fold increased risk compared with the general population (standardized incidence ratio, 9.2; 95% confidence interval [CI], 6.6-12). Twenty-two SOTRs died from melanoma after transplantation, corresponding to 52-fold increased risk (standardized mortality ratio, 52; 95% CI, 33-79). Risk factors for posttransplant melanoma included age at transplantation (adjusted hazard ratio [HR], 2.86; 95% CI, 1.24-6.60; for age 55+ vs <55 years) and maintenance immunosuppression with cyclosporine/azathioprine (adjusted HR, 2.53; 95% CI, 1.08-5.90). Melanoma mortality was strongly elevated after a posttransplant melanoma diagnosis (HR, 35.6; 95% CI, 14.0-90.4; adjusted for cyclosporine/azathioprine maintenance therapy and calendar year of transplantation). In conclusion, SOTRs with a pretransplant melanoma are at risk of adverse melanoma-related outcomes after transplantation. These findings support thorough dermatologic evaluation prior to transplantation and frequent posttransplant surveillance.
Subject(s)
Melanoma , Organ Transplantation , Skin Neoplasms , Transplant Recipients , Humans , Melanoma/diagnosis , Melanoma/mortality , Male , Female , Middle Aged , Organ Transplantation/adverse effects , Adult , Skin Neoplasms/mortality , Skin Neoplasms/diagnosis , Skin Neoplasms/etiology , Risk Factors , Follow-Up Studies , Incidence , Prognosis , Aged , Registries , Young Adult , Adolescent , Survival Rate , United States/epidemiology , Immunosuppressive Agents/therapeutic use , Postoperative Complications/diagnosisABSTRACT
Autophagy is essential for the turnover of damaged organelles and long-lived proteins. It is responsible for many biological processes such as maintaining brain functions and aging. Impaired autophagy is often linked to neurodevelopmental and neurodegenerative diseases in humans. However, the role of autophagy in neuronal pruning during development remains poorly understood. Here, we report that autophagy regulates dendrite-specific pruning of ddaC sensory neurons in parallel to local caspase activation. Impaired autophagy causes the formation of ubiquitinated protein aggregates in ddaC neurons, dependent on the autophagic receptor Ref(2)P. Furthermore, the metabolic regulator AMP-activated protein kinase and the insulin-target of rapamycin pathway act upstream to regulate autophagy during dendrite pruning. Importantly, autophagy is required to activate the transcription factor CncC (Cap "n" collar isoform C), thereby promoting dendrite pruning. Conversely, CncC also indirectly affects autophagic activity via proteasomal degradation, as impaired CncC results in the inhibition of autophagy through sequestration of Atg8a into ubiquitinated protein aggregates. Thus, this study demonstrates the important role of autophagy in activating CncC prior to dendrite pruning, and further reveals an interplay between autophagy and CncC in neuronal pruning.
Subject(s)
Drosophila Proteins , Drosophila , Quaternary Ammonium Compounds , Animals , Humans , Autophagy/physiology , Dendrites/metabolism , Drosophila/metabolism , Drosophila Proteins/metabolism , Neuronal Plasticity , Ubiquitinated Proteins/metabolismABSTRACT
BACKGROUND: Males have 2-3-fold greater risk of cancer than females at most shared anatomic sites, possibly reflecting enhanced immune surveillance against cancer in females. We examined whether these sex differences remained among immunocompromised adults. METHODS: Using the Transplant Cancer Match (TCM) study, we estimated the male-to-female incidence rate ratio in TCM (M:F IRRTransplant) for 15 cancer sites diagnosed between 1995 and 2017 using Poisson regression. Male to female IRRs in the general population (M:F IRRGP) were calculated using expected cancer counts from the Surveillance, Epidemiology, and End Results Program, standardized to the transplant population on age, race and ethnicity, and diagnosis year. Male to female IRRs were compared using a chi-square test. RESULTS: Among 343â802 solid organ transplants, 211â206 (61.4%) were among men and 132â596 (38.6%) among women. An excess cancer incidence in males was seen in transplant recipients, but the sex difference was attenuated for cancers of the lip (M:F IRRTransplant: 1.81 vs M:F IRRGP: 3.96; P < .0001), stomach (1.51 vs 2.09; P = .002), colorectum (0.98 vs 1.43; P < .0001), liver (2.39 vs 3.44; P = .002), kidney (1.67 vs 2.24; P < .0001), bladder (2.02 vs 4.19; P < .0001), Kaposi sarcoma (1.79 vs 3.26; P = .0009), and non-Hodgkin lymphoma (1.34 vs 1.64; P < .0001). The M:F IRRTransplant was not statistically different from the M:F IRRGP for other cancer sites. CONCLUSIONS: Although male solid organ transplant recipients have higher cancer incidence than female recipients, the attenuation in the male to female ratio for many cancers studied relative to the general population might suggest the importance of immunosurveillance, with some loss of advantage in female recipients due to immunosuppression after transplantation.
