Efficacy of anti-PD-1 therapy in a patient with brain metastasis of parotid carcinoma: A case report.

CheckMate 141, an open-label, randomized phase III trial of nivolumab, indicated that treatment with nivolumab prolonged overall survival of patients with platinum-refractory, recurrent head and neck squamous cell carcinoma. Herein, we describe a case of brain metastasis of parotid carcinoma in which a good response was achieved after nivolumab treatment. The patient was a 67-year-old woman with parotid carcinoma (cT4bN0M0) who received induction chemotherapy followed by chemoradiation. Computed tomography and magnetic resonance imaging performed 10 weeks after the primary treatment revealed a residual tumor and brain and lung metastases. Thereafter, chemotherapy comprising cisplatin, 5-FU, and cetuximab was performed. Unfortunately, the tumor volume increased 5 months after chemotherapy, after which she received immunotherapy with biweekly nivolumab. After six cycles of nivolumab administration, the brain and lung metastases shrank markedly. Nivolumab had an intracranial effect in the patient with brain metastases of parotid carcinoma. This case report highlights the efficacy of nivolumab in the management of head and neck cancer with brain metastasis.

[Clinical Features of the Pediatric Acquired Cholesteatoma Based on the Staging Criteria for Cholesteatoma 2010 Japan].

In this study, we retrospectively evaluated the clinical features of the pediatric acquired cholesteatoma based on the staging criteria for cholesteatoma 2010 Japan. Between 2001 and 2012, total of 36 pediatric patients underwent otologic surgery at our hospital, 29 patients (29 ears) with pars flaccida cholesteatoma and 7 patients (7 ears) with pars tensa cholesteatoma. The age range was 4 to 15 years, (median was 10.5 years). Stage 11 was the most common for both the pars flaccida and pars tensa. A staged operation was performed in 24 ears with pars flaccida cholesteatoma, and 4 ears with pars tensa cholesteatoma. The success rate of hearing improvement was 72% (21/29) in pars flaccida cholesteatoma and 57% (4/7) in pars tensa cholesteatoma. Hearing improvement decreased in advanced cases. In staged operations, residual cholesteatoma was found in 11 ears (46%) with pars flaccida cholesteatoma and 2 ears (50%) with pars tensa cholesteatoma. These results suggest that the residual rate of cholesteatoma in the pediatric population is high. In conclusion, a high rate of residual cholesteatoma in the pediatric population was observed in our study. Thus a staged operation would be the recommended treatment approach in pediatric acquired cholesteatoma.

Evaluation of X-ray doses and their corresponding biological effects on experimental animals in cone-beam micro-CT scans (R-mCT2).

Studies show that the radiation dose received during a micro-CT examination may have adverse effects on living subjects. However, the correlations between the biological effects and the radiation doses have never been thoroughly evaluated in the majority of cases. In this study, we evaluated the biological radiation effects of measured radiation doses in ICR mice using cone-beam micro-CT scans. Long-term in vivo whole-body micro-CT scans of ICR mice were performed for a duration of 4 weeks. Although a scanning frequency of three scans per week is higher than that necessary for conventional studies, this study represents particular cases where the subjects may undergo an extreme number of examinations. The average X-ray dose of a CT scan measures 16.19 mGy at the center of a phantom and 16.24 mGy at an offset position of 7.5 mm from the center of the phantom. The total average dose at the center of the phantom during the 4-week scanning period was 194.3 mGy. No significant radiation effects were observed in the weight gain curves, organ weights, blood analyses, litter sizes, reared offspring sizes, and the histopathologic results. Therefore, it is unlikely that the measured doses for the CT scans caused any radiation damage in the mice.

A Comparison of Analgesic Effect between Loxoprofen and Celecoxib and the Frequency of the Hemorrhage Following Tonsillectomy.

