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1.
Curr Oncol ; 31(10): 5919-5928, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39451745

RESUMO

BACKGROUND: Oncocytic thyroid carcinoma (OTC) was previously considered a variant of follicular thyroid carcinoma (FTC) but has recently been reclassified as a separate form of thyroid cancer. This study aimed to demonstrate that FTC and OTC are fundamentally distinct entities that can potentially be differentiated preoperatively through cytology and/or molecular testing. METHODS: A retrospective chart review of patients diagnosed with FTC and OTC operated upon at two university health centers from January 2016 to September 2023 (n = 3219) was conducted. Molecular testing results were correlated with histopathologic diagnosis. RESULTS: Fifty patients met the inclusion criteria. FTC was identified in 27 (54.0%) patients, and OTC in 23 (46.0%) patients. Patients with OTC were older (61.8 years) than FTC patients (51.2 years) (p = 0.013). Moreover, aggressive tumors were found in 39.1% (9/23) of OTCs compared to 11.1% (3/27) of FTCs (p = 0.021). Amongst Bethesda category III and IV nodules, 17 out of 20 (85.0%) OTC cytology reports demonstrated an oncocytic subtype compared to only 5 out of 24 FTC cytology reports (20.8%) (p = 0.002). On molecular testing, the EIF1AX alteration was exclusively present in OTCs while the PAX8/PPARy and PTEN alterations were exclusively found in FTCs. Copy number alterations (CNAs) were found to be more prevalent in OTC (66.7%) compared to FTC (33.3%), and they were not indicative of tumor aggressiveness. Within the OTC group, all three patients who had a TP53 alteration were diagnosed with aggressive cancer. Lastly, the OTCs exhibited a higher frequency of multiple alterations on molecular testing (66.7%) compared to FTCs (33.3%). CONCLUSION: To our knowledge, this is the largest study to date comparing the clinical application of abnormalities found on molecular testing for FTC and OTC. It further demonstrates the distinct clinicopathological and molecular characteristics of OTC.


Assuntos
Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Testes Genéticos/métodos , Idoso , Adulto
2.
Artigo em Inglês | MEDLINE | ID: mdl-39342503

RESUMO

OBJECTIVE: Limited progress has occurred in treating operable human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). Accessing timely care remains challenging in public health care systems, potentially resulting in disease progression before treatment initiation. STUDY DESIGN: A prospective cohort of patients receiving neoadjuvant capecitabine (NC) was compared to stage-matched patients undergoing standard of care (SC). SETTING: This study was performed at 2 academic centers in Montreal, Canada. METHODS: To ascertain the effect of 2 cycles of NC in operable HPV-negative HNSCC patients on clinical-to-pathologic stage migration. Comparison to an SC group was performed to site and TNM stage matched patients. Pathologic treatment response was measured using the modified Ryan score. RESULTS: We compared 16 NC patients (11 oral cavity, 3 skin, 2 larynx) with 32 SC patients. Ten NC patients exhibited a pathologic response (1 complete, 3 major, 6 minor). Clinical-to-pathologic stage migration differed significantly between NC and SC groups: downstage (6 vs 1), upstage (3 vs 14), no change (7 vs 17, P = .0047). There was no severe treatment toxicity related to capecitabine. All patients in the NC group underwent surgery. CONCLUSION: NC followed by surgery demonstrates measurable pathologic response in HPV-negative HNSCC, suggesting potential utility in resource-limited health care settings.

3.
J Clin Oncol ; : JCO2400119, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39303189

RESUMO

Radiotherapy (RT) and transoral robotic surgery (TORS) are both curative-intent treatment options for oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report the final outcomes of the ORATOR trial comparing these modalities, 5 years after enrollment completion. We randomly assigned 68 patients with T1-2N0-2 OPSCC to RT (with chemotherapy if node-positive) versus TORS plus neck dissection (± adjuvant RT/chemoradiation). The primary end point was swallowing quality of life (QOL) assessed with the MD Anderson Dysphagia Inventory (MDADI). Secondary end points included overall and progression-free survival (OS, PFS), adverse events (AEs), and other QOL metrics. The primary end point has been previously reported (Nichols 2019). In this report, the median follow-up was 5.1 years (IQR, 5.0-5.3 years). MDADI total scores converged by 5 years and were not significantly different across the follow-up period (P = .11). EORTC QLQ-C30 and H&N35 scores demonstrated differing profiles, including worse dry mouth in the RT arm (P = .032) and worse pain in the TORS arm (P = .002). Grade 2-5 AE rates did not differ between arms (91% [n = 31] v 97% [n = 33] respectively, P = .61), with more neutropenia and hearing loss in the RT arm, and more dysphagia and other pain in the TORS arm based on grades 2-5 (all P < .05). There were no differences in OS or PFS. In conclusion, toxicity and QOL profiles differ in some domains between RT and TORS, but oncologic outcomes were excellent in both arms. Choice of treatment should remain a shared decision between the patient and their providers.