Subject(s)
Neoplasms , Organ Transplantation , Adult , Female , Humans , Male , Incidence , Sex Characteristics , Transplant Recipients , Risk Factors , Neoplasms/epidemiology , Neoplasms/etiology , Neoplasms/pathology , Organ Transplantation/adverse effectsABSTRACT
PURPOSE: Two Epstein-Barr virus (EBV)-based testing approaches have shown promise for early detection of nasopharyngeal carcinoma (NPC). Neither has been independently validated nor their performance compared. We compared their diagnostic performance in an independent population. METHODS: We tested blood samples from 819 incident Taiwanese NPC cases (213 early-stage, American Joint Committee on Cancer version 7 stages I and II) diagnosed from 2010 to 2014 and from 1,768 controls from the same region, frequency matched to cases on age and sex. We compared an EBV antibody score using immunoglobulin A antibodies measured by enzyme-linked immunosorbent assay (EBV antibody score) and plasma EBV DNA load measured by real-time PCR followed by next-generation sequencing (NGS) among EBV DNA-positive individuals (EBV DNA algorithm). RESULTS: EBV antibodies and DNA load were measured for 2,522 (802 cases; 1,720 controls) and 2,542 (797 cases; 1,745 controls) individuals, respectively. Of the 898 individuals positive for plasma EBV DNA and therefore eligible for NGS, we selected 442 (49%) for NGS testing. The EBV antibody score had a sensitivity of 88.4% (95% CI, 86.1 to 90.6) and a specificity of 94.9% (95% CI, 93.8 to 96.0) for NPC. The EBV DNA algorithm yielded significantly higher sensitivity (93.2%; 95% CI, 91.3 to 94.9; P = 1.33 × 10-4) and specificity (98.1%; 95% CI, 97.3 to 98.8; P = 3.53 × 10-7). For early-stage NPC, the sensitivities were 87.1% (95% CI, 82.7 to 92.4) for the EBV antibody score and 87.0% (95% CI, 81.9 to 91.5) for the EBV DNA algorithm (P = .514). For regions with a NPC incidence of 20-100/100,000 person-years (eg, residents in southern China and Hong Kong), these two approaches yielded similar numbers needed to screen (EBV antibody score: 5,656-1,131; EBV DNA algorithm: 5,365-1,073); positive predictive values ranged from 0.4% to 1.7% and 1.0% to 4.7%, respectively. CONCLUSION: We demonstrated high sensitivity and specificity of EBV antibody and plasma EBV DNA for NPC detection, with slightly inferior performance of the EBV antibody score. Cost-effectiveness studies are needed to guide screening implementation.