Hemorrhage following tonsillectomy is still a major complication despite the progress in medical technology. Celecoxib is a selective COX-2 inhibitor and has a lower effect of platelet aggregation compared with conventional non-steroidal anti-inflammatory drugs (NSAIDs). We investigated whether or not the selection of celecoxib would reduce the risk of hemorrhage and provide a good analgesic effect following tonsillectomy in comparison with the use of loxoprofen (a conventional NSAID). 　We divided 107 cases of tonsillectomy into two groups by the kind of analgesic prescribed; the celecoxib group (n=55) and the loxoprofen group (n=52). Regarding the effective rate of the analgesic effect, the loxoprofen group scored 93.3% and the celecoxib group scored 68.6%. There was a significant difference between them (p=0.0003). Regarding side effects, the celecoxib group showed no side effects, whereas 8.0% of the loxoprofen group developed abdominal pain. There were no statistically significant differences between the changes in the VAS scale regarding the pain (p=0.834), the prescription periods of analgesic (p=0.485), the amount of food intake during the hospitalization (p=0.579), the rescue dosage rate (p=0.585), periods of usage (p=0.198) and the last dosage day. As for the tendency and the grade of postoperative hemorrhage, there were no statistically differences between the two groups (p=0.220). The rates of occurrence of late-onset hemorrhage (i.e. after the postoperative eleventh day) were 0.0% (0/11) in the the celecoxib group (n=11) and 31.2% (5/16) in the the loxoprofen group showing a statistically differences between them (p=0.049). 　Our results suggest that Celecoxib might reduce the risk of late-onset hemorrhage after the postoperative eleventh day with few side effects, so it could be a useful analgesic drug following tonsillectomy. However, it might be necessary to consider administration in combination with acetaminophen because Celecoxib has insufficient analgesic effect following tonsillectomy.

[Submucosal Partial-turbinectomy (SPT) Preceding an Endoscopic Sinus Surgery (ESS) Procedure].

Preceding a endoscopic sinus surgery (ESS), we have proposed performing a submucosal partial-turbinectomy (SPT) which removes a part of the inferior nasal concha bone attached to maxillary sinus with an antrostomy. By this method, we could not only make a large antrostomy but also obtain good maneuverability by opening the middle nasal meatus in ESS. We performed SPT preceding ESS in 140 cases (261 sides) between January 2012 and June 2014. The stenosis rates of the middle nasal meatus were 14.2% (37 sides from 261 sides) in one month, 7.4% (18 sides from 243 sides) in three months and 3.7% (6 sides from 163 sides) in 6 months after surgery. The closing rates of the antrostomy were 1.5% (4 sides from 261 sides) in one month, 2.9% (7 sides from 243 sides) in three months and 6.7% (11 sides from 163 sides) in 6 months after surgery. We considered that the SPT method would contribute to secure sufficient ventilation routes for wound healing of sinusitis following surgery on the mucous membrane. In addition, the SPT method has merit from the point of deceasing risks of atrophic rhinitis and empty nose syndrome by preserving most of the inferior nasal concha.

[The Significance of Resection of the Cricoid Cartilage as a Surgical Procedure in Laryngotracheal Surgery].

The cricoid cartilage has been regarded as an extremely important organ because it plays important role in both of phonation and breathing. We herein report on two different types of surgical procedure for laryngotracheal diseases with aggressive resection of the cricoid cartilage. The first procedure is a tracheostomaplasty by partial resection of the cricoid cartilage. A tracheostoma is made by resection of the cricoid cartilage in the range of approximately a one-third front. This method is effective for such cases having difficulty in tracheostomy owing their backgrounds with such condition as neck stiffness, obesity, higher displacement of the brachiocephalic artery, short neck, thyroid disease and so on. We applied this procedure for eight cases with such difficult backgrounds. In all cases, we were able to make a good tracheostoma and the postoperative courses were uneventful. The second procedure is a glottic closure with resection of the cricoid cartilage and thyroid cartilage. We applied this procedure for six cases with intractable dysphagia. One case had a postoperative bleeding. We were able to make good conditions in all cases with a large tracheostoma and no pharyngeal-tracheal leakage. In conclusion, the surgical procedure involving resection of the cricoid cartilage can be applied to some laryngotracheal diseases.

