Etiology, diagnosis, treatment, and prevention of human papilloma virus-associated oropharyngeal squamous cell carcinoma.

Classical oropharyngeal squamous cell carcinoma (OPSCC) caused by alcohol consumption and smoking and HPV-associated OPSCC caused by human papillomavirus (HPV) infection have different etiologies, incidences, and prognoses. Therefore, the 8th American Joint committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM classifications propose distinguishing HPV-associated OPSCC from classical OPSCC and classifying it as an independent disease. Therefore, this review provides an overview of HPV-associated OPSCC from the perspectives of epidemiology, carcinogenesis, development, diagnosis, treatment, and prevention. The incidence of HPV-associated OPSCC is increasing. Although HPV vaccination has been shown to be effective at reducing the incidence of cervical cancer, it is still unclear how it affects the incidence of HPV-associated OPSCC. Additionally, the prognosis of patients with HPV-associated OPSCC is extremely favorable compared to that of patients with classical OPSCC. Therefore, patients with HPV-associated OPSCC may undergo reduced-dose therapy, although attempts to reduce treatment intensity should be carefully planned to ensure they do not compromise oncological outcomes, and large-scale trials aimed at reducing treatment intensity are ongoing.

Incidence and spread pattern of lymph node metastasis from submandibular gland cancer.

OBJECTIVES: To clarify the indication of neck dissection (ND) for patient with submandibular gland (SMG) cancer. METHODS: A total of 43 patients with SMG cancer were retrospectively analyzed. Forty-one patients underwent ND: Levels I-V in 19 patients, Levels I-III in 18 patients, and Level Ib in 4 patients. The other two patients did not undergo ND, since preoperative diagnoses were benign. Postoperative radiotherapy was performed in 19 patients with positive surgical margin, high grade cancer or stage IV disease. RESULTS: LN metastases were pathologically confirmed in all patients with cN + and 6 out of 31 patients with cN-. No patients developed regional recurrence during follow-up periods. Ultimately, LN metastases were pathologically confirmed in 17 of 27 high grade, one out of 9 intermediate grade, but not in 7 low grade. CONCLUSIONS: Prophylactic neck dissection should be considered in T3/4 and high grade SMG cancers.

Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF-CRT) for locally advanced squamous cell carcinoma of the external auditory canal.

PURPOSE: Chemoradiotherapy with docetaxel (DOC), cisplatin (CDDP), and 5-FU (TPF-CRT) for locally advanced external auditory canal cancer (EACC) has favorable oncological and functional outcomes. To establish TPF-CRT as a standard of care for advanced EACC, we conducted this study to determine the maximum tolerated (MTD) and recommended dose (RD) of DOC in TPF-CRT for locally advanced EACC. METHODS: To determine the recommended (RD) and maximum tolerated dose (MTD) of DOC in TPF-CRT for EACC, a phase I trial was conducted using the standard "3 + 3" design for maximum dose finding. DOC was administered twice every 4 weeks, CDDP at 70 mg/m2 and 5-FU at 700 mg/m2; patients were also receiving radiotherapy (66 Gy). Eight patients with T3 or T4 EACC were prospectively enrolled. RESULTS: Two patients treated with DOC, 50 mg/m2, and one out of six patients treated with DOC, 40 mg/m2, had dose-limiting toxicities. Prolonged febrile neutropenia was observed in three patients. Grade 3 non-hematological toxicities were observed in only three patients. At study completion, six patients survived, five of whom were disease free. CONCLUSION: The RD and MTD of DOC in TPF-CRT for locally advanced EACC are 40 mg/m2 when doses of CDDP and 5-FU are 70 mg/m2 and 700 mg/m2, respectively.

Botulinum toxin injection into the intrinsic laryngeal muscles to treat spasmodic dysphonia: A multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial.

