Gingival Cancer Research Articles

Combined intra-arterial infusion and systemic chemoradiotherapy for stage IV squamous cell carcinoma of the mandibular gingiva

The purpose of this study was to show the effectiveness of combining intra-arterial infusion and systemic chemotherapy with concurrent radiotherapy for treatment of stage IV mandibular gingival cancer. A total of 23 patients with mandibular gingival cancer were treated with either docetaxel by intra-arterial infusion followed by systemic chemoradiotherapy with cisplatinum and 5-fluorouracil as a monthly regimen, or with docetaxel and cisplatinum by intra-arterial infusion followed by systemic chemoradiotherapy with 5-fluorouracil as a weekly or biweekly regimen. Tumor responses, locoregional control, overall survival, disease-specific survival, and adverse events were evaluated. Of the 23 patients enrolled in the study, 22 completed the treatment. With regard to clinical stages, 82 % were diagnosed as IVA and 18 % IVB. Complete and partial response was observed in 82 and 18 %, respectively. Five-year overall survival, disease-specific survival, and locoregional control were 51, 70, and 72 %, respectively. No statistically significant difference was seen between the monthly regimen and the weekly plus biweekly regimen, although the latter resulted in longer survival and 88 % control. Combined intra-arterial infusion and systemic chemoradiotherapy may be an effective treatment for patients with stage IV mandibular gingival cancer.

Depression of p53-independent Akt survival signals in human oral cancer cells bearing mutated p53 gene after exposure to high-LET radiation

Although mutations and deletions in the p53 tumor suppressor gene lead to resistance to low linear energy transfer (LET) radiation, high-LET radiation efficiently induces cell lethality and apoptosis regardless of the p53 gene status in cancer cells. Recently, it has been suggested that the induction of p53-independent apoptosis takes place through the activation of Caspase-9 which results in the cleavage of Caspase-3 and poly (ADP-ribose) polymerase (PARP). This study was designed to examine if high-LET radiation depresses serine/threonine protein kinase B (PKB, also known as Akt) and Akt-related proteins. Human gingival cancer cells (Ca9–22 cells) harboring a mutated p53 (mp53) gene were irradiated with 2Gy of X-rays or Fe-ion beams. The cellular contents of Akt-related proteins participating in cell survival signaling were analyzed with Western Blotting 1, 2, 3 and 6h after irradiation. Cell cycle distributions after irradiation were assayed with flow cytometric analysis. Akt-related protein levels decreased when cells were irradiated with high-LET radiation. High-LET radiation increased G2/M phase arrests and suppressed the progression of the cell cycle much more efficiently when compared to low-LET radiation. These results suggest that high-LET radiation enhances apoptosis through the activation of Caspase-3 and Caspase-9, and suppresses cell growth by suppressing Akt-related signaling, even in mp53 bearing cancer cells.

Gingival cancer: 11 year follow-up at Karolinska University Hospital (2000-2010).

5536 Background: In Sweden, approximately 500-600 cases of oral cancer are diagnosed every year. These include cancer of the gingiva, retromolar trigonum, bucca, hard palate, tongue and floor of the mouth. Each year, around 15 cases of gingival cancer (GC) are diagnosed in the Stockholm region. The goal of this study was to study the onset of symptoms, treatment, prognosis, and sequelae of GC in order to optimize the treatment. Methods: The study consists of a retrospective review of medical records of all diagnosed cases of GC in Stockholm region between 2000-2010, identified through the ENT-clinic Karolinska Hospital patient database. Results: Our retrospective study comprised 156 patients diagnosed with GC. The average age was 72 years sharing equally between the sexes, 50% were smokers. 98% had a squamous cell carcinoma (scc). Presenting symptoms were often lump or ulceration in the gums, pain, bleeding or discomfort/misfit of dentures. Around 30% had premalignant lessons in the oral cavity before diagnosis. 3/4-th of all GC was localized in the lower jaw. 66% of the GC-patients presented as aT4 cancer. At presentation, 26% had a regional metastasis and of those 90% had their primary tumor in the lower jaw. Six cases had bilateral neck disease. 81% of the patients with regional metastasis had low to medium grade of scc differentiation of the primary tumor. 84% of all patients with regional metastasis had a T4 primary tumor. Neck dissection was performed in 38% (n=59). Of these 35 cases where staging neck, i.e. N0 at presentation and in 7 cases (20%) a positive neck disease was found. The risk for second primary was 15%. The overall 5-year survival was 24%. Conclusions: Advanced age and high number of T4 cancer at diagnosis partly explains the poor survival statistics. Almost 30% of the patients in our material have had premalignant lessons in the oral cavity before the cancer diagnosis and are at high risk for new tumors (second primary); therefore patients with GC should be followed up for at least 5 years, possibly longer in the presence of premalignant lessons. GC of the lower jaw is more likely to metastasize than GC of the upper jaw. Due to 20% occult metastasis occurrence in the staging neck cases, we recommend staging neck dissection for patients with GC.

