OBJECTIVE: In cases of cancer patients with sarcopenia, many adverse effects such as postoperative complications and prognosis have been reported with head and neck cancer. We examined the prevalence and prognosis of sarcopenia according to the site in head and neck cancer in order to clarify the site that require early intervention as the primary endpoints. METHODS: From October 2016 to March 2021, we retrospectively studied 388 cases of 448 primary cases of head and neck cancer who visited our department and for whom measurement using bioelectrical impedance analysis (BIA) and grip strength were possible. 339 cases that had undergone radical treatment were retrospectively examined. RESULT: Of the 388 primary cases of head and neck cancer, 102 patients were diagnosed with sarcopenia. The most common site is oral cancer, followed by oropharyngeal cancer, and hypopharyngeal cancer. In terms of the patient background, sarcopenia was significantly more common in patients aged "65 years or older," in those in "stage III or higher, in those in "T3 or higher," in those with a history of drinking alcohol and in those with "site-related swallowing (oral cavity, oropharynx, and hypopharynx)". The prevalence of sarcopenia in terms of stage classification was 25% or more in advanced cancer cases for all sites of head and neck cancers; however, it was observed from stage I or higher for oropharyngeal cancer and stage II or higher for hypopharyngeal cancer. The 3-year overall survival rate for oral cancer, oropharyngeal cancer, and hypopharyngeal cancer was significantly worse in sarcopenic patients than in non-sarcopenic patients; however, for laryngeal cancer and other cancers, while the 3-year overall survival rate was worse in sarcopenic patients than in non-sarcopenic patients, no significant difference was observed. CONCLUSION: In cases of head and neck cancer, elderly patients and those with oral, oropharyngeal, or hypopharyngeal cancers, which are closely related to swallowing, tend to be more susceptible to sarcopenia. As prognosis of these sites is also affected by sarcopenia, careful attention should be paid to the presence or absence of sarcopenia. In particular, because patients with oropharyngeal cancer and/or hypopharyngeal cancer are prone to sarcopenia from an early stage, the presence or absence of sarcopenia should be confirmed in the event a suspected lesion is observed in the oropharynx and/or hypopharynx.

BACKGROUND: JCOG1212 is a dose-finding and efficacy confirmatory study of concurrent superselective intra-arterial infusion of cisplatin and radiotherapy (RADPLAT) for locally advanced primary squamous cell carcinoma of the maxillary sinus (cT4a,bN0M0). In this study, we report the results of the final analysis of the efficacy confirmation phase for the T4a cohort with 5-year follow-up data to evaluate the late adverse events and long-term efficacy. METHODS: Based on the results of the dose-finding phase, the efficacy confirmation phase consisted of seven weekly intra-arterial infusions of cisplatin 100 mg/m2 combined with radiotherapy (70 Gy). The 5-year prognosis and late adverse events were evaluated. RESULTS: Between April 2014 and August 2018, 64 patients were included in the analysis (one ineligible patient was excluded); 31 patients were treated with three-dimensional conformal radiation therapy (3D-CRT) and 33 with intensity modulated radiation therapy (IMRT). The 5-year overall survival, event-free survival, and local event-free survival was 71.9, 54.7, and 57.5%, respectively. In terms of late adverse events, grade 3 or higher non-hematologic toxicity was observed in 42.9% of 63 patients (retinopathy: 12, cataract: 10, osteonecrosis of mandible: 4, etc.). Grade 3 and 4 cataracts of affected side appeared in 22.6% (7/31) of the 3D-CRT group compared to 3.1% (1/32) in the IMRT group. Twenty-one patients had died, with 15 from the primary disease, 5 from other causes, and 1 from treatment-related cause. CONCLUSION: The prognosis of RADPLAT was favorable after 5-year follow-up with acceptable late adverse events and low proportion of treatment related death.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have demonstrated clinical efficacy in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, it remains a matter of debate which patient populations derive clinical benefit from salvage chemotherapy (SCT) following disease progression after ICI therapy. PATIENTS AND METHODS: This retrospective study included 97 patients with R/M HNSCC who received ICI therapy (nivolumab or pembrolizumab). Patients were classified into SCT (n=54) and non-SCT (n=43) groups after ICI failure. Survival outcomes, response rates, and clinical variables were compared between groups. RESULTS: The SCT group showed a significantly longer median overall survival (OS) compared to the non-SCT group (16.6 vs. 2.4 months, p<0.0001). These findings indicate that patients who received SCT had markedly better outcomes. Multivariate analysis identified SCT [hazard ratio (HR)=4.93, p<0.00001] and ECOG PS0,1 (HR=2.42, p=0.0257) as independent prognostic factors for OS. Patients treated with paclitaxel plus cetuximab (PTX + Cmab) had higher objective response rate (ORR) (50%) and disease control rate (DCR) (68.4%) compared to other regimens. CONCLUSION: SCT after ICI failure significantly improves survival in R/M HNSCC, particularly when using PTX+Cmab. Patients who received SCT had substantially better outcomes than those who did not. ECOG PS and sarcopenia status should be considered in treatment selection.

BACKGROUND/AIM: Poor nutritional status is one of the key contributing factors to sarcopenia, which negatively influences postoperative complications and clinical outcomes in patients with head and neck squamous cell carcinoma (HNSCC). This study aimed to investigate the potential association between sarcopenia and clinical outcomes in patients with recurrent and/or metastatic HNSCC treated with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: A retrospective review was conducted on the medical records of 119 patients with recurrent and/or metastatic HNSCC who received ICI therapy. RESULTS: The objective response rates (ORRs) were 30.7% in the non-sarcopenia group and 15.8% in the sarcopenia group, showing a statistically significant difference between the two groups (p=0.048). Patients with good performance status (PS), absence of sarcopenia, and distant metastasis exhibited significantly longer overall survival (OS) compared to those with poor PS, sarcopenia, and locoregional recurrence, respectively (p=0.014, p=0.003, p=0.026). Multivariate analysis identified sarcopenia and locoregional recurrence as independent prognostic factors for OS. The incidence of immune-related adverse events (irAEs) did not significantly differ between patients with and without sarcopenia. CONCLUSION: These findings underscore the detrimental impact of sarcopenia on the efficacy of immune checkpoint inhibitor therapy in patients with recurrent and/or metastatic HNSCC. Careful consideration of sarcopenia is warranted in the clinical management of these patients.

BACKGROUND: Previously reported results from phase III KEYNOTE-048 demonstrated similar or improved overall survival (OS) with pembrolizumab or pembrolizumab-chemotherapy versus cetuximab-chemotherapy (EXTREME) in Japanese patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We report results in Japanese patients from KEYNOTE-048 after 5 years of follow-up. METHODS: Patients with R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Primary endpoints were OS and progression-free survival. Efficacy was evaluated in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, PD-L1 CPS ≥ 1, and total Japanese populations. RESULTS: In Japan, 67 patients were enrolled (pembrolizumab, n = 23; pembrolizumab-chemotherapy, n = 25; EXTREME, n = 19). Median follow-up was 71.0 months (range, 61.2-81.5); data cutoff, February 21, 2022. 5-year OS rates with pembrolizumab versus EXTREME were 35.7% versus 12.5% (hazard ratio [HR] 0.38; 95% CI 0.13-1.05), 23.8% versus 12.5% (HR 0.70; 95% CI 0.34-1.45), and 30.4% versus 10.5% (HR 0.54; 95% CI 0.27-1.07) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. 5-year OS rates with pembrolizumab-chemotherapy versus EXTREME were 20.0% versus 14.3% (HR 0.79; 95% CI 0.27-2.33), 10.5% versus 14.3% (HR 1.18; 95% CI 0.56-2.48), and 8.0% versus 12.5% (HR 1.11; 95% CI 0.57-2.16) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. CONCLUSION: After 5 years of follow-up, pembrolizumab and pembrolizumab-chemotherapy showed long-term clinical benefits; results further support these treatments as first-line options for Japanese patients with R/M HNSCC. CLINICAL TRIAL REGISTRATION: NCT02358031.

Most elements of filamentous fungi seen in human tissue by pathologists are hyphae, and encountering other elements may interfere with diagnosis. Sporangia and chlamydospores are such elements that have been described in only a few case reports. We present an autopsy case with the extremely rare coexistence of Mucorales sporangia and chlamydospores in the lung. These fungal elements must be recognized and identified accurately because they can easily be mistaken for other fungi, microorganisms, or degenerated tissue structures.

Sarcopenia is a disease in which a decline in muscle mass with age is associated with a decline in physical performance. In the field of otorhinolaryngology, head and neck surgery, sarcopenia is gaining attention as a cause of swallowing disorders and as a problem in the treatment of head and neck cancer. Head and neck cancer occurs in anatomical sites related to swallowing, so patients with head and neck cancer are prone to swallowing disorders and "nutrition-related sarcopenia." Since it is a cancer, it also becomes a "disease-related sarcopenia," making it easy for patients to develop secondary sarcopenia. Medical intervention against sarcopenia is important in order to decrease the number of adverse events related to treatments for cases with sarcopenia, with reports stating that proactive exercise and nutritional therapy prior to treatment for cases with sarcopenia contributes to a decrease in serious complications as well as improving the survival rate. It is the same for head and neck cancer patients with sarcopenia, so intervention prior to treatment of head and neck cancer is an area that is expected to see reports in the future. However, if the disease is malignant, it is highly likely that sarcopenia cannot be sufficiently improved due to the short period of time from diagnosis to the beginning of treatment. In this case, choosing a treatment that takes sarcopenia into consideration is another way to handle it. Assessing sarcopenia prior to treatment may help avoid post-treatment pneumonia related to sarcopenia, postoperative complications including fistula, radiation-induced toxicity including swallowing disorders, and chemotherapy-related toxicity, and it is believed to greatly contribute to the prognosis of the overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS).

BACKGROUND/AIM: There is limited evidence about the significance of head and neck surgical observation at the time of diagnosis and follow-up of oral cancer after treatment. The aim of this study was to elucidate the prognosis and prognostic factors of oral squamous cell carcinoma (OSCC), analyze cases of double cancers, and highlight the importance of examinations during both diagnosis and post-treatment for OSCC. PATIENTS AND METHODS: We performed a retrospective analysis of 272 OSCC cases treated for the first time during a 10-year period from April 2013 to March 2023 at Kyushu University Hospital. Information obtained in the clinical setting, such as age, stage, prognosis, and presence of double cancers, was used in the analysis. RESULTS: The mean age of 272 patients was 69 years; 203 patients were males and 69 were females. The most common oral cancer sites were the tongue (54.4%). The 5-year overall survival rate was 63.8%. Double cancer was found in 93 patients (34.2%). Synchronous double cancers were found in 38 patients (14.0%), 50% of whose cancer types were head and neck cancers. CONCLUSION: We analyzed 272 OSCC patients treated at the Kyushu University Hospital, and the results were comparable to those reported by other institutions. Tumor site, age, and stage were identified as prognostic factors. Half of the patients with synchronous double cancers had head and neck cancer, and 3-10% of patients with double cancers after treatment for OSCC also had head and neck cancer, suggesting the importance of otorhinolaryngological observation at the time of the diagnosis and after treatment.

INTRODUCTION: Radiation and intra-arterial cisplatin infusion chemotherapy (RADPLAT) for advanced maxillary sinus cancer has accumulated evidence as a treatment with fewer complications and better 5-year survival rates. In this study, we report a case in which pterygoid muscle necrosis occurred 6 months following RADPLAT treatment for maxillary sinus cancer. CASE PRESENTATION: The 45-year-old woman had a long history of taking immunosuppressants against rheumatoid arthritis (RA) prior to treatment. Although achieving complete response (CR) to RADPLAT, the patient developed trismus (1 fingerbreadth or less) 6 months following treatment. Abscess formation and recurrence were suspected from the imaging findings; however, the biopsy with endoscopy indicated necrotic tissue. Currently, 18 months have passed without cancer recurrence. Although trismus temporarily improved with rehabilitation, the width of the mouth opening is currently a few millimeters, so the patient can only take liquid food. CONCLUSION: Pterygoid muscle necrosis should be recognized as a new major complication.

BACKGROUND/AIM: Sarcopenia has an adverse effect on postoperative complications and prognoses in head and neck cancer. This study focused on hypopharyngeal and laryngeal cancer patients with sarcopenia and analyzed the body composition following treatment when the larynx was preserved and when total laryngectomy was performed to examine the usefulness of laryngectomy. PATIENTS AND METHODS: We retrospectively reviewed 88 primary hypopharyngeal and laryngeal cancer patients aged 65 years or older with cT2N0M0 or higher who visited our department. RESULTS: There were no significant differences in the 3-year overall survival rate and the 1-year local control rate between the laryngeal preservation group and laryngectomy group. The average change one year following treatment in the laryngeal preservation group, when compared to prior to treatment, was a significant decrease in the body weight (BW) of -0.035, skeletal muscle mass (SMM) of -0.030, skeletal muscle mass index (SMI) of -0.026, body mass index (BMI) of -0.034, and grip strength (GS) of -0.066. The average change one year following treatment in the laryngectomy group, compared with prior to treatment, was an increase in BW of +0.028, SMM of +0.026, SMI of +0.008, BMI of +0.032, and GS of +0.026. Although no changes in serum biochemical testing after treatment were observed in the laryngeal preservation group, albumin, transferrin, and transthyretin all exhibited significant improvement or a tendency toward improvement in the laryngectomy group. The patients with sarcopenia before treatment in the laryngeal preservation group had a significantly higher incidence of aspiration pneumonia. CONCLUSION: The presence or absence of sarcopenia before starting treatment is considered to be an index for selecting total laryngectomy.

BACKGROUND/AIM: Lacrimal sac tumors are rare tumor types, with a long time interval from disease onset to diagnosis. We aimed to investigate the characteristics and outcomes of patients with lacrimal sac tumors. PATIENTS AND METHODS: The medical records of 25 patients with lacrimal sac tumors initially treated at the Kyushu university hospital from January 1996 to July 2020 were reviewed. RESULTS: Our analysis included 3 epithelial benign tumors (12.0%) and 22 malignant (88.0%) tumors (squamous cell carcinoma, n=6; adenoid cystic carcinoma, n=2; sebaceous adenocarcinoma, n=2; mucoepidermoid carcinoma, n=1; malignant lymphoma, n=10). The average time from symptom onset to diagnosis was 14.7 months (median=8 months; range=1-96 months). The analysis of patients revealed that lacrimal sac mass (22/25, 88.0%) was the most frequent symptom and a possible tumor marker. Most epithelial benign (n=3) and malignant epithelial (n=12) tumors were treated surgically (14/15, 93.3%). One malignant case was treated with heavy ion beam therapy. Eight patients were treated with postoperative (chemo)radiation therapy because of positive surgical margins (including one unanalyzed case). Local control was ultimately achieved in all but one case. The patient survived for 24 months with immune checkpoint inhibitors and subsequent chemotherapy for local and metastatic recurrence. CONCLUSION: We report our experience in the diagnosis and treatment of lacrimal sac tumors and analyze the clinical trends in cases involving these tumors. Postoperative radiotherapy and pharmacotherapy, including immune checkpoint inhibitors, may be useful for recurrent cases.

BACKGROUND/AIM: The advent of immune checkpoint inhibitor (ICI) treatment has transformed the treatment of recurrent or metastatic head and neck cancer; however, nasopharyngeal carcinoma (NPC) has not been included in major phase III trials. The clinical outcomes of ICI for NPC in real-world practice remain to be fully elucidated. PATIENTS AND METHODS: We retrospectively reviewed 23 patients with recurrent or metastatic NPC treated with nivolumab or pembrolizumab at 6 institutions from April 2017 to July 2021 and investigated the correlation of clinicopathological factors and immune-related adverse events with the effects of ICI therapy and the prognosis. RESULTS: The objective response rate was 39.1% and the disease control rate was 78.3%. The median progression-free survival was 16.8 months and overall survival has not been reached. As with other treatment procedures, the efficacy and the prognosis tended to be better in EBER-positive cases than in EBER-negative cases. The rate of significant immune-related adverse events that necessitated discontinuation of treatment was only 4.3%. CONCLUSION: ICI monotherapy (e.g., nivolumab and pembrolizumab) was effective and tolerable for NPC in a real-world setting.