4.
J Geriatr Oncol ; : 102064, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39271411

RESUMO

INTRODUCTION: Frailty is a recognized condition associated with poorer outcomes in patients with head and neck cancer (HNC). The objective of this study was to ascertain the prognostic significance of various frailty metrics on short-term treatment toxicity in patients with HNC undergoing curative-intent therapy. MATERIALS AND METHODS: A systematic review was performed searching multiple databases. An inverse-variation, random-effects model was used to perform the meta-analysis to evaluate the prognostic significance of various frailty metrics on short-term treatment-related toxicity in this population. RESULTS: A total of 292,560 patients with HNC originating from 36 observational studies were analyzed. The most frequently reported frailty metrics were the modified frailty index (mFI), Geriatric 8 questionnaire (G8), Adjusted Clinical Groups (ACG), Groningen Frailty Indicator (GFI), and comprehensive geriatric assessment (CGA). The overall prevalence of frailty using any metric in all included studies was 7.5 %. The combined odds ratio (OR) for short-term treatment toxicity using the mFI was 2.60 (95 % CI of 1.81-3.72), G8 2.69 (95 % CI 1.37-5.28), ACG 3.43 (95 %CI 2.52-4.67), GFI 2.71 (95 % CI 1.11-6.62), and CGA 3.36 (95 % CI 1.18-9.53). The association of frailty with short-term treatment toxicity using various frailty metrics was more pronounced in patients with upfront surgery (OR 3.00, 95 %CI of 2.35-3.81) compared to definitive (chemo)radiotherapy 2.64 (95 % CI 1.04-6.68). DISCUSSION: Various frailty metrics exists in the HNC literature, with the most common being the mFI, G8, ACG, GFI, and CGA. Patients with HNC and frailty are more than twice as likely to suffer a short-term treatment-related toxicity when undergoing curative-intent HNC treatment than patients without frailty. This effect is more pronounced in patients undergoing upfront surgery.

5.
J Otolaryngol Head Neck Surg ; 53: 19160216241248670, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38888957

RESUMO

BACKGROUND: Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with radiation-based therapy suffer from short- and long-term toxicities that affect quality of life (QOL). Transoral robotic surgery (TORS) has an established role in the management of early OPSCC but adjuvant treatment is often indicated postoperatively due to the high incidence of nodal metastasis associated with advanced human papillomavirus (HPV)-related OPSCC. To overcome the need for adjuvant radiation therapy (RT), neoadjuvant chemotherapy followed by TORS and neck dissection (ND) is proposed. This study aimed to assess if QOL in HPV-associated OPSCC receiving neoadjuvant chemotherapy followed by TORS and ND returns to baseline within 12 months of completing treatment. METHODS: A 12 month longitudinal study was carried out at McGill University Health Centre in Montreal, Canada, among a convenience sample of patients with American Joint Committee on Cancer Seventh Edition stage III and IVa HPV-related OPSCC who were treated with neoadjuvant chemotherapy followed by TORS and ND. QOL data were obtained pretreatment and at 1, 3, 6, and 12 months following treatment completion using the European Organisation for Research and Treatment of Cancer Core and Head and Neck extension modules. Paired t tests and mixed models for repeated measures analysis were used to assess changes in QOL from baseline to 12 months postoperatively and over time, respectively. RESULTS: Nineteen of 23 patients (median age 58 years) who received the study treatment fulfilled the eligibility criteria. OPSCC subsites were palatine tonsil (n = 12) and base of tongue (n = 7). All 19 patients were treated per protocol and none required adjuvant RT as per pathology review and protocol requirements at a postoperative multidisciplinary team tumor board discussion. No significant differences were found when comparing 12 month QOL follow-up scores to pretreatment scores in measures that would likely be affected by RT [eg, swallowing (P = .7), social eating (P = .8), xerostomia (P = .9)]. CONCLUSION: In HPV-related OPSCC, neoadjuvant chemotherapy followed by TORS and ND as definitive treatment is associated with excellent QOL outcomes. Postoperative QOL scores returned to baseline by 3 months and were maintained for all measures, indicating a return to normal function.


