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A patient was 70-year-old female. Because unknown fever following operation of left knee in December 20XX-1, abdominal simple CT was performed, diagnosed as cholecystitis and liver abscesses. However, her unknown fever did not improve with antibiotics therapy. Abdominal enhanced CT and MRI revealed to gallbladder cancer with liver invasion and metastases. These lesions were relatively localized in liver S4a/S5 and gallbladder, hepatoduodenal mesentery. Because unknown fever was exhausting, cholecystectomy, S4a+S5 hepatectomy with extrahepatic bile duct resection and lymph node dissemination were performed in January 20XX+1. In these pathological findings, there were moderate to poorly differentiated adenocarcinoma with squamous cell differentiation in almost area of gallbladder, diagnosed as adeno-squamous carcinoma with liver invasion and metastasis(pT3a[SI][H-inf], int, INF-β, ly1, v3, pn1, pN1, pM1, pStage ⅣB). One months after operation, abdominal CT revealed multiple liver metastatic recurrences. She died 7 months after operation. Although gallbladder adeno-squamous carcinoma has a poor prognosis, these many cases had a tendency to local infiltration accompanied with tumor fever. If curative resection might be obtained and the symptoms might be improved, aggressive resection should be performed.

Background: The purpose of this study was to retrospectively describe the characteristics and outcomes of patients with oral squamous cell carcinoma and level IV/V metastasis and to compare patients who underwent no postoperative therapy with those who underwent postoperative radiotherapy (RT) and concomitant chemoradiotherapy (CCRT)., Methods: We evaluated 669 patients. Clinicopathological data, postoperative therapy, and clinical course were investigated., Results: Sixty-one patients (9.1%) developed level IV/V metastasis. The 3-year cumulative overall survival rates of patients with and without level IV/V metastasis were 47.3% and 64.3%, respectively. Tongue tumors, pN2 or N3 classification, and moderate or poor differentiation were significantly associated with the development of level IV/V metastasis. The surgery+RT/CCRT group was associated with better 3-year cumulative disease-specific survival and overall survival rates than the surgery only group., Conclusion: Adjuvant therapy (RT alone or CCRT) after surgery is recommended for patients with level IV/V metastasis., (© 2019 Wiley Periodicals, Inc.)

Background and Objective: Forearm free flaps are used after hemiglossectomy. However, no investigation has been performed on whether oral functions are better preserved when sizes of the resection and reconstruction flap are exact matches, or whether the size of the resection should be changed. We aimed to retrospectively examine whether size differences between the resection and reconstruction flap affect speech and swallowing functions postoperatively, and to determine whether there are more favorable flap size ratios., Methods: This is a retrospective cohort study of patients undergoing hemiglossectomy using a forearm free flap between 2006 and 2016 at Kobe University Hospital, Japan. The effect of size difference between the resection and reconstruction flap on maintained oral function was assessed. Speech and swallowing functions were assessed, and their correlation with the ratio of the flap size to that of the resected area was determined. With these data, distribution maps of the relationship between the functional level and reconstructed dimension ratio were prepared. The more suitable reconstructed dimension ratio was examined and evaluated. The Fisher exact test, Kruskal-Wallis test, and Scheffe test were used in statistical analyses., Results: Eighty-eight patients underwent hemiglossectomy using a forearm free flap during a 10-year period. Of these cases, 66 patients were included in this study, while 22 were excluded. The ratio of the area of the reconstruction flap to that of the resection site was 0.59-2.79 (median: 1.61). Sixty patients had flaps greater than the resection area, whereas 6 had smaller flaps. Significant differences were found in speech intelligibility and swallowing function when the reconstructed dimension ratio was categorized as follows: ≤1.3, 1.3-1.8, and ≥1.8., Conclusion: Our findings suggest that postoperative deterioration of oral functions after hemiglossectomy could be reduced if reconstruction is performed using a forearm free flap with a surface area 1.3 to 1.8 times greater than that of the resection area., (Copyright © 2019. Published by Elsevier Ltd.)

Background and Objectives: Some patients with early-stage oral cancer have a poor prognosis owing to the delayed neck metastasis (DNM). Tumor budding is reportedly a promising prognostic marker in many cancers. Moreover, the tissue surrounding a tumor is also considered to play a prognostic role. In this study, we evaluated whether tumor budding and adjacent tissue at the invasive front can be potential novel predictors of DNM in early tongue cancer., Methods: In total, 337 patients with early-stage tongue squamous cell carcinoma were retrospectively reviewed. The patient characteristics and histopathological factors were evaluated for association with DNM. DNM rates were calculated; items which were significant in the univariate analysis were used as explanatory variables, and independent factors for DNM were identified by the multivariate analysis., Results: The univariate analysis identified T classification, depth of invasion, tumor budding, vascular invasion, and adjacent tissue at the invasive front as significant predictors of DNM; the multivariate analysis using these factors revealed all the above variables except vascular invasion, which are independent predictors of DNM., Conclusion: In addition to conventional predictors, high grade tumor budding and adjacent tissue at the invasive front can serve as useful predictors of DNM in early tongue cancer., (© 2018 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc.)

Background/aim: We recently investigated the contribution of the iPS-related genes SOX2, OCT4, and Nanog to de-differentiation by assaying for their mRNA levels. Given that mRNA expression does not always correlate with the protein levels, the aim of this study was to retrospectively determine the expression of these four iPS-related factors in human OSCC specimens by immunohistochemistry and examine their association with patient prognosis., Materials and Methods: iPS cell-related gene expression in 89 OSCC patients by tissue microarray, and its correlation with clinicopathological factors, differentiation, metastasis, and poor prognoses were investigated., Results: No evidence of statistically significant relationships was found between the expression of iPS cell-related genes and clinicopathological parameters. However, our data indicated that KLF4 expression was associated with survival, and poor tumor differentiation. In addition, high expression of KLF4 was an independent poor prognostic factor (p=0.004) for OSCC patients., Conclusion: In preoperative biopsies, higher KLF4 and poor differentiation may be clinically effective predictors for the prognosis of oral cancer., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: This multicenter retrospective study aimed to determine whether elective neck dissection (END) can be performed for T1-2N0M0 tongue cancer., Methods: Patients with T1-2N0M0 tongue squamous cell carcinoma who received treatment between January 2000 and December 2012 were enrolled at 14 multicenter study sites. The 5-year overall survival (OS) and 5-year disease-specific survival (DSS) were compared between the propensity score-matched END and observation (OBS) groups., Results: The results showed that the OS rates among the 1234 enrolled patients were 85.5% in the END group and 90.2% in the OBS group (P = 0.182). The DSS rates were 87.0% in the END group and 94.3% in the OBS group (P = 0.003). Among the matched patients, the OS rates were 87.1% in the END group and 76.2% in the OBS group (P = 0.0051), and the respective DSS rates were 89.2% and 82.2% (P = 0.0335)., Conclusion: This study showed that END is beneficial for T1-2N0M0 tongue cancer. However, END should be performed for patients with a tumor depth of 4-5 mm or more, which is the depth associated with a high rate of lymph node metastasis. The use of END should be carefully considered for both elderly and young patients.