下顎歯肉癌術後顎動脈に仮性動脈瘤を発症した1例

We describe a rare patient with mandibular gingival cancer in whom a pseudoaneurysm of the maxillary artery developed after segmental mandibular resection, including the region from the floor of the mouth to the pharynx, and neck dissection, followed by reconstruction using a metal plate and a rectus abdominis myocutaneous flap. A mass measuring 35×25×20 mm was detected at the inner side of the reconstruction plate on postoperative contrast-enhanced CT, and angiography was immediately performed to confirm that it was a pseudoaneurysm. The aneurysm was located in the maxillary artery and was treated by coil embolization. Pseudoaneurysms occurring in the head and neck region, which usually develop secondary to acute neck injury, are rare, and few cases of pseudoaneurysm involving the external carotid artery have been reported. However, the mortality rate associated with carotid artery aneurysms is estimated to be as high as 30％, and early imaging diagnosis and treatment are therefore important for preventing fatal complications.

Narrow band imaging endoscopy for unknown primary tumor sites of the neck

Examinations used to search for unknown primary tumors of squamous cell carcinomas of the neck include CT, MRI, laryngoscopy, gastrointestinal endoscopy, and positron-emission tomography (PET). Narrow band imaging (NBI) endoscopy in which an optical color-separation filter is used to narrow the bandwidth of spectral transmittance is also used. Twenty-eight patients in whom primary squamous cell carcinomas could not be detected with conventional white light laryngoscopy underwent NBI endoscopy and PET. Primary lesions were detected with NBI endoscopy in 3 patients, but no primary lesions were detected with PET. However, PET was used to detect a lower gingival cancer and a palatine tonsillar cancer. Both PET and NBI endoscopy is effective for detecting unknown primary tumors of squamous cell carcinomas of the neck.

S3. Treatment of the neck in gingival cancer

S3. Treatment of the neck in gingival cancer

PERIOD1 (PER1) has anti-apoptotic effects, and PER3 has pro-apoptotic effects during cisplatin (CDDP) treatment in human gingival cancer CA9-22 cells

PERIOD (PER) proteins are transcriptional regulators that are involved in circadian rhythms, sleep homeostasis, cell proliferation and tumour progression. We previously showed that the expression of PER1 was related to the regulation of apoptosis in human pancreatic cancer and hepatocellular carcinoma cells. However, the significance of PER in oral cancer has not been reported, and the detailed molecular mechanisms by which anti-tumour drug induces apoptosis in gingival cancer cells are not well understood. We examined whether PER1 and PER3 are involved in the regulation of apoptosis in human gingival cancer CA9-22 cells. The expression of PER1 and PER3 was upregulated and downregulated, respectively, by cis-diamminedichloroplatinum (II) (cisplatin: CDDP) treatment in CA9-22 cells, whereas CDDP treatment had little effects on the expression of PER1 and PER3 in human gingival fibroblasts (HGF-1). We found that short interference RNA (siRNA)-mediated knockdown of PER1 enhanced apoptosis of CA9-22 cells, and that PER1 regulated the amount of Bim, an apoptosis-related molecule. On the other hand, PER3 knockdown had an inhibitory effect on the apoptosis of CA9-22 cells induced by CDDP treatment. These results suggest that the alternation of expression of PER1 and PER3 was related to the apoptosis of CA9-22 cells. Furthermore, PER1 was intensely stained in the gingival cancer tissues, whereas PER3 was significantly stained in the non-tumour tissues by immunohistochemistry. These findings suggest that PER1 and PER3 have anti-apoptotic and pro-apoptotic effects in human gingival cancer CA9-22 cells, respectively. The balance of PER1 and PER3 may modulate apoptotic reactions in gingival cancer cells.

