Potentiation of Anticancer Activity of G2/M Blockers by Mild Hyperthermia.

BACKGROUND/AIM: Hyperthermia (HT), combined with chemotherapy, has been used to treat various types of cancer. This study aimed to investigate the HT-sensitivity of malignant and non-malignant cells, and then evaluate the combination effect of docetaxel (DTX) and a newly synthesized chromone derivative (compound A) with HT. MATERIALS AND METHODS: The number of viable cells was determined using the MTT method. Cell cycle distribution was analyzed using a cell sorter, and DNA fragmentation pattern was detected using agarose gel electrophoresis. RESULTS: Among 12 cultured cells, oral squamous cell carcinoma (OSCC), especially Ca9-22 cells, and myelogenous leukemia cells showed higher sensitivity to HT than lung carcinoma and glioblastoma cell lines, while normal oral cells were the most resistant. Cytotoxicity of DTX on Ca9-22 cells was maximum at 41-42°C and 45~60 min exposure to HT. DXT, compound A, and HT induced G2/M arrest of Ca-22 cells. Mild HT enhanced the DTX- and compound A-induced subG1 arrest, in a synergistic fashion. CONCLUSION: The combination G2/M blockers and mild-HT can potentially be used for the treatment of OSCC.

Drug concentration estimation using contrast-enhanced MRI in intra-arterial chemotherapy for head and neck cancers.

OBJECTIVE: In cases of head and neck cancer treated with intra-arterial chemotherapy, no objective indices are available for determining the distribution of anticancer drugs administered to multiple arteries. To establish such indices, noninvasive measurements of drug concentrations are required in the arterial perfusion area of each artery. In MRI, changes in 1/T1 (Δ1/T1) are correlated with the contrast agent concentration. We focused on these properties and investigated whether it is possible to estimate anticancer drug concentrations within tissue based on Δ1/T1. METHODS: We employed the fast spin echo (FSE) sequence to determine optimum imaging parameters using a phantom. Subsequently, contrast agent was administered via the lingual and external carotid arteries for seven cases of tongue cancer. Δ1/T1 were then measured in tumor and nontumor tissues. The results of this study were compared with those of a previous study in which intratumor concentrations of anticancer agent were measured in excised specimens. RESULTS: The optimum imaging parameters for the FSE was two repetition times (TR, 500 and 1000 ms). When compared with the external carotid artery administration, the lingual artery administration of contrast agent resulted in significantly higher Δ1/T1 in both tumor and nontumor tissues (2.13 and 2.62 times, respectively). The multiplying factor for the nontumor tissue and high homogeneity of the contrast agent concentration were reasonably consistent with the results of the previous study. CONCLUSION: This method can be applied to estimating intratissue concentrations of intra-arterially administered anticancer drugs, thus possibly providing useful information in determining the distribution of anticancer drugs.

Complications of minimally invasive tibial bone harvesting: Risk factors and treatment.

PURPOSE: The aim of this retrospective study was to analyze complications, risk factors, and corresponding treatment regarding the medial approach to harvesting tibial bone. MATERIALS AND METHODS: Consecutive cases at Yokohama City University Hospital were analyzed for complications of tibial particulated bone and marrow harvesting with the medial approach. The condition of bone marrow, duration of harvesting, and complications were evaluated. The complication rate and correlations between bone marrow conditions and duration of bone harvesting were assessed. The corresponding treatments for the complication were also observed. RESULTS: Thirty cases of tibial particulated bone and marrow harvesting for alveolar ridge or sinus floor augmentation before implant therapy from 2005 to 2014 were analyzed. Twenty-one patients had healthy bone marrow, whereas nine patients had fatty bone marrow. The duration of operation in patients who had both spontaneous pain and gait disturbance was approximately 56 minutes, which was significantly longer than that (approximately 40 minutes) in patients who had only gait disturbance (P < .05). A strong correlation between fatty bone marrow condition and bone harvesting time was seen. The correlation between bone marrow condition and bone harvesting time for fatty marrow was stronger than that for healthy marrow with a trend to significant difference (P = .082). The minor and major complication rate was 96.7% and 6.6%, respectively. Two patients showed postoperative infection on the tibia harvesting site. One of them, who had fatty bone marrow, showed methicillin-resistant Staphylococcus aureus-caused osteomyelitis of the tibia, which needed to be debrided and reconstructed with vancomycin containing bone cement. CONCLUSION: A duration of less than 40 minutes for harvesting time may decrease the risk of minor complications. Bone marrow condition influenced tibial bone harvesting duration, which may result in increasing the risk of complications. Regarding major complications, it was considered that wound protection was more important even if the marrow condition was healthy.

