Comparative analyses of short- and long-term outcomes between endoscopic submucosal dissection and endoscopic laryngo-pharyngeal surgery for superficial pharyngeal carcinomas.

Objectives: Endoscopic treatment of superficial pharyngeal carcinomas includes endoscopic submucosal dissection (ESD; usually performed by endoscopists), and endoscopic laryngo-pharyngeal surgery (ELPS; primarily performed by otolaryngologists). Few studies have compared the efficacy of the two techniques in treating superficial pharyngeal carcinomas. In this study, we compared the outcomes of these two techniques to determine the advantages. Methods: We retrospectively examined the short- and long-term outcomes of 93 consecutive patients with superficial pharyngeal carcinoma who either underwent an ESD or ELPS between August 2008 and December 2021. Results: There were 35 lesions among 29 patients and 93 lesions among 71 patients in the ESD and ELPS groups, respectively. The ELPS group had a significantly shorter procedure time (121.2 ± 97.4 min vs. 54.7 ± 40.2 min, p<0.01), greater procedure speed (0.10 ± 0.06 min/min vs. 0.30 ± 0.23 min/min, p<0.01), and less laryngeal edema than that of the ESD group. There were no significant differences in the 3-year overall, relapse-free, or disease-specific survival rates between the two groups. Intervention with ESD during ELPS was most commonly required when it was difficult to secure the visual field. Conclusions: There were no differences in batch resection rates or long-term prognoses between the two groups; nevertheless, the ELPS group had a shorter treatment time and less laryngeal edema than the ESD group. However, the treatment of narrow areas, such as the esophageal inlet patch, is a technical limitation of ELPS; thus, ELPS should be combined with ESD techniques.

Enhanced computed tomography radiomics predicts solute carrier family 7, member 11 in head and neck squamous cell carcinoma.

Introduction: Traditional prognostic indicators for head and neck squamous cell carcinoma (HNSCC), such as clinicopathological features, human papillomavirus status, and imaging examinations, often lack precision in guiding medical therapy. Therefore, discovering novel tumor biomarkers that can accurately assess prognosis and aid in personalized medical treatment for HNSCC is critical. Solute carrier family 7, member 11 (SLC7A11), is implicated in ferroptosis, and various malignant tumor therapies regulate its expression. However, the mechanisms regulating SLC7A11 expression, the transporter activity, and its specific role in controlling ferroptosis in cancer cells remain unknown. Thus, in this study, we aimed to develop an improved computed tomography (CT) radiomics model that could predict SLC7A11 expression in patients with HNSCC. Methods: We used patient genomic data and corresponding augmented CT images for prognostic analysis and building models. Further, we investigated the potential molecular mechanisms underlying SLC7A11 expression in the immune microenvironment. Our radiomics model successfully predicted SLC7A11 mRNA expression in HNSCC tissues and elucidated its association with relevant genes and prognostic outcomes. Results: SLC7A11 expression level was high within tumor tissues and was connected to the infiltration of eosinophil, CD8+ T-cell, and macrophages, which was associated with poor overall survival. Our models demonstrated robust predictive power. The distribution of radiomics scores (RAD scores) within the training and validation sets was markedly different between the high- and low-expression groups of SLC7A11. Conclusion: SLC7A11 is likely an important factor in the prognosis of HNSCC. SLC7A11 expression can be predicted effectively and reliably by radiomics models based on enhanced CT.

A bioengineered tumor matrix-based scaffold for the evaluation of melatonin efficacy on head and neck squamous cancer stem cells.

Head and neck squamous cell carcinoma (HNSCC) presents a significant challenge worldwide due to its aggressiveness and high recurrence rates post-treatment, often linked to cancer stem cells (CSCs). Melatonin shows promise as a potent tumor suppressor; however, the effects of melatonin on CSCs remain unclear, and the development of models that closely resemble tumor heterogeneity could help to better understand the effects of this molecule. This study developed a tumor scaffold based on patient fibroblast-derived decellularized extracellular matrix that mimics the HNSCC microenvironment. Our study investigates the antitumoral effects of melatonin within this context. We validated its strong antiproliferative effect on HNSCC CSCs and the reduction of tumor invasion and migration markers, even in a strongly chemoprotective environment, as it is required to increase the minimum doses necessary to impact tumor viability compared to the non-scaffolded tumorspheres culture. Moreover, melatonin exhibited no cytotoxic effects on healthy cells co-cultured in the tumor hydrogel. This scaffold-based platform allows an in vitro study closer to HNSCC tumor reality, including CSCs, stromal component, and a biomimetic matrix, providing a new valuable research tool in precision oncology.

