Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on Cl- Channels.

Airway remodeling caused by asthma is characterized by structural changes of subepithelial fibrosis, goblet cell metaplasia, submucosal gland hyperplasia, smooth muscle cell hyperplasia, and angiogenesis, leading to symptoms such as dyspnea, which cause marked quality of life deterioration. In particular, fibrosis exacerbated by asthma progression is reportedly mediated by epithelial-mesenchymal transition (EMT). It is well known that the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling is closely associated with several signaling pathways, including the TGF-ß1/Smad, TGF-ß1/non-Smad, and Wnt/ß-catenin signaling pathways. However, the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling has not yet been fully clarified. Given that Cl- transport through Cl- channels causes passive water flow and consequent changes in cell volume, these channels may be considered to play a key role in EMT, which is characterized by significant morphological changes. In the present article, we highlight how EMT, which causes fibrosis and carcinogenesis in various tissues, is strongly associated with activation or inactivation of Cl- channels and discuss whether Cl- channels can lead to elucidation of the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling.

Neoadjuvant Superselective Intra-Arterial Cisplatin Chemoradiotherapy Combined With Surgery in Patients With T4 Squamous Cell Carcinoma of the Maxillary Sinus.

PURPOSE: Squamous cell carcinoma of the maxillary sinus (SCC-MS) is often diagnosed at a locally advanced stage, which is associated with poor prognosis. The purpose of the present study was to investigate clinical outcomes in patients with locally advanced T4 SCC-MS including originally inoperable T4b disease treated with neoadjuvant superselective intra-arterial chemoradiotherapy combined with surgery. METHODS: This study is a retrospective case series. We examined clinical outcomes in the patients with T4 SCC-MS between 2005 and 2017. The outcome variables were 5-year overall survival rate, 5-year disease-free survival rate, and 5-year local control rate. Covariates included age, sex, T classification, N classification, stage classification, type of surgery, number of administrations and total dose of cisplatin, and radiation dose. Descriptive statistics were computed for each study variable. RESULTS: Ten patients with T4 SCC-MS (6 T4a and 4 T4b) were treated. All patients were men, and the median age was 60.5 years (range, 45 to 77). Total maxillectomy was performed in 4 patients, and extended total maxillectomy in 6. The total number of intra-arterial chemotherapy administrations ranged between 2 and 4 for patients with T4a disease and between 3 and 4 for those with T4b disease. The median intra-arterial cisplatin dose was 360 mg (range, 250 to 400) for patients with T4a disease and 360 mg (range, 320 to 480) for those with T4b disease. The 5-year overall survival, 5-year disease-free survival, and 5-year local control rates of all patients were 100%, 70%, and 80%, respectively. The 5-year disease-free survival rate and 5-year local control rate were 83% and 83%, respectively, in the 6 T4a patients and 50% and 75%, respectively, in the 4 T4b patients. CONCLUSION: Neoadjuvant intra-arterial chemoradiotherapy in patients with T4 SCC-MS can achieve good clinical outcomes, and it may enable surgical resection of T4b lesions.

Dysfunction of Cl- channels promotes epithelial to mesenchymal transition in oral squamous cell carcinoma via activation of Wnt/ß-catenin signaling pathway.

Oral squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a high incidence of recurrence and distant metastasis. However, the mechanism of epithelial to mesenchymal transition (EMT) during tumor progression and metastasis in OSCC has not yet been fully elucidated. It is well known that the Cl- channel controls cell volume and activates several signaling pathways for cell differentiation. The aim of the present study was to investigate the role of the Cl- channel on EMT in the OSC 20 cell line, which is an OSCC line. OSC-20 cells were cultured with low serum medium containing a Cl- channel blocker NPPB. Morphological changes, gene expression, immunoreactivity, cell volume, and signaling pathway of the NPPB-treated OSC-20 cells were evaluated. The NPPB-treated OSC-20 cells showed typical morphology of mesenchymal cells. The expression levels of the epithelial marker E-cadherin in the NPPB-treated OSC-20 cells were lower than those of the untreated and TGF-ß1-treated OSC-20 cells. On the other hand, mesenchymal markers such as vimentin, ZEB1, and Snail, in the NPPB-treated OSC-20 cells were higher than those in the untreated and TGF-ß1-treated OSC-20 cells. Furthermore, a large number of vimentin-positive cells also appeared in the NPPB-treated OSC-20 cells. Additionally, the cell volume of these cells was significantly increased compared to that of the untreated and TGF-ß1-treated cells. Interestingly, NPPB did not activate the TGF-ß/smad signaling pathway, but activated the Wnt/ß-catenin signaling pathway. These results suggest that Cl- channel dysfunction promoted EMT via activation of the Wnt/ß-catenin signaling pathway in OSCC.

