Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.

Factors influencing comfort level in head and neck neoplasm patients receiving radiotherapy

Objective:To determine factors that influence comfort in head and neck neoplasm patients receiving radiotherapy.Methods:In total,200 head and neck neoplasm patients receiving radiotherapy were recruited from three tertiary first class hospitals.They were assessed by Radiotherapy Comfort Questionnaire for patients with head and neck neoplasm,Social Support Scale,and Medical Coping Modes Questionnaire.Results:The total score of comfort was 60.54±8.32.Multiple linear regression analysis indicated that number of radiation treatments,family accompaniment,educational level,resignation coping mode,complications due to diabetes,accompanying chemotherapy,and the utilization of social support significantly influenced comfort level(p<0.05).Among these,number of radiation treatments,complications due to diabetes,accompanying chemotherapy,and resignation coping were negative factors.Conclusion:Encouraging utilization of social support systems and a positive coping mode is important for increasing comfort level in head and neck neoplasm patients during radiotherapy.Nurses should pay particular attention to those patients during later stages of radiotherapy or chemotherapy,with diabetes,without family accompaniment,and with lower education level.

Boron neutron capture therapy: moving towards targeted therapy for locally recurrent head and neck squamous cell carcinoma

Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues.However,the relationships among the dose resulting from BNCT,tumor response to BNCT,and survival are not completely understood.Recently,a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival.In this article,the findings,strengths and limitations of this study are discussed in depth,and the significance of the study and motivations for future research are highlighted.

Classificatory updates in verrucous and cuniculatum carcinomas:Insights from the 5^(th) edition of WHO-IARC head and neck tumor classification

The International Agency for Research on Cancer(IARC)and World Health Organization(WHO)collaboratively produce the'WHO Blue Books'essential tools standardizing the diagnostic process for human cancers.Regular updates in this classification accommodate emerging molecular discoveries,advances in immunohistochemical techniques,and evolving clinical insights.The 5th edition of the WHO/IARC classification of head and neck tumors refines the'Oral Cavity and Mobile Tongue'chapter,including sections for non-neoplastic lesions,epithelial tumors,and tumors of uncertain histogenesis.Notably,the epithelial tumors section is rearranged by tumor behavior,starting with benign squamous papillomas and progressing through potentially malignant oral disorders to oral squamous cell carcinoma(OSCC).The section on OSCC reflects recent information on epidemiology,pathogenesis,and histological prognostic factors.Noteworthy is the specific categorization of verrucous carcinoma(VC)and carcinoma cuniculatum(CC),both associated with the oral cavity and distinct in clinical and histologic characteristics.This classification adjustment emphasizes the oral cavity as their predominant site in the head and neck.Designating specific sections for VC and CC aims to provide comprehensive insights into these unique subtypes,elucidating their clinical features,distinct histological characteristics,prevalence,significance,and clinical relevance.By categorizing these subtypes into specific sections,the 5th edition of the WHO classification aims to provide a more nuanced and detailed account,enhancing our understanding of these specific variants within the broader spectrum of head and neck tumors.

Nutritional Therapy for Head and Neck Cancer

Patients with head and neck cancer face great challenges in maintaining optimal nutrition since both the disease itself and treatments,especially surgery and concurrent chemoradiotherapy,have a significant negative impact on the nutritional status.A fundamental understanding of the nutrient metabolism of patients with head and neck cancer will aid in treatment selection.In this review,metabolic abnormalities presented in patients with head and neck cancer are discussed,together with methods of nutritional support,dietary intervention,and potential roles of phytonutrients,probiotics,and exercise in nutritional therapy for head and neck cancer patients.