BACKGROUND AND PURPOSE: Botulinum toxin (BT) injection into the laryngeal muscles has been a standard treatment for spasmodic dysphonia (SD). However, few high-quality clinical studies have appeared, and BT is used off-label in most countries. METHODS: We performed a multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial to obtain approval for BT (Botox) therapy in Japan. Twenty-four patients (22 with adductor SD and two with abductor SD) were enrolled. The primary end point was the change in the number of aberrant morae (phonemes) at 4 weeks after drug injection. The secondary end points included the change in the number of aberrant morae, GRBAS scale, Voice Handicap Index (VHI), and visual analog scale (VAS) over the entire study period. RESULTS: In the adductor SD group, the number of aberrant morae at 4 weeks after injection was reduced by 7.0 ± 2.30 (mean ± SE) in the BT group and 0.2 ± 0.46 in the placebo group (p = 0.0148). The improvement persisted for 12 weeks following BT injections. The strain element in GRBAS scale significantly reduced at 2 weeks after BT treatment. The VHI and VAS scores as subjective parameters also improved. In the abductor SD group, one patient responded to treatment. Adverse events included breathy hoarseness (77.3%) and aspiration when drinking (40.9%) but were mild and resolved in 4 weeks. CONCLUSIONS: Botulinum toxin injection was safe and efficacious for the treatment of SD. Based on these results, BT injection therapy was approved as an SD treatment in Japan.

Optimization of therapeutic strategy for p16-positive oropharyngeal squamous cell carcinoma: Multi-institutional observational study based on the national Head and Neck Cancer Registry of Japan.

BACKGROUND: Although the American Joint Committee on Cancer TNM classification has been amended to include human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) as an independent entity, to the authors' knowledge the optimized de-escalating treatment modality has not been established to date. METHODS: The authors conducted a retrospective, nationwide, observational study in patients with HPV-related OPSCC who were treated from 2011 to 2014 in Japan to determine the best treatment modality. RESULTS: A total of 688 patients who were newly diagnosed with HPV-related OPSCC who were treated with curative intent at 35 institutions and had coherent clinical information and follow-up data available were included in the current study. In patients with T1-T2N0 disease (79 patients), both the 3-year recurrence-free survival and overall survival (OS) rates were 100% in the group treated with radiotherapy (RT) as well as the group receiving concurrent chemoradiotherapy (CCRT). The 3-year OS rates were 94.4% (for patients with T1N0 disease) and 92.9% (for patients with T2N0 disease) among the patients treated with upfront surgery. In patients with stage I to stage II HPV-related OPSCC, the 5-year recurrence-free survival and OS rates were 91.4% and 92%, respectively, in the patients treated with CCRT with relatively high-dose cisplatin (≥160 mg/m2 ; 114 patients) and 74.3% and 69.5%, respectively, in the patients treated with low-dose cisplatin (<160 mg/m2 ; 17 patients). CONCLUSIONS: Despite it being a retrospective observational trial with a lack of information regarding toxicity and morbidity, the results of the current study demonstrated that patients with T1-T2N0 HPV-related OPSCC could be treated with RT alone because of the equivalent outcomes of RT and CCRT, and patients with stage I to stage II HPV-related OPSCC other than those with T1-T2N0 disease could be treated with CCRT with cisplatin at a dose of ≥160 mg/m2 .

Extent of neck dissection for patients with clinical N1 oral cancer.

BACKGROUND: No clear consensus has been reached on the indication of supraomohyoid neck dissection (SOHND) for clinically positive lymph-node metastasis. PATIENTS: Consecutive 100 patients with previously untreated oral cancer treated at Kobe University Hospital were included in this study. All patients were clinically staged as anyTN1M0 and underwent radical dissection of the primary site and level I-V neck dissection as the initial treatment. RESULTS: None of the 100 patients had pathological lymph-node metastasis (pLN) to level V. pLN to level IV was observed in two patients with tongue cancer in whom clinical lymph-node metastasis was preoperatively observed at level II. CONCLUSIONS: Level V may be excluded in the neck dissection for patients with N1 oral cancers. Level IV dissection should be considered in the patient with tongue cancer and clinical lymph-node metastasis at level II.

Salvage surgery for structural local recurrence of papillary thyroid cancer: recurrence patterns and surgical outcome.

