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Background: We aimed to define the indications for sentinel lymph node biopsy (SLNB), the third option for cervical treatment in oral cancer with negative cervical lymph nodes., Methods: The greatest depth of invasion (DOI) and long diameter (LD) of the primary site were used as exposures. SLN metastasis was considered the outcome., Results: In three trials conducted between 2009 and 2016, 158 patients were eligible and reassigned to this study group. The scatterplot based on the respective values of DOI and LD would eventually be divided into three sections. In cases of sections T1, T2, and T3, the proportions of SLN metastasis positivity were 21.3%, 35.3%, and 51.2%, respectively. In certain cases of T1 with 2 mm < DOI ≤ 5 mm and 8 mm < LD ≤ 20 mm, the proportion of SLN metastasis positivity was 40.9%., Conclusions: SLNB-navigated or assisted neck dissection can be added as an effective procedure for N0 neck control., (© 2023 Wiley Periodicals LLC.)

Poorly differentiated adenosquamous carcinoma (glassy cell carcinoma) of the cervix is extremely rare, accounting for 1-2% of all cervical cancers. Herein, we report a case with coexistent poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), "usual-type" adenocarcinoma, and squamous cell carcinoma in situ of the cervix. A female patient in her 60 s was referred to our hospital and diagnosed with poorly differentiated adenosquamous carcinoma based on cervical cytology and biopsy. The tumor was classified as clinical stage IB1 cervical cancer following magnetic resonance imaging; radical hysterectomy was performed. Histopathological examination revealed poorly differentiated adenosquamous carcinoma (glassy cell carcinoma), usual-type adenocarcinoma, and squamous cell carcinoma in situ, all coexisting. All carcinoma regions showed identical sizes to high-risk human papillomavirus (HPV) in fragment analysis. The patient is currently alive, without evidence of recurrence, 31 months post surgery. In this case, three different carcinomas coexisted. Fragment analysis of the patient's HPV status suggested that all carcinomas were related to an infection with the same high-risk HPV type. To determine the precise mechanism of tumor development, i.e., whether the tumors were of the mixed or collision type, further studies are needed, including clonal analysis for the loss of heterozygosity pattern., (© 2023. The Author(s).)

A new version of the highly parallelized general-purpose molecular dynamics (MD) simulation program MODYLAS with high performance on the Fugaku computer was developed. A benchmark test using Fugaku indicated highly efficient communication, single instruction, multiple data (SIMD) processing, and on-cache arithmetic operations. The system's performance deteriorated only slightly, even under high parallelization. In particular, a newly developed minimum transferred data method, requiring a significantly lower amount of data transfer compared to conventional communications, showed significantly high performance. The coordinates and forces of 101 810 176 atoms and the multipole coefficients of the subcells could be distributed to the 32 768 nodes (1 572 864 cores) in 2.3 ms during one MD step calculation. The SIMD effective instruction rates for floating-point arithmetic operations in direct force and fast multipole method (FMM) calculations measured on Fugaku were 78.7% and 31.5%, respectively. The development of a data reuse algorithm enhanced the on-cache processing; the cache miss rate for direct force and FMM calculations was only 2.74% and 1.43%, respectively, on the L1 cache and 0.08% and 0.60%, respectively, on the L2 cache. The modified MODYLAS could complete one MD single time-step calculation within 8.5 ms for the aforementioned large system. Additionally, the program contains numerous functions for material research that enable free energy calculations, along with the generation of various ensembles and molecular constraints., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

We conducted a charge-charge clustering experiment of positively and negatively charged colloidal particles in aqueous media under a microgravity environment at the International Space Station. A special setup was used to mix the colloid particles in microgravity and then these structures were immobilized in gel cured using ultraviolet (UV) light. The samples returned to the ground were observed by optical microscopy. The space sample of polystyrene particles with a specific gravity ρ (=1.05) close to the medium had an average association number of ~50% larger than the ground control and better structural symmetry. The effect of electrostatic interactions on the clustering was also confirmed for titania particles (ρ ~ 3), whose association structures were only possible in the microgravity environment without any sedimentation they generally suffer on the ground. This study suggests that even slight sedimentation and convection on the ground significantly affect the structure formation of colloids. Knowledge from this study will help us to develop a model which will be used to design photonic materials and better drugs., (© 2023. The Author(s).)