Thermochemoradiotherapy Using Superselective Intra-arterial Infusion for Patients With Oral Cancer With Cervical Lymph Node Metastases.

AIM: We aimed to retrospectively investigate the outcomes and pathological effects of retrograde superselective intra-arterial chemoradiotherapy (IACRT) combined with hyperthermia on metastatic lymph nodes of patients with oral squamous cell carcinoma. PATIENTS AND METHODS: Patients with lymph node metastasis from oral cancer were treated with IACRT using cisplatin plus docetaxel combined with hyperthermia prior to surgical removal 8 weeks after completion of IACRT and hyperthermia. The locoregional control and overall survival rates were calculated using the Kaplan-Meier method. RESULTS: A total of 35 patients received the combination therapy of whom 26 received it as definitive treatment and in the rest, it was administered as preoperative treatment. The 5-year locoregional control and overall survivaI rates were 95.6% and 80.2% in the definitive-treatment group, and 100% and 66.6% in the preoperative-treatment group, respectively. CONCLUSION: The combination therapy provided good outcomes in patients with lymph node metastases from advanced oral cancer.

Retrograde superselective intra-arterial chemoradiotherapy combined with hyperthermia and cetuximab for carcinoma of the buccal mucosa with N3 lymph node metastasis: a case report.

We herein report a case of squamous cell carcinoma of the buccal mucosa with N3 cervical lymph node metastasis in a 63-year-old man. The patient was treated with combination therapy comprising radiotherapy (2 Gy/day, total of 70 Gy), superselective intra-arterial chemotherapy via a superficial temporal artery (docetaxel, total of 70 mg/m2 and cisplatin, total of 175 mg/m2), cetuximab (initial dose of 400 mg/m2 with subsequent weekly doses of 250 mg/m2 intravenously), and four sessions of hyperthermia for cervical lymph node metastases. The patient responded well to the therapy, with a complete response of the primary tumor. Radical neck dissection was performed with reconstructive surgery, including resection of the overlying skin. A pathologic complete response was achieved for the N3 and all other cervical lymph node metastases. The patient showed no evidence of recurrence in the 3 years following treatment. Based on the findings in the present case, the use of retrograde superselective intra-arterial chemoradiotherapy combined with hyperthermia and cetuximab seems to be a promising modality for patients with N3 cervical lymph node metastasis of oral cancer.

Swallowing function in advanced tongue cancer patients before and after bilateral neck dissection following superselective intra-arterial chemoradiotherapy for organ preservation: a case-control study.

OBJECTIVE: This study aimed to evaluate swallowing function in advanced tongue cancer patients before and after bilateral neck dissection following superselective intra-arterial chemoradiotherapy (CRT). METHODS: A videofluoroscopic swallowing study (VFSS) was used to evaluate swallowing function in 10 patients with advanced tongue cancer before and after bilateral neck dissection. RESULTS: Laryngeal penetration increased in the postoperative VFSS. Temporal analysis comparing two time points revealed that, after surgery, oral transit time increased significantly, but there was no difference in pharyngeal delay time or pharyngeal transit time. Spatial analysis revealed significant decreases after surgery in the maximum distance of upper esophageal sphincter (UES) opening, the maximum distance of hyoid bone movement in both the anterior and superior direction, and the maximum velocity of hyoid bone movement. CONCLUSIONS: Laryngeal penetration and aspiration increased as a result of limited hyoid movement and diminished UES opening after bilateral neck dissection following superselective intra-arterial CRT for advanced tongue cancer.