Monitoring photodynamic therapy of head and neck malignancies with optical spectroscopies

In recent years there has been significant developments in photosensitizers(PSs), light sources and light delivery systems that have allowed decreasing the treatment time and skin phototoxicity resulting in more frequent use of photodynamic therapy(PDT) in the clinical settings. Compared to standard treatment approaches such as chemo-radiation and surgery, PDT has much reduced morbidity for head and neck malignancies and is becoming an alternative treatment option. It can be used as an adjunct therapy to other treatment modalities without any additive cumulative side effects. Surface illumination can be an option for pre-malignant and early-stage malignancies while interstitial treatment is for debulking of thick tumors in the head and neck region. PDT can achieve equivalent or greater efficacy in treating head and neck malignancies, suggesting that it may be considered as a first line therapy in the future. Despite progressive development, clinical PDT needs improvement in several topics for wider acceptance including standardization of protocols that involve the same administrated light and PS doses and establishing quantitative tools for PDT dosimetry planning and response monitoring. Quantitative measures such as optical parameters, PS concentration, tissueoxygenation and blood flow are essential for accurate PDT dosimetry as well as PDT response monitoring and assessing therapy outcome. Unlike conventional imaging modalities like magnetic resonance imaging, novel optical imaging techniques can quantify PDT-related parameters without any contrast agent administration and enable real-time assessment during PDT for providing fast feedback to clinicians. Ongoing developments in optical imaging offer the promise of optimization of PDT protocols with improved outcomes.

Robustness Evaluation of a Novel Proton Beam Geometry for Head and Neck Patients Treated with Pencil Beam Scanning Therapy

Background: To evaluate the robustness of head and neck treatment using proton pencil beam scanning (PBS) technique with respect to range uncertainty (RU) and setup errors (SE), and to establish a robust PBS planning strategy for future treatment. Methods and Materials: Ten consecutive patients were planned with a novel proton field geometry (combination of two posterior oblique fields and one anterior field with gradient dose match) using single-field uniform dose (SFUD) planning technique and the proton plans were dosimetrically compared to two coplanar arc VMAT plans. Robustness of the plans, with respect to range uncertainties (RU = ± 3% for proton) and setup errors (SE = 2.25 mm for proton and VMAT), in terms of deviations to target coverage (CTV D98%) and OAR doses (max/mean), were evaluated and compared for each patient under worst case scenarios. Results: Dosimetrically, PBS plans provided better sparing to larynx (p = 0.005), oral cavity (p < 0.001) and contralateral parotid (p = 0.004) when compared to VMAT. CTV D98% variations were higher from SE than from RU for proton plans (-1.1% ± 1.3 % vs -0.4% ± 0.7% for nodal CTV and -1.4% ± 1.2 vs -0.4% ± 0.5% % for boost CTV). Overall, the magnitudes of variation of CTV D98% to combined SE and RU were found to be similar to the impact of the SE on the VMAT plans (-1.6% ± 1.9% vs -1.7% ± 1.4% for nodal CTV and -1.9% ± 1.6% vs -1.3% ± 1.5% for boost CTV). Compared to VMAT, a larger range of relative dose deviations were found for OARs in proton plans, but safe doses were maintained for cord (41.8 ± 3.6 Gy for PBS and 41.7 ± 3.9 Gy for VMAT) and brainstem (35.2 ± 8.4 Gy for PBS and 36.2 ± 5.1 Gy for VMAT) in worst case scenarios. Conclusions: Compared to VMAT, proton plans containing three SFUD fields with superior-inferior gradient dose matching had improved sparing to larynx, contralateral parotid and oral cavity, while providing similar robustness of target coverage. Evaluation of OAR dose robustness showed higher sensitivities to uncertainties for proton plans, but safe dose levels were maintained for cord and brainstem.

The Reproducibility of Patient Setup for Head and Neck Cancers Treated with Image-Guided and Intensity-Modulated Radiation Therapies Using Thermoplastic Immobilization Device