NIRS external dose estimation system for Fukushima residents after the Fukushima Dai-ichi NPP accident.

The great east Japan earthquake and subsequent tsunamis caused Fukushima Dai-ichi Nuclear Power Plant (NPP) accident. National Institute of Radiological Sciences (NIRS) developed the external dose estimation system for Fukushima residents. The system is being used in the Fukushima health management survey. The doses can be obtained by superimposing the behavior data of the residents on the dose rate maps. For grasping the doses, 18 evacuation patterns of the residents were assumed by considering the actual evacuation information before using the survey data. The doses of the residents from the deliberate evacuation area were relatively higher than those from the area within 20 km radius. The estimated doses varied from around 1 to 6 mSv for the residents evacuated from the representative places in the deliberate evacuation area. The maximum dose in 18 evacuation patterns was estimated to be 19 mSv.

Expression of Trefoil factor family peptides in the nasal allergic mucosa.

OBJECTIVE: Trefoil factor family peptides (TFFs) are the secretory products of mucous cells and are closely associated with mucins. TFFs appear to be important in mucosal healing processes. Although TFF1/3 are expressed in the human respiratory tract, their role in the nasal mucosa is not thoroughly understood. We investigated the association between TFFs and mucins and the role TFFs in the human nasal mucosa. MATERIAL AND METHODS: Patients undergoing turbinectomy were included and it was determined whether patients had nasal allergies or not. The localization of TFF1/3, MUC5AC/5B expression was investigated using immunohistochemistry. The levels of the mRNA transcripts were examined using quantitative real-time PCR. RESULTS: TFF1/3 had a similar pattern of localization in epithelial goblet cells and submucosal glandular cells. TFF1/3 co-localized with MUC5AC in the epithelium, and co-localized with MUC5B in the epithelium and the submucosal glandular cells. The levels of TFF1/3 and MUC5B mRNA in allergic patients were significantly increased. CONCLUSION: Our results suggest that TFF1/3 may associate with MUC5AC and MUC5B in the nasal mucosa, and that up-regulation of TFF1/3 and MUC5B may play an important role in the clinical condition of the nasal allergic mucosa.

Dose-response effect of charged carbon beam on normal rat retina assessed by electroretinography.

PURPOSE: To compare the effects of carbon beam irradiation with those of proton beam irradiation on the physiology of the retina of rats. METHODS AND MATERIALS: Eight-week-old Wister rats were used. The right eyes were irradiated with carbon beam (1, 2, 4, 8, and 16 Gy) or proton beam (4, 8, 16, and 24 Gy) with the rats under general anesthesia. Electroretinograms were recorded 1, 3, 6, and 12 months after the irradiation, and the amplitudes of the a and b waves were compared with those of control rats. RESULTS: The amplitude of b waves was reduced more than that of a waves at lower irradiation doses with both types of irradiation. With carbon ion irradiation, the amplitudes of the b wave were significantly reduced after radiation doses of 8 and 16 Gy at 6 months and by radiation doses of 4, 8, and 16 Gy at 12 months. With proton beam irradiation, the b-wave amplitudes were significantly reduced after 16 and 24 Gy at 6 months and with doses of 8 Gy or greater at 12 months. For the maximum b-wave amplitude, a significant difference was observed in rats irradiated with carbon beams of 4 Gy or more and with proton beams of 8 Gy or more at 12 months after irradiation. CONCLUSIONS: These results indicate that carbon beam irradiation is about two times more damaging than proton beam irradiation on the rat retina at the same dose.

Measurement of microdosimetric spectra produced from a 290 MeV/n Spread Out Bragg Peak carbon beam.

