RESUMO
A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Papillomavirus Humano 16 , Papillomavirus Humano , Neoplasias de Cabeça e Pescoço/diagnósticoRESUMO
OBJECTIVES: Anterior cruciate ligament (ACL) reconstruction after injury does not prevent post-traumatic osteoarthritis (PTOA). Circulating microRNA (miRNA) and metabolite changes emerging shortly after ACL injury and reconstruction remain insufficiently defined, potentially harbouring early cues contributing to PTOA evolution. Moreover, their differential expression between females and males also may influence PTOA's natural trajectory. This study aims to determine alterations in plasma miRNA and metabolite levels in the early stages following ACL reconstruction and between females and males. METHODS: A cohort of 43 ACL reconstruction patients was examined. Plasma was obtained at baseline, 2 weeks, and 6 weeks post-surgery (129 biospecimens in total). High-throughput miRNA sequencing and metabolomics were conducted. Differentially expressed miRNAs and metabolites were identified using negative binomial and linear regression models, respectively. Associations between miRNAs and metabolites were explored using time and sex as co-variants, (pre-surgery versus 2 and 6 weeks post-surgery). Using computational biology, miRNA-metabolite-gene interaction and pathway analyses were performed. RESULTS: Levels of 46 miRNAs were increased at 2 weeks post-surgery compared to pre-surgery (baseline) using miRNA sequencing. Levels of 13 metabolites were significantly increased while levels of 6 metabolites were significantly decreased at 2 weeks compared to baseline using metabolomics. Hsa-miR-145-5p levels were increased in female subjects at both 2 weeks (log2-fold-change 0.71, 95%CI 0.22,1.20) and 6 weeks (log2-fold-change 0.75, 95%CI 0.07,1.43) post-surgery compared to males. In addition, hsa-miR-497-5p showed increased levels in females at 2 weeks (log2-fold-change 0.77, 95%CI 0.06,1.48) and hsa-miR-143-5p at 6 weeks (log2-fold-change 0.83, 95%CI 0.07,1.59). Five metabolites were decreased at 2 weeks post-surgery in females compared to males: L-leucine (-1.44, 95%CI -1.75,-1.13), g-guanidinobutyrate (-1.27, 95%CI 1.54,-0.99), creatinine (-1.17, 95%CI -1.44,-0.90), 2-methylbutyrylcarnitine (-1.76, 95%CI -2.17,-1.35), and leu-pro (-1.13, 95%CI -1.44,-0.83). MiRNA-metabolite-gene interaction analysis revealed key signalling pathways based on post-surgical time-point and in females versus males. CONCLUSION: MiRNA and metabolite profiles were modified by time and by sex early after ACL reconstruction surgery, which could influence surgical response and ultimately risk of developing PTOA.
Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , MicroRNAs , Humanos , Masculino , Feminino , Adulto , MicroRNAs/sangue , Lesões do Ligamento Cruzado Anterior/cirurgia , Adulto Jovem , Fatores Sexuais , Biomarcadores/sangue , Metabolômica , Osteoartrite do Joelho/cirurgia , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/metabolismo , Pessoa de Meia-IdadeRESUMO
Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.
Assuntos
Neoplasias de Cabeça e Pescoço , Proteínas Oncogênicas Virais , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Papillomavirus Humano , Marcadores Genéticos , Fatores de Risco , Papillomavirus Humano 16/genética , Anticorpos Antivirais , Fatores de Transcrição/genética , Proteínas Oncogênicas Virais/genéticaRESUMO
BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.