Assessing Long-Term Quality of Life Concerns Through Survivorship Clinic in Head and Neck Cancer Patients.

OBJECTIVE: To characterize the concerns of head and neck cancer (HNC) patients and discern changes in quality-of-life (QoL) during long-term follow-up. STUDY DESIGN: Retrospective review. SETTING: Survivorship clinic at a tertiary academic center. METHODS: A retrospective review was conducted on HNC patients seen in our survivorship clinic between 1/2020 and 1/2024 using the University of Washington Quality of Life (UW-QOL) Questionnaire. RESULTS: Three hundred and forty-two patients were seen for 914 encounters. Patients were divided into 4 groups: pretreatment (n = 326), 0 to 12 months posttreatment (n = 247), 1 to 3 years posttreatment (n = 248), and more than 3 years posttreatment (n = 64). The average follow-up after treatment was 459 days (range: 0-5.2 years). Multivariable analysis revealed significant improvements in overall QoL, health-related QoL, social-emotional composite scores, activity, anxiety, appearance, chewing, mood, pain, speech, and recreation at more than 1-year posttreatment compared to less than 1-year posttreatment. However, declines were noted in saliva and taste scores. No differences in scores were observed between patients 1 to 3 years posttreatment and those >3 years posttreatment. At all timepoints before and after treatment, top concerns were pain, activity, and swallowing. Patients with oral cancer followed for more than 1-year posttreatment had worse scores in appearance, chewing, pain, and speech compared to those with oropharyngeal cancer. CONCLUSIONS: Understanding the evolving concerns of HNC patients is imperative for enhancing care. Most QoL domains improve at 1-year posttreatment except for saliva, taste, swallowing, and shoulder function. QoL scores stabilize after 1-year post-treatment. Pain, activity, and swallowing remain the top concerns at all time points.

A multicentre observational study of paediatric head and neck abscesses.

INTRODUCTION: In winter of 2022/3 paediatric ENT surgeons across the UK observed that the incidence of severe abscesses in the head and neck and associated complications was higher than seen in previous years. We aimed to collate and evaluate data from across the UK to establish if this was a true rise in cases, and to describe the factors associated. METHODS: A multicentre retrospective data collection was undertaken from 13 units across the UK. Patients admitted between September 2022-February 2023 with a head and neck abscess including sinogenic, otogenic, deep and superficial neck abscesses were included. Demographic, disease specific, management and outcome data were collected. Hospital episode statistic data were also requested and analysed to allow for comparison with previous 10 years of head and neck abscesses. RESULTS: 262 patients with abscesses of the head and neck were admitted during the study period, 100 between September and November and 163 between December and February. Mastoid abscesses were the most common abscess across both groups. The rate of group A streptococcus + culture results rose significantly from 12 % in autumn group to 30 % in winter (p = 0.02). The rate of intracranial complications rose from 10 % to 18 % (p = 0.11) and the rate of venous thrombosis rose over the same timeframe from 3 % to 14 % (p = 0.01). DISCUSSION: This study demonstrated a statistically significant rise in the rate of group A streptococcus associated abscesses when comparing Autumn and Winter 2022/2023. Over the same timeframe a statistically significant rise in the proportion of patients with venous thromboses associated with H&N abscesses was noted. Interestingly, despite perceived national consensus regarding a spike in abscess incidence, the number of abscesses seen in winter 2022/2023 was in keeping with expected rates of paediatric H&N abscesses, based on pre covid year-on-year rise in incidence.

Retrospective analysis of treatment-positioning accuracy and dose error in boron neutron capture therapy using a sitting-position treatment system for head and neck cancer.

