Slide tracheoplasty for congenital tracheal stenosis: A systematic review.

INTRODUCTION: Slide tracheoplasty has become the gold standard surgery for congenital tracheal stenosis (CTS). This condition is rare and the surgery can be challenging and is performed by experienced surgeons in tertiary centers. A few reports involving relatively small cohorts have been published. The aim of this review is to evaluate the post-operative mortality and morbidity of pediatric slide tracheoplasty for CTS. METHODS: A systematic literature review was performed according to PRISMA guidelines. The Medline and EMBASE databases were screened using a search strategy defined in collaboration with a librarian. We included articles reporting the post-operative mortality rate of slide tracheoplasties for treatment of CTS in children, when at least 10 patients were included. RESULTS: A total of 932 articles were reviewed, and 15 studies were eligible with a total of 845 patients. The overall post-operative mortality rate was 9.3 %, and most deaths were airway related. The open revision surgery rate after surgery was 2.8 % and the endoscopic revision rate was 27.6 %. DISCUSSION: This study highlights key factors to consider before the surgery and helps anticipate post-operative follow-up considerations for children with CTS. Several factors were identified as predictors of mortality including young age, weight at the time of surgery and association with lung hypoplasia or aplasia. CONCLUSION: Although slide tracheoplasty has gained popularity in recent years due to better outcomes, it remains a major surgery with mortality risk and the need for multidisciplinary management.

Application of the galactomannan gel from Cassia grandis seeds for biomedical purposes: Study of the incorporation of collagenases and their release profile.

The galactomannan-based gel from Cassia grandis seeds was used to incorporate Penicillium sp. UCP 1286 and commercial collagenases. Experiments were carried out according to a 23-full factorial design to identify the most significant parameters for the incorporation process. The pH of the incorporation solution (pHi), stirring time (t), and initial protein concentration in the crude extract (PCi) were selected as the three independent variables, and the efficiency of collagenase incorporation (E) and collagenolytic activity (CA) after 360 min as the responses. pHi and PCi showed positive statistically significant effects on E, while CA was positively influenced by pHi and t, but negatively by PCi. The fungi collagenase was released from the gel following a pseudo-Fickian behavior. Additionally, no <76 % of collagenase was efficiently incorporated into the gel retaining a high CA (32.5-69.8 U/mL). The obtained results for the commercial collagenase (E = 93.88 %, CA = 65.8 U/mL, and n = 0.10) demonstrated a pseudo-Fickian behavior similar to the fungi-collagenase. The results confirm the biotechnological potential of the gel as an efficient matrix for the incorporation of catalytic compounds; additionally, the incorporation of collagenases was achieved by retaining the proteases CA and releasing them in a controlled manner.

Rethinking treatment paradigms: Neoadjuvant therapy and de-escalation strategies in HPV-positive head and neck cancer.

Head and neck cancer (HNC) is the 6th most common cancer across the world, with a particular increase in HNC associated with human papilloma virus (HPV) among younger populations. Historically, the standard treatment for this disease consisted of combined surgery and radiotherapy or curative platinum-based concurrent chemoradiotherapy, with associated long term and late toxicities. However, HPV-positive HNC is recognized as a unique cancer subtype, typically with improved clinical outcomes. As such, treatment de-escalation strategies have been widely researched to mitigate the adverse effects associated with the current standard of care without compromising efficacy. These strategies include treatment de-escalation, such as novel surgical techniques, alternative radiation technologies, radiation dose and volume reduction, as well as neoadjuvant chemotherapies, immunotherapies, and combined therapies. Although these therapies show great promise, many of them are still under investigation due to hesitation surrounding their widespread implementation. The objective of this review is to summarize the most recent progress in de-escalation strategies and neoadjuvant therapies designed for HPV-positive HNC. While specific treatments may require additional research before being widely adopted, encouraging results from recent studies have highlighted the advantages of neoadjuvant chemotherapy and immunotherapy, as well as radiation and surgical de-escalation approaches in managing HPV-positive HNC.

Onabotulinum Toxin A (BoNT-A) for Drooling in Children: A Systematic Review and Meta-Analysis.