Atypical Protein Kinase C λ/ι Expression Is Associated with Malignancy of Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Atypical protein kinase C λ/ι (aPKCλ/ι) is a cell polarity-regulator localized in the tight junction and apical membrane in epithelial cells. Previous studies suggested that aPKCλ/ι overexpression and abnormal localization were involved in tumor progression in several cancers. We investigated the relationship between aPKCλ/ι and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The correlation between the aPKCλ/ι expression and the clinicopathological parameters in 76 OSCC cases was examined using immunohistochemical analyses. RESULTS: aPKCλ/ι overexpression was observed in 36.8% of cases. aPKCλ/ι expression was more intense in poorly differentiated OSCC and younger patients (<60 years of age). Although expression of aPKCλ/ι was not significantly associated with clinical parameters, the correlation was found between aPKCλ/ι localization and progression-free survival. CONCLUSION: This is the first study to assess the association of aPKCλ/ι expression in OSCC with clinical results. Expression and localization of aPKCλ/ι may be involved in the degree of malignancy in OSCC.

Effect of Photofunctionalization on Early Implant Failure.

PURPOSE: This study retrospectively evaluated the effects of bone density, staging strategy, implant stability, healing process, implant length, surface type, and photofunctionalization on early implant failure. MATERIALS AND METHODS: Consecutive study samples at Yokohama City University Hospital were analyzed for their early implant failure potentially influenced by patient-, surgical protocol-, and implant-related factors. Through the screening process using univariate analysis for those factors, candidate influential factors such as bone density, staging strategy, the level of initial implant stability, postoperative wound breakdown, the length of implants, the surface type of implants, and use or nonuse of photofunctionalization were selected as independent variables in forward multivariate logistic regression analysis. The odds ratio (OR) for candidate factors was calculated. RESULTS: A total of 563 implants placed in 219 patients from 2005 to 2017 were analyzed for their early implant failure. Stepwise logistic regression analysis finally identified postoperative wound breakdown (OR = 0.21) and the use of photofunctionalization (OR = 0.30) that significantly reduced the risk of early implant failure (P < .01 and P < .05, respectively). The implant failure rate was 10.0% with postoperative wound breakdown and 1.0% without it, whereas it was 4.3% without photofunctionalization and 1.3% with it. CONCLUSION: Among various patient-, surgical protocol-, and implant-related factors, the absence of postoperative wound breakdown and use of photofunctionalization significantly reduced the risk of early implant failure. It was notable that photofunctionalization, a unique, chairside measure to improve implant surfaces, was effective exclusively among implant-related factors.

Proton Beam Therapy in Combination with Intra-Arterial Infusion Chemotherapy for T4 Squamous Cell Carcinoma of the Maxillary Gingiva.

This study aimed to evaluate the therapeutic effect and toxicity of proton beam therapy in combination with intra-arterial infusion chemotherapy in patients with squamous cell carcinoma of the maxillary gingiva. Between December 2010 and March 2016, 30 patients with T4 squamous cell carcinoma of the maxillary gingiva were treated with radiotherapy and retrograde intra-arterial infusion chemotherapy using cisplatin (20⁻40 mg/m², 4⁻6 times). Radiotherapy was basically administered using boost proton beam therapy for primary tumor and neck lymph node tumors, following 36⁻40 Gy photon radiation therapy delivered to the prophylactic area, to a total dose of 70.4⁻74.8 Gy. The median follow-up was 33 months. The 3-year local control and overall survival rates were 69% and 59%, respectively. Major grade 3 or higher acute toxicities included mucositis, neutropenia, and dermatitis in 12 (40%), 5 (17%), and 3 (10%) patients, respectively. No grade 3 or higher late toxicities were observed. These results suggested that proton beam therapy in combination with intra-arterial infusion chemotherapy was not inferior to other treatment protocols and should be considered as a safe and effective option in patients with T4 squamous cell carcinoma of the maxillary gingiva.

Perspectives of Immune Suppression in the Tumor Microenvironment Promoting Oral Malignancy.

INTRODUCTION: In order to survive, cancers control immune systems and evade immune detection using mediators consisting of immune checkpoint molecules and cellular systems associated with immune suppression. METHODOLOGY: During the development of cancer and chronic infections, the immune checkpoints and cellular components including regulatory T cells, myeloid derived suppressor cells and cancer associated fibroblasts are often enhanced as a mechanism of immune subversion and have therefore become very important therapeutic targets. CONCLUSION: In this review, we will discuss the complexity of immune-suppressive mechanisms in the tumor milieu of cancers, including oral malignancy.