The neutron beam in boron neutron capture therapy (BNCT) exhibits poor directionality and significantly decreasing neutron flux with increasing distance. Therefore, the treatment site must be close to the irradiation aperture. Some patients with head and neck cancer may benefit from a sitting-position setup. The study aim was to evaluate the treatment-positioning accuracy and dose error in sitting patients receiving BNCT. Thirty-two patients with head and neck cancer who underwent sitting-position BNCT at Southern Tohoku BNCT Research Center were included in the study. Horizontal (ΔX) and vertical (ΔY) errors were defined as the displacement between the treatment planning system (TPS) digital reconstructed radiograph and the pre-treatment X-ray image. Using in-house software, image matching was performed. The beam-axial directional (ΔZ) error was compared with the parameters entered into the TPS and the actual pre-treatment measured values. The translational-position error was reflected in the TPS's patient coordinate system with respect to the reference plan. Re-dose calculations were performed to evaluate the effect of positional error on tumor and normal-tissue doses. The [ΔX, ΔY, ΔZ] DRR-CR mean ± 1SD were - 0.40 ± 2.0, 0.30 ± 2.3, and - 1.4 ± 1.5 mm, respectively. The Dmean and D98% tumor-dose errors were 1.22 % ± 1.44 % and 0.99 % ± 1.63 %, respectively. The D2% pharyngeal and oral mucosal-dose errors were 0.98 % ± 1.91 % and 1.21 % ± 1.78 %, respectively. The tumor- and normal-tissue dose errors were typically < 5 %. High-precision treatment was feasible in sitting-positioned BNCT.

Loss of MACROD2 drives radioresistance but not cisplatin resistance in HPV-positive head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide. In recent years, there has been an increase in the rate of HNSCC cases attributed to the infection of the oropharynx by the human papillomavirus (HPV). Given the significant treatment-related toxicities of the current standard of care for HPV-positive HNSCC, there is an urgent need for the development of precision patient stratification and treatment strategies to improve patients' quality of life while maintaining excellent survival rates. We have previously carried out whole genome sequencing of HPV+ HNSCC tumors that failed concurrent cisplatin and radiation treatment and discovered that MACROD2 deletion is enriched among these tumors. In the current study, we sought to investigate the mechanistic role of MACROD2 in HPV+ HNSCC treatment resistance. Our results indicate that MACROD2 depletion in HNSCC cell lines leads to increased cell viability and colony formation capacity. Interestingly, MACROD2 depletion did not alter cisplatin sensitivity but led to an increase in radiation resistance of HPV+ HNSCC cell lines. RNA sequencing and immunofluorescence microscopy demonstrated that MACROD2-depleted HPV+ HNSCC cells displayed elevated levels of hypoxia and an altered DNA damage response. Taken together, this study establishes and characterizes the role of MACROD2 in HPV+ HNSCC radioresistance. Further work is needed to validate MACROD2 as a biomarker of treatment failure and to understand how to overcome the identified molecular mechanisms of resistance.

Unveiling therapeutic avenues targeting xCT in head and neck cancer.

Head and neck cancer (HNC) remains a major global health burden, prompting the need for innovative therapeutic strategies. This review examines the role of the cystine/glutamate antiporter (xCT) in HNC, specifically focusing on how xCT contributes to cancer progression through mechanisms such as redox imbalance, ferroptosis, and treatment resistance. The central questions addressed include how xCT dysregulation affects tumor biology and the potential for targeting xCT to enhance treatment outcomes. We explore recent developments in xCT-targeted current and emerging therapies, including xCT inhibitors and novel treatment modalities, and their role in addressing therapeutic challenges. This review aims to provide a comprehensive analysis of xCT as a therapeutic target and to outline future directions for research and clinical application.

Head and Neck Paragangliomas: 16-year Single-center Experience and Mini Review on Diagnosis, Treatment, and Follow-up.