This study describes measurements on secondary particles produced by a 290 MeV/n Spread Out Bragg Peak (SOBP) carbon beam. Microdosimetric distributions of secondary fragments from the SOBP carbon beam have been measured by using a new tissue equivalent proportional counter (TEPC) system at the Heavy Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences. The new TEPC system consists of a TEPC, two solid-state detectors (SSD) and a scintillation counter (FSC: forward scintillation counter). The SSDs and FSC can separately identify charged fragments and secondary neutrons produced by the incident carbon ions. Microdosimetric distributions were measured for secondary particles including neutrons produced by a body-simulated phantom consisting of various PMMA plates (thickness: 0, 34.81, 55.2, 60.95, 64.83, 95.03, 114.79, 124.69, 135.2 and 144.98 mm, respectively) to cover the SOBP (at 60-125 mm depth). The new system can separately determine produced fragments from the incident SOBP carbon beam in a body-simulated phantom.

Analysis of syndecan-1 and TGF-beta expression in the nasal mucosa and nasal polyps.

OBJECTIVE: Increased understanding of cytokines and their associated proteoglycans will contribute to the investigation of the formation of nasal polyps. Recently, some studies have suggested that syndecan-1 ectodomains are shed in response to low respiratory infection, but no studies regarding nasal and paranasal diseases have been reported. Transforming growth factor-beta (TGF-beta) is involved in the regulation of nasal polyps, especially in processes crucial to the initiation, maintenance, and resolution of inflammatory responses. In the nasal mucosa and nasal polyps, we analyzed the expression of syndecan-1, which readily promotes infection, and TGF-beta, which plays a role in syndecan-1 activity. METHODS: Fifteen patients who underwent turbinectomy for the treatment of nasal obstruction and seventeen patients with nasal polyps who underwent nasal endoscopic sinus surgery were included in this study. The localization of syndecan-1 and TGF-beta in the nasal mucosa and nasal polyps was investigated by immunohistochemistry, and mRNA transcript levels of syndecan-1 and TGF-beta were examined using quantitative real-time PCR. RESULTS: Immunohistochemical staining revealed that the expression of syndecan-1 in the nasal mucosa and nasal polyps was co-localized with TGF-beta. The mean mRNA expression values for syndecan-1 and TGF-beta were higher in nasal polyps compared to the nasal mucosa. CONCLUSIONS: This is the first report showing expression of syndecan-1 in the nasal mucosa and nasal polyps. In nasal polyps, syndecan-1 expression may be increased by an unknown mechanism, permitting infection and inducing larger nasal polyps. We hypothesize that the accumulation of TGF-beta, which is involved in the pathophysiological development of nasal polyps, may result in a change in the binding properties of syndecan-1 at inflammatory sites.

International intercomparisons of integrating radon detectors in the NIRS radon chamber.

An international intercomparison of integrating detectors was conducted at NIRS (National Institute of Radiological Science, Japan) with a 24.4 m(3) inner volume walk-in radon chamber that has systems to control radon concentration, temperature and humidity. During the first intercomparison (05.2007) four groups participated from four countries and for the second intercomparison (10.2007) 17 participants were involved from 11 countries. Most of detectors are in good agreement with each other when compared to the radon level provided by the radon chamber. It appeared that the 70% of detectors are unified within the 20% margin of uncertainty.

Calculation of dose contributions of electron and charged heavy particles inside phantoms irradiated by monoenergetic neutron.

The radiation-transport code PHITS with an event generator mode has been applied to analyze energy depositions of electrons and charged heavy particles in two spherical phantoms and a voxel-based mouse phantom upon neutron irradiation. The calculations using the spherical phantoms quantitatively clarified the type and energy of charged particles which are released through interactions of neutrons with the phantom elements and contribute to the radiation dose. The relative contribution of electrons increased with an increase in the size of the phantom and with a decrease in the energy of the incident neutrons. Calculations with the voxel-based mouse phantom for 2.0-MeV neutron irradiation revealed that the doses to different locations inside the body are uniform, and that the energy is mainly deposited by recoil protons. The present study has demonstrated that analysis using PHITS can yield dose distributions that are accurate enough for RBE evaluation.