EBV infection is prevalent in the adenoid and palatine tonsils in adults.

Epstein-Barr virus (EBV) is associated with the pathogenesis of several diseases in both adults and children. However, there have been no reports on the prevalence and amount of EBV in the adenoids of adults; thus, it is important to investigate these in the adenoids and tonsils of adults and children. In this study, 67 patients who underwent tonsillectomy or adenotonsillectomy were included and divided into two groups: adults aged ≥ 16 years (n = 35) and children aged <16 years (n = 32). Patients' adenoid and tonsil tissues were analyzed using quantitative polymerase chain reaction for EBV DNA. EBV was detected in 26 (74%) adenoids and 25 (71%) tonsils among the adult group and was detected 21 (66%) adenoids and 20 (63%) tonsils in the child group. There was no significant difference in EBV DNA prevalence between the adenoids and tonsils for each group. However, there was a significant correlation between EBV DNA load in the adenoids and tonsils of the same individual in both groups (r = 0.579, P < 0.01, adult group; r = 0.919, P < 0.01, child group). In conclusion, EBV infection is prevalent in the adenoids and tonsils in adults and children. These results indicate that EBV continuously reside in the nasopharyngeal region after primal infection and may develop several diseases.

Expression of interferon regulatory factor 7 correlates with the expression of Epstein-Barr Virus latent membrane protein 1 and cervical lymph node metastasis in nasopharyngeal cancer.

Interferon regulatory factor 7 (IRF7) has oncogenic properties in several malignancies such as Epstein-Barr virus (EBV)-associated lymphoma. However, there is no evidence whether IRF7 is associated with the oncogenesis of nasopharyngeal cancer (NPC), the pathogenesis of which is closely associated with EBV. Herein, we report that expression of IRF7 was increased in normal nasopharyngeal cells that expressed the EBV principal oncoprotein, latent membrane protein 1 (LMP1). In addition, IRF7 was mainly expressed in the nucleus in both normal nasopharyngeal cells and nasopharyngeal cancer cells that expresses LMP1. On immunohistochemical analysis, IRF7 was predominantly localized in the nucleus in biopsy samples of NPC tissues. In total, IRF7 expression was detected with 36 of 49 specimens of these tissues. Furthermore, the expression score of IRF7 correlated with the expression score of LMP1. Moreover, the expression score of IRF7 is associated with cervical lymph-node metastasis, which reflects the highly metastatic nature of this cancer. Taken together, our results suggest that expression of IRF7 is one of the metastatic effectors of LMP1 signalling in EBV-associated NPC.

Preoperative identification of the internal opening with the modified Killian's method in a case of pyriform sinus fistula.

Pyriform sinus fistula is a rare branchial pouch anomaly, which causes recurrent neck abscess. Although complete excision of the fistula tract is considered as a definitive treatment for pyriform sinus fistula, it has been suggested that chemocauterization with trichloroacetic acid (TCA) of the internal opening is a reasonable treatment. For this purpose identifying the existence of an internal opening is important. Here, we describe the Modified Killian's method, a recently proposed simple endoscopic technique to observe a wider area of the hypopharyngeal space, and show that it is helpful to identify the internal opening of the pyriform sinus fistula. The Modified Killian's method is a suitable examination for pyriform sinus fistula prior to TCA chemocauterization.

[Pharyngoesophageal Reconstruction Using a Laryngotracheal Flap Following Resection for Hypopharyngeal Cancer].