Objective: To investigate head and neck paraganglioma cases treated at a tertiary center from 2007 to 2023. The research includes a thorough examination of published studies that have focused on long-term outcomes. The additional goal is to contribute to the existing knowledge on head and neck paraganglioma, with a particular emphasis on refining diagnostic algorithms, treatment selection, and follow-up procedures. Methods: A total of 44 patients were retrospectively analyzed, and 39 were included. Demographic information, symptoms, radiological examination results, types, stages, and postoperative complications were recorded. A review was conducted to select articles that reported single-center experiences with large cohorts, long follow-ups, and different treatment modalities since 2010. Results: The mean age of the patients was 54 years, and the female/male ratio was 3.55:1. Among the 39 cases examined, 18 and 19 were identified as cervical paraganglioma and 19 as temporal bone paraganglioma. All patients initially underwent surgical resection. The mean follow-up duration was 5.42 years. Four residual cases and two recurrences were identified postoperatively, and a Gamma Knife was used as additional treatment. Subsequently, 17 articles were selected and summarized, and then a flowchart was prepared showing the possible options for diagnosis, treatment, and follow-up. Conclusions: Preoperative staging is essential for surgical planning and predicting potential intraoperative complications. Based on our findings and review of the articles, we have prepared a flowchart that includes all possibilities depending on the tumor stage to help in the diagnosis, treatment, and follow-up of head and neck paragangliomas.

Supervised deep learning-based synthetic computed tomography from kilovoltage cone-beam computed tomography images for adaptive radiation therapy in head and neck cancer.

PURPOSE: To generate and investigate a supervised deep learning algorithm for creating synthetic computed tomography (sCT) images from kilovoltage cone-beam computed tomography (kV-CBCT) images for adaptive radiation therapy (ART) in head and neck cancer (HNC). MATERIALS AND METHODS: This study generated the supervised U-Net deep learning model using 3,491 image pairs from planning computed tomography (pCT) and kV-CBCT datasets obtained from 40 HNC patients. The dataset was split into 80% for training and 20% for testing. The evaluation of the sCT images compared to pCT images focused on three aspects: Hounsfield units accuracy, assessed using mean absolute error (MAE) and root mean square error (RMSE); image quality, evaluated using the peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM) between sCT and pCT images; and dosimetric accuracy, encompassing 3D gamma passing rates for dose distribution and percentage dose difference. RESULTS: MAE, RMSE, PSNR, and SSIM showed improvements from their initial values of 53.15 ± 40.09, 153.99 ± 79.78, 47.91 ± 4.98 dB, and 0.97 ± 0.02 to 41.47 ± 30.59, 130.39 ± 78.06, 49.93 ± 6.00 dB, and 0.98 ± 0.02, respectively. Regarding dose evaluation, 3D gamma passing rates for dose distribution within sCT images under 2%/2 mm, 3%/2 mm, and 3%/3 mm criteria, yielded passing rates of 92.1% ± 3.8%, 93.8% ± 3.0%, and 96.9% ± 2.0%, respectively. The sCT images exhibited minor variations in the percentage dose distribution of the investigated target and structure volumes. However, it is worth noting that the sCT images exhibited anatomical variations when compared to the pCT images. CONCLUSION: These findings highlight the potential of the supervised U-Net deep learningmodel in generating kV-CBCT-based sCT images for ART in patients with HNC.

Mild hyperthermia upregulates PD-L1 in the tumor microenvironment and enhances antitumor efficacy of PD-L1 blockade in murine squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) has a low five-year survival rate because of its high rate of recurrence and metastasis. After surgical resection or radiation, the main treatments for HNSCC, patients sometimes experience functional or aesthetic disorders. Therefore, there is a great demand for the development of non-surgical treatment strategies to improve clinical outcomes and patients' quality of life. One such non-surgical treatment is mild hyperthermia (mHT). Many studies have investigated combination treatments with mHT and immune checkpoint inhibitors in preclinical settings. However, there have been no detailed reports on the effects of mHT on immune checkpoint molecules. Here, we investigated the effects of mHT on the tumor microenvironment (TME), particularly on programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1), in SCCVII cells and a squamous cell carcinoma mouse model. First, we found that PD-L1 mRNA levels and surface PD-L1 expression significantly increased after mHT. Second, a single tumor model was used to determine the effect of HT on the TME. mHT enhanced the accumulation of CD4+ and CD8+ T cells, elevated PD-L1 expression in the TME, and decreased the PD-1 positive rate of CD4+ T cells. Finally, using a bilateral tumor model, we found that anti-PD-L1 monotherapy and combination therapy resulted in longer survival than the isotype control or mHT monotherapy. Moreover, the combination therapy resulted in a significantly higher survival rate than anti-PD-L1 monotherapy. In conclusion, our findings elucidate changes in PD-L1 expression in the TME and strengthen the rationale for mHT and PD-L1 blockade combination therapy.

