Boron neutron capture therapy using cyclotron-based epithermal neutron source and borofalan (10B) for recurrent or locally advanced head and neck cancer (JHN002): An open-label phase II trial.

BACKGROUND AND PURPOSE: Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (10B) for recurrent or locally advanced head and neck cancer. MATERIALS AND METHODS: In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (10B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (10B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS). RESULTS: Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4-76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%). CONCLUSION: These data suggest that BNCT using C-BENS with borofalan (10B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.

Long-Term Efficacy and Dose-Finding Trial of Japanese Cedar Pollen Sublingual Immunotherapy Tablet.

BACKGROUND: Japanese cedar (JC) pollinosis is a common allergic rhinitis in Japan. The JC pollen sublingual immunotherapy (SLIT) tablet was developed using the highest concentration of JC pollen extract. OBJECTIVE: This was a randomized, double-blind, placebo-controlled phase II/III trial to investigate the optimal dose of the JC pollen SLIT tablet and examine long-term efficacy and safety for 3 years with the selected dose, and 2-year follow-up. METHODS: A total of 1042 patients with JC pollinosis (aged 5-64 years) were equally randomized into 4 groups and received daily treatment with 2,000, 5,000, or 10,000 Japanese allergy unit (JAU) or placebo. The primary end point was the total nasal symptom and medication score (TNSMS) during the peak symptom period in the first season. Key secondary end points were TNSMS for the JC pollen dispersion season and total nasal and ocular symptom and medication score for the peak symptom period and JC pollen dispersion season. RESULTS: For the primary end point, absolute reductions and relative mean reductions in TNSMS compared with placebo were 1.50 and 21.4%, 2.24 and 32.1%, and 2.18 and 31.2% for 2,000, 5,000, and 10,000 JAU, respectively (P < .001 in all groups). For all key secondary end points, efficacy was confirmed for all doses (P < .001 in all groups). The treatment was well tolerated. Long-term efficacy of 5,000 JAU was shown over the 3 years. CONCLUSIONS: The optimal dose of the JC pollen SLIT tablet was 5,000 JAU, with good efficacy and safety over a 3-year treatment period. This sustained effect was dependent on treatment duration.

[INVESTIGATION OF TREATMENT GOAL IN ALLERGEN IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS].

BACKGROUND/OBJECTIVE: As few reports are available on treatment goal for Japanese cedar pollinosis treated with allergen immunotherapy, therapeutic effect has to be assessed based on subjective symptoms in clinical practice. This research was conducted to investigate the informative treatment goal in clinical practice by using the results of TO-194SL phase III clinical trial. METHODS: In this investigation, correlation between total nasal symptom medication score (TNSMS), which was predefined as the primary endpoint, and secondary endpoints evaluated by severe symptom day, quality of life (QOL) score, and overall evaluation by subject, was firstly investigated. Based on the results, stratified analyses of the secondary endpoints to confirm relationships on the stratified results, TNSMS, and cedar season were performed. RESULTS: Correlation between TNSMS and evaluations which were severe symptom day, QOL score, and overall evaluation by subject was reasonably observed. TNSMS generally showed 3 or below (classified as mild) throughout the entire pollen season when these evaluations reached each threshold. CONCLUSIONS: The results of this investigation suggest that a few evaluation items would help patients to realize the therapeutic effects of allergen immunotherapy if they could be the treatment goal in clinical practice.

An analysis of factors related to the effect of sublingual immunotherapy on Japanese cedar pollen induced allergic rhinitis.

BACKGROUND: Sublingual immunotherapy (SLIT) can improve the symptoms of allergic rhinitis and modify its natural history; however, its efficacy varies among patients. This study aimed to determine which factors modify the effect of SLIT through post hoc analysis of a previous phase 3 trial of standardized Japanese cedar (JC) pollen extract (CEDARTOLEN®). METHODS: The study included 482 patients who had previously completed a phase 3 trial during two seasons. The SLIT and placebo groups each contained 241 subjects. Because pollen dispersal differed in the two seasons, we identified good and poor responders from the SLIT group in the 2nd season. We compared patient baseline characteristics, changes in serum immunoglobulin, and severity of symptoms in the 1st season between good and poor responders, as well as between SLIT and placebo groups. RESULTS: When we compared the baseline characteristics of good and poor responders, a significant difference was observed in body mass index (BMI) such that the patients with BMI ≥25 presented with lower treatment efficacy. No significant difference was observed in correlation with any other factors or treatment-induced alterations of serum immunoglobulin levels. We found that 75.3% of the patients with moderate symptoms and 50.9% of the patients with severe or very severe symptoms in the 1st season met our criteria for good responders in the 2nd season. CONCLUSIONS: BMI might modify the effect of SLIT; however, other factors were not related clearly. The severity of symptoms in the 1st season of treatment does not predict that in the 2nd season.