症例1は25歳女性で、舌の異物感を主訴とした。舌根の正中やや左に境界明瞭で表面平滑な白色腫瘤を認め、CT画像では骨と同コントラストの腫瘤を認め、手術にて長径1.2cmの粘膜に覆われた腫瘤を摘出した。症例2は38歳男性で、舌の異物感を主訴とした。症例1と同様の腫瘤を舌根に認め、CTも同様の所見であり、手術にて長径1.1cmの粘膜に覆われた腫瘤を摘出した。2例とも病理組織所見で骨性分離腫と診断され、成熟した緻密骨組織のみを認めたことから鰓弓遺残によるものと考えられた。術後再発は認めていない。

OBJECTIVES: Hematoma in the retropharyngeal space (RPS) is a life-threatening condition that leads to rapid airway obstruction. However, the indication for airway management remains unclear. Additionally, the requirement for surgical hematoma evacuation remains undetermined. Therefore, we attempt to suggest some criteria for the management of hematoma in such cases. METHODS: We report three cases of hematoma in the RPS wherein one patient was treated without surgery and the other two underwent tracheotomy followed by hematoma evacuation. RESULTS: We found that airway management should be based on whether the glottis could be visible on laryngoscopy and dyspnea severity. The degree of hematoma, swelling, subcutaneous bleeding in the anterior neck, and emotional stability should also be considered. Proper management during the acute phase may allow for conservative treatments. Hematomas extending below the tracheal bifurcation may help ease upper airway obstruction due to pressure distribution, allowing for conservative treatment. When hematomas are surgically evacuated, tracheotomy should be performed simultaneously. Our report suggests that mediastinal hematoma evacuation could be avoided. CONCLUSION: We should determine a therapeutic strategy for hematoma in RPS based on glottis visualization, patient's condition, and extent of hematoma growth under careful observation.

BACKGROUND/AIM: This study investigated the effectiveness of pembrolizumab with or without chemotherapy on advanced-stage head and neck cancer (HNC), including nasopharyngeal, sinonasal cavity and external auditory canal cancer, in a real-world setting. PATIENTS AND METHODS: We retrospectively collected data from 97 HNC patients who were treated with pembrolizumab alone (n=60) or with chemotherapy (n=37), and we investigated the association between clinicopathological findings and treatment response or prognosis. RESULTS: Patients treated with pembrolizumab and chemotherapy had a 1-year overall survival (OS) of 72.8%, objective response rate (ORR) of 48.6%, and serious (≥G3) adverse events (AEs) of 29.7%. Patients treated with pembrolizumab alone had a 1-year OS of 51.9%, ORR of 21.7%, and ≥G3 AEs of 6.7%. Both the ORR and disease control rate (DCR) in the pembrolizumab with chemotherapy group were significantly better than those in the pembrolizumab group (p=0.074 and p=0.00101, respectively). Among patients with distant metastasis, patients on pembrolizumab with chemotherapy achieved significantly better OS than pembrolizumab alone (p=0.0039). Among patients in the pembrolizumab group, both AE-positive and better performance status were associated with longer OS (p=0.011 and p=0.0037, respectively). CONCLUSION: Our real-world experience reinforces the durability and effectiveness of pembrolizumab for HNC patients. Additionally, our results suggest that pembrolizumab with chemotherapy might be recommended for patients with distant metastasis and no prior treatment. Further studies are needed to determine the optimal treatment strategy for HNC.

BACKGROUND/AIM: The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed. RESULTS: The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors. CONCLUSION: Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.

High-risk human papillomavirus (HPV) infection in conjunctival and lacrimal sac squamous cell carcinomas (SCCs) has been sporadically reported; however, its prevalence, clinicopathologic significance and surrogate markers have not been fully elucidated. Here, we attempted to clarify these questions in Japanese patients with conjunctiva and lacrimal sac SCCs. We retrospectively collected 51 conjunctival SCC and 7 lacrimal sac SCC samples and analyzed them for (1) transcriptionally active high-risk HPV infection using messenger RNA in situ hybridization and (2) protein expressions of p16 and Rb using immunohistochemistry (IHC). Among a total of 58 cases, 25 (43.1%) and 16 (27.6%) tumors were positive for p16-IHC and HPV in situ hybridization, respectively. Ten (19.6%) of the 51 conjunctival SCCs, especially in the palpebral conjunctiva, and 6 (85.7%) of the 7 lacrimal sac SCCs were positive for high-risk HPV. High-risk HPV infection was significantly associated with younger patients, nonkeratinizing SCC histology, p16-positivity and partial loss of Rb expression, but not with recurrence risk. Notably, p16-IHC was not a perfect surrogate marker for high-risk HPV infection; only 64% (16/25) of p16-positive tumors were positive for high-risk HPV. In contrast, the p16+/Rb partial loss pattern was exclusively correlated with high-risk HPV-positivity. The results suggest that the combination of p16 and Rb expression patterns by IHC could be a useful method to predict high-risk HPV infection in conjunctival and lacrimal sac SCCs. HPV infection may be of less prognostic value in this field of cancers.

Nasopharyngeal carcinoma (NPC) has seen improved treatment outcomes and a decrease in incidence worldwide in recent years due to developments in medicine and improved public health. However, 70% of cases are still diagnosed at advanced stages and these advanced NPC cases show a poor prognosis. Reports on current and future treatment in advanced NPC are summarized. Chemoradiotherapy is the mainstay of treatment for advanced NPC. The administration of platinum agents as a concurrent drug and intensity modulated radiotherapy (IMRT) is the most appropriate irradiation method, and is associated with high local control rates. For induction and adjuvant chemotherapy, platinum-based two- or three-drug combination chemotherapy is recommended. The tumour volume, plasma Epstein-Barr virus (EBV)-DNA levels, and the tumour site are used to determine the indication for adjuvant and neo-adjuvant chemotherapy. The tolerability of induction chemotherapy is controversial, and the indications and timing should be carefully considered in each case. Chemotherapy is used for patients with distant metastasis. Gemcitabine/cisplatin is the first-line regimen. The efficacy of immune checkpoint inhibitor (ICI) treatment has recently been reported for NPC and, as in other areas of the head and neck, it is expected to be effective for patients with recurrent/distant metastasis. Trials are underway for various uses of ICIs, including induction chemotherapy, postoperative treatment, and use in combination with chemoradiotherapy. Immunotherapy for NPC, an EBV-associated cancer, has been reported to have some efficacy with immunotherapy used in other EBV-associated cancers. Immunotherapy may be introduced for NPC in the future, depending on the results of clinical trials. Future changes in the treatment of NPC are expected to include risk classification based on plasma EBV-DNA levels and the development of personalized treatment with individual selection of timing and type of therapy.

BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

Carcinoma showing thymus-like differentiation (CASTLE) outside the thyroid gland is extremely rare. Here we report two cases of CASTLE of the major salivary gland. The tumors occurred in the parotid gland of a 31-year-old female (Case 1) and in the submandibular gland of a 40-year-old female (Case 2). Both tumors showed a lobulated growth pattern, and were histologically composed of a nested or sheet-like proliferation of carcinoma cells with round- to oval-shaped nuclei, distinct nucleoli and pale eosinophilic cytoplasm, accompanied by various degrees of lymphocytic infiltration. Immunohistochemical staining revealed that the tumors were positive for pan-cytokeratin, p40, CD5, CD117 and bcl-2. In addition, PD-L1 expression was seen in 10-90% of tumor cells. After the initial surgery, Case 1 remained tumor-free for 20 months, while Case 2 suffered lymph node recurrence at 4 months, followed by lung metastasis, which was treated with chemoradiotherapy and anti-PD-1 immune checkpoint inhibitor, resulting in a partial response. The present findings indicate that an extrathyroid counterpart of CASTLE can occur as a primary salivary gland neoplasm. Salivary CASTLEs seem to show a wide range of biological behavior, and long-term follow-up may be needed. Immune checkpoint inhibitor targeting PD-1 might become a promising treatment option in patients with CASTLE; however, further study with a larger number of cases is necessary to establish the optimal therapeutic strategy and prognostic factors for this rare cancer.

PURPOSE: To evaluate the usefulness of magnetic resonance imaging (MRI) to differentiate basal cell adenomas (BCAs) from other parotid tumors. METHOD: A total of 136 patients with histologically proven parotid gland tumors (13 BCAs, 66 pleomorphic adenomas [PAs], 30 Warthin tumors [WTs], and 27 parotid cancers [PCs]) who underwent a cervical MRI study between December 2011 and March 2019 were retrospectively enrolled. The MRI findings of the tumors were evaluated by two board-certified radiologists. RESULTS: All 13 of the BCAs showed smooth margins, while 19 of the 27 PCs showed irregular margins (p < 0.0001). Eleven BCAs had some cystic components, and five were cyst-dominant. The BCAs had significantly more cystic components than the PAs (p = 0.0077). The mean apparent diffusion coefficient (ADC) value of the BCAs was 1.21 ± 0.20 × 10-3 mm2/sec, which was equivalent to that of the PCs (1.12 ± 0.25 × 10-3 mm2/sec, p = 0.76), significantly lower than that of the PAs (1.61 ± 0.32 × 10-3 mm2/sec, p < 0.0001), and significantly higher than that of the WTs (0.81 ± 0.19 × 10-3 mm2/sec, p = 0.0004). The plateau time-intensity curve (TIC) was the most common type for both BCAs and PCs, seen in 8 of 12 BCAs and 21 of 26 PCs, with no significant difference between these groups (p = 0.34). CONCLUSIONS: BCA should be considered a possibility when a parotid lesion has smooth margins with an entire capsule and includes a cystic component, even if the TIC and diffusion-weighted MR images suggest a malignant pattern.

症例は72歳男性で、左側口蓋部の腺様嚢胞癌と診断され、全身麻酔下に口腔内アプローチ・鼻腔内視鏡アプローチを併用して腫瘍切除術を施行した。腫瘍摘出術後、硬口蓋・軟口蓋移行部の口腔側左寄りに40×40mm程度、軟口蓋鼻腔側に20×20mmほどの粘膜欠損が生じ、口腔内と鼻腔内との交通が生じたため、口腔側は右側茎の硬口蓋粘膜骨膜弁、鼻腔側左鼻中隔粘膜弁で再建した。術後9日目に硬口蓋粘膜弁に小範囲の表層壊死および小瘻孔を認めデブリードマンおよび再縫合を施行したが、その後経過は良好で、術後20日目に経管栄養併用で経口摂取を再開し、術後27日目には食事全量摂取が可能となった。術後8ヵ月経過現在、鼻咽腔逆流はなく経口摂取も可能であり、開鼻声などの機能障害も認めていない。

Although immune checkpoint inhibitors (ICIs) have emerged as new therapeutic options for refractory cancer, they are only effective in select patients. Tumor antigen-pulsed dendritic cell (DC) vaccine therapy activates tumor-specific cytotoxic T lymphocytes, making it an important immunotherapeutic strategy. Salivary ductal carcinoma (SDC) carries a poor prognosis, including poor long-term survival after metastasis or recurrence. In this study, we reported a case of refractory metastatic SDC that was treated with a tumor lysate-pulsed DC vaccine followed by a single injection of low-dose nivolumab, and a durable complete response was achieved. We retrospectively analyzed the immunological factors that contributed to these long-lasting clinical effects. First, we performed neoantigen analysis using resected metastatic tumor specimens obtained before treatment. We found that the tumor had 256 non-synonymous mutations and 669 class I high-affinity binding neoantigen peptides. Using synthetic neoantigen peptides and ELISpot analysis, we found that peripheral blood mononuclear leukocytes cryopreserved before treatment contained pre-existing neoantigen-specific T cells, and the cells obtained after treatment exhibited greater reactivity to neoantigens than those obtained before treatment. Our results collectively suggest that the rapid and long-lasting effect of this combination therapy in our patient may have resulted from the presence of pre-existing neoantigen-specific T cells and stimulation and expansion of those cells following tumor lysate-pulsed DC vaccine and ICI therapy.

AIMS: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC), but it is not sufficient in all clinical settings. METHODS AND RESULTS: We examined the p16 and Rb expression status in 177 OPSCC cases by immunohistochemistry and the presence of transcriptionally active HR-HPV infection by mRNA in situ hybridization. The 177 cases were divided into p16+ /HPV+ (n=105, 59.3%), p16+ /HPV- (n=8, 4.5%) and p16- /HPV- (n=64, 36.2%) groups. The p16+ /HPV- group and p16- /HPV- group had a trend toward worse overall survival (OS) or a significantly worse OS than the p16+ /HPV+ group (n=105) (p=0.0610, p=0.0004, respectively). We divided the Rb status into preserved expression (>90%, n=68), partial loss (PL) (10%-90%, n=97) and complete loss (CL) (<10%, n=12). Among the HPV-positive cases (n=105), the Rb pattern was typically PL (n=97, 92.4%) and rarely CL (n=8, 7.6%) but never preserved expression (0%). In contrast, among the HPV-negative cases (n=72), the Rb pattern was typically preserved expression (n=68, 94.4%) and rarely CL (n=4, 5.6%) but never PL (0%). Compared to p16 alone, the combination of p16 overexpression and Rb-PL/CL showed equally excellent sensitivity (each 100%) and improved specificity (97.2% vs. 88.9%) and positive predictive values (98.1% vs. 92.9%). CONCLUSIONS: These results suggest that the combined use of p16 and Rb immunohistochemistry could be a reliable, cost-effective method to predict HR-HPV infection in OPSCCs; however, HPV specific testing is necessary on inconclusive cases. We propose a diagnostic algorithm for practical use of these markers.

OBJECTIVE: The purpose of this study was to clarify sequential volumetric changes of anterolateral thigh (ALT) flaps transferred to head and neck lesions. PATIENTS AND METHODS: We retrospectively analyzed volumetric changes in fat and muscle of 22 ALT flaps. We assessed "true" flap volume using the water-displacement method intraoperatively. Postoperative flap volume was assessed using three-dimensional volume-calculating software. RESULTS: The average duration until the entire flap volume decreased to its minimal size was 8.7 months. After 8.7 months, entire flap volume decreased to 47.4% of its initial intraoperative volume. The fat volume decreased to 62.5%, and the muscle volume decreased to 30.2%. The rate of muscle volume decrease was significantly larger than that of fat volume decrease (p<0.005). The only significant factor which affected entire flap volume decrease was the recipient site where the ALT flap was transferred (oral and pharyngeal lesions) (p=0.001), and the factor that affected fat volume decrease was postoperative body-weight loss (p=0.046). CONCLUSION: To minimize the influence of postoperative ALT flap volume decrease, an ALT flap should mainly comprise fatty tissue, and its size should be 1.6-times larger (100/62.5) than the ideal volume intraoperatively. Maintaining the body weight is crucial to avoid ALT flap volume decrease.

OBJECTIVE/HYPOTHESIS: Squamous cell carcinoma (SCC) of the temporal bone is an extremely rare condition. This rarity has led to a delay in the establishment of a standard treatment protocol and adequate staging system. Identification of prognostic markers of this disease from a variety of fields is desirable in the establishment of treatment guidelines for temporal bone SCC. The aim of this study is to assess the prognostic role of inflammation-based prognostic scores in cases of temporal bone SCC. STUDY DESIGN: Case reries with chart review. METHODS: A total of 71 cases of primary malignancy eligible for curative treatment at a single tertiary medical institute were retrospectively analyzed. Univariate and multivariate regression analyzes were used to investigate the association between the inflammation-based scores and 5-year overall survival. RESULTS: Univariate Cox regression analyzes showed that a high neutrophil-to-lymphocyte ratio, high platelet-to-lymphocyte ratio, low lymphocyte-to-monocyte ratio, a Glasgow prognostic score of 2, and the systemic inflammation score of 2 were significantly associated with a poor prognosis, as well as a classification of T4 stage, presence of cervical lymph node metastasis, high white blood cell counts, and high C-reactive protein levels. The multivariate analysis showed that a clinical stage of T4 and a systemic inflammation score of 2 were independent prognostic markers. CONCLUSIONS: Inflammation-based prognostic markers are associated with the survival of patients with temporal bone SCC, as well as other head and neck SCCs. LEVEL OF EVIDENCE: 4 Laryngoscope, 2021.

The antitumor efficacies of immune checkpoint inhibitors (ICIs) and the usefulness of potential predictive markers such as programmed death-ligand 1 (PD-L1) expression, density of tumor-infiltrating lymphocytes (TILs) and microsatellite instability (MSI) in sinonasal squamous cell carcinoma (SNSCC) have not been fully elucidated. We retrospectively analyzed 131 SNSCCs with immunohistochemistry for PD-L1 expression, TIL subpopulations and loss of mismatch repair (MMR) proteins as a surrogate for MSI-high. We also comprehensively evaluated the mutual relationships among these immuno-markers, high-risk human papillomavirus (HPV) infection, epidermal growth factor receptor (EGFR) gene status, and KRAS mutation. PD-L1 expression (tumor proportion score ≥ 1%) was detected in 60 (45.8%) SNSCC cases and was significantly associated with worse overall survival (OS) (p = 0.0240). High density of cluster of differentiation 8 (CD8)-positive TILs was significantly associated with better progression-free survival (PFS) (p = 0.0368), and high density of forkhead box protein P3-positive TILs was significantly associated with better PFS and OS (p = 0.0007 and 0.0143, respectively). With respect to the combination of CD8 + TIL and PD-L1 expression, the high-CD8/PD-L1-negative group showed the most favorable prognosis, whereas the low-CD8/PD-L1-positive group showed the worst prognosis. MMR loss was detected in 3 (2.3%) of the 131 cases. HPV infection (6.1%), EGFR mutation (14.5%), EGFR copy number gain (26%), and MMR loss were essentially mutually exclusive; patients in these molecular groups showed significant differences in prognosis but not in the degree of PD-L1 expression or TILs. Among the nine ICI-treated patients, three (33.3%) were responders, and the EGFR-wild type cases (n = 7) showed better clinical responses to an ICI compared to the EGFR-mutant cases (n = 2). Among the patients with residual/recurrent EGFR-wild type tumors (n = 43), ICI treatment significantly improved OS (p = 0.0281). The results suggest that the evaluation of immuno-markers and molecular subclassification may be helpful for prognostic prediction and selecting an individualized therapeutic strategy for patients with SNSCC.