Assuntos
Terapia Neoadjuvante , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Qualidade de Vida , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virologia , Neoplasias Orofaríngeas/cirurgia , Infecções por Papillomavirus/complicações , Idoso , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/virologia , Estudos Longitudinais , Esvaziamento Cervical , Quimioterapia Adjuvante , Adulto , Papillomavirus Humano
6.
JAMA Otolaryngol Head Neck Surg ; 150(7): 598-606, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38814668

RESUMO

Importance: Although patients with head and neck cancer (HNC) have been shown to experience high distress, few longitudinal studies include a comprehensive evaluation of biopsychosocial factors affecting quality of life (QoL), including genetic risk for depression. Objective: To identify factors at the time of cancer diagnosis associated with QoL scores at 3 months after treatment in patients newly diagnosed with a first occurrence of HNC. Design, Setting, and Participants: This prospective longitudinal study of 1464 participants with a 3-month follow-up, including structured clinical interviews and self-administered measures was carried out at the Department of Otolaryngology Head and Neck Surgery at 2 tertiary care McGill University Affiliated Hospitals, McGill University Health Centre, and Jewish General Hospital. Eligible patients were adults newly diagnosed within 2 weeks with a primary first occurrence of HNC, had a Karnofsky Performance Scale score higher than 60, and an expected survival of more than 6 months. Two hundred and twenty-three patients (72%) consented to participate and completed the baseline questionnaire, and 71% completed the 3-month follow-up measures. Exposures: An a priori conceptual model including sociodemographics, medical variables, psychosocial risk factors, and a polygenic risk score for depression (PRS-D) was tested. Main outcomes and measures: The Functional Assessment of Cancer Therapy-Head and Neck measured QoL at baseline and at 3 months. Results: Participants were mostly men (68.7%), with a mean (range) age of 62.9 (31-92) years, 36.6% having a university degree, 35.6% living alone, and 71.4% diagnosed with advanced HNC with mostly cancers being of the oropharynx (42.2%), oral cavity (17%), and larynx (16.3%). QoL at 3 months after HNC diagnosis was associated with higher PRS-D (B = -4.71; 95% CI, -9.18 to -0.23), and a diagnosis of major depressive disorder within 2 weeks of an HNC diagnosis (B = -32.24; 95% CI, -51.47 to 13.02), lifetime suicidal ideation (B = -22.39; 95% CI, -36.14 to -8.65), living with someone (B = 12.48; 95% CI, 3.43-21.52), having smoked cigarettes in the past 30 days pre-HNC diagnosis (B = -15.50; 95% CI, -26.07 to -4.93), chemotherapy type (B = -11.13; 95% CI, -21.23 to -1.02), and total radiotherapy dose (Gy) (B = -0.008; 95% CI, -0.01 to -0.002). Conclusions and relevance: This study identified the predictive value of a genetic predisposition to depression on QoL and function immediately after oncologic treatments. These findings highlight the potential importance of genetic profiling pretreatment to identify those most susceptible to experience QoL and functional compromise. Depression is a clear area of public health concern and should be a central focus in the treatment of patients with HNC.


Assuntos
Depressão , Neoplasias de Cabeça e Pescoço , Qualidade de Vida , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias de Cabeça e Pescoço/psicologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Estudos Prospectivos , Idoso , Adulto , Predisposição Genética para Doença , Estudos Longitudinais , Fatores de Risco , Inquéritos e Questionários
7.
Talanta ; 274: 125970, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38621320

RESUMO

The use of collision cross section (CCS) values derived from ion mobility studies is proving to be an increasingly important tool in the characterization and identification of molecules detected in complex mixtures. Here, a novel machine learning (ML) based method for predicting CCS integrating both molecular modeling (MM) and ML methodologies has been devised and shown to be able to accurately predict CCS values for singly charged small molecular weight molecules from a broad range of chemical classes. The model performed favorably compared to existing models, improving compound identifications for isobaric analytes in terms of ranking and assigning identification probability values to the annotation. Furthermore, charge localization was seen to be correlated with CCS prediction accuracy and with gas-phase proton affinity demonstrating the potential to provide a proxy for prediction error based on chemical structural properties. The presented approach and findings represent a further step towards accurate prediction and application of computationally generated CCS values.