To clarify the patterns of the recurrence and to assess the oncological and functional outcomes after salvage surgery for the patients with structural local recurrence of papillary thyroid cancer (PTC), twenty-five patients who underwent salvage surgery for structural local recurrence of PTC were retrospectively reviewed. Structural recurrences were observed in the tracheal lumen in 5 patients, intraluminal or intramuscular esophagus in 5 patients, trachea, and cricoid cartilage in 9 patients, cricoid and thyroid cartilage in 2 patients, intra-lumen of the larynx in 1 patient and soft tissue around thyroid in 3 patients, respectively. Although all local disease was resected with macroscopically negative margin, 10 patients diagnosed as microscopically positive margin. Major surgical complications occurred in 6 patients, including common carotid artery injury (n = 1), unintentional pharyngeal or esophageal injury (n = 2), recurrent laryngeal nerve paralysis (n = 2), and pharyngeal fistula resulting in common carotid artery rupture (n = 1), and were successfully managed. During the follow-up periods, 6 patients were alive without disease, 15 patients survived with distant metastases and/or locoregional recurrence, and 4 patients died of the disease. While tracheocutaneous fistula remained in 7 patients, the vocal function was preserved in all patients but one who underwent total laryngectomy. Normal oral intake was retained in all patients. In conclusion, although salvage surgery for structural recurrence of PTC has a high risk of complications, it may be worthwhile when macroscopic curative resection is available. The decision should be made considering various factors including curability, risk of surgical procedure, functional outcome, and life expectancy.

Clinical impact of a cytological screening system using cyclin D1 immunostaining and genomic analysis for the diagnosis of thyroid nodules.

BACKGROUND: Fine-needle aspiration (FNA) is the most reliable method for diagnosing thyroid nodules; however, some features such as atypia of undetermined significance or follicular lesion of undetermined significance can confound efforts to identify malignancies. Similar to BRAF, cyclin D1 may be a strong marker of cell proliferation. METHODS: One hundred two patients with thyroidal nodule were enrolled in this prospective study. Expression of cyclin D1 in thyroid nodules was determined by immunohistochemistry using both surgical specimens and their cytological specimens. The identification of the optimal cut off points for the diagnosis of malignancy were evaluated using the receiver operating characteristic (ROC) curves and the assessment of the area under the ROC curve (AUC). The specificity, sensitivity, positive predictive value (PPV) of markers were evaluated from crosstabs based on cut off points and significance were calculated. We also analyzed genetic variants by target NGS for thyroid nodule samples. RESULTS: The positive predictive value (PPV) and median stain ratio (MSR) of cyclin D1 nuclear staining was determined in papillary thyroid carcinoma (PPV = 91.5%, MSR = 48.5%), follicular adenoma (PPV = 66.7%, MSR = 13.1%), and adenomatous goiter and inflammation controls (MSR = 3.4%). In FNA samples, a threshold of 46% of immunolabelled cells allows to discriminate malignant lesions from benign ones (P < 0.0001), with 81% sensitivity and 100% specificity. A 46% cutoff value for positive cyclin D1 immunostaining in thyroid cells demonstrated 81% sensitivity and 100% specificity. In surgical specimens, ROC curve analysis showed a 5.8% cyclin D1 immunostaining score predicted thyroid neoplasms at 94.4% sensitivity and 92.3% specificity (P = 0.003), while a 15.7% score predicted malignancy at 86.4% sensitivity and 80.5% specificity (P < 0.0001). Finally, three tested clinico-pathological variables (extra thyroidal extension, intraglandular metastasis, and lymph node metastasis) were significant predictors of cyclin D1 immunostaining (P < 0.001). CONCLUSION: Our cytological cyclin D1 screening system provides a simple, accurate, and convenient diagnostic method in precision medicine enabling ready determination of personalized treatment strategies for patients by next generation sequencing using cytological sample.

Functional and oncological outcomes after retropharyngeal node dissection for papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma frequently metastasizes to central and lateral neck lymph nodes, but metastasis to retropharyngeal lymph nodes (RPLN) is rare. PATIENTS AND METHODS: We retrospectively reviewed 16 patients with RPLN metastasis of PTC who underwent therapeutic dissection of RPLN metastases. RESULTS: Among 16 patients, 7 patients underwent RPLN dissection with initial surgery and remaining 9 patients as salvage surgery. RPLN metastasis arose unilaterally in 15 patients and bilaterally in 1 patient. Eleven patients showed temporal dysphagia and four patients showed temporal vocal cord paralysis, but both symptoms eventually recovered in all cases. Two patients with salvage RPLN dissection died of distant metastasis and six patients survived with distant metastasis and/or persistent loco-regional disease. Other eight patients have been alive without disease. CONCLUSIONS: Although transcervical approach for RPLN metastases of PTC provided acceptable functional and oncological outcomes, half of the patients with RPLN metastasis have had distant metastasis and/or persistent locoregional disease. Indications of surgery for patients with RPLN metastasis need to be performed carefully in consideration of patients' prognosis and quality of life.