Aim: This study aimed to explore novel metabolite biomarker candidates for screening oral squamous cell carcinoma (OSCC)., Patients & Methods: We collected plasma samples from 48 patients with OSCC and 29 with an oral disease and conducted a plasma metabolomics analysis of patients with OSCC using gas chromatography mass spectrometry. Then, we used the cross-validation procedure to ensure the accuracy of biomarker candidates., Results: We selected four biomarker candidates against OSCC. Their sensitivity was more than 90%, and the AUC was over 0.9 according to the receiver operating characteristic curve analysis., Conclusions: The findings of this study suggest four potential metabolites as biomarkers for OSCC screening.

Radiotherapy (RT) is one of the main treatment modalities for oral squamous cell carcinoma (OSCC), however, radioresistance is a major impediment to its clinical success and poses as a concern that needs to be addressed. Tumor hypoxia is known to be significantly associated with radioresistance in various malignancies, hence, resolving the hypoxic state of a tumor may improve the antitumor effect of RT on OSCC. We have previously revealed that transcutaneous CO2 induced mitochondrial apoptosis and suppressed tumor growth in OSCC by resolving hypoxia. Considering the previous study, we hypothesized that transcutaneous CO2 may enhance the antitumor effect of RT on OSCC by improving intratumoral hypoxia, thereby overcoming radioresistance. In the present study, the combination of transcutaneous CO2 and RT significantly inhibited tumor growth compared with other treatments. This combination therapy also led to decreased expression of HIF-1α in parallel with increased expression of the cleaved forms of caspase-3-8-9 and PARP, which play essential roles in mitochondrial apoptosis. Additionally, the combination therapy increased the expression of ROS modulator 1 and subsequent mitochondrial ROS production, compared to RT alone. These results indicated that transcutaneous CO2 could potentially improve the antitumor effect of RT by decreasing the intratumoral hypoxia and increasing the mitochondrial apoptosis. Our findings indicated that CO2 therapy may be a novel adjuvant therapy in combination with RT for OSCC.

Background: Oral squamous cell carcinoma (OSCC) containing single lymph node metastasis (pN1) with extra nodal extension (ENE) is a rare clinical situation. Therefore, it is unclear whether pN1 with ENE is at high risk of recurrence among the OSCC population, or whether postoperative radiotherapy (RT)/concomitant chemoradiotherapy (CCRT) is effective in these cases., Objectives: The purpose of this retrospective study was to investigate the prognosis and compare between no postoperative therapy and postoperative RT/CCRT in pN1 with ENE OSCC patients., Methods: Clinicopathological data and treatment modalities were investigated. The evaluated endpoints were overall survival (OS) and type of recurrence., Results: The 3-year cumulative OS rates for the pN1 only, multiple lymph node metastasis (MLM) only, ENE + MLM, and ENE + pN1 groups were 77.2%, 66.8%, 43.3%, and 66.6%, respectively. In the ENE + pN1 group, the most common cause of death in the surgery only group was from regional failure. The surgery + RT/CCRT group was associated with better disease-specific survival and OS rates than the surgery only groups (P < 0.05)., Conclusions: The prognosis of ENE + pN1 was not as poor as that of ENE + MLM, although both these groups feature ENE. Adjuvant therapy (RT/CCRT) after surgery is recommend for cases of ENE + pN1., (© 2018 Wiley Periodicals, Inc.)

Objectives: The progression level of extracapsular spread (ECS) for cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) was previously divided into three types, and their relationships with the prognosis of patients were re-examined., Patients and Methods: The Kaplan-Meier method was used to examine overall survival (OS) and relapse-free survival (RFS) curves. Prognosis factor for recurrence was analyzed with univariate and multivariate analysis., Results: ECS was detected in 216 cases of OSCC and analyzed. The 5-year overall survival and RFS rates of patients with type C, which was microscopically defined as tumor invasion to perinodal fat or muscle tissue, were significantly poor at 40.6 and 37.8%, respectively. The results of a univariate analysis suggested that the prognosis of ECS in OSCC patients is associated with its progression level, particularly type C. The 5-year RFS rate of type C with tumor budding was significantly poor at 31.5%. Type C with tumor budding correlated with local and regional recurrence as well as distant metastasis. In a multivariate analysis, tumor budding was identified as an independent prognostic factor., Conclusions: These results suggest that the progression level of ECS and tumor budding are useful prognostic factors in OSCC patients., Clinical Relevance: This study indicated that the progression level and tumor budding of ECS for cervical lymph node metastasis were useful prognostic factors in OSCC patients.

Objective: The purpose of this study was to retrospectively evaluate the postoperative results of partial glossectomy for early tongue cancer using a carbon dioxide laser (CO 2 laser)., Background Data: CO 2 lasers are frequently used for the excision or treatment of soft tissue in a range of diseases, including oral cancer, leukoplakia, mucocele, anomalies of the labial and lingual frenum, and peri-implantitis., Materials and Methods: We retrospectively reviewed 31 primary cases of early superficial tongue cancer that were treated using CO 2 lasers. In this study, early superficial cancer of the tongue is defined as a T1 or T2 tumor (TNM classification, NOMO; type, superficial spread, or exophytic; depth, <5 mm). The lesions were stained with 10% Lugol's solution and excised with a 5- or 10-mm safety margin from the nonstained area or induration using a CO 2 laser. The raw surface was covered with a polyglycolic acid sheet using fibrin glue spray (n = 23), sutures (n = 6), or both (n = 2). Five of the patients showed a bleeding tendency: 1 was taking warfarin 100 mg per day, 1 was taking 350 mg per day, 2 were taking aspirin 100 mg per day, and 1 was taking aspirin 200 mg per day., Results: There were no cases of postoperative bleeding. Regarding postoperative pain, all patients could stop taking analgesic drugs by 1 month after undergoing the operation. In regards to postoperative difficulty to swallow, all could start swallowing rice gruel 2 days after the operation. The surgical margin was unclear in two cases due to the thermal denaturation of the excisional margin. The 2-year local control rate was 100% and subsequent cervical lymph node metastasis rate was 6.5%., Conclusions: In terms of recurrence, metastasis, postoperative bleeding, postoperative pain, and swallowing, partial glossectomy for early tongue cancer using a CO 2 laser might therefore help improve the postoperative course.

