Yasunao Kogashiwa

Successful treatment of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) patients with sitafloxacin: New strategies for the treatment of BRONJ

BRONJ has become a well-known, occasionally severe side effect of bisphosphonate therapy, as well as a clinical problem. Although treatment recommendations exist, no standard therapy has yet been established for BRONJ. Also, these recommendations identify several limitations that prevent clinicians from confidently diagnosing BRONJ. The aim of the present study was to establish a treatment approach in which all patients with exposed, infected bone or intraoral/extraoral fistulas were treated with sitafloxacin (STFX). We examined 20 BRONJ patients, fourteen with cancer and six with osteoporosis. We used the current updated definition of BRONJ (12), except that we included patients who had shown symptoms for a minimum of only one month, rather than two months. Thus half of our patients had infection with no exposed, necrotic bone in the oral cavity. We purposely excluded all patients exhibiting no signs of infection (current Stages 0 and 1). In addition, each potentially causative organism was isolated from pus collected from an intraoral or extraoral fistula in ten patients on their first visit to our department. 90% of the patients had received a course of treatment with common antibiotics. STFX was administered to all patients. We then re-evaluated the lesion every other week, to determine whether epithelialization was present. We recommended surgical treatment for cases without epithelialization within 4 weeks after the onset of administration of STFX even if bone was not exposed at the lesion. 19 of our 20 cases of Stages 2-3 BRONJ responded to 2-10 weeks of STFX treatment by entering either a remission or healed phase. While surgery was done on thirteen cases, seven others reached such phases without surgery. Every patient had at least one bacterial species that showed resistance to common antibiotics. All species in all patients were susceptible to STFX. Our results indicate that STFX, with or without minor surgery, gives a high probability of controlling infection in BRONJ patients with persistent infection after use of common antibiotics, leading to remission and/or complete healing in 95% of patients.

Diagnostic evaluation of sentinel lymph node biopsy in early head and neck squamous cell carcinoma: A meta-analysis

The purpose of this study was to evaluate the efficacy of sentinel lymph node biopsy (SLNB) in early head and neck squamous cell carcinoma (HNSCC).

Docetaxel suppresses invasiveness of head and neck cancer cells in vitro

The combination of docetaxel, cisplatin, and fluorouracil significantly enhances the survival of head and neck cancer patients compared to cisplatin and fluorouracil. We hypothesized that docetaxel may affect invasiveness of the head and neck cancer cells in addition to its tumor‐killing effect. Two different head and neck cancer cell lines (HEp‐2 and Ca9‐22) were treated with docetaxel at IC10 and IC50 concentrations. Cell migration and invasive growth was evaluated by wound healing assay and three‐dimensional (3D) culture of multicellular tumor spheroids, respectively. Expression levels of possible downstream effectors for cell migration/invasiveness were measured by immunoblotting in conditions with or without docetaxel. Docetaxel, but not cisplatin, suppressed filopodia formation compared with no treatment (control) condition. Consistent with this, docetaxel suppressed two‐dimensional (2D) cell migration and 3D cell invasion compared with control or cisplatin. Only docetaxel treated cells exhibited thick tubulin bundle and had lower activity of Cdc42, a member of the Rho family of small GTPases. In conclusion, Docetaxel treatment suppressed migration and invasiveness of head and neck cancer cells in vitro, which is likely to be mediated by regulating Cdc42 activity. (Cancer Sci 2010; 00: 000–000)

Quantitative expression study of four cytokeratins and p63 in squamous cell carcinoma of the tongue: suitability for sentinel node navigation surgery using one-step nucleic acid amplification