8.
Otolaryngol Head Neck Surg ; 171(2): 431-438, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38643406

RESUMO

OBJECTIVE: To ascertain the effect of curative-intent surgery on loss of independence (LOI) in patients with oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: Retrospective observational study of patients diagnosed from 2014 to 2021. SETTING: Single tertiary care academic center. Patients having undergone curative-intent surgical treatment for OCSCC from 2014 to 2021 in the cancer registry. METHODS: LOI as the primary outcome was measured based on a combination of decrease in activities of daily living (ADLs) and/or decline in mobility during treatment. Descriptive statistics were used to compare baseline demographics and multivariable logistic regression was used to assess the association between LOI and perioperative variables of interest. RESULTS: Of the 180 patients included in this study, 139 (79%) were fully independent in ADLs/instrumental ADLs prior to surgery. The average age of the cohort was 74 with 49% males. Thirty-seven (21%) experienced a decline in mobility or increased care needs following surgery, and 18 (10%) experienced an independent decline in functional status. Increasing age, osseous flap reconstruction, high Charlson Comorbidity Index, and major postoperative adverse events were associated with LOI. Fifty-five percent of patients with LOI had recovered to baseline within 7 months from surgery. LOI was associated with poor treatment tolerance (odds ratio: 4.77, 95% confidence interval: 1.87-12.2) while adjusting for multiple confounders. CONCLUSION: LOI is common in older adults undergoing curative-intent surgery for OCSCC and associated with poor treatment tolerance.


Assuntos
Atividades Cotidianas , Neoplasias Bucais , Humanos , Masculino , Feminino , Estudos Retrospectivos , Idoso , Neoplasias Bucais/cirurgia , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Limitação da Mobilidade
9.
Anal Chem ; 96(15): 5869-5877, 2024 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-38561318

RESUMO

Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) has emerged as a powerful tool to probe protein dynamics. As a bottom-up technique, HDX-MS provides information at peptide-level resolution, allowing structural localization of dynamic changes. Consequently, the HDX-MS data quality is largely determined by the number of peptides that are identified and monitored after deuteration. Integration of ion mobility (IM) into HDX-MS workflows has been shown to increase the data quality by providing an orthogonal mode of peptide ion separation in the gas phase. This is of critical importance for challenging targets such as integral membrane proteins (IMPs), which often suffer from low sequence coverage or redundancy in HDX-MS analyses. The increasing complexity of samples being investigated by HDX-MS, such as membrane mimetic reconstituted and in vivo IMPs, has generated need for instrumentation with greater resolving power. Recently, Giles et al. developed cyclic ion mobility (cIM), an IM device with racetrack geometry that enables scalable, multipass IM separations. Using one-pass and multipass cIM routines, we use the recently commercialized SELECT SERIES Cyclic IM spectrometer for HDX-MS analyses of four detergent solubilized IMP samples and report its enhanced performance. Furthermore, we develop a novel processing strategy capable of better handling multipass cIM data. Interestingly, use of one-pass and multipass cIM routines produced unique peptide populations, with their combined peptide output being 31 to 222% higher than previous generation SYNAPT G2-Si instrumentation. Thus, we propose a novel HDX-MS workflow with integrated cIM that has the potential to enable the analysis of more complex systems with greater accuracy and speed.


Assuntos
Medição da Troca de Deutério , Espectrometria de Massa com Troca Hidrogênio-Deutério , Deutério/química , Medição da Troca de Deutério/métodos , Espectrometria de Massa com Troca Hidrogênio-Deutério/métodos , Peptídeos/química
10.
Head Neck ; 46(6): 1500-1509, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38353170

RESUMO

Sarcopenia is an increasingly recognized biomarker associated with poorer outcomes. The objective of this study was to ascertain the effect of sarcopenia on treatment tolerance and short-term toxicity in head and neck cancer (HNC). A systematic review was performed using multiple databases. An inverse-variation, random-effects model was used to perform the meta-analysis to evaluate the effect of sarcopenia on severe treatment toxicity and poor treatment tolerance. Sixteen observational studies, including 3187 patients with HNC, were analyzed. The combined odds ratio (OR) for severe treatment toxicity and tolerance was 2.22 (95%CI 1.50-3.29) and 1.40 (95%CI 0.84-2.32), respectively. The effect of sarcopenia on short-term severe treatment toxicity was similar with upfront surgery (OR 2.03, 95%CI 1.22-3.37) and definitive radiotherapy (OR 2.24, 95%CI 1.18-4.27) Patients with sarcopenia are more than twice as likely to suffer a short-term treatment-related toxicity when undergoing curative-intent HNC treatment.


