Yasushi Fujimoto

Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727). INTERPRETATION 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDING Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

Intratumoral injection of herpes simplex virus HF10 in recurrent head and neck squamous cell carcinoma

We have developed a novel replication-competent, oncolytic herpes simplex virus (HSV), named HF10, and have evaluated its anticancer efficacy in a variety of animal models. We report a pilot study of intratumoral injection of HF10 into subcutaneous nodules in patients with head and neck squamous cell carcinoma (HNSCC). HF10 efficiently infected human HNSCC cells and caused extensive tumor cell death without any significant adverse effects, suggesting that HF10 represents a promising therapy for HNSCC in humans. To assess the therapeutic potential of HF10 in human HNSCC, we performed a preliminary study of toxicity and efficacy in two patients with recurrent metastatic HNSCC. For each patient, a metastatic skin nodule was injected with HF10 once a day for 3 days. They were monitored for systemic adverse effects, and the injected nodules were excised at day 13 (patient 1) or day 15 (patient 2) after injection for histochemical examination. HF10 replicated, spread well in the tumor nodules, and caused cell death in a considerable population of tumor cells without any significant adverse effects.

The Relationship of Shape of Tumor Invasion to Depth of Invasion and Cervical Lymph Node Metastasis in Squamous Cell Carcinoma of the Tongue

Several investigators have suggested that there is a strong correlation between tumor depth and lymph node involvement in tongue carcinoma. The purpose of this study was to investigate the relationship between the shape of tumor, tumor depth, and lymph node metastasis in tongue carcinoma. Fifty-four patients with T1 abd T2 tongue carcinomas who underwent surgical treatment were included in this study. Tumors were divided into four categories according to their shape of invasion: superficial, exophytic, endophytic, and a combination of endophytic and exophytic. Forty cases of endophytic and combination types were divided into two groups according to the shape of invasion: (1) reductive bottom of invasion (n = 17) and (2) expansive bottom of invasion (n = 23). Tumors with a reductive bottom of invasion showed a variety of tumor depths and had low lymph node involvement (4/17, 23.5%). However, tumors with an expansive bottom of invasion showed deeper invasion and a high incidence of lymph node metastasis (16/23, 69.6%). These results suggested that the macroscopic shape of invasion is a feature that may provide important information about the prognosis of the primary tumor especially in relation to cervical lymph node involvement.

Reconstruction using a three-dimensional orbitozygomatic skeletal model of titanium mesh plate and soft-tissue free flap transfer following total maxillectomy.

The surgical strategy for maxillary reconstruction after maxillectomy has yet to be standardized. The authors developed a technique using a three-dimensional orbitozygomatic skeletal model of a titanium mesh for skeletal reconstruction after maxillectomy. From May of 1996 to September of 2000, 18 patients underwent reconstruction using the titanium mesh model in conjunction with a soft-tissue free flap following total maxillectomy for a maxillary malignancy. The soft-tissue free flap was conventional and consisted of two skin paddles to the maxillary defect. One skin paddle became the lateral nasal wall and the other was used to close the palatal defect. After modeling, the titanium mesh plate was implanted between the orbital contents and the upper edge of the free flap to lie over the front of the flap. The model was fixed to the residual zygoma laterally and to the nasal or frontal bone medially. The palatal skin paddle was anchored by three or four dermal stitches to the bottom edge of the titanium mesh to create a concave neopalate that allowed the patient to wear a denture. Thirteen of 18 patients who underwent implantation had good facial appearance and oral function. This procedure prevented lagophthalmos, facial deformity, and sagging of the palatal skin paddle caused by gravitational force. Five patients (27.8 percent) developed exposure or infection of the implant and lost the benefit of having the prosthesis. However, treatment did not require total removal of the implant. Maintaining adequate tissue volume during soft-tissue transfer on either side of the mesh plate may minimize the complication rate. Titanium mesh implantation for skeletal reconstruction after maxillectomy avoids the need for bone grafting and may be especially beneficial in fragile or aged patients.