Epigenetic down-regulation of SOX2 is an independent poor prognostic factor for hypopharyngeal cancers.

AIMS: We recently reported that a small subset (7%) of oesophageal squamous cell carcinomas completely lacking SOX2 expression had unique clinicopathological features and a dismal prognosis. The aim of the present study was to elucidate whether the findings obtained in oesophageal cancers are applicable to hypopharyngeal squamous cell carcinomas (HPSCCs) or oropharyngeal squamous cell carcinomas (OPSCCs). METHODS AND RESULTS: The study cohort consisted of consecutive patients with HPSCC (n = 130) and OPSCC (n = 65) who underwent surgery without preoperative therapy. On immunostaining, SOX2 was almost entirely negative in 10 of 130 HPSCCs (8%) and seven of 65 OPSCCs (11%). No significant differences were observed in clinicopathological features, including p16 status, between SOX2-positive and SOX2-negative cancers. However, patients with SOX2-negative HPSCC had significantly worse overall and recurrence-free survival than those with SOX2-positive HPSCC, whereas such a prognostic relationship was not confirmed in patients with OPSCC. In a multivariate analysis, the loss of SOX2 expression appeared to be an independent poor prognostic factor for patients with HPSCC. In a sequencing analysis, no mutation was found in SOX2. As SOX2 is known to contain an extensive CpG island before the transcription start site, methylation-specific polymerase chain reaction for the SOX2 promoter was performed. Methylated alleles were found in nine of 10 SOX2-negative HPSCCs but in none of SOX2-positive HPSCCs. CONCLUSIONS: Similarly to oesophageal cancers, a small subset (8%) of HPSCCs characteristically almost completely lacking SOX2 expression appeared to be aggressive neoplasms with high recurrence rates. Promoter hypermethylation was determined to be a major mechanism underlying epigenetic SOX2 silencing.

Role of intensive nutrition support and prophylactic percutaneous endoscopic gastrostomy during concomitant chemoradiotherapy for oropharyngeal cancer.

BACKGROUND: Concomitant chemoradiotherapy (CCRT) produces severe mucositis and swallowing dysfunction, often resulting in malnutrition. Intensive nutrition support (INS) in addition to percutaneous endoscopic gastrostomy (PEG) is reported to decrease adverse effects during CCRT. PATIENTS AND METHODS: Fifty-eight patients with oropharyngeal cancer treated by CDDP-based CCRT were retrospectively analyzed. Twenty-nine patients treated with INS in addition to PEG were classified as INS group, and other 29 patients treated with PEG but without INS were classified as control group. RESULTS: INS in addition to PEG significantly increased calorie intake in the second half of CCRT and reduced adverse events including mucositis (p = 0.0019), leukopenia (p = 0.04), and renal function (p = 0.006). Moreover, 21 out of 29 patients had successfully administration of 200 mg/m2 or more of CDDP, while only 10 out of 29 patients had enough amount of CDDP in control group. CONCLUSIONS: These results suggest that INS in addition to prophylactic PEG not only decreases adverse effects but also may potentially improve oncological outcome of the patients with oropharyngeal cancer treated by CCRT.

Translational research in head and neck cancer: Molecular and immunological updates.

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Each year, approximately 880,000 patients are newly diagnosed with HNSCC worldwide, and 450,000 patients with HNSCC die. Risk factors for developing HNSCC have been identified, with cigarette smoking, alcohol consumption, and viral infections being the major factors. Owing to the prevalence of human papillomavirus infection, the number of HNSCC cases is increasing considerably. Surgery and chemoradiotherapy are the primary treatments for HNSCC. With advancements in tumor biology, patients are eligible for novel treatment modalities, namely targeted therapies, immunotherapy, and photoimmunotherapy. Because this area of research has rapidly progressed, clinicians should understand the basic biology of HNSCC to choose an appropriate therapy in the upcoming era of personalized medicine. This review summarized recent developments in tumor biology, focusing on epidemiology, genetic/epigenetic factors, the tumor microenvironment, microbiota, immunity, and photoimmunotherapy in HNSCC, as well as how these findings can be translated into clinical settings.