Background: The purpose of this study was to investigate the feasibility of postoperative concomitant chemoradiotherapy (CRT) with cisplatin (CDDP), and compare the prognosis in 3 groups-without postoperative therapy (S-only), with radiotherapy (RT) alone (S+RT), and with CRT (S+CRT)-in oral squamous cell carcinoma (OSCC) patients at high risk of recurrence., Methods: Clinicopathologic data and treatment modality were investigated. Endpoints evaluated were locoregional control (LRC), relapse-free survival, overall survival (OS), and type of recurrence., Results: The S+CRT group was associated with a better LRC rate than the S-only (P < .001) and S+RT groups (P = .044). However, there was no significant difference in OS rates between the S+RT and S+CRT groups., Conclusion: The addition of concomitant CDDP to postoperative RT improved LRC. However, there may be no benefit from the addition of concomitant CDDP to postoperative RT for improvement of distant metastasis and OS rates in OSCC patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background/aim: Cancer stem cells are suspected to contribute to malignancy in tumors. Hypoxia affects cell differentiation and induces stem-cell-like characteristics in malignancies. Induced pluripotency was demonstrated in mouse fibroblasts by reprogramming with four transcriptional factors: Oct3/4, Sox2, c-Myc, and Klf4. Conversely, oncogenic transformations frequently express transcriptional factors and Nanog. Therefore, cancer cells present some similarities with induced pluripotent stem (iPS) cells., Materials and Methods: We investigated the expression of iPS-related genes in vitro and in clinical samples to identify their relationships with hypoxia and tumorigenesis., Results: Oral squamous cell carcinoma (SCC) cells were used to show that expression levels of Oct3/4, Sox2, and Nanog were significantly increased in hypoxic condition in vitro and in moderately- and poorly-differentiated samples., Conclusion: We propose that Oct3/4, Sox2 and Nanog are associated with tumor hypoxia characterized in oral SCC and that these factors may also contribute to the undifferentiated potency observed in oral SCC clinically., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The aim of this study was to investigate the prognostic value of dual-time-point (DTP) 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) imaging in primary oral tongue squamous cell carcinoma (OTSCC). The study included 52 patients who underwent preoperative 18 F-FDG PET scans at two time points, namely 1 h and 2 h after injection. The following PET parameters were calculated: maximum standardized uptake value (SUVmax) for both time points (SUV early, SUV delayed); retention index (RI); and SUVmax increment (ΔSUVmax). Receiver operating characteristic (ROC) curve analysis was performed to define the optimal cutoff point for these parameters. Overall survival was calculated using the Kaplan-Meier method. Prognostic factors for patients with OTSCC were evaluated using the univariate log-rank test and a multivariate Cox proportional hazards model. ROC analysis revealed that the area under the curve was higher and more accurate for ΔSUVmax than for the other parameters. Additionally, patients with a ΔSUVmax ≥0.9 had significantly worse survival outcomes (28.9% vs 92.6%; p < 0.01). Univariate analysis showed that prognosis was significantly correlated with clinical T stage, local recurrence, perineural invasion, vascular invasion, and PET parameters ( p < 0.05 for all). Multivariate analysis showed that local recurrence (hazard ratio = 3.60; p = 0.02) and ΔSUVmax (hazard ratio = 8.43; p < 0.01) were independent prognostic factors. ΔSUVmax determined using DTP 18 F-FDG PET may be an additional prognostic factor in OTSCC patients.

Objectives: Transient receptor potential cation channel (subfamily V, members 1-4) (TRPV1-4) are expressed in skin and neurons and activated by external stimuli in normal mucosae of all oral cavity sites. The oral cavity is exposed to various stimuli, including temperature, mechanical stimuli, chemical substances, and changes in pH, and, notably, the risk factors for oncogenic transformation in oral squamous epithelium are the same as the external stimuli received by TRPV1-4 receptors. Hence, we examined the relationship between oral squamous cell carcinoma (SCC) and TRPV1-4 expression., Materials and Methods: Oral SCC patients (n = 37) who underwent surgical resection were included in this study. We investigated the expression of TRPV1-4 by immunohistochemical staining and quantification of TRPV1-4 mRNA in human oral mucosa. In addition, we compared the TRPV1-4 levels in mucosa from patients with SCC to those in normal oral mucosa., Results: The receptors were expressed in oral mucosa at all sites (tongue, buccal mucosa, gingiva, and oral floor) and the expression was stronger in epithelia from patients with SCC than in normal epithelia. Furthermore, alcohol consumption and tobacco use were strongly associated with the occurrence of oral cancer and were found to have a remarkable influence on TRPV1-4 receptor expression in normal oral mucosa. In particular, patients with a history of alcohol consumption demonstrated significantly higher expression levels., Conclusion: Various external stimuli may influence the behavior of cancer cells. Overexpression of TRPV1-4 is likely to be a factor in enhanced sensitivity to external stimuli. These findings could contribute to the establishment of novel strategies for cancer therapy or prevention., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The objectives of this study were to retrospectively describe the characteristics and outcomes of patients with oral squamous cell carcinoma (OSCC) with level IV/V metastases, and to evaluate the multivariate relationships among potential risk factors for metastasis and prognosis., Materials and Methods: We evaluated 291 patients (178 men and 113 women; mean age, 65.9 ± 13.5 years). Clinicopathological data, time of development of level IV/V metastases, and clinical course were investigated., Results: Twenty-three patients (7.9%) developed level IV/V metastases. The 3-year overall survival rates when level IV/V metastasis first developed were 27.3% upon initial treatment, 57.1% when metachronous neck metastasis developed, and 40.0% when the tumor recurred. Oral tongue tumor subsite, high N staging, neck dissection when metachronous neck metastasis developed, as well as recurrence were independent risk factors for level IV/V metastasis., Conclusion: We demonstrate here the multivariate relationships among the risk factors indicated above for level IV/V metastasis and their prognostic significance for patients with OSCC. Oral tongue tumors, high N staging, and neck dissection upon the occurrence of metachronous neck metastasis or recurrence were risk factors for level IV/V metastasis and positive extracapsular spread, presence of multiple lymph metastases, and moderate or poor differentiation were poor prognostic factors., (Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

A multi-institutional study was undertaken to determine whether mandibular canal (MC) invasion and mandibular medullary bone invasion are independent factors in lower gingival squamous cell carcinoma (SCC). A total of 345 patients with lower gingival SCC were retrospectively reviewed. Mandibular bone invasion was categorized into three types; no bone invasion; invasion through cortical bone (medullary); and MC invasion. The overall survival rate and factors affecting local, regional, and distant failures were assessed by Cox proportional hazards regression analysis and Kaplan-Meier estimates. Bone invasion was present in 201 (58%) patients, of whom 107 (31%) had medullary invasion and 94 (27%) had MC invasion. Using the International Union Against Cancer (UICC) staging system and American Joint Committee on Cancer (AJCC) system, 171 (50%) patients were classified as T4a. When the bone invasion criteria were excluded from the UICC/AJCC system definition, 152 T4a tumors were downstaged and reclassified to T1 in 12 (3%), to T2 in 98 (28%), and to T3 in 42 (12%). In Cox multivariate analysis, MC invasion was an independent predictor of overall survival but medullary bone invasion was not. Medullary bone invasion was an independent variable for distant control. The current T staging system has restricted prognostic utility. The authors recommend a modified T staging system, whereby tumors with MC invasion instead of medullary bone invasion are classified as T4a, and tumors are first classified as T1 to T3 based on size and then upstaged by one T classification in the presence of medullary invasion., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT., Methods: HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC+G). Gabapentin was maintained at 900mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events., Results: Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC+G (n=11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC+G arm (47 in SPC vs. 74 in SPC+G, p=0.517; 215mg vs. 745.3mg, p=0.880; and 1260mg vs. 1537.5mg, p=0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC+G arm for weight gain (p=0.005). Adverse events related to gabapentin were manageable., Conclusions: This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Mitochondrial dysfunction and altered respiration have long been suspected to affect the development and progression of cancer. Although quantitative changes in mitochondrial DNA (mtDNA) have been reported in head and neck squamous cell carcinoma (SCC), differences in mtDNA copy numbers between normal and cancerous tissues from same patients have not been assessed., Methods: We compared mtDNA copy numbers and expressions of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) between normal mucous membrane and cancerous tissues resected from 35 patients with oral SCC, using TaqMan quantitative real-time polymerase chain reaction (PCR) and immunohistochemical staining., Results: We found mtDNA copy numbers and expressions of PGC-1α and TFAM were decreased in cancerous tissues compared with normal tissues from the same patients., Conclusion: The PGC-1α-TFAM mitochondrial pathway may be associated with malignant potential in human oral SCC, and could be an attractive therapeutic target. © 2016 Wiley Periodicals, Inc. Head Neck 38:1170-1175, 2016., (© 2016 Wiley Periodicals, Inc.)