INTRODUCTION: Sialorrhea, also known as drooling, hypersalivation, or ptyalism, has a significant impact on the medical and psychosocial well-being of children. Onabotulinum toxin A (BoNT-A) is the most commonly used botulinum toxin worldwide for the treatment of sialorrhea in children. OBJECTIVES: To conduct a comprehensive systematic review and meta-analysis to assess the clinical efficacy and potential adverse effects of BoNT-A as a treatment for drooling in children. METHODS: Cochrane, Embase, and Medline databases were systematically searched (up to May 2023). Out of 535 identified publications, 20 were found eligible for inclusion. A systematic review and meta-analysis were performed to determine the efficacy of BoNT-A treatment in children in reducing the frequency and severity of drooling. RESULTS: Out of the 20 studies included, a meta-analysis was conducted on the complete dataset of eight studies involving 131 patients. BoNT-A was found to significantly decrease the severity of drooling in patients with sialorrhea (standardized mean difference [SMD], -2.07; 95% confidence interval [CI], -2.91 to -1.23; p < 0.0001) when compared with the conditions before injections using random-effects models. Six studies out of 20 reported dysphagia as an adverse effect after injection. Other side effects included thickness of saliva and pain at the site of injection. CONCLUSION: BoNT-A is a clinically effective therapy that improves drooling severity in children with sialorrhea. Although there were some adverse side effects reported, they were transient and not severe. Future studies are needed to further evaluate the best techniques and to identify the ideal dosages required to achieve the optimal outcomes. Laryngoscope, 134:3012-3017, 2024.

Emerging histopathological parameters in the prognosis of oral squamous cell carcinomas.

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy, representing 90% of all malignant neoplasms in the head and neck region. Patients with this aggressive tumor have an overall 5-year survival rate of approximately 50%, which drops to less than 30% when tumors are diagnosed at advanced clinical stages. Over decades, several studies provided high-level evidence of the impact of histopathological features on treatment guidelines and prognosis of OSCC. The 8th American Joint Committee on Cancer (AJCC) TNM staging system recognized the importance of depth of invasion to the T category and extranodal extension to the N category for OSCC. This review provides the current knowledge on emerging histopathological parameters identified as potential biomarkers for OSCC, such as depth of invasion, tumor thickness, the pattern of invasion, inflammatory profile, and tumor-stroma ratio, evaluating their clinical relevance on patient outcomes. Analysis, limitations, and potential biological mechanisms are highlighted and discussed. Assessing and reporting these markers are cost-effective and can be incorporated into daily practice.

Evidence-Based Checklist to Delay Cardiac Arrest in Brain-Dead Potential Organ Donors: The DONORS Cluster Randomized Clinical Trial.

Importance: The effectiveness of goal-directed care to reduce loss of brain-dead potential donors to cardiac arrest is unclear. Objective: To evaluate the effectiveness of an evidence-based, goal-directed checklist in the clinical management of brain-dead potential donors in the intensive care unit (ICU). Design, Setting, and Participants: The Donation Network to Optimize Organ Recovery Study (DONORS) was an open-label, parallel-group cluster randomized clinical trial in Brazil. Enrollment and follow-up were conducted from June 20, 2017, to November 30, 2019. Hospital ICUs that reported 10 or more brain deaths in the previous 2 years were included. Consecutive brain-dead potential donors in the ICU aged 14 to 90 years with a condition consistent with brain death after the first clinical examination were enrolled. Participants were randomized to either the intervention group or the control group. The intention-to-treat data analysis was conducted from June 15 to August 30, 2020. Interventions: Hospital staff in the intervention group were instructed to administer to brain-dead potential donors in the intervention group an evidence-based checklist with 13 clinical goals and 14 corresponding actions to guide care, every 6 hours, from study enrollment to organ retrieval. The control group provided or received usual care. Main Outcomes and Measures: The primary outcome was loss of brain-dead potential donors to cardiac arrest at the individual level. A prespecified sensitivity analysis assessed the effect of adherence to the checklist in the intervention group. Results: Among the 1771 brain-dead potential donors screened in 63 hospitals, 1535 were included. These patients included 673 males (59.2%) and had a median (IQR) age of 51 (36.3-62.0) years. The main cause of brain injury was stroke (877 [57.1%]), followed by trauma (485 [31.6%]). Of the 63 hospitals, 31 (49.2%) were assigned to the intervention group (743 [48.4%] brain-dead potential donors) and 32 (50.8%) to the control group (792 [51.6%] brain-dead potential donors). Seventy potential donors (9.4%) at intervention hospitals and 117 (14.8%) at control hospitals met the primary outcome (risk ratio [RR], 0.70; 95% CI, 0.46-1.08; P = .11). The primary outcome rate was lower in those with adherence higher than 79.0% than in the control group (5.3% vs 14.8%; RR, 0.41; 95% CI, 0.22-0.78; P = .006). Conclusions and Relevance: This cluster randomized clinical trial was inconclusive in determining whether the overall use of an evidence-based, goal-directed checklist reduced brain-dead potential donor loss to cardiac arrest. The findings suggest that use of such a checklist has limited effectiveness without adherence to the actions recommended in this checklist. Trial Registration: ClinicalTrials.gov Identifier: NCT03179020.