Differential expression of epidermal growth factor receptor in various pathological types of salivary gland cancers.

OBJECTIVE: While several studies reported epidermal growth factor receptor (EGFR) expression in salivary gland cancer (SGC), results varied due to a lack of unified definition of EGFR positivity. In this study, we assessed the EGFR expression level using both EGFR positive score and cumulative EGFR score in the patients with SGC. METHODS: Between January 2010 and April 2021, 102 patients with SGC who underwent surgical resection were reviewed retrospectively by immunohistochemistry. The membrane staining intensity was scored as follows: no staining (0), weak staining (1+), intermediate staining (2+), and strong staining (3+). The cumulative EGFR score was determined on a continuous scale of 0-300 using the formula:1 × (1+: percentage of weakly stained cells) + 2 × (2+: percentage of moderately stained cells) + 3 × (3+: percentage of strongly stained cells). RESULTS: EGFR expression in SGC varied widely even among the same as well as different histopathological types. The average EGFR positive scores were 46.0 %, 55.7 %, 51.6 %, 1.0 %, 26.8 %, 50 %, and 76.8 % for mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), adenoid cystic carcinoma (AdCC), acinic cell carcinoma (AcCC), adenocarcinoma NOS (ACNOS), carcinoma ex pleomorphic adenoma (CAexPA), and squamous cell carcinoma (SqCC), respectively. The average cumulative EGFR scores were 82, 91, 80, 1, 52, 93, and 185 for MEC, SDC, AdCC, AcCC, ACNOS, CAexPA, and SqCC, respectively. CONCLUSIONS: EGFR positive scores and cumulative EGFR scores in SGCs varied among the various histological types, and even in the same histological type. These scores may predict the clinical outcome of SGC treated with EGFR-targeting therapies, such as head and neck photoimmunotherapy, and need to be evaluated in future studies.

A Case of Olfactory Neuroblastoma Developing Bilateral Retropharyngeal Lymph Node Metastasis 14-years After Skull Base Surgery.

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor and is usually treated by a multidisciplinary approach includes surgery, radiotherapy, and chemotherapy. A 62 years-old male had a tumor in the nasal cavity and diagnosed as ONB with Kadish A stage. Anterior skull base surgery was performed as radical treatment. Since the surgical margin was negative, no postoperative radiotherapy was administered. 14 years after the surgery, bilateral otitis media with effusion (OME) was occurred, we found the recurrence tumor at bilateral retropharyngeal lymph node (RPLN) which surrounded the internal carotid arteries. Since these were unresectable, we planned chemoradiotherapy which was 70Gy of intensity modulated radiotherapy combined with two courses of carboplatin and etoposide. The tumor volume was reduced and bilateral OME were improved. He has been alive for 3 years after salvage treatment. Although ONB has a relatively good prognosis, it is known to often cause cervical lymph node metastasis. Grades III and IV of Hyams classification are considered high risk. This case, initial tumor was limited in the nasal cavity and its clinical classification was early stage, but Hyams classification was grade III. In reference to this case, considering that RPLN metastasis are difficult to radically resect at the salvage surgery, including this area in postoperative radiotherapy was considered an option.

Oncological Outcomes of Concurrent Chemoradiotherapy and Surgical Treatment for Patients With T3 Hypopharyngeal Cancer: A Single-Center Retrospective Analysis.