Inhibitory Effects of Glycerol on Growth and Invasion of Human Oral Cancer Cell Lines

It has been reported that glycerol enhances susceptibility to radiotherapy and chemotherapy by a chemical chaperone-like effect which restores mutated protein higher-order structures of the p53 protein because p53 functions are recovered to induce p53-dependent apoptosis through radiotherapy and chemotherapy. On the other hand, based on in vitro and in vivo experiments glycerol alone has not been considered to inhibit growth and invasion of cancer cell lines. In the present in vitro study, glycerol alone was added to oral cancer cell lines (tongue cancer, cervical lymph node [CLN] metastasis of tongue cancer, mandibular gingival cancer) and a cisplatin (CDDP) resistant cell line. The results showed that glycerol inhibited the growth and invasive capacities of the cancer cell lines concentration-dependently. Further, it was demonstrated that the mechanisms of glycerol for inhibiting growth and invasion of the cancer cell lines are inhibition of G1/S phase transition of the cancer cell lines, apoptosis induction, and an inability of cancer cells to use glycerol as an energy substrate. Clinically, this may suggest that glycerol has a potential inhibitory effect on the growth and invasion of CDDP-resistant oral cancer as well as primary and CLN metastatic lesions of oral cancer.

Kinetics of p120-catenin in a human gingival cancer cell line treated with ZD1839

Kinetics of p120-catenin in a human gingival cancer cell line treated with ZD1839

Epithelial-mesenchymal transition in osteogenic sarcoma of the neck following oral squamous cell carcinoma

Postirradiation extraosseous osteogenic sarcomas are uncommon in the head and neck, despite the extensive use of high-dose radiation. It has been described as de novo radiation-induced neoplasm. We present a 73-year-old male who had been treated by radiotherapy for gingival cancer 7 years earlier and later developed extraosseous osteogenic sarcomas (EOSs) of the neck. Microscopically, the neck mass was composed with mesenchymal malignant cells with cartilaginous and osteogenic differentiation. Immunohistochemical stain demonstrated strong positivity of tumor cells for Snail, the one of major epithelial-mesenchymal transition (EMT) inducer. The E-cadherin expression was scarce, showing inverse relationship to Snail expression. Compared with previous squamous cell carcinoma (SCC) of the gingiva, the present EOS sample revealed the remained epithelial cells on cytokeratin immunohistochemistry, suggesting the tumor arise from the cells of epithelial origin. We have also reviewed the previous 6 cases of head and neck EOSs carefully. The clinicopathologic features of the unusual lesion suggest that it is an incomplete EMT of precedent epithelial malignancy rather than de novo pathology.

Diagnosis of pulmonary tuberculosis among dialysis patients by enzyme-linked immunospot assay for interferon-

Sir, We read with interest the analysis of the usefulness of a whole-blood interferon-γ (INF-γ) release assayQuantiFERON (QFT) test in the diagnosis of active tuberculosis in dialysis patients [1]. The authors suggested that the QFT test may be a useful supplementary tool for the detection of active tuberculosis among dialysis patients. An enzyme-linked immunospot (ELISPOT, Oxford Immunotec Ltd, Oxford, UK) assay, like the QFT test, was developed to detect IFN-γ produced by activated T cells after exposure to two specific antigens of Mycobacterium tuberculosis, i.e. early secretory antigenic target 6, and culture filtrate protein 10 [2]. Several studies have demonstrated that ELISPOT assays are useful for diagnosis of active pulmonary and extrapulmonary tuberculosis [2–5]. We hereby postulate that the ELISPOT assay may be another sensitive tool for the diagnosis of active tuberculosis in dialysis patients. We carried out a study to evaluate the performance of ELISPOT assays in 29 dialysis patients with suspected pulmonary tuberculous over a 2-year period. A total of 9 subjects (31.0%) were defined to have culture-confirmed tuberculosis, 3 (10.3%) had probable tuberculosis and the remaining 17 (58.6%) had no tuberculosis. Among 12 patients with pulmonary tuberculosis, the mean age was 66.3 years (ranged from 46 to 83 years), and 3 (25.0%) of them were female. Six of them had diabetes mellitus and one had liver cirrhosis. Three patients had underlying malignancy with one each of hepatocellular carcinoma, melanoma and gingival cancer. Four patients received prior anti-tuberculous treatment before enrolment. The mean values of white blood cell count (WBC) and lymphocyte cell count were 9029 cells/μl (ranged from 396 to 21180 cells/μl) and 1083 cells/μl (ranged from 411 to 1782 cells/μl), respectively. Eleven of the 12 patients with active tuberculosis had positive results for the ELLISPOT assay. The only one false negative result was in a cirrhotic patient with a lymphocyte count of 411 cells/μl and no tuberculosis developed after thefollowup of 189 days. Six of 17 patients without active tuberculosis had positive ELISPOT assays. Taking together the confirmed and probable tuberculosis groups for analysis, the overall sensitivity and specificity were 91.7% (11/12) and 64.7% (11/17), respectively.

