Comprehensive genomic profiling of salivary gland carcinoma: Analysis of the Center for Cancer Genomics and Advanced Therapeutics database in Japan.

Comprehensive information on genetic alterations in salivary gland cancer (SGC) is limited. This study aimed to elucidate the genetic and clinical characteristics of patients with SGC using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, a Japanese national genomic database. We analyzed data of 776 patients with SGC registered in the C-CAT database between June 1, 2019, and June 30, 2023. Adenoid cystic carcinoma was the most common histologic type, followed by salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified. Genetic data of 681 patients receiving FoundationOne® CDx were analyzed. We identified specific features of the combination of TP53 and CDKN2A alterations among the histological types. Specific LYN amplification was mainly detected in carcinoma ex pleomorphic adenoma and myoepithelial carcinoma. For SDC, the frequency of ERBB2 and BRAF alterations were higher in cases with metastatic lesions than in those with primary lesions. Although 28.6% patients were offered recommended treatment options, only 6.8% received the recommended treatments. This study highlights the differences in genetic alterations among the histological types of SGC, with comprehensive genomic profiling tests revealing lower drug accessibility. These findings could contribute to the development of personalized treatment for patients with SGC.

Subsite-specific trends in mid- and long-term survival for head and neck cancer patients in Japan: A population-based study.

Advances in diagnostic techniques and treatment modalities have impacted head and neck cancer (HNC) prognosis, but their effects on subsite-specific prognosis remain unclear. This study aimed to assess subsite-specific trends in mid- and long-term survival for HNC patients diagnosed from 1993 to 2011 using data from population-based cancer registries in Japan. We estimated the net survival (NS) for HNC by subsite using data from 13 prefectural population-based cancer registries in Japan. Changes in survival over time were assessed by multivariate excess hazard model of mortality. In total, 68,312 HNC patients were included in this analysis. We observed an overall improvement in 5-year NS for HNC patients in Japan. However, survival varied among subsites of HNC, with some, such as naso-, oro- and hypopharyngeal cancers, showing significant improvement in both 5- and 10-year NS, whereas others such as laryngeal cancer showed only a slight improvement in 5-year NS and no significant change in 10-year NS after adjustment for age, sex and stage. In conclusion, the study provides insights into changing HNC survival by site at the population level in Japan. Although advances in diagnostic techniques and treatment modalities have improved survival, these improvements are not shared equally among subsites.

Survival Outcome Superiority of Total Pharyngolaryngectomy Compared with Chemoradiotherapy for T4aM0 Hypopharyngeal Squamous Cell Carcinoma: A Nationwide Database Study of Japan.

BACKGROUND: The purpose of this study is to elucidate whether total pharyngolaryngectomy (TPL) or chemoradiotherapy (CRT) provides a better prognostic outcome in patients with T4aM0 hypopharyngeal carcinoma (HPSCC) using a nationwide database. METHODS: All data were obtained from the Head and Neck Cancer Registry of Japan, and information from patients who were newly diagnosed with T4aM0 HPSCC between 2011 and 2015 was extracted. The primary endpoint was disease-specific survival (DSS), and the secondary endpoint was overall survival (OS). The inverse probability of treatment weighting (IPTW) adjustments was used for survival analyses. RESULTS: Our cohort included 1143 patients. The TPL and CRT groups included 724 and 419 patients, respectively. Following IPTW adjustments, both the OS and DSS of the TPL group were significantly longer than those of the CRT group (P = .02 and P = .002, respectively). CONCLUSIONS: Survival superiority was demonstrated for patients with T4aM0 HPSCC treated with TPL compared with those treated with CRT.

Definitive radiotherapy for nasopharyngeal carcinoma in Japan: analysis of cases in the National Head and Neck Cancer Registry from 2011 to 2014.