Assuntos
Neoplasias de Cabeça e Pescoço , Sarcopenia , Sarcopenia/etiologia , Sarcopenia/terapia , Humanos , Neoplasias de Cabeça e Pescoço/terapia , Masculino , Feminino
11.
JAMA Otolaryngol Head Neck Surg ; 150(1): 65-74, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38060238

RESUMO

Importance: Efforts are underway to deintensified treatment protocols for patients with human papillomavirus virus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) to achieve similar excellent oncologic outcomes while reducing treatment-related adverse effects. Transoral robotic surgery (TORS) as primary treatment often requires adjuvant therapy due to the high incidence of nodal metastasis. Treatment with neoadjuvant chemotherapy followed by TORS and neck dissection (NECTORS), reserving radiation therapy for salvage, yields excellent oncologic outcomes. Objective: To assess patient-reported quality of life (QOL) and functional outcomes among patients with HPV-OPSCC who undergo NECTORS. Design, Settings, and Participants: This was a multicenter prospective cohort study of patients with HPV-OPSCC treated with the NECTORS protocol in 2017 to 2022. Consecutive patients with stage III or IVa HPV-OPSCC treated with NECTORS in 2017 to 2022 who had completed the primary QOL questionnaire at baseline and at least once during the 24-month follow-up period were included. Ninety-four patients were eligible, and 67 were included in the analyses. Outcome Measures: QOL questionnaires at baseline, and at month 1, 3, 6, 12, 18, and 24 posttreatment. Global score on the 30-item European Organization for Research and Treatment of Cancer Core quality of life questionnaire (EORTC QLQ-C30) was the primary outcome; the head and neck extension module (EORTC QLQ-HN35); the MD Anderson Dysphagia Inventory for dysphagia-related QOL; and the Decision Regret Scale were also used. Paired t tests assessed change between the baseline and 12- or 24-month patient-reported outcomes. Results: Among the study population of 67 patients (median [range] age, 63 [58-67] years; 54 [80.6%] male) with HPV-OPSCC, the most frequent cancer subsites were palatine tonsil (41 [61%]) and base of tongue (26 [39%]); none required adjuvant RT. Global QOL at 24 months improved compared with baseline (mean difference, 9.49; 95% CI, 2.45 to 16.53). All EORTC QLQ-C30 functional scores returned to baseline or improved within 3 to 6 months posttreatment and remained stable at 24 months. EORTC QLQ-HN35 symptom scale scores improved or were stable at 24 months. The MD Anderson Dysphagia Inventory scores demonstrated no significant difference between baseline and month 12 for global scores (mean difference, 6.15; 95% CI, -4.18 to 16.49) and composite scores (mean difference, 2.73; 95% CI, -1.62 to 7.09). Median (range) score on the Decision Regret Scale was 5 of 100 (0-30), representing mild overall regret. Conclusion and Relevance: The findings of this multicenter cohort study indicate that use of the NECTORS protocol is associated with excellent QOL outcomes. QOL measures returned to baseline levels or were better than baseline, which represents positive outcomes for patients with HPV-OPSCC who undergo this treatment regimen.


Assuntos
Carcinoma de Células Escamosas , Transtornos de Deglutição , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Qualidade de Vida , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/tratamento farmacológico , Terapia Neoadjuvante , Estudos de Coortes , Estudos Prospectivos , Neoplasias Orofaríngeas/cirurgia , Neoplasias Orofaríngeas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço
12.
Front Oncol ; 13: 1264646, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37916168

RESUMO

Introduction: In North America and in most European countries, Human Papillomavirus (HPV) is responsible for over 70% of oropharyngeal squamous cell carcinomas. The burden of OPSCC, in high-income countries, has been steadily increasing over the past 20 years. As a result, in the USA and in the UK, the burden of HPV-related oropharyngeal squamous cell carcinoma in men has now surpassed that of cervical cancer in women. However, the oncogenic impact of high-risk HPV integration in oropharyngeal squamous cell carcinomas hasn't been extensively studied. The present study aimed to explore the patterns of HPV integration in oropharyngeal squamous cell carcinomas and to assess the feasibility and reliability of long-read sequencing technology in detecting viral integration events in oropharyngeal head and neck cancers. Methods: A cohort of eight HPV-positive OPSCC pre-treatment patient tumors (four males and four females), were selected. All patients received a p16INK4A positive OPSCC diagnosis and were treated at the McGill University Health Centre, a quaternary center in Montreal. A minimum of 20mg of tumor tissue was used for DNA extraction. Extracted DNA was subjected to Nanopore long-read sequencing to detect and analyze for the presence of high-risk HPV sequences. PCR and Sanger sequencing experiments were performed to confirm Nanopore long-read sequencing readings. Results: Nanopore long-read sequencing showed that seven out of eight patient samples displayed either integrated or episomal high-risk HPV sequences. Out of these seven samples, four displayed verifiable integration events upon bioinformatic analysis. Integration confirmation experiments were designed for all four samples using PCR-based methods. Sanger sequencing was also performed. Four distinct HPV integration patterns were identified: concatemer chromosomal integration in a single chromosome, bi-chromosomal concatemer integration, single chromosome complete integration and bi-chromosomal complete integration. HPV concatemer integration also proved more common than full HPV integration events. Conclusion and relevance: Long-read sequencing technologies can be effectively used to assess HPV integration patterns in OPSCC tumors. Clinically, more research should be conducted on the prognostication value of high-risk HPV integration in OPSCC tumors using long-read sequencing technology.