We used hemilaryngotracheal tissue without tumor involvement as a laryngotracheal flap (LTF) for immediate repair of a pharyngoesophageal defect following resection for hypopharyngeal cancer. Five cases of lateralized advanced hypopharyngeal cancer were treated in our department. The median age was 82 years, ranging from 64 to 90 years. Four tumors were T3 stage, and the other was T2. A pharyngocutaneous fistula developed in one patient. The postoperative swallowing function was satisfactory, but one patient developed difficulty in eating a normal diet, because of pharyngoesophageal stenosis at 7 months after chemoradiotherapy. During the follow-up period, there was no locoregional recurrence. One patient had lung metastasis, and died of the disease. One patient died of another cause. Three patients are alive without evidence of the disease. Reconstruction of the hypopharynx with an LTF is a minimally invasive method compared with the radial forearm free flap and free jejunal flap. For selected cases of advanced hypopharyngeal cancer, this method would be one of the choices to reconstruct the pharyngoesophageal defect.

[A Case Treated with Selective Embolization for Hemorrhage during Tonsillectomy].

Though tonsillectomy is one of the most common surgical procedures in otorhinolaryngology generally for benign diseases and mainly for young people, uncontrollable perioperative bleeding associated with tonsillectomy is a rare but potentially life-threatening event. We report herein on a case of a 19-year-old female with uncontrollable hemorrhage during a tonsillectomy, which was controlled through selective embolization. To the best of our knowledge, this is the first report on endovascular treatment in the management of tonsillectomy-associated intraoperative uncontrollable hemorrhage rather than postoperative bleeding. Selective embolization for perioperative bleeding during a tonsillectomy is considered as an efficient and important therapeutic option in the definitive treatment of this life-threatening occurrence. We also reviewed patients who underwent tonsillectomy in our hospital in the past five years. The ratio of postoperative hemorrhage was 11.8%. All patients with post-tonsillectomy hemorrhage were classified as grade 1 bleeding (spontaneous cessation).

Induction of epithelial-mesenchymal transition and loss of podoplanin expression are associated with progression of lymph node metastases in human papillomavirus-related oropharyngeal carcinoma.

AIMS: To examine human papillomavirus (HPV) status, the expression of podoplanin and epithelial-mesenchymal transition (EMT) markers and lymphatic vessel counts (LVC) in oropharyngeal squamous cell carcinoma (OPSCC) tissues, and to evaluate whether these factors were associated with survival and nodal status. METHODS AND RESULTS: A total of 53 OPSCC specimens were evaluated for HPV status and expression of proteins such as podoplanin and EMT markers by immunohistochemistry. E-cadherin-negative and vimentin-positive specimens were defined as EMT-positive. Twenty-two OPSCCs were HPV-positive. There was significant progression of nodal status in patients with HPV-positive tumours (P = 0.0475). HPV-positive cases had significantly lower expression of podoplanin (P = 0.0016) and were more frequently EMT-positive (P = 0.0172). Podoplanin-negative cases and EMT-positive cases showed significantly more advanced nodal status than their respective counterparts (P = 0.0082 and P = 0.0186, respectively). LVC correlated with neither HPV nor nodal status. Multivariate analyses revealed that HPV infection was an independent marker of longer disease-specific survival (P = 0.014). CONCLUSIONS: HPV-positivity in OPSCC was associated with loss of podoplanin expression and with EMT induction, which resulted in progression of nodal status. The mechanisms leading to an improved prognosis in HPV-positive OPSCC patients requires elucidation, as this is inconsistent with the aggressive phenotype with lymph node metastases.

Progress and controversy for the role of chemotherapy in nasopharyngeal carcinoma.

Since the publication of Intergroup Study 0099, representing a superiority of concurrent chemoradiotherapy with cisplatin followed by adjuvant chemotherapy to radiotherapy alone for the treatment of locoregionally advanced nasopharyngeal carcinoma, an efficacy of concurrent setting of cisplatin-based chemotherapy with radiotherapy has been repeatedly validated. In meanwhile, the role of adjuvant part of the protocol has been controversial. There is an increasing evidence for the positive role of neoadjuvant chemotherapy with following concurrent chemoradiotherapy whereas favorable contribution was not proven in the last century. This article reviews the role of chemotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Factors associated with gastrostomy tube dependence after concurrent chemoradiotherapy for hypopharyngeal cancer.

