Risk factors for immune-related adverse effects during CPI therapy in patients with head and neck malignancies - a single center study.

Introduction: Checkpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications. Material and methods: Data from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs. Results: IrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels. Discussion: Even though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out.

Integrative Analysis Identified CD38 As a Key Node That Correlates Highly with Immunophenotype, Chemoradiotherapy Resistance, And Prognosis of Head and Neck Cancer.

Head and neck cancer (HNC) is mainly treated by surgery, radiotherapy, and adjuvant chemotherapy; however, the prognosis of some patients with HNC is poor because of radiotherapy and chemotherapy resistance. In recent years, anti­PD­1 monoclonal antibodies have shown certain efficacy, and a change of the tumor immune microenvironment is the main reason for the failure of HNC immunotherapy. The present study aimed to identify and verify that CD38, which is closely related to the prognosis of HNC, is a potential biological marker of radiotherapy and chemotherapy resistance and PD-L1 immunotherapy resistance via a comprehensive bioinformatic analysis in The Cancer Genome Atlas and Gene Expression Omnibus databases. According to the UALCAN database, the transcript level of CD38 in HNC was analyzed using cluster analysis, and the expression of CD38 mRNA in HNC was detected using the Oncomine database. The characteristics of CD38-related oncogenes were identified by gene cluster enrichment analysis in LinkedOmics. The R2 and SEER databases were used to further evaluate the prognostic significance of the CD38 gene in HNC using receiver operating characteristic curve analysis of Kaplan-Meier (KM) survival and the clinical characteristics of the subjects. The protein-protein interaction network of the top 50 genes showing significant positive correlations with CD38 in HNC was analyzed using STRING. Finally, we used a nasopharyngeal carcinoma (NPC) cell line to verify the biological function. The results showed that the levels of CD38 mRNA expression in patients with HNC were significantly higher than those in healthy controls. The levels of CD38 mRNA expression in patients with HNC of different ages, sexes, and races were significantly higher than those in the healthy controls. CD38 is an independent prognostic factor for HNC, and high expression of CD38 indicates poor prognosis. CD38 expression correlated positively with the markers of many kinds of immune cells, and correlated significantly with the expression of PD-L1. We found that the high expression of CD38 suggested a poor prognosis in the subgroup of tumors treated with chemotherapeutic drugs in the G1/S phase. We used HNC cell lines to verify that the high expression of CD38 promoted the proliferation of NPC cells and produced radiotherapy tolerance. Through comprehensive bioinformatics analysis, we suggested that CD38 is a key gene involved in radiotherapy, chemotherapy, and immune drug resistance in HNC. This study provides a reliable biomarker to predict the prognosis of patients with HNC and a reference for clinical comprehensive treatment of HNC. Individualization combined with CD38 monoclonal antibodies might provide a promising treatment strategy for this fatal disease, and this comprehensive treatment might reduce the damage to normal tissue and improve the prognosis and quality of life of patients with HNC.

National and international guidelines on the replacement of missing teeth with dentures for head and neck cancer patients post-radiotherapy: A rapid review.

Background: Replacement of missing teeth is not a straightforward task in head and neck cancer (HNC) patients post-radiotherapy. There is debate regarding the best way to care for these patients as it has been reported that using dentures by HNC patients after receiving treatment with radiotherapy might initiate the development of osteoradionecrosis. Aim: This rapid review aimed to collate and compare the national and international guidelines for the use of dentures following radiotherapy for HNC patients. Materials and methods: Three steps were included in data collection of this rapid review (first step; identification of dental and relevant non-dental associations/societies, second step, identification of national and international guidelines regarding the dental management of HNC patients, and third step; identification of recommendations about the replacement of missing teeth in HNC patients). Results: In the 193 countries recognized by the United Nations, there were 238 relevant societies found, from those 175 confirmed that they do not have clear guidelines. Only 32 associations/societies (all in either Europe and North America) recommend guidelines for their dentists (N = 12 guidelines) about the dental management of HNC patients and show their position regarding the use of dentures for HNC patients after receiving treatment with radiotherapy. Conclusions: There are very few guidelines and those that do exist differ, lack detail, and rarely go beyond routine advice. Accordingly, clear, detailed, and evidence-based guidelines are required to inform the management of patients with missing teeth following radiotherapy for HNC patients.

Artificial intelligence to predict outcomes of head and neck radiotherapy.