Oral squamous cell carcinoma (OSCC) is the most common form of oral cancers. Recent studies have shown that the malignant transformation of various carcinomas, including OSCC, is associated with epithelial-mesenchymal transition (EMT), and that expression of the EMT factors are significantly associated with tumor invasion, tumor metastasis, and survival rates in OSCC patients. Hence, there is a possibility that EMT suppression may improve the prognosis of OSCC patients. Hypoxia inducible factor-1α (HIF-1α) is a crucial microenvironmental factor in tumor progression, which induces the expression of EMT factors. We previously reported that transcutaneous CO2 suppresses both human OSCC tumor growth and metastasis to the regional lymph nodes by improving hypoxia in treated tissue. According to this background, we hypothesized that increased EMT with HIF-1α expression may increase the progression and the metastatic potential of OSCC, and that decreased hypoxia by transcutaneous CO2 could suppress EMT. In the present study, in vitro studies showed that hypoxic conditions increased the expression of HIF-1α and EMT factors in OSCC cells. In addition, in vivo studies revealed that transcutaneous CO2 increased E-cadherin expression with the decreased expression of HIF-1α, Snail, Slug, N-cadherin, and Vimentin in tumor treatment. These results suggest that transcutaneous CO2 could suppress EMT by improving hypoxia, resulting in the reduction of metastatic potential of OSCC. The findings indicate that transcutaneous CO2 may be able to improve the prognosis of OSCC patients through the suppression of EMT.

Only a few reports on the level of progression of extracapsular spread (ECS) have been published. The aim of this study was to evaluate the efficacy of the level of progression of ECS in identifying those patients with oral squamous cell carcinoma (OSCC) at a high risk of recurrence who would benefit most from the intensification of adjuvant therapy. The level of progression of ECS for cervical lymph node metastasis in OSCC was divided into three types (A-C), and their relationships with patient prognosis were examined. ECS was observed in 87 of 441 patients with OSCC. The recurrence rate in patients with type C, which was defined as macroscopic tumour invasion into perinodal fat or muscle tissue, was high (69.8%), with 13 cases of death due to distant metastasis. The 3-year disease-specific survival rate for patients with type C was 49.0% and these patients also had a significantly poorer prognosis (P<0.01). The results of the multivariate analysis suggested that the prognosis of ECS in OSCC patients was associated with the level of progression of ECS, especially type C (P<0.01). Overall, the results of this study suggest that the level of progression of ECS is a useful prognostic factor in OSCC patients., (Copyright © 2015 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Spindle cell carcinoma (SpCC) an aggressive squamous cell carcinoma, variant, frequently metastasizes to regional lymph nodes and distant organs. Unfortunately, an effective treatment method for oral SpCC distant metastasis has not yet been established. Here we present 2 of oral SpCC cases that showed distant metastases after initial treatment, and 2 that showed distant metastases following during surgery. We calculated the tumor doubling time (TDT) and onset of the pulmonary metastatic and examined the TDT of the pulmonary metastatic tumor in patients with or without chemotherapy to determine the effect of anticancer drugs on oral SpCC. Tumor growth curves revealed that pulmonary metastasis likely grew to 1mm, 122 days before the initial examination, indicating that most oral SpCC patients should be treated for metastases. Three patients underwent chemotherapy for pulmonary metastatic tumor, complete response (CR) in one patient and no change (NC) in two. Thus, SpCC patients may have pulmonary micro-metastases even at the initial examination. We recommend wide resection for oral SpCC patients, followed by chemotherapy to prevent metastases.

Background: The presence of pathologically positive lymph nodes (pN+) is a well-known prognostic factor in oral squamous cell carcinoma (OSCC). The aims of this retrospective multicenter study were to assess the prognosis of OSCC patients with pN+ disease; to compare the prognosis of patients with pN+ disease who underwent surgery plus radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) with that of patients who underwent surgery only; and to account for biases associated with treatment selection of adjuvant RT or CCRT., Methods: The records of 313 OSCC patients with pN+ disease were retrospectively reviewed. The main outcome measures were 5-year disease-specific survival (DSS) and overall survival (OS) rates. To reduce selection biases associated with retrospective data, the treatment groups were evaluated by Cox proportional hazard analysis with propensity score as a covariate., Results: The 5-year OS and DSS survival rates for the entire patient cohort were 51.8 and 59.2 %, respectively. T3-4 stage, closed (<5 mm) margin distance, ≥4 involved nodes, and extracapsular spread were significant poor prognostic factors for OS and DSS. In the propensity score analysis, postoperative RT/CCRT significantly improved OS and DSS compared to surgery only. However, OS and DSS were not significantly different between patients who received postoperative RT and CCRT., Conclusion: The addition of cytotoxic chemotherapy to RT does not provide additional survival benefit in OSCC patients with pN+ disease. Alternative strategies, such as molecular targeted therapies, are needed to further improve the survival of high-risk OSCC patients with pN+ disease.

Objective: We evaluated predictive factors for cervical lymph node metastasis of tongue squamous cell carcinoma (SCC)., Study Design: We present a retrospective analysis of 90 patients with T1-2 N0 SCC who underwent primary excision as initial treatment without preoperative radiotherapy or chemotherapy. We examined the clinicopathologic factors (gender, age, clinical stage, surgical margin, grade of differentiation, lymphatic invasion, tumor depth of invasion, pattern of invasion [POI]) and immunohistochemical factors (vascular endothelial growth factor [VEGF]-A and VEGF-C expression) to predict the probability of lymph node metastasis., Results: The local progression-free 5-year survival rate was 100%. Tumor depth of invasion (≥4 mm, P = .022), POI (score >4, P = .000), and VEGF-C expression (P = .008) were associated with the lymph node metastasis of tongue SCC in a multiple logistic regression analysis (odds ratios [ORs]: 5.075, 17.383, and 9.533, respectively)., Conclusions: The local control rate of tongue SCC in the early stages has significantly improved as a result of development of surgical techniques. On the other hand, we believe that tumor depth of invasion (≥4 mm), POI, and VEGF-C expression all need to be considered in the preoperative and postoperative planning stages for tongue cancer treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to retrospectively evaluate the incidence of distant metastasis (DM) after curative surgical treatment and assess the multivariate relationships among various risk factors for DM in patients with oral squamous cell carcinoma (OSCC)., Study Design: Case series with chart review., Setting: Tertiary referral center., Subjects and Methods: The medical records of all patients with OSCC without DM who underwent curative surgery with or without postoperative adjuvant chemoradiation between January 2001 and February 2014 at our institution were retrospectively reviewed. There were a total of 451 patients, including 271 men and 180 women, with a mean age of 65.9 ± 13.5 years., Results: Of these patients, 30 (6.7%) developed DM. During the follow-up period, the 5-year overall survival rate was 76.2%. Sites of DM comprised the lungs (80.0%), skin (13.3%), liver (10.0%), bone (6.7%), and brain (3.3%). We found the T classification and N classification as well as the histologic grade to be significant risk factors associated with the development of DM in the univariate analysis only (P = .003), whereas locoregional failure (odds ratio [OR], 4.03), multiple lymph node metastases (more than 4 positive nodes; OR, 3.32) and positive extracapsular spread (OR, 3.06) were identified to be significant risk factors associated with the development of DM in the multivariate analysis., Conclusion: We demonstrated multivariate relationships among various risk factors for DM in OSCC patients. Clinicians should consider these risk factors and pay special attention to detecting DM early during the postoperative management of OSCC patients with these risk factors., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Background: C-reactive protein (CRP) screening has been reported to be reliable for detection of infectious complications. Postoperative abnormal response of CRP can predict wound infection in colorectal surgery. This study aimed to determine the efficacy of CRP monitoring to detect infectious complications in oral oncologic surgery., Methods: One hundred patients who underwent oral cancer resection with primary reconstruction were enrolled. Postoperative kinetics of CRP were classified into a normal or abnormal response., Results: A normal CRP response after surgery was observed in 61 patients and an abnormal response was observed in 39. There were postoperative infectious complications in 21 patients, with surgical site infections in 13 patients (early onset in six and late onset in seven). Non-wound infections were found in nine patients. Sensitivity, specificity, the positive predictive value, and the negative predictive value for abnormal CRP response as a predictor for early infectious complications were 100%, 70.1%, 35.9%, and 100%, respectively., Conclusion: Postoperative serial CRP screening is a useful test as an indicator of infectious complications in oral oncologic surgery. Normal CRP responses can rule out almost all early infectious complications.