Evaluating the reproducibility and validity of maximal mouth opening measurement techniques.

OBJECTIVES: A limitation of the maximal mouth opening (MMO) is a frequent complication of oral (cancer) surgery. The measurement between the right central incisors is considered the golden standard for assessing MMO, although it has been noted to overestimate MMO in edentulous patients. This study aims to evaluate the reproducibility and validity of four MMO techniques and to determine the extent to which they are dependent on the remaining dentition. MATERIALS AND METHODS: Four methods for capturing the MMO were recorded in consecutive patients with mixed dentition. The degree of agreement between the different measurement methods was compared using Bland-Altman plots. To investigate the reproducibility of each method, intersession, interobserver and intraobserver reliability were calculated for measurements performed by two clinicians across two sessions. Two subgroups were created based on dentition: (A) cases missing at least one right central incisor, and (B) patients with both right central incisors present. RESULTS: All but one intraclass correlation coefficient (ICC) demonstrated excellent reproducibility (ICC > .9). The highest ICC values were found for the intraoral MMO(iMMO) and corrected intraoral MMO(ciMMO) method. A significant relationship between the MMO in both subgroups was identified only for the intraoral Range of Motion (iROM) method (p=.010*). CONCLUSION: The findings suggest that the current golden standard for measuring MMO does not adequately account for the absence of the right central incisor(s). Two of the proposed methods, which include corrections for missing incisors, should be incorporated into future clinical trials on MMO.

Roles of ZEB1 and ZEB2 in E-cadherin expression and cell aggressiveness in head and neck cancer.

Zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in cancer cell differentiation and metastasis, and has been well studied in the field of cancer cell biology. ZEB2 has a highly similar conformation to ZEB1, but its role in head and neck squamous cell carcinoma (HNSCC) cells is not fully understood. Here, we separately overexpressed ZEB1 and ZEB2 in C57BL/6 mouse oral cancer (MOC) cells and investigated their cellular characteristics, including E-cadherin levels, motile properties, chemoresistance, and metastatic ability in immunocompetent mice. Both ZEB1 and ZEB2 overexpression reduced epithelial traits and converted cells to an aggressive phenotype. Surprisingly, ZEB1 overexpression increased the endogenous level of ZEB2 in MOC cells, and vice versa. The molecular mechanisms underlying these findings remain unclear. However, the in vitro anchorage-independent growth of MOC cells overexpressing ZEB2 was considerably greater than that of MOC cells overexpressing ZEB1. These findings suggest that ZEB2, like ZEB1, has the ability to induce the differentiation of cancer cells into those with highly aggressive traits.

One-stage scalp reconstruction using single-layer dermal regeneration template and split-thickness skin graft: a case series.

PURPOSE: Scalp full-thickness defects reconstruction following the resection of skin carcinoma poses significant challenges due to scalp anatomy complexity and limited vascularity. Despite various techniques available, including tissue expansion and local flaps, no single method stands as the gold standard. Moreover, cases requiring adjuvant radiotherapy further complicate reconstruction, demanding durable solutions. This study explores the efficacy of Integra® Dermal Regeneration Template Single Layer (Integra DRTSL) followed by split-thickness skin grafting (STSG) in one-stage scalp reconstruction post oncologic resection. METHODS: A retrospective analysis was conducted on patients undergoing this procedure from January 2020 to October 2023. Surgical outcomes, including graft take rates, complications, and adjuvant therapy tolerability, were assessed. RESULTS: Results demonstrated successful reconstruction in the majority of cases, with a complete graft take rate of 77% and minimal complications. Notably, the single-stage approach facilitated timely initiation of adjuvant therapy, crucial for oncologic management. Healing times were notably reduced (< 60 days), enabling early radiotherapy commencement. No local recurrences were observed during the 16-month follow-up. CONCLUSION: The use of Integra DRTSL with STSG in one-stage reconstruction presents a promising alternative, offering optimal cosmetic and functional outcomes with low complication rates. This approach streamlines the reconstruction process, ensuring timely adjuvant therapy initiation and maximizing patient outcomes, especially in the context of scalp cutaneous tumors requiring radiotherapy. CLINICAL TRIAL NUMBER: This research was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University of Campania "Luigi Vanvitelli" (protocol code N. 0013333, 29 April 2021).