Head and neck radiotherapy induces important toxicity, and its efficacy and tolerance vary widely across patients. Advancements in radiotherapy delivery techniques, along with the increased quality and frequency of image guidance, offer a unique opportunity to individualize radiotherapy based on imaging biomarkers, with the aim of improving radiation efficacy while reducing its toxicity. Various artificial intelligence models integrating clinical data and radiomics have shown encouraging results for toxicity and cancer control outcomes prediction in head and neck cancer radiotherapy. Clinical implementation of these models could lead to individualized risk-based therapeutic decision making, but the reliability of the current studies is limited. Understanding, validating and expanding these models to larger multi-institutional data sets and testing them in the context of clinical trials is needed to ensure safe clinical implementation. This review summarizes the current state of the art of machine learning models for prediction of head and neck cancer radiotherapy outcomes.

Exogenous lipoid pneumonia due to silent aspiration following surgery and radiotherapy for cancer of the tongue.

A man with a history of cancer of the base of the tongue presenting with hemoptysis, recurrent pneumonia and crazy-paving patterns on CT was ultimately diagnosed with lipoid pneumonia, subsequently found to be associated with use of fish oil capsules and possible Parkinson's disease. Pulmonary alveolar proteinosis and invasive mucinous adenocarcinoma as differential diagnoses were considered and dismissed. Risk of aspiration and lipoid pneumonia should be considered in patients with similar radiological findings and history.

IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes.

Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

Dose-volume predictors of post-radiation primary hypothyroidism in head and neck cancer: A systematic review.

BACKGROUND AND PURPOSE: This systematic review aims to identify radiation dose-volume predictors of primary hypothyroidism after radiotherapy in patients with head and neck cancer (HNC). MATERIALS AND METHODS: We performed a systematic literature search of Medline, EMBASE and Web of Science from database inception to July 1, 2021 for articles that discuss radiation dose-volume predictors of post-radiation primary hypothyroidism in patients with HNC. Data on the incidence, clinical risk factors and radiation dose-volume parameters were extracted. A meta-analysis was performed using the random-effects model to estimate the pooled odds ratio (OR) of thyroid volume as a predictor of the risk of post-radiation hypothyroidism, adjusted for thyroid radiation dosimetry. RESULTS: Our search identified 29 observational studies involving 4,530 patients. With median follow-up durations ranging from 1.0 to 5.3 years, the average crude incidence of post-radiation primary hypothyroidism was 41.4 % (range, 10 %-57 %). Multiple radiation dose-volume parameters were associated with post-radiation primary hypothyroidism, including the thyroid mean dose (Dmean), minimum dose, V25, V30, V35, V45, V50, V30-60, VS45 and VS60. Thyroid Dmean and V50 were the most frequently proposed dosimetric predictors. The pooled adjusted OR of thyroid volume on the risk of post-radiation primary hypothyroidism was 0.89 (95 % confidence interval, 0.85-0.93; p < 0.001) per 1 cc increment. CONCLUSION: Post-radiation primary hypothyroidism is a common late complication after radiotherapy for HNC. Minimizing inadvertent exposure of the thyroid gland to radiation is crucial to prevent this late complication. Radiation dose-volume constraints individualized for thyroid volume should be considered in HNC radiotherapy planning.

ERK1/2-EGR1-SRSF10 Axis Mediated Alternative Splicing Plays a Critical Role in Head and Neck Cancer.

Aberrant alternative splicing is recognized to promote cancer pathogenesis, but the underlying mechanism is yet to be clear. Here, in this study, we report the frequent upregulation of SRSF10 (serine and arginine-rich splicing factor 10), a member of an expanded family of SR splicing factors, in the head and neck cancer (HNC) patients sample in comparison to paired normal tissues. We observed that SRSF10 plays a crucial role in HNC tumorigenesis by affecting the pro-death, pro-survical splice variants of BCL2L1 (BCL2 Like 1: BCLx: Apoptosis Regulator) and the two splice variants of PKM (Pyruvate kinase M), PKM1 normal isoform to PKM2 cancer-specific isoform. SRSF10 is a unique splicing factor with a similar domain organization to that of SR proteins but functions differently as it acts as a sequence-specific splicing activator in its phosphorylated form. Although a body of research studied the role of SRSF10 in the splicing process, the regulatory mechanisms underlying SRSF10 upregulation in the tumor are not very clear. In this study, we aim to dissect the pathway that regulates the SRSF10 upregulation in HNC. Our results uncover the role of transcription factor EGR1 (Early Growth Response1) in elevating the SRSF10 expression; EGR1 binds to the promoter of SRSF10 and promotes TET1 binding leading to the CpG demethylation (hydroxymethylation) in the adjacent position of the EGR1 binding motif, which thereby instigate SRSF10 expression in HNC. Interestingly we also observed that the EGR1 level is in the sink with the ERK1/2 pathway, and therefore, inhibition of the ERK1/2 pathway leads to the decreased EGR1 and SRSF10 expression level. Together, this is the first report to the best of our knowledge where we characterize the ERK 1/2-EGR1-SRSF10 axis regulating the cancer-specific splicing, which plays a critical role in HNC and could be a therapeutic target for better management of HNC patients.