Lateral Bone Window Approach with Micross Mini Bone Scraper for Sinus Floor Elevation.

OBJECTIVE: The purpose of this article is to describe a technique with a mini bone scraper for lateral bone window approach and simultaneous bone harvesting during sinus floor elevation. METHODS: This study included five consecutive patients with the atrophic posterior maxilla. After elevation of mucoperiosteal flap, a bone window was then opened safely using a Micross Mini Bone Scraper® with small shape and easy handling. Data were recorded on the residual alveolar bone height, number of implants, site of implant placement, collected particulate bone volume, and bone harvesting time. RESULTS: There was no injury of the Schneiderian membrane, and one to two implants of 11.5 mm length were placed simultaneously after sinus floor elevation in all cases. Mean residual bone height was 4.6 mm. The mean volume of particulate bone collected from the anterior wall of the maxilla using this technique was 0.74 cm3. Supplementary allogeneic materials were not required in all cases. Mean bone harvesting time was 4.6 min. CONCLUSIONS: Our technique with Micross Mini Bone Scraper® is a simple and safe procedure in lateral bone window approach and simultaneous bone harvesting during sinus floor elevation, because it is performed under better visualization of the membrane without irrigation.

Treatment of oral cancer using magnetized paclitaxel.

N,N'-Bis(salicylidene)ethylenediamine iron (Fe(Salen)) is an anti-cancer agent with intrinsic magnetic property. Here, we covalently linked Fe(Salen) to paclitaxel (PTX), a widely used anti-cancer drug, to obtain a magnetized paclitaxel conjugate (M-PTX), which exhibited magnetic characteristics for magnet-guided drug delivery and MRI visualization. M-PTX increased apoptosis and G2/M arrest of cultured human oral cancer cell lines in the same manner as PTX. Furthermore, marked contrast intensity was obtained in magnetic resonance imaging (MRI) of M-PTX. In a mouse oral cancer model, a permanent magnet placed on the body surface adjacent to the tumor resulted in distinct accumulation of M-PTX, and the anti-cancer effect was greater than that of M-PTX without the magnet. We believe that this strategy may improve future cancer chemotherapy by providing conventional anti-cancer drugs with novel functionalities such as magnet-guided drug delivery or MRI-based visualization/quantitation of drug distribution.

[Assessing Patient Factors Influencing the Discontinuation of Opioids after Intra-Arterial Chemotherapy for Oral Cancer - A Retrospective Study].

Superselective intra-arterial chemoradiation therapy for oral cancer induces the complication of mucositis. Although the associated pain is controlled using opioids, major questions from patients in clinical practice are as follows:(1)the mean number of days from the completion of superselective intra-arterial chemoradiation therapy to the discontinuation of opioid administration, and(2)patient factors enabling the discontinuation of opioids. The purpose of this study was to clarify these points. A retrospective follow-up study was conducted from April 2016 to March 2017 on patients who underwent superselective intra-arterial chemoradiation therapy at our department of oral surgery. The patients were divided into 2 groups:one who discontinued opioids, and the other who did not. Clinical backgrounds and data were compared between the 2 groups. The mean number of days from the completion of superselective intra-arterial chemoradiation therapy to the discontinuation of opioid administration was 51±34.4 days. The absence of diabetes and deliria during treatment were determined as factors contributing to the discontinuation of opioids.

[Patient Factors Enabling the Decannulation of the Gastrostomy Tube after Superselective Intra-Arterial Chemoradiation Therapy for Locally Advanced Oral Cancer - A Retrospective Study].

Superselective intra-arterial chemoradiation therapy for locally advanced oral cancer induces complications such as mucositis, which impedes oral intake. Thus, at our hospital, a gastrostomy is performed in almost all patients during the treatment period to ensure the presence of an alternative administration route for nutrition and drugs. The purpose of this study was to calculate the mean number of days from completion of superselective intra-arterial chemoradiation therapy to the decannulation of gastrostomy, and extract patient factors for the decannulation. A retrospective follow-up study was conducted from April 2016 to March 2017 on patients who underwent superselective intra-arterial chemoradiation therapy at our department of oral surgery. The patients were divided into 2 groups:one who was decannulated and the other who did not. Clinical backgrounds and data were compared between the 2 groups. In the group with the decannulation, the mean period from treatment completion to the decannulation was 132±51.6 days. Heavy alcohol consumption, absence of haphalgesia before treatment, and possible securement of the opening with the breadth of 3 fingers, were determined as factors contributing to the decannulation of gastrostomy tube.