OBJECTIVE: This study aimed to analyze the nationwide prognosis of patients with nasopharyngeal carcinoma who underwent definitive radiotherapy in Japan, utilizing the National Head and Neck Cancer Registry data. METHODS: A total of 741 patients diagnosed with primary nasopharyngeal carcinoma were screened from 2011 to 2014. The inclusion criteria were histologically proven nasopharyngeal squamous cell carcinoma, receiving definitive radiotherapy, and no distant metastases. Patients with unclear prognoses or unknown staging were excluded. The primary endpoint was 5-year overall survival, and secondary endpoints were 5-year progression-free survival and survival by stage. RESULTS: A total of 457 patients met the inclusion criteria. The median age was 60 years, and 80% were male. The proportions of patients with performance status 0, 1, 2 and 3 were 69, 10, 1 and 1%, respectively. Chemoradiotherapy was administered to 84.7%. Radiotherapy modalities were recorded only for 29 patients (three received intensity-modulated radiotherapy and 26 received two/three-dimensional radiotherapy). Of those included, 7.4, 24.7, 35.7, 24.5 and 7.7% had Stage I, II, III, IVA and IVB disease, respectively. The 5-year overall survival was 72.5% for all patients: 82.6, 86.6, 76.0, 51.4 and 66.5% for Stage I, II, III, IVA and IVB disease, respectively. The 5-year progression-free survival was 58.6%: 75.6, 66.8, 61.5, 43.7 and 46.5% for Stage I, II, III, IVA and IVB disease, respectively. CONCLUSIONS: This nationwide survey demonstrated favorable prognoses and provided valuable foundational data for similar future surveys to monitor the penetration of appropriate treatment and changes in clinical structures based on new evidence.

Radiotherapy with or without chemotherapy for locally advanced head and neck cancer in elderly patients: analysis of the Head and Neck Cancer Registry of Japan.

BACKGROUND: Whether concurrent chemotherapy with radiotherapy (CRT) is effective for elderly patients with head and neck cancer is a controversial topic. This study aimed to analyze the effectiveness of CRT vs. radiation therapy (RT) among elderly patients in Japan. METHODS: Data from the Head and Neck Cancer Registry of Japan were extracted and analyzed. Patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who received definitive CRT or RT between 2011 and 2014 were included. RESULTS: CRT was administered to 78% of the 1057 patients aged ≥ 70 years and 67% of the 555 patients aged ≥ 75 years. For the patients aged ≥ 75 years, the overall survival (OS) rate was significantly better in the CRT group than in the RT group (P < 0.05), while the progression-free survival (PFS) rate was not significantly different (P > 0.05). The add-on effect of CRT was significantly poor in elderly patients (P < 0.05), and it was not a significant factor in the multivariate analysis for patients aged ≥ 75 years. After propensity score matching, there were no significant differences in the OS and PFS rates between the patients aged ≥ 70 years and those aged ≥ 75 years (all, P > 0.05). CONCLUSION: Although aggressive CRT is administered to elderly patients in Japan, its effectiveness is uncertain. Further prospective randomized trials are needed to verify whether CRT is superior to RT alone for elderly patients.

Survival impact of sequential chemotherapy following pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Pembrolizumab alone or combined with chemotherapy is the standard of care for first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) with positive programmed death-ligand 1 combined positive scores. However, data on second-line chemotherapy following pembrolizumab are scarce. METHODS: A single-center, retrospective study was conducted to determine the efficacies of pembrolizumab and pembrolizumab plus chemotherapy as first-line treatments and the efficacy of second-line chemotherapy for patients with R/M HNSCC who were refractory or intolerant to first-line treatment. RESULTS: Fifty-four patients were treated with pembrolizumab, and 29 received second-line therapy, with 27 opting for cetuximab-containing regimens. The median progression-free survival (PFS), overall survival (OS), and PFS on next-line therapy for first-line treatment were 4.7 (95% confidence interval [CI], 2.1-8.7), 22.1 (95% CI, 12.6-not reached), and 15.6 months (95% CI, 9.7-not reached) in the pembrolizumab group and 5.4 (95% CI, 3.3-6.8), 15.8 (95% CI, 8.6-not reached), and 13.7 months (95% CI, 8.1-not reached) in the pembrolizumab plus chemotherapy group, respectively. The overall response rate and median PFS for second-line treatment were 48.3% (95% CI, 30.4-67.0) and 6.1 months (95% CI, 2.30-8.84). The median OS for patients who received second-line treatment was 18.4 months, which was superior to the median OS of 6.0 months for patients who received the best supportive care (log-rank p = 0.10). CONCLUSION: This study indicates that cetuximab-containing second-line chemotherapy can improve outcomes in R/M HNSCC, even after first-line therapy failure or intolerance.