Tumor-associated macrophages (TAMs) are known to be involved in the progression of various human malignancies. We previously demonstrated that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of human esophageal squamous cell carcinoma (ESCC). We also showed that conditioned media of ESCC cell lines induced CD204 expression in THP-1 human monocytic leukemia cells. Here, we performed a cDNA microarray analysis between THP-1 cells stimulated with TPA (macrophage [MΦ]-like THP-1 cells) treated with and without conditioned medium of ESCC cell line to clarify the molecular characteristics of TAMs in ESCC. From the microarray data, we discovered that Cyr61 was induced in CD204-positive-differentiated THP-1 cells (TAM-like THP-1 cells). In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61. Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry. Recombinant human Cyr61 (rhCyr61) promoted cell migration and induced the expression of CD204 along with the activation of the MEK/ERK pathway in MΦ-like THP-1 cells. Pretreatment with a MEK1/2 inhibitor significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression in the MΦ-like THP-1 cells. These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Previous studies on postoperative long-term results in patients who underwent reconstructive free flap transfer following hemiglossectomy had some issues, including the heterogeneity of the patient population and the observation period. The present study aimed to evaluate changes of reconstructed tongues in patients who underwent radial forearm free flap (RFFF) after hemiglossectomy with long-term follow-up. We enrolled 23 patients who underwent RFFF after hemiglossectomy with a postoperative follow-up of 5 years or more. Postoperative status (eating, speech, sensation function) was assessed by concise medical inquiries. Morphological changes of flaps were evaluated by reviewing clinical photographs. Hemiglossectomy involving the base of the tongue was performed in 4 cases (17.4%) and was limited to the mobile tongue in 19 cases (82.6%). The mean follow-up was 85.4 months (range, 60-122 months). All patients experienced gradually improved postoperative status. The most significant improvement was found between 1 and 5 years after surgery (P = 0.007), but not between 1 and 3 years (P = 0.075) or between 3 and 5 years (P = 0.530). In almost all of the flaps, there were few morphological changes throughout the follow-up period. Postoperative status in patients who underwent reconstructive RFFF following hemiglossectomy improved sequentially.

Squamous cell carcinoma (SCC) is the main histological type of oral cancer. Its growth rate and incidence of metastasis to regional lymph nodes is influenced by various factors, including hypoxic conditions. We have previously reported that transcutaneous CO2 induces mitochondrial apoptosis and decreases lung metastasis by reoxygenating sarcoma cells. However, previous studies have not determined the sequential mechanism by which transcutaneous CO2 suppresses growth of epithelial tumors, including SCCs. Moreover, there is no report that transcutaneous CO2 suppresses lymphogenous metastasis using human cell lines xenografts. In this study, we examined the effects of transcutaneous CO2 on cancer apoptosis and lymphogenous metastasis using human SCC xenografts. Our results showed that transcutaneous CO2 affects expressions of PGC-1α and TFAM and protein levels of cleavage products of caspase-3, caspase-9 and PARP, which relatives mitochondrial apoptosis. They also showed that transcutaneous CO2 significantly inhibits SCC tumor growth and affects expressions of HIF-1α, VEGF, MMP-2 and MMP-9, which play essential roles in tumor angiogenesis, invasion and metastasis. In conclusion, transcutaneous CO2 suppressed tumor growth, increased mitochondrial apoptosis and decreased the number of lymph node metastasis in human SCC by decreasing intra-tumoral hypoxia and suppressing metastatic potential with no observable effect in vivo. Our findings indicate that transcutaneous CO2 could be a novel therapeutic tool for treating human SCC.

Nodal metastasis in oral squamous cell carcinoma (OSCC) is considered to be a predictor of a poor prognosis. The aim of this study was to investigate the relationship between the number of positive lymph nodes and the prognosis in OSCC patients with nodal metastases and to assess the effects of postoperative radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) on this patient group. A retrospective investigation of 98 patients with OSCC who underwent radical neck dissection and had at least three pathologically positive lymph nodes was performed. The 5-year disease-specific survival rate was 66.7% for patients with 3 positive nodes, while it was significantly lower for those with 4 positive nodes and those with ≥ 5 positive nodes (21.5% and 46.1%, respectively; P < 0.01). The loco-regional control and disease-specific survival rates for the surgery alone, surgery plus RT, and surgery plus CCRT groups were 46.2% and 40.5%, 66.3% and 54.4%, and 81.7% and 52.4%, respectively. For patients with ≥ 4 positive nodes, the loco-regional control rate after surgery plus CCRT was better than that observed after surgery alone (77.5% vs. 32.6%, P = 0.01). Postoperative RT and CCRT have positive impacts on the prognosis of OSCC patients with advanced stage neck disease., (Copyright © 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

The congenital absence of a skeletal muscle is a rare cause of congenital muscular torticollis, and the condition is associated with various unusual anatomical structures. We describe a rare case of congenital absence of the sternocleidomastoid muscle associated with squamous cell carcinoma of the tongue in a patient who underwent neck dissection. In this case, both the external jugular vein and the spinal accessory nerve were absent. However, we found that branches of the C3 nerve extended from the cervical plexus to the trapezius muscle and seemed to be acting as trapezius muscle motor nerves in place of the accessory nerve. After the operation, the patient was able to lift and abduct his right arm, and his shoulder did not droop.