Assuntos
Neoplasias de Cabeça e Pescoço , Abandono do Hábito de Fumar , Produtos do Tabaco , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Prognóstico , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
This study examined associations between HPV status and weight change in oropharyngeal cancer (OPC). OPC patients receiving concurrent chemoradiotherapy in Toronto, Canada were included. Relationships were assessed between HPV status and weight loss grade (WLG, combining weight loss and current body mass index); weight change during treatment; and HPV status and WLG/weight change on overall (OS) and cancer-specific (CSS) survival. Of 717 patients, WLG pre-radiation was less severe among HPV-positive compared to HPV-negative, though weight loss during treatment was greater. The adjusted odds ratio for greater WLG among HPV-positive versus HPV-negative was 0.47 (95%CI 0.28-0.78). Grade-4 WLG (worst category) experienced poorer OS and CSS (OS adjusted hazard ratio (aHR) 4.08; 95%CI 1.48-11.2, compared to Grade-0); and was non-significant for HPV-negative (aHR 2.34; 95%CI 0.69-7.95). Relationships between weight change before/during treatment and survival had similar direction between HPV-positive and HPV-negative, but of greater magnitude in HPV-positive patients.
Assuntos
Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Neoplasias Orofaríngeas/terapia , Modelos de Riscos Proporcionais , QuimiorradioterapiaRESUMO
BACKGROUND: Sarcopenia indicates poor prognosis in various malignancies. We evaluated the association of sarcopenia with overall (OS) and progression-free survival (PFS) in metastatic esophageal cancer (MEC) patients, a population often presenting with poor nutritional status. METHODS: In newly diagnosed MEC patients managed at the Princess Margaret (PM) Cancer Centre (diagnosed 2006-2015), total muscle area, visceral adiposity (VA), and subcutaneous adiposity (SA) were quantified on abdominal computed tomography at L3. Sarcopenia was determined using published cutoffs, based on sex and height. RESULTS: Of 202 MEC patients, most were male (166/82%), < 65 years (116/57%), and had adenocarcinoma histology (141/70%); 110/54% had recurrent MEC after initial curative-intent treatment; 92/46% presented with de novo MEC. At stage IV diagnosis, 20/10% were underweight, 97/48% were normal-weight and 84/42% were overweight/obese; 103/51% were sarcopenic. Sarcopenia was associated with worse median OS (4.6 vs. 7.9 months; log-rank p = 0.03) and 1-year survival, even after adjusting for other body composition variables (e.g., BMI, VA, and SA): adjusted-HR 1.51 [95% CI 1.1-2.2, p = 0.02]. In post hoc analysis, sarcopenia was highly prognostic in adenocarcinomas (p = 0.003), but not squamous cell carcinomas (SCC). In patients receiving palliative systemic treatment (104/51%), sarcopenia was associated with shorter PFS (p = 0.004) in adenocarcinoma patients (75/72%). CONCLUSIONS: In metastatic esophageal adenocarcinomas, sarcopenia is associated with worse PFS and OS. In metastatic esophageal SCC, there was a non-significant trend for worse PFS but no association with OS. In order to offset the poor prognosis associated with sarcopenia particularly in metastatic esophageal adenocarcinoma patients, future research should focus on possible countermeasures.
Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Sarcopenia , Humanos , Masculino , Feminino , Sarcopenia/complicações , Prognóstico , Recidiva Local de Neoplasia , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Obesidade/complicaçõesRESUMO
BACKGROUND: This study examined long-term health utility and symptom-toxicity trajectories among patients with head and neck cancer (HNC). METHODS: For patients diagnosed with HNC (2014-2019), Health Utility Index 3 (HUI-3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI-3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. RESULTS: In 800 patients, the treatment modality and the tumor subsite produced unique HUI-3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI-3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI-3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI-3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI-3 trajectories. HUI-3 had mild to moderate correlations (ρ = 0.2-0.5) with individual symptom-toxicity trajectories. CONCLUSIONS: Long-term HUI-3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom-toxicity studies of HNC. LAY SUMMARY: This study indicates that the long-term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities. Generalizations across all head and neck cancers should be strongly discouraged. Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Idoso , Quimiorradioterapia , Feminino , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Cancer patients may turn to social media (SM) to cope with distress. We investigated associations between distress and internet/SM use for cancer information/support. METHODS: Adult patients at a Canadian cancer centre completed a cross-sectional survey on sociodemographics, health status, use of cancer online resources and distress (EQ5D-5L). Statistical models adjusted for relevant variables. RESULTS: Of 376 participants, median age was 52 years, time since diagnosis was 1.63 years, 272 (74%) had post-secondary education and 192 (51%) were female. For cancer information/support, 276 (73%) used internet and 147 (39%) SM. Dose response relationships were observed between distress and cancer-related internet (p = 0.02), and SM use (p < 0.001). Respondents using internet/SM for cancer information/support reported greater internet confidence (internet OR = 4.0, 95% CI: 1.9-8.3; SM OR = 4.18, 95%, CI: 1.9-11.3), higher education (internet OR = 3.0, 95% CI: 1.7-5.2; SM OR = 2.21, 95% CI: 1.2-4.1) and were more likely female (internet OR = 2.6, 95% CI 1.5-4.6; SM OR = 2.1, 95% CI: 1.3-3.4). For SM for cancer information/support, more used SM > 30 min daily (OR = 3.4; 95% CI: 2.1-5.7), and were distressed (OR = 1.67, 95% CI: 1.0-2.7). SM benefits were to learn about cancer (93; 25%), distract from cancer (85; 23%) and connect with survivors (81; 22%). SM limitations were privacy (161; 43%), quality (90; 24%) and personal applicability (85; 23%). Females used SM more to connect with survivors than males (p = 0.001). CONCLUSIONS: Greater internet confidence, higher education and being female were associated with cancer-related internet/SM use. Distressed cancer patients were also more likely to turn to SM. Privacy concerns may limit SM use for coping. Future research should determine how to optimize SM in caring for and connecting with patients and reduce cancer-related distress.
Assuntos
Neoplasias , Mídias Sociais , Canadá , Sobreviventes de Câncer , Estudos Transversais , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
PURPOSE: The skull base inventory (SBI) was developed to better assess health-related quality of life (HR-QOL) in patients with anterior and central skull base neoplasms treated by endoscopic and open approaches. The primary objective of this study was to prospectively assess the psychometric properties of the SBI. METHODS: This study is part of a multi-center study of patients undergoing endoscopic and open procedures completed between 2012 and 2018. Participants were eligible if they were over 18 years of age; had benign or malignant anterior, antero-lateral, or central skull base tumors; and required either an open or endoscopic skull base surgical approach. In order to assess the psychometric properties of the SBI, patients completed the instrument at six time points (preoperative, 2 weeks, 3 months, 6 months, 12 months postoperative). Patients also completed the Anterior Skull Base (ASB) questionnaire and the Sinonasal Outcome Test (SNOT-22) to allow comparison to the SBI. RESULTS: One hundred and eighty-seven patients were included across five centers, with 121 having an endoscopic procedure. Internal consistency (Cronbach's alpha = 0.95) and test-retest at 12 months and 12 months plus 2 weeks (intraclass correlation > 0.90) were excellent. Concurrent validity was demonstrated by very strong correlation between total SBI scores and ASB scores (r = 0.810 to 0.869, p < 0.001) and moderate correlation between nasal domain SBI scores and SNOT-22 scores (r = - 0.616 to - 0.738, p < 0.001). Convergent validity was demonstrated by moderate correlation between change in SBI scores and global QOL change (rs = 0.4942, p < 0.001). The minimally important clinical difference (global HR-QOL change of "a little better" or "a little worse") was 6.0. CONCLUSION: The SBI questionnaire is reliable and valid for patients treated by both endoscopic and open approaches and can be used for assessment of HR-QOL in these settings.