Microdosimetric study for secondary neutrons in phantom produced by a 290 MeV/nucleon carbon beam.

Absorbed doses from main charged-particle beams and charged-particle fragments have been measured with high accuracy for particle therapy, but there are few reports for doses from neutron components produced as fragments. This study describes the measurements on neutron doses produced by carbon beams; microdosimetric distributions of secondary neutrons produced by 290 MeV/nucleon carbon beams have been measured by using a tissue equivalent proportional counter at the Heavy Ion Medical Accelerator in Chiba, Japan at the National Institute of Radiological Sciences. The microdosimetric distributions of the secondary neutron were measured on the distal and lateral faces of a body-simulated acrylic phantom (300 mm height x 300 mm width x 253 mm thickness). To confirm the dose measurements, the neutron energy spectra produced by incident carbon beams in the acrylic phantom were simulated by the particle and heavy ion transport code system. The absorbed doses obtained by multiplying the simulated neutron energy spectra with the kerma factor calculated by MCNPX agree with the corresponding experimental data fairly well. Downstream of the Bragg peak, the ratio of the neutron dose to the carbon dose at the Bragg peak was found to be a maximum of 1.4 x 10(-4) and the ratio of neutron dose was a maximum of 3.0 x 10(-7) at a lateral face of the acrylic phantom. The ratios of neutrons to charged particle fragments were 11% to 89% in the absorbed doses at the lateral and the distal faces of the acrylic phantom. We can conclude that the treatment dose will not induce serious secondary neutron effects at distances greater than 90 mm from the Bragg peak in carbon particle therapy.

Microdosimetric evaluation of secondary particles in a phantom produced by carbon 290 MeV/nucleon ions at HIMAC.

Microdosimetric single event spectra as a function of depth in a phantom for the 290 MeV/nucleon therapeutic carbon beam at HIMAC were measured by using a tissue equivalent proportional counter (TEPC). Two types of geometries were used: one is a fragment particle identification measurement (PID-mode) with time of flight (TOF) method without a backward phantom, and the other is an in-phantom measurement (IPM-mode) with a backward phantom. On the PID-mode geometry, fragments produced by carbon beam in a phantom are identified by the DeltaE-TOF distribution between two scintillation counters positioned up- and down-stream relative to the tissue equivalent proportional counter (TEPC). Lineal energy distributions for carbon and five ion fragments (proton, helium, lithium, beryllium and boron) were obtained in the lineal-energy range of 0.1-1000 keV/microm at eight depths (7.9-147.9 mm) in an acrylic phantom. In the IPM-mode geometry, the total lineal energy distributions measured at eight depths (61.9-322.9 mm) were compared with the distributions in the PID-mode. Both spectra are consistent with each other. This shows that the PID-mode measurement can be discussed as the equivalent of the phantom measurement. The dose distribution of the carbon beam and fragments were obtained separately. In the depth dose curve, the Bragg peak was observed. Relative biological effectiveness (RBE) for the carbon beam in the acrylic phantom was obtained based on a biological response function as a lineal-energy. The RBE of carbon beam had a maximum of 4.5 at the Bragg peak. Downstream of the Bragg peak, the RBE rapidly decreases. The RBE of fragments is dominated by Boron particles around the Bragg peak region.

Irradiation System for HIMAC.