Background Since the larynx and pharynx are vital for respiration, swallowing, and speech, chemoradiotherapy (CRT) has been widely applied for T3 hypopharyngeal cancer (HPC) as an organ-preserving treatment. However, CRT can lead to severe late adverse events such as dysphagia and aspiration pneumonia, especially in patients who have difficulty swallowing and/or aspiration at the time of initial diagnosis. Patients and methods Between 2012 and 2020, 86 patients with T3 HPC treated with curative intent at Kobe University Hospital were included in this study. The average age was 69 years old, ranging from 43 to 89. Diseases were classified as Stage III in 29 patients, Stage IVA in 52 patients, and Stage IVB in five patients. Thirty-five (41%) patients were treated by CRT, and 51 (59%) patients were treated by surgery. Patients were followed up for at least two years, and the follow-up period ranged from four to 128 months (median: 45 months). Results Three-year progression-free survival (PFS) rates of patients treated by CRT and patients treated by surgery were 56.2% and 60.3%, respectively. Three-year disease-specific survival (DSS) rates of patients treated by CRT and surgically treated patients were 79.0% vs. 70.8%, respectively. Three-year overall survival (OS) rates of patients treated by CRT and surgically treated patients were 64.5% and 69.0%, respectively. Of note, a significant difference was observed between three-year DSS and three-year PFS (79.0% vs. 56.2%, p = 0.0014) in the patients treated by CRT but not in the patients treated by surgery. Conclusions No significant differences were observed between the PFS, DSS, and OS rates of patients treated by CRT and those of surgically treated patients. Locoregional recurrences after CRT were significantly successfully salvaged by surgical intervention. These results suggest that CRT can be applied as an alternative to surgery without reducing survival, especially for patients without severe clinical symptoms. Meticulous follow-up is mandatory for early detection of recurrence to salvage by surgery and for the management of late adverse events.

Induction of Immunological Antitumor Effects by the Combination of Adenovirus-Mediated Gene Transfer of B7-1 and Anti-Programmed Cell Death-1 Antibody in a Murine Squamous Cell Carcinoma Model.

BACKGROUND: The goal of this study was to evaluate the antitumor immune effects of B7-1 gene expression in addition to immune checkpoint inhibitor against squamous cell carcinoma. METHODS: A murine SCC cell line, KLN205, was infected with adenoviral vector carrying B7-1 (AdB7). Infected cells were injected subcutaneously in the flanks of DBA/2 mice. Three weeks after implantation, anti-mouse PD-1 antibody (antiPD1) was intraperitonially administrated twice a week for a total of six times. RESULTS: CD80 was significantly overexpressed in the AdB7-infected tumors. IFN-gamma in the T cells in the spleen was significantly increased and tumor size was significantly reduced in the mice treated with both AdB7 and antiPD1. Targeted tumors treated with both AdB7 and antiPD1 exhibited significantly increased cell densities of total immune cells as well as Ki-67+ CD8+ T cells and decreased regulatory T cells. CONCLUSIONS: These results suggest that the B7-1 gene transfer may enhance the antitumor effect of anti-PD1 antibody against SCC.

Expression of EGFR and p16 in Squamous Cell Carcinoma of External Auditory Canal.

The expression of EGFR and p16 in the external auditory canal squamous cell carcinoma (EACSCC) and their impacts on oncological outcomes were not well studied. Seventeen-one consecutive patients who were treated for EACSCC at Kobe University Hospital from 1995 to 2018 were enrolled in this study. The expression of EGFR, and p16 were evaluated and their impacts on oncological outcomes were statistically analyzed. Positive expression of EGFR was observed in 62 patients (87%). Strong positive expression of p16 were observed in 18 patients (32.4%), and weakly positive expression in 30 patients (42.3%), respectively. While the number of the patients with negative EGFR expression were limited, all the surgically treated patients with negative EGFR expression have been alive without disease. In the patients with T3 & T4a EACSCC, prognosis of the patients with positive p16 expression EACSCC tended to be better than those with negative p16 expression. These results suggest the clinical significance of EGFR and p16 expressions in the patients with advanced EACSCC to predict oncological outcomes.

Dose-Finding and Efficacy Confirmation Trial of the Superselective Intra-arterial Infusion of Cisplatin and Concomitant Radiation Therapy for Locally Advanced Maxillary Sinus Cancer (JCOG1212): Results of the Efficacy Confirmation Phase in Patients with T4aN0M0.