Assuntos
Endoscopia/métodos , Psicometria/métodos , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The treatment of head and neck cancer (HNC) may cause significant financial toxicity to patients. Herein, the authors have presented the development and validation of the Financial Index of Toxicity (FIT) instrument. METHODS: Items were generated using literature review and were based on expert opinion. In item reduction, items with factor loadings of a magnitude <0.3 in exploratory factor analysis and inverse correlations (r < 0) in test-retest analysis were eliminated. Retained items constituted the FIT. Reliability tests included internal consistency (Cronbach α) and test-retest reliability (intraclass correlation). Validity was tested using the Spearman rho by comparing FIT scores with baseline income, posttreatment lost income, and the Financial Concerns subscale of the Social Difficulties Inventory. Responsiveness analysis compared change in income and change in FIT between 12 and 24 months. RESULTS: A total of 14 items were generated and subsequently reduced to 9 items comprising 3 domains identified on exploratory factor analysis: financial stress, financial strain, and lost productivity. The FIT was administered to 430 patients with HNC at 12 to 24 months after treatment. Internal consistency was good (α = .77). Test-retest reliability was satisfactory (intraclass correlation, 0.70). Concurrent validation demonstrated mild to strong correlations between the FIT and Social Difficulties Inventory Money Matters subscale (Spearman rho, 0.26-0.61; P < .05). FIT scores were found to be inversely correlated with baseline household income (Spearman rho, -0.34; P < .001) and positively correlated with lost income (Spearman rho, 0.24; P < .001). Change in income was negatively correlated with change in FIT over time (Spearman rho, -0.25; P = .04). CONCLUSIONS: The 9-item FIT demonstrated internal and test-retest reliability as well as concurrent and construct validity. Prospective testing in patients with HNC who were treated at other facilities is needed to further establish its responsiveness and generalizability.
Assuntos
Estresse Financeiro/psicologia , Neoplasias de Cabeça e Pescoço/economia , Neoplasias de Cabeça e Pescoço/psicologia , Psicometria , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estresse Financeiro/economia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida/psicologia , Inquéritos e QuestionáriosRESUMO
PURPOSE: Adolescents and young adults (AYA) with cancer are increasingly using the internet and social media (SM) for cancer-related information. AYA face specific challenges and thus require tailored resources that meet their needs. We describe the internet and SM preferences of AYA related to their cancer information seeking behaviors and their preferences for a future resource compared to middle-aged adults (MAA). METHODS: Cancer patients completed a cross-sectional survey related to their internet and SM usage, cancer information, and preferences for future resources. Chi-square tests were used to compare AYA and MAA. RESULTS: The mean (±SD) age in the AYA group was 30±6.1 years (n = 129); in MAA 55±6.7 years (n = 157). In general, AYA preferred internet sites over SM platforms for cancer-related information and prefer a website platform over a SM platform for a new resource. Few AYA were aware of hospital-based AYA-specific resources. MAA were less likely to use SM compared with AYA (13% vs 4%, p = 0.01); however, websites and SM platforms that were used were similar between the 2 groups. Participants endorsed having already researched certain topics - yet, these were also those desired in a new resource. Compared to MAA, AYA sought more information on diet/nutrition, physical activity, exercise/fitness, fertility, sexual health, and body image (all p values < 0.05). CONCLUSION: AYA and MAA use similar resources on the internet and SM, but AYA sought information related to specific needs. Development of future resources should focus on an internet-based platform rather than a SM platform, coupled with promoting awareness of the resource.
Assuntos
Comportamento de Busca de Informação , Neoplasias/diagnóstico , Neoplasias/terapia , Educação de Pacientes como Assunto/métodos , Mídias Sociais/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/psicologia , Educação de Pacientes como Assunto/estatística & dados numéricos , Adulto JovemRESUMO
Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.