Distinct phenotypes of speech and voice disorders in Parkinson's disease after subthalamic nucleus deep brain stimulation

Objectives To elucidate the phenotypes and pathophysiology of speech and voice disorders in Parkinsons disease (PD) with subthalamic nucleus deep brain stimulation (STN-DBS). Methods We conducted a cross-sectional study on 76 PD patients treated with bilateral STN-DBS (PD-DBS) and 33 medically treated PD patients (PD-Med). Speech and voice functions, electrode positions, motor function and cognitive function were comprehensively assessed. Moreover, speech and voice functions were compared between the on-stimulation and off-stimulation conditions in 42 PD-DBS patients. Results Speech and voice disorders in PD-DBS patients were significantly worse than those in PD-Med patients. Factor analysis and subsequent cluster analysis classified PD-DBS patients into five clusters: relatively good speech and voice function type, 25%; stuttering type, 24%; breathy voice type, 16%; strained voice type, 18%; and spastic dysarthria type, 17%. STN-DBS ameliorated voice tremor or low volume; however, it deteriorated the overall speech intelligibility in most patients. Breathy voice did not show significant changes and stuttering exhibited slight improvement after stopping stimulation. In contrast, patients with strained voice type or spastic dysarthria type showed a greater improvement after stopping stimulation. Spastic dysarthria type patients showed speech disorders similar to spastic dysarthria, which is associated with bilateral upper motor neuron involvement. Strained voice type and spastic dysarthria type appeared to be related to current diffusion to the corticobulbar fibres. Conclusions Stuttering and breathy voice can be aggravated by STN-DBS, but are mainly due to aging or PD itself. Strained voice and spastic dysarthria are considered corticobulbar side effects.

The Feasibility Study of Docetaxel in Patients with Anaplastic Thyroid Cancer

There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.

Swallowing Function Following Extensive Resection of Oral or Oropharyngeal Cancer With Laryngeal Suspension and Cricopharyngeal Myotomy

Objective: To investigate factors that influence postoperative swallowing function in patients who underwent tongue and oropharynx resection.

Non-Engineered, Naturally Oncolytic Herpes Simplex Virus HSV1 HF-10:Applications for Cancer Gene Therapy

Oncolytic HSV-1 has been developed as a novel anticancer agent. According to the properties and functions of HSV-1 encoded proteins, several genes have been targeted for engineering of oncolytic HSV-1. As a result, a variety of strategies have been applied to the engineering of oncolytic HSV-1. Success in cancer therapy for solid tumors requires a maximal oncolytic effect; however, recombinant HSV-1 that has been adapted to meet neurotoxicity requirements for the treatment of brain tumors may be too highly attenuated for effective use in solid tumors outside the brain. Recently, there has been renewed interest in the high potency of naturally oncolytic viruses. In this review, we will overview the engineered oncolytic HSV developed thus far, as well as its mechanism of selectivity and its mode of spreading within tumors. We also discuss the preclinical and clinical studies of HF-10, a non-engineered oncolytic HSV-1 virus, and its potential for use in cancer gene therapy.

Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte–macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus

Direct viral infection of solid tumors can cause tumor cell death, but these techniques offer the opportunity to express exogenous factors to enhance the antitumor response. We investigated the antitumor effects of a herpes simplex virus (HSV) amplicon expressing mouse granulocyte–macrophage colony-stimulating factor (mGM-CSF) using the replication-competent HSV type 1 mutant HF10 as a helper virus. HF10-packaged mGM-CSF-expressing amplicon (mGM-CSF amplicon) was used to infect subcutaneously inoculated murine colorectal tumor cells (CT26 cells) and the antitumor effects were compared to tumors treated with only HF10. The mGM-CSF amplicon efficiently replicated in CT26 cells with similar oncolytic activity to HF10 in vitro. However, when mice subcutaneously inoculated with CT26 cells were intratumorally injected with HF10 or mGM-CSF amplicon, greater tumor regression was seen in mGM-CSF amplicon-treated animals. Furthermore, mGM-CSF amplicon treatment prolonged mouse survival. Immunohistochemical analysis revealed increased inflammatory cell infiltration in the solid tumor in the mGM-CSF amplicon-treated animals. These results suggest that expression of GM-CSF enhances the antitumor effects of HF10, and HF10-packaged GM-CSF-expressing amplicon is a promising agent for the treatment of subcutaneous tumors.