[A Case of Cavernous Sinus Metastasis following of the Postoperative Maxillary Gingival Carcinoma].

We report a case of cavernous sinus metastasis following postoperative maxillary gingival squamous cell carcinoma. An 83-year-old man was referred to our hospital due to pain in the left maxillary gingiva. Contrast-enhanced computed tomography imaging showed a mass lesion with bone destruction in the left maxillary gingiva. Biopsy indicated the presence of squamous cell carcinoma(T4bN1M0, Stage ⅣB), and the tumor was resected under general anesthesia. Four months after surgery, the patient experienced headache, and orbital pain, failing vision, and movement disorder of the left eye appeared. Magnetic resonance imaging revealed a tumor invading the cavernous sinus and orbit. The lesion was clinically diagnosed as metastatic cavernous sinus following postoperative left maxillary gingival carcinoma. Although the patient underwent chemotherapy, he died from multiple organ failure about 5 months after surgery.

A canine case of malignant melanoma carrying a KIT c.1725_1733del mutation treated with toceranib: a case report and in vitro analysis.

BACKGROUND: Canine malignant melanoma is highly aggressive and generally chemoresistant. Toceranib is a kinase inhibitor drug that inhibits several tyrosine kinases including the proto-oncogene receptor tyrosine kinase KIT. Although canine malignant melanoma cells often express KIT, a therapeutic effect for toceranib has yet to be reported for this tumor, with only a small number of patients studied to date. This is a case report of a dog with malignant melanoma that experienced a transient response to toceranib. Furthermore, the KIT expressed in the tumor of this case was examined using molecular analysis. CASE PRESENTATION: A Shiba Inu dog presented with a gingival malignant melanoma extending into surrounding structures with metastasis to a submandibular lymph node. The dog was treated with toceranib (Palladia®; 2.6-2.9 mg/kg, orally, every other day) alone. Improvement of tumor-associated clinical signs (e.g., halitosis, tumor hemorrhage, trismus, and facial edema) with reduced size of the metastatic lymph node was observed on Day 15. The gingival tumor and associated masses in the masseter and pterygoid muscles decreased in size by Day 29 of treatment. Toceranib treatment was terminated on Day 43 due to disease progression and the dog died on Day 54. The tumor of this dog had a novel deletion mutation c.1725_1733del within KIT and the mutation caused ligand-independent phosphorylation of KIT, which was suppressed by toceranib. This mutation was considered to be an oncogenic driver mutation in the tumor of this dog, thereby explaining the anti-tumor activity of toceranib. CONCLUSIONS: This is the first report that presents a canine case of malignant melanoma that responded to toceranib therapy. KIT encoded by KIT harboring a mutation c.1725_1733del is a potential therapeutic target for toceranib in canine malignant melanoma. Further investigation of the KIT mutation status and toceranib therapy in canine malignant melanoma will need to be undertaken.

Impact of superselective intra-arterial and systemic chemoradiotherapy for gingival carcinoma; analysis of treatment outcomes and prognostic factors.

BACKGROUND: We compared outcomes and toxicities between concurrent retrograde super-selective intra-arterial chemoradiotherapy (IACRT) and concurrent systemic chemoradiotherapy (SCRT) for gingival carcinoma (GC). METHODS: We included 84 consecutive patients who were treated for non-metastatic GC ≥ stage III, from 2006 to 2018, in this retrospective analysis (IACRT group: n = 66; SCRT group: n = 18). RESULTS: The median follow-up time was 24 (range: 1-124) months. The median prescribed dose was 60 (6-70.2) Gy (IACRT: 60 Gy; SCRT: 69 Gy). There were significant differences between the two groups in terms of 3-year overall survival (OS; IACRT: 78.8, 95% confidence interval [CI]: 66.0-87.6; SCRT: 50.4, 95% CI: 27.6-73.0; P = 0.039), progression-free survival (PFS; IACRT: 75.6, 95% CI: 62.7-85.2; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.028) and local control rates (LC; IACRT: 77.2, 95% CI: 64.2-86.4; SCRT: 42.0, 95% CI: 17.7-70.9; P = 0.015). In univariate analysis, age ≥ 65 years, decreased performance status (PS) and SCRT were significantly associated with worse outcomes (P < 0.05). In multivariate analysis, age ≥ 65 years, clinical stage IV, and SCRT were significantly correlated with a poor OS rate (P < 0.05). Patients with poorer PS had a significantly worse PFS rate. Regarding acute toxicity, 22 IACRT patients had grade 4 lymphopenia, and osteoradionecrosis was the most common late toxicity in both groups. CONCLUSIONS: This is the first report to compare outcomes from IACRT and SCRT among patients with GC. ALL therapy related toxicities were manageable. IACRT is an effective and safe treatment for GC.

Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells.

BACKGROUND: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. METHODS: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3',5,5'-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. RESULTS: Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-ß1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. CONCLUSIONS: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-ß expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.

Squamous Cell Carcinoma of Maxillary Gingiva Progressing to Disseminated Carcinomatosis of Bone Marrow.

Disseminated carcinomatosis of the bone marrow (DCBM) is characterized by diffuse metastasis to bone marrow and sudden mortality. To the best of our knowledge, no studies to date have reported progression of oral squamous cell carcinoma to DCBM. Herein, we report a case of squamous cell carcinoma in the maxillary gingiva suspected of progressing to DCBM. A 64-year-old woman presented with white lesions on the left maxillary gingiva. The lesions were diagnosed as squamous cell carcinoma (T2, N0, M0), and partial maxillectomy performed. Two years and 5 months after surgery, metastasis was noted in the left cervical lymph node and left radical neck dissection carried out. The subsequent diagnosis was right cervical lymph node metastasis and multiple bone metastases. The patient also presented with thrombocytopenia, anemia, and elevated levels of alkaline phosphatase, probably due to metastatic bone disease. Although various antitumor therapies were administered, the patient died 6 months after diagnosis of multiple bone metastases.

Initial periodontal therapy for the treatment of gingival pregnancy tumor.

The purpose of this study was to evaluate the clinical efficacy of initial periodontal therapy in gingival pregnancy tumors. Thirty-nine patients diagnosed with gingival tumors of pregnancy between 2007 and 2015 were enrolled in this study. The patients received initial periodontal therapy, then supportive periodontal therapies at 3- to 6-month intervals. The patients underwent follow up for 6 months to 8 years after treatment. After plaque control, supragingival scaling, and root planning, the tumors in 25 patients were gradually eliminated without the necessity of surgery. In 3 patients, tumors <5 mm in size disappeared in a mean time of 3.6 months, 4 patients with tumors 5-10 mm disappeared in a time of 7.5 months, 11 patients with tumors 10-15 mm disappeared in 10.2 months, 6 patients with tumors 15-20 mm disappeared in 15 months, and one patient with a tumor >20 mm disappeared in 20 months. No recurrence of gingival pregnancy tumors was noted during subsequent follow-up. Initial periodontal therapy combined with oral hygiene maintenance is efficacious in treating gingival pregnancy tumors of patients with normal hormone levels, which can potentially serve as an option to avoid surgery.

[Failure to Remove Long-Term Indwelling Central Venous Catheters in Two Patients].

The use ofa central venous(CV)port system has become common for the treatment of patients with tumors. We report on the failure to remove CV catheters in 2 patients. The first patient was a 50 years woman with acute myeloid leukemia. She underwent CV port implantation via the left brachial approach 11 years previously. The second patient was an 80 years man with a lower gingival carcinoma. He underwent CV port implantation via the left brachial approach 6 years previously. CV catheter removal was attempted in both patients, but was unsuccessful because of strong adhesion to the vessel wall. Based on our experience, if catheter removal is impossible, its retention is more suitable.