The reproducibility of patient setup is an important issue for head and neck cancers treated with intensity-modulated radiation therapy (IMRT). In this study, an image-guided radiation therapy (IGRT) system has been used to minimize the uncertainty of patient setup while standard thermoplastic masks were used to provide adequate immobilization for the head and neck. However, they do not provide sufficient immobilization of the shoulders, which is an important requirement in comprehensive nodal irradiation. Therefore, we investigated the setup and rotational shifts in head and neck cancer patients undergoing IMRT for which this immobilization device had been used together with an IGRT system. The setup and rotational shifts of patients were analyzed using the ExacTrac X-ray 6D IGRT system. The patients were classified as having head and neck tumors in the upper or lower regions. The upper neck nodes included lymph nodal level II while the lower neck nodes included lymph nodal levels III and IV. Clinical data from 227 treatment sessions of 12 head and neck cancer patients were analyzed. The random translational error in inter-and intra-fraction errors of the anterio-posterior (AP) direction might influence the rotational errors of pitch and roll in the upper region. At the same time, the random translational error in the inter-and intra-fraction errors of the AP direction might influence the rotational error of roll in the lower region. We believe that these random translational errors should be considered during treatment. We found variability in random translational errors for different regions in the anatomy of head and neck cancer patients due to rotational shifts. Depending on the location of the primary lesion or the selected nodal treatment targets, these relative positional variations should be considered when setup and rotational shifts are corrected with IGRT systems before treatment.

Usability of Deformable Image Registration for Adaptive Radiotherapy in Head and Neck Cancer and an Automatic Prediction of Replanning

Deformable image registration (DIR) has been an important component in adaptive radiotherapy (ART). Our goal was to examine the accuracy of ART using the dice similarity coefficient (DSC) and to determine the optimal timing of replanning. A total of 22 patients who underwent volume modulated arc therapy (VMAT) for head and neck (H&N) cancers were prospectively analyzed. The planning target volume (PTV) was to receive a total of 70 Gy in 33 fractions. A second planning CT scan (rescan) was performed at the 15th fraction. The DSC was calculated for each structure on both CT scans. The continuous variables to predict the need for replanning were assessed. The optimal cut-off value was determined using receiver operating characteristic (ROC) curve analysis. In the correlation between body weight loss and DSC of each structure, weight loss correlated negatively with DSC of the whole face (rs = -0.45) and the face surface (rs = -0.51). Patients who required replanning tended to have experienced rapid weight loss. The threshold DSC was 0.98 and 0.60 in the whole face and the face surface, respectively. Patients who showed low DSC in the whole face and the face surface required replanning at a significantly high rate (P < 0.05 and P < 0.01). Weight loss correlated with DSC in both the whole face and the face surface (P < 0.05 and P < 0.05). The DSC values in the face predicted the need for replanning. In addition, weight loss tended to correlate with DSC. DIR during ART was found to be a useful tool for replanning.

Regenerative Surgery for the Rehabilitation of a Patient after Surgery and Radiation Therapy for Head and Neck Cancer: A Case Report

Oral cancer is usually treated combining surgery, radiation therapy and chemotherapy, following effective therapeutic protocols. Severe maxillary and mandibular bone atrophy resulting after therapies are usually treated with autologous bone grafting procedures even though these techniques often present a significant risk of postoperative complications and disadvantages. We describe the case of a 59-year-old woman presenting severe bone defect after being treated with surgery and radiotherapy for recurrent oral verrucous squamous cell carcinoma. We performed bone regeneration using Platelet-Derived Growth Factors (PDGF) in combination with autologous bone chips. Our procedure of bone regeneration allowed the placement of dental implants and the achievement of a good aesthetic and functional result. Regenerative surgery may enable the regeneration of substantial bone defects. Moreover, PDGF application decreases the risk of implant failure in irradiated patients.

Evaluation of Quality of Life and Oral Changes of Patients in Head and Neck Radiotherapy: Observational Study