Surgical management of symptomatic ossified anterior longitudinal ligament: A case report.

BACKGROUND: Ossified anterior longitudinal ligament (OALL) of the cervical spine can cause dysphagia, dyspnoea, and dysphonia, although these symptoms are rare. CASE DESCRIPTION: A 71-year-old male presented with gradually progressive dysphagia secondary to OALL. He underwent fiber optic endoscopy and lateral video fluoroscopy. The OALL extended from C4 to C7 and contributed to significant compression of the pharynx as demonstrated on plain cervical radiography, magnetic resonance (MR) imaging, and computed tomography (CT). Following microsurgical resection of the OALL, his symptoms improved. CONCLUSIONS: This study focuses on the clinical and radiographic presentation of OALL; the latter utilizing plain X-rays, MR, and CT studies. Notably, surgical resection is straightforward and allows for immediate decompression of the pharynx as long as it is truly the symptomatic problem.

Efficacy and safety of the SQ house dust mite sublingual immunotherapy tablet in Japanese adults and adolescents with house dust mite-induced allergic rhinitis.

BACKGROUND: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT) tablet has been approved in 11 European countries and Japan for patients with HDM-induced respiratory allergic disease. OBJECTIVE: This trial was conducted to confirm the efficacy and safety of the SQ HDM SLIT tablet in Japanese patients with moderate-to-severe HDM-induced allergic rhinitis (AR). METHODS: The trial was a randomized, double-blind, placebo-controlled trial including 946 Japanese adults and adolescents (12-64 years). Subjects were randomly assigned to daily treatment with the SQ HDM SLIT tablet at a dose of 10,000 Japanese allergy units (JAU) or 20,000 JAU or to placebo (1:1:1). The primary end point was the total combined rhinitis score (TCRS), which is composed of AR symptom and medication scores during the efficacy evaluation period. Symptom and medication scores of AR and conjunctivitis, rhinitis quality of life, and symptom-free and symptom-severe days were evaluated as secondary end points. RESULTS: Analysis of the primary end point demonstrated statistically significant reductions in TCRSs of 1.15 (22%, P < .001) in the 10,000-JAU group and 0.99 (19%, P < .001) in the 20,000-JAU group compared with the placebo group. The statistically significant treatment effect was evident from 12 weeks of treatment onward. All secondary end points, except AR medication score, were statistically significant in favor of active treatment compared with placebo. Post hoc analysis of TCRSs in adolescents showed the same efficacy as in adults (P < .05). The treatment was well tolerated by both adults and adolescents. CONCLUSION: The trial confirmed the efficacy and safety profile of the SQ HDM SLIT tablet in Japanese adult and adolescent patients with moderate-to-severe HDM-induced AR. These data support the robust efficacy and safety profile of previously reported European data.

[A Clinical Study of a Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma of Salivary Glands].

Malignant lymphoma involving the salivary glands is a rare entity that accounts for only 1 to 4% of all salivary gland tumors. We have analyzed the clinical features of MALT lymphoma of the salivary glands in 7 patients whom we have treated in the past 10 years, including data from 43 patients in the literature. The most common symptom was persistent or progressive swelling of the salivary glands without pain or facial palsy. The affected glands were the unilateral parotid in 62%, the unilateral submandibular gland in 6.8%, and the bilateral parotid or submandibular gland in 6.8%. The salivary gland swelling as evaluated by MRI or ultrasonography consisted of a localized solitary tumor in 68.9%, multiple tumors in 10.3%, and diffuse swelling of the gland in 26.1%. In 24 out of 50 patients, MALT lymphoma developed on the basis of Sjögren's syndrome. As for diagnosis, malignant lymphoma was suspected only in 4 cases out of 11 (36.7%) based on the fine needle aspiration cytology. In all patients, a definitive diagnosis was obtained based on histopathological study of the localized tumor or the biopsy specimens. When patients with Sjögren's syndrome have developed persistent swelling of the salivary glands, it is necessary to rule out malignant lymphomas, especially MALT lymphoma, by combination of ultrasonography, MRI, FNA, and biopsy or open surgery depending on image findings. The treatment of MALT lymphoma has not yet been standardized because MALT lymphoma is a rare entity. The choice of initial treatment is important because it is related to its prognosis. If MALT lymphoma remains in a local site, we should undertake an operation or radiotherapy. If MALT lymphoma has dissemineated systemically, we should choose chemotherapy.