Development of a Preclinical Double Model of Mandibular Irradiated Bone and Osteoradionecrosis in New Zealand Rabbits.

PURPOSE: Radiotherapy (RT) plays a crucial role in head and neck (HN) cancer treatment. Nevertheless, it can lead to serious and challenging adverse events such as osteoradionecrosis (ORN). A preclinical rabbit model of irradiated bone and ORN is herein proposed, with the aim to develop a viable model to be exploited for investigating new therapeutic approaches. METHODS: Nine New Zealand white rabbits were irradiated using a single beam positioned to the left of the mandible and directed perpendicular to the left mandible. A 10 × 10 mm2 region of interest (ROI) located below the first molar tooth on the left side was identified and irradiated with 7 Gy each fraction, once every 2 days, for five fractions. Dose distributions demonstrated that the corresponding ROI on the contralateral (right) mandibular side received approximately 5 Gy each fraction, thus bilateral irradiation of the mandible was achieved. ROIs were categorized as ROIH on the left side receiving the high dose and ROIL on the right side receiving the low dose. Rabbits were followed up clinically and imaged monthly. After 4 months, the irradiated bone was excised, and histological examination of ROIs was performed. RESULTS: Radiological signs suggestive for ORN were detected in the entire population (100%) 16 weeks after irradiation on ROIH, which consisted of cortical erosion and loss of trabeculae. ROIL did not show any radiological evidence of bone damage. Histologically, both sides showed comparable signs of injury, with marked reduction in osteocyte count and increase in empty lacunae count. CONCLUSIONS: A preclinical double model was successfully developed. The side receiving the higher dose showed radiological and histological signs of bone damage, resulting in an ORN model. Whereas the contralateral side, receiving the lower dose, presented with histological damage only and a normal radiological appearance. This work describes the creation of a double model, an ORN and irradiated bone model, for further study using this animal species.

Keratin-based topical cream for radiation dermatitis during head and neck radiotherapy: a randomised, open-label pilot study.

Introduction: Radiation dermatitis (RD) is a frequent toxicity during radiotherapy (RT) for head and neck cancer (HNC). We report the first use of KeraStat® Cream (KC), a topical, keratin-based wound dressing, in patients with HNC receiving RT. Methods: This pilot study randomized HNC patients treated with definitive or postoperative RT (≥60 Gy) to KC or standard of care (SOC), applied at least twice daily during and for 1-month after RT. Outcomes of interest included adherence to the assigned regimen (at least 10 applications per week of treatment), clinician- and patient-reported RD, and skin-related quality of life. Results: 24 patients were randomized and completed the study. Most patients had stage III-IV disease and oropharynx cancer. Median RT dose was 68 Gy; the bilateral neck was treated in 19 patients, and 18 patients received concurrent chemotherapy. Complete adherence was observed in 7/12 (SOC) vs. 10/12 (KC, p = 0.65). Adherence by patient-week was 61/68 versus 64/67, respectively (p = 0.20). No differences in RD were observed between groups. Conclusion: A randomized trial of KC versus SOC in HNC patients treated with RT is feasible with good adherence to study agent. An adequately powered randomized study is warranted to test the efficacy of KC in reducing RD.

Epithelioid sarcoma of the pretragus: a rare pediatric entity with an unusual site.