BACKGROUND: To examine the effect of prior use of cetuximab and neck dissection on the effectiveness of nivolumab, we conducted a large-scale subgroup analysis in Japanese patients with recurrent/metastatic head and neck cancer. METHODS: Data on the effectiveness of nivolumab were extracted from patient medical records. All patients were analyzed for effectiveness by prior cetuximab use. In the analyses for prior neck dissection, only patients with locally advanced disease were included. RESULTS: Of 256 patients analyzed, 155 had received prior cetuximab. Nineteen of 50 patients with local recurrence underwent neck dissection. The objective response rate was 14.7 vs 17.2% (p = 0.6116), median progression-free survival was 2.0 vs 3.1 months (p = 0.0261), and median overall survival was 8.4 vs 12 months (p = 0.0548) with vs without prior cetuximab use, respectively. The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was 9.1 vs 9.9 months (p = 0.5289) with vs without neck dissection, respectively. CONCLUSIONS: These findings support the use of nivolumab for patients with recurrent/metastatic head and neck cancer regardless of prior cetuximab use or neck dissection history. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

OBJECTIVES: The aim of this multicenter retrospective cohort study was to compare efficacy and subsequent postoperative treatment between transoral robotic surgery (TORS) and any non-robotic transoral surgery in Japanese patients with early oropharyngeal squamous cell carcinoma (OPSCC), hypopharyngeal SCC (HPSCC), or supraglottic SCC (SGSCC). MATERIALS AND METHODS: Clinical information and surgical outcomes were compared between patients with early-stage OPSCC, HPSCC, and SGSCC who underwent TORS (TORS cohort) and those who underwent non-robotic transoral surgery, including transoral videolaryngoscopic surgery (TOVS), endoscopic laryngopharyngeal surgery (ELPS), and transoral laser microsurgery (TLM) (non-robotic cohort). The data of the Head and Neck Cancer Registry of Japan (registry cohort) were used to validate the comparison. The main outcomes were the presence of positive margins under pathology and the requirement for postoperative therapy, including radiotherapy or chemoradiotherapy. RESULTS: Sixty-eight patients in the TORS cohort, 236 patients in the non-robotic cohort, and 1,228 patients in the registry cohort were eligible for this study. Patients in the TORS cohort were more likely to have oropharyngeal tumor disease and T2/3 disease than those in the other cohorts (P<0.001 and P=0.052, respectively). The TORS cohort had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.018), as well as fewer patients who underwent postoperative treatment, although the difference was not significant (P=0.069). In the subgroup analysis of patients with OPSCC, a total of 57 patients in the TORS cohort, 73 in the non-robotic cohort, and 171 in the registry cohort were eligible for the present study. Patients with OPSCC who underwent TORS were more likely to have lateral wall lesions than those in the other cohorts (P=0.003). The TORS cohort also had significantly fewer patients with positive surgical margins than the non-robotic cohort (P=0.026), and no patients in the TORS cohort underwent any postoperative treatment for OPSCC, although the difference was not significant (P=0.177). CONCLUSIONS: Our results suggest that TORS leads to fewer positive surgical margins than non-robotic transoral surgeries. The clinical significance of TORS may be further validated through the results of all-case surveillance for patients who underwent TORS running in Japan in the future.

PURPOSE: Patients with liver metastasis of head-and-neck carcinoma and esophageal carcinoma are generally not treated with hepatic resection, but there are no established standard treatment methods. We report 11 cases of hepatic resection for liver metastasis of head-and-neck carcinoma or esophageal carcinoma performed at 5 Japanese institutions. METHODS: The subjects of this retrospective analysis were 11 patients who underwent hepatic resection for metastatic liver tumors, originating from head-and-neck carcinoma in 5 and from esophageal cancer in 6, between January, 2010 and March, 2020 RESULTS: There were nine men and two women (median age, 64 years; range 40-72 years). The primary disease was esophageal carcinoma in six patients and pharyngeal carcinoma in five patients. All cancers were squamous cell carcinoma. The time from the initial treatment to the diagnosis of liver metastasis was 15.3 months and the 1-year and 3-year overall survival rates after hepatic resection were 72% and 32%, respectively. The overall and disease-free survival rates after hepatic resection were significantly higher for patients who underwent hepatic resection more than 12 months after the initial treatment than for those who underwent hepatic resection within 12 months after the initial treatment (p = 0.0172 and p = 0.0120, respectively). CONCLUSIONS: Liver resection may prolong the survival of patients with liver metastases controlled for more than 12 months after the initial treatment of head and neck or esophageal carcinoma.

OBJECTIVE: Early detection of hypopharyngeal squamous cell carcinoma (SCC) is important for both an improved prognosis and less-invasive treatment. We retrospectively analyzed the detection rates of early hypopharyngeal SCCs according to the evaluation methods and the clinical management of early hypopharyngeal SCCs. METHODS: Sixty-eight patients with early hypopharyngeal SCC who were diagnosed were reviewed. RESULTS: The number of early hypopharyngeal cancer patients with asymptomatic or synchronous or metachronous esophageal cancer examined by upper gastrointestinal endoscopy with narrow-band imaging (NBI) was significantly higher than those examined by laryngopharyngeal endoscopy with NBI. The 3-year disease-specific survival rates according to T classification were as follows: Tis, 100%; T1, 100%; T2, 79.8%; and overall, 91.2%, respectively. CONCLUSIONS: Early-stage hypopharyngeal SCC can be cured by minimally invasive transoral surgery or radiotherapy. Observation of the pharynx using NBI in patients with a history of head and neck cancer, esophageal cancer, gastric cancer, or pharyngeal discomfort is very important, and routinely examining the pharynx with NBI, even in patients undergoing endoscopy for screening purposes, is recommended.

BACKGROUND: To fill the data gap between clinical trials and real-world settings, this study assessed the overall effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) during Japanese real-world clinical practice. METHODS: This was a multicenter, retrospective study in Japanese patients with recurrent or metastatic HNC who received nivolumab for the first time between July and December 2017. Data on the clinical use, effectiveness, and safety of nivolumab were extracted from patient medical records. RESULTS: Overall, 256 patients were enrolled in this study. The median duration of nivolumab treatment was 72.5 days, with patients receiving a median of 6.0 (range 1-27) doses. Median overall survival (OS) was 9.5 (95% confidence interval [CI] 8.2-12.0) months and the estimated 12-month OS rate was 43.2%. The objective response rate (ORR) was 15.7% overall and 21.1%, 7.1%, and 13.6% in patients with primary nasopharynx, maxillary sinus, and salivary gland tumors, respectively, who had been excluded from CheckMate 141. Grade ≥ 3 immune-related adverse events occurred in 5.9% of patients. No new safety signals were identified compared with adverse events noted in CheckMate 141. CONCLUSIONS: The effectiveness and safety of nivolumab in real-world clinical practice are consistent with data from the CheckMate 141 clinical trial. Therapeutic response was also observed in the groups of patients excluded from CheckMate 141. TRIAL REGISTRATION NUMBER: UMIN-CTR (UMIN000032600), Clinicaltrials.gov (NCT03569436).

BACKGROUND: Drug-induced interstitial lung disease (DI-IP) is one of the most serious adverse reactions associated with the use of anticancer drugs. DI-IP prevalence among molecular-targeting drugs and immune checkpoint inhibitors (ICIs) is relatively high in Japanese patients. To assess the risk of cetuximab and/or nivolumab-related IP is important. PATIENTS AND METHODS: The medical records of 138 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with cetuximab-containing chemotherapy and/or nivolumab monotherapy were retrospectively reviewed. RESULTS: The incidence of DI-IP with R/M HNSCC was 7.2%. DI-IP occurred more frequently in patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy than in patients with other regimens. However, tumor suppression was detected in all patients treated with cetuximab-containing chemotherapy following nivolumab monotherapy, and two achieved a complete response. CONCLUSIONS: Although patients treated with cetuximab-containing chemotherapy following nivolumab showed dramatic efficacy, careful monitoring should be recommended.

OBJECTIVES/HYPOTHESIS: The extreme rarity of temporal bone squamous cell carcinoma (TB-SCC) has delayed the accumulation of high-quality clinical evidence. For the purposes of retrospective meta-analysis in the future, a large dataset with information from various institutions would be ideal. Our objective here was to retrospectively review cases of TB-SCC encountered at a single tertiary referral center and explore survival outcomes and prognostic factors. STUDY DESIGN: Retrospective chart review. METHODS: The medical records of all TB-SCC cases were retrospectively reviewed. The resulting dataset contained 71 cases of primary cancer eligible for initial definitive (curative) treatment. RESULTS: T4 status was associated with lower disease-specific 5-year survival than T1 to T3 staging (T1: 100%, T2: 92%, T3: 86%, T4: 51%). Survival was significantly higher in operable than in inoperable cases, even when restricted to advanced (T3/T4) cancers. The tumor extension to the middle ear cavity was observed in 13/17 of T3 cases, but it was not associated with poor survival. In addition, among operable cases, negative surgical margins were associated with significantly higher survival than positive margins. CONCLUSIONS: Definitive treatments can offer disease-specific 5-year survival of over 85% in T1 to T3 cases of TB-SCC. The tumor extension to the middle ear cavity is not associated with poor survival. T4 status, inoperability, nodal invasion, and positive surgical margin are identified as a predictor of poor prognosis. Still, the matter of how to deal with unresectable tumors remains an outstanding issue in the treatment of TB-SCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2020.

Provox^® is used as a substitute voice after laryngectomy, but we may sometimes need to remove this device. This time, we report that we had difficulty in closing a tracheoesophageal fistula after removing a Provox^®. The patient was a 78-year-old man. After removing the Provox^®, we could not close the tracheoesophageal fistula by repeated simple suturing. We finally succeeded in closing the fistula by interpositioning the previously transferred pectoral major muscle flap between the esophagus and the trachea. The closure of the fistula after Provox^® removal may require a procedure to separate the trachea from the esophagus and then to interposition well vascularized tissue. This case suggests that there is a high possibility of encountering difficulty in closing such a fistula, especially in cases who have undergone radiation therapy. As a result the decision to select Provox^® placement should be made very carefully and after such placement it should only be removed when it is absolutely necessary.

BACKGROUND: The genetic basis of sinonasal inverted papilloma (SNIP)-derived squamous cell carcinoma (SCC) has not yet been well characterized. AIM: To characterize the genetic abnormalities of SNIP and SNIP-derived SCC and to uncover their differences. MATERIALS AND METHODS: Mutations of 409 genes were analyzed using amplicon targeted sequencing in a total of six papilloma/carcinoma samples from four patients with SNIP-derived SCC. RESULTS: The genes that were mutated in multiple cases were epidermal growth factor receptor (EGFR) (3/6), cyclin-dependent kinase inhibitor 2A (CDKN2A) (3/6), lysine methyltransferase 2D (KMT2D) (3/6), tumor protein p53 (TP53) (3/6), neurofibromin 1 (NF1) (3/6), phosphodiesterase 4D interacting protein (PDE4DIP) (3/6), cytochrome P450 family 2 subfamily D member 6 (CYP2D6) (2/6), fms-related receptor tyrosine kinase 4 (FLT4) (2/6) and myosin heavy chain 9 (MYH9) (2/6). Of the two cases analyzed in the papilloma-oncology carcinoma pair, one did not have any common mutations; the other showed a staged functional deletion of TP53 during the process of malignant transformation from SNIP to SCC. CONCLUSION: CDKN2A, KMT2D, NF1, PDE4DIP, CYP2D6, FLT4, and MYH9 were identified as candidate novel SNIP-derived SCC-related genes.

Sinonasal squamous cell carcinoma (SNSCC) is sometimes associated with high-risk human papillomavirus (HR-HPV) infection and inverted sinonasal papilloma or oncocytic sinonasal papilloma. Frequent mutations of EGFR and KRAS are reported in inverted sinonasal papilloma-related sinonasal squamous cell carcinoma (ISP-SCC) and oncocytic sinonasal papilloma-related SNSCC, respectively. Here, we attempted to determine the prevalence and the prognostic significances of these alterations in SNSCC. We retrospectively collected 146 SNSCCs, including 14 ISP-SCCs, and comprehensively analyzed the HR-HPV infection by human papillomavirus (HPV)-RNA in situ hybridization, EGFR gene copy number gain (CNG) by chromogenic in situ hybridization, and gene mutations in EGFR and KRAS by Sanger sequencing. HR-HPV was detected in 11 cases (7.5%), whereas all 14 ISP-SCCs were negative. EGFR mutations were present in 21 (14.7%) of 143 SNSCCs, including 13/14 (92.9%) ISP-SCCs and 8/129 (6.2%) non-ISP-SCCs (P<0.0001). The majority of EGFR mutations were exon 20 insertions, with the remainder composed of deletions and single-nucleotide substitutions in exons 19 and 20. All of 142 SNSCCs harbored no KRAS mutation. EGFR CNG was detected in 41 (28.1%) of 146 SNSCCs; all of them were HPV negative and 3 had EGFR mutations. Collectively, EGFR mutation, EGFR CNG, and HR-HPV were essentially mutually exclusive, and each subgroup had distinct clinicopathologic features. The HPV-negative/EGFR-mutant group, the HPV-negative/EGFR CNG-positive group, and the triple-negative group had significantly worse prognoses than the HPV-positive group (P=0.0265, 0.0264, and 0.0394, respectively). In conclusion, EGFR mutation may play a pathogenetically important role in some populations of SNSCCs, especially ISP-SCCs. The molecular subclassification of SNSCCs may contribute to prognostic prediction and molecular-targeted precision medicine.

OBJECTIVES: To determine added value of permeability MRI in parotid tumor characterization to T2-weighted imaging (T2WI), semi-quantitative analysis of time-intensity curve (TIC), and intra-voxel incoherent motion diffusion-weighted imaging (IVIM-DWI). METHODS: This retrospective study was approved by the institutional review board, and the informed consent was waived. Sixty-one parotid tumors in 61 patients were examined using T2WI, IVIM-DWI, and permeability MRI. TIC patterns were categorized as persistent, washout, or plateau. Signal intensity ratio of lesion-to-muscle on T2WI, apparent diffusion coefficients (ADCs), D and f values from IVIM-DWI, and Ktrans, kep, Ve, and Vp values from permeability MRI were measured. Multiple comparisons were applied to determine whether any differences among 4 histopathologic types (pleomorphic adenomas, Warthin's tumors, other benign tumors, and malignant tumors) existed. Diagnostic accuracy was compared before and after modification diagnosis referring to permeability MRI. In a validation study, 60 parotid tumors in 60 patients were examined. RESULTS: ADC and D values of malignant tumors were significantly lower than those of benign tumors other than Warthin's tumors, but higher than those of Warthin's tumors. kep and Vp values of Warthin's tumors were significantly higher than those of malignant tumors. Multivariate analyses showed that TIC pattern, D, and kep values were suitable parameters. McNemar's test showed a significant increase of sensitivity (11/12, 92%) and specificity (46/49, 94%) with adding kep. The validation study yielded high sensitivity (14/16, 88%) and specificity (41/44, 93%). CONCLUSION: Permeability MRI offers added value to IVIM-MRI and semi-quantitative TIC analysis of DCE-MRI in characterization of parotid tumors KEY POINTS: • Permeability MR imaging offers added value in the characterization of parotid gland tumors in combination with semi-quantitative TIC analysis and IVIM analyses with D parameter. • The combination of TIC pattern, D, and kep might facilitate accurate characterization of parotid gland tumor, thereby avoiding unnecessary surgery for benign tumors or delayed treatment for malignant tumors. • A combination of permeability and diffusion MR imaging can be used to guide the selection of an appropriate biopsy site.

BACKGROUND: Significant immune-related adverse events (irAEs) requiring therapy discontinuation sometimes occur. The influence of discontinuation on disease control after an irAE is unclear. OBJECTIVES: The aim of this study was to investigate whether or not patients continued to show a response or durable disease control even after stopping therapy following an irAE. MATERIAL AND METHODS: The response after nivolumab monotherapy discontinuation was examined for 14 patients in whom therapy was stopped without progression. RESULTS: The best response was CR in 5 (36%) patients, PR in 8 (57%) patients and SD in 1 (7%) patient. The estimated 1-year overall and progression-free survival rates were 92.9% and 78.6%, respectively. The best response during nivolumab therapy in patients who developed PD was CR in 0 of 5 patients (0%), PR in 3 of 8 patients (38%) and SD in 1 patient (100%). Patients obtaining CR tended to have a lower risk of PD than those with PR or SD. CONCLUSIONS AND SIGNIFICANCE: Patients with CR status may continue to show a response or durable disease control even after stopping therapy due to an irAE.

NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. Among the pan-Trk IHC-positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC-positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC-positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC-positive/FISH-negative cases had BRAF gene mutation with conventional PTC morphology. In the ATC group, neither ALK nor ROS1 IHC was positive, whereas pan-Trk IHC was positive in 1 case (6.3%) in which NTRK1 gene rearrangement was confirmed by FISH. These results suggest that NTRK, ALK, and ROS1 rearrangements are rare molecular events in nonradiation-exposed Japanese patients with PTC and ATC. Although IHC is not an entirely specific surrogate for these abnormalities and does not serve as a stand-alone companion diagnosis, the combined use of IHC and molecular testing may be helpful for determining promising therapeutic strategies with tyrosine kinase inhibitors.

Background: Total pharyngolaryngoesophagectomy (TPLE) is associated with major complications and is extremely invasive. In 2011, our institution introduced thoracoscopic esophagectomy in the left hemi-prone position and laparoscopic reconstruction with a gastric tube in patients undergoing TPLE. Herein, we describe the use of this operative method in 26 patients, focusing on the technical aspects of the surgery. Materials and methods: From January 2011 to December 2018, 26 patients underwent minimally invasive TPLE with gastric tube reconstruction in our institute. The thoracoscopic procedure was performed with the patient in the semi-prone position. The patient was then moved to the supine position, and the laparoscopic procedure and pharyngolaryngectomy were started simultaneously. After pharyngolaryngectomy, microvascular anastomoses or free jejunal flap interposition were performed at the site of the gastric tube reconstruction. The data from these 26 patients were retrospectively analyzed. Results: The median age was 66 years, and 3.8% of the patients were female. The Union for International Cancer Control stages of esophageal cancer were 0 (n = 2), I (n = 4), II (n = 7), III (n = 8), and IV (n = 5). Eight patients had concomitant esophageal cancer and head and neck cancer. Reconstruction with only a narrow gastric tube was used in 16 patients, while free jejunal flap interposition was used in 10 patients. The surgical procedures resulted in minimal complications. Postoperative complications of Clavien-Dindo grade ≥1 included anastomotic leakage in two patients and pneumonia in one. Conclusion: Thoracoscopic esophagectomy in the left hemi-prone position and laparoscopic reconstruction with a gastric tube in patients undergoing TPLE was safe and effective. The complications were improved via the development of various procedures. Further improvement is necessary before this thoracoscopic approach is established as a standard procedure for TPLE.

OBJECTIVE: The immune checkpoint inhibitor Nivolumab was approved for the treatment of platinum-refractory head and neck squamous cell carcinoma (SCC), expanding the treatment options for recurrent or advanced head and neck SCC. However, since temporal bone squamous cell carcinoma (TB-SCC) is very rare cancer, the effectiveness of Nivolumab remains unclear. We investigated the effects of Nivolumab for TB-SCC. METHOD: Chart information was collected for all patients who underwent the first administration of Nivolumab for recurrent or residual TB-SCC in our hospital between September 2017 and December 2019. Tumor staging followed the modified Pittsburgh classification. Changes in the tumor burden and survival outcome were examined. RESULTS: We examined 9 patients with recurrent or residual TB-SCC who started administration of Nivolumab. In these cases, recurrent or residual SCC was observed after chemotherapy and/or chemoradiotherapy including platinum. The duration of Nivolumab was 2-54 weeks (median 20.0 weeks). The evaluation of the therapeutic effect according to the RECIST method showed partial response in 1 case, stable disease in 2 cases, progressive disease in 4 cases, and size unevaluated in 2 case. Although the number of cases was small, comparing with 5 cases without Nivolumab, these cases showed longer overall survival (1-year OS 33.3% vs 20.0%). CONCLUSION: We used Nivolumab as palliative chemotherapy in 9 patients with recurrent/residual TB-SCC, and we were able to obtain a certain therapeutic effect on TB-SCC as well as other head and neck SCC.

Recent studies have suggested the benefit of salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) treatment for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). We retrospectively examined the outcome of SCT and the usefulness of the serum C-reactive protein level (CRP) and neutrophil-to-lymphocyte ratio (NLR) as prognostic biomarkers. Thirty-nine patients with R/M HNSCC were enrolled in this study. Twenty-five patients (64.1%) received combination chemotherapy of weekly paclitaxel and cetuximab (PC) as SCT, and 14 patients (35.9%) received tegafur-gimestat-otastat potassium (S1), an oral fluoropyrimidine. In all patients, the response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 45.2%, 85.7%, 6.5 months, and 13.5 months, respectively. No chemotherapy-related deaths were observed. These PC groups had low CRP (<1.2 mg/dL) or low NLR (<7.0) values at the time of SCT induction, which was significantly associated with an improved OS (p = 0.0440, p = 0.0354). A multivariate analysis also showed that a lower CRP value was significantly associated with a better OS (p = 0.0078). We clarified the usefulness of the PC and S1 regimens as SCT. In addition, SCT with the PC regimen showed a better prognosis with a lower CRP or NLR at induction than a higher CRP or NLR. This is the first report on biomarkers of SCT in R/M HNSCC.

OBJECTIVE: This study aimed to investigate the incidence of postoperative pneumonia (PP) and surgical site infection (SSI) in head and neck cancer (HNC) patients and clarify the relationship between oral care and postoperative infection. METHODS: We conducted a retrospective observation survey based on the medical records of 209 HNC surgery patients managed at a University Hospital in 2016-2018. The incidence of PP and SSI were assessed in patients who underwent operations of the nose and paranasal sinuses to the larynx. Factors associated with PP and SSI in a univariate analysis were included in a multiple logistic regression analysis. A Cox proportional hazards model was used analyze the incidence of PP according to time after surgery. The present study was approved by the ethical review board of our Institute. RESULTS: The rates of PP and SSI in our study population were 20.5% and 23.0%. Operative time (P < 0.01), blood loss (P = 0.004), tracheostomy (P < 0.01), reconstruction (P < 0.01), and preoperative plaque control record (PCR) (P < 0.01) were significantly associated with PP. The PCR depicted the oral hygiene based on the percentage of plaque attached to the tooth neck. A multiple logistic regression analysis indicated that the incidence of PP was significantly higher in patients with PCR values of ≥50% after preoperative oral care (OR=10.174, 95% CI 2.14-48.32, P = 0.004). Tracheostomy (P < 0.01), reconstruction (P = 0.044), a lower preoperative albumin level (P = 0.019), and a lower preoperative hemoglobin level (P < 0.01) were significantly associated with SSI. CONCLUSIONS: The incidence of PP among patients who received oral care was high in those patients with high PCR values, indicating the importance of increasing compliance to preoperative oral care.

Background: Sinonasal squamous cell carcinoma (SCC) is a rare tumor arising either de novo or in association with inverted papillomas (IPs).Objectives: The aim of this study was to investigate and compare the oncological features and prognosis of patients with sinonasal SCCs based on their etiology.Material and methods: The medical records of 117 patients who had been diagnosed with de novo SCC or those arising from IP (IP-SCC) were retrospectively reviewed. In situ hybridization analyses to detect HPV 16/18DNA and p16 immunohistochemistry were also performed in 10 cases with IP-SCC.Results: The three-year disease-specific survival (DSS) rate was higher in cases with T1, 2 and 3 than in cases with T4 in both tumor groups. T4 cases with de novo SCC had a better DSS than those with IP-SCCs. HPV16/18 was not detected in any of the 10 IP-SCCs.Conclusions and significance: T4 cases with de novo SCC tended to have a better DSS than those with IP-SCC. Since some T4 patients with IP-SCC were found to have a highly aggressive disease, careful treatment planning should be performed. High-risk HPV may not play a vital role in the carcinomatous transformation of most IP-SCC cases.

PURPOSE: To assess the usefulness of amide proton transfer (APT) imaging in differentiating parotid tumors. MATERIAL AND METHODS: We retrospectively analyzed 43 histopathologically proven parotid solid tumors with diameters ≥2 cm. Twenty-one tumors were benign and 12 tumors were malignant. Two-dimensional APT imaging was performed using a saturation pulse with a duration of 2 s and a saturation power level of 2 μT. For acquiring Z-spectra, the imaging was repeated at 25 saturation frequency offsets from ω = -6 to +6 ppm with a step of 0.5 ppm as well as one scan acquired far off-resonance (-1560 ppm) for signal normalization. For the APT imaging, the asymmetry analysis at 3.5 ppm downfield from the water signal was calculated. The mean APT signal intensity (SI) was compared between the benign and malignant tumors. RESULTS: The mean APT SI was 2.23 ± 0.80 % in the benign tumors and significantly higher at 2.99 ± 0.99 % in the malignant tumors (P = 0.01). A receiver operating curve analysis revealed that the optimal APT SI threshold was 2.40 for distinguishing malignant tumors from benign tumors with an area under the curve of 0.74. The sensitivity, specificity, and accuracy were 83.3%, 61.3%, and 67.4%, respectively. CONCLUSION: The mean APT SI of the malignant parotid tumors was significantly higher than that of the benign parotid tumors.

BACKGROUND: As the base of the tongue (BOT) plays essential roles in speech and swallowing, surgical resection of BOT cancer is typically avoided. Moreover, standard reconstructive procedures for larynx-preserving BOT defects have not yet been established. We performed immediate flap reconstruction after wide resection of BOT cancer with laryngeal preservation. Herein, the functional and oncological results of our strategy were analysed. METHODS: We retrospectively evaluated patients who underwent extended BOT resection (including the oral tongue, upper/lateral oropharyngeal wall, epiglottis and false vocal cord) with laryngeal preservation between April 2006 and April 2016. We classified defects involving the oral tongue or upper/lateral oropharyngeal wall as the lateral extension type and those involving the epiglottis or false vocal cord as the laryngeal extension type. Lateral extension-type defects were closed primarily and filled with a deepithelialised skin or muscle flap. Laryngeal extension-type defects were reconstructed using a bulky skin flap plus hyo-thyroid-pexy to create a neo-epiglottis. Postoperative functional and oncologic outcomes were assessed. RESULTS: We enrolled 18 patients with extended BOT defects. Of them, 11 had a history of irradiation. The tracheal cannula was removed in all cases, although laryngeal extension defects were associated with a longer duration to removal. All patients achieved complete oral intake and retained intelligible speech, with preservation of laryngeal function. There was no local recurrence, and the 5-year overall survival was 88.9%. CONCLUSIONS: Following wide BOT resection, reconstruction with laryngeal preservation is feasible even in cases involving irradiated tumours with laryngeal extension.

The prevalence and prognostic value of human papillomavirus (HPV) infection and epidermal growth factor receptor (EGFR) alteration in sinonasal squamous cell carcinoma (SNSCC) are not known. The reliability of p16 overexpression as a surrogate for HPV infection in SNSCC is also unclear. We investigated the prognostic and diagnostic significances of HPV infection, EGFR alteration, and p16 expression in SNSCC. We analyzed high-risk HPV infection by HPV-RNA in situ hybridization and EGFR gene copy number gain (CNG) by chromogenic in situ hybridization and by determining the protein expressions of p16, Rb, and EGFR by immunohistochemistry in 101 SNSCC cases. HPV infection (n=9, 8.9%) and p16 overexpression (n=15, 14.9%) were associated with better overall survival (P=0.0042 and 0.005, respectively). The HPV cases were located predominantly at the nasal cavity with nonkeratinizing histology and partial loss of Rb. Notably, 40% (6/15) of p16 SNSCCs were HPV. Two of these cases showed complete loss of Rb expression by immunohistochemistry, suggesting a reason for the above discrepancy. EGFR CNG, detected in 30.5% of the SNSCCs, was correlated with EGFR protein overexpression (P=0.0001). HPV infection and EGFR CNG were mutually exclusive. The HPV/EGFR CNG group had significantly better overall survival than the HPV/EGFR CNG and HPV/EGFR CNG groups (P=0.0471 and 0.0343, respectively). Our results suggest that HPV infection is a favorable prognostic marker in SNSCC, but p16 is not a perfect surrogate marker; the Rb expression pattern may improve the diagnostic accuracy. The molecular subclassification of SNSCCs based on HPV infection and EGFR copy number status might provide important information for therapeutic strategies.

OBJECTIVE: Although nivolumab treatment is effective in extending the overall survival (OS) in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), only a few patients benefit from this treatment. Recent studies have reported that chemotherapy and cetuximab might be effective for R/M HNSCC after nivolumab treatment. In the present study, we aimed to elucidate the effectiveness of chemotherapy after nivolumab treatment in patients with R/M HNSCC. METHODS: This retrospective study included 10 patients with R/M HNSCC who were mainly treated with paclitaxel plus cetuximab (7/10, 70%) or S-1 (3/10, 30%) following nivolumab treatment. Chemotherapy was administered as a second-line or higher palliative treatment. The performance status of all patients ranged from 0 to 2. The progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: The response rate (RR), clinical benefit rate, and median PFS were 60%, 90%, and 5.4 months, respectively. Regarding adverse effects, Grade 3 neutropenia and hypomagnesemia due to salvage chemotherapy administered after immunotherapy were observed in one patient. The treatment significantly increased the RR compared to that achieved with other palliative chemotherapies reported so far. CONCLUSION: A higher RR and clinical benefit rate were observed for our strategy than for any first-line regimen, suggesting that our strategy might improve the PFS. Palliative chemotherapy with/without cetuximab after nivolumab treatment might be useful in patients with R/M HNSCC. Although the results of this retrospective study are limited, this strategy can be a good treatment option for patients with R/M HNSCC because of its strong clinical benefits and acceptable toxicity.

OBJECTIVES: Immune-related adverse events (irAEs) have been shown to be associated with higher antitumor responses and a clinical benefit in non-small cell lung carcinoma, renal cell carcinoma, and melanoma patients. However, little is known regarding the association between irAEs and the clinical effect of nivolumab for recurrent/metastatic head and neck squamous cell carcinoma (R/MHNSCC). MATERIALS AND METHODS: We evaluated 108 patients treated with nivolumab for R/MHNSCC at 2 participating institutions. IrAEs were identified and profiled. We analyzed the association of each immune-related adverse effect with the clinical outcome of the patients. RESULTS: Among 108 patients, the objective response rate (ORR) was 29.6% (32/108 patients), and the disease control rate (DCR) was 50.0% (54/108 patients). IrAEs were observed in 41 patients (38.0%). Patients with irAEs had a significantly higher ORR and DCR than those without irAEs (46.3% vs. 19.4%, P = 0.004 and 75.6% vs. 34.3%, P < 0.001, respectively). The median progression-free and overall survival rates in patients with irAEs were significantly longer than in those without irAEs. CONCLUSIONS: There was a significant relationship between irAEs and efficacy in R/MHNSCC patients treated with nivolumab. Our results indicate that the development of irAEs may aid in the earlier prediction of anticancer effects in patients with recurrent or metastatic HNSCC during nivolumab monotherapy.

Distant metastasis occurs occasionally in differentiated thyroid cancer patients, with the lungs and bones being the most frequent locations. An extremely rare location of distant metastasis is the pancreas, as reported in only 16 published cases.
In this article we report a case with pancreatic metastases from thyroid papillary carcinoma. A 71-year-old woman underwent total thyroidectomy for thyroid papillary carcinoma with lung metastases. While the patient was undergoing TSH suppression therapy, the thyroid cancer spread to the pancreas. She began receiving Lenvatinib, a molecular-targeted drug, which was very effective, and the lung and pancreatic metastases diminished during 15 months.
In rare cases like pancreatic metastasis from differentiated thyroid cancer, the standard of care is unclear. If the case has a condition that cannot be removed with surgery, or cannot be treated by RAI therapy, we believe that molecular-targeted drugs might be a good treatment as one of the choices.

Because malignant tumor cells cause the production of blood coagulation agent and activation of platelet-induced agglutination, cancer patients are in a state of hypercoagulability and easily develop thrombosis. We report four cases who developed thrombosis during treatment for head and neck cancer. In two cases, clots formed in lower limb arteries; in the other two cases, clots formed in the pulmonary artery and brachial vein. Two cases recovered and remain alive now, but two cases died suddenly within a few days from the onset of thrombosis. There are various types of patients with thrombosis, and the treatment and severity differ accordingly. However, cases that develop thrombosis are forced to discontinue cancer treatment and may die suddenly. Since it is predicted that the number of patients with cancer who survive for a long time will increase in the future, greater awareness of thrombosis as a disease state is needed.

The TNM classification was revised to the 8th edition in 2016. In the revision for oral cancer, the depth of invasion（DOI）in classification T and the extranodal extension（ENE）in classification N were newly introduced. Between 2007 and 2016, 93 patients with tongue cancer were treated in our hospital and evaluated for TNM classification according to the 7th and 8th editions. The 3-year disease-specific survival rate based on the 8th edition was 72.3％; stageⅠ（25 cases）: 89.9％, stageⅡ（17 cases）: 80％, stageⅢ（15 cases）: 70％, stageⅣA（31 cases）: 64.2％, and stageⅣB（5 cases）: 20％. Twenty-nine cases developed recurrences and the total salvage rate of recurrence was 36％（10 cases）. The 8th TNM classification reflected the prognosis more clearly than the 7th edition.