Radiotherapy (RT) in the head and neck, despite coming from technological evolution, is challenged by the acute and late side effects of local irradiation, including permanent loss of saliva, osteoradionecrosis, dental caries induced by radiation and necrosis of the oral cavity, mucositis, xerostomia and secondary infections like candidiasis. Since these manifestations are limiting and the integrity of the vital organs contemplates the patient’s general health status, the oral health-related quality of life (OHRQoL) can be significantly affected by the treatment of head and neck cancer (HNC), since cancer can cause important changes in vital functions related to communication, food and social contact, causing disturbances in the patient’s life. An observational and longitudinal study was carried out with 16 cancer patients submitted to RT in the head and neck, between the years 2019-2020 with the objectives of collecting clinical and epidemiological data on the main oral changes caused by RT in the head and neck and correlating them with the impact on OHRQoL. To analyze the OHRQoL, the University of Washington’s Quality of Life Assessment questionnaire (UW-QOL) was applied once a week for 4 weeks and to observe oral manifestations, a dental clinic file standardized by the researchers was applied. The main oral manifestations clinically observed were hyposalivation, trismus and oral mucositis. The UW-QOL presented pain, chewing and taste as the main complaints reported by patients, however, appearance, salivation and chewing showed statistically significant differences over the weeks. The main manifestations observed were hyposalivation, trismus and oral mucositis, the physical limitations resulting from these manifestations impact the OHRQoL of cancer patients in terms of appearance, salivation and chewing.

Targeting head and neck tumoral stem cells： From biologicalaspects to therapeutic perspectives

Head and neck squamous cell cancer(HNSCC) is the sixth most common cancer in the world. Effective therapeutic modalities such as surgery, radiation, chemotherapy and combinations of each are used in the management of the disease. In most cases, treatment fails to obtain total cancer cure. In recent years, it appears that one of the key determinants of treatment failure may be the presence of cancer stem cells(CSCs) that escape currently available therapies. CSCs form a small portion of the total tumor burden but may play a disproportionately important role in determining outcomes. CSCs have stem features such as self-renewal, high migration capacity, drug resistance, high proliferation abilities. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In HNSCC, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In the light of such observations, the present review summarizes biological characteristics of CSCs in HNSCC, outlines targeted strategies for the successful eradication of CSCs in HNSCC including targeting the self-renewal controlling pathways, blocking epithelial mesenchymal transition, niche targeting, immunotherapy approaches and highlights the need to better understand CSCs biology for new treatments modalities.

Clinical Investigation of ^(99m)Tc-MIBI Imaging in Head and Neck Tumors

Objective： To investigate the diagnostic potential value of ^99Tc-MIBI imaging in head and neck tumors. Methods： Ninety-one patients with malignant and benign head and neck lesions were subjected to ^99mTc-MIBI tomography, and 20 healthy volunteers served as control group. Results： The overall sensitivity,specificity, accuracy and positive predictive accuracy of early/delay ^99mTc-MIBI imaging in diagnosis of head and neck malignant tumors were 78.7%/72.3%, 72.1%/88.4%, 75.6%/80.0% and 75.5%/87.2% respectively. The results of ^99mTc-MIBI Imaging in diagnosis of nasopharyngeal cancer and sinonasal non-Hodgkin＇s lymphoma were more satisfactory than those in maxillary sinus cancer. In distinguishing recurrent/residual nasopharyngeal carcinoma and sinonasal non-Hodgkin＇s lymphoma, ^99mTc-MIBI scintigraphy was superior to CT/MRI. Conclusion： ^99mTc-MIBI imaging is a promising useful tool in identifying head and neck tumor, and it has a special value to evaluate the local invasion and metastasis involved.

Application of fluorodeoxyglucose positron emission tomography in the management of head and neck cancers

The use of fluorodeoxyglucose positron emission to-mography(FDG PET) scan technology in the manage-ment of head and neck cancers continues to increase. We discuss the biology of FDG uptake in malignant lesions and also discuss the physics of PET imaging. The various parameters described to quantify FDG up-take in cancers including standardized uptake value, metabolic tumor volume and total lesion glycolysis are presented. PET scans have found a significant role in the diagnosis and staging of head and neck cancers. They are also being increasingly used in radiation ther-apy treatment planning. Many groups have also used PET derived values to serve as prognostic indicators of outcomes including loco-regional control and overall survival. FDG PET scans are also proving very useful in assessing the efficacy of treatment and management and follow-up of head and neck cancer patients. This review article focuses on the role of FDG-PET com-puted tomography scans in these areas for squamous cell carcinoma of the head and neck. We present the current state of the art and speculate on the future applications of this technology including protocol de-velopment, newer imaging methods such as combinedmagnetic resonance and PET imaging and novel ra-diopharmaceuticals that can be used to further study tumor biology.