The presence of depressive symptoms and cognitive performance among older individuals with and without self-reported chronic diseases.

Dementias secondary to cardiovascular diseases are the second cause of neurogenerative diseases. These conditions can be prevented by controlling risk factors, and it is necessary to observe the relationship between chronic diseases. Objective: to know the influence of chronic non-communicable diseases on cognition and depressive symptoms in the elderly, amid the COVID-19 pandemic. Methods: 578 older adults were evaluated using a sociodemographic questionnaire, the Brazilian Telephone version of the Mini Mental State Examination (Braztel-MMSE), the Geriatric Depression Scale (GDS-15) and an open questionnaire related to NCDs. Results: the association of Non-Communicable Diseases (NCD) with age, depressive symptoms and schooling was confirmed. Conclusion: no association with cognitive decline was evident due to the relationship of high schooling of participants and control of NCDs.

As demências secundárias às doenças cardiovasculares são a segunda causa de doenças neurodegenerativas. Essas condições podem ser prevenidas pelo controle de fatores de risco, sendo necessário observar a relação entre doenças crônicas. Objetivo: Conhecer a influência das doenças crônicas não transmissíveis (DCNT) na cognição e nos sintomas depressivos em pessoas idosas, em meio à pandemia da COVID-19. Métodos: Foram avaliados 578 idosos utilizando um questionário sociodemográfico, o Brazilian telephone version of the Mini Mental State Examination (Braztel-MMSE), a Escala de Depressão Geriátrica (GDS-15) e um questionário aberto relacionado às DCNT. Resultados: Foi confirmada a associação das DCNT crônicas com idade, sintomas depressivos e escolaridade. Conclusão: Nenhuma associação com declínio cognitivo foi evidente em razão da relação da alta escolaridade dos participantes com o controle das DCNT.

The Difference in Clinical Behavior of Gene Fusions Involving RET/PTC Fusions and THADA/IGF2BP3 Fusions in Thyroid Nodules.

BACKGROUND: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions, RET/PTC and THADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. METHODS: We performed a retrospective, single-centered study at a McGill University teaching hospital in Montreal, Canada, from January 2016 to August 2021. We included patients who underwent surgery for thyroid nodules that pre-operatively underwent molecular testing showing either RET/PTC or THADA/IGF2BP3 gene fusion. RESULTS: This study included 697 consecutive operated thyroid nodules assessed using molecular testing, of which five had the RET/PTC fusion and seven had the THADA/IGF2BP3 fusion. Of the five nodules in the RET/PTC group, 100% were malignant and presented as Bethesda V/VI. Eighty percent (4/5) were found to have lymph node metastasis. Twenty percent (1/5) had extrathyroidal extensions. Sixty percent (3/5) were a diffuse sclerosing variant of papillary thyroid carcinoma, and the rest were the classical variant. Of the seven THADA/IGF2BP3 nodules, all presented as Bethesda III/IV and 71.4% (5/7) were malignant based on the final pathology analysis, and 28.6% (2/7) were NIFTP. All the THADA/IGF2BP3 fusion malignancies were a follicular variant of papillary thyroid carcinoma. None had lymph node metastasis or displayed extrathyroidal extensions. CONCLUSIONS: RET/PTC nodules presented as Bethesda V/VI and potentially had more aggressive features, whereas THADA/IGF2BP3 nodules presented as Bethesda III/IV and had more indolent behavior. This understanding may allow clinicians to develop more targeted treatment plans, such as the extent of surgery and adjuvant radioactive iodine treatment.