Methanolic extracts of Solieria robusta inhibits proliferation of oral cancer Ca9-22 cells via apoptosis and oxidative stress.

Many red algae-derived natural products are known to have anticancer effects. The biological functions of the red alga Solieria robusta from the Karachi coast (Pakistan) remain unclear. Here, we prepared a methanolic extracts of S. robusta (MESR) to examine its possible anti-oral cancer effects and the corresponding mechanism of action. Cell viability of MESR-incubated oral cancer Ca9-22 cells was dose-responsively decreased (p<0.001). According to a propidium iodide (PI)-based assay the cell cycle distribution was dramatically changed, especially for subG1 accumulation. Annexin V/PI assay of apoptosis using flow cytometry also showed that MESR-incubated Ca9-22 cells were dose-responsively increased (p<0.001). For evaluation of oxidative stress in MESR-incubated Ca9-22 cells, we found that reactive oxygen species (ROS) were overexpressed dose- and time-responsively and mitochondrial depolarization was also increased (p<0.001). Taken together, MESR showed inhibitory effects on oral cancer proliferation coupled with apoptosis and oxidative stress.

Anlotinib treatment for rapidly progressing pediatric embryonal rhabdomyosarcoma in the maxillary gingiva: a case report.

BACKGROUND: Embryonal rhabdomyosarcoma (ERMS) is a highly aggressive form of soft-tissue sarcoma that predominantly affects children. Due to limited benefits and resistance to therapy, there is an unmet need to explore alternative therapeutic strategies. CASE PRESENTATION: In this report, we present a rare case of pediatric ERMS located on the right side of the maxillary gingiva. A composite reference guide integrating clinical, radiographic, and histopathologic findings was used for a definitive diagnosis. Targeted next-generation sequencing of tumor biopsy was performed to identify genetic alterations. A 12-year-old female was admitted to the Pediatric Intensive Care Unit (PICU) and underwent a tracheotomy to relieve asphyxiation caused by a 5.5 cm diameter mass compressing the tongue root and pharyngeal cavity. Hematoxylin and eosin staining revealed a hybrid morphology characterized by clusters of round and spindle cells. Further immunohistochemistry assays indicated positive immunoreactivity for desmin, myogenin, and MyoD1. Various genetic alterations were identified, including mutations in GNAS, HRAS, LRP1B, amplification of MDM2 and IGF1R, and two novel IGF1R fusions. Negative PAX-FOXO1 fusion status supported the clinical diagnosis of ERMS. Initial treatment involved standard chemotherapy; however, the tumor persisted in its growth, reaching a maximum volume of 12 cm × 6 cm × 4 cm by the completion of treatment. Subsequent oral administration of anlotinib yielded a significant antitumor response, characterized by substantial tumor necrosis and size reduction. Following the ligation of the tumor pedicle and its removal, the patient developed a stabilized condition and was successfully discharged from PICU. CONCLUSIONS: Our study highlights the importance of accurate diagnosis established on multifaceted assessment for the effective treatment of ERMS. We present compelling evidence supporting the clinical use of anlotinib as a promising treatment strategy for pediatric ERMS patients, especially for those resistant to conventional chemotherapy.

Eugenol as a potential adjuvant therapy for gingival squamous cell carcinoma.