On-site disinfection techniques are beneficial during a pandemic when there is a marked shortage of personal protective equipment (PPE), as experienced during the coronavirus disease 2019 outbreak. Ozone gas has been considered an alternative on-site disinfectant during a pandemic because it has antimicrobial activities, can be produced from air by electricity without the need for storage, and can be easily deactivated after use. However, ozone gas might become distributed at the lower layer because it has a larger molecular weight than air. This study aimed to reveal the applicability of ozone gas for the on-site disinfection of PPE. The lockers meant for changing dresses were used as ozone gas exposure boxes, and the distribution of ozone was assayed. Considering that the determined ozone levels were not consistent in the types of ozone analysers, we studied the chemical and biological activities of ozone, which were evenly detected in the locker. The gown in the locker was also uniformly exposed to ozone. Results showed that ozone gas could be used for the on-site disinfection of PPE in a closed box, such as a locker. This finding is valuable during a pandemic when PPE is in short supply., Competing Interests: The authors declare the following conflict of interests: S.I. received research grants from Tamura Teco Co., Ltd, Osaka, Japan. All other authors have no conflict of interest to declare., (© 2023 The Authors.)

Aims: Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population., Methods: We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate., Results: Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6 . None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m 2 and BMI < 25 kg/m 2 ., Conclusions: The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population., Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00618-0., Competing Interests: Conflict of interestTakuya Sakashita is an employee of Takara Bio, Inc., Japan. Dr. Hachiya is a board member of Genome Analytics Japan Inc. Dr. Nakatochi reports receiving grants from Boehringer Ingelheim outside the submitted work. All other authors declare that they have no conflicts of interest associated with this study., (© The Japan Diabetes Society 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objective: Both 90 Y and 177 Lu are attractive β-emitters for radionuclide therapy and have been used in clinical practice. Nevertheless, comparative evaluation between 90 Y- and 177 Lu-labeled molecules has not been fully conducted. Thus, in this study, the features of 90 Y and 177 Lu for radionuclide therapy were assessed in tumor-bearing mice., Methods: Two tumor cell lines with different growth rates were used. Biodistribution studies of 177 Lu-labeled antibodies ( 177 Lu-Abs) were conducted in each tumor-bearing mouse model. Subsequently, the therapeutic effect of 90 Y- and 177 Lu-Ab were assessed in tumor-bearing mice. The absorbed radiation dose for the tumor was estimated using the Monte Carlo simulation., Results: 177 Lu-Abs demonstrated high tumor accumulation in both tumor-xerograph. In the fast-growing tumor model, 90 Y-Ab showed a better therapeutic effect than 177 Lu-Ab, reflecting a higher absorbed radiation dose of 90 Y-Ab than that of 177 Lu-Ab. In the slow-growing tumor model, both 90 Y- and 177 Lu-Ab showed an excellent therapeutic effect; however, 177 Lu-Ab had a longer efficacy period than 90 Y-Ab, which could be attributed to the longer half-life and better dose uniformity of 177 Lu than those of 90 Y., Conclusions: To accomplish a maximum therapeutic effect, selecting 90 Y or 177 Lu, to depend on the growth rate of individual cancer, would be helpful., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first-generation ALK-TKI)-refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counteractivated EGFR and/or Her3 and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be overcome by identifying precise resistance mechanisms., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Meta-[ 211 At]astato-benzylguanidine ([ 211 At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also distributed in normal tissues non-specifically. Meta-[ 131 I]iodo-benzylguanidine ([ 131 I]MIBG), an iodine-labeled analog of [ 211 At]MABG, is known to be transported by not only NET but also organic cation transporter (OCT). The involvement of OCT in [ 211 At]MABG uptake is still largely unknown. We investigated the involvement of OCT in the non-NET-driven uptake of [ 211 At]MABG both in vitro and in vivo., Methods: [ 123 I]MIBG and [ 211 At]MABG uptake was investigated in PC-12 (rat pheochromocytoma cell line), NIH/3T3 (mouse fibroblasts cell line), ACHN (human renal cancer cell line), and BxPC-3 (human pancreatic cancer cell line). Herein, we used desipramine and dl-norepinephrine to inhibit NET, and we used steroids (hydrocortisone and