Reliability and validity of the Chinese version of the Head and Neck Information Needs Questionnaire for patients with head and neck cancer and their caregivers

Objectives:This study aimed to assess the reliability and validity of the Chinese version of the Head and Neck Information Needs Questionnaire(HaNiQ).Methods:The HaNiQ was translated into a Chinese version using internationally recognized forwardand back-translation procedures.The reliability and validity of the HaNiQ were measured using Cronbach’s a coefficient,split-half reliability,exploratory factor analysis,and Pearson correlation analysis.Results:A total of 207 patients in different head and neck cancer(HNC)stages and 174 caregivers completed the Chinese version of the HaNiQ.Internal consistencies varied between good and very well(Cronbach’s α coefficient 0.74-0.90);the split-half coefficient and the content validity index(CVI)of the questionnaire were 83.5%and 83.33%,respectively.The cumulative contribution rates of the 5 subscales in patients with HNCand their caregivers were 62.41%and 61.19%,respectively.However,there are some differences between the Chinese questionnaire for caregiver and the original questionnaire regarding the attribution of items.Items 22,23,and 27 in the Psychosocial subscale of the English version were assigned to the Survivorship subscale in the Chinese version for caregivers.Conclusions:The results demonstrated that the Chinese version of the HaNiQ is a reliable and valid instrument for measuring the information needs of patients with HNC and that of their caregivers.Though the structure of the Chinese versionwas different from the English version for caregivers of HNC patients,the Chinese version of the HaNiQ appears to be reliable and would benefit from further testing.

Restricting carbohydrates to fight head and neck cancer——is this realistic?

Head and neck cancers(HNCs) are aggressive tumors that typically demonstrate a high glycolytic rate, which results in resistance to cytotoxic therapy and poor prognosis. Due to their location these tumors specifically impair food intake and quality of life, so that prevention of weight loss through nutrition support becomes an important treatment goal. Dietary restriction of carbohydrates(CHOs) and their replacement with fat, mostly in form of a ketogenic diet(KD), have been suggested to accommodate for both the altered tumor cell metabolism and cancer-associated weight loss. In this review, I present three specific rationales for CHO restriction and nutritional ketosis as supportive treatment options for the HNC patient. These are(1) targeting the origin and specific aspects of tumor glycolysis;(2) protecting normal tissue from but sensitizing tumor tissue to radiation- and chemotherapy induced cell kill;(3) supporting body and muscle mass maintenance. While most of these benefits of CHO restriction apply to cancer in general, specific aspects of implementation are discussed in relation to HNC patients. While CHO restriction seems feasible in HNC patients the available evidence indicates that its role may extend beyond fighting malnutrition to fighting HNC itself.

MANAGEMENT OF HEAD AND NECK TUMORS

The experience of management of head and neck tumors was summarized by author’s and some other Chinese literatures. This paper mainly introduced the epidemiology, diagnosis, treatment and prognosis of head and neck tumors, especially the malignancies in China. It emphasized that to assign protocols on a case-by-case basis (custom made) and the combined therapy are key points to improve the cure rate or survival rate for head and neck malighancies. Up to now, the 5-year survival rate for squamous cell carcinoma of head and neck was about 62% (1986), and about 71% (1987) for carcinoma of salivary gland origin.

Glucocorticoid reduces the efficacy of afatinib on the head and neck squamous cell carcinoma

Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal growth factor receptor(EGFR)-targeted therapy of head and neck squamous cell carcinoma(HNSCC)remaining to be elucidated.The primary aim of the present study was to probe into the GC-induced resistance of EGFR-targeted drug afatinib and the underlying mechanism.HNSCC cell lines(HSC-3,SCC-25,SCC-9,and H-400)and the human oral keratinocyte(HOK)cell lines were assessed for GC receptor(GR)expression.The promoting tumor growth effect of GC was evaluated by the CCK-8 assay and flow cytometry.Levels of signaling pathways participants GR,mTOR,and EGFR were determined by quantitative polymerase chain reaction and western blotting.GC increased the proliferation of HNSCC cells in a GR-dependent manner and promoted AKT/mTOR signaling.But GC failed in counteracting the inhibition of rapamycin in the mTOR signaling pathway.Besides,GC also induced resistance to EGFR-targeted drug afatinib through AKT/mTOR instead of the EGFR/ERK signaling pathway.Thus,GCs reduce the efficacy of afatinib on HNSCC,implicating a cautious use of glucocorticoids in clinical practice.