Role of hormonal risk factors in oral cancer development

Male: female ratio of oral cancer cases (OC) is fairly high. Lower rate of female cases as compared with males suggests that some endocrine factors may play role in the development of tumors. The aim of the present study was to clarify the differences of risk factors for OC among male and female cases. In the Oral and Maxillofacial Department of Semmelweis University 2660 OC (2130 males and 530 females) patients were included into the study. Ratio of smoking, alcohol consumption, elevated serum glucose level and menopausal data of the female patients were registered. Concordant to the literary data, smoking and excessive alcohol consumption proved to be an important risk factor for OC both among male and female patients. However, moderate alcohol consumption was a weak risk factor among male and no risk factor among female cases. Elevated serum glucose level was not significant OC risk among male cases, but was a high risk factor among female patients, especially in gingival cancer cases. The female OC cases were near exclusively postmenopausal, and the term between the time of menopause and clinical OC diagnosis was fairly long (average: 17 year). These results suggest that estrogen-deficiency may play an important role in the initiation of OC. In the female OC cases menopause appeared in significantly younger age, and the rate of hysterectomy was also significantly higher as compared with the tumor-free control cases. These data also support the estrogen-deficiency theory of cancer initiation. In postmenopausal female patients both estrogen-deficiency and elevated fasting glucose proved to be risk factors for OC. These results reveal new aspects concerning the etiology of OC and give a possible explanation how smoking-associated tumors may develop even without smoking.

Apoptotic mechanism of paclitaxel‐induced cell death in human head and neck tumor cell lines

Paclitaxel (taxol) is clinically used to treat various human tumors. However, the cellular and molecular mechanism regarding apoptotic effect of paclitaxel on head and neck squamous cell carcinoma (HNSCC) remains elusive. The apoptotic effect and the mechanism of paclitaxel on FaDu hypopharyngeal cancer cell line, OEC-M1 gingival cancer cell line, and OC3 betel quid chewing-related buccal cancer cell lines were investigated by morphological observations, cell viability assay, flow cytometry assay and Western blotting methods. Rounded-up cell number increased with membrane blebbing as the treatment of paclitaxel (50-500 nM) increased from 24 to 48 h among these cell lines. In cell viability assay, cell surviving rate significantly decreased from 87 to 27% as the dosage and duration of paclitaxel treatment increased (P < 0.05). Flow-cytometry analysis further demonstrated that 50 nM paclitaxel induced G2/M phase cell arrest among these cell lines within 8 h treatment, and then G2/M phase cell fraction significantly decreased as subG1 phase cell fraction significantly increased after 24 h treatment (P < 0.05), suggesting that cells underwent apoptosis. Furthermore, the activated caspases-8, -9, -3, -6 and poly ADP-ribose polymerase cleavage could all be significantly detected in FaDu, OEC-M1 and OC3 cells (P < 0.05). Paclitaxel activated cell cycle arrest and caspase protein expressions to induce apoptosis in HNSCC cell lines.

再発上顎歯肉癌患者に発現しRamsay Hunt症候群を併発した汎発性帯状疱疹の1例

再発上顎歯肉癌患者に発現しRamsay Hunt症候群を併発した汎発性帯状疱疹の1例

High LET radiation enhances apoptosis in mutated p53 cancer cells through Caspase‐9 activation

Although mutations in the p53 gene can lead to resistance to radiotherapy, chemotherapy and thermotherapy, high linear energy transfer (LET) radiation induces apoptosis regardless of p53 gene status in cancer cells. The aim of this study was to clarify the mechanisms involved in high LET radiation-induced apoptosis. Human gingival cancer cells (Ca9-22 cells) containing a mutated p53 (mp53) gene were irradiated with X-rays, C-ion (13-100 KeV/microm), or Fe-ion beams (200 KeV/microm). Cellular sensitivities were determined using colony forming assays. Apoptosis was detected and quantified with Hoechst 33342 staining. The activity of Caspase-3 was analyzed with Western blotting and flow cytometry. Cells irradiated with high LET radiation showed a high sensitivity with a high frequency of apoptosis induction. The relative biological effectiveness (RBE) values for the surviving fraction and apoptosis induction increased in a LET-dependent manner. Both RBE curves reached a peak at 100 KeV/microm, and then decreased at values over 100 KeV/microm. When cells were irradiated with high LET radiation, Caspase-3 was cleaved and activated, leading to poly (ADP-ribose) polymerase (PARP) cleavage. In addition, Caspase-9 inhibitor suppressed Caspase-3 activation and apoptosis induction resulting from high LET radiation to a greater extent than Caspase-8 inhibitor. These results suggest that high LET radiation enhances apoptosis by activation of Caspase-3 through Caspase-9, even in the presence of mp53.