Overexpression of heat-shock protein 47 impacts survival of patients with oral squamous cell carcinoma.

BACKGROUND: The expression of heat-shock protein 47 (HSP47) has been linked to collagen synthesis control and implicated in fibrotic disorders, but more recent studies have demonstrated its role in solid tumors. In this study, we explored the prognostic impact of HSP47 in oral squamous cell carcinomas (OSCC) and determined the in vitro effects of its loss-of-function on viability, proliferation, migration, invasion, and resistance to cisplatin of OSCC cells. METHODS: The HSP47 expression in tumor samples was assessed by immunohistochemistry in two independent cohorts totaling 339 patients with OSCC, and protein levels were associated with clinicopathological features and survival outcomes. The OSCC cell lines HSC3 and SCC9 were transduced with lentivirus expressing short hairpin RNA to stably silence HSP47 and used in assays to measure cellular viability, proliferation, migration, and invasion. RESULTS: HSP47 was overexpressed in OSCC samples, and its overexpression was significantly and independently associated with poor disease-specific survival and shortened disease-free survival in both OSCC cohorts. The knockdown of HSP47 showed no effects on cell viability or cisplatin sensitivity, but impaired significantly proliferation, migration, and invasion of OSCC cells, with stronger effects on SCC9 cells. CONCLUSION: Our results show a significant prognostic impact of HSP47 overexpression in OSCC and reveal that HSP47 inhibition impairs the proliferation, migration, and invasion of OSCC cells. HSP47 may represent a potential therapeutic target for OSCC.

Characteristics of PTEN Mutation in Thyroid Tumours: A Retrospective Chart Review.

While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies are aggressive. This multicenter study involved 316 patients who underwent preoperative molecular testing, and subsequent lobectomy or total thyroidectomy at two quaternary care hospitals. A four-year retrospective review was performed on the 16 charts of patients that opted for surgery following a positive PTEN mutation on molecular testing results from January 2018 to December 2021. Of the total 16 patients, 37.5% (n = 6) had malignant tumours, 18.75% (n = 3) had non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), and 43.75% (n = 7) had benign disease. Aggressive features were detected in 33.33% of the malignant tumours. Malignant tumours were found to have a statistically significant higher allele frequency (AF). The aggressive nodules were all poorly differentiated thyroid carcinomas (PDTCs) with copy number alterations (CNAs) and the highest AFs.

E-liquid alters oral epithelial cell function to promote epithelial to mesenchymal transition and invasiveness in preclinical oral squamous cell carcinoma.

The gaining popularity of tobacco and nicotine delivery products, such as electronic cigarettes (e-cigarettes) being perceived as relatively safe is of a medical concern. The long-term safety of these new products remains uncertain for oral health. In this study, in vitro effects of e-liquid were assessed in a panel of normal oral epithelium cell lines (NOE and HMK), oral squamous cell carcinoma (OSCC) human cell lines (CAL27 and HSC3), and a mouse oral cancer cell line (AT84) using cell proliferation, survival/cell death, and cell invasion assays. In addition, signaling pathways underlying the pro-invasive activity of e-cigarettes were evaluated by gene and protein expression analysis. We demonstrated that e-liquid promotes proliferation and anchorage-independent growth of OSCC and induces morphological changes associated with enhanced motility and invasive phenotypes. Furthermore, e-liquid-exposed cells express significantly reduced cell viability, regardless of e-cigarette flavour content. At the gene expression level, e-liquid induces changes in gene expression consistent with epithelial to mesenchymal transition (EMT) revealed by reduced expression of cell epithelial markers such as E-cadherin and enhanced expression of mesenchymal proteins like vimentin and B-catenin seen both in OSCC cell lines and normal oral epithelium cells. In summary, the ability of e-liquid to induce proliferative and invasive properties along the activation of the EMT process can contribute to the development of tumorigenesis in normal epithelial cells and promote aggressive phenotype in pre-existing oral malignant cells.

Association between acute disease severity and one-year quality of life among post-hospitalisation COVID-19 patients: Coalition VII prospective cohort study.