BACKGROUND: Because of the difficulty of airtight sealing and risk of salivary contamination, negative-pressure wound therapy (NPWT) has rarely been applied for postoperative fistula following head and neck surgery; thus, its utility remains unclear. METHODS: We applied NPWT in 34 patients who developed orocutaneous and pharyngocutaneous fistula after head and neck surgery. Here we retrospectively analyzed the utility of NPWT for managing those fistulas. RESULTS: Thirty-two patients (94.1%) underwent NPWT as scheduled without adverse events. In 28 patients (82.4%), fistula closure was completed only by NPWT, and the mean period to fistula closure was 30.4 days. The mean period to closure did not differ significantly between fistulas with (21.7 days) and without (39.1 days) previous irradiation. CONCLUSIONS: Airtight sealing can be maintained and postoperative fistula can be closed by NPWT with a high success rate, even after previous irradiation. NPWT is an effective and minimally invasive treatment for postoperative fistula.

OBJECTIVES: Small cell carcinomas in extrapulmonary sites (ESmCCs) are very rare. ESmCCs originating in the head and neck account for approximately 10% of all ESmCCs, and there are few reports about this disease. ESmCCs have an aggressive natural history characterized by widespread metastasis. The aim of this study was to investigate the characteristics and outcomes of patients with ESmCCs of the head and neck. METHODS: The outcomes of 21 patients with ESmCCs of the head and neck treated between January 2001 and December 2015 at the authors' hospital and associated facilities were reviewed. RESULTS: There were 18 men and 3 women, and the median age was 74 years (range, 53-91 years). The tumor site was the larynx in 6 patients; the paranasal sinus in 5; the hypopharynx in 3; the oropharynx in 2; the nasopharynx in 2; and the oral cavity, salivary gland, and primary unknown in 1 patient each. The extent of the disease was staged as follows: stage I or II, 3 cases; stage III, 4 cases; stage IVA, 9 cases; stage IVB, 1 case; and stage IVC, 4 cases. The median observation time was 17 months (range, 1-103 months). Four patients (19%) had distant metastasis at initial treatment, and 13 patients (62%) developed distant metastasis within 3 years. Treatments were administered, including radical surgery (9 patients), radiation therapy (5 patients), chemoradiotherapy (7 patients), and chemotherapy (6 patients). The 1- and 3-year overall survival rates of patients were 56% and 37%, respectively. More than half of the patients died of distant metastasis. CONCLUSIONS: ESmCCs of the head and neck have a poor prognosis, similar to those of carcinomas in many other sites. Control of distant metastasis would contribute to improving the prognosis of ESmCCs of the head and neck. Further studies are required for better understanding these disease entities and their response to treatment modalities.

BACKGROUND: Predicting the response to treatment with nivolumab and the survival in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) remains a challenge. We investigated whether or not the neutrophil-to-lymphocyte ratio (NLR) kinetics could be used to predict the anticancer effect of nivolumab. PATIENTS AND METHODS: Forty-one patients with recurrent or metastatic HNSCC who had been treated with nivolumab were retrospectively analyzed. The NLR was calculated using pretreatment blood test results until the end of the treatment. RESULTS: The posttreatment NLR was higher than the pretreatment value in 13 of 17 patients (76%) patients with progressive disease within the first 3 months, whereas the posttreatment NLR was lower than the pretreatment value in 10 of 11 patients (91%) with stable disease or partial response during the follow-up period. CONCLUSION: Our results indicate that monitoring the NLR may aid in the earlier confirmation of treatment failure in patients with recurrent or metastatic HNSCC during nivolumab monotherapy.

BACKGROUND/AIM: ANRIL is a long noncoding RNA located on INK4 locus, which encodes p15 and p16 that cause G1 phase arrest in the cell cycle. ANRIL positively regulates proliferation of several kinds of cancer cells such as lung and gastric cancers. This study, examined the effect of ANRIL in head and neck squamous cell carcinoma cells. MATERIALS AND METHODS: Cells were transfected with siRNA oligonucleotides targeting ANRIL. Transfected cells were subjected to cell-cycle and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. RESULTS: Depletion of ANRIL increased p15 mRNA in FaDu cells, and p15 and p16 mRNA in CAL27 cells and inhibited proliferation of these cells. Cell cycle analysis showed that depletion of ANRIL caused arrest at the G1 phase of the cell cycle. CONCLUSION: ANRIL promotes G1 phase progression by repressing p15 and p16, and thus promotes FaDu and CAL27 cell proliferation.

The main treatment for head and neck cancer with distant metastasis is the administration of antitumor drugs. Antitumor drugs cause various adverse events, but fatal ones are rare. We herein report a patient with recurrent oral cancer who developed acute limb ischemia caused by thrombosis in the common iliac artery. While being administered cisplatin, cetuximab and 5-FU, the patient's left leg suddenly became paralyzed. As a result an emergency thrombectomy was performed, and the patient's life and lower limb were saved. Cancer patients have a 4 to 7 times higher risk of thrombosis than non cancer patients. In particular the administration of CDDP and C-mab is associated with such an increased risk. The thrombosis may rarely become fatal, and therefore it is necessary to pay close attention to when administering antitumor drugs.

OBJECTIVE: The usefulness of pretreatment measurement of SCC antigen in patients with head and neck SCC is still controversial. Our aim of this study was to evaluate the clinical usefulness of serum SCC antigen, SCCA1 and SCCA2 in the management of patients with head and neck SCC. METHODS: Serum samples for the analysis of SCCA1, SCCA2 and SCC antigen were taken from head and neck SCC patients before treatment. Serum SCC antigen was assayed with a solid phase immunoradiometric assay. The SCCA1 and SCCA2 protein level was determined by a sandwich ELISA. RESULTS: Fifty-two of 96 cases (54%) showed evaluated serum SCC antigen levels above the upper limit. The serum SCCA2 level was significantly higher in the head and neck SCC patients than in control group, whereas there were no significant differences in the serum SCCA1 level between head and neck SCC patients and control group. 72% of head and neck SCC patients demonstrated SCCA2 levels higher than 0.15, whereas 68% of the control subjects had SCCA2 levels less than 0.15. CONCLUSION: The serum SCCA2 levels were increased during the progression of cancer and might be a useful tool for the management of head and neck SCC.

The tolerability of cisplatin （CDDP） was retrospectively examined in 87 patients who received CDDP with concurrent chemoradiotherapy from May 2015 to July 2018. The CDDP doses were 80mg/m² （80mg group） every 3 weeks until 2016 and 100mg/m² （100mg group） every 3 weeks after January 2017. The 87 patients included 63 in the 80mg group and 24 in the 100mg group; 61.9％ and 70.8％ of patients received the full dose （240mg/m² and 300mg/m²）, respectively. Grade 3 or worse adverse events were reported in 52.4％ and 70.8％ in the 80mg group and the 100mg group, respectively. The percentage of patients who received 200mg/m² or more, which is the clinical recommended dose, was 68.3％ and 91.7％ of patients in the 80mg group and 100mg group, respectively. Chemoradiotherapy with CDDP 100mg/m² would be a well-tolerated, high-dose treatment in Japan.

BACKGROUND: Differentiating inverted papilloma from squamous cell carcinoma (SCC) is sometimes difficult. We evaluated the clinical usefulness of serum SCCA1 and SCCA2 in the management of patients with inverted papilloma or SCC. METHODS: Serum and tissue samples for the analysis of SCCA1, SCCA2, and SCC antigen were taken from 18 patients with sinonasal inverted papilloma and 23 cases with sinonasal SCC. The SCCA1, SCCA2, and SCC antigen levels were determined. RESULTS: The serum SCCA1 concentration was significantly higher in the inverted papilloma group than in the SCC group, whereas the serum SCCA2 level was significantly higher in the SCC group than in the inverted papilloma group. CONCLUSION: Patients with sinonasal inverted papilloma predominantly express SCCA1 protein, whereas those with SCC predominantly express SCCA2. This suggests that combined measurements of both serum SCCA1 and SCCA2 concentrations can be very useful for distinguishing sinonasal inverted papilloma from SCC.

We treated 26 cases of cervical lymph node metastasis from unknown primary sites at Kyushu University between 2007 and 2016. The N classifications of the cervical lymph nodes were as follows：N1, 1；N2, 23；N3, 2. The histopathological diagnosis of the cervical lymph nodes was squamous cell carcinoma in all cases. The 3-year overall survival rate was 52%. Seven cases showed the expression of p16 in the metastatic lymph node. The primary site was found in 5 of 7 p16 positive cases. They primary tumor sites were the tonsil, (n = 4) and the hypopharynx (n = 1). Further study usingof a larger cohort is therefore needed.

BACKGROUND: Facial edema is a common complication after neck dissection and/or chemoradiotherapy for head and neck cancer. Edema subsides spontaneously in most cases but sometimes persists, in which case surgical intervention is required. We report a case of severe facial edema that showed significant improvement upon lymphovenous anastomosis (LVA). METHODS: A 66-year-old man with oral floor cancer developed progressive facial lymphedema after tumor resection, bilateral neck dissections, chemoradiotherapy, and fibular and rectus abdominis musculocutaneous flap transfer. His eyesight was completely disturbed due to severe eyelid edema. The LVAs were performed in the bilateral preauricular area. Surgical findings showed stagnation of the lymphatic fluids in dilated lymphatic vessels, which were drained to the superficial temporal veins by LVA. RESULTS: The edema subsided rapidly and the patient's eyesight returned as soon as 4 days postoperatively. CONCLUSION: Using LVA in the preauricular region can be a choice of surgical treatment for severe facial edema.

OBJECTIVES: Primary squamous cell carcinoma (SCC) of the thyroid is a rare disease. It usually presents with locally advanced disease and has an overall poor prognosis. In this study, we investigated the characteristics and outcomes of patients with SCC of the thyroid, and reported our experience with chemotherapy with lenvatinib in the treatment of SCC of the thyroid. METHODS: The management outcome of 10 patients who had SCC of the thyroid between January 2000 and 2015 at Kyushu University Hospital or associated facilities was reviewed. RESULTS: There were 3 males and 7 females, ranging in age from 53 to 77 years. Extent of disease was staged as follows: stage IVA, 3 cases; stage IVB, 3 cases; stage IVC, 4 cases. Only tracheostomy was applied for 2 cases, surgical resection, such as total thyroidectomy and neck dissection, for the other 8 cases. Radiotherapy following surgical treatment was applied for 9 cases. Four patients started on oral lenvatinib due to recurrent or progressive SCC of the thyroid. The one year actuarial survival rate of patients was 22.7%. There was no 2-year survivor of all patients. CONCLUSIONS: Treatment should primarily be targeted at surgical resection with negative margins in patients with resectable disease. Lenvatinib may show promise to potentially extend survival.

INTRODUCTION: Facial onset motor and sensory neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, upper trunk, and upper extremities in a rostral-caudal direction. Although bulbar involvement is frequently observed in FOSMN, dysphagia in these patients has not been fully described. In this study, we aimed to characterize dysphagia as a prognostic factor in FOSMN by investigating our institutional case series. METHODS: We retrospectively reviewed the medical records, including swallowing function tests, of six patients with FOSMN (three men and three women) who were thoroughly examined at Kyushu University Hospital between 1 January 2005 and 30 November 2017. RESULTS: Average age at onset was 58.5 years; average disease duration was 5.7 years. All patients developed bulbar dysfunction and dysphagia (at an average of 1.8 and 2.6 years from onset, respectively), resulting in choking episodes in three patients, percutaneous endoscopic gastrostomy placement in three, and recurrent aspiration pneumonia in one. Four of five patients evaluated with videofluoroscopic swallowing studies had poor oral retention, leading to bolus flowing into the pharynx before swallowing; the fifth patient showed poor lingual transfer. Fiberoptic endoscopic evaluation of swallowing revealed leakage of blue-dyed water from the mouth to the pharynx in three patients because of poor oral retention, but only mild pharyngeal phase dysphagia in all four cases evaluated. CONCLUSIONS: Oral phase dysphagia predominates in the early stage of FOSMN.

Differential diagnosis among basal cell adenoma (BCA), basal cell adenocarcinoma (BCAC), adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) of the salivary gland can be challenging due to their similar histological appearance. Although frequent nuclear β-catenin expression and CTNNB1 mutations have been reported in BCA, further details of the Wnt/β-catenin signal alterations are unclear. The aim of this study was to assess the diagnostic utility of Wnt/β-catenin signal alteration in BCA and morphological mimics. We performed immunohistochemical staining for β-catenin and mutation analysis for Wnt/β-catenin-related genes (CTNNB1, APC, AXIN1 and AXIN2) in BCA (n = 34), BCAC (n = 3), ACC (n = 67) and PA (n = 31). We also analyzed ACC-specific MYB and MYBL1 gene rearrangements by fluorescence in situ hybridization (FISH). Nuclear β-catenin expression (≥3%) was present in 32/34 cases (94.1%) of BCA, and the nuclear β-catenin labeling index was significantly higher than in other tumor types (p = < 0.0001). In BCA, we found mutations in CTNNB1, APC and AXIN1 genes (41.1%, 2.9% and 8.8%, respectively). In BCAC, nuclear β-catenin expression with CTNNB1 mutation was present in 1/3 cases (33.3%). As for ACC, nuclear β-catenin expression was observed in 3/67 cases (4.4%), but all 3 cases harbored either MYB or MYBL1 gene rearrangement. The results suggest that nuclear β-catenin immunoreactivity with appropriate criteria may be helpful to distinguish BCA from histologically similar tumors. However, a minor subset of ACCs with nuclear β-catenin expression require careful diagnosis. In addition, Wnt/β-catenin signal alteration may play a role in the pathogenesis of BCA and BCAC.

BACKGROUND: The role of induction chemotherapy (IC) in the treatment of resectable advanced head and neck squamous cell carcinoma has not been elucidated, and the most effective IC regimen for chemoselection is still unknown. At our institute we have not used the triple combination of docetaxel, cisplatin, fluorouracil (TPF) for chemoselection, but rather the double combination of docetaxel + cisplatin (TP). The aim of this study is to report the outcome of patients with advanced hypopharyngeal cancer treated by single cycle of IC with TP followed by chemoradiation (CRT) or surgery. METHODS: A total of 29 patients with resectable advanced hypopharyngeal cancer who were treated with a single cycle of IC were entered into the study. Responders were treated by CRT while nonresponders underwent surgery. Outcomes were analyzed using the Kaplan-Meier method. RESULTS: A single cycle of IC with TP achieved response in 21 of the 29 patients. The major side effect was neutropenia which could be managed without delaying the sequential treatment. The 2-year overall survival and disease-specific survival were both 74.0% (stage III 100%, stage IVA 69.1%). The cumulative 2-year laryngeal preservation rate was 100% for stage III and 53.6% for stage IVA. CONCLUSION: A single cycle of IC with the combination of docetaxel + cisplatin may be sufficient to select advanced hypopharyngeal cancer patients with radio-sensitivity. IC intended for organ preservation strategies should be low toxic. Our strategy may be a useful for providing the benefits of IC and the opportunity for curative surgery without delay.

OBJECTIVE: The aim of this study was to investigate the clinical features and prognosis of patients with squamous cell carcinoma (SCC) associated with sinonasal inverted papilloma (IP). METHODS: The medical records of 95 patients who were diagnosed with IP or SCC associated with IP were retrospectively reviewed. Out of 95 patients, 15 were diagnosed with SCC associated with IP. The clinical characteristics, treatment modalities, and survival outcomes of the patients were analyzed. RESULTS: The incidence of SCC associated with IP was 15.8%. Although differential diagnosis between IP and SCC associated with IP is difficult, epistaxis may be the specific symptom in SCC associated with IP cases. The 3-year disease-specific survival rate was higher in cases with T1, 2 and 3 than in cases with T4. There was no significant difference in survival rate between maxillary sinus and other primary sites. On the other hand, there was a significant difference in survival rate between the microscopic SCC with IP cases and the other cases. In addition, the patients with <70 years old better than those with >70 years old with a 3-year disease free survival of 80% versus 0%. CONCLUSIONS: Some T4 patients were found to have a highly aggressive disease. Therefore, complete surgical resection followed by chemo-radiation therapy is the recommended treatment for patients with T4 disease to control of the primary tumor site.