13.
Mol Ther Methods Clin Dev ; 31: 101142, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38027055

RESUMO

Studies of recombinant adeno-associated virus (rAAV) revealed the mixture of full particles with different densities in rAAV. There are no conclusive results because of the lack of quantitative stoichiometric viral proteins, encapsidated DNA, and particle level analyses. We report the first comprehensive characterization of low- and high-density rAAV serotype 2 particles. Capillary gel electrophoresis showed high-density particles possessing a designed DNA encapsidated in the capsid composed of (VP1 + VP2)/VP3 = 0.27, whereas low-density particles have the same DNA but with a different capsid composition of (VP1 + VP2)/VP3 = 0.31, supported by sedimentation velocity-analytical ultracentrifugation and charge detection-mass spectrometry. In vitro analysis demonstrated that the low-density particles had 8.9% higher transduction efficacy than that of the particles before fractionation. Further, based on our recent findings of VP3 clip, we created rAAV2 single amino acid variants of the transcription start methionine of VP3 (M203V) and VP3 clip (M211V). The rAAV2-M203V variant had homogeneous particles with higher (VP1+VP2)/VP3 values (0.35) and demonstrated 24.7% higher transduction efficacy compared with the wild type. This study successfully provided highly functional rAAV by the extensive fractionation from the mixture of rAAV2 full particles or by the single amino acid replacement.

14.
Cancer ; 129(20): 3263-3274, 2023 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-37401841

RESUMO

BACKGROUND: The objective of this study was to examine the utility of postoperative radiation for low and intermediate grade cancers of the parotid and submandibular glands. METHODS: The authors conducted a retrospective, Canadian-led, international, multi-institutional analysis of a patient cohort with low or intermediate grade salivary gland cancer of the parotid or submandibular gland who were treated from 2010 until 2020 with or without postoperative radiation therapy. A multivariable, marginal Cox proportional hazards regression analysis was performed to quantify the association between locoregional recurrence (LRR) and receipt of postoperative radiation therapy while accounting for patient-level factors and the clustering of patients by institution. RESULTS: In total, 621 patients across 14 tertiary care centers were included in the study; of these, 309 patients (49.8%) received postoperative radiation therapy. Tumor histologies included 182 (29.3%) acinic cell carcinomas, 312 (50.2%) mucoepidermoid carcinomas, and 137 (20.5%) other low or intermediate grade primary salivary gland carcinomas. Kaplan-Meier LRR-free survival at 10 years was 89.0% (95% confidence interval [CI], 84.9%-93.3%). In multivariable Cox regression analysis, postoperative radiation therapy was independently associated with a lower hazard of LRR (adjusted hazard ratio, 0.53; 95% CI, 0.29-0.97). The multivariable model estimated that the marginal probability of LRR within 10 years was 15.4% without radiation and 8.8% with radiation. The number needed to treat was 16 patients (95% CI, 14-18 patients). Radiation therapy had no benefit in patients who had early stage, low-grade salivary gland cancer without evidence of nodal disease and negative margins. CONCLUSIONS: Postoperative radiation therapy may reduce LLR in some low and intermediate grade salivary gland cancers with adverse features, but it had no benefit in patients who had early stage, low-grade salivary gland cancer with negative margins.


Assuntos
Recidiva Local de Neoplasia , Neoplasias das Glândulas Salivares , Humanos , Estudos Retrospectivos , Radioterapia Adjuvante , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/patologia , Canadá/epidemiologia , Neoplasias das Glândulas Salivares/radioterapia , Neoplasias das Glândulas Salivares/cirurgia , Glândulas Salivares/patologia , Estadiamento de Neoplasias
15.
J Affect Disord ; 331: 149-157, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-36948466