Clinical trials of carbon radiotherapy started at HIMAC in 1994 using three treatment rooms and four beam ports, two horizontal and two vertical. The broad beam method was adopted to make a three-dimensionally uniform field at an isocenter. A spot beam extracted from an accelerator was laterally spread out by using a pair of wobbler magnets and a scatterer. A bar ridge filter modulated the beam energy to obtain the spread out Bragg peak (SOBP). The SOBP was designed to be flat in terms of the biological dose based on the consideration that the field consisted of various beams with different LET. Finally, the field of 20 cm in diameter with +/- 2.5% uniformity was formed at the isocenter. The width of the maximum SOBP was 15 cm. When treating the lung or liver, organs that move due to breathing, the beam was irradiated only during the expiration period in a respiration-gated irradiation method. This reduced the treatment margin of the moving target. In order to prevent normal tissues adjacent to the target volume from irradiation by an unwanted dose, a layer-stacking method was developed. In this method, thin SOBP layers which have different ranges were piled up step by step from the distal end to the entrance of the target volume. At the same time, a multi-leaf collimator was used to change the aperture shape to match the shape of each layer to the cross-sectional shape of the target. This method has been applied to rather large volume cancers including bone and soft-tissue cancers. Only a few serious problems in the irradiation systems have been encountered since the beginning of the clinical trials. Overall the systems have been working stably and reliably.

Arpc1b gene is a candidate prediction marker for choroidal malignant melanomas sensitive to radiotherapy.

PURPOSE: Choroidal malignant melanomas (CMMs) are the most common primary intraocular tumors in adult humans. Although radiotherapy is commonly used to treat the melanomas, the therapeutic effects are unpredictable. The purpose of this study was to search for a gene(s) that can predict the success of radiotherapy for CMMs. METHODS: The cell lines 92-1, OCM-1, and OMM-1 were established from patients with CMM, and radiation sensitivity was determined using the colony-formation assay. RNA was extracted from nonirradiated cells, and gene expression analysis was performed using a microarray containing 10,800 genes. The up- or downregulated genes were verified by real-time PCR using other cancerous cell lines in which radiation sensitivity had been documented. RESULTS: Analysis of radiation survival curves showed that cell line 92-1 was radiation sensitive and OCM-1 and OMM-1 lines were radiation resistant. The results of microarray analyses showed that 34 genes were differentially expressed in the OCM-1 and OMM-1 cell lines compared with the 92-1 cell line. The validity of the expression level of 13 of the 34 genes that were identified by microarray was confirmed by PCR. From the analysis of the different radio-sensitivity cancer cell lines, the Arpc1b gene was selected as a prediction marker gene for sensitivity of CMM to radiotherapy. CONCLUSIONS: Gene expression analysis of CMM cell lines can be used to search for radiation sensitivity prediction markers. Comprehensive gene expression profiles of radiation-sensitive and/or resistant cell lines may provide new insights into the mechanisms of resistance or sensitivity to radiation therapy.

[Improvement of dose distributions at NIRS's 70 MeV proton eye treatment beam course]

In order to improve dose distributions at NIRS's 70 MeV proton eye treatment beam course, we introduced finer bar ridge filters, and examined the effects of range compensators. The pitch of new bar ridge filters was 5mm in contrast to 15mm pitch of old ones. A NC-machine recently available enabled this refinement. The spread out Bragg peak (SOBP) widths were 10, 15, 20 and 30 mm. The new ridge filters improved the field uniformity considerably. In the ridge filter design we assumed parallel beam condition in which the mono-energetic proton should proceed in parallel with the central axis, and bar ridges only changes the proton ranges. We searched empirically for the optimum wobbler radius in view of field flatness and depth dose distribution. Range shifter and compensator did not affect the field flatness and depth dose distribution at the optimum condition thus searched. We measured dose distribution in a phantom using a compensator of stairs-shape, which fairly modulated the beam. A 50% isodose line almost coincided with the compensator shape, and these results suggested that improvements of dose distributions should be possible using compensators. However width between 50% and 80% isodose lines depended on the thickness of phantom. This might be due to scattering in the compensator and suggests that it is necessary to calculate dose distribution taking account of such effects.