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Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Pleurais/genética , Fumar/efeitos adversos , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas , Fatores de Risco , Fumar/genéticaRESUMO
This study aimed to compare the detection of neuroendocrine tumor liver metastases (NLMs) in hepatobiliary-specific contrast-enhanced MRI (pMR) versus 68Ga-DOTATATE PET/CT (DT-PET). This retrospective study cohort included 30 patients with well-differentiated neuroendocrine tumors who underwent both DT-PET and pMR. Two readers independently assessed NLMs count, SUVmax on DT-PET, and signal characteristics on pMR. A consensus review by two additional readers resolved discrepancies between the modalities. Results showed concordance between DT-PET and pMR NLM count in 14/30 patients (47%). pMR identified more NLMs in 12/30 patients (40%), of which 4 patients showed multiple deposits on pMR but only 0-1 lesions on DT-PET. DT-PET detected more in 4/30 patients (13%). Overall, pMR detected more metastases than DT-PET (p = 0.01). Excluding the four outliers, there was excellent agreement between the two methods (ICC: 0.945, 95%CI: 0.930, 0.958). Notably, pMR had a higher NLM detection rate than DT-PET, with correlations found between lesion size on pMR and DT-PET detectability, as well as diffusion restriction on pMR and SUVmax on DT-PET. In conclusion, in consecutive patients with well-differentiated NETs, the detection rate of NLM is higher with pMR than with DT-PET. However, when excluding patients whose tumors do not overexpress somatostatin receptors (13% of the cohort), high concordance in the detection of NLM is observed between DT PET and pMR.
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Gadolínio DTPA , Neoplasias Hepáticas , Tumores Neuroendócrinos , Tomografia por Emissão de Pósitrons , Cintilografia , Humanos , Radioisótopos de Gálio , Tumores Neuroendócrinos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Elétrons , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Neoplasias Hepáticas/diagnóstico por imagemRESUMO
Introduction: Lepidic growth is considered noninvasive in lung nonmucinous adenocarcinoma, whereas other patterns are invasive. Considerable interobserver variability in assessing "invasion" has been reported. We assessed the utility of cytokeratin 7 (CK7) stain and recently proposed International Association for the Study of Lung Cancer criteria to improve assessment of noninvasion in lung adenocarcinoma. Methods: Four pathologists (two staff, two trainees) assessed 158 hematoxylin and eosin (HE)- and CK7-stained slides of 108 pT1N0-2 nonmucinous lung adenocarcinoma cases. Scoring took place in four rounds. First, sections were independently scored for percentage of noninvasive or probable noninvasive and invasive or probable invasive patterns. Second, after a consensus scoring algorithm for CK7 was formulated, the slides were rescored. Subsequent third-round scoring was conducted only on HE slides using the 2023 International Association for the Study of Lung Cancer proposed criteria, and fourth-round scoring on both HE and CK7 slides simultaneously. Intraclass correlation coefficient (ICC) was calculated for each round. Recurrence-free survival was assessed using Cox proportional hazards regression methods. Results: In the first two rounds, interobserver concordance was consistently higher with CK7 (ICC range = 0.44-0.6) than HE (range = 0.24-0.49) scores. The IASLC proposed algorithm improved ICC of HE scores to 0.60 (95% confidence interval: 0.52-0.67), and round 4 HE and CK7 combined improved ICC to 0.75 (95% confidence interval: 0.70-0.80). Continuous measures of averaged noninvasive and probable noninvasive scores on HE were associated with improved recurrence-free survival (hazard ratio: 0.83-0.86). Conclusions: CK7 staining consistently increased interobserver concordance in assessment of invasive versus noninvasive patterns than HE. Combining CK7 with the 2023 IASLC criteria for morphologic features of invasion may further improve the interobservers' concordance for the recognition of lepidic growth in nonmucinous lung adenocarcinoma.