Mature dendritic cells enriched in regulatory molecules may control regulatory T cells and the prognosis of head and neck cancer.

We previously reported that regulatory T (Treg) cells expressing CTLA-4 on the cell surface are abundant in head and neck squamous cell carcinoma (HNSCC). The role of expanded Treg cells in the tumor microenvironment of HNSCC remains unclear. In this study, we reveal that the tumor microenvironment of HNSCC is characterized by the high expression of genes related to Treg cells, dendritic cells (DCs), and interleukin (IL)-17-related molecules. Increased expression of IL17A, IL17F, or IL23A contributes to a favorable prognosis of HNSCC. In the tumor microenvironment of HNSCC, IL23A and IL12B are expressed in mature dendritic cells enriched in regulatory molecules (mregDCs). The mregDCs in HNSCC are a migratory and mature phenotype; their signature genes strongly correlate with Treg signature genes in HNSCC. We also observed that IL17A was highly expressed in Th17 cells and exhausted CD8+ T cells in HNSCC. These data suggest that mregDCs in HNSCC may contribute to the prognosis by balancing Treg cells and effector T cells that produce IL-17. Targeting mregDCs may be a novel strategy for developing new immune therapies against HNSCC.

The Landscape of MYB/MYBL1- and Peri-MYB/MYBL1-Associated Rearrangements in Adenoid Cystic Carcinoma.

Approximately 60% of adenoid cystic carcinoma (AdCC) cases are positive for MYB::NFIB or MYBL1::NFIB, whereas MYB/MYBL1 oncoprotein, a key driver of AdCC, is overexpressed in most cases. Juxtaposition of superenhancer regions in NFIB and other genes into the MYB/MYBL1 locus is an attractive oncogenic hypothesis for AdCC cases, either negative or positive for MYB/MYBL1::NFIB. However, evidence supporting this hypothesis is insufficient. We examined 160 salivary AdCC cases for rearrangements in MYB/MYBL1 loci and peri-MYB/MYBL1 areas (centromeric and telomeric areas of 10 Mb each) using formalin-fixed, paraffin-embedded tumor sections. For the detection of the rearrangements, we employed conventional fluorescence in situ hybridization split and fusion assays and a 5 Mb fluorescence in situ hybridization split assay. The latter is a novel assay that enabled us to detect any possible splits within a 5 Mb distance of a chromosome. We found MYB/MYBL1- and peri-MYB/MYBL1-associated rearrangements in 149/160 patients (93%). AdCC cases positive for rearrangements in MYB, MYBL1, the peri-MYB area, and the peri-MYBL1 area numbered 105 (66%), 20 (13%), 19 (12%), and 5 (3%), respectively. In 24 peri-MYB/MYBL1 rearrangement-positive cases, 14 (58%) were found to have a juxtaposition of the NFIB or RAD51B locus into the MYB/MYBL1 loci. On comparing with a tumor group positive for MYB::NFIB, a hallmark of AdCC, other genetically classified tumor groups had similar features of overexpression of the MYB transcript and MYB oncoprotein as detected by semiquantitative RT-qPCR and immunohistochemistry, respectively. In addition, clinicopathological and prognostic features were similar among these groups. Our study suggests that peri-MYB/MYBL1 rearrangements may be a frequent event in AdCC and may result in biological and clinicopathological consequences comparable to MYB/MYBL1 rearrangements. The landscape of MYB/MYBL1 and peri-MYB/MYBL1 rearrangements shown here strongly suggests that juxtaposition of superenhancers into MYB/MYBL1 or peri-MYB/MYBL1 loci is an alteration that acts as a key driver for AdCC oncogenesis and may unify MYB/MYBL1 rearrangement-positive and negative cases.