Epithelioid sarcoma (ES) is a rare soft tissue tumor that is commonly misdiagnosed. It is a mesenchymal tumor that shows both mesenchymal and epithelial features. It tends to occur in the distal upper extremity in children and young adults but may appear in any location and any age group. Less than 1% of ES involve the head and neck. Clinically, the tumor can be mistakenly confused with a benign lesion as it can mimic nonspecific ulcers or infected warts. Histologically, ES is characterized by a nodular architecture and epithelioid appearance of cells centered with necrosis, mimicking a granulomatous process. We present the clinical history of a 12-year-old male who presented with an ES of the pretragus with a brief review of the literature to raise awareness on this rare entity and to discuss the challenges in managing histopathological differential diagnosis in front of this unusual clinical presentation.

Delay in the Diagnosis of Patients With Head and Neck Cancer: Impact of Different Patient- and Healthcare Provider-Related Factors.

Background In our setup, head and neck cancer (HNC) is the most common, and patients frequently present at an advanced stage, which results in dismal outcomes. Delays on the part of the patient (such as resistance to seeking treatment) or the provider (such as misdiagnosis or an extended wait period for consultation) may be the cause of a late presentation. The presentation stage may vary depending on several factors, including age, gender, smoking status, job status, and education. Objectives The study aims to identify factors that lead to advanced-stage presentations of HNCs and to determine the delays brought on by patient- or healthcare provider-related factors and how these factors affect HNC disease staging among biopsy-proven HNC patients. Materials and methods Participants in the study were those who initially presented with a biopsy-verified HNC at the cancer clinic of the department of otolaryngology-head and neck surgery at Pakistan Institute of Medical Sciences (PIMS), Islamabad. Patients answered questions on their first symptom presentation, past healthcare professional visits, and intervals between visits on a Cancer Symptom Interval Measure (C-SIM) questionnaire. For every patient, clinical and demographic information was gathered. TNM staging was completed. The test of significance was applied where applicable. Results Age, gender, education level, and smoking status had no bearing on the presentation stage. Patients without jobs present at a statistically significant higher stage (p = 0.038). The most prevalent histological form of HNC was squamous cell carcinoma 79 (82.29%), with the oral cavity and larynx being the most common sites of the disease 30 (31.25%) and 29 (30.21%) respectively. Patients took an average of 5.28 ± 9.12 months from the onset of symptoms to their first appointment with a healthcare provider. Prior to diagnosis, the majority of patients saw three or more healthcare providers (range: 1-8). The duration from the initial visit to a healthcare provider to the initiation of treatment was 3.06 ± 5.88 months. Based on the stage at presentation, there were no discernible variations in the times to presentation (p>0.05). Conclusion Significant delays and high stage of presentation are caused by unemployment. The majority of the delay was caused by the patient's tardiness in seeing a medical practitioner, yet the presentation stage was not greatly impacted by this delay.

Cancer cell-specific PD-L1 expression is a predictor of poor outcome in patients with locally advanced oral cavity squamous cell carcinoma.

BACKGROUND: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment. METHODS: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1hi or PD-L1lo cancer cells in these tumors. RESULTS: Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1hi tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8+ T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1lo locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage. CONCLUSION: Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1hi locally advanced OCSCC.

Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses.

BACKGROUND: Antibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity. METHODS: This study examined the therapeutic efficacy and potential mechanisms of a bispecific ADC (BsADC) in laryngeal squamous cell carcinoma. This BsADC selectively targets the immune checkpoints programmed cell death ligand-1 (PD-L1) and B7-H3, and the precise delivery of the small-molecule toxin monomethyl auristatin E. RESULTS: Our findings demonstrated that the BsADC outperformed its bispecific antibody and PD-L1 or B7-H3 ADC counterparts, particularly in terms of in vitro/in vivo tumor cytotoxicity, demonstrating remarkable immune cytotoxicity. Additionally, we observed potent activation of tumor-specific immunity and significant induction of markers of immunogenic cell death (ICD) and potential endoplasmic reticulum stress. CONCLUSION: In conclusion, this novel BsADC, through immune checkpoint inhibition and promotion of ICD, amplified durable tumor immune cytotoxicity, providing novel insights and potential avenues for future cancer treatments and overcoming resistance.