PURPOSE: We aimed to identify tumor- and treatment-related factors predicting gastrostomy tube dependence after concurrent chemoradiotherapy (CCRT) for hypopharyngeal cancer. METHODS: We performed a retrospective review of all patients with hypopharyngeal cancer treated with CCRT between 2002 and 2012 except for those with residual or recurrent disease at evaluation. The incidence of gastrostomy tube dependence, defined as complete or almost complete dependence on tube feeding, at 6 months after the completion of treatment was the endpoint. A total of 75 patients were analyzed in this study. RESULTS: Twelve patients (16 %) showed gastrostomy tube dependence. Among tumor-related factors, the subsite (posterior wall versus pyriform sinus plus postcricoid) was the most significant factor correlated with gastrostomy tube dependence (p < 0.01 by multivariate analysis). The T category of the primary tumor was also correlated with gastrostomy tube dependence on univariate analysis (p < 0.01). Among treatment-related factors, the radiation dose was not associated with gastrostomy tube dependence. On the other hand, gastrostomy tube dependence was also correlated with the requirement of supportive nutrition with a nasogastric tube at the beginning of and during treatment (both p < 0.01). CONCLUSION: Risk factors for gastrostomy tube dependence after the completion of CCRT for hypopharyngeal cancer were identified.

HPV Status Determines the Efficacy of Adjuvant Chemotherapy With S-1, an Oral Fluorouracil Prodrug, in Oropharyngeal Cancer.

OBJECTIVES: A subgroup of oropharyngeal squamous cell carcinoma (OPC) is infected with high-risk human papillomavirus (HPV). The object of this study is to evaluate the efficacy of adjuvant chemotherapy with S-1, an oral 5-fluorouracil prodrug, on survival of patients with OPC according to HPV status. METHODS: Among OPC patients of stage III or IV who received definitive treatment from 1998 to 2008, 38 who were confirmed tumor-free after primary treatment were analyzed. Before 2003, none of the patients received S-1 adjuvant chemotherapy (S-1(-)-group); however, all patients who were eligible were administered S-1 (S-1(+)-group) after 2003. The expression of thymidylate synthase (TYMS) involved in 5-FU metabolism was also examined in protein and mRNA levels. RESULTS: Although there was a trend to disease-free and overall survival benefit in HPV-negative patients with S-1, it did not achieve statistical significance (P=.082 and P=.065, respectively). For the HPV-positive patients, the survivals were similar with or without S-1 administration. TYMS-expression in HPV-positive OPC tissues was significantly higher than in HPV-negative ones in both protein and mRNA levels (P=.0489 and P=.0446, respectively). CONCLUSION: The current study provides a rationale to plan a randomized trial to compare the efficacy of S-1 according to the HPV status in OPCs.

Factors affecting outcomes of alternating chemoradiotherapy for nasopharyngeal cancer.

OBJECTIVE: Nasopharyngeal cancer (NPC) is radiosensitive and chemosensitive. We evaluated the efficacy of alternating chemoradiotherapy in patients with advanced NPC. METHODS: Alternating chemoradiotherapy was initiated in 30 patients with NPC, and 27 patients with cancer stages II (n = 6), III (n = 8), IVA (n = 9), and IVB (n = 4) were retrospectively analyzed. Chemotherapy was initially administered followed by radiotherapy, and chemotherapy, radiotherapy, and chemotherapy were alternately administered. Of the 27 patients, 22 patients received cisplatin (50 mg/m2/day, days 6 and 7) and 5-fluorouracil (5-FU; 800 mg/m2/day, days 1-5), whereas 5 patients received carboplatin (AUC 4-5, day 6) and 5-FU. RESULTS: Of the 27 patients, 19 (70%) received 3 chemotherapy courses. The total duration of alternating chemoradiotherapy was 81 to 101 days (median, 90 days). At a median follow-up of 53 months, the 5-year progression-free survival (PFS) was 71%. Multivariate analysis showed that weight loss and the number of chemotherapy courses had a significant effect on PFS. CONCLUSION: Alternating chemoradiotherapy led to similar or higher survival rates compared with concurrent chemoradiotherapy, which was characterized by good compliance and adaptable intensity.

Intraoperative free jejunum flap monitoring with indocyanine green near-infrared angiography.

The free jejunum flap technique has been regarded as the optimal approach during circumferential pharyngolaryngectomy reconstruction. Although classical patency tests are available, an intraoperative guarantee of the patency of anastomoses and microcirculations is inevitable. Indocyanine green near-infrared angiography (ICGA) was intraoperatively performed in six patients after reconstruction using the free jejunum flap. An adequate arterial as well as venous phase was observed. In addition to classical patency tests and doppler, we have successfully monitored the flap after total pharyngolalyngectomy intraoperatively using the ICGA. Our preliminary results implicate that this novel technique offers secure intraoperative monitoring of a free jejunum graft. This technique will provide us with advantages over regular patency test in selected cases.