Adoption of plant-derived compounds for the management of oral cancer is encouraged by the scientific community due to emerging chemoresistance and conventional treatments adverse effects. Considering that very few studies investigated eugenol clinical relevance for gingival carcinoma, we ought to explore its selectivity and performance according to aggressiveness level. For this purpose, non-oncogenic human oral epithelial cells (GMSM-K) were used together with the Tongue (SCC-9) and Gingival (Ca9-22) squamous cell carcinoma lines to assess key tumorigenesis processes. Overall, eugenol inhibited cell proliferation and colony formation while inducing cytotoxicity in cancer cells as compared to normal counterparts. The recorded effect was greater in gingival carcinoma and appears to be mediated through apoptosis induction and promotion of p21/p27/cyclin D1 modulation and subsequent Ca9-22 cell cycle arrest at the G0/G1 phase, in a p53-independent manner. At these levels, distinct genetic profiles were uncovered for both cell lines by QPCR array. Moreover, it seems that our active component limited Ca9-22 and SCC-9 cell migration respectively through MMP1/3 downregulation and stimulation of inactive MMPs complex formation. Finally, Ca9-22 behaviour appears to be mainly modulated by the P38/STAT5/NFkB pathways. In summary, we can disclose that eugenol is cancer selective and that its mediated anti-cancer mechanisms vary according to the cell line with gingival squamous cell carcinoma being more sensitive to this phytotherapy agent.

Cellular mechanisms mediating the anti-cancer effects of carnosol on gingiva carcinoma.

Carnosol, a rosemary polyphenol, displays anticancer properties and is suggested as a safer alternative to conventional surgery, radiotherapy, and chemotherapy. Given that its effects on gingiva carcinoma have not yet been investigated, the aim of this study was to explore its anti-tumor selectivity and to unravel its underlying mechanisms of action. Hence, oral tongue and gingiva carcinoma cell lines exposed to carnosol were analyzed to estimate cytotoxicity, cell viability, cell proliferation, and colony formation potential as compared with those of normal cells. Key cell cycle and apoptotic markers were also measured. Finally, cell migration, oxidative stress, and crucial cell signaling pathways were assessed. Selective anti-gingiva carcinoma activity was disclosed. Overall, carnosol mediated colony formation and proliferation suppression in addition to cytotoxicity induction. Cell cycle arrest was highlighted by the disruption of the c-myc oncogene/p53 tumor suppressor balance. Carnosol also increased apoptosis, oxidative stress, and antioxidant activity. On a larger scale, the alteration of cell cycle and apoptotic profiles was also demonstrated by QPCR array. This was most likely achieved by controlling the STAT5, ERK1/2, p38, and NF-ĸB signaling pathways. Lastly, carnosol reduced inflammation and invasion ability by modulating IL-6 and MMP9/TIMP-1 axes. This study establishes a robust foundation, urging extensive inquiry both in vivo and in clinical settings, to substantiate the efficacy of carnosol in managing gingiva carcinoma.

Utilization of a nanostructured lipid carrier encapsulating pitavastatin-Pinus densiflora oil for enhancing cytotoxicity against the gingival carcinoma HGF-1 cell line.

Oral squamous cell carcinoma (OSCC) is the most common epithelial tumor of the oral cavity. Gingival tumors, a unique type of OSCC, account for 10% of these malignant tumors. The antineoplastic properties of statins, including pitavastatin (PV), and the essential oil of the Pinus densiflora leaf (Pd oil) have been adequately reported. The goal of this investigation was to develop nanostructured lipid carriers (NLCs) containing PV combined with Pd oil and to determine their cytotoxicity against the cell line of human gingival fibroblasts (HGF-1). A central composite quadratic design was adopted to optimize the nanocarriers. The particle size and stability index of the nano-formulations were measured to evaluate various characteristics. TEM analysis, the entrapment efficiency, dissolution efficiency, and the cytotoxic efficiency of the optimized PV-loaded nanostructured lipid carrier drug delivery system (PV-Pd-NLCs) were evaluated. Then, the optimal PV-Pd-NLCs was incorporated into a Carbopol 940® gel base and tested for its rheological features and its properties of release and cell viability. The optimized NLCs had a particle size of 98 nm and a stability index of 89%. The gel containing optimum PV-Pd-NLCs had reasonable dissolution efficiency and acceptable rheological behavior and acquired the best cytotoxic activity against HGF-1 cell line among all the formulations developed for the study. The in vitro cell viability studies revealed a synergistic effect between PV and Pd oil in the treatment of gingival cancer. These findings illustrated that the gel containing PV-Pd-NLCs could be beneficial in the local treatment of gingival cancer.