PURPOSE: To assess the association between acute disease severity and 1-year quality of life in patients discharged after hospitalisation due to coronavirus disease 2019 (COVID-19). METHODS: We conducted a prospective cohort study nested in 5 randomised clinical trials between March 2020 and March 2022 at 84 sites in Brazil. Adult post-hospitalisation COVID-19 patients were followed for 1 year. The primary outcome was the utility score of EuroQol five-dimension three-level (EQ-5D-3L). Secondary outcomes included all-cause mortality, major cardiovascular events, and new disabilities in instrumental activities of daily living. Adjusted generalised estimating equations were used to assess the association between outcomes and acute disease severity according to the highest level on a modified ordinal scale during hospital stay (2: no oxygen therapy; 3: oxygen by mask or nasal prongs; 4: high-flow nasal cannula oxygen therapy or non-invasive ventilation; 5: mechanical ventilation). RESULTS: 1508 COVID-19 survivors were enrolled. Primary outcome data were available for 1156 participants. At 1 year, compared with severity score 2, severity score 5 was associated with lower EQ-5D-3L utility scores (0.7 vs 0.84; adjusted difference, - 0.1 [95% CI - 0.15 to - 0.06]); and worse results for all-cause mortality (7.9% vs 1.2%; adjusted difference, 7.1% [95% CI 2.5%-11.8%]), major cardiovascular events (5.6% vs 2.3%; adjusted difference, 2.6% [95% CI 0.6%-4.6%]), and new disabilities (40.4% vs 23.5%; adjusted difference, 15.5% [95% CI 8.5%-22.5]). Severity scores 3 and 4 did not differ consistently from score 2. CONCLUSIONS: COVID-19 patients who needed mechanical ventilation during hospitalisation have lower 1-year quality of life than COVID-19 patients who did not need mechanical ventilation during hospitalisation.

The Impact of BRAF V600E Mutation Allele Frequency on the Histopathological Characteristics of Thyroid Cancer.

BACKGROUND: A BRAF V600E mutation in papillary thyroid cancer (PTC) has been shown to be associated with aggressive behavior. Nevertheless, not all BRAF V600E PTCs behave aggressively. Allele frequency (AF) is the number of mutated molecules divided by the total number of wild-type molecules at a specific location in the genome. The relationship between BRAF V600E AF and the histopathological features of thyroid malignancies is not well understood. We hypothesized that the BRAF V600E AF will correlate directly with aggressive histopathological behavior. The aim of this study was to examine this relationship. METHODS: A retrospective chart review was performed for patients treated for BRAF V600E thyroid malignancies from 2019 to 2022 at McGill University tertiary care hospitals (n = 317). Patients with BRAF V600E-positive malignancies that included information on AF were included (n = 44). The correlation between AF and tumor histopathological features was analyzed. RESULTS: Out of the 44 nodules with a BRAF V600E mutation, those with aggressive features of PTC had a mean AF of 25.8%, which was significantly higher than the non-aggressive group with a mean AF of 10.25% (p = 0.020). Additionally, there was a statistically significant difference in mean AF between patients with a positive sentinel LN (29%) and those with a negative sentinel LN (17.8%) (p = 0.021). Classical PTC was present in 29.5% (13/44) of nodules, with a mean AF of 15.6%. The tall cell subtype was found in 64% (28/44) of nodules, with a mean AF of 23%. Solid and hobnail subtypes were less common in this study, and there was no statistically significant relationship between AF and histopathological subtypes (p = 0.107). Nodules smaller than 1cm had a mean AF of 13.3%, while nodules ranging from 1 2cm had a mean AF of 20.6%, and those larger than 2cm had a mean AF of 27.7%. However, no statistical difference was observed between AF and nodule size (p = 0.160). CONCLUSION: In this study, BRAF V600E mutations in conjunction with AF help to determine whether thyroid malignancies will display aggressive behavior. This pre-operative finding can help thyroid specialists to determine the extent of thyroidectomy and whether lymph node dissection is required.

Genetic Mutations Associated with Inflammatory Response Caused by HPV Integration in Oropharyngeal Squamous Cell Carcinoma.