OBJECTIVE: The objectives of this retrospective study were to elucidate the clinicopathological features and recent surgical results of cervical esophageal cancer. SUMMARY BACKGROUND DATA: Cervical esophageal cancer has been reported to have a dismal prognosis. Accurate knowledge of the clinical characteristics of cervical esophageal cancer is warranted to establish appropriate therapeutic strategies. METHODS: The clinicopathological features and treatment results of 63 consecutive patients with cervical esophageal cancer (Ce group) who underwent surgical resection from 1980 to 2013 were analyzed and compared with 977 patients with thoracic or abdominal esophageal cancer (T/A group) who underwent surgical resection during that time. RESULTS: Among the patients who received curative resection, the 5-year overall and disease-specific survival rates of the Ce patients were significantly better than those of the T/A patients (overall: 77.3% vs 46.5%, respectively, P = 0.0067; disease-specific: 81.9% vs 55.8%, respectively, P = 0.0135). Although total pharyngo-laryngo-esophagectomy procedures were less frequently performed in the recent period, the rate of curative surgical procedures was markedly higher in the recent period (2000-1013) than that in the early period (1980-1999) (44.4% vs 88.9%, P = 0.0001). The 5-year overall survival rate in the recent period (71.5%) was significantly better than that in the early period (40.7%, P = 0.0342). CONCLUSIONS: Curative resection for cervical esophageal cancer contributes to favorable outcomes compared with other esophageal cancers. Recent surgical results for cervical esophageal cancer have improved, and include an increased rate of curative resection and decreased rate of extensive surgery.

OBJECTIVE: Eyelid carcinomas are rare, and the management strategy of regional lymph node metastasis linked to eyelid carcinomas has not been standardized to date. The aim of the present study was to analyze the patterns of regional metastasis and to assess the optimal extent of surgical treatment for lymph node metastasis of eyelid carcinoma. METHODS: This study was a retrospective review of patient data from a single institution. From a series of 268 eyelid carcinomas, we selected the 21 patients with lymph node metastasis, and we analyzed the patterns of lymphatic spread, approach to treatment and outcomes. RESULTS: The most common histological type of eyelid carcinoma with regional metastasis was sebaceous carcinoma (17/21, 81.0%). Submandibular area metastases were seen only in the patients with the primary tumor originating in the medial half of the eyelid, but parotid area metastases were seen in both the patients whose tumors had a medial-half origin and those with a lateral-half origin. Although 11 of the 16 patients with parotid-area metastases underwent a tumorectomy or superficial parotidectomy (which resulted in four cases of recurrence in the parotid area), none of the five patients who underwent a total parotidectomy developed parotid-area recurrence. The incidence of regional recurrence of the patients who received adjuvant radiotherapy (14.3%) was lower than that of the patients without adjuvant radiotherapy (57.1%). CONCLUSION: Continued surveillance and optimal management of regional lymph node metastases are important for the control and survival of eyelid carcinomas.

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.

Reports of drug-induced interstitial pneumonia caused by Cetuximab have been increasing. Pneumocystis pneumonia is important as a differential diagnosis of drug-induced interstitial pneumonia. We report herein on a 64-year-old man with pneumocystis pneumonia after cetuximab-based bioradiotherapy for laryngeal cancer. After radiotherapy, the patient developed multi-drug resistant pneumonia. Chest CT imaging revealed diffuse ground-glass opacities in the lung field. He was diagnosed as having pneumocystis pneumonia based on the bronchoalveolar lavage (BAL) findings, and then his symptoms improved after treatment with Trimethoprim/Sulfamethoxazole. It is important to assess the risk factor for pneumocystis pneumonia for early its detection and treatment.

Between 1996 and 2009, 30 patients with adenoid cystic carcinoma of the head and neck were treated in our department. The patients consisted of 17 males and 13 females. Mean patient age was 52 years old, ranging from 24 to 78 years old. The site of the lesion was salivary gland in 12, nasal cavity and paranasal sinuses in 9, oropharynx in 3, external auditory canal in 2, nasopharynx in 1, oral cavity in 1, orbit in 1, and trachea in 1. Cumulative 5- and 10-year disease-specific survival rates in these 30 cases were 74% and 38%, respectively, and the survival rate gradually decreased in the long term. 25 of the 30 patients underwent radical cure; 16 of these 25 patients developed recurrence; 9 of these 16 patients underwent salvage. The 5-year survival rate of the 9 patients who underwent salvage was 54%, while that of the patients who did not undergo salvage was 21%. There was a statistically significant difference between the two. We concluded that patients with recurrence and metastasis should be treated, if possible, to improvement the prognosis.

Between January 1998 and March 2011, 16 patients with cervical lymph node metastasis from an unknown primary carcinoma were treated at Kyushu University Hospital. In terms of the N classification, there was one patient with N1, twelve with N2 and three with N3 disease. One patient already had distant metastasis before the treatment. The five-year survival rate was 60%, and the five-year disease-specific survival rate was 66%. The five-year survival rate of patients who received neck dissection surgery was 74%, while that of patients who did not receive the surgery was 33%. It is therefore considered that neck dissection surgery was effective. Based on a comparison between the treatment outcomes of several hospitals, the combination of surgery and chemoradiotherapy provided the best treatment results. We consider that a combination of neck dissection surgery and chemoradiotherapy is an effective treatment for cervical metastasis from an unknown primary carcinoma.

A retrospective review was performed on 27 patients with primary hyperparathyroidism who were initially treated at our hospital between 2009 and 2012. The 27 patients ( 4 males, 23 females) ranged in age from 23 to 82 years. Histological examinations revealed 26 parathyroid adenomas and one parathyroid hyperplasia. Ultrasonography, computed tomography and ^99mTc Sestamibi scintigraphy were useful modalities for accurately diagnosing the localization of the parathyroid gland tumors. When parathyroid gland tumors were not detectable by ^99m Tc Sestamibi scintigraphy, ²⁰¹TL-^99mTc subtraction scintigraphy was useful for diagnosing the localization. A resection of the enlarged gland was performed in 23 patients, a hemithyroidectomy and parathyroidectomy was performed in three patients and bilateral parathyroidectomy (two glands) was performed in one patient. The serum intact PTH concentration degreased in 16 patients during the operation. Twenty-six of the 27 patients were normocalcemic,however, the other patient had persistent hypercalcemia after the operation. This analysis suggests that measuring the serum intact PTH concentration during surgery is useful. Recurrent laryngeal nerve palsy was not observed in any of the patients, but the tetany and hypocalcemia were noted after the operation in six of the 27 patients.

We herein report a case of transient thyroid swelling which occurred after fine needle aspiration cytology (FNAC) of an adenomatous goiter. A 71-year-old man was diagnosed with nodular goiter of the left lobe of his thyroid gland at another hospital, and was referred to our hospital because the thyroid had increased in size. He has no history of allergy. FNAC was performed with a 22-gauge needle on the left lobe. 3 hours later, he complained of swelling and pain in the neck. No airway obstruction was observed. The next day, the tumor in the left lobe was observed to have swollen from 30 mm to 40 mm in size on US. Both steroids and antibiotics were administered orally,and the symptoms improved within a few days. We thereafter performed a partial thyroidectomy, and the patient was discharged without any complications. Inflammatory cell infiltration and a bacterial colony were identified pathologically. The mechanisms for the observed swelling, such as allergy, infection, and hemorrhaging were suspected. The occurrence of swelling of the thyroid following fine needle aspiration is discussed.

CONCLUSIONS: There was a moderate chance of cure after surgical salvage of recurrent hypopharyngeal squamous cell carcinoma (SCC). However, surgical salvage was only feasible for early recurrent tumor. Close follow-up surveillance to detect early recurrence is essential after primary treatment of patients. OBJECTIVES: Despite improvements in surgery, radiotherapy, and chemotherapy, hypopharyngeal SCC has one of the worst prognoses among head and neck malignant diseases. To improve the overall survival and cure rates in patients with hypopharyngeal SCC, the management of recurrent disease as well as initial treatment is important. In this study, the efficacy and results of salvage treatment of recurrent hypopharyngeal SCC after primary curative treatment were evaluated. METHODS: The management outcomes of 49 patients who were treated for recurrent hypopharyngeal SCC between January 2002 and December 2010 at Kyushu University Hospital were reviewed. RESULTS: The median time for detection of recurrence from the initial curative treatment was 10.3 months (range 2.1-61.1 months). The total salvage rates of recurrence were 45% (local, 85%; locoregional, 100%; regional, 23%; distant, 19%). The 1- and 3-year tumor-free actuarial survival rates of those patients who received salvage surgery followed by chemotherapy and/or radiotherapy were 96% and 79%, respectively. There was no 3-year survivor among the patients who received only chemotherapy and/or radiotherapy.

Tuberculosis is a rare cause of otitis media (called TOM). It often takes time to establish a diagnosis of TOMbecause of the clinical variability of the disease. We herein report three cases of TOM recently treated atHamanomachi Hospital between April 2005 and March 2013. It took seven days, six months and four months toestablish the diagnosis of TOM from the first visit to our hospital and it took one year, eight months and six monthfrom the first visit to a medical institution until the diagnosis. TOM can induce serious complications, likesensorineural hearing loss and facial palsy, so an early diagnosis and early treatment are needed. Therefore, TOMshould be suspected in cases of intractable otitis media, and it benefits patients to start antituberculosis treatmentearly, because it may prevent the development of severe complications.

Objectives. Clinical records of 27 patients with extracranial head and neck schwannoma were retrospectively reviewed. Methods. Ultrasonography (US) was performed in all cases. Seven patients underwent CT. Twenty-five patients underwent MRI. Fine needle aspiration cytology (FNAC) was performed for 12 of the 27 patients. Clinical history, surgical data, and postoperative morbidity were analyzed. Results. The images of US showed a well-defined, hypoechoic, primarily homogeneous solid mass. At CT, only one of 7 cases (14%) was able to suggest the diagnosis of schwannoma. At MRI, twenty of 25 cases (80%) suggested the diagnosis of schwannoma. Only three of 12 cases (25%) displayed a specific diagnosis of schwannoma rendered on FNAC. The distribution of 27 nerves of origin was 10 (37%) vagus nerves, 6 (22%) sympathetic trunks, 5 (19%) cervical plexuses, 3 (11%) brachial plexuses, 2 (7%) hypoglossal nerves, and 1 (4%) accessory nerve. Complete tumor resection was performed in 11 patients, and intracapsular enucleation of the tumor was performed in 16 patients. The rate of nerve palsy was 100 (11/11) and 31% (5/16). Conclusions. MRI is sensitive and specific in the diagnosis of schwannoma. Intracapsular enucleation was an effective and feasible method for preserving the neurological functions.

Human-papillomavirus- (HPV-) positive oropharyngeal squamous cell carcinomas (OPSCC) are reported to be more responsive to treatment and to be related to a favorable prognosis compared with non-HPV carcinomas. However, the molecular basis of the responsiveness is unclear. Interferon inducible IFI16, which is implicated in the control of cell growth, apoptosis, angiogenesis, and immunomodulation in various types of cancers, is reported to be frequently expressed in the HPV-positive head and neck SCC and to correlate with a better prognosis. In this study, we hypothesized that HPV related OPSCC expresses IFI16 resulting in favorable prognosis. To clarify the relationship between the prognosis of HPV related OPSCC patients and IFI16 status, we examined immunohistologically the pretreatment specimens of OPSCC for the expression of p16 as a surrogate marker of HPV infection and IFI16. We could not show that the expression of IFI16 is associated with that of p16. There was no significant difference in the survival rate between IFI16 positive and negative groups. Patients with p16 negative tumor exhibited worse survival rate regardless of IFI16 status. In this limited case series, we could not conclude that IFI16 expression is altered in p16 positive OPSCC and that it would be a new predictive marker or a useful therapeutic tool.

5-Fluorouracil (5-FU) is a widely used drug in head and neck squamous cell carcinoma (HNSCC). In the anabolic pathway of 5-FU, the first step in activation of the drug is phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT), which directly metabolizes 5-FU to 5-fluorouridine monophosphate (FUMP) in the presence of 5-phosphoribosyl-1-pyrophosphate. To date, OPRT expression in the tumors has been related to the clinical response or survival of cancer patients receiving 5-FU-based chemotherapy. In this study, we examined whether OPRT expression correlates with the chemosensitivity to 5-FU and cell proliferation in HNSCC. We constitutively expressed an OPRT cDNA in an HNSCC cell line. The effects of OPRT expression on in vitro cell growth and 5-FU cytotoxicity were examined. OPRT transfection increases the cytotoxicity of 5-FU without affecting cell proliferation of HNSCC cells in vitro. These results indicate that OPRT expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy.

Free flaps are considered to revascularize from the surrounding tissue and survive without their original pedicle flow after a certain period postoperatively. We report 2 patients who developed mucosal ischemia of the transferred jejunum by ligation of its vascular pedicle 10 and 25 months after microvascular free jejunal transfer. Both patients had a history of heavy smoking, and had undergone definitive radiotherapy and previous surgery to the recipient bed. Both were treated conservatively; however, a stenotic change of the transferred jejunum remained in 1 patient. If poorly revascularized flaps, such as jejunal flaps, were transferred to the irradiated and scarred recipient bed, revascularization might never reach completion. If pedicle division is required in such cases, reanastomosis of the pedicle would be ideal regardless of the time after the transfer.

Recent studies in animal models of bronchopulmonary dysplasia (BPD) suggest that antioxidant treatments may be beneficial for the disease. However, the mechanisms by which these drugs improve the course of BPD are not completely known. Alpha1-antitrypsin (α1-AT) is one of the major serine protease inhibitors in human plasma that has antielastase and antiapoptotic activities. Both activities of α1-AT are dependent on its reactive site loop (RSL), which is highly susceptible to oxidative inactivation. In this study, we investigated the elastase inhibitory activity of α1-AT in two different baboon models of BPD, the "new BPD" and the "severe BPD" models, and determined the effect of treatment with a catalytic antioxidant, Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP), on the elastase inhibitory activity of α1-AT in the severe BPD model. Our results demonstrate the presence of sufficient elastase inhibitory activity of the airway α1-AT in the new but not in the severe BPD model. Treatment of severe BPD group baboons with the catalytic antioxidant MnTE-2-PyP resulted in augmentation of the elastase inhibitory activity of α1-AT. These findings suggest that prevention of the oxidative inactivation of α1-AT may be one of the mechanisms by which antioxidant therapy improves the pulmonary outcomes in animal models of severe BPD.

OBJECTIVE: The aim of this study was to evaluate the immunohistochemical TS expression in patients with maxillary sinus SCC. METHODS: The value of immunohistochemical TS expression as a predictive indicator for 5-FU efficacy was retrospectively examined in 47 patients with maxillary sinus SCC. RESULTS: Of the 47 patients, 29 (62%) showed complete response for 5-FU based chemoradiotherapy. Seventeen of 19 (89%) TS low cases showed a complete response, whereas 12 of 28 (43%) TS high cases showed complete response for 5-FU based chemoradiotherapy. Low TS patients had significantly better response rates compared with high TS patients. CONCLUSION: These findings suggest that TS expression affects the chemotherapeutic effect of 5-FU in patients with maxillary sinus SCC and the assessment of TS expression level might be useful both in the management and in the treatment of maxillary sinus SCC.

We noted a marked increase in IFNγ mRNA in newborn (NB) murine lungs after exposure to hyperoxia. We sought to evaluate the role of IFNγ in lung injury in newborns. Using a unique triple-transgenic (TTG), IFNγ-overexpressing, lung-targeted, externally regulatable NB murine model, we describe a lung phenotype of impaired alveolarization, resembling human bronchopulmonary dysplasia (BPD). IFNγ-mediated abnormal lung architecture was associated with increased cell death and the upregulation of cell death pathway mediators caspases 3, 6, 8, and 9, and angiopoietin 2. Moreover, an increase was evident in cathepsins B, H, K, L, and S, and in matrix metalloproteinases (MMPs) 2, 9, 12, and 14. The IFNγ-mediated abnormal lung architecture was found to be MMP9-dependent, as indicated by the rescue of the IFNγ-induced pulmonary phenotype and survival during hyperoxia with a concomitant partial deficiency of MMP9. This result was concomitant with a decrease in caspases 3, 6, 8, and 9 and angiopoietin 2, but an increase in the expression of angiopoietin 1. In addition, NB IFNγ TTG mice exhibited significantly decreased survival during hyperoxia, compared with littermate controls. Furthermore, as evidence of clinical relevance, we show increased concentrations of the downstream targets of IFNγ chemokine (C-X-C motif) ligands (CXCL10 and CXCL11) in baboon and human lungs with BPD. IFNγ and its downstream targets may contribute significantly to the final common pathway of hyperoxia-induced injury in the developing lung and in human BPD.

OBJECTIVES/HYPOTHESIS: Salvage surgery after definitive chemoradiotherapy is often associated with a higher rate of perioperative complications and poor prognosis. The objective of this study is to examine the safety and efficacy of free jejunal transfer after salvage pharyngolaryngectomy for patients with locally recurrent hypopharyngeal carcinoma after definitive chemoradiotherapy. STUDY DESIGN: A retrospective analysis of patients with advanced hypopharyngeal carcinoma who underwent pharyngolaryngectomy and reconstruction using free jejunum. METHODS: Forty patients who underwent pharyngolaryngectomy with jejunal transfer were included in this study. Fourteen patients underwent surgery after definitive chemoradiotherapy (the salvage-surgery group), whereas 26 patients underwent surgery after planned preoperative chemoradiotherapy (the planned-surgery group). The perioperative conditions, mortality, morbidity, functional outcomes, and oncologic outcomes in each group were compared. RESULTS: The patients in the salvage-surgery group lost an average of 9 kg in weight before surgery, which thus indicated a malnourished condition. However, the incidence of all perioperative complications did not differ significantly between the groups. All patients in both groups achieved oral intake without tube feeding, and the intervals to start oral intake were 12.8 days in the salvage-surgery group and 15.6 days in the planned-surgery group, which was not significantly different. The 5-year disease-free survival was 57.1% in the salvage-surgery group and 50.4% in the planned-surgery group, which was not significantly different. CONCLUSIONS: Salvage pharyngolaryngectomy and jejunal transfer can be performed safely and reliably for patients with locally recurrent hypopharyngeal carcinoma, and it is an excellent option after a failure of definitive chemoradiotherapy.