Gingival metastasis of a radiotherapy-induced breast angiosarcoma: diagnosis and multidisciplinary treatment achieving a prolonged complete remission.

Angiosarcoma is a rare and highly malignant mesenchymal tumor. Similar to other soft tissue sarcomas, it may arise in any organ, although it occurs more frequently within skin structures like the scalp. Angiosarcoma has a characteristic pattern of local and distant relapse involving primary site, regional lymph nodes, and lung. Patients affected by unresectable relapses or metastases have a dismal prognosis with a median overall survival of less than 9 months. We present the case of a 74-year-old woman who previously underwent total mastectomy for a radiotherapy-induced angiosarcoma of the breast. She subsequently developed a rapidly growing gingival tumor lesion that was in fact a unique distant metastasis of her angiosarcoma. In general, surgery is the mainstay of angiosarcoma treatment, and even metastases are aggressively resected whenever feasible. We describe the successful multidisciplinary treatment that avoided a likely mutilating surgery and review the literature regarding primary and metastatic gingival angiosarcoma.

Mandibular reconstruction using free bone flap after preoperative chemoradiation.

When treating head and neck cancer of an advanced stage, additional therapy modalities are often combined with surgery. This sets new challenges for the reconstructive surgery, especially after segmental mandibulectomy. There is continuous discussion considering the optimal timing of the surgery with relation to other treatment methods such as radiation therapy and chemotherapy. In this work, we have analyzed a series of 10 patients treated with segmental mandibulectomy and preoperative irradiation or chemoradiation in our institute between 1999 and 2006. Surgery was scheduled within 5 weeks from the radiation therapy. 9 out of 10 reconstruction flaps were vital at the last follow-up. In general the outcome of these patients was consistent with the results published earlier by other institutes using postoperative irradiation or chemoradiation. We conclude that preoperative irradiation does not have negative impact on microvascular reconstruction with free bone flap and this procedure offers an equal option for the treatment of these patients.

Primary gingival angiosarcoma successfully treated by radiotherapy with concurrent intra-arterial chemotherapy.

The occurrence of angiosarcoma in the oral cavity is extremely rare, and optimal management of this tumor is undefined. These tumors are aggressive, with a high propensity for local recurrence. We present here a case of primary gingival angiosarcoma successfully treated by intra-arterial chemotherapy concurrent with radiation therapy. A 69-year-old female with a primary angiosarcoma in the right maxillary gingiva was admitted to our hospital. The diagnosis of angiosarcoma was established by immunohistochemistry. The patient refused surgical treatment, and so intra-arterial cisplatin and concurrent radiation were given. The gingival tumor disappeared after completion of the therapeutic regimen. However, the patient died 8 months after initial treatment because of multiple lung metastases. Locoregional control was achieved up to her death. To our knowledge, this is the first report of this treatment for angiosarcoma of the oral cavity.

[A case of advanced upper gingival carcinoma responding completely to concurrent chemoradiotherapy with S-1].

We report a case of advanced upper gingival carcinoma with a contralateral metastatic lymph node invading the maxillary sinus (T4aN2cM0). An 83-year-old man was treated concurrently with chemoradiotherapy and S-1. S-1 (80 mg/body/day) was administered for 2 weeks followed by a 1-week rest period as one course. Radiation therapy involved a total of 60 Gy (2 Gy/day; 5 days/week). There were side effects of mild leucopenia and a grade 2 stomatitis. After the completion of 2 courses and radiation therapy, the primary tumor disappeared, and the patient achieved a pathologically complete response. The metastatic lymph node also completely disappeared. S-1 was then administered in the same regimen for 1 year. Neither local recurrence nor distant metastasis has been detected 2 years after the completion of the concurrent chemoradiotherapy with S-1.

The natural product lapiferin inhibits cell proliferation and promotes cell apoptosis in gingival squamous cell carcinoma via P21 regulation.