DIM-C-pPhtBu induces lysosomal dysfunction and unfolded protein response - mediated cell death via excessive mitophagy.

Despite technological advances in cancer treatment, the survival rate of patients with head and neck cancer (HNC) has not improved significantly. Many studies have shown that endoplasmic reticulum (ER) stress-related signals are associated with mitochondrial damage and that these signals determine whether cells maintain homeostasis or activate cell death programs. The unfolded protein response (UPR) is regulated by ER membrane proteins such as double-stranded RNA-activated protein kinase R(PKR)-like ER kinase (PERK), which directly activate transcription of chaperones or genes that function in redox homeostasis, protein secretion, or cell death programs. In this study, we focused on the role of mitophagy and ER stress-mediated cell death induced by DIM-C-pPhtBu in HNC cancer. We found that DIM-C-pPhtBu, a compound that activates ER stress in many cancers, induced lysosomal dysfunction, excessive mitophagy, and cell death in HNC cells. Moreover, DIM-C-pPhtBu strongly inhibited HNC progression in a xenograft model by altering mitophagy related protein expression. Taken together, the results demonstrate that DIM-C-pPhtBu induces excessive mitophagy and eventually UPR-mediated cell death in HNC cells, suggesting that new anti-cancer drugs could be developed based on the connection between mitophagy and cancer cell death.

Cardiovascular Manifestations From Therapeutic Radiation: A Multidisciplinary Expert Consensus Statement From the International Cardio-Oncology Society.

Radiation therapy is a cornerstone of cancer therapy, with >50% of patients undergoing therapeutic radiation. As a result of widespread use and improved survival, there is increasing focus on the potential long-term effects of ionizing radiation, especially cardiovascular toxicity. Radiation therapy can lead to atherosclerosis of the vasculature as well as valvular, myocardial, and pericardial dysfunction. We present a consensus statement from the International Cardio-Oncology Society based on general principles of radiotherapy delivery and cardiovascular risk assessment and risk mitigation in this population. Anatomical-based recommendations for cardiovascular management and follow-up are provided, and a priority is given to the early detection of atherosclerotic vascular disease on imaging to help guide preventive therapy. Unique management considerations in radiation-induced cardiovascular disease are also discussed. Recommendations are based on the most current literature and represent a unanimous consensus by the multidisciplinary expert panel.

The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment.

A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.

Prospective quantitative quality assurance and deformation estimation of MRI-CT image registration in simulation of head and neck radiotherapy patients.

BACKGROUND: MRI-guided radiotherapy planning (MRIgRT) may be superior to CT-guided planning in some instances owing to its improved soft tissue contrast. However, MR images do not communicate tissue electron density information necessary for dose calculation and therefore must either be co-registered to CT or algorithmically converted to synthetic CT. No robust quality assessment of commercially available MR-CT registration algorithms is yet available; thus we sought to quantify MR-CT registration formally. METHODS: Head and neck non-contrast CT and T2 MRI scans acquired with standard treatment immobilization techniques were prospectively acquired from 15 patients. Per scan, 35 anatomic regions of interest (ROIs) were manually segmented. MRIs were registered to CT rigidly (RIR) and by three commercially available deformable registration algorithms (DIR). Dice similarity coefficient (DSC), Hausdorff distance mean (HD mean) and Hausdorff distance max (HD max) metrics were calculated to assess concordance between MRI and CT segmentations. Each DIR algorithm was compared to DIR using the nonparametric Steel test with control for individual ROIs (n = 105 tests) and for all ROIs in aggregate (n = 3 tests). The influence of tissue type on registration fidelity was assessed using nonparametric Wilcoxon pairwise tests between ROIs grouped by tissue type (n = 12 tests). Bonferroni corrections were applied for multiple comparisons. RESULTS: No DIR algorithm improved the segmentation quality over RIR for any ROI nor all ROIs in aggregate (all p values >0.05). Muscle and gland ROIs were significantly more concordant than vessel and bone, but DIR remained non-different from RIR. CONCLUSIONS: For MR-CT co-registration, our results question the utility and applicability of commercially available DIR over RIR alone. The poor overall performance also questions the feasibility of translating tissue electron density information to MRI by CT registration, rather than addressing this need with synthetic CT generation or bulk-density assignment.