Subject(s)
Epstein-Barr Virus Infections , Nasopharyngeal Neoplasms , Humans , Nasopharyngeal Carcinoma/diagnosis , Herpesvirus 4, Human/genetics , Nasopharyngeal Neoplasms/diagnosis , Feasibility Studies , DNA, Viral/genetics , Antibodies, ViralABSTRACT
Incompatible living donor kidney transplant recipients (ILDKTr) require desensitization to facilitate transplantation, and this substantial upfront immunosuppression may result in serious complications, including cancer. Methods: To characterize cancer risk in ILDKTr, we evaluated 858 ILDKTr and 12 239 compatible living donor kidney transplant recipients (CLDKTr) from a multicenter cohort with linkage to the US transplant registry and 33 cancer registries (1997-2016). Cancer incidence was compared using weighted Cox regression. Results: Among ILDKTr, the median follow-up time was 6.7 y (maximum 16.1 y) for invasive cancers (ascertained via cancer registry linkage) and 5.0 y (maximum 16.1 y) for basal and squamous cell carcinomas (ascertained via the transplant registry and censored for transplant center loss to follow-up). Invasive cancers occurred in 53 ILDKTr (6.2%) and 811 CLDKTr (6.6%; weighted hazard ratio [wHR] 1.01; 95% confidence interval [CI], 0.76-1.35). Basal and squamous cell carcinomas occurred in 41 ILDKTr (4.8%) and 737 CLDKTr (6.0%) (wHR 0.99; 95% CI, 0.69-1.40). Cancer risk did not vary according to donor-specific antibody strength, and in an exploratory analysis, was similar between CLDKTr and ILDKTr for most cancer types and according to cancer stage, except ILDKTr had a suggestively increased risk of colorectal cancer (wHR 3.27; 95% CI, 1.23-8.71); however, this elevation was not significant after correction for multiple comparisons. Conclusions: These findings indicate that the risk of cancer is not increased for ILDKTr compared with CLDKTr. The possible elevation in colorectal cancer risk is unexplained and might suggest a need for tailored screening or prevention.
ABSTRACT
BACKGROUND: Solid organ transplant recipients (ie, "recipients") have elevated cancer risk and reduced survival after a cancer diagnosis. Evaluation of cancer mortality among recipients can facilitate improved outcomes from cancers arising before and after transplantation. METHODS: We linked the US transplant registry to the National Death Index to ascertain the causes of 126 474 deaths among 671 127 recipients (1987-2018). We used Poisson regression to identify risk factors for cancer mortality and calculated standardized mortality ratios to compare cancer mortality in recipients with that in the general population. Cancer deaths verified with a corresponding cancer diagnosis from a cancer registry were classified as death from pretransplant or posttransplant cancers. RESULTS: Thirteen percent of deaths were caused by cancer. Deaths from lung cancer, liver cancer, and non-Hodgkin lymphoma (NHL) were the most common. Heart and lung recipients had the highest mortality for lung cancer and NHL, whereas liver cancer mortality was highest among liver recipients. Compared with the general population, cancer mortality was elevated overall (standardized mortality ratio 2.33; 95% confidence interval, 2.29-2.37) and for most cancer sites, with large increases from nonmelanoma skin cancer (23.4, 21.5-25.5), NHL (5.17, 4.87-5.50), kidney cancer (3.40, 3.10-3.72), melanoma (3.27, 2.91-3.68), and, among liver recipients, liver cancer (26.0, 25.0-27.1). Most cancer deaths (93.3%) were associated with posttransplant cancer diagnoses, excluding liver cancer deaths in liver recipients (of which all deaths were from pretransplant diagnoses). CONCLUSIONS: Improved posttransplant prevention or screening for lung cancer, NHL, and skin cancers and management of liver recipients with prior liver cancer may reduce cancer mortality among recipients.