(1) Background: Head and neck cancer (HNC) ranks as the sixth most prevalent cancer in the world. In addition to the traditional risk factors such as alcohol and tobacco consumption, the implication of the human papillomavirus (HPV) is becoming increasingly significant, particularly in oropharyngeal cancer (OPC). (2) Methods: This study is based on a review analysis of different articles and repositories investigating the mutation profile of HPV-related OPC and its impact on patient outcomes. (3) Results: By compiling data from 38 datasets involving 8311 patients from 12 countries, we identified 330 genes that were further analyzed. These genes were enriched for regulation of the inflammatory response (RB1, JAK2, FANCA, CYLD, SYK, ABCC1, SYK, BCL6, CEBPA, SRC, BAP1, FOXP1, FGR, BCR, LRRK2, RICTOR, IGF1, and ATM), among other biological processes. Hierarchical cluster analysis showed the most relevant biological processes were linked with the regulation of mast cell cytokine production, neutrophil activation and degranulation, and leukocyte activation (FDR < 0.001; p-value < 0.05), suggesting that neutrophils may be involved in the development and progression of HPV-related OPC. (4) Conclusions: The neutrophil infiltration and HPV status emerge as a potential prognostic factor for OPC. HPV-infected HNC cells could potentially lead to a decrease in neutrophil infiltration. By gaining a better molecular understanding of HPV-mediated neutrophil immunosuppression activity, it is possible to identify a meaningful target to boost antitumor immune response in HNC and hence to improve the survival of patients with HNC.

Prognostic Indicators of EIF1AX-Mutated Thyroid Tumor Malignancy and Cancer Aggressiveness.

The risk of malignancy (ROM) of EIF1AX-mutated thyroid nodules has been theorized to be contingent on the position of the mutation within the gene and the presence of co-existing mutations. However, due to EIF1AX's low mutation frequency, sample sizes currently reported in the literature are too diminutive to appraise the clinical utility of molecular diagnostic testing. The objective of this study was to elucidate prognostic indicators of EIF1AX-mutated thyroid tumors and cancer aggressiveness by examining a large cohort of cytologically indeterminate thyroid nodules (CITNs) that underwent molecular testing and subsequent surgical resection. This is a multicenter study involving 764 subtotal and total thyroidectomy patients that underwent preoperative molecular testing at two quaternary care hospitals. A five-year retrospective review was performed on the 42 charts of patients that opted for surgery following a positive EIF1AX mutation on ThyroseqV3 results from January 2018 to May 2022. Patient demographics, cytopathology results, molecular testing results, and postoperative histopathology were reviewed. Of the 42 surgically resected nodules that harbored an EIF1AX mutation, 16 (38.1%) were benign, six (14.3%) were non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) or well-differentiated thyroid neoplasms of uncertain malignant potential (WDT-UMPs), and 20 (47.6%) were malignant. An isolated EIF1AX mutation conferred a ROM of 47.6%, whereas the ROM for nodules with at least one additional molecular alteration was 72.7%. The ROM increased to 100% for nodules with at least one additional molecular alteration and the A113_splice site mutation. Six malignant nodules were aggressive, with five having variegated components of poorly differentiated thyroid carcinoma (PDTC). EIF1AX-mutated thyroid nodules are more susceptible to malignancy in the presence of the A113_splice site mutation and when co-mutated with RAS and/or TP53. This deleterious amalgam is associated with aggressive disease and renders these nodules PDTC. A preoperative molecular test finding of an EIF1AX mutation can be a useful tool for thyroid specialists to optimize clinical management.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification.

BACKGROUND: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients. METHODS: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. FINDINGS: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation. INTERPRETATION: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned. FUNDING: CIHR, European Union, and the NIH.

Implications and Emerging Therapeutic Avenues of Inflammatory Response in HPV+ Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC.

Therapeutic Vaccines for HPV-Associated Oropharyngeal and Cervical Cancer: The Next De-Intensification Strategy?

The rise in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has prompted a quest for further understanding of the role of high-risk HPV in tumor initiation and progression. Patients with HPV-positive OPSCC (HPV+ OPSCC) have better prognoses than their HPV-negative counterparts; however, current therapeutic strategies for HPV+ OPSCC are overly aggressive and leave patients with life-long sequalae and poor quality of life. This highlights a need for customized treatment. Several clinical trials of treatment de-intensification to reduce acute and late toxicity without compromising efficacy have been conducted. This article reviews the differences and similarities in the pathogenesis and progression of HPV-related OPSCC compared to cervical cancer, with emphasis on the role of prophylactic and therapeutic vaccines as a potential de-intensification treatment strategy. Overall, the future development of novel and effective therapeutic agents for HPV-associated head and neck tumors promises to meet the challenges posed by this growing epidemic.