Macroscopic and multiple metastases in sentinel lymph node biopsy are respectively associated with poor prognosis in early oral cancer.

BACKGROUND: A multicenter, randomized controlled phase III trial was conducted on sentinel lymph node biopsy (SLNB) and elective neck dissection for T1 (depth of invasion ≥ 4 mm)-T2N0M0 oral cavity squamous cell carcinoma. This study identified factors associated with poor prognosis in patients who underwent SLNB based on a subgroup analysis of this trial. METHODS: We analyzed 418 sentinel lymph nodes (SLNs) from 132 patients who underwent SLNB. The metastatic SLNs were classified into three categories based on size-isolated tumor cells: < 0.2 mm, micrometastasis: ≥ 0.2 mm and < 2 mm, and macrometastasis: ≥ 2 mm. Three groups were formed based on the number of metastatic SLNs: no metastasis, 1 metastatic node, and ≥ 2 metastatic nodes. The size and number of metastatic SLNs on survival were evaluated using Cox proportional hazard models. RESULTS: Patients with macrometastasis and ≥ 2 metastatic SLNs had worse overall survival (OS) and disease-free survival (DFS) after adjustment for potential confounders (HR for OS: macrometastasis, 4.85; 95% CI 1.34-17.60; ≥ 2 metastatic SLN, 3.63; 95% CI 1.02-12.89; HR for DFS: macrometastasis, 2.94; 95% CI 1.16-7.44; ≥ 2 metastatic SLN, 2.97; 95% CI 1.18-7.51). CONCLUSIONS: In patients who underwent SLNB, a poorer prognosis was associated with macrometastasis or having ≥ 2 metastatic SLNs.

Salivary mucoepidermoid carcinoma: histological variants, grading systems, CRTC1/3-MAML2 fusions, and clinicopathological features.

AIMS: To investigate the histological diversity of salivary mucoepidermoid carcinoma (MEC), its clinicopathological features, and its associations with CRTC1/3-MAML2 fusions. METHODS AND RESULTS: Salivary MEC cases (n = 177) were examined for CRTC1/3-MAML2 fusions, histological variants were classified, and tumours were graded according to four different grading systems. Adverse histological features considered to be unusual in MEC were also investigated. Of the 177 MEC cases, 110 were positive for CRTC1/3-MAML2 fusions. The classical variant was the most frequent in the fusion-positive case group, the fusion-negative case group, and the total case group. The clear/oncocytic variant was the second most frequent in the fusion-positive and total case groups. Oncocytic, Warthin-like and spindle variants were seen in the fusion-positive case group only. Clear cell, sclerosing, mucinous and central variants were seen in both the fusion-positive case group and the fusion-negative case group. No case was classified as a ciliated variant, as a mucoacinar variant, or as a high-grade transformation. As compared with the classical variant, non-classical variants were characterised by frequent CRTC1/3-MAML2 fusions and a low clinical stage in all cases. Of the four histological features considered to be unusual in MEC, marked nuclear atypia, frequent mitoses (>10/10 high-power fields) and extensive necrosis were found independently of the fusion status, and were present in 3-5% of all cases. However, none of the cases showed overt keratinisation. On comparison, the Armed Forces Institute of Pathology and modified Healey grading systems downgraded tumours, the Brandwein system upgraded tumours, and the Memorial Sloan Kettering system provided a moderate means of assessment. CONCLUSION: Recognition of the histological diversity of MEC, its clinicopathological features and its associations with CRTC1/3-MAML2 fusions is helpful for an accurate diagnosis of this carcinoma.