prednisolone) to inhibit OCT3. The [ 211 At]MABG uptake in OCT3-knockdown cells established with OCT3-selective siRNA was also investigated. We investigated the biodistribution of [ 211 At]MABG in PC-12 tumor-bearing mice after a preloading of phosphate-buffered saline (PBS) or hydrocortisone solution., Results: The uptake of both [ 123 I]MIBG and [ 211 At]MABG was significantly inhibited by desipramine in PC-12 cells but not the other cell lines. The expression of OCT3 was relatively higher than those of the other OCT subtypes in ACHN and BxPC-3 cells. The expression of OCTs was not observed in NIH/3T3 cells. The uptake of both [ 123 I]MIBG and [ 211 At]MABG in ACHN and BxPC-3 cells was significantly inhibited by the steroid treatments. The [ 211 At]MABG uptake was also reduced in OCT3-knockdown cells (p < 0.001). The radioactivity of [ 211 At]MABG was significantly reduced in normal tissues by the preloading of hydrocortisone. In contrast, there was an increasing trend of [ 211 At]MABG uptake in the PC-12 tumors. The tumor-to-normal tissue ratio was significantly increased by the preloading of hydrocortisone compared to that of PBS., Conclusion: Our results suggest that OCT3 is involved in non-NET-driven [ 211 At]MABG uptake. The preloading of hydrocortisone selectively reduced [ 211 At]MABG accumulation in normal organs in vivo. OCT3 inhibition may therefore be beneficial for a reduction of the radiation risk in healthy organs in the treatment of malignant pheochromocytomas., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Multilayered approaches to suicide prevention combine universal, selective, and indicated prevention interventions. These approaches may be more successful in reducing suicide rates among older adults if they link these layers more systematically: that is, if the programs are designed so that interventions at a lower level facilitate involvement at a higher level when appropriate. This study aimed to examine the effect on suicide rates of the structure of multilayered approaches, and in particular the types of interventions and the connections or linkages between them. We also wished to consider any different effects by sex. A literature search used PubMed and PsycINFO to identify systematic reviews of interventions in this age group. From the reference lists of these articles, we identified controlled studies assessing the impact of a multilayered program on suicide incidence among older adults. We were particularly interested in initiatives linking different kinds of prevention interventions. We found three relevant systematic reviews, and from these, we identified nine eligible studies. These included seven non-randomized controlled studies from rural areas in Japan (average eligible population: 3,087, 59% women, average duration: 8 years). We also found two cohort studies. The first was from a semi-urban area in Padua, Italy (18,600 service users, 84% women, duration: 11 years). The second was from urban Hong Kong, with 351 participants (57% women) over a 2-year follow-up period. We used a narrative synthesis of these studies to identify five different multilayered programs with different forms of connections or linkages between layers. Two studies/programs (Italy and Hong Kong) involved selective and indicated prevention interventions. One study/program (Yuri, Japan) included universal and selective prevention interventions, and the final six studies (two programs in northern Japan) involved linkages between all three layers. We also found that these linkages could be either formal or informal. Formal linkages were professional referrals between levels. Informal linkages included advice from professionals and self-referrals. Several of the studies noted that during the program, the service users developed relationships with services or providers, which may have facilitated movements between levels. All five programs were associated with reduced suicide incidence among women in the target groups or communities. Two programs were also associated with a reduction among men. The study authors speculated that women were more likely to accept services than men, and that the care provided in some studies did less to address issues that are more likely to affect men, such as suicidal impulsivity. We therefore suggest that it is important to build relationships between levels, especially between selective and indicated prevention interventions, but that these can be both formal and informal. Additionally, to reach older men, it may be important to create systematic methods to involve mental health professionals in the indicated prevention intervention. Universal interventions, especially in conjunction with systematically linked indicated and selective interventions, can help to disseminate the benefits across the community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sakashita and Oyama.)