The purpose of this study was to determine the detailed background of cases of oral squamous cell carcinoma (OSCC) with microscopic extracapsular spread (ECS) in the cervical lymph nodes. The cases of 78 patients with primary OSCC, who attended hospital from October 2007 to July 2011 and underwent resection of the primary tumour with neck dissection, were reviewed. The subjects were classified into three categories: pN0, pN+/ECS-, and pN+/ECS+; the outcomes of pN+/ECS+ patients were compared in detail with those of the other categories. Thirty-one cases (39.7%) were pN0, 25 cases (32.1%) were pN+/ECS-, and 22 cases (28.2%) were pN+/ECS+. The 3-year overall survival rate was 82.1% in pN0, 74.1% in pN+/ECS-, and 39.8% in pN+/ECS+ (pN0 vs. pN+/ECS+, P=0.0004; pN+/ECS- vs. pN+/ECS+, P=0.0086). The 3-year disease-specific survival rate was 96.2% in pN0, 77.2% in pN+/ECS-, and 39.8% in pN+/ECS+ (pN0 vs. pN+/ECS+, P<0.0001; pN+/ECS- vs. pN+/ECS+, P=0.0038). Patients with poorly differentiated carcinoma, those with three or more ECS+ nodes, and those with ECS+ node(s) located at levels III, IV, and V, had the worst prognosis among pN+/ECS+ subjects., (Copyright © 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Tumor associated macrophages (TAMs) are the most abundant cancer stromal cells educated by tumor microenvironment to acquire trophic functions facilitating angiogenesis, matrix breakdown and cancer cell motility. Tumor associated macrophages have anti-inflammatory properties or "alternatively" activated (M2) phenotype expressing CD204 and/or CD163. To know the role of TAMs in the growth and progression of esophageal squamous cell carcinomas (ESCCs), we calculated intratumoral CD204, CD163 or CD68 expressing macrophage count (MϕC) and CD34-positive microvessel density (MVD) by immunohistochemistry in 70 cases of surgically resected ESCCs and compared them with the clinicopathological factors and prognosis of patients. MϕC had positive linear association with MVD. High CD204(+) MϕC were significantly correlated with more malignant phenotypes including depth of tumor invasion, lymph and blood vessel invasion, lymph node metastasis as well as clinical stages. On the other hand, CD163(+) MϕC did not associate with these clinicopathological factors with the exception of depth of tumor invasion and blood vessel invasion. Patients with high CD204(+) MϕC ESCCs showed poor disease-free survival (P = 0.021). Conditioned media of five ESCC cell lines (TE-8, -9, -10, -11 and -15) induced mRNA as well as protein expression of CD204 but not of CD163 with upregulation of vascular endothelial growth factor-A mRNA in TPA treated human acute monocytic leukemia cell line THP-1. These results overall indicate that CD204 is a useful marker for TAMs contributing to the angiogenesis, progression and prognosis of ESCCs whose specific tumor microenvironment may educate macrophages to be CD204(+) M2 TAMs., (© 2013 Japanese Cancer Association.)

Purpose: The purpose of this study is to know an outcome of the treatment for oral squamous cell carcinoma having more than 10 unilateral pathologically positive lymph nodes (pN)s., Patients and Methods: We reviewed 212 primary cases of oral squamous cell carcinoma that visited our hospital from January 1999 to December 2011 and underwent resection of the primary tumor with neck dissection. The patients were classified into 3 categories of pN0, pN1-9, and pN ≥ 10 cases, and an outcome of pN ≥ 10 was studied specifically in comparison with the other categories., Results: Of the patients studied, 103 cases (48.6%) were pN0, 103 cases (48.6%) were pN1-9, and 6 cases (2.8%) were pN ≥ 10. The pN ≥ 10 group, which had positive nodes of 10 to 30 on the ipsilateral side, was predominantly male and had no cases of well-differentiated squamous cell carcinoma. Extracapsular spread (ECS) was found in all pN ≥ 10 cases, and postoperative distant metastasis occurred in cases with ECS, which was localized in levels higher than III. The proportion of distant metastasis was 0% (0 cases) in pN0, 8.7% (9 cases) in pN1-9, and 66.7% (4 cases) in pN10. Overall survival rate in pN ≥ 10 was 20.8%, whereas it was 89.0% in pN0, and 34.9% in pN1-9., Conclusion: Oral squamous cell carcinoma having multiple neck metastases (pN ≥ 10) had a poor prognosis because the proportion of distant metastasis was higher in comparison with the other groups of pN0 and pN1-9., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Our aim was to investigate the prognosis of patients with squamous cell carcinoma (SCC) of the gingiva who had preoperative dental operations. We studied 102 patients who were being operated on for SCC of the gingiva with special reference to the effects of preoperative dental operations on the prognosis. Twenty-six patients had dental procedures such as tooth extraction, or incision, or curettage before they visited our hospital, while the remaining 76 had no such interventions. The percentage of patients with advanced T stage disease (T3 or T4) was higher among those who had interventions (17/26, 65%) than among those who had not (35/76, 46%). The difference was not significant. Histopathologically invaded nodes were detected in half the patients in the intervention group (13/26), while they were found in only 18/76 (24%) of those in the no intervention group (p<0.02). The incidence of nodal metastases with extranodal spread was significantly higher in the intervention group than in the no intervention group (p<0.05), and those in the intervention group were more likely to develop distant metastases than those in the other group (p<0.001). The 5-year survival in the two groups was 65% and 92%, respectively (p<0.01). Preoperative dental operations such as tooth extraction, incision, or curettage possibly lead to regional and distant metastases and therefore a poor prognosis in patients with SCC of the gingiva., (Copyright © 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to develop a new in vitro model of cancer invasion using a human dermal equivalent, AlloDerm®. A squamous cell carcinoma line (HSC-2, HSC-3 and OSC20) and a malignant melanoma line (G361) were cultured on AlloDerm® and evaluated histologically to examine destruction of the basement membrane and invasion into the dermis of AlloDerm®. HSC-3 and G361 cells invaded through the basement membrane of AlloDerm® at 21-28 days after seeding, while HSC-2 and OSC20 cells did not. Next, these cells were transplanted into the tongues of nude mice, and the degree of local invasiveness was examined histologically. HSC-3 and G361 cells invaded diffusely to the surrounding tongue tissue, although HSC-2 and OSC20 showed only expansive growth. Further, these cells were transplanted subcutaneously in nude mice to study metastatic activity. Regional and distant metastases were rarely observed after transplantation of HSC-2 and OSC20 cells. On the other hand, HSC-3 and G361 cells frequently metastasized. These findings show a close relationship among in vitro invasiveness on AlloDerm®, in vivo invasiveness, and metastatic activity. This experimental model using AlloDerm® is a potentially new in vitro model of cancer invasion.

Oral squamous cell carcinoma (OSCC) is often surrounded by epithelial dysplasia; leaving it unresected can result in local recurrence. Staining with Lugol's iodine solution detects epithelial dysplasia in oral mucosa, but whether it decreases local recurrence after OSCC surgery is unknown. This study investigated local recurrence rates in patients with early tongue cancer who underwent surgery using Lugol's staining. 93 patients with T1-2N0 tongue SCC underwent partial glossectomy using Lugol's staining during surgery. Resection was performed at least 5mm from the margin of the unstained area. Patients were investigated retrospectively for local recurrence status. Postoperative histology revealed negative surgical margins for SCC or epithelial dysplasia in 81 patients, close margins for SCC in 5, positive margins for mild epithelial dysplasia in 6, and a positive margin for SCC in one. Those with a positive or a close margin for SCC underwent additional resection 2-4 weeks after surgery; one was proved histologically to have residual SCC. No patients developed local recurrence, but 2 died of neck metastasis and 2 of distant metastasis. The 5-year disease specific survival rate was 93.8%. Lugol's staining during surgery can reduce local recurrence and improve survival in patients with early tongue SCC., (Copyright © 2011 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

To improve the prognosis of advanced esophageal cancer, neoadjuvant chemotherapy (NACT) followed by surgery is a promising treatment strategy. NACT has been shown to improve the prognosis of responders. However, non-responders not only suffer from side-effects, but they also lose precious time to take advantage of other possible treatments. Therefore, it is crucial to establish a reliable method that allows prediction of response before chemotherapy. A biopsy sample can provide valuable information on the biological characteristics of an individual esophageal cancer, which can affect chemosensitivity. Comprehensive gene expression profiling (GEP) using oligonucleotide microarray covering 30,000 human probes was performed in 50 pretreatment endoscopic biopsy samples from 25 patients with esophageal squamous cell cancer (ESCC) who underwent cisplatin-based chemotherapy (two samples per patient). Chemotherapeutic responses were evaluated by the reduction rate of the tumor area on CT scans. Responders were defined as patients with reduction rates of ≥50% and non-responders were defined as patients with <50% decrease. The diagnostic system, that predicts responses to chemotherapy, was constructed with the 199 most informative genes, and showed 82% of accuracy. Furthermore, the predictive performance of this system was confirmed using an additional ten samples with an accuracy of 80%. This study shows that GEP of pretreatment ESCC biopsy samples has the potential to predict responses to chemotherapy.