Reconstruction surgery in head and neck cancer patients amidst the COVID-19 pandemic:Current practice and lessons for the future

The coronavirus disease 2019(COVID-19)pandemic has imposed a radical change in daily life and work routine.In this context,health systems have suffered important and serious repercussions in all fields.Among the changes brought about by the state of global health emergency,adjustments to guidelines,priorities,structures,professional teams,and epidemiological data stand out.In light of this,the oncological field has witnessed several changes in the approach to cancer,whether due to delay in diagnosis,screening deficit,personnel shortage or the psychological impact that the pandemic has had on cancer patients.This article focuses on the management of oral carcinoma and the surgical approaches that oral and maxillofacial specialists have had at their disposal during the health emergency.In this period,the oral and maxillofacial surgeons have faced many obstacles.The proximity of maxillofacial structures to the airways,the need of elective and punctual procedures in cancerous lesions,the aggressiveness of head and neck tumors,and the need for important healthcare costs to support such delicate surgeries are examples of some of the challenges imposed for this field.One of the possible surgical'solutions'to the difficulties in managing surgical cases of oral carcinoma during the pandemic is locoregional flaps,which in the pre-COVID-19 era were less used than free flaps.However,during the health emergency,its use has been widely reassessed.This setback may represent a precedent for opening up new reflections.In the course of a long-term pandemic,a reassessment of the validity of different medical and surgical therapeutic approaches should be considered.Finally,given that the pandemic has highlighted vulnerabilities and shortcomings in a number of ways,including the issues of essential resource shortages,underinvestment in public health services,lack of coordination and versatility among politicians,policymakers and health leaders,resulting in overloaded health systems,rapid case development,and high mortality,a more careful analysis of the changes needed in different health systems to satisfactorily face future emergencies is essential to be carried out.This should be directed especially towards improving the management of health systems,their coordination as well as reviewing related practices,even in the surgical field.

Rupture of carotid artery pseudoaneurysm in the modern era of definitive chemoradiation for head and neck cancer:Two case reports

BACKGROUND Carotid blowout syndrome(CBS)is a rupture of the carotid artery and is mainly caused by radiation and resection of head and neck cancers or direct tumor invasion of the carotid artery wall.It is a life-threatening clinical situation.There is no established and effective mode of management of CBS.Furthermore,there is no established preceding sign or symptom;therefore,preventive efforts are not clinically meaningful.CASE SUMMARY We described two cases of CBS that occurred in patients with head and neck cancer after definitive chemoradiotherapy(CRT)using three-dimensional conformal intensity-modulated radiation therapy.Two men aged 61 and 56 years with locally advanced head and neck cancer were treated with definitive CRT.After completing CRT,both of them achieved complete remission.Subsequently,they had persistent severe pain in the oropharyngeal mucosal region and the irradiated neck despite the use of opioid analgesics and rehabilitation for relief of contracted skin.However,continuous follow-up imaging studies showed no evidence of cancer recurrence.Eleven to twelve months after completing CRT,the patients visited the emergency room complaining about massive oronasal bleeding.Angiograms showed rupture of carotid artery pseudoaneurysms on the irradiated side.Despite attempting to secure hemostasis with carotid arterial stent insertion and coil embolization,both patients died because of repeated bleeding from the pseudoaneurysms.CONCLUSION In patients with persistent pain in irradiated sites,clinicians should be suspicious of progressing or impending CBS,even in the three-dimensional conformal intensity-modulated radiation therapy era.