Efficacy and safety of sublingual immunotherapy for two seasons in patients with Japanese cedar pollinosis.

BACKGROUND: Japanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Standardized JC pollen extract is available for subcutaneous immunotherapy, but this treatment is limited by potentially serious side effects. The aim of this double-blind, randomized comparative study was to evaluate the efficacy and safety of standardized JC pollen extract in a new oral formulation (CEDARTOLEN®, Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for sublingual immunotherapy (SLIT) for JC pollinosis. METHODS: A total of 531 subjects with JC pollinosis were randomized into 2 groups at a ratio of 1:1 to receive daily sublingual administration of standardized JC pollen extract with a maintenance dose of 2,000 Japanese allergy units (JAU) or placebo for 2 consecutive pollen seasons. The efficacy was evaluated using the total nasal symptom and medication score (TNSMS) as the primary end point. Secondary end points included the total ocular symptom and medication score (TOSMS) and scores for individual symptoms and medication. RESULTS: The TNSMS was significantly lower (p < 0.0001) in the SLIT group than in the placebo group in the peak symptom period by 18 and 30% in the first and second seasons, respectively. All secondary end points were also significantly lower in the SLIT group in both seasons. No systemic anaphylaxis occurred. CONCLUSIONS: SLIT with daily administration of standardized JC pollen extract was effective for improving nasal and ocular symptoms of JC pollinosis and reducing the use of relief medication. The JC pollen extract was well tolerated with only local adverse events.

[A Clinical Study of the Sclerotherapy for Large Venous Malformations of the Pharyngolarynx with Airway Stenosis].

We treated four cases of airway stenosis associated with large venous malformations of the pharyngolarynx. The patients ranged in age from 33 to 53 years, and consisted of one male and three females. The venous malformation was located in the posterior wall of the oropharynx in two cases, in the hypopharynx in. one case, and in the anterior wall of the oropharynx in one case. All the patients complained of shortness of breath upon adopting the supine position. The patients were tracheotomized under general anesthesia and treated by sclerotherapy under videolaryngoscopic guidance. We used absolute ethanol, polidocanol or monoethanolamine oleate, as appropriate, depending on the case. In regard to the efficacy of the sclerotherapy, the venous malformation disappeared in one case and reduced in size in the remaining three cases, and no severe adverse events were recognized in any of the cases. All the patients were discharged from the hospital within two weeks and did not need tracheostomy. Sclerotherapy umder videolaryngoscopic guidance is effective for the treatment of large venous malformations in the pharyngolarynx.

[The efficacy of superselective intra-arterial chemo-radiotherapy for cervical neck lymph node metastases].

We report herein on 32 cases of head and neck carcinoma with cervical lymph node metastases treated by radiotherapy and concomitant intraarterial cisplatin (RADPLAT) from April 2009 to May 2013. N3 cases revealed residual disease of the cervical lymph nodes in 7/9 cases. Among the 22 patients excluding N1 and N3 cases, the pathological CR rate was 63.6%. Among the 13 patients in whom the anticancer drug was directly infused into the cervical lymph nodes, the pathological CR rate was 76.9%, whereas in the 9 patients without direct infusion of the cervical lymph nodes, the pathological CR rate was 44.4%. Therefore, we recommend the direct infusion into cervical lymph node metastases for not only N3 cases but also N2 cases if a feeding artery is identified easily. When clinical examination after RADPLAT leads to suspected residual disease, neck dissection should be adapted. If the clinical examination leads to a diagnosis of CR, we recommend a biopsy of the original cervical lymph nodes because the cases which we diagnosed as CR revealed residual disease of the cervical lymph nodes in 4/16.