Prophylactic elective neck dissection (ND) with navigation surgery using radioisotope-based sentinel lymph node biopsy (SLNB) is non-inferior to elective ND in terms of survival but has an advantage in postoperative functional disability. We conducted a subgroup analysis to identify predictive factors for false-negative (FN)-SLNB in patients with early oral cavity cancer. This study is a supplementary analysis using the dataset of a previously reported randomized clinical trial on SLN navigation surgery for oral cancers. This study investigated the association of clinical and SLN-related factors with false-negative cases in the SLNB group. From 2011 to 2016, 275 patients were enrolled and randomly assigned to the ND and SLNB study groups, with 134 patients assigned to the SLNB group. In the SLNB group, seven cases with negative SLNs and neck recurrences were judged as FN-SLNBs according to the general definition. The number of detected SLNs with and without adjusting for the propensity score was significantly associated with FNs in the logistic analysis. FN-SLNB was associated with the number of identified SLNs, suggesting the need for careful postoperative monitoring for neck recurrence in patients with one or two identified SLNs after acquiring sufficient experience in the identification technique., (© 2022. The Author(s).)

Background: The global point prevalence survey (Global-PPS) is the standard for the surveillance of prescribed antimicrobials among inpatients and provides data for the development of hospital antimicrobial stewardship programs., Aim: To evaluate the prevalence and quality of antimicrobial prescriptions using the universally standardized Global-PPS protocol in a non-acute care hospital in Saitama Prefecture, Japan., Methods: Antimicrobial prescriptions for inpatients, staying at the hospital overnight, were surveyed on three separate week days in November 2018, January 2019, and May 2019. Information on the prescribed antimicrobials on the survey target day was obtained from the in-hospital pharmacy. Survey data were collected by physicians, based on the extracted information. Patient information was anonymized and entered in the Global-PPS Web application by physicians. We report the antimicrobial use prevalence, the indication for prescription, diagnosis, the most prescribed antimicrobials, and a set of quality indicators related to antimicrobial prescribing., Results: In total, 6.7% of the surveyed inpatients (120/1796) were prescribed antimicrobials on the survey day. Sulfamethoxazole/trimethoprim was the most commonly prescribed, with 20.0% of systemic antibiotic prescriptions (ATC J01). Of all antibiotics for systemic use, up to 58.4% were Watch antibiotics, as defined by the World Health Organization AWaRe classification. The most prescribed group of systemic antibiotics was non-penicillin beta-lactam antibiotics (34.4%), followed by penicillin antibiotics in combination with beta-lactamase inhibitors (25.6%), and sulfonamides with trimethoprim (20.8%). Healthcare-associated infections and medical prophylaxis were the most common indications reported in 69.3% and 26.3% of prescriptions, respectively. The most common diagnosis for systemic antibiotic prescriptions was pneumonia (49.6%). Reasons for antimicrobial prescriptions were indicated in the medical records for 67.1% of prescriptions, and the stop/review date was documented to be 50.3%. Compliance with local guidelines reached 66.7%., Conclusions: This study highlights important challenges related to antimicrobial prescription in a highly specific, non-acute care patient population., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Noriomi Ishibashi et al.)