Partial glossectomy and low-dose-rate (LDR) brachytherapy are both effective in early-stage tongue cancer without lymph node metastasis, although head and neck surgeons and radiation oncologists disagree on which treatment is superior. Because our subjects select the treatment modality, we compared treatment results between 39 subjects undergoing partial glossectomy and 107 undergoing brachytherapy for stage I/II tongue cancer.
Local recurrence was observed in 10% and cervical lymph node recurrence in 23% following partial glossectomy, versus local recurrence in 13% and cervical lymph node recurrence in 24% following brachytherapy. Disease-free 5-year survival was 87.0% following partial glossectomy and 90.7% following brachytherapy. Because incidence of local recurrence, nodal metastasis, and prognosis were the same regardless of treatment modality, treatment should be based on the age, performance status, and quality of life among subjects.

Thymidylate synthase (TS) is a major target of 5-fluorouracil (5-FU) and dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the degradation of 5-FU. There are no studies investigating the comparison of TS and DPD mRNA expressions in oral tongue SCC (OSCC) and nontumor tissues obtained from the same patients. In addition, increased interest has been focused on the biological roles of TS and DPD as the independent prognostic factors as well as responsive determinants for cancer patients with 5-FU based therapy. We determined the expression levels of TS and DPD in tumor (T) and nontumor squamous epithelial tissues (N) of OSCC using real-time reverse transcription-polymerase chain reaction and evaluated whether the T/N ratio would correlate with clinicopathological factors. The mRNA expressions of TS and DPD were significantly higher in tumor areas than in nontumor areas. No correlation was found between the T/N ratio of each mRNA expression and gender, clinical stage, T classification, N classification or differentiation. The T/N ratio of TS in patients that died of disease was significantly higher than in patients with free of disease, whereas there were no relationships between The T/N ratio of DPD and disease status. Clinical follow-up data showed shorter overall survival periods for cases with high T/N ratio of TS than for cases with low T/N ratio of TS with the statistically significant. Our study showed that TS but not DPD seems to have prognostic value in OSCC. These findings suggest that the assessment of TS activity may be useful both in the management and in the treatment of OSCC.

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs to treat cancer patients. However, the presence of drug resistant tumor cells may cause a poor response to 5-FU based chemotherapy. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and is also responsible for the degradation of 5-FU. In this study, we examined whether DPD expression affects the cytotoxic activity of 5-FU against head and neck squamous cell carcinoma (HNSCC) and the role of DPD in the biological regulation of HNSCC. We constitutively expressed the DPD cDNA in a HNSCC cell line. The effect of DPD expression on in vitro cell growth, cell cycle and 5-FU cytotoxicity was examined. In addition, we also evaluated the association between DPD expression and the proliferation of tumor cells in surgical specimens, and prognosis of the patients with HNSCC. DPD overexpression decreases the cytotoxicity of 5-FU. CDHP, a strong DPD inhibitor, enhances the cytotoxic effect of 5-FU in HNSCC cells in vitro. DPD expression level does not effect cell proliferation and does not seem to have prognostic value in HNSCC. The present results strongly indicate that DPD expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy, suggesting the possibility of personalized chemotherapy including the prediction of response and adverse effects.

BACKGROUND: 5-Fluorouracil (5-FU) is a widely used drug in head and neck squamous cell carcinoma (HNSCC). Thymidylate synthase (TS), which is the target enzyme of 5-FU, has been demonstrated to be a key regulatory enzyme. In this study, we examined whether TS expression is correlated with chemosensitivity to 5-FU, cell proliferation and clinical outcome in HNSCC. METHODS: An antisense TS cDNA was constitutively expressed in the HNSCC cell line. The effects of TS expression on in vitro cell growth and 5-FU cytotoxicity were examined. We also evaluated the association between TS expression and cell proliferation in surgical specimens, and prognosis in HNSCC patients. RESULTS: Antisense TS transfection increases the cytotoxicity of 5-FU and inhibits cell proliferation in HNSCC cells in vitro. Immunohistochemical expression of TS may have prognostic value in patients with HNSCC. CONCLUSIONS: These results indicate that TS expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy.

Overexpression of vascular endothelial growth factor (VEGF) is associated with angiogenic phenotypes and poor prognosis of numerous tumors, including head and neck squamous cell carcinoma (HNSCC). However, the precise mechanism that causes VEGF overexpression in HNSCC remains unknown. Since there is evidence that a transcriptional factor, signal transducers and activators of transcription 3 (Stat3), is constitutively activated in HNSCC and this activation is significantly associated with aggressive phenotypes of this disease, we investigated the roles of Stat3 activation on VEGF production and tumor angiogenesis in HNSCC both in vitro and in clinical samples. VEGF promoter assays with YCU-H891 cells demonstrated that dominant negative Stat3 significantly inhibited VEGF promoter activity in the full length (-2279 to +54) and two truncated forms of VEGF promoter luciferase-reporter construct (-1179 to 54) or (-1014 to +54), which retain the putative Stat3 responsive elements (-849 to -842). However, this was not seen in the shorter construct (-794 to +54), which lacks the putative Stat3 responsive elements. In the derivative of YCU-891 cells that stably express dominant negative Stat3 protein, cellular levels of VEGF mRNA and VEGF protein were significantly inhibited. In the 51 clinical samples obtained from the patients with tongue carcinoma, the expression levels of phosphorylated (activated) form of Stat3 protein were significantly correlated with VEGF (P<0.05) production and intratumoral microvessel density IMVD (P<0.01). These results strongly indicate that Stat3 directly up-regulates VEGF transcription and thereby promotes angiogenesis in HNSCC. Inhibition of Stat3 activity may provide a new anti-angiogenic therapy in HNSCC.

Bronchopulmonary dysplasia (BPD) continues to be a major cause of morbidity in premature infants. An imbalance between neutrophil elastase and its inhibitors has been implicated in BPD. Serine protease inhibitor (SERPIN)B1 is an inhibitor of neutrophil proteases, including neutrophil elastase (NE) and cathepsin G (cat G). Recent studies suggest that SERPINB1 could provide protection in the airways by regulating excess protease activity associated with inflammatory lung disorders. In this study, we determined the distribution and ontogeny of SERPINB1 in the baboon lung and characterized the expression of SERPINB1 in baboon models of BPD. SERPINB1 expression was detected in the conducting airway and glandular epithelial cells in addition to neutrophils, macrophages, and mast cells. SERPINB1 mRNA and protein expression increased with advancing gestational age and in the new BPD model. In contrast, SERPINB1 expression levels were decreased in the old BPD model. Furthermore, SERPINB1 was detected as a high-molecular-mass (HMM) complex in lung tissue and bronchoalveolar lavage fluid samples from the BPD group. Analysis of the HMM complex by coimmunoprecipitation showed that these complexes were formed between SERPINB1 and NE or cat G. High-performance liquid chromatography (HPLC) ion trap mass spectrometry verified the presence of SERPINB1 in HMM complexes. Finally, NE activity level was compared between new and old baboon models of BPD and was found to be significantly lower in new BPD. Thus SERPINB1 upregulation in new BPD may be protective by contributing to the regulation of neutrophil proteases NE and cat G.

OBJECTIVE: Adenoid cystic carcinoma (ACC) of the head and neck grows slowly with structural differentiation, however, this tumor nevertheless also shows a highly invasive potential and a high recurrence rate. Extracellular matrices have been suggested to play an important role in the differentiation and growth of ACC. The aim of this study is to understand the roles of laminin 5 basement membrane (BM) components, including collagen IV and laminin gamma2 for the high degree of invasiveness and the recurrence of ACC. METHODS: Collagen IV and laminin gamma2 were immunohistochemically localized in tissue sections from nine patients with ACCs. RESULTS: Cribriform structures with pseudocysts were preserved in small invading tumor nests, and the expression of both of collagen IV and laminin gamma2 was observed in the inner border of the pseudocysts and the surrounding area of the tumor nests. In areas of perineural invasion, the BM components continued to be expressed around the long tumor nests. Recurrent tumors consisted of multiple small nests with a few tumor cell layers, and the expression of the BM components was observed on both the inside of the inner tumor cells and the outside of the outer tumor cells, which was an obviously different appearance from that of the primary tumor. CONCLUSION: ACC appears to possibly grow and invade using the laminin 5 BM matrices while also preserving their differentiated architecture. The laminin 5 BM matrices might play an important role not only in the differentiation and growth, but also in the invasion and recurrence of ACC of the head and neck.

RATIONALE: Bronchopulmonary dysplasia (BPD) continues to be a major morbidity in preterm infants. The lung pathology in BPD is characterized by impaired alveolar and capillary development. An imbalance between proteases and protease inhibitors in association with changes in lung elastic fibers has been implicated in the pathogenesis of BPD. OBJECTIVE: To investigate the expression and activity levels of papain-like lysosomal cysteine proteases, cathepsins B, H, K, L, S, and their inhibitors, cystatins B and C, in a baboon model of BPD. METHODS: Real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry, immunoblotting, active site labeling of cysteine proteases, and in situ hybridization were performed. MEASUREMENTS AND MAIN RESULTS: The steady-state mRNA and protein levels of all cathepsins were significantly increased in the lung tissue of baboons with BPD. In contrast, the steady-state mRNA and protein levels of two major cysteine protease inhibitors, cystatin B and C, were unchanged. Correlating with these alterations, the activity of cysteine proteases in lung tissue homogenates and bronchoalveolar lavage fluid was significantly higher in the BPD group. The levels of cathepsin B, H, and S increased and cathepsin K decreased with advancing gestation. All cathepsins, except for cat K, were immunolocalized to macrophages in BPD. In addition, cathepsin H and cystatin B were colocalized in type 2 alveolar epithelial cells. Cathepsin L was detected in some bronchial epithelial, endothelial, and interstitial cells. Cathepsin K was localized to some perivascular cells by in situ hybridization. CONCLUSIONS: Cumulatively, these findings demonstrate an imbalance between cysteine proteases and their inhibitors in BPD.

BACKGROUND: Recent studies provide evidence that the constitutive activation of nuclear factor-kappa B, NF-kappaB plays a critical role in enhancing the growth of several types of malignancies, including head and neck squamous cell carcinoma (HNSCC). METHODS: In this study, we examined the effects of a newly synthesized NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on growth, induction of apoptosis, gene expression, and chemosensitivity in two HNSCC cell lines (YCU-H891 and KB), which expressed high levels of nuclear NF-kappaB protein. RESULTS: DHMEQ showed strong growth inhibitory effects on these two cell lines, with a 50% cell growth inhibition (IC50) concentration of approximately 20 microg/mL. These growth inhibitory effects were associated with inhibition of the NF-kappaB activity. Treatment with DHMEQ induced apoptosis in a dose-dependent manner accounting, at least in part, for the growth inhibition by DHMEQ. DHMEQ strongly inhibited cyclin D1 and vascular endothelial growth factor (VEGF) promoter activity and decreased the levels of cyclin D1 protein and VEGF mRNA in KB cells. In addition, low concentrations of DHMEQ (1.0 or 5.0 microg/mL) synergistically enhanced the cellular sensitivity of YCU-H and KB cells to cisplatin, which is a key chemotherapeutic agent in the treatment of HNSCC. CONCLUSIONS: These results suggest that DHMEQ may be effective when used alone or in combination with other agents in the treatment of HNSCC.

BACKGROUND: Serine proteases have important roles in tumor invasion and metastasis, and their inhibitors, serine protease inhibitors (serpins), are attractive targets for therapeutic strategies. On chromosome 18q21, there is a cluster of serpins: maspin, headpin, and squamous cell carcinoma antigen 1 (SCCA1)/SCCA2. Others and we have reported that the expression of these serpins is down regulated in head and neck squamous cell carcinoma (HNSCC) cells compared with normal squamous epithelial cells. In this study, we hypothesized that expression of SCCA1 is biologically disadvantageous to HNSCC cells. METHODS: HNSCC cell lines were transfected with a mammalian expression vector with SCCA1 cDNA. In vitro proliferation, migration, or invasive potential (matrigel assay) of the transfectants were assayed. In addition, the in vivo growth and invasion was analyzed using the floor-of-mouth model of nude mice. RESULTS: SCCA1 expression did not alter the in vitro growth rate of established HNSCC cells. However, SCCA1 expression significantly inhibited the in vitro invasion in matrigel assays. Furthermore, the in vivo growth and invasion in nude mice was also inhibited by SCCA1 expression. CONCLUSIONS: Overexpression of SCCA1 in a HNSCC cell line inhibited its invasive potential. Loss of expression of the serpin SCCA1 may play a role in the malignant progression of HNSCC.

Overexpression of cyclin D1 in head and neck cancer has been suggested to be a poor prognostic factor. To understand the role of cyclin D1 expression in head and neck cancer, we overexpressed cyclin D1 in TU182 (a cell line derived from pharyngeal cancer) using a retroviral vector. Stable transfectants were isolated by neomycin (G418) selection. Compared to the parental and control-vector transfected cells, the cyclin D1 transfected cells revealed a decrease of the G1/G0 population and resulted in continuous proliferation under low serum conditions. Proliferation assays revealed an increase in resistance to cisplatin in cyclin D1 overexpressing cells. These observation suggest that deregulation of cyclin D1 may reduce growth factor requirements and contribute to the resistance to some chemotherapeutic agents among head and neck cancer patients.

BACKGROUND: Although sinonasal inverted papilloma (IP) is a rare benign tumor, it has a tendency to recur and is sometimes associated with squamous cell carcinoma (SCC). Therefore, postoperative long-term follow-up of these patients is recommended. We previously reported that serum SCC antigen might be a useful tumor marker for sinonasal IP. In this study, we investigated whether serum SCC antigen level has a correlation with disease status and is useful in the early detection of recurrent disease. METHODS: Blood samples for the analysis of serum SCC antigen were taken from 28 IP patients before and after surgical treatment. RESULTS: Twenty-five (89%) of 28 cases showed evaluated serum SCC antigen levels above the upper limit. This marker level decreased in all cases after surgical resection. Four of these patients had a recurrence. None of the patients with recurrent tumor showed symptoms at the time of detection of their recurrent tumor, and recurrence was discovered from elevated levels of SCC antigen. CONCLUSIONS: Serum SCC antigen level has a correlation with disease status of IP and has a potential to serve as a useful tool for monitoring the course of disease. SCC antigen is a reliable tumor marker in the management of sinonasal IPs.

Adenoid cystic carcinoma is a malignant tumor of salivary gland origin. It tends to grow slowly, but shows frequent recurrence and metastasis. Cyclin D1, a cell-cycle regulation protein, has been reported to be overexpressed in various types of cancer and to correlate with poor survival of the patients. However, the prognostic significance of cyclin D1 expression in ACC of the salivary glands has not yet been determined. To evaluate the role of cyclin D1 in the biological regulation of ACC, we constitutively expressed an antisense cyclin D1 complementary DNA (cDNA) in an established ACC cell line that exhibits high endogenous expression of cyclin D1. The effect of cyclin D1 expression on in vitro cell growth and cell cycle were examined. In addition, we also examined the immunohistochemical expression of cyclin D1 protein in 31 cases of ACC of the salivary gland and correlated its expression with proliferative activity or prognosis. There were no significant differences of the in vitro growth and in the percentage of the total cell population in the G1 phase and S phase between antisense cyclin D1 clones and control clones. Thirty-two percent of tumors derived from surgical specimens examined were immunohistochemically positive for cyclin D1 protein. No association was found between cyclin D1 expression and cell proliferation or the clinical outcome of the patients. It is concluded that cyclin D1 overexpression alone does not induce a marked increase in the proliferative activity of ACC cells and that expression of this protein is not linked to poor prognosis in adenoid cystic carcinoma of the salivary gland.

