Dodecaborate Conjugates Targeting Tumor Cell Overexpressing Translocator Protein for Boron Neutron Capture Therapy.

We developed novel closo-dodecaborate ([B12H11]2-) anion-containing translocator protein (TSPO) ligand as a boron carrier for boron neutron capture therapy. This compound shows high water solubility and can deliver boron to TSPO highly expressed in breast cancer cells. We describe the synthesis and in vitro evaluation of a dodecaborate-based pyrazolopyrimidine.

Change in smoking cessation stage over 1 year in patients with schizophrenia: a follow up study in Japan.

BACKGROUND: We performed a follow up study about willingness and behaviors to quit smoking among smokers with schizophrenia in Japan. METHODS: Participants were outpatients with schizophrenia aged 20-69 years who had been visiting the hospital for ≥1 year as of April 1, 2016, and had visited the hospital more than once in the previous 6 months. A baseline survey on smoking behaviors including current smoking status and smoking cessation stage, was administered in 420 participants that were randomly extracted from a patient pool (n = 680) in 2016, and a follow-up survey was administered in 2017. We calculated the distribution and change in smoking cessation stage, number of smokers and nonsmokers after 1 year, and quitting rate from a naturalistic 1-year smoking-cessation follow up. RESULTS: The number of baseline respondents was 350; 113 current smokers and 68 former smokers. Among the 113 current smokers, 104 (92.0%) were followed for 1 year, 79 (70.0%) were interested in smoking cessation, and only 7 had received smoking cessation treatments at baseline. Among the tracked 104 participants, only 6 (5.8%) stopped smoking after 1 year. Among the 25 participants who had intentions to quit smoking within 6 months at baseline, 6 (24.0%) maintained their intention to quit smoking for 1 year, and 16 (64.0%) did not maintain their intention to quit smoking. CONCLUSIONS: Our findings showed that many smokers with schizophrenia were interested in quitting smoking, but few patients received treatment and actually quit smoking. Timely intervention, including the option to receive smoking cessation treatment, is necessary for those patients with schizophrenia who smoke. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000023874, registered on August 31, 2016).

Case of ovarian hyperstimulation and oocyte pick-up during very early period of unnoticed pregnancy followed by ongoing normal pregnancy.

We report a case of unnoticed pregnancy that was maintained during low estrogen and progesterone circumstances, that showed menses-like bleeding, and was then discovered after ovarian hyperstimulation during the next period. The patient was 39 years old and primigravid. She underwent intrauterine insemination, followed by luteal support with human chorionic gonadotrophin and progestin; however, she experienced menstruation-like bleeding 15 days later. As low estradiol and progesterone levels were confirmed on the 2nd day of bleeding, ovarian hyperstimulation of short protocol for in vitro fertilization was commenced. Although 13 mature follicles were observed, only six oocytes were retrieved and one developed into a blastocyst. Four days after oocyte pick-up, a gestational sac was seen in utero. The fetus is currently growing uneventfully. This case suggests that pregnancy can be maintained during ovarian hyperstimulation, even if menstruation-like bleeding is shown in low-progesterone circumstances.

Detection of boronic acid derivatives in cells using a fluorescent sensor.

The detection of boron-containing compounds requires very expensive facilities and/or tedious sample pretreatments. In an effort to develop a convenient detection method for boronic acid derivatives, boron chelating-ligands were synthesized for use as fluorescent sensors. In this paper, the synthesis and properties of fluorescent sensors for boronic acid derivatives are reported.

Synthesis and in vitro evaluation of thiododecaborated α, α- cycloalkylamino acids for the treatment of malignant brain tumors by boron neutron capture therapy.

Boron-neutron capture therapy (BNCT) is an attractive technique for cancer treatment. As such, α, α-cycloalkyl amino acids containing thiododecaborate ([B12H11](2-)-S-) units were designed and synthesized as novel boron delivery agents for BNCT. In the present study, new thiododecaborate α, α-cycloalkyl amino acids were synthesized, and biological evaluation of the boron compounds as boron carrier for BNCT was carried out.

Japanese Guideline for Allergic Rhinitis 2014.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 7th edition was published in 2013, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2013. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Role of cytokines in lavage or drainage fluid after hemithyroidectomy in wound healing: involvement of histamine in the acceleration and delay of wound healing.