RESUMO

OBJECTIVE: The primary purpose of this study was to investigate the contribution of genetic predispositions to depression and inflammation, as measured through polygenic risk scores, on symptom burden (physical and psychological) in patients with head and neck cancer in the immediate post-treatment period (i.e., at three months post-diagnosis), as well as on 3-, 6-, 12-, 24- and 36-month survival. METHODS: Prospective longitudinal study of 223 adults (72 % participation) newly diagnosed with a first occurrence of primary head and neck cancer, paired with genetic data (Illumina PsychArray), validated psychometric measures, Structured Clinical Interviews for DSM Disorders (SCID-I), and medical chart reviews. RESULTS: Symptom burden at 3 months was predicted by (R2 adj. = 0.38, p < 0.001): a baseline SCID-I Anxiety Disorder (b = 1.69, B = 0.23, 95%CI = 0.43-2.94; p = 0.009), baseline levels of HADS anxiety (b = 0.20, B = 0.29, 95%CI = 0.07-0.34; p = 0.003), the polygenic risk score (PRS) for depression (b = 0.66, B = 0.18, 95%CI = 0.003-1.32; p = 0.049), and cumulated dose of radiotherapy (b = 0.002, B = 0.46, 95%CI = 0.001-0.003; p < 0.001). When controlling for factors known to be associated with cancer survival, patients with a higher PRS associated with depression and inflammation, respectively, presented higher risk of death within 36 months (b = 1.75, Exp(B) = 5.75, 95%CI = 1.55-21.27, p = 0.009 and b = 0.14, Exp(B) = 1.15, 95%CI = 1.01-1.30, p = 0.03). CONCLUSIONS: Our results outline three potential pathways of symptom burden in patients with head and neck cancer: a genetic predisposition towards depression; an initial anxiety disorder upon being diagnosed with cancer or high levels of anxiety upon diagnosis; and a dose-related response to radiotherapy. One may want to investigate early interventions in these areas to alleviate symptom burden in patients faced with a life-threatening disease, as well as consider targeting genetic predisposition towards depression and inflammation implicated in survival. The high prevalence of distress in patients with head and neck cancer is an opportunity to study genetic predispositions, which could potentially be broadly generalized to other cancers and diseases.


Assuntos
Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço , Adulto , Humanos , Estudos Longitudinais , Predisposição Genética para Doença/genética , Estudos Prospectivos , Depressão/genética , Depressão/diagnóstico , Ansiedade/genética , Ansiedade/psicologia , Neoplasias de Cabeça e Pescoço/genética , Inflamação/genética
17.
J Otolaryngol Head Neck Surg ; 52(1): 15, 2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36782236

RESUMO

BACKGROUND: The COVID-19 pandemic placed considerable strain on the healthcare system, leading to the re-allocation of resources and implementation of new practice guidelines. The objective of this study is to assess the impact of COVID-19 guideline modifications on head and neck cancer (HNC) care at two tertiary care centers in Canada. METHODS: A retrospective cohort study was conducted. HNC patients seen at two tertiary care centers before and after the onset of the COVID-19 pandemic (pre-pandemic: July 1st, 2019, to February 29th, 2020; pandemic: March 1st, 2020, to October 31st, 2020) were included. The pre-pandemic and pandemic cohorts were compared according to patient and tumor characteristics, duration of HNC workup, and treatment type and duration. Mean differences in cancer care wait times, including time to diagnosis, tumor board, and treatment as well as total treatment package time and postoperative hospital stay were compared between cohorts. Univariate and multivariate analyses were used to compare characteristics and outcomes between cohorts. RESULTS: Pre-pandemic (n = 132) and pandemic (n = 133) patients did not differ significantly in sex, age, habits, or tumor characteristics. The percentage of patients who received surgery only, chemo/radiotherapy (CXRT) only, and surgery plus adjuvant CXRT did not differ significantly between cohorts. Pandemic patients experienced a significant time reduction compared to pre-pandemic patients with regards to the date first seen by a HNC service until start of treatment ([Formula: see text] = 48.7 and 76.6 days respectively; p = .0001), the date first seen by a HNC service until first presentation at tumor board ([Formula: see text] = 25.1 and 38 days respectively; p = .001), mean total package time for patients who received surgery only ([Formula: see text] = 3.7 and 9.0 days respectively; p = .017), and mean total package time for patients who received surgery plus adjuvant CXRT ([Formula: see text] = 80.2 and 112.7 days respectively; p = .035). CONCLUSION: The time to treatment was significantly reduced during the COVID-19 pandemic as compared to pre-pandemic. This transparent model of patient-centered operative-room prioritization can serve as a model for improving resource allocation and efficiency of HNC care during emergency and non-emergency scenarios.