Gingival squamous cell carcinoma (GSCC) is responsible fora large proportion of oral cavity malignancies. GSCC is characterized by rapid cell growth, and progressive invasion and migration. P21 is a widely recognized tumor suppressor, which is induced by P53 activation; however, drugs that aim to promote P21­mediated tumor suppression remain to be identified. A natural compound library was used to perform broad­spectrum screening of drugs that could promote P21 expression. Subsequently, the effects of the screened drug on GSCC cell proliferation and apoptosis were evaluated. The results of the present study suggested that lapiferin was the most effective natural compound that promoted the expression of P21 at both mRNA and protein levels. Lapiferin inhibited proliferation and enhanced apoptosis of YD­38 GSCC cells in a dose­dependent manner. Furthermore, following treatment with lapiferin, the critical cell cycle regulators cell division cycle 25C and cyclin B1 and tumor cell proliferation markers proliferating cell nuclear antigen and Ki67 were markedly decreased. In addition, pro­apoptotic proteins were promoted following treatment of YD­38 cells with lapiferin. Following the depletion ofP21 expression, lapiferin­mediated inhibition of cell proliferation and enhancement of cell apoptosis were significantly reduced. These results indicated that lapiferin may exert potent antitumor effects on GSCC via regulation of P21; therefore, lapiferin may be considered a potential, natural therapeutic agent for the treatment of GSCC.

Aspirin Inhibition of Group VI Phospholipase A2 Induces Synthetic Lethality in AAM Pathway Down-Regulated Gingivobuccal Squamous Carcinoma.

BACKGROUND: To elucidate the role of iPLA2/PLA2G6 in gingivobuccal squamous cell carcinoma (GB-SCC) and to ascertain the synthetic lethality-based chemoprevention role of aspirin in arachidonic acid metabolism (AAM) pathway down-regulated GB-SCC. METHODS: The in vitro efficacy of aspirin on GB-SCC cells (ITOC-03 and ITOC-04) was assessed by cell proliferation, colony formation, apoptosis, cell migration, cell cycle assay and RNA-seq, while inhibition of PLA2G6 and AAM pathway components was affirmed by qPCR, Western blot and immunofluorescence staining. The in vivo effect of aspirin was evaluated using NOD-SCID mice xenografts and immunohistochemical analysis. RESULTS: We found that aspirin, which has been reported to act through the COX pathway, is inhibiting PLA2G6, and thereby the COX and LOX components of the AAM pathway. The findings were validated using PLA2G6 siRNA and immunohistochemical marker panel. Moreover, a pronounced effect in ITOC-04 cells and xenografts implied aspirin-induced synthetic lethality in the AAM pathway down-regulated GB-SCC. CONCLUSIONS: This study reveals that aspirin induces the anti-tumor effect by a previously unrecognized mechanism of PLA2G6 inhibition. In addition, the effect of aspirin is influenced by the baseline AAM pathway status and could guide precision prevention clinical trials of AAM pathway inhibitors.

[Granulocytic sarcoma in the mandibular gingiva of an HIV+ patient]. / Sarcome granulocytique gingival mandibulaire chez un patient VIH positif.

INTRODUCTION: The association between malignant tumors and HIV infection is well known. We report a rare case of gingival granulocytic sarcoma (GS) associated to HIV infection. OBSERVATION: A 31 year-old HIV patient consulted for left maxillary tumefaction. His viral load was high (40,112 copies/ml) and CD4 count low (287cells/mm(3)). After biopsy-exeresis, histology and an immunohistochemical study confirmed the diagnosis of GS. Chemotherapy similar to that of acute myeloid leukemia (AML) completed the treatment. The remission was complete at 5 years. DISCUSSION: Only one case of intra-oral GS associated to HIV infection has been reported so far. The clinical and radiological presentation is unspecific. Histology proves the diagnosis. The treatment is comparable to that of AML. The prognosis is usually bad.