PURPOSE: Locally advanced maxillary sinus cancers require radical surgery as a standard treatment, but this often results in significant disfigurement and impairment of function. JCOG1212 seeks to evaluate the safety and efficacy of the superselective intra-arterial infusion of cisplatin and concomitant radiation therapy (RADPLAT) for T4aN0M0 and T4bN0M0 maxillary sinus squamous cell carcinomas. We herein report the results of the efficacy confirmation phase in the T4a cohort. METHODS AND MATERIALS: Patients received 100 mg/m2 cisplatin intra-arterially weekly for 7 weeks with concomitant radiation therapy (total 70 Gy) as determined by the results of the preceding dose-finding phase. The trial aimed to evaluate the primary endpoint of 3-year overall survival (OS), comparing RADPLAT with the historical control for 3-year OS in surgery (80%). RESULTS: From April 2014 to August 2018, 65 patients were registered in the T4a cohort from 18 institutions, consisting of 54 men and 11 women with a median age of 64 years (range, 40-78 years) and Eastern Cooperative Oncology Group performance status 0/1 (58/7). After excluding 1 ineligible patient, 64 patients were included in the primary analysis of efficacy and safety. The median follow-up was 4.5 years in all eligible patients, and the primary endpoint for 3-year OS was 82.8% (90% CI, 73.4%-89.2%). With regard to acute adverse events, mucositis (grade ≥3), neutropenia (grade ≥3), increased creatinine (grade ≥2), hearing impairment (grade ≥2), and stroke (grade ≥2) were observed in 20.3%, 14.1%, 3.1%, 3.1%, and 1.6% of patients, respectively. One treatment-related death due to a thromboembolic event was reported. CONCLUSIONS: We demonstrated that RADPLAT showed favorable results for patients with T4aN0M0 maxillary sinus squamous cell carcinomas compared with the historical control for 3-year OS in surgery, which was from an earlier period, and showed some specific toxicities. Therefore, RADPLAT, as well as surgery, can be regarded as a possible treatment option for these patients.

Targeting Anterior Commissure Involvement with Hyperfractionated Radiotherapy for T1-T2 Squamous Cell Carcinoma of the Glottic Larynx.

Anterior commissure is involved in about 20% of early-stage glottic squamous cell carcinomas (EGSCCs). Treatment outcomes and prognostic factors for EGSCC with anterior commissure involvement (ACI) were evaluated by focusing on hyperfractionated radiotherapy (74.4 Gy in 62 fractions). One-hundred and fifty-three patients with T1-T2 EGSCC were included in this study. The median total doses for T1a, T1b, and T2 were 66, 74.4, and 74.4 Gy, respectively. Overall, 49 (32%) patients had T1a, 38 (25%) had T1b, and 66 (43%) had T2 disease. The median treatment duration was 46 days. The median follow-up duration was 5.1 years. The 10-year overall and cause-specific survival rates were 72% and 97%, respectively. The 10-year local control rates were 94% for T1a, 88% for T1b, and 81% for T2 disease. Local control rates in patients with ACI were slightly better than those in patients without ACI with T1a and T1b diseases; however, the difference was not significant. The 10-year laryngeal preservation rate was 96%. Six patients experienced grade 3 mucositis, and four patients had grade 3 dermatitis. Hyperfractionated radiotherapy was effective for T1 disease with ACI, but insufficient for T2 disease with ACI. Our treatment strategy resulted in excellent laryngeal preservation.

Summary of Japanese clinical practice guidelines for head and neck cancer - 2022 update edited by the Japan society for head and neck cancer.

The aim of the "Japanese Clinical Practice Guidelines for Head and Neck Cancer - 2022 Update" is to review the latest evidence regarding head and neck cancer and to present the current standard approaches for diagnosis and treatment. These evidence-based recommendations were created with the consensus of the Guideline Committee, which is composed of otorhinolaryngologists and head and neck surgeons, together with radiologists, radiation oncologists, medical oncologists, plastic surgeons, dentists, palliative care physicians, and rehabilitation physicians. These guidelines were created by the Clinical Practice Guideline Committee of the Japan Society for Head and Neck Cancer based on the "Head and Neck Cancer Treatment Guidelines 2018 Edition," and the revised draft was compiled after evaluation by the Assessment Committee and public comments. The 'Clinical questions and recommendations' section consists of 13 categories, and 59 clinical questions are described in total. Here we describe 6 clinical questions specific to other sets of guidelines with recommendations and comments.