Subject(s)
Kidney Neoplasms , Liver Neoplasms , Lung Neoplasms , Organ Transplantation , Skin Neoplasms , Humans , United States/epidemiology , Organ Transplantation/adverse effects , Skin Neoplasms/epidemiology , Risk Factors , Transplant Recipients , Lung Neoplasms/etiology , Liver Neoplasms/etiology , Registries , IncidenceABSTRACT
Gut barrier dysfunction can result in the liver being exposed to an elevated level of gut-derived bacterial products via portal circulation. Growing evidence suggests that systemic exposure to these bacterial products promotes liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). However, prospective studies have not examined the association between biomarkers of gut barrier dysfunction and HCC risk in a population of hepatitis B or C viral (HBV/HCV) carriers. We investigated whether prediagnostic, circulating biomarkers of gut barrier dysfunction were associated with HCC risk, using the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-HBV and REVEAL-HCV cohorts from Taiwan. REVEAL-HBV included 185 cases and 161 matched controls, and REVEAL-HCV 96 cases and 96 matched controls. The biomarkers quantitated were immunoglobulin A (IgA), IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and LPS-binding protein (LBP). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarker levels and HCC were calculated using multivariable-adjusted logistic regression. A doubling of the circulating levels of antiflagellin IgA or LBP was associated with a 76% to 93% increased risk of HBV-related HCC (OR per one unit change in log2 antiflagellin IgA = 1.76, 95% CI: 1.06-2.93; OR for LBP = 1.93, 95% CI: 1.10-3.38). None of the other markers were associated with an increased risk of HBV-related or HCV-related HCC. Results were similar when cases diagnosed in the first 5 years of follow-up were excluded. Our findings contribute to understanding the interplay of gut barrier dysfunction and primary liver cancer etiology.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B , Hepatitis C , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/epidemiology , Liver Neoplasms/epidemiology , Hepatitis B virus , Prospective Studies , Lipopolysaccharides , Hepatitis B/complications , Hepatitis B/epidemiology , Cohort Studies , Biomarkers , Immunoglobulin A , Hepatitis C/complications , Risk FactorsABSTRACT
A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have an overall poorer outcomes, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of the tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases, with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with an antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.
Subject(s)
BK Virus , Organ Transplantation , Polyomavirus Infections , Urinary Bladder Neoplasms , Humans , Polyomavirus Infections/complications , Polyomavirus Infections/epidemiology , BK Virus/genetics , Carcinogenesis , Urinary Bladder Neoplasms/genetics , Antigens, Viral, Tumor , Organ Transplantation/adverse effectsABSTRACT
A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)-based approaches to screen for early stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.
Subject(s)
Carcinoma , Epstein-Barr Virus Infections , Nasopharyngeal Neoplasms , Humans , Nasopharyngeal Carcinoma/diagnosis , Nasopharyngeal Neoplasms/diagnosis , Herpesvirus 4, Human/genetics , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Early Detection of Cancer/methods , DNA, Viral/geneticsABSTRACT
BACKGROUND: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). METHODS: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. RESULTS: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. CONCLUSIONS: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. IMPACT: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.
Subject(s)
Burkitt Lymphoma , Epstein-Barr Virus Infections , Nasopharyngeal Neoplasms , Humans , Herpesvirus 4, Human , Proteome , Immunity, Humoral , Nasopharyngeal Carcinoma , Antibodies, Viral , Nasopharyngeal Neoplasms/pathology , Immunoglobulin G , Glycoproteins , Immunoglobulin AABSTRACT
Low student engagement and motivation in online classes are well-known issues many universities face, especially with distance education during the COVID-19 pandemic. The online environment makes it even harder for teachers to connect with their students through traditional verbal and nonverbal behaviours, further decreasing engagement. Yet, addressing such problems with 24/7 synchronous communication is overly demanding for faculty. This paper details an automated Question-Answering chatbot system trained in synchronous communication and instructor immediacy techniques to determine its suitability and effectiveness in attending to students undergoing an online Chemistry course. The chatbot is part of a new wave of affective focused chatbots that can benefit students' learning process by connecting with them on a relatively more humanlike level. As part of the pilot study in the development of this chatbot, qualitative interviews and self-report data capturing student-chatbot interactions, experiences and opinions have been collected from 12 students in a Singaporean university. Thematic analysis was then employed to consolidate these findings. The results support the chatbot's ability to display several communication immediacy techniques well, on top of responding to students at any time of the day. Having a private conversation with the chatbot also meant that the students could fully focus their attention and ask more questions to aid their learning. Improvements were suggested, in relation to the chatbot's word detection and accuracy, accompanied by a framework to develop communication immediacy mechanics in future chatbots. Our findings support the potential of this chatbot, once modified, to be used in a similar online setting. Supplementary Information: The online version contains supplementary material available at 10.1007/s10639-023-11602-1.