Wound healing is a sophisticated biologic process. In the case of hemithyroidectomy, the operation time is relatively short with small tissue damage and without skin excision, and bacterial contamination before, during, and after the operation is uncommon. Here, we explored which cytokine(s) affected the rates of healing of skin wounds after hemithyroidectomy of 29 patients. We assessed the amounts of cytokines (e.g., interleukin-6, platelet-derived growth factor, basic fibroblast growth factor, vascular endothelial growth factor, and tumor necrosis factor-α) in either the preoperative or postoperative lavage fluids, or in the drainage fluids on postoperative days (PODs) 1-8. All of these cytokines showed a similar pattern; after reaching a peak on POD1, the production fell sharply on POD2-8, revealing that wound healing commenced on POD1. The rates of wound healing were inversely related to the levels of histamine in six patients (i.e., those with the three largest and those with the three smallest total volumes of drainage fluid on POD1): high (or low) levels of histamine in the postoperative lavage fluids with low (or high) levels in the drainage fluids on POD1 caused earlier (or the delay of) wound healing, suggesting involvement of histamine in the acceleration and delay of wound healing.

Essential role of macrophages in the initiation of allergic rhinitis in mice sensitized intranasally once with cedar pollen: regulation of class switching of immunoglobulin in B cells by controlling interleukin-4 production in T cells of submandibular lymph nodes.

The production of allergen-specific IgE antibodies (Abs) in allergen-sensitized patients or animals has a mutual relationship with the immunologic response leading to allergic rhinitis. We recently reported that, after an intranasal injection of cedar pollen into mice, an interleukin-4 (IL-4)-dependent increase in serum nonspecific IgE Abs was a prerequisite for the production of serum allergen-specific IgE Abs. Here, we explored which lymphoid organs were responsive to the intranasally injected allergen and how IL-4 and IgE Abs were produced in the lymphocytes. Time-dependent changes in the total cell numbers and in in vitro IgE Ab production in various lymphoid organs revealed that the submandibular lymph nodes were the main responsible organ. After treatment with allergen (for IgE production) or allergen and complete Freund's adjuvant (for IgG production), we separated submandibular lymph node cells into macrophage-, lymphocyte-, and granulocyte-rich populations by discontinuous Percoll density-gradient centrifugation. Unexpectedly, bulk cells, but not the lymphocyte- or macrophage-rich populations, produced significant amounts of IL-4, IgE, and IgG; whereas production was restored by addition of Mac-1(+) cells from the macrophage-rich to the lymphocyte-rich fraction. Furthermore, a combination of the lymphocyte-rich population (for IgG [or IgE]) production) and the macrophage-rich population (for IgE [or IgG]) production) produced a large amount of IgE (or IgG). These results indicate that, in the initiation of allergic rhinitis, macrophages in the submandibular lymph nodes are essential not only for IL-4 or immunoglobulin production, but also for class switching of immunoglobulin in lymphocytes.

Clinical epidemiological study of 553 patients with chronic rhinosinusitis in Japan.

BACKGROUND: The relationship between chronic rhinosinusitis (CRS) and asthma has been known for a long time. However, no large studies on the relationship between CRS and lower airway diseases have been reported to date in Japan. Additionally, eosinophilic chronic rhinosinusitis (ECRS) in Japan is considered to be a subgroup of CRS with nasal polyps (CRSwNP) characterized by eosinophil-dominant inflammation. However, the diagnostic criteria of ECRS have not been established. METHODS: To investigate clinical and epidemiological features of patients with CRS from the aspect of their associations with lower airway diseases, 553 patients with CRS who visited one of six local university hospitals were examined and interviewed. Local eosinophilic infiltration was evaluated pathologically by examining NPs. RESULTS: The prevalences of olfactory dysfunction (OD) in the patients with nasal polyps (NPs) and those without NPs were 57.0% and 13.7%, respectively (p < 0.0001). The prevalence of asthma in all patients was 23.1%. Furthermore, the prevalences of NPs and OD in the patients with asthma and those without asthma were 81.0% and 50.1% (p < 0.0001) and 64.2% and 35.7% (p < 0.0001), respectively. 97.4% of the patients with asthma had ≥ 15% mucosal eosinophils, and 87.9% of the patients without asthma had <15% mucosal eosinophils. CONCLUSIONS: Similar to the relationship between nasal allergy and asthma, CRSwNP may be applicable to the concept of "one airway, one disease".

Interleukin-19 downregulates interleukin-4-induced eotaxin production in human nasal fibroblasts.