Background: We recently reported a new absorbed dose conversion method, RAP (RAtio of Pharmacokinetics), for 211 At-meta-astatobenzylguanidine ( 211 At-MABG) using a single biodistribution measurement, the percent injected dose/g. However, there were some mathematical ambiguities in determining the optimal timing of a single measurement of the percent injected dose/g. Thus, we aimed to mathematically reconstruct the RAP method and to examine the optimal timing of a single measurement., Methods: We derived a new formalism of the RAP dose conversion method at time t. In addition, we acquired a formula to determine the optimal timing of a single measurement of the percent injected dose/g, assuming the one-compartment model for biological clearance., Results: We investigated the new formalism's performance using a representative RAP coefficient with radioactive decay weighting. Dose conversions by representative RAP coefficients predicted the true [ 211 At]MABG absorbed doses with an error of 10% or less. The inverses of the representative RAP coefficients plotted at 4 h post-injection, which was the optimal timing reported in the previous work, were very close to the new inverses of the RAP coefficients 4 h post-injection. Next, the behavior of the optimal timing was analyzed by radiolabeled compounds with physical half-lives of 7.2 h and 10 d on various biological clearance half-lives. Behavior maps of optimal timing showed a tendency to converge to a constant value as the biological clearance half-life of a target increased. The areas of optimal timing for both compounds within a 5% or 10% prediction error were distributed around the optimal timing when the biological clearance half-life of a target was equal to that of the reference. Finally, an example of RAP dose conversion was demonstrated for [ 211 At]MABG., Conclusions: The RAP dose conversion method renovated by the new formalism was able to estimate the [ 211 At]MABG absorbed dose using a similar pharmacokinetics, such as [ 131 I]MIBG. The present formalism revealed optimizing imaging time points on absorbed dose conversion between two radiopharmaceuticals. Further analysis and clinical data will be needed to elucidate the validity of a behavior map of the optimal timing of a single measurement for targeted alpha-nuclide therapy., (© 2021. The Author(s).)

Radiation damages many cellular components and disrupts cellular functions, and was previously reported to impair locomotion in the model organism Caenorhabditis elegans . However, the response to even higher doses is not clear. First, to investigate the effects of high-dose radiation on the locomotion of C. elegans , we investigated the dose range that reduces whole-body locomotion or leads to death. Irradiation was performed in the range of 0-6 kGy. In the crawling analysis, motility decreased after irradiation in a dose-dependent manner. Exposure to 6 kGy of radiation affected crawling on agar immediately and caused the complete loss of motility. Both γ-rays and carbon-ion beams significantly reduced crawling motility at 3 kGy. Next, swimming in buffer was measured as a motility index to assess the response over time after irradiation and motility similarly decreased. However, swimming partially recovered 6 h after irradiation with 3 kGy of γ-rays. To examine the possibility of a recovery mechanism, in situ GFP reporter assay of the autophagy-related gene lgg-1 was performed. The fluorescence intensity was stronger in the anterior half of the body 7 h after irradiation with 3 kGy of γ-rays. GFP::LGG-1 induction was observed in the pharynx, neurons along the body, and the intestine. Furthermore, worms were exposed to region-specific radiation with carbon-ion microbeams and the trajectory of crawling was measured by image processing. Motility was lower after anterior-half body irradiation than after posterior-half body irradiation. This further supported that the anterior half of the body is important in the locomotory response to radiation.

We present pathology of the peripheral nerves of a patient with Adult-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation p.D651N. The patient was a 72-year-old woman. She had hoarseness and underwent continuous positive airway pressure therapy at night due to sleep apnea. The patient died abruptly. Remarkable demyelination with tomacula formation was found in the phrenic nerve, vagal nerve, recurrent laryngeal nerve, and oculomotor nerves. The cause of death could have been insufficient reactivity to the aspiration or sudden onset of bilateral vocal cord palsy. We must pay attention to respiratory function and cranial nerve palsies in hereditary demyelinating neuropathies., Competing Interests: None., (© 2021 The Authors.)