Seven cases illustrating difficulties in the treatment of MPO-ANCA-positive refractory otitis media.

There are increasing reports of patients with refractory otitis media caused by anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), especially myeloperoxidase (MPO)-ANCA-positive middle ear disease.　However, making a definitive diagnosis can be difficult, which can adversely affect the outcome of treatment.　We reviewed the diagnostic features of MPO-ANCA-positive middle ear disease and here discuss the difficulties of timely diagnosis and treatment.　Seven cases were eligible (6 women, 1 man;aged 57-83 years), and all were MPO-ANCA positive and proteinase 3 (PR3)-ANCA negative.　The patients were referred to our institution for management of intractable otitis media (2/7), progressive hearing loss (7/7) with facial palsy (1/7), and/or a high MPO-ANCA titer (5/7).　All patients underwent tapering steroid therapy and their MPO-ANCA titer was monitored.　Refractory MPO-ANCA-positive otitis media was noted:5 of 7 cases showed improvement with tapering steroid therapy but cure was not achieved in the remaining 2 cases.　This study demonstrates the difficulties in the diagnosis and treatment of localized AAV.　Early diagnosis and treatment can improve the prognosis of patients with AAV but global diagnostic criteria for ear disease have not been established.　Additional cases should be prospectively examined to establish a treatment for MPO-ANCA-positive middle ear disease.

Effectiveness of FEES with artificial intelligence-assisted computer-aided diagnosis.

OBJECTIVES: FEES is a standard procedure for diagnosing dysphagia. However, appropriate evaluation of FEES findings is difficult for inexperienced evaluators. Recent progress in deep learning has highlighted the use of artificial intelligence-assisted computer-aided diagnosis (AI-assisted CAD) in medical applications. We investigated the detection accuracy of FEES findings evaluated by inexperienced evaluators with and without the use of CAD. METHODS: The algorithm for FEES-CAD was developed using 25,630 expert-annotated images. A total of 45 inexperienced evaluators from three groups of people (resident doctors, nurses, and medical students), evaluated 32 FEES videos from 32 patients. To confirm the effectiveness of FEES-CAD, first, 32 FEES videos were evaluated without the use of CAD. Second, one half was evaluated with, and one half without, the use of CAD. The detection accuracy of the FEES findings was investigated, and the evaluation results obtained with CAD were statistically compared with those obtained without CAD. RESULTS: In the first FEES evaluation, the total detection accuracy was 82.2 %. In the second evaluation, the total detection accuracy with CAD was 84.3 %, and that without CAD was 81.7 %. The detection accuracies by the resident doctors, nurses, and medical students with CAD were 90.1 %, 82.6 %, and 79.4 %, respectively, and those without CAD were 83.7 %, 80.9 % and 80.1 %, respectively. In the resident doctors, the detection accuracy was significantly better when CAD was used for evaluation, compared with the non-CAD evaluations. CONCLUSION: The present study demonstrated the effectiveness of FEES-CAD in improving the detection accuracy of resident doctors, however, the differences were small.

Relationship between sleep position and otitis media in infants: The Japan environment and children's study.

OBJECTIVE: Otitis media is a disease that commonly occurs in infants. Various risk factors have been reported. Sleep position has been reported to be associated with various diseases. There is no report on the relationship between otitis media and sleep position. We examined the incidence of otitis media and sleep position in infants. METHODS: We used data from the Japan Environment Children's Study. We used multivariate logistic analysis to examine the relationship between sleep position and the incidence of otitis media in infants aged up to 6 months. In addition, we conducted a stratified analysis based on whether the child was able to turn over in bed at 6 months of age. RESULTS: The study population comprised 85,731 participants. The incidence of otitis media by sleep position was significantly higher when the infant was in the prone position compared to any other position (adjusted odds ratio, 1.206; 95 %CI, 1.038-1.401). Stratified analysis of turning showed that otitis media was more common in the prone position in all groups. CONCLUSION: In the current study, infants aged 6 months or younger who slept in the prone position were more likely to have otitis media. Sleep position interview and guidance on changing sleep position may be useful for the prevention of otitis media.

Feasibility of totally implantable venous access ports in the upper arm for patients with head and neck cancer in the modern era of chemotherapy.