BACKGROUND: Interleukin-19 (IL-19), a member of the IL-10 family, is characterized as the cytokine suppressing the release and function of several proinflammatory cytokines. For regulation of local reaction in allergic rhinitis (AR), IL-19 might play an especially important role. METHODS: We examined effects of IL-19 on IL-4-induced eotaxin production by human nasal fibroblasts. Early receptor-mediated events (expression of the suppressors of cytokine signaling (SOCS) and phosphorylation of signal transducer and activator of transcription 6 [STAT6]) by IL-19 was examined. Knockdown methods by RNAi were administered to investigate the involvement of those signal transductions. RESULTS: Pretreatment with IL-19 downregulates IL-4-induced eotaxin production, but not interferon-γ(IFN-γ)-induced RANTES. Pretreatment with IL-19 suppressed the IL-4-induced STAT6 phosphorylation. The IL-19 induced SOCS-1, but not SOCS-3 or SOCS-5. The SOCS-1 knockdown by RNAi diminished pretreatment with IL-19-induced down-regulation of eotaxin production. CONCLUSIONS: These results suggest that IL-19 down-regulates IL-4-induced eotaxin production via SOCS-1 in human nasal fibroblasts. In non-hematopoietic cells in AR, IL-19 might be an immunosuppressive factor.

Expression of cyclooxygenase-2 and microsomal prostagalandin E synthase-1 in head and neck squamous cell carcinoma.

OBJECTIVE: Our aim was to examine the expression of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1), and compare the results with clinical data. PATIENTS AND METHODS: Expression of COX-1, COX-2, and mPGS-1 was evaluated by immunohistochemistry in head and neck squamous cell carcinoma (HNSCC) from 25 patients and mRNA levels were determined by the quantitative reverse transcription polymerase chain reaction. RESULTS: COX-2 overexpression was noted in tumor cells from 19 of the 25 carcinoma patients and mPGES was expressed by tumor cells from 21 patients. Localization of COX-2 and mPGES-1 was very similar, and well-differentiated tumors showed stronger expression than poorly/moderately differentiated tumors. The COX-2/GAPDH and mPGES/GAPDH mRNA ratios were significantly higher in well-differentiated carcinomas and N0 patients. CONCLUSIONS: There was overexpression of COX-2 and its downstream enzyme mPGES-1, and their localization in tumor cells was similar, suggesting that these enzymes play both an important role in the development and proliferation of HNSCC. Furthermore, COX-2 and mPGES-1 were strongly expressed by well-differentiated carcinomas, suggesting their involvement in the differentiation of cancer.

Indication for elective neck dissection for N0 carcinoma of the parotid gland: a single institution's 20-year experience.

CONCLUSIONS: Elective neck dissection (END) may not be necessary in patients with low-grade malignancy. However, currently, END should be performed in all patients with parotid carcinoma because the preoperative diagnosis of lymph node metastasis is limited and the accuracy of preoperative grade diagnosis is low. OBJECTIVE: Our aim was to examine the indication for END in N0 patients and the extent of dissection by investigating the accuracy of diagnosing the grade and lymph node metastasis of parotid carcinoma. PATIENTS AND METHODS: The subjects were 77 patients with parotid carcinoma. Among N0 patients, modified radical neck dissection (MRND) was conducted in those in whom the histological grade was evaluated as high, and selective neck dissection (SND) in other patients. RESULTS: Lymph node metastasis was detected in 27 of 71 patients who underwent neck dissection. Node metastasis was detected in 19 (61.3%) of 31 patients in whom high-grade malignancy was suggested and in 8 (22.9%) of 35 patients in whom intermediate-grade malignancy was suggested preoperatively. There was no metastasis in any of the five patients in whom low-grade malignancy was suggested. Occult metastasis was noted in 8 of 51 patients. The rate at which the histological grade was accurately diagnosed before surgery was low, especially in patients with low-grade malignancy.

Basal cell adenoma of the parotid gland: a clinicopathological study of nine cases--basal cell adenoma versus pleomorphic adenoma and Warthin's tumor.

The aim of this study is to investigate the clinical and pathological characteristics of basal cell adenoma (BCA) and to compare the diagnosis/treatment of BCA with those of Warthin's tumor (WT) and pleomorphic adenoma (PA). Among 192 patients with benign tumors of the parotid gland who underwent surgery, 9 had BCA. All of these tumors showed a benign pattern on computed tomography and magnetic resonance imaging. The accuracy of fine needle aspiration biopsy (FNAB) for diagnosis of BCA was slightly lower than for PA and WT. Most PA and BCA lesions developed in the upper part of the parotid gland. Considering the gender difference, tumor site, and age, it is necessary to differentiate BCA from PA rather than from WT. There were no significant differences in the duration of surgery, the blood loss, and the incidence of transient facial paralysis between surgical resection of BCA and surgery for PA or WT. BCA is the third most common of the benign parotid tumors, following WT and PA, although its incidence is low. When PA and WT are ruled out by FNAB after a tentative diagnosis of benign tumor has been based on imaging findings, BCA should be considered.