In the era of exascale supercomputers, large-scale, and long-time molecular dynamics (MD) calculations are expected to make breakthroughs in various fields of science and technology. Here, we propose a new algorithm to improve the parallelization performance of message passing interface (MPI)-communication in the MPI-parallelized fast multipole method (FMM) combined with MD calculations under three-dimensional periodic boundary conditions. Our approach enables a drastic reduction in the amount of communication data, including the atomic coordinates and multipole coefficients, both of which are required to calculate the electrostatic interaction by using the FMM. In communications of multipole coefficients, the reduction rate of communication data in the new algorithm relative to the amount of data in the conventional one increases as both the number of FMM levels and the number of MPI processes increase. The aforementioned rate increase could exceed 50% as the number of MPI processes becomes larger for very large systems. The proposed algorithm, named the minimum-transferred data (MTD) method, should enable large-scale and long-time MD calculations to be calculated efficiently, under the condition of massive MPI-parallelization on exascale supercomputers., (© 2021 Wiley Periodicals LLC.)

Tardigrades are microscopic animals of which terrestrial species are capable of tolerating extreme environments by entering a desiccated ametabolic state known as anhydrobiosis. Intriguingly, they survive high dosage gamma rays (>4,000 Gy), possibly through a mechanism known as cross-tolerance. We hypothesized that anhydrobiosis genes are also regulated during cross-tolerance, thus we submitted Ramazzottius varieornatus to 500 Gy 60 Co gamma-ray and conducted time-course low-input RNA-Seq. The gene expression was quantified with RSEM and differential expression was determined with DEseq2. Differentially expressed genes were submitted to gene ontology enrichment analysis with GOStat. The transcriptome dynamically shifted nine hours post-exposure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2021 The Author(s). Published by Elsevier Inc.)

Introduction: The prevalence of ulcerative colitis (UC) is increasing in Japan but recent disease burden estimates are unavailable. This study was conducted to explore the prescription pattern and to estimate the economic burden in Japanese patients with UC., Methods: This retrospective cohort study was conducted from 1 January 2009 to 30 June 2018 using healthcare claims data from the Japan Medical Data Center (JMDC) database. Patients with a UC diagnosis before the index date (the first UC treatment claim) or within 6 months after the index date, a UC treatment claim registered within ≥ 6 months during the selection period, and a continuous enrollment for 6 months pre-index and 12 months follow-up period were included in the study. Prescription pattern was analyzed by calendar years and lines of treatment (LoT). Healthcare resource utilization and cost per month were determined by LoTs., Results: Among 10,337 patients with UC diagnosis, 1,861 (18.0%) met the eligibility criteria for this study. 5-Aminosalicylic acid (5-ASA) was the most used treatment over the study period and across all LoTs. 5-ASA was also the most prescribed treatment (88.7%) across all the first LoTs, followed by steroids (20.4%). Use of biologics increased over the study period (biologics + 5-ASA: 0.0% in 2009 to 3.0% in 2018). Biologics were most used as the sixth LoT (7.1%, biologics + 5-ASA; 7.1%, biologics + 5-ASA + steroids). Mean total cost per month was JPY 52,782, with the highest (JPY 112,997) total healthcare cost per month in the fourth LoT and the lowest in the first LoT (JPY 56,782)., Conclusion: Prescription pattern in Japanese patients with UC enrolled in the JMDC database were largely consistent with the clinical guidelines in Japan. UC puts a substantial economic burden on patients, and an effective treatment is warranted to reduce the UC disease burden.

Objective: We aimed to estimate in vivo 211 At-labeled meta-benzylguanidine ( 211 At-MABG) absorbed doses by the two dose conversion methods, using 131 I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works., Methods: We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211 At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131 I to that of 211 At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g., Results: Virtual experiments showed that 211 At-MABG and 131 I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211 At-MABG dose. Simulated 211 At-MABG doses from 131 I-MIBG using the RAP method were in agreement with those from 211 At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data., Conclusions: The present RAP dose conversion method could estimate 211 At-MABG absorbed doses from the pharmacokinetics of 131 I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.