RESUMO
BACKGROUND: Concomitant high-dose cisplatin with radiotherapy is commonly used for treating head and neck squamous cell carcinoma (HNSCC). Cisplatin, often used with radiotherapy, is known for causing irreversible sensorineural hearing loss, with individual variability suggesting a genetic component. This study aims to enhance the predictive ability of the clinical prediction model for cisplatin-induced hearing loss (CIHL) in HNSCC patients, as outlined in Theunissen et al., by incorporating significant genetic variants. METHODS: Conducted at the Netherlands Cancer Institute, this retrospective study included 74 patients treated between 1997 and 2011. Thirty-one SNPs that were previously associated with CIHL or other cisplatin-induced toxicities were identified and incorporated into the model. The primary outcome measured was the change in decibels at posttreatment 1-2-4 kHz hearing levels per additional minor allele of these SNPs, evaluated using linear mixed-effects regression models. The model's predictive accuracy was determined by the area under the curve (AUC) using 10-fold cross-validation. RESULTS: The rs2289669 SNP in the SLC47A1/MATE1 gene was linked to a significant 2.67 dB increase in hearing loss per allele (95% CI 0.49-4.86, p = 0.017). Incorporating rs2289669 improved the model's AUC from 0.78 to 0.83, a borderline significant improvement (p = 0.073). CONCLUSIONS: This study underscores the importance of the rs2289669 SNP in CIHL and demonstrates the potential of combining genetic and clinical data for enhanced predictive models in personalized treatment strategies.
Assuntos
Quimiorradioterapia , Cisplatino , Polimorfismo de Nucleotídeo Único , Humanos , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Estudos Retrospectivos , Idoso , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Adulto , Perda Auditiva/genética , Perda Auditiva/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
BACKGROUND: Cisplatin-based chemoradiation is a standard treatment for many patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), an etiologically distinct subset of head and neck cancer. Although associated with good long-term survival, clinical risk factors for ototoxicity have been understudied in this population. This study aimed to evaluate clinical predictors associated with ototoxicity in HPV-positive OPSCC patients treated with cisplatin chemoradiation. METHODS: This retrospective case-control study included 201 adult patients (>18 years) with histologically confirmed HPV-positive OPSCC who received cisplatin chemoradiation as their primary treatment from 2001 and 2019 at a single tertiary cancer center. Ototoxicity was determined using baseline and follow-up audiometry and the Common Terminology Criteria for Adverse Events v5.0 grading criteria (Grade ≥2). Multivariable logistic regression [adjusted odds ratio (aOR)] identified significant predictors that increased the odds of ototoxicity. RESULTS: A total of 201 patients [165 males; median (IQR) age, 57 (11) years] were included in the study. The incidence of ototoxicity in the worst ear was 56.2%, with the greatest hearing loss occurring at high frequencies (4-8 kHz), resulting in a loss of 12.5 dB at 4 to 6 kHz and 20 dB at 6 to 8 kHz. High-dose cisplatin administration compared to weekly administration [aOR 4.93 (95% CI: 1.84-14.99), P = .003], a higher mean cochlear radiation dose [aOR 1.58 (95% CI: 1.12-2.30), P = .01], smoking history [aOR 2.89 (95% CI: 1.51-5.63), P = .001], and a 10 year increase in age [aOR 2.07 (95% CI: 1.25-3.52), P = .006] were each independently associated with increased odds of ototoxicity. CONCLUSIONS: Clinical predictors of ototoxicity in HPV-positive OPSCC patients treated with cisplatin-based chemoradiation include the use of a high-dose cisplatin regimen, higher cochlear radiation doses, a history of smoking, and older age. With the rising incidence of this malignancy in Western countries and overall improved survivorship, our research motivates future studies into risk stratification and earlier interventions to mitigate and reduce the risk of ototoxicity.