Diagnostic criteria of ultrasonographic examination for lateral node metastasis of papillary thyroid carcinoma.

CONCLUSION: Considering the incidence of metastasis from papillary thyroid carcinoma (PTC) with respect to the lateral cervical regions and limited detection on preoperative ultrasonography (US), level II to IV dissection may be essential when lateral node metastasis (LNM) is detected on preoperative US. OBJECTIVES: LNM is frequent in patients with PTC. However, a consensus regarding its preoperative diagnosis and the indication/extent of lateral node dissection (LND) has not been reached. We prepared criteria for diagnosing LNM from PTC using US. Furthermore, we investigated the usefulness and limits of US and appropriate extent of dissection. PATIENTS AND METHODS: We conducted a retrospective study in 70 patients with PTC (80 sides) in whom LNM was detected preoperatively, and level II to V LND was performed. We compared the results of the preoperative diagnosis of LNM using US in accordance with the criteria with those of histopathological diagnosis after LND. RESULTS: Diagnostic criteria for LNM were a minor axis of 6 mm or more and a minor/major axis ratio of 0.5 or more. Histopathologically, metastasis was detected in 467 lymph nodes. Of these, 199 (43%) were detected on US, and met the diagnostic criteria.

Endoscopy-assisted surgery with topical mitomycin for a cholesterol granuloma in the petrous apex.

OBJECTIVES/HYPOTHESIS: We present the case of a 21-year-old woman who underwent endoscopy-assisted surgery with topical mitomycin for a large cholesterol granuloma in the petrous apex that involved the eustachian tube. STUDY DESIGN: Case report. METHODS: Minimally invasive surgery was performed on the cholesterol granuloma with endoscopic assistance, and topical mitomycin (0.4 mg/mL) was administered to prevent scarring of the newly created drainage/ventilation route. With the endoscopic approach, the drainage/ventilation route was secured not only from the tympanic cavity, but also using a guidewire inserted from the pharyngeal orifice of the eustachian tube. RESULTS: The drainage/ventilation route between the nasopharynx and middle ear cavity involving the cholesterol granuloma has been preserved more than for 9 months postoperatively. Her hearing has recovered. CONCLUSIONS: This less invasive technique is a surgical option for patients with a large cholesterol granuloma in the petrous apex involving the eustachian tube.

Postoperative aeration in the middle ear and hearing outcome after canal wall down tympanoplasty with soft-wall reconstruction for cholesteatoma.

OBJECTIVE: Canal wall down (CWD) tympanoplasty with soft-wall reconstruction (SWR) is a unique technique for cholesteatoma surgery. The external auditory canal shape after surgery-retracted like a radical mastoid cavity or preserved intact-depends on postoperative aeration in the mastoid cavity. However, the relationship between postoperative middle ear aeration and hearing outcome with this procedure is unknown. We characterized this relationship and propose an ideal state of middle ear aeration to obtain satisfactory postoperative hearing after CWD tympanoplasty with SWR. STUDY DESIGN: Retrospective case series. PATIENTS: Seventy-eight patients (78 ears) with fresh cholesteatomas treated surgically at our hospital by planned 2-stage CWD tympanoplasty and SWR were included. MAIN OUTCOME MEASURES: Postoperative middle ear aeration was scored 1 year after second-stage surgery by computed tomography. The patients were divided into 4 bins according to postoperative audiometric air-bone (A-B) gaps: 0-10, 11-20, 21-30, and greater than 30 dB. RESULTS: Postoperative middle ear aeration was significantly greater in the smaller gap bins (0-10 and 11-20 dB) compared with the larger A-B gap bins (21-30 and >30 dB). In contrast to the larger A-B gap bins, those with smaller A-B gaps showed reaeration of the antrum and mastoid cavity. No significant differences were observed in postoperative middle ear aeration or hearing outcome between the 2 cholesteatoma types. CONCLUSION: Promoting postoperative aeration of the entire middle ear is necessary to achieve better hearing outcome in patients undergoing CWD tympanoplasty and SWR for cholesteatoma.

Planned fractionated boron neutron capture therapy using epithermal neutrons for a patient with recurrent squamous cell carcinoma in the temporal bone: a case report.