The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding. In a transgenic mouse model overexpressing the antigen systemically, the ATP switch antibody binds to the antigen in tumors with minimal binding in normal tissues and plasma and inhibits tumor growth. Thus, we demonstrate that elevated extracellular ATP concentration can be exploited to specifically target the TME, giving therapeutic antibodies the ability to overcome on-target off-tumor toxicity., Competing Interests: Declaration of Interests All authors except for J.K. and M.I. are employees of Chugai Pharmaceutical Co., Ltd. K. Ohara, K.A., H.K., H.K., T.I., E.T., M.M., Y.A., Y.S., K.H., T.K., T.M., M.N., S.K., S.T., T.B., M.E., and F.M. own stock in the company. H.K., K.T, S.S., M.K., T.I., S.T., H.K., A.H., F.M., T.K., and M.H. are inventors on intellectual property related to this work. J.K. and M.I. receive research support from Chugai Pharmaceutical Co., Ltd. This study was funded by Chugai Pharmaceutical Co., Ltd., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

An 80-year-old woman was diagnosed with miliary tuberculosis. Laboratory findings showed marked thrombocytopenia (3000/μl). Immune thrombocytopenia (ITP) was diagnosed because platelet transfusion was ineffective, and bone marrow puncture demonstrated a normal number of megakaryocytes. Anti-tuberculosis treatment was started promptly, followed by prednisolone 20 mg. However, the platelet count did not increase. The effect of high-dose intravenous immunoglobulin was temporary. She was not responded to prednisolone, and eltrombopag 12.5 mg was added. The eltrombopag dose was increased by 12.5 mg every two weeks. When the eltrombopag dose reached 50 mg, the thrombocytopenia improved sufficiently (44,000/μl). She didn't have any severe bleeding and thrombotic complications. The treatment of tuberculosis went well and there was no side effect of anti-tuberculosis treatment. Eltrombopag can be a useful treatment for ITP due to tuberculosis., Competing Interests: The authors state that they have no conflict of interest to declare., (© 2020 Published by Elsevier Ltd.)

Purpose: A fluorescence-based technique for the detection of parathyroid glands (PGs) intraoperatively was previously reported. The technique was based on the phenomenon in which PGs emit autofluorescence when exposed to near-infrared light and we undertook an evaluation to consider the pathological accuracy of the method., Methods: The study comprised 17 patients (18 specimens) who underwent thyroid surgery at Kushiro City General Hospital between November 2018 and June 2019. We searched for PGs intraoperatively using a fluorescence spectroscopy system and evaluated the pathological accuracy of the system. We statistically evaluated the clinical factors associated with the accuracy of the system, including age, gender, body mass index, laterality, disease state, renal function, and comorbidity., Results: Eighteen specimens were evaluated pathologically, with 13 specimens confirmed as PGs. These were evaluated as "true positive," giving a positive predictive value of 72.2% (13/18). Among the false-negative cases, one specimen was a metastatic lymph node in a patient with papillary thyroid carcinoma. There was a significant difference in the true-positive rates between malignant (25%) and benign (85.7%) disease (P = 0.044)., Conclusion: We consider that this technique is useful, however, we have to exercise care in malignant cases as the true-positive rate may be low.

Purpose: Recently it was reported that the parathyroid glands (PGs) emit autofluorescence when exposed to near infrared light, and a technique using fluorescence to detect the PGs intraoperatively was found to be useful. In some cases, however, it was difficult to detect the PGs. We sought to clarify the situation regarding such undetectable cases., Methods: The study comprised 45 patients (50 sides) who underwent thyroid or parathyroid surgery at Kushiro city general hospital between November 2018 and June 2019. We searched for the PGs intraoperatively using a fluorescence spectroscopy system. We statistically considered the factors related to the fluorescence patterns of background in cases in which two PGs could not be confirmed using