Aims Sentinel node navigation surgery (SNNS) is currently considered to provide better staging of regional metastasis. For rapid and accurate sentinel lymph node analysis, one-step nucleic acid amplification using cytokeratin 19 (CK19) has been applied, particularly in breast cancer. On the other hand, additional quantitative reverse transcription PCR targets containing cytokeratins have been reported recently in head and neck cancer. In this report, CK19 and p63 were immunohistochemically examined in primary tumours for use as molecular markers and were compared with cytokeratin 903 (CK903), cytokeratin 8/18 (CK8/18) and cytokeratin (AE1/AE3), which are used in diagnostic immunohistochemistry for head and neck squamous cell carcinoma. Methods The study reviewed 17 patients with T1/T2, N0 (UICC) oral squamous cell carcinoma of the tongue who were treated surgically at Kyorin University Hospital between 2002 and 2009. The intensity and proportion of tumour cells stained for CK19, CK903, p63, CK8/18 and AE1/AE3 were evaluated. Results CK19 and CK8/18 staining in cytoplasm was patchy among carcinoma cells, indicating weak expression. Staining proportion for p63, CK903 and AE1/AE3 was greater than for CK19 and CK8/18, although staining intensity for CK903 was weaker than for p63 and AE1/AE3. The difference in total score between CK19 and CK8/18 staining and p63, CK903 and AE1/AE3 staining was statistically significant (p<0.001). p63 and AE1/AE3 may be better markers than CK903, CK19 and CK8/18. Conclusions This suggests that p63 is of clinical utility in SNNS and that CK19 is unsuitable for early tongue carcinoma. Further studies are needed before clinical application of these markers.

Sentinel Node Biopsy for the Head and Neck Using Contrast-Enhanced Ultrasonography Combined with Indocyanine Green Fluorescence in Animal Models: A Feasibility Study

Background Sentinel node navigation surgery is gaining popularity in oral cancer. We assessed application of sentinel lymph node navigation surgery to pharyngeal and laryngeal cancers by evaluating the combination of contrast-enhanced ultrasonography and indocyanine green fluorescence in animal models. Methods This was a prospective, nonrandomized, experimental study in rabbit and swine animal models. A mixture of indocyanine green and Sonazoid was used as the tracer. The tracer mixture was injected into the tongue, larynx, or pharynx. The sentinel lymph nodes were identified transcutaneously by infra-red camera and contrast-enhanced ultrasonography. Detection time and extraction time of the sentinel lymph nodes were measured. The safety of the tracer mixture in terms of mucosal reaction was evaluated macroscopically and microscopically. Results Sentinel lymph nodes were detected transcutaneously by contrast-enhanced ultrasonography alone. The number of sentinel lymph nodes detected was one or two. Despite observation of contrast enhancement of Sonazoid for at least 90 minutes, the number of sentinel lymph nodes detected did not change. The average extraction time of sentinel lymph nodes was 4.8 minutes. Indocyanine green fluorescence offered visual information during lymph node biopsy. The safety of the tracer was confirmed by absence of laryngeal edema both macro and microscopically. Conclusions The combination method of indocyanine green fluorescence and contrast-enhanced ultrasonography for detecting sentinel lymph nodes during surgery for head and neck cancer seems promising, especially for pharyngeal and laryngeal cancer. Further clinical studies to confirm this are warranted.

Phase I study of S-1 plus nedaplatin in patients with advanced/recurrent head and neck cancer.

Background: Cisplatin plus fluorouracil is widely used for the treatment of head and neck cancer. However, the cisplatin plus fluorouracil regimen necessitates hospitalization. Therefore, we planned to develop a new regimen that can be administered on an outpatient basis and performed a phase I study of S-1 + nedaplatin. Methods: S-1 was given orally at a fixed dose for 14 days, and nedaplatin was administered intravenously on day 8 of S-1 administration. The dose of nedaplatin was increased in 10-mg/m2 steps to find the maximum tolerated dose, depending on the appearance of dose-limiting toxicities. Results: A total of 14 patients were registered. The maximum tolerated dose of nedaplatin was determined to be 90 mg/m2. The main toxicities were neutropenia and thrombocytopenia. The response rate was 57.1%. Conclusion: The recommended dose of nedaplatin for a phase II study was determined to be 80 mg/m2. We concluded that our regimen was well tolerated and that the response rate was acceptable.