Objectives: The first stage in the metastasis of squamous cell carcinoma (SCC) of the oral cavity involves the destruction of the basement membrane and invasion into the submucosal tissue. The purpose of this study is to develop a new in vitro model of cancer invasion using a human dermal equivalent, AlloDerm., Study Design: Normal epithelial cells from a gingiva and a SCC line originating from human tongue cancer (HSC-3 and 4 cells) were cultured on AlloDerm, and composites of these cells and AlloDerm were evaluated histologically by HE staining and immunostaining with anti-laminin and type IV collagen antibodies. Furthermore, HSC-3 and 4 cells were transplanted into the tongues of nude mice, and regional lymph node metastases were examined histologically., Results: HSC-3 cells had invaded through the basement membrane into the AlloDerm dermis at 25 days after seeding. Decreases in the levels of laminin and type IV collagen were observed in the locations where HSC-3 had invaded. Metastasis to regional lymph nodes was observed at 3 weeks after transplantation in 4 of 10 (40%) mice. On the other hand, normal epithelial cells and HSC-4 cells did not show invasion into AlloDerm. Lymph node metastasis was not observed in the mice bearing HSC-4 cells., Conclusion: This experimental model using AlloDerm is a potential new in vitro model of cancer invasion.

Cancer of the tongue or the floor of the mouth sometimes metastasizes to the lingual lymph node. We present two patients with squamous cell carcinoma of the floor of the mouth who developed metastases to the lateral lingual lymph nodes. Case 1, a 62-year old male, had squamous cell carcinoma of the floor of the mouth (T3N2cM0). He underwent tumor resection and bilateral neck dissection, and histological examination revealed five metastatic nodes including the lateral lingual node near the hyoid bone. No recurrent tumors were evident, but he died of pneumonia 10 months after the surgery. Case 2, a 62-year old male, had squamous cell carcinoma of the floor of the mouth (T2N2cM0). He underwent tumor resection and bilateral neck dissection, and histological examination revealed three metastatic nodes including the lateral lingual node near the sublingual gland. No recurrence was found in the oral and neck regions, but he died of liver metastasis 18 months after the surgery. Metastasis to the lingual lymph node may cause a recurrence of oral cancer in the neck, since conventional neck dissection cannot remove this node even in the case of en bloc resection of the primary tumor and the neck. When CT, MRI, or intra-operative palpation findings lead to a suspicion of metastasis to the lingual lymph node, the area of neck dissection should be extended to include this node.

Carcinoma of the oral cavity sometimes metastasizes to the lateral retropharyngeal lymph node (LRPLN), especially when posteriorly invading the soft palate or oropharynx. CT or MRI imaging has enabled detection of LRPLN metastasis in the early stage, but the prognosis of patients with metastasis to this node is extremely poor. The authors report three patients with squamous cell carcinoma of the oral cavity with no posterior invasion who developed metastasis to LRPLN during observation. The primary sites of these three cases were gingiva of the upper incisor region, gingiva of the lower premolar region, and maxillary bone of the upper incisor region. Each patient underwent surgery as their initial therapy, but a recurrent tumor in the LRPLN was detected by CT or MRI despite good loco-regional control. A salvage operation with postoperative radiation therapy was performed for two patients, but only one is still alive with no evidence of tumor 14 months after the last surgery. Management of LRPLN metastasis in oral cancer patients is a challenge for oral surgeons, but early detection by CT or MRI and surgery with postoperative radiation therapy is likely to yield the best local control.

Advanced esophageal cancer has been recently treated by multimodal therapy including preoperative chemotherapy or chemoradiotherapy and surgery. A biopsy sample provides a valuable specimen for understanding the biological characteristics of individual esophageal cancer. Pretreatment prediction of the response to chemotherapy or radiotherapy based on biological characteristics using biopsy samples is a desirable goal. In using biopsy samples for molecular analysis, there are two problems; the proportion of cancer cells and the intratumor heterogeneity. This study was conducted to investigate the feasibility of using endoscopic biopsy samples of esophageal squamous cell cancer (ESCC) for comprehensive gene expression profiling (GEP). Comprehensive GEP was performed in 40 bulky ESCC specimens and 10 normal esophageal epithelial specimens from patients who underwent esophageal resection and 52 endoscopic ESCC biopsy samples from 26 patients (two samples per one patient). Unsupervised hierarchical cluster analysis showed distinct profiles between the bulky ESCC specimens and normal epithelial specimens. Also, unsupervised hierarchical cluster analysis revealed distinct profiles between the biopsy ESCC samples and normal epithelial specimens. Moreover, a couple of biopsy samples taken from different locations of the same tumor were closely clustered together. That is, biopsy ESCC samples were distinguished from normal esophageal epithelial specimens and the intratumor heterogeneity of GEP was smaller than intertumor heterogeneity. GEP using biopsy ESCC samples is feasible and has the potential to represent the biological properties.

In this study, the expressions of Ror2 in the normal mucosa, the epithelium dysplasia, and squamous cell carcinoma (SCC) of the oral cavity were investigated, and possible differences in the expression patterns of Ror2 and of p53, Ki67, or PCNA were examined. In Western blotting analyses, Ror2 expression in oral cancer was significantly higher than that in the normal oral mucosa. Immunohistochemically, Ror2 was localized on the plasmalemma and in the rough endoplasmic reticulum (rER). The tissue area with an Ror2-positive expression tended to differ from the area with a positive expression of p53, ki67, or PCNA, and the number of cells with an Ror2 expression tended to increase as the degree of malignancy rose in the epithelial tissues. These results suggest that Ror2 was not related to cell proliferation, but rather associated with cell polarity and cell motility, and that it was also closely associated with the degree of malignancy in oral epithelial tissue.

The essential contribution of the epithelial-mesenchymal transition (EMT) to carcinoma progression is the loss of their epithelial characters, gain of mesenchymal marker expression, acquisition of migration, invasive activity and capability to pass through the basement membrane. In this study, we aimed to clarify the role of EMT regulator Snail, a zinc finger transcription factor, in human oesophageal squamous cell carcinoma (OESCC). Most OESCC cell lines expressed epithelial cell-cell adhesion molecules such as E-cadherin and claudin-1 and -7; however, TE-8 (Snail-positive) cells expressed mesenchymal marker vimentin but not E-cadherin and claudins. Transduction of ectopic Snail in TE-15 (Snail-negative) cells diminished expression of these epithelial adhesion molecules with promotion of cell migration, invasion and proliferation as well as the shift from cobblestone-like appearance to spindle morphology. In OESCC tissue samples, immunohistochemical analyses revealed that the nuclear Snail expression at the invasive front was correlated with the high levels of vimentin expression (p = 0.0061), which was conversely associated with reduced expressions of E-cadherin (p = 0.023), claudin-1 (p = 0.0246) and claudin-7 (p = 0.0161). Interestingly, elevated Snail expression at the invasive front of the OESCC was associated with higher incidence of lymphatic (p = 0.0143) and venous vessels invasion (p = 0.0029), lymph node metastasis (p = 0.0074) and clinicopathological tumour stage (p = 0.0057). According to the expressions of epithelial and mesenchymal markers, the tumours were subclassified into three groups, the epithelial-type OESCC and the complete or incomplete EMT-type OESCCs. Snail-positive tumours were frequently categorized into the complete- or incomplete-type EMT phenotypes. Our present results suggest the significance of Snail-associated EMT in the progression of OESCC. Snail-induced EMT at the invasive front of the OESCC can be a novel marker for the prediction of metastasis., (Copyright (c) 2008 Pathological Society of Great Britain and Ireland.)