[Four cases of extracranial trigeminal benign neurogenic tumors].

Extracranial trigeminal schwannomas are rare tumors accounting for about 10% of all trigeminal schwannomas. We report herein on four cases of extracranial trigeminal benign neurogenic tumors. The patients were aged between 39 and 75 years; they consisted of one male and three females. The origins of the schwannomas consisted of the maxillary nerve in two cases and the mandibular nerve in two cases. All cases were surgically treated using a transmaxillary approach in three cases, and a combination of the transcervical-parotid approach with a midline mandibulotomy in one case. In two cases, the schwannomas located in the pterygopalatine fossa were removed using a transmaxillary approach with the endoscope and the surgical microscope. Two patients underwent selective intravascular embolization of the feeding artery to reduce intraoperative bleeding, and they were less invasively treated via the transmaxillary approach.

[A clinical study on 8 cases of sarcoidosis with a cervical mass as a symptom].

Sarcoidosis is a multiorgan granulomatous disease of unknown origin, which frequently involves the lung and the eyes. It is rare that sarcoidosis causes cervical lymphadenopathy and a chronic continuous salivary gland swelling. In the present study, we examined how to diagnose sarcoidosis in patients complaining of a cervical mass and its clinical presentation according to 8 cases which we experienced. We undertook biopsy of the cervical lymph nodes in 7 cases, and biopsy of the parotid gland in 1 case. In cases non-caseating epithelioid cell granuloma was proved, diagnosed as sarcoidosis histopathlogically. In 6 patients, the sarcoidal lesion was in other organs, whereas in 2 patients the sarcoidal lesion was confined in the head and neck. Bilateral hilar lymphadenopathy and an elevated level of angiotensin-converting enzyme which are typical in sarcoidosis were confirmed in only one of our patients. Therefore, the diagnostic value of these tests is low for the diagnosis of sarcoidosis in the patients whose chief complaint is a cervical mass. Because 4 out of 7 cases were positive for the tuberculin test, it is imperative to distinguish between sarcoidosis and cervical tuberculous lymphadenitis by combining the culture of acid-bacilli and TB-PCR with histopathological evaluation of the biopsy specimen. We experienced one patient in whom the sarcoidal lesion developed in the skin and the eyes 20 years after the onset of cervical lymphadenopathy. It is important to follow the patients carefully, even if we diagnose the disease as sarcoidosis confined in the head and neck.

[A clinical study on 10 cases of cervical tuberculous lymphadenitis].

Cervical tuberculous lymphadenitis is sometimes difficult to differentiate from sarcoidosis. We treated 10 patients with cervical tuberculous lymphadenitis from April 2002 to December 2011. Their ages ranged from 42 to 78 years old (mean 63.2 years), and the male-to-female ratio was 4: 6. All patients presented to our hospital with the chief complaint of a cervical mass. All patients underwent open biopsy of the cervical lymph nodes, and 8 patients were diagnosed histopathologically as having cervical tuberculous lymphadenitis. In the remaining 2 patients, caseous necrosis could not be recognized histopathologically and they were diagnosed as having sarcoidosis. However 8 weeks later, the culture of the acid-fast bacilli turned positive, and the diagnosis was corrected to cervical tuberculous lymphadenitis. In our cases, the culture of acid-fast bacilli was positive in 6 out of 9 cases (66.7%), and TB-PCR was positive in 4 out of 9 cases (44.4%). These results show that sensitivity of individual tests is rather low. For the diagnosis of cervical tuberculous lymphadenitis, it is important to suspect this disease from the findings of the sedimentation rate, tuberculin test, and ultrasonography with fine needle aspiration cytology. On performing an open biopsy of the cervical lymph nodes in the suspected patients, it is essential to combine histopathological study, TB-PCR and the culture of the acid-fast bacilli simultaneously.

[Two cases of spontaneous cerebrospinal fluid (CSF) otorrhea with meningitis].

We report on two cases of spontaneous CSF otorrhea, which were considered to have been caused by enlarged arachnoid granulation with bone erosion of the posterior fossa. Both cases visited us complaining of severe headache, due to bacterial meningitis. In the first patient, a 68-year-old male, a high resolution CT scan showed a bony defect in the posterior fossa plate in the right temporal bone, where CSF leakage was confirmed during the operation. In the second patient, a 54-year-old female, a bony defect was located in the posterior fossa in the left temporal bone. In both cases, the bony defects were repaired by occlusion with the pedicled temporal muscles after the meningitis had been treated. CSF otorrhea disappeared after the surgery, and has not recurred during the postoperative observation period of 1 to 3 years.