BACKGROUNDS: With recent developments in chemotherapy, the prognosis of head and neck cancer patients has been prolonged, and it is expected that totally implantable venous access devices will be developed for use as feasible and safe chemotherapy routes. We investigated the feasibility of implanting totally implantable venous access ports in the upper arms of head and neck cancer patients in this modern era of chemotherapy. METHODS: Relevant data of a cohort of 210 patients with head and neck cancer who had had totally implantable venous access devices implanted between January 2013 and December 2022 were investigated retrospectively. The totally implantable venous access ports were used for chemoradiotherapy, chemotherapy, radiotherapy, and palliative treatment. Adverse events related to totally implantable venous access devices were investigated and the associated variables subjected to statistical analysis. RESULTS: There were 22 (10.5%) adverse events, representing 0.201 adverse events per 1000 catheter days. Non-ultrasound-guided puncture (p = 0.015) and forearm implantation (p = 0.005) were associated with higher risk of adverse events according to univariate analysis. According to multiple logistic analysis, non-ultrasound-guided puncture was significantly associated with age and sex (OR = 2.89; 95% CI, 1.14, 7.36; p = 0.026). CONCLUSION: Peripherally implanted totally implantable venous access devices in the upper arm are feasible and safe for head and neck cancer patients. Ultrasound-guided implantation of totally implantable venous access ports into the upper arms of head and neck cancer patients may reduce the adverse event rate.

Association between specific human leukocyte antigen alleles and development of thyroid immune-related adverse event.

Aim: Inherent variations in human leukocyte antigen (HLA) alleles have been revealed epidemiologically to influence the development of autoimmune diseases. HLA alleles may thus also be associated with the development of immune-related adverse events (irAEs), such as thyroid irAE.Materials & methods: In this case-control study, 71 cancer patients who received immune checkpoint inhibitors were enrolled and HLA-genotyped and the frequency of HLA alleles was compared.Results: A*26:01, DPA1*01:03 and DPB1*02:01 were significantly more frequent in patients with thyroid irAE than in patients without any irAEs (35.0 vs 3.2% [p = 0.004], 80.0 vs 45.2% [p = 0.020] and 55.0 vs 25.8% [p = 0.044], respectively).Conclusion: A*26:01, DPA1*01:03 and DPB1*02:01 appear to be associated with thyroid irAE.

Everyone has a unique combination of human leukocyte antigens (HLAs) in their body that help the immune system identify threats. HLAs were named from the fact that they were first identified on the surface of human leukocytes. Afterward, HLAs were also found on all human cells. HLAs present antigens to immune cells. These HLAs also influence how the immune system attacks cancer cells. Immune checkpoint inhibitors are drugs that can help the immune system fight cancer, but they sometimes cause severe adverse events. In this study, we investigated whether specific HLA genes are related to the development of an adverse event that affects the thyroid in cancer patients treated with immune checkpoint inhibitors. We found an association between three HLA genes (A*26:01, DPA1*01:03 and DPB1*02:01) and the development of the thyroid adverse event. However, larger studies are needed to confirm and generalize these initial exploratory findings.

Tumor-targeted chemotherapy with the nanopolymer-based drug NC-6004 for oral squamous cell carcinoma.

Cisplatin (CDDP) has been a key drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity is one of its adverse reactions that are dose limiting. To increase its antitumor effects and reduce such toxicity problems, polymeric micelles carrying CDDP (NC-6004) have been developed. The present study was designed to evaluate the efficacy and safety of NC-6004 for oral squamous cell carcinoma. In vitro antitumor activity was assayed in four oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of NC-6004, nude mice bearing OSC-19 were administered NC-6004 or CDDP. The in vitro growth-inhibitory effect of NC-6004 was significantly less than that of CDDP. However, both NC-6004 and CDDP showed equivalent antitumor effects in vivo. Mice with CDDP developed renal cell apoptosis; however, those injected with NC-6004 were almost free of renal cell injury. Moreover, in an orthotopic tongue cancer model using OSC-19, NC-6004 reduced the rate of sentinel lymph node metastasis to lower than that with CDDP. In conclusion, considering the potential advantages in terms of noticeable antitumor activity, lymphatic drug delivery and reduced nephrotoxicity, NC-6004 represents a significant structural improvement in the development of a platinum complex.