We attempted to establish an in vivo experimental model of metastasis of oral caner. The HSC-3 cell line, originating from human oral squamous cell carcinoma, was transplanted into nude mice, and metastases to the lymph node and the lung were investigated using genetic analysis. The HSC-3 cells, transplanted subcutaneously into the lateral back of nude mice, and punctured repeatedly after cyst formation, could metastasize to the lymph node and the lung. Genetic analysis using human beta-globin gene demonstrated that the frequency of metastasis to the lymph node and the lung at 12 weeks after the transplantation was 45% and 40%, respectively. Mutant allele-specific amplification of p53 gene could also detect micrometastasis with almost equal sensitivity of polymerase chain reaction with beta-globin gene. Subcutaneous transplantation is easy with excellent reproducibility compared with intravenous or orthotopic transplantation, and we think that this experimental model can be one of standard models of cancer metastasis.

Early in tumorigenesis, a DNA damage-response network is activated in preneoplastic cells that delays or prevents cancer. Activation of the Chk2 G(2)/M checkpoint kinase and loss of fragile histidine triad (Fhit) tumor suppressor expression increase cellular susceptibility to DNA-damaging 'oncogenic' stressors, particularly in precursor or precancerous lesions. To understand the mechanism of oral carcinogenesis, we assessed the association between phosphorylated Chk2 (pChk2) and Fhit expression in oral squamous cell carcinoma. Loss of Fhit expression was an early event during oral carcinogenesis, whereas a decrease in the number of pChk2-positive cells was associated with tumor progression. Although tyrosine 114 is known to be essential to Fhit's tumor-suppressing activity, both wild-type and tyrosine 114 mutant Fhit increased the population of subG(1) DNA-containing HSC-3 OSCC cells with elevated pChk2 levels. In particular, when cells were exposed to ionizing radiation, pChk2 levels were upregulated dramatically, as were those of its downstream target Cdc25C. Knockdown of Fhit with FHIT small interfering RNA diminished the ionizing radiation-induced Chk2 phosphorylation in HEK293 cells. Furthermore, Fhit-deficient mice demonstrated a decrease in the number of pChk2-positive cells not only in dysplastic lesions but also in N-nitrosobenzylamine-induced papilloma of the forestomach, suggesting that lack of Fhit expression and the resultant defects of the ataxia telangiectasia mutated-Chk2 pathway can cause a difference in the incidence of N-nitrosobenzylamine-induced forestomach lesions. These findings suggest that Fhit plays a key role in the regulation of the ataxia telangiectasia mutated-Chk2 DNA damage response during oral carcinogenesis.

Claudins are transmembrane proteins that seal tight junctions, bind with peripheral protein zonula occludens (ZO)-1, and are known to play an important role in several normal tissues and cancers. However, the role of claudin-1 and claudin-7 expressions in esophageal squamous cell carcinoma remains to be clarified. In the present study, we confirmed the expressions of claudin-1, claudin-7, and ZO-1 in the prickle cell layer of the normal human esophageal squamous epithelium. The expressions of claudin-1 and claudin-7 at the invasive front of the esophageal squamous cell carcinoma were analyzed immunohistochemically to clarify their role in tumor progression. Reduced expression of claudin-7 at the invasive front of the esophageal cancer was significantly associated with the depth of invasion (P = .004), stage (P = .038), lymphatic vessel invasion (P = .001), and lymph node metastasis (P = .014). In contrast, significant association was not detected between claudin-1 expression and clinicopathologic factors except for histologic differentiation of the tumor (P = .0029). Comparison of claudin-7 expression at the invasive front of the primary tumor and its corresponding metastatic lymph nodes revealed significant reduction in claudin-7 expression in the metastatic lymph nodes (P = .007). These results suggest that the reduced expression of claudin-7 at the invasive front of esophageal squamous cell carcinoma may lead to tumor progression and subsequent metastatic events. Thus, claudin-7 can be a novel marker for the prediction of lymph node metastasis.

The treatment method for early stage tongue cancer is still controversial in Japan. The aim of this study is to compare the prognosis for patients with early tongue cancer treated with brachytherapy and surgery. A retrospective study was conducted to compare the efficacy of low-dose-rate brachytherapy (LDR), high-dose-rate brachytherapy (HDR), and surgery for early tongue cancer. A total of 180 patients with stage I-II tongue cancer were divided into three treatment groups: LDR (78), HDR (26), and surgery (71). Local recurrence was seen in thirteen patients (17%) of the LDR, nine (35%) of the HDR, and four (6%) of the surgery group. After salvage therapy, final local cure was obtained for 71 patients (91%) of the LDR, 22 (85%) of the HDR, and 71 (100%) of the surgery group. Neck failure was recorded for eight patients in the LDR, six in the HDR, and three in the surgery group. The respective 5-year overall survival rates for the LDR, HDR and surgery groups were 84.0%, 72.9%, 95.4% for stage I, and 72.2%, 51.5%, 93.8% for stage II. These findings show that surgery is the optimal treatment method for patients with stage I-II tongue cancer.

Objectives: Although sentinel lymph node biopsy (SLNB) may reduce surgery-related complications related to unnecessary lymph node dissection and is now widely used for many patients with cutaneous melanoma and breast cancer, its use for oral cancer patients remains controversial. One of the main reasons for the reluctance to initiate SLNB for oral cancer is that the frequency of skip metastasis has not been clarified. The objectives of this study are to examine the frequency of skip metastasis and to evaluate SLNB for oral cancer., Study Design: To shed light on these concerns, we first conducted a retrospective study of 296 patients with squamous cell carcinoma of the oral cavity who underwent neck dissection. Next, the accuracy of lymph node biopsy with and without detecting sentinel lymph node was examined., Results: Ten patients showed skip neck metastasis in the level III-V region without level I-II involvement. Of these patients, 7 underwent neck dissection when their initially N0 neck progressed to N+, 2 underwent neck dissection when local recurrence occurred, and only 1 underwent surgery as an initial therapy. Most patients who underwent neck dissection as the initial therapy showed skip metastasis. Intraoperative lymph node biopsy without any attempt to detect sentinel lymph nodes by means of blue dye or lymphoscintigraphy was performed on 68 patients with oral cancer. Sixty-one (90%) were diagnosed correctly, whereas 7 diagnosed as N- actually had neck metastasis. SLNB with blue dye was performed on 21 patients. In 17 of them, sentinel lymph node was easily detected, resulting in a correct diagnosis for 16 patients (94%), while 1 with a false negative result actually had micrometastasis., Conclusion: These findings seem to suggest that SLNB is useful and can be applied to patients with oral cancer who undergo surgery as the initial therapy.