Pathological evaluation of tumor grade for salivary adenoid cystic carcinoma: A proposal of an objective grading system.

Three pathological grading systems advocated by Perzin/Szanto, Spiro, and van Weert are currently used for adenoid cystic carcinoma (AdCC). In these systems, the amount or presence of the solid tumor component in AdCC specimens is an important index. However, the "solid tumor component" has not been well defined. Salivary AdCC cases (N = 195) were collected after a central pathology review. We introduced a novel criterion for solid tumor component, minAmax (minor axis maximum). The largest solid tumor nest in each AdCC case was histologically screened, the maximum oval fitting the solid nest was estimated, and the length of the minor axis of the oval (minAmax) was measured. The prognostic cutoff for the minAmax was determined using training and validation cohorts. All cases were evaluated for the four grading systems, and their prognostic impact and interobserver variability were examined. The cutoff value for the minAmax was set at 0.20 mm. Multivariate prognostic analyses showed the minAmax and van Weert systems to be independent prognostic tools for overall, disease-free, and distant metastasis-free survival while the Perzin/Szanto and Spiro systems were selected for overall survival but not for disease-free or distant metastasis-free survival. The highest hazard ratio for overall survival (11.9) was obtained with the minAmax system. The reproducibility of the minAmax system (kappa coefficient of 0.81) was scored as very good while those of the other three systems were scored as moderate. In conclusion, the minAmax is a simple, objective, and highly reproducible grading system useful for prognostic stratification for salivary AdCC.

Prognostic impact of CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma: A multiinstitutional retrospective study.

Mucoepidermoid carcinoma (MEC) is rare, but the most common primary malignancy of the salivary gland and not infrequent in young individuals. CRTC1/3-MAML2 fusions are frequently detected in MEC and are useful as a diagnostic biomarker. However, there has been debate as to whether the fusions have prognostic significance. In this study, we retrospectively collected 153 salivary gland MEC cases from 11 tertiary hospitals in Japan. As inclusion criteria, the MEC patients in this study had curative surgery as the initial treatment, received no preoperative treatment, and had no distant metastasis at the time of the initial surgery. The MEC diagnosis was validated by a central pathology review by five expert salivary gland pathologists. The CRTC1/3-MAML2 fusions were detected using FISH and RT-PCR. In 153 MEC cases, 90 (58.8%) were positive for CRTC1/3-MAML2 fusions. During the follow-up period, 28 (18.3%) patients showed tumor recurrence and 12 (7.8%) patients died. The presence of the fusions was associated with favorable tumor features. Of note, none of the fusion-positive patients died during the follow-up period. Statistical analysis showed that the presence of the fusions was a prognostic indicator of a better overall survival in the total and advanced-stage MEC cohorts, but not in the early-stage MEC cohort. In conclusion, CRTC1/3-MAML2 fusions are an excellent biomarker for favorable overall survival of patients with salivary gland MEC.

Adverse respiratory outcomes among head and neck cancer survivors in the Utah Cancer Survivors Study.

BACKGROUND: The number of head and neck cancer (HNC) survivors has been increasing because of improving survival in the United States. The aim of this study was to evaluate the incidence of respiratory disease diagnoses in HNC survivors in comparison with cancer-free individuals. A second aim was to investigate risk factors for respiratory disease among HNC survivors. METHODS: Patients with HNC diagnosed from 1996 to 2012 were identified in the Utah Cancer Registry (n = 1901). Up to 5 cancer-free individuals from the general population (n = 7796) were matched to each HNC survivor by birth year, sex, birth state, and follow-up time. Electronic medical records and statewide health care facility data were used to identify a disease diagnosis after the cancer diagnosis. Cox proportional hazards models were used to estimate the risks of respiratory diseases. RESULTS: The median follow-up times were 4.5 years for HNC survivors and 7.8 years for the general population cohort. The risks of respiratory infection (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.40-1.90), chronic obstructive pulmonary diseases and bronchiectasis (HR, 2.65; 95% CI, 2.13-3.29), and aspiration pneumonitis (HR, 6.21; 95% CI, 3.98-9.68) were higher among HNC survivors than the general population cohort more than 5 years after the cancer diagnosis. Age at diagnosis, baseline body mass index, sex, baseline smoking status, treatment modality, primary site, and stage were associated with the risk of adverse respiratory outcomes among HNC survivors. CONCLUSIONS: The risk of adverse respiratory outcomes was much higher among HNC survivors than the general population cohort. Multidisciplinary care is needed to prevent the occurrence of adverse respiratory outcomes among HNC survivors.

