Combination therapy with adefovir dipivoxil (ADV) and lamivudine (LAM) is recommended for patients infected with LAM-refractory hepatitis B virus (HBV). However, the effects of such therapy on renal function and serum phosphorus levels have not been fully evaluated. Combination therapy with ADV and LAM was given to 37 patients infected with LAM-refractory HBV, including 17 with hepatic cirrhosis. Serum HBV DNA levels decreased to below 2.6 log(10) copies/mL in 23 (62%) of 37 patients at 12 months, 25 (78%) of 32 patients at 24 months, and 16 (84%) of 19 patients at 36 months. Except for one cirrhotic patient, serum alanine aminotransferase levels were below 50 IU/L in all patients during combination therapy. Serum creatinine levels increased in 14 (38%) of 37 patients, and serum phosphate levels decreased to below 2.5 mg/mL in 6 (16%) of 37 patients during combination therapy. Patients who received combination therapy for 36 months or longer had a significantly incidence of elevated serum creatinine levels. Fanconi syndrome occurred in a 57-year-old woman with cirrhosis after ADV was added to LAM. Combination therapy with ADV and LAM can maintain biochemical remission in patients with LAM-refractory HBV. However, the dosing interval of ADV should be adjusted according to renal function and serum phosphate levels in patients receiving long-term treatment.

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

Cyclooxygenase-2 (COX-2) is one of the two isoforms of COX, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 is associated with the progression in various types of cancer, and its expression has been associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC). Furthermore, COX-2 expression has been associated with resistance to anticancer drugs. However, the precise mechanism of COX-2 for chemoresistance in HNSCC has not been fully elucidated. The present study aimed to investigate the effect of COX-2 on cancer stem cell (CSC) property and to reveal its effect on chemoresistance using in vitro and clinicopathological assays in HNSCC cells and tissues. The current study analyzed the immunohistochemical expression levels of COX-2 and clinicopathological factors using matched samples of pretreatment biopsy and surgical specimens from patients with hypopharyngeal carcinoma who underwent tumor resection with preoperative chemotherapy, including docetaxel. Additionally, the chemoresistance to docetaxel with or without a COX-2 inhibitor (celecoxib) was examined in HNSCC cell lines by MTS assays. To evaluate the association of COX-2 expression with stemness property, the expression levels of CSC-associated genes after exposure to celecoxib were assessed by reverse transcription-quantitative PCR. A sphere formation assay was also performed using ultra-low attachment dishes and microscopic imaging. The immunohistochemical analysis of biopsy specimens revealed a negative association between COX-2 expression in biopsy specimens and the pathological effect of induction chemotherapy in surgical specimens. The cell survival rate under exposure to docetaxel was decreased by the addition of celecoxib. COX-2 inhibition led to downregulation of CSC-associated gene expression and sphere formation. The present findings suggested that COX-2 expression may be associated with chemoresistance through the cancer stemness property, and inhibition of COX-2 may enhance chemo-sensitivity in HNSCC. Therefore, COX-2 may be an attractive target for the treatment of HNSCC.

ObjectiveSalivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy.Materials and MethodsThe EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases).ResultsEZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups.ConclusionsA high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

Gunshot injuries involving the head and neck region yield profound morbidity and mortality rates. Projectile-related factors comprising various physical and dynamic properties of a bullet, as well as tissue-related factors, determine the disruptive effects of projectiles on living tissues. We experienced an extremely unusual case of a gunshot injury to the neck, wherein the bullet transversely penetrated across the deep neck structures to the contralateral side of the shoulder without damaging any vital organs. A 51-year-old man presented with a gunshot wound to the neck from a point-blank range. A bullet entry hole was observed on the left side of the neck without an exit hole; however, the patient was conscious, vital signs were normal, and no active bleeding, cranial nerve palsy, or aero-digestive tract injury was found. Imaging tests revealed a bullet lying in front of the right humeral head, which was extracted by emergency surgery. The patient was uneventfully discharged. According to the localization of the damaged tissues and the positional relationship between the bullet’s entrance and its destination, the bullet was estimated to have nonlinearly traversed the neck by traveling through the interstructural spaces associated with the least tissue resistance. Our experience strongly suggests the importance of realizing the unpredictable nature of a bullet trajectory in a body. An appropriate understanding of various ballistic factors and wounding mechanisms can be of great help in the adequate assessment and management of patients with gunshot injuries.