Effects of aging on the natural history of seasonal allergic rhinitis in middle-aged subjects in South chiba, Japan.

BACKGROUND: The natural history of allergic rhinitis has been examined in a few longitudinal studies. The purpose of the study was to investigate the course, development and remission of seasonal allergic rhinitis (SAR) over 10 successive years in middle-aged subjects. METHODS: An annual questionnaire survey on allergic rhinitis symptoms combined with an examination of specific IgE has been undertaken in a rural town in south Chiba since 1995. The analyzed subjects were 703 residents who underwent every examination in 1995, 2004 and 2005. In the last 15 years, the annual pollen count in Chiba was highest in 2005. RESULTS: The sensitization rates to cedar pollen decreased with age in the same subject groups over 10 years, but the prevalence of SAR was higher in 2005 compared with 1995. Of the 52 subjects with SAR in 1995, the symptoms had disappeared in 10 subjects in 2005. Specific IgE had converted to negative or borderline in 4 of these patients, had decreased but was still positive in 4 and was increased or unchanged in 2. During the 10-year period, 22 subjects developed SAR, of whom 12 had increased specific IgE and 10 had similar or decreased specific IgE in 2005. CONCLUSION: SAR induced by cedar pollen takes a chronic course in the majority of middle-aged patients in south Chiba, Japan. The prevalence of SAR increased over 10 years due to a high level of pollen exposure. Changes in specific IgE were not directly associated with the development or remission of SAR.

The influence of environmental exposure to formaldehyde in nasal mucosa of medical students during cadaver dissection.

BACKGROUND: Environmental exposure to formaldehyde is commonly associated with clinical symptoms such as mucosal irritation and olfactory disorders. However, the impact of such exposure on the development of mucosal inflammation and its outcome has not been carefully evaluated. METHODS: The observational non-comparative study was planned. The study population consisted of group of 41 medical students who had signed up for a cadaver dissection course as part of their gross anatomy teaching at the school of medicine Chiba University in Japan. During such dissection course, the students are exposed to variable levels of environmental formaldehyde routinely employed for the preservation the cadavers. The subjects were evaluated by a detailed medical examination. We measured their serum IgE levels. In addition, an olfaction test and nasal mucosal sensitivity to histamine was serially determined, immediately before and after the course and 6 months after the completion of the course. RESULTS: Olfactory abnormalities were observed in 13/41 (32%) subjects and increased nasal mucosal hypersensitivity to histamine was observed in 17/41 (41%) during and immediately after completion of the course. These subjects had evidence of preexisting allergic rhinitis. 6/41 (15%) other students with no prior evidence of allergic rhinitis also exhibited formaldehyde associated clinical symptoms during the dissecting course. However, the symptoms disappeared upon completion of the course in all subjects studied. CONCLUSIONS: Temporary abnormalities in the olfaction test and increased nasal mucosal hypersensitivity to histamine were observed in a few students with preexisting allergic rhinitis after environmental exposure of high concentrations of formaldehyde. These effects appeared to be transient.

Historical, pathophysiological, and therapeutic aspects of vidian neurectomy.

Vidian neurectomy yields dramatic relief of nasal hypersecretion in patients with allergic rhinitis. Clinical studies conducted on vidian neurectomized nasal mucosa have shown that nasal hypersecretion observed after challenging the nasal mucosa with antigen is caused by reflexively induced activation of the parasympathetic center secondary to stimulation of the sensory nerve terminals in the nasal mucosa by histamine. On the contrary, nasal mucosal swelling is caused mostly by the direct effects of chemical mediators on the nasal vasculature, although vascular reflex mediated by the noncholinergic parasympathetic nerve may be partially involved in the onset of nasal mucosal swelling after antigen challenge. Considering the long-term side effects of inhibition of lacrimation and possible partial recurrence of hyperreactive nasal symptoms observed after vidian neurectomy, less invasive endoscopic posterior nasal neurectomy is considered the treatment of choice for patients with allergic rhinitis who require surgical intervention.