Clinicopathological significance of EGFR pathway gene mutations and CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma.

AIMS: Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland carcinomas. Epidermal growth factor receptor (EGFR) signalling pathway gene mutations are important in predicting a patient's prognosis, selecting molecularly targeted drugs and estimating the efficacy of a molecular therapy. However, their significance in MEC have been poorly clarified. CRTC1/3-MAML2 fusions are specific to MEC and may be associated with favourable characteristics in these patients. METHODS AND RESULTS: We looked for CRTC1/3-MAML2 fusions and gene alterations in the EGFR, RAS family (KRAS, HRAS and NRAS), PIK3CA, BRAF and AKT1 in 101 MEC cases. We also examined mutations in TP53. CRTC1/3-MAML2 fusions were found in 62.4% of the cases. KRAS, HRAS and PIK3CA mutations were detected in 6.9%, 2.0% and 6.9%, respectively, but other EGFR pathway genes were not mutated. In total, gene mutations (RAS/PIK3CA) in the EGFR pathway were detected in 14.9% of the cases. TP53 mutations were found in 20.8%. CRTC1/3-MAML2 fusions were associated with a better prognosis and RAS/PIK3CA mutations a worse prognosis of the patients, respectively, and both were selected as independent prognostic factors for the overall survival of the patients. TP53 mutations had no prognostic impact. CRTC1/3-MAML2 fusion-positive rates were inversely associated with the patients' age and the fusions were found in 82% of patients aged < 30 years. CONCLUSIONS: RAS/PIK3CA mutations were frequently detected, and may be a biomarker for a poorer prognosis in MEC patients. CTRC1/3-MAML2 fusions were positive in most of the young MEC patients.

Next-generation sequencing assay in salivary gland cytology: A pilot study.

BACKGROUND: Preoperative diagnosis of salivary gland tumors (SGTs) by fine-needle aspiration (FNA) cytology is challenging. Next-generation sequencing (NGS)-based assays for somatic mutations have a great advantage in that a large number of genes can be analyzed simultaneously. Although NGS may have an enormous diagnostic potential in cytology, to our knowledge, the significance of NGS in SGT cytology remains to be clarified. METHODS: In this pilot study, we retrospectively examined 32 frozen SGT samples obtained at surgery (14 malignant and 18 benign). After the stored frozen tumor tissues were thawed, aspirate samples were obtained using 22-gauge needles and subjected to smear tumor samples and to DNA extraction for an NGS assay employing the Illumina AmpliSeq Cancer Hotspot Panel v2. The results were correlated to preoperative cytological diagnosis. RESULTS: The preoperative diagnoses obtained by FNA cytology included 23 negative lesions (no malignancy in 6 and benign tumor in 17) and nine positive lesions (suspicious for malignancy in 4 and malignancy in five), providing a sensitivity and a specificity of 9/14 (64%) and 18/18 (100%), respectively. The NGS assay detected somatic mutations in 10/14 malignant and 1/18 benign SGT cases, providing a sensitivity and a specificity of 71% and 94%, respectively. CONCLUSION: The NGS assay may be helpful for detecting the malignant potential in SGT cases and can be used as an ancillary test for SGT cytology.

The impact of clinicopathological factors on clinical outcomes in patients with salivary gland adenoid cystic carcinoma: a multi-institutional analysis in Japan.