BACKGROUND: We describe the first case of extensive squamous cell carcinoma in the temporal bone recurring after surgery, conventional radiotherapy, and chemotherapy, which was treated using planned fractionated boron neutron capture therapy (BNCT). METHODS: A 42-year-old patient received BNCT twice with a 1-month interval to ensure neutron capture in the deep lesion. We used an epithermal neutron beam as the neutron source and boronophenylalanine as the boron compound. The total radiation doses in the tumor beneath the skin, at the deepest point of the tumor, and in the skin around the right auricle were estimated as 41.8, 36.9, and 15.8 Gy-Eq, respectively. RESULTS: Radiological studies performed 6 months after the first BNCT showed obvious tumor shrinkage and no evidence of residual tumor. CONCLUSION: We believe that planned fractionated BNCT is an effective treatment option for patients with inoperative extended carcinomas in the temporal bone.

Ultrasonography for preoperative localization of enlarged parathyroid glands in secondary hyperparathyroidism.

OBJECTIVE: Parathyroidectomy (PTx) is sometimes performed to treat secondary hyperparathyroidism (2HPT) related to long-term dialysis. In this procedure, all four parathyroid glands should be resected. However, in patients with 2HPT, the four glands are not uniformly enlarged; therefore, preoperative diagnosis is difficult in comparison with primary hyperparathyroidism. We compared glands detected on preoperative ultrasonography (US) with those resected during PTx to examine the usefulness and limitations of US. METHODS: The subjects were 44 patients with 2HPT who underwent PTx between December 2003 and November 2007. Surgery was indicated for patients meeting the following three conditions: a serum intact PTH (iPTH) level of 500 pg/ml or more; a maximum glandular volume of 500 mm3 or more; and increased bone metabolism. Before surgery, we detected the parathyroid glands using US, and three-dimensionally measured their sizes. PTx was performed based on US diagnosis, and resected glands were weighed. RESULTS: Assuming that four parathyroid glands are present in each patient, the total number of glands in the 44 patients was 176. Of the 176 glands, 139 were detected on preoperative US. However, 27 could not be resected. Therefore, the detection rate on US was 63.6% (112/176). Of 37 glands that could not be detected on preoperative US, 30 were detected during surgery, and resected. There was a positive correlation between the glandular volume measured on US and isolated gland weight. However, there was no correlation between the preoperative serum iPTH level and the sum of the four isolated gland weights. CONCLUSION: On preoperative US, approximately 80% of the glands were detected. However, the misdiagnosis rate was approximately 20%. The rate of accurate diagnosis was 63.6%. Even when glands were misdiagnosed or could not be confirmed on preoperative US, approximately 80% of them could be detected and resected during surgery. It may be impossible to estimate the glandular volume based on the preoperative serum iPTH level.

Canal wall-down tympanoplasty with soft-wall reconstruction using the pedicled temporoparietal fascial flap: technique and preliminary results.

OBJECTIVES: We compared the use of the pedicled temporoparietal fascial flap (TPFF) with the use of free deep temporal fascia (DTF) in soft-wall reconstruction after canal wall-down tympanoplasty. METHODS: In the TPFF group (6 ears), the pedicled TPFF that includes the superficial temporal artery and vein was raised ipsilaterally and rotated into the eradicated mastoid cavity. The tympanic membrane and external auditory canal (EAC) were reconstructed by gluing one side of the TPFF to the mucosal layer of the tympanic membrane and the reverse side of the posterior EAC skin. In the DTF group (21 ears), reconstruction was performed similarly with free DTF. The postoperative period for epithelialization of the tympanic membrane and EAC skin, postoperative complications, and reaeration in the middle ear revealed by computed tomography were reviewed in both groups. RESULTS: In the TPFF group, the mean (+/- SD) period to epithelialization was 25.5 +/- 2.8 days versus 38.4 +/- 12.0 days in the DTF group; the two groups differed statistically (Welch's t-test, p = 0.0002). No postoperative complications occurred in the TPFF group, whereas 2 patients in the DTF group underwent graft necrosis with infection. Three of the 6 patients in the TPFF group showed reaeration not only in the tympanic cavity, but also in the mastoid cavity. However, no statistical differences between the two groups were observed in terms of postoperative complications or reaeration of the mastoid cavity. CONCLUSIONS: Our preliminary findings suggest that the pedicled TPFF has positive effects on quick epithelialization. Further prospective studies are needed to reveal the superiority of the pedicled TPFF over free DTF with regard to postoperative infection and recovery of mastoid aeration.