Identifying organs at risk for radiation-induced late dysphagia in head and neck cancer patients.

BACKGROUND AND PURPOSE: Dysphagia is a common, severe and dose-limiting toxicity after oncological treatment of head and neck cancer (HNC). This study aims to investigate relationships between radiation doses to structures involved in normal swallowing and patient-reported as well as clinically measured swallowing function in HNC patients after curative (chemo-) radiation therapy (RT) with focus on late effects. MATERIALS AND METHODS: Patients (n = 90) with HNC curatively treated with RT ±â€¯chemotherapy in 2007-2015 were assessed for dysphagia post-treatment by telephone interview and videofluoroscopy (VFS). A study-specific symptom score was used to determine patient-reported dysphagia. The Penetration-Aspiration Scale (PAS) was applied to determine swallowing function by VFS (PAS ≥ 4/ ≥ 6 = moderate/severe dysphagia). Thirteen anatomical structures involved in normal swallowing were individually delineated on the patients' original planning CT scans and associated dose-volume histograms (DVHs) retrieved. Relationships between structure doses and late toxicity were investigated through univariable and multivariable logistic regression analysis (UVA/MVA) accounting for effects by relevant clinical factors. RESULTS: Median assessment time was 7 months post-RT (range: 5-34 months). Mean dose to the contralateral parotid gland and supraglottic larynx as well as maximum dose to the contralateral anterior digastric muscle predicted patient-reported dysphagia (AUC = 0.64-0.67). Mean dose to the pharyngeal constrictor muscle, the larynx, the supraglottic larynx and the epiglottis, as well as maximum dose to the contralateral submandibular gland predicted moderate and severe dysphagia by VFS (AUC = 0.71-0.80). CONCLUSION: The patients in this cohort were consecutively identified pre-treatment, and were structurally approached and assessed for dysphagia after treatment at a specific time point. In addition to established dysphagia organs-at-risk (OARs), our data suggest that epiglottic and submandibular gland doses are important for swallowing function post-RT. Keeping DVH thresholds below V60 = 60% and V60 = 17%, respectively, may increase chances to reduce occurrence of severe late dysphagia. The results need to be externally validated in future studies.

Detection of high PD-L1 expression in oral cancers by a novel monoclonal antibody L1Mab-4.

Programmed cell death-ligand 1 (PD-L1), which is a ligand of programmed cell death-1 (PD-1), is a type I transmembrane glycoprotein that is expressed on antigen-presenting cells and several tumor cells, including melanoma and lung cancer cells. There is a strong correlation between human PD-L1 (hPD-L1) expression on tumor cells and negative prognosis in cancer patients. In this study, we produced a novel anti-hPD-L1 monoclonal antibody (mAb), L1Mab-4 (IgG2b, kappa), using cell-based immunization and screening (CBIS) method and investigated hPD-L1 expression in oral cancers. L1Mab-4 reacted with oral cancer cell lines (Ca9-22, HO-1-u-1, SAS, HSC-2, HSC-3, and HSC-4) in flow cytometry and stained oral cancers in a membrane-staining pattern. L1Mab-4 stained 106/150 (70.7%) of oral squamous cell carcinomas, indicating the very high sensitivity of L1Mab-4. These results indicate that L1Mab-4 could be useful for investigating the function of hPD-L1 in oral cancers.

Dusquetide: Reduction in oral mucositis associated with enduring ancillary benefits in tumor resolution and decreased mortality in head and neck cancer patients.

Innate immunity is a key component in the pathogenesis of oral mucositis, a universal toxicity of chemoradiation therapy (CRT). Dusquetide, a novel Innate Defense Regulator, has demonstrated both nonclinical and clinical efficacy in ameliorating severe oral mucositis (SOM). Long term follow-up studies from the Phase 2 clinical study evaluating dusquetide as a treatment for SOM in head and neck cancer (HNC) patients receiving CRT have now been completed. Extended analysis indicates that dusquetide therapy was well-tolerated and did not contribute to increased infection, tumor growth or mortality. Potential ancillary benefits of duquetide therapy were also identified.