Assuntos
COVID-19 , Neoplasias de Cabeça e Pescoço , Humanos , COVID-19/epidemiologia , Pandemias , SARS-CoV-2 , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/terapia , Assistência ao Paciente
18.
J Otolaryngol Head Neck Surg ; 52(1): 5, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36703217

RESUMO

BACKGROUND: This study aims to develop and validate, a clinically useful modified index of fragility (mIFG) to identify patients at risk of fragility and to predict postoperative adverse events. METHOD: An observational study was performed using the American College of Surgeons National Surgical Quality Improvement Program database, from 2006 to 2018. All patients undergoing nonemergency head and neck cancer surgery were included. A seven-item index (mIFG) was developed using variables associated with frailty, cachexia, and sarcopenia, drawn from the literature (weight loss, low body mass index, dyspnea, diabetes, serum albumin, hematocrit, and creatinine). Multivariable logistic regression was used to model the association between mIFG, postoperative adverse events and death. A validation cohort was then used to ascertain the diagnostic accuracy of the mIFG. RESULTS: A total of 23,438 cases were included (16,407 in the derivation group and 7031 in the validation group). There was a total of 4273 postoperative major adverse events (AE) and deaths, 1023 postoperative pulmonary complications and 1721 wound complications. Using the derivation cohort, the 7-item mIFG was independently associated with death, major AEs, pulmonary and wound complications, when controlling for significant covariates. The mIFG predicted death and major adverse events using the validation cohort with an accuracy of 0.70 (95% CI: 0.63-0.76) and 0.64 (95% CI: 0.63-0.66), respectively. The mIFG outperformed the modified Frailty index. CONCLUSION: The modified index of fragility is a reliable and easily accessible tool to predict risk of postoperative adverse events and death in patients undergoing head and neck cancer surgery.


Assuntos
Fragilidade , Neoplasias de Cabeça e Pescoço , Humanos , Fragilidade/diagnóstico , Fragilidade/complicações , Complicações Pós-Operatórias/etiologia , Modelos Logísticos , Melhoria de Qualidade , Neoplasias de Cabeça e Pescoço/cirurgia , Neoplasias de Cabeça e Pescoço/complicações , Fatores de Risco , Estudos Retrospectivos , Medição de Risco
19.
J Am Soc Mass Spectrom ; 34(1): 36-47, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36488200

RESUMO

Identification of lipopeptides (LpAA) synthesized from bacteria involves the study of structural characterization. Twenty LpAA have been characterized using commercial tandem high-resolution mass spectrometers in negative electrospray, employing nonresonant excitation in "RF only" collision cells and generally behave identically. However, [LpAA-H]- (AA = Asp or Glu) shows surprising fragmentation pathways, yielding a complementary fatty acid carboxylate and dehydrated amino acid fragment anions. In this study, the dissociation mechanisms of [C12Glu-H]- were determinate using energy-resolved mass spectrometry (ERMS). Product ion breakdown profiles are, generally, unimodal with full width at half-maximum (fwhm) increasing as product ion m/z ratios decrease, except for the two product ions of interest (fatty acid carboxylate and dehydrated glutamate) characterized by broad and composite profiles. Such behavior was already shown for other ions using a custom-built guided ion beam mass spectrometer. In this study, we investigate the meaning of these particular profiles from an ERMS breakdown, using fragmentation mechanisms depending on the collision energy. ERMS on line with ion mobility spectrometry (IMS), here called ER-IMS, provides a way to probe such questions. Broad or composite profiles imply that the corresponding product ions may be generated by two (or more) pathways, resulting in common or isomeric product ion structures. ER-IMS analysis indicates that the fatty acid carboxylate product ion is produced with a common structure through different pathways, while dehydrated glutamate has two isomeric forms depending on the mechanism involved. Drift time values correlate with the calculated collision cross section that confirms the product ion structures and fragmentation mechanisms.


Assuntos
Ácido Glutâmico , Espectrometria de Mobilidade Iônica , Íons/química , Espectrometria de Massas/métodos , Isomerismo , Espectrometria de Massas por Ionização por Electrospray/métodos
20.
JACS Au ; 2(9): 2013-2022, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-36186554

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder, and identification of robust biomarkers to complement clinical diagnosis will accelerate treatment options. Here, we demonstrate the use of direct infusion of sebum from skin swabs using paper spray ionization coupled with ion mobility mass spectrometry (PS-IM-MS) to determine the regulation of molecular classes of lipids in sebum that are diagnostic of PD. A PS-IM-MS method for sebum samples that takes 3 min per swab was developed and optimized. The method was applied to skin swabs collected from 150 people and elucidates ∼4200 features from each subject, which were independently analyzed. The data included high molecular weight lipids (>600 Da) that differ significantly in the sebum of people with PD. Putative metabolite annotations of several lipid classes, predominantly triglycerides and larger acyl glycerides, were obtained using accurate mass, tandem mass spectrometry, and collision cross section measurements.

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