PURPOSE: Recently, it has been reported that angiotensin-I converting enzyme (ACE) inhibitors have anticancer activity. In particular, the ACE inhibitor, perindopril, significantly inhibits tumor growth and angiogenesis in hepatocellular carcinoma cells along with suppression of the VEGF level. However, the mechanisms of suppression of the VEGF level are still unclear, and there are no previous reports on this subject related to head and neck squamous cell carcinoma (HNSCC). In some previous studies, angiotensin II, which is produced from angiotensin I by ACE, directly stimulates VEGF expression. METHODS: In the present study, we focused upon angiotensin II, and investigated the effect of perindopril on VEGF expression, angiogenesis, and tumor development of HNSCC with in vitro and in vivo studies. RESULTS: In the in vitro cell proliferation assays, there was no significant difference between the perindopril-treated group and the control group. However, the perindoprilat-treated group showed a significant reduction in mRNA expression of VEGF and inhibited the induction activity of the VEGF promoter in comparison to the control group. Perindoprilat treatment also significantly suppressed angiotensin II production in vitro. In the in vivo studies, perindopril had a significant inhibitory effect on tumor growth, and reduced blood vessel formation surrounding the tumors. CONCLUSIONS: Our findings suggest that perindopril has no direct cytotoxicity against tumor cells, but has a potential to inhibit tumor growth due to suppression of VEGF-induced angiogenesis in vivo. Angiotensin II might have an important role in carcinogenesis, and the antiangiogenic activity of perindopril is at least partly mediated by angiotensin II inhibition. The ACE inhibitor perindopril has clinical potential as a useful antitumor agent.

Laminin γ2 chain (LNγ2) expression and its clinical relevance were examined in squamous cell carcinomas of the tongue. When tumor cells were attached to each other and showed expansive growth, LNγ2 was expressed only in the peripheral cells of the tumor nests (peripheral expression). In contrast, when tumor cells showed infiltrative growth diminishing cell-cell adhesion, LNγ2 expression was diffusely observed in almost all of the cells (diffuse expression). Patients with caricinoma cells of the primary lesions showing peripheral LNγ2 expression were classified as the peripheral expression type. whereas patients with carcinoma cells showing diffuse LNγ2 expression at least in part of the invasive fronts were classified as the diffuse expression type. Among 30 patients with tongue carcinomas of more than stage II, 19 patients were the peripheral expression type and 11 patients were the diffuse expression type. The 3-year diseasespecific survival rates for the peripheral type and diffuse type were 64% and 34%, respectively. LNγ2 may play an important role in growth and invasion of tongue carcinomas. In particular, it seems likely that the diffuse LNγ2 expression in carcinoma cells has a significant relevance to the malignant characteristics of infiltrative carcinoma cells. In addition, LNγ2 expression may be a useful prognostic factor for the patients with carcinomas of the tongue.

The precise mechanism responsible for the frequent overexpression of cyclinD1 in human head and neck squamous cell carcinoma (HNSCC) is not known. In view of the fact that signal transducers and activators of transcription 3 (Stat3) is often activated in HNSCC cells, we examined the effects of Stat3 on cyclin D1 expression and cell proliferation in the YCU-H891 HNSCC cell line that displays constitutive activation of Stat3. Expression of a dominant negative Stat3 construct in YCU-H891 cells inhibited proliferation, cyclin D1 promoter activity, and cellular levels of cyclin D1 mRNA and protein. The levels of the antiapoptotic Bcl-2 and Bcl-X(L) proteins were also inhibited. In 51 primary tumor samples from patients with squamous cell carcinoma of the p.o. tongue, there was a significant correlation between increased levels of the activated form of Stat3, phosphorylated-Stat3, and increased levels of cyclin D1 (P < 0.0001). Increased tumor levels of phosphorylated-Stat3 were also associated with lower survival rates (P < 0.01). This study provides the first evidence that in HNSCC, constitutive activation of Stat3 plays a causative role in overexpression of cyclin D1, and in clinical studies, Stat3 activation may provide a novel prognostic factor. Furthermore, agents that target Stat3 may be useful in the treatment of HNSCC.

BACKGROUND: Inverted papilloma (IP) is a frequent benign sinonasal tumor that is characterized histologically by squamous metaplasia, epithelial acanthosis, and hyperplasia of the nasal epithelium. Because of its high recurrence rate and malignant transformation potential, careful long-term follow up is necessary. METHODS: The purpose of the current report was to study the expression of squamous cell carcinoma (SCC) antigen in sinonasal IPs and to evaluate the usefulness of SCC antigen as a biologic marker for the follow-up of patients with sinonasal IP. The expression of SCCA1 in three sinonasal IP cases, three sinonasal SCC cases, and cases of normal nasal epithelium were examined by Western blot analysis, and the SCCA1 expression pattern in 31 IP specimens and 4 carcinoma in IP specimens were evaluated immunohistochemically. The serum levels of SCC antigen in 11 patients with sinonasal IP also were analyzed. RESULTS: SCCA1 was overexpressed in all three sinonasal IP tissues compared with sinonasal SCC tissues or normal nasal epithelium. SCCA1 cytoplasmic immunoreactivity was detected in the suprabasal epidermal keratinocytes of all 31 sinonasal IP cases. In the four carcinoma in IP specimens, SCCA1 expression in the papillomatous lesion was more intense than in the cancerous lesion. The serum SCC antigen level was high in 10 of 11 patients with IP (91%) and significantly decreased after surgical resection of the tumors. CONCLUSIONS: The results of the current study indicate that SCCA1 frequently is overexpressed and may play a biologic role in the development of sinonasal IPs. Serum SCC antigen may be a useful biologic marker in patients with sinonasal IP.

A retrospective review was performed on 17 patients with submandibular gland cancer initially treated in our hospital between 1972 and 1997. The most common histological type was adenoid cystic carcinoma (41%). Sixteen cases were treated with surgery and some cases received added postoperative irradiation (4 cases) and chemotherapy (2 cases). A case with distant metastasis was treated with chemotherapy.
The five-year and ten-year cumulative survival rates calculated by the Kaplan-Meier method were 74 and 41%, respectively. The five-year survival rate according to stage was as follows: stage I (11 cases), 82%; stage II (2 cases), 100%; and stage IV (4 cases), 33%. Prognosis of the cases with .neck lymph node metastatis was remarkably poor. To improve the prognosis of submandibular gland cancer, prophylactic supraomohyoid neck dissection should be necessary for the N0 cases.

A clinical study was performed on 42 patients with parotid cancers initially treated in our hospital from 1972 to 1997. The five-year cumulative survival rate was 69% in the whole group and 72% in the radical surgical treatment group (n=40). The five-year survival rates according to stage were as follows: stage I, 95% (21); stage II, 75% (4); stage III, 0% (1); and stage IV, 37% (16). The factors influencing prognosis were cases of T3 and T4 (p<0.05), stage III and IV (p<0.01), and cervical lymph node metastasis (p<0.01).
Regarding treatment modalities, a partial parotidectomy appeared to be a curable surgical procedure for T1 cases. However, a lobectomy is recommended for T2 cases.
Furthermore our study proposed that prophylactic supraomohyoid neck dissection should be necessary for mucoepidermoid carcinoma (high-grade malignancy) and undifferentiated carcinoma of T4N0 cases.

2021年度は、前年同様癌化メカニズム解明のための遺伝子網羅的解析を検体数を増やして行った。 癌部分3検体、乳頭腫部分３検体の計6検体についてアンプリコンシークエンスを用いた遺伝子変異解析を行った。FFPE標本から、レーザーマイクロダイセクション法を用いることで 乳頭腫部分と癌部分に分離しDNAを抽出した。 その結果、前回の結果と併せて既知の変異であるTP53は7例中6例(86%)、APCは7例(100%)に認めた。またARID1A 5例 (71%)、NF1 3例（43%)といったこれまで乳頭腫由来癌では報告されていないがん抑制遺伝子の不活化変異を認めた。 一方レディオミクスに基づいた画像検査から乳頭腫由来癌を予測する方法の確立に関する課題については多くの画像を収集し、予後や悪性度との関連について解析を継続中である。

外耳道癌の治療のブレークスルーがないことが、現状での大きな問題である。そのためには、1)現在コンセンサスの得られているステージ分類が、微小外科解剖学的知見による病変の 広がりを加味して十分に細分化されていない。さらに、腫瘍の悪性度・浸潤性を加味した、 治療戦略が確立していない。 2)発癌・癌進展の分子生物学的メカニズムがゲノムレベル・トランスクリプトームレレベルでも何れも解析が進んでいないため、治療標的となる分子が同定されていない。 3)深部再発した際および治療耐性化の早期発見マーカーが存在しないため、早期発見が遅 れる傾向にある。の３つが必要である。今年度は、２）の外耳道癌の分子生物学的解析を行うために、２つの実験を同時並行してきた。一つ目は、外耳道癌のターゲット遺伝子検索にWhole exome sequence、遺伝子発現プロファイル検索にRNA sequence解析を、当院で採取した検体を用いて解析に提出している。現在は解析結果待ちの状態である。もう一つは、解析用の細胞株を作成するために、当研究室では、細胞株の樹立を試みた。患者から原発巣の検体を採取して、顔細胞の樹立を試みた。採取検体を、培養液に浸し、検体ブロックの周囲から増生してきたがん細胞をPick upした。その細胞をFeeder cell (TGI) などと共培養することで、がん細胞のコロニーの作成を試みた。Feeder Cell内に、小さなコローニーの形成が確認できたため、それらを、p53 SCCなどで免疫組織染色を行い、がん細胞由来のコロニーであることを確認できた。しかし、コローニーはある一定の大きさで増殖が止まるため、細胞培養株として現状では樹立できていない。現在、原因の解明と、種々の方法を用いて、コロニーを増大させる方法を模索中である。

Sinonasal inverted papilloma (IP) is a histologically benign tumor. Differentiating IP from squamous cell carcinoma (SCC) is sometimes difficult. We evaluated the clinical usefulness of serum SCCA1 and SCCA2 in the management of patients with IP or SCC. As a result, the serum SCCA1 concentration was significantly higher in the IP group than in the SCC group, whereas the serum SCCA2 level was significantly higher in the SCC group than in the IP group. This suggests that combined measurements of both serum SCCA1 and SCCA2 concentrations can be very useful for distinguishing sinonasal IP from SCC. Regarding the relationship high risk HPV infection and SCC-associated IP, we could not find any correlations among them.Our results suggest that high-risk HPV does not play a common role in either the development of IP or in its transformation into carcinoma.

Squamous cell carcinoma antigen (SCCA) belongs to the ovalbumin-serpin family and is a known tumor marker. Recent studies demonstrated that the expression of SCCA2 was increasing in HNSCC. However its physiologic function in HNSCC is unknown. The aim of this study was to evaluate the biological role of SCCA2 in HNSCC, and the relationship between SCCA2 protein level and tumor volume. SCCA2 expression did not alter the in vitro growth rate of established HNSCC cells, the in vitro invasion in matrigel assays, the in vivo tumor growth and the in vivo invasion in nude mice. However, antitumoragent could only inhibit tumor growth in low SCCA2 expression tumor group in vivo. Serum SCCA2 protein level correlated with tumor volume. In addition, the SCCA2/SCCA1 ratio of protein level in the carcinoma tissue was higher than in the normal tissue. Further examination is necessary to conclude that SCCA2 is reliable tumor marker in HNSCC.

Management of second primary cancers in head nad neck cancer(HNC) patients has been important for head and neck surgeons. There are 20-30% incidence of second primary cancer due to field cancerization of the upper aerodigestive tract. This study investigated the efffect of retinoic acids for the chemoprevention of HNC utilizing an animal (hamster) model. 13-cis retinoic acid had a effect for preventing cancer in the animal, however no stastisical significance was obtained because the number of animals in the experiment was still small. The experiments are still in progress.

Thymidylate Synthase (TS) and Dihydropyrimidine Dehydrogenase (DPD) are key enzymes for 5-FU metabolism. The relationship between the expression of TS/DPD and 5-FU sensitivity in head and neck squamous carcinoma (HNSCC) cells was analyzed in vitro. Increasing the expression of TS or DPD decreased the cytotoxicity of 5-FU against HNSCC cells. Clinico-pathological analysis was also performed utilizing specimens from oral cancer and maxillary sinus cancer. There was a correlation between high TS expression and poor prognosis of the patients. Assessment of TS/DPD activity may be useful in predicting the effect and prognosis of HNSCC patients who are receiving 5-FU based chemo(radio)therapy.

SCCA1 is the member of the clade B serpin and is an inhibitor of cysteine proteases, cathepsin (cat) K, L, and S. However its physiologic function in HNSCC is unknown. Recent studies demonstrated that the expression of SCCA1 was increasing in HNSCC. We hypothesized that altered expression of SCCA1 in HNSCC could contribute to block the protease activity and investigated whether SCCA1 could make the complex with the new protease in HNSCC. In this study, however, we could not find any new proteases which could make the complex with SCCA1 protein. Further examination is necessary to conclude that SCCA1 can block the new protease in patients with HNSCC.

Serine proteases have important roles in tumor invasion and metastasis and their inhibitors, serine protease inhibitors (serpins) are attractive targets for therapeutic strategies. On chromosome 18q21,there is a cluster of serpins ; maspin, headpin, and SCCA1. Others and we have reported that the expression of these serpins are down-regulated in HNSCC cells as compared to normal squamous epithelial cells. We have hypothesized that expression of SCCA1 is biologically disadvantageous to HNSCC cells. The in vitro and in vivo invasion of established HNSCC cell lines stably transfected with a mammalian expression vector with SCCA1 cDNA was significantly inhibited compared to the vector control. SCCA1 may function to inhibit the invasive potential of HNSCC. We also reported that Serum SCC antigen level has a correlation with disease status of sinonasal inverted papilloma(IP) and has a potential to serve as a useful tool for monitoring the course of disease. SCC antigen is a reliable tumor marker in the management ofsinonasal IPs.

We have investigated the significance of extra-cellular matrices, laminin and collagen, in the invasion and metastasis of squamous cell carcinomas (SCCs) of the tongue and adenoid cystic carcinomas (ACCs) of the head and neck. Results and conclusions are described as follows: 1.Laminin expression in the tongue SCCs. The expression patterns of laminin γ2 chain (LNγ2) in the surgically removed specimens of the tongue SCCs were classified as two categories. When tumor cells were attached to each other and showed expansive growth, LNγ2 was expressed only in the peripheral cells of the tumor nests (peripheral expression). In contrast, when tumor cells showed infiltrative growth diminishing cell-cell adhesion, LNγ2 expression was diffusely observed in almost all of the cells (diffuse expression). The tumors cells with LNγ2 diffuse expression highly showed pen-neural invasions and vascular invasions, and closely related to the poor prognosis. It was suggested that the tumor cells showing expansive growth preserved the characters of normal squamous epithelium and matrix-dependent growth capacities, and that the tumor cells showing infiltrative growth highly expressed LNγ2 and thus obtained migration and matrix-independent capacities. It seems likely that the diffuse LNγ2 expression induce metastatic potentials and malignant phenotypes of tongue SCCs. 2.Laminin and collagen expression m ACCs of the head and neck. The expression of LNγ2 and type 4 collagen was examined in the surgically removed specimens of ACCs of the head and neck. The two matrices were expressed in the surrounding areas of large tumor nests as well as in the inner borders of pseudo-cysts of cribriform type ACCs. In contrast, the matrices expression was observed only in the surrounding areas of tumor nests of tubular type ACCs. Small tumor nests budding from the large cribriform tumor nests were elongated along the nerves in areas of the pen-neural invasion. The matrices expression was still observed in the inner border of the pseudocysts as well as around the invading long tumor nests. It was reported that the tumor cells located in the peripheral area of the tumor nests and inner border of the pseudo-cysts were derived from myoepithelial origin. Therefore, our results suggest that the myoepithelial cells of ACC are lined with basement membrane matrices containing laminin and collagen, and that these cells invade through the pen-neural areas by use of the basement membrane matrices.

Serine proteases have important roles in tumor invasion and metastasis and their inhibitors, serine protease inhibitors (serpins) are attractive targets for therapeutic strategies. On chromosome 18q21, which is recognized as a region for frequent loss of heterozygosity (LOH) in head and neck squamous cell carcinoma (HNSCC), there is a cluster of serping; maspin, headpin, and SCCA1. Others and we have reported that the expression of maspin, headpin and SCCA1 are down-regulated in HNSCC cells as compared to normal squamous epithelial cells. In this study, we hypothesized that expression of these serpins are biologically disadvantageous to HNSCC cells. We also hypothesized that alterations in these serpin expression will produce differences in the phenotypic behavior of oral SCC tumors in patients. Established HNSCC cell lines were stably transfected with a mammalian expression vector with SCCA1 or headpin cDNA. In vitro proliferation, migration, or invasive potential (Matrigel assay) of the transfectans were assayed. In addition, archival paraffin embedded specimens of primary tongue tumors from patients were analyzed for SCCA1, maspin, and headpin mRNA and/or protein expression using quantitative RT-PCR and/or imunohistochemistry respectively. The relationship between the expression and invasiveness, clinical courses of the patients were analyzed. Headpin or SCCA1 expression did not alter the in vitro growth rate of established HNSCC cells. However, SCCA1 and headpin expression both significantly inhibited the in vitro invasion in matrigel assays. The absence of maspin expression in oral SCC specimens was found more frequently in cases of subsequent cervical lymph node metastasis than in cases without metastasis. SCCA1 and headpin may function to inhibit the invasive potential of HNSCC. Loss of expression of 18q21 serpins; maspin, headpin and SCCA1 may play a role in the malignant progression of HNSCC. Serpins which locate as 18q21; maspin, headpin and SCCA1 have potential to be the molecular targets in the treatment of HNSCC.