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Background: Tumor cell-derived VEGF-C has been considered to promote lymphangiogenesis by activating Flt-4 (VEGFR-3) expressed on lymphatic endothelial cells via a paracrine mechanism in tumor microenvironment. Recent studies have shown that Flt-4 is expressed not only in endothelial cells but also selectively in certain subsets of a variety of cancer cells. In addition, the VEGF-C/Flt-4 autocrine loop on lung adenocarcinoma cells was reported to enhance cell motility and invasiveness through up-regulation of the neural cell adhesion molecule Contactin-1 (CNTN-1), although little of such mechanism is known in head and neck squamous cell carcinoma (HNSCC). Present study was aimed to examine Flt-4 expression and VEGF-C/Flt-4 autocrine loop in HNSCC cells, and clinicopathological significance of the expressions of Flt-4, VEGF-C, and CNTN-1 in the tumor specimens of the patients with HNSCC. Methods: We examined expression of Flt-4 in HNSCC cell lines using quantitative real-time PCR, RT-PCR, and immunocytochemistry. The role of the VEGF-C/Flt-4 axis in Flt-4-positive HNSCC cells in vitro was investigated by stimulating or blocking Flt-4. Immunohistochemical studies were performed on 56 oral tongue squamous cell carcinoma (TSCC) specimens. The associations of the immunohistochemical expressions of Flt-4, VEGF-C, and CNTN-1 with the clinicopathological factors were statistically analyzed. Results: Real-time PCR detected Flt-4 mRNA expression in several HNSCC cells, which was further confirmed by RT-PCR and immunocytochemistry in SAS and HO1U1. Stimulation of Flt-4 using recombinant VEGF-C up-regulated expression of CNTN-1 and VEGF-C itself in SAS, whereas blocking using neutralizing anti-Flt-4 antibody or Flt-4 inhibitor down-regulated expression of CNTN-1 in both SAS and HO1U1, and that of VEGF-C itself in SAS. Immunohistochemical analyses using TSCC specimens found significant correlation of CNTN-1 expression with both VEGF-C and Flt-4 expressions, but not between VEGF-C and Flt-4. With regard to clinicopathological factors, expressions of all the three molecular markers in tumor cells significantly correlated with lymph node (LN) metastasis, which was also correlated with T classification and lymphatic invasion in univariate analysis. Multivariate analysis elucidated that T classification (p=0.003), lymphatic invasion (p=0.024), and expression of Flt-4 in tumor cells (p=0.046) were independent predictors of LN metastasis. Conclusions: Our results suggest that VEGF-C activates FLt-4 expressed not only on lymphatic endothelial cells but also selectively on subset of HNSCC cells, resulting in VEGF-C/Flt-4 autocrine mechanism that up-regulates CNTN-1 and VEGF-C itself in tumor cells. Therefore, both paracrine and autocrine mechanisms of VEGF-C/Flt-4 may contribute to progression of HNSCC including LN metastasis. Citation Format: Seiji Shigetomi, Yorihisa Imanishi, Masayuki Shimoda, Kaori Kameyama, Katsushi Shibata, Nobuya Sakai, Koji Sakamoto, Ryoichi Fujii, Noboru Habu, Kuninori Ootsuka, Kaoru Ogawa. Flt-4 expression on tumor cells and its autocrine mechanism with VEGF-C/contactin-1 stimulate progression of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2818. doi:10.1158/1538-7445.AM2013-2818

Background : Preoperative diagnosis of lymph node metastasis from thyroid carcinoma is usually confirmed by using fine needle aspiration cytology FNAC when thyroid carcinoma is suspected based on the clinical findings. However, the result of FNAC sometimes leads to a false negative, especially in cases of hypocellular lesions such as metastases with cystic change. Thyroglobulin measurement in fine needle aspirates FNA Tg has been shown to be a useful tech-