Correlation of Inflammatory Markers, Survival, and COX2 Expression in Oral Cancer and Implications for Prognosis

Objective Peripheral blood–derived inflammation-based scores, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and the combination of platelet count and NLR, have recently been proposed as prognostic markers in solid tumors. The purpose of this study was to investigate the validity of inflammatory markers as predictive prognostic factors for locally advanced oral squamous cell carcinoma (OSCC). In addition, we evaluated the potential correlation between systemic inflammation and local expression of COX2. Study Design Retrospective chart review and histologic analysis. Setting Tertiary referral academic center. Subjects and Methods We conducted a retrospective analysis of 94 patients with advanced OSCC treated with surgery at our hospital between 2007 and 2015. The relationship among patient survival, systemic inflammatory markers, and local COX2 expression was evaluated. Local COX2 expression in surgical specimens was measured by immunohistochemistry. Results High NLR and high PLR were associated with significantly shorter overall survival and cancer-specific survival. Multivariate analysis revealed that cN stage, NLR, and postoperative radiation/chemoradiation were significantly associated with overall survival and cancer-specific survival. PLR and combination of platelet count and NLR were significantly correlated with tumor expression of COX2. Finally, patients with cN2 stage disease and high local COX2 expression had a significantly worse prognosis than other patient groups. Conclusion Pretreatment inflammatory markers are useful as prognostic factors in advanced OSCC. Our study suggests that local COX2 may be affected by systemic inflammation and that the prognostic impact of COX2 expression depends on host factors and tumor characteristics.

The Effect of Topical Application of Royal Jelly on Chemoradiotherapy-Induced Mucositis in Head and Neck Cancer: A Preliminary Study

Purpose. One of the common side effects experienced by head and neck cancer patients on chemoradiotherapy is mucositis. Severe mucositis may be controllable by limiting cancer therapy, but it has resulted in decreasing the completion rate of chemoradiotherapy. The efficacy of royal jelly (RJ) as prophylaxis against chemoradiotherapy-induced mucositis was evaluated through clinical scoring of oral and pharyngeal mucositis. Methods. In this randomized, single-blind (physician-blind), clinical trial, 13 patients with head and neck cancer requiring chemoradiation were randomly assigned to two groups. Seven patients assigned to the study group received RJ, and 6 patients were assigned to the control group. RJ group patients took RJ three times per day during treatment. The patients in both groups were evaluated twice a week for the development of mucositis using Common Terminology Criteria for Adverse Events version 3.0. Results. A significant reduction in mucositis was seen among RJ-treated patients compared with controls (P < 0.001). Conclusion. This study demonstrated that prophylactic use of RJ was effective in reducing mucositis induced by chemoradiotherapy in head and neck cancer patients. However, further studies are needed because of the small sample size and the absence of double blinding.

Head and Neck Cancer with Dermatomyositis: A Report of Two Clinical Cases

Dermatomyositis is well known to be associated with several types of malignancy and patients with dermatomyositis have higher rates of mortality from cancer. Although rare in Japan, head and neck cancer, especially nasopharyngeal cancer, is the predominant type of cancer associated with dermatomyositis in several areas in Asia, including Hong Kong and Singapore. Here we report two cases of head and neck cancer with dermatomyositis as well as a literature review. Both cases were treated with chemotherapy and radiotherapy. Although the patients were immunosuppressed due to dermatomyositis treatment, no grade 3 or 4 adverse events occurred.

Inhibition of epithelial–mesenchymal transition by cetuximab via the EGFR‐GEP100‐Arf6‐AMAP1 pathway in head and neck cancer

Despite improved survival by the addition of a monoclonal antibody against epidermal growth factor receptor (EGFR), cetuximab, to chemotherapy or radiotherapy for squamous cell carcinoma of the head and neck (SCCHN), cetuximab by itself is not a potent antiproliferative agent against SCCHN. We aimed to elucidate working mechanism of cetuximab in SCCHN.