Radiation therapy for malignant tumors

Radiation therapy uses ionizing radiation to kill cancer cells and shrink tumors, with consideration to minimize harmful damages to health tissues. About 30% of all people with cancer are treated with radiation therapy, either alone or in combination with chemotherapy. Radiation therapy may be internal or external. In brachytheraphy as the internal radiation therapy the radioisotope is implanted into or near the tumor by tubes as the container. And it is often used for patients with the tongue cancer. External radiation, the type most often used, comes from a machine outside the body. It is usually used for shrinking tumors with bony invasions such as gingival cancer and improving the pain in patients with bony metastasis. For the primary bone tumor the radiation therapy is not always used because the radiosensitivity of the almost primary bone tumor is low.

パラタルランプを用いて咀嚼機能回復を行った下顎骨区域切除再建症例

A 70-year-old patient with reconstructed mandibulectomy presented to our clinic with a complaint of denture instability. Due to left mandibular gingival cancer, she had received segmental resection of the left mandible and reconstruction with the fibula. An intraoral examination revealed few intermaxillary occlusal contacts due to the deviation of the mandibular dental arch. A mandibular denture and maxillary prosthesis with palatal ramp were fabricated to provide sufficient occlusal contacts and bilateral balanced occlusion. Regardless of reconstruction, a careful case history, combined with meticulous clinical evaluation was demanded in this mandibulectomy patient. The ramp on maxillary prosthesis could provide not only proper occlusal scheme but also stability of mandibular denture. To improve masticatory function in a reconstructed mandibulectomy patient with deviated mandibular movement and disagreement of occlusion, maxillary prosthesis with palatal ramp was effective.

Anticancer Effect of Sirolimus in Renal Allograft Recipients With De Novo Malignancies

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.

Gender-related hormonal risk factors for oral cancer

Oral cancer (OC) is a neoplasm with fairly high male to female ratio in most populations. The conspicuously lower incidence of this tumor among women than man is suggestive of certain endocrine involvement in its development. The aim of the present case-control study was to clarify the origin of this gender-specific risk of OC incidence. 2660 inpatients (530 females and 2130 males) with squamous cell OC at the Department of Oral and Maxillofacial Surgery were included in a case-control study. Smoking, alcohol consumption, elevated fasting serum glucose level and menopausal histories of female cases were registered. Smoking and excessive alcohol intake proved to be strong risk factors for OC both in the male and female group. However, moderate alcohol consumption was a weaker risk factor for male patients, and it presented no risk for female cases. Elevated fasting glucose level was not a demonstrable OC risk factor among males, however, it proved to be strong risk factor for OC among female patients, especially in gingival cancer cases. The almost exclusively postmenopausal state of female OC patients and the long mean interval (17 years) between their menopause and OC diagnosis suggested an important role of estrogen deficiency in OC epidemiology. The significantly younger mean age at menopause and the significantly higher rate of hysterectomy among female OC cases in comparison with their controls also support the estrogen deficiency hypothesis. This novel hypothesis of estrogen deficiency and elevated fasting glucose as risk factors for OC in postmenopausal women may provide new insights into the etiology of oral malignancies.

A Preliminary Comparative Study of the Prognostic Implications of Type 2 Diabetes Mellitus for Patients With Primary Gingival Carcinoma Treated With Surgery and Radiation Therapy

Type 2 diabetes mellitus (DM2) may be a risk factor in determining cancer progression. The aim of this study was to compare the progression of primary gingival cancer in patients with DM2 and nondiabetic patients. Prospective follow-up studies involved patients with gingival squamous cell carcinoma in stage T2-3N0M0. Treatment comprised surgical tumor extirpation, block resection of the mandible, functional cervical dissection, and 60 Gy of adjuvant irradiation. The patients were divided into a group of patients with DM2 (DM group) and a nondiabetic, control group. Progression data was recorded after a 2-year period of clinical follow-up. Surgical samples were assessed histopathologically from the aspect of tumor spread. At the end of a 2-year follow-up period, the DM group demonstrated significantly worse clinical results in terms of cervical lymph node metastases (P<.05) and mortality rate (P<.001). Histologically, the degree of tumor invasion was significantly different in the DM group and controls (P<.01). DM2 can be considered a possible prognostic factor in cases of gingival carcinoma, forecasting an unfavorable course.