Role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in predicting pathological response to preoperative super-selective intra-arterial chemoradiotherapy for advanced squamous cell carcinoma of the mandible.

INTRODUCTION: Although chemoradiotherapy (CRT) for oral squamous cell carcinoma (SCC) has been shown to preserve organ function and improve cosmetic results, site-specific data, especially mandible, are limited. The aim of this study was to evaluate the predictability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) on response to super-selective intra-arterial CRT for advanced SCC of the mandible. METHODS: Fifteen patients with advanced SCC of the mandible underwent super-selective intra-arterial CRT followed by radical resection. Maximum standardized uptake value (SUVmax) of the mandibular lesion was evaluated with FDG-PET/CT before and after CRT. The SUVmax before and after CRT was defined as pre-SUVmax and post-SUVmax, respectively. The difference between pre- and post-SUVmax was calculated as SUVmax reduction rate to evaluate treatment response of the mandibular lesion. Each SUVmax reduction rate and surgical specimen of the corresponding lesion was analyzed to evaluate an accuracy of the modality for predicting pathological response. RESULTS: The median of pre-SUVmax was significantly lower than that of post-SUVmax (p = 0.001). Of the 15 patients, 6 had a pathological complete response (pCR) and 9 had a non-pCR. Neither pCR patients nor non-pCR patients showed significant difference of the median of SUVmax between pre- and post-CRT (pre-CRT p = 0.099 post-CRT p =0.074). The SUVmax reduction rate in patients with pCR was significantly higher than that with non-pCR (p = 0.002). Receiver operating characteristic analysis revealed that the optimal cut-off point of the reduction rate was 64.7%, with 83% sensitivity and 100% specificity. CONCLUSIONS: These results concluded that SUVmax reduction rate can predict pathological complete response of preoperative super-selective intra-arterial CRT for advanced SCC of the mandible.

Chemoradiotherapy using retrograde superselective intra-arterial infusion for tongue cancer: Analysis of therapeutic results in 118 cases.

OBJECTIVES: To evaluate the therapeutic results and rate of organ preservation in patients with squamous cell carcinoma of the tongue treated with retrograde superselective intra-arterial chemoradiotherapy. MATERIALS AND METHODS: Between June 2006 and June 2015, 118 patients with tongue cancer were treated with intra-arterial chemoradiotherapy. Treatment consisted of radiotherapy (total 50-70 Gy) and daily concurrent intra-arterial chemotherapy (docetaxel, total 50-70 mg/m2; cisplatin, total 125-175 mg/m2) for 5-7 weeks. Locoregional control and overall survival rates were calculated by the Kaplan-Meier method. Cox's proportional hazards model was used for both univariate and multivariate analyses. RESULTS: The median follow-up for all patients was 38.5 months (range, 3-129 months). After intra-arterial chemoradiotherapy, primary site complete response was achieved in 113 (95.8%) of 118 cases. Three-year locoregional control and overall survival rates were 80.3% and 81.5%, respectively. Grade 3 or 4 toxicities included neutropenia in 16.1% and mucositis in 87.3%. Grade 3 toxicities included anemia in 12.7%, thrombocytopenia in 3.4%, nausea/vomiting in 3.4%, dermatitis in 45.7%, dysphagia in 74.6%, and fever in 2.5% of patients. Late toxicity consisting of grade 3 osteoradionecrosis of the jaw occurred in 4.2% of patients. On univariate analysis, T stage and overall stage were significantly associated with locoregional control, and N stage and overall stage were significantly associated with overall survival. On multivariate analysis, the only significant predictor of overall survival was overall stage classification. CONCLUSION: Retrograde superselective intra-arterial chemoradiotherapy for tongue cancer provided good overall survival and locoregional control.