ABSTRACT
Little is known about the outcomes among solid organ transplant recipients with a pretransplant cancer diagnosis. We used linked data from the Scientific Registry of Transplant Recipients with 33 US cancer registries. Cox proportional hazards models assessed associations of pretransplant cancer with overall mortality, cancer-specific mortality, and development of a new posttransplant cancer. Among 311 677 recipients, the presence of a single pretransplant cancer was associated with increased overall mortality (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.15-1.23) and cancer-specific mortality (aHR, 1.93; 95% CI, 1.76-2.12); results for 2+ pretransplant cancers were similar. Cancer-specific mortality was not significantly increased for uterine, prostate, or thyroid cancers (aHRs were 0.83, 1.22, and 1.54, respectively) but strongly elevated for lung cancer and myeloma (aHRs were 3.72 and 4.42, respectively). A pretransplant cancer diagnosis was also associated with increased risk of developing posttransplant cancer (aHR, 1.32; 95% CI, 1.23-1.40). Among 306 recipients whose cancer death was confirmed by cancer registry data, 158 deaths (51.6%) were from a de novo posttransplant cancer and 105 (34.3%) from the pretransplant cancer. Pretransplant cancer diagnoses are associated with increased mortality after transplantation, but some deaths are related to posttransplant cancers and other causes. Improved candidate selection and cancer screening and prevention may reduce mortality in this population.
Subject(s)
Neoplasms , Organ Transplantation , Male , Humans , Risk Factors , Transplant Recipients , Neoplasms/complications , Neoplasms/diagnosis , Proportional Hazards Models , Registries , Organ Transplantation/adverse effects , IncidenceABSTRACT
INTRODUCTION: Pancreatic cancer (PC) in solid organ transplant (SOT) recipients is not well studied. Some PC cases may be incidentally detected during hepatobiliary imaging. METHODS: We evaluated PC among 374,106 SOT recipients during 1995-2017 in the United States using linked data from the national transplant registry and multiple state/regional cancer registries. Standardized incidence ratios (SIRs) were used to compare PC risk in recipients to the general population. We used multivariate Poisson regression to identify independent risk factors for PC. We assessed survival after PC diagnosis using Kaplan-Meier curves and log-rank tests. RESULTS: SOT recipients had elevated incidence for PC compared with the general population (SIR 1.40, 95% CI 1.29-1.52), and this increase was strongest in liver recipients (1.65, 1.41-1.92). Among all recipients, PC incidence was especially increased for cases arising in the head of the pancreas (SIR 1.50, 95% CI 1.34-1.68) and for cases diagnosed at localized stage (1.85, 1.37-2.44). Among SOT recipients, factors independently associated with increased incidence were consistent with those in general population including male sex, older age, non-O blood type, and history of diabetes. Additionally, compared to other organ recipients, liver transplant recipients had higher PC incidence (adjusted incidence rate ratio 1.28; 95% CI 1.06-1.54). Overall survival after PC diagnosis was poor (median 4 months) and similar between liver and other organ transplant recipients (p = 0.08). CONCLUSIONS: PC incidence is elevated among SOT recipients, and more commonly diagnosed in liver transplant recipients perhaps related to incidental detection. However, survival is poor even in liver recipients, arguing against routine PC screening.
Subject(s)
Organ Transplantation , Pancreatic Neoplasms , Humans , Male , United States/epidemiology , Organ Transplantation/adverse effects , Risk Factors , Pancreatic Neoplasms/epidemiology , Incidence , Pancreatic NeoplasmsABSTRACT
Small ruler tapes are commonly placed on the surface of the human body as a simple and efficient reference for capturing on images the physical size of a lesion. In this paper, we describe our proposed approach for automatically extracting the measurement information from a ruler in oral cavity images which are taken during oral cancer screening and follow up. The images were taken during a study that aims to investigate the natural history of histologically defined oral cancer precursor lesions and identify epidemiologic factors and molecular markers associated with disease progression. Compared to similar work in the literature proposed for other applications where images are captured with greater consistency and in more controlled situations, we address additional challenges that our application faces in real world use and with analysis of retrospectively collected data. Our approach considers several conditions with respect to ruler style, ruler visibility completeness, and image quality. Further, we provide multiple ways of extracting ruler markings and measurement calculation based on specific conditions. We evaluated the proposed method on two datasets obtained from different sources and examined cross-dataset performance.