BACKGROUND: Owing to the low incidence of adenoid cystic carcinoma (AdCC), reliable survival estimates and prognostic factors remained unclarified. METHODS: In this multi-institutional retrospective analysis, we collected 192 AdCC cases, and investigated the impact of clinicopathological factors on clinical outcomes of the patients. All AdCC cases were of salivary gland origin and were surgically treated with curative intent. Diagnoses of AdCC were validated by a central pathology review by expert pathologists. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 92.5 and 50.0%, respectively. Treatment failure occurred in 89 patients (46%) with the distant failures in 65 (34%). Multivariate analysis indicated that pN2 and a pathologically positive surgical margin were independent prognostic factors for both OS and DFS. Histological grade III was an independent prognostic factor for OS. A primary site in the submandibular gland, pT3/4, pN1, and histological grade II were independent prognostic factors for DFS. Postoperative radiation therapy (PORT) improved the locoregional control (LRC) rate. Prophylactic neck dissection was not associated with a better OS or better LRC among patients with cN0. Facial nerve dissection did not improve clinical outcomes in parotid AdCC cases without facial nerve palsy. CONCLUSIONS: A higher TN classification, a pathologically positive surgical margin, and a higher histological grade were associated with a lower OS. PORT improved LRC rates but neck dissection failed to improve clinical outcomes in patients with cN0. As the distant metastasis was frequent, effective systemic therapy is imperative to improve the survival of AdCC patients.

Fiber intake and the risk of head and neck cancer in the prostate, lung, colorectal and ovarian (PLCO) cohort.

Although the protective role of dietary fiber on cancer risk has been reported in several epidemiological studies, the association of fiber intake on head and neck cancer (HNC) risk is still unclear. We investigated the association between fiber intake and the risk of HNC using data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Among 101,700 participants with complete dietary information, 186 participants developed HNC during follow-up (January 1998 to May 2011). Dietary data were collected using a self-administered food-frequency questionnaire (1998-2005). We estimated hazard ratios (HRs) and the corresponding 95% confidence intervals (CI), using the Cox proportional hazards model. Higher intake of total fiber, insoluble fiber and soluble fiber was associated with decreased HNC risks, with a significant trend. The HRs of highest vs. the lowest tertile of intake were 0.43 (95%CI: 0.25-0.76) for total fiber, 0.38 (95%CI: 0.22-0.65) for insoluble fiber, and 0.44 (95%CI: 0.25-0.79) for soluble fiber. These inverse association were consistent in oral cavity and pharyngeal cases, but the impact of fiber intake was weaker in laryngeal cases. We did not observe any significant interaction of potential confounders, including smoking and drinking, with total fiber intake on HNC risk. These findings support evidence of a protective role of dietary fiber on HNC risk.

Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer.

FOXP3+ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4+ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface-CTLA-4+ and surface-CTLA-4- Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4+ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4+ Treg cells were PD-1+ , actively proliferated and associated with CD45RA- FOXP3high Treg cells with strong suppressive function. Thus, surface-CTLA-4+ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4+ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer.

Alcohol and head and neck cancer.

In this article, we reviewed the association between alcohol drinking and head and neck cancer (HNC) and its subsites, using the available literature. Alcohol drinking is an established risk factor for HNC, and this association may be stronger among cancers of the oropharynx and hypopharynx than the oral cavity or larynx. In addition, higher alcohol consumption over a shorter period was more harmful than fewer alcohol consumption over a longer period, and the most frequently consumed alcoholic beverages in a population is likely to be associated with the highest risk of HNC in that population. The risk of HNC after ≥ 20 years of alcohol cessation appear to be similar to the risk among never drinkers. The interaction between genetic polymorphisms related to alcohol metabolism and alcohol drinking on the risk of HNC has been noted, and the prevalence of these genetic polymorphisms in each population should be of concern. Finally, the association between alcohol drinking and the survival of individuals with HNC remains unclear, and mortality due to competing causes should be considered in future research to evaluate this association.