Multicenter retrospective study of cetuximab plus platinum-based chemotherapy for recurrent or metastatic oral squamous cell carcinoma.

PURPOSE: The purpose of this study was to assess the efficacy and safety of cetuximab plus platinum-based chemotherapy for patients specifically diagnosed with recurrent or metastatic oral squamous cell carcinoma (OSCC). METHODS: We conducted a multicenter retrospective observational study of patients who underwent first-line cetuximab plus platinum-based chemotherapy between December 2012 and June 2015. 65 patients received weekly cetuximab (week 1, 400 mg/m2; subsequent weeks, 250 mg/m2) plus a maximum of six 3-weekly cycles of cisplatin (80 or 100 mg/m2, day 1) or carboplatin (at an area under the curve of 5 mg/mL/min as a 1-h intravenous infusion on day 1) and 5-fluorouracil (800 or 1000 mg/m2/day, days 1-4). Patients with stable disease who received cetuximab plus platinum-based chemotherapy continued to receive cetuximab until disease progression or unacceptable toxicities, whichever occurred first. RESULTS: The median follow-up was 10.5 (range 1.2-34.2) months. The best overall response and the disease control rates were 46.2 and 67.7%, respectively. The median overall survival and progression-free survival rates were 12.1 and 7.8 months, respectively. The most common grades 3-4 adverse events were skin rash (9.2%) followed by leukopenia (6.2%). None of the adverse events were fatal. CONCLUSION: The results of our multicenter retrospective study, which was the largest of its kind to date, suggest that first-line cetuximab plus platinum-based chemotherapy is suitable and well-tolerated for the systemic therapy of recurrent or metastatic OSCC.

Orthognathic Surgery and Implant-Supported Bridge in a Class III Patient Injured in a Motor Vehicle Accident.

Occlusal and esthetic rehabilitation of jaw deformities in patients with partially edentulous maxilla are challenging procedures. This article describes a patient involving a skeletal Class III, 36-year-old male patient with a single bilateral anterior partially edentulous maxilla resulting from injuries sustained in a motor vehicle accident; his anterior teeth had been lost for more than 10 years. His lip protruded from the lateral view due to the proclined upper incisors and mandibular protrusion.Because of the facial deformity and inadequate prosthesis of the maxilla, the prosthesis had dropped out repeatedly. Bone deficiency was prominent in the area of the anterior maxillary region and required augmentation for implant restoration.Consultation among the prosthodontist, orthodontist, and patient led to a decision to perform an orthognathic surgery and bone graft before implant treatment. After orthodontic treatment combined with orthognathic surgery, 3 dental implants were placed with simultaneous iliac bone graft for prosthetic rehabilitation. The treatment restored the maxillary dental arch, which supported the upper lip with appropriate occlusion, both esthetically and functionally. After a 2-year clinical follow-up, the orthoprosthesis of the maxilla remained stable, and the patient was satisfied with the outcome of treatment. The combination of orthodontic, surgical, and dental implant treatment could be an option for skeletal Class III patients with bone-deficient, edentulous jaws.

Sialendoscopic removal of fish bone-induced sialoliths in the duct of the submandibular gland.

Obstructive sialadenitis of the submandibular gland is commonly caused by sialoliths, but more rarely by foreign body-induced sialoliths. Here, we report minimally invasive sialendoscopic removal of fish bone-induced sialoliths in the duct of the submandibular gland. A 43-year-old woman presented with recurrent swelling of the right submandibular gland at other hospital. Computed tomography (CT) showed an 8-mm linear calcification in the posterior part of Wharton's duct. The lesion was deemed difficult to remove and she was followed up. However, because the lesion did not resolve spontaneously within 9 months and chronic sialadenitis symptoms persisted, she was referred to our department for endoscopic removal. CT showed a linear calcification (5.6×1.2×0.8mm) connecting 2 spherical calcifications (2.3×2.1×1.9mm; 1.8×1.4×1.1mm) in the anterior part of Wharton's duct. The patient underwent endoscopic removal of the lesion using a 1.6-mm-diameter sialendoscope under local anesthesia. The specimen contained a fish bone connecting 2 sialoliths. The patient was unaware of the fish-bone injury. After removal, there was no recurrence of submandibular gland swelling during 6 months follow-up.