Assuntos
Quimiorradioterapia , Cisplatino , Neoplasias Orofaríngeas , Ototoxicidade , Humanos , Masculino , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Pessoa de Meia-Idade , Feminino , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Estudos Retrospectivos , Quimiorradioterapia/efeitos adversos , Estudos de Casos e Controles , Ototoxicidade/etiologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Infecções por Papillomavirus/complicações , Fatores de Risco , Idoso , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologiaRESUMO
Patient-derived xenografts (PDXs) are increasingly utilized in preclinical drug efficacy studies due to their ability to retain the molecular, histological, and drug response characteristics of patient tumors. This study aimed to investigate the factors influencing the successful engraftment of PDXs. Lung adenocarcinoma PDXs were established using freshly resected tumor tissues obtained through surgery. Radiological data of pulmonary nodules from this PDX cohort were analyzed, categorizing them into solid tumors and tumors with ground-glass opacity (GGO) based on preoperative CT images. Gene mutation status was obtained from next generation sequencing data and MassARRAY panel. A total of 254 resected primary lung adenocarcinomas were utilized for PDX establishment, with successful initial engraftment in 58 cases (22.8 %); stable engraftment defined as at least three serial passages was observed in 43 cases (16.9 %). The stable engraftment rates of PDXs from solid tumors and tumors with GGO were 22.1 % (42 of 190 cases) and 1.6 % (1 of 64 cases), respectively (P < 0.001). Adenocarcinomas with advanced stage, poor differentiation, solid histologic subtype, and KRAS or TP53 gene mutations were associated with stable PDX engraftment. Avoiding tumors with GGO features could enhance the cost-effectiveness of establishing PDX models from early-stage resected lung adenocarcinomas.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Mutação , Humanos , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/cirurgia , Adenocarcinoma de Pulmão/genética , Masculino , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/genética , Animais , Idoso , Pessoa de Meia-Idade , Camundongos , Xenoenxertos , Estadiamento de Neoplasias , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Ensaios Antitumorais Modelo de Xenoenxerto , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
BACKGROUND: Immune response to COVID-19 vaccine is diminished in patients with hematologic malignancy. There is limited data regarding response to vaccine doses in these patients. PURPOSE: To quantify the humoral immune response engendered by 4th and subsequent doses of SARS-CoV-2 vaccination as measured by anti-Spike (anti-S) antibody levels, based on dried blood spot (DBS) testing, in patients with hematologic malignancies. Anti-S binds to the spike protein of the SARS-CoV-2 virus and is indicative of vaccine immunogenicity. METHODS: We conducted a prospective study of hematologic malignancies between August 2021 and January 2023 at 12 sites across Canada. Participants were followed longitudinally and submitted finger-prick DBS cards at set intervals associated with vaccination. Samples were processed via high throughput ELISA assay to detect serum antibodies against nucleocapsid (N) and spike (S) proteins. RESULTS: We obtained 3071 samples on 790 unique patients. Of these, 372 unique participants with 1840 samples had anti-S results available post-4th, 5th or 6th COVID-19 vaccine dose and were included for analysis. Three hundred thirty-three patients of the 372 participants submitted a DBS sample post 4th dose. Of these, 257 patients (77.2%) had a positive anti-S antibody. A total of 198 patients had paired samples pre- and post-dose 4, of which 59 (29.7%) had a negative anti-S antibody pre-dose 4. Of these, 20 (33.4%) developed positive anti-S antibody post-dose 4. One hundred forty-nine patients submitted a DBS sample post-dose 5. Of these, 135 patients (90.6%) had positive anti-S antibody. A total of 52 had paired samples pre- and post-dose 5. Six (8.7%) had a negative anti-S antibody pre-dose 5, of which two (33.3%) developed positive anti-S antibody post-dose 5. Of these 372 patients, 123 (34%) reported COVID-19 infection and 4 (1%) had a COVID-19 related hospitalization. There were no reported deaths from COVID-19. CONCLUSIONS: This prospective cohort study showed that humoral immune response improved with subsequent doses of COVID-19 vaccines.
RESUMO
PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.
Assuntos
Neoplasias de Cabeça e Pescoço , Osteorradionecrose , Radioterapia de Intensidade Modulada , Humanos , Osteorradionecrose/etiologia , Osteorradionecrose/classificação , Masculino , Neoplasias de Cabeça e Pescoço/radioterapia , Feminino , Pessoa de Meia-Idade , Idoso , Radioterapia de Intensidade Modulada/efeitos adversos , Fatores de Risco , Medição de Risco , Índice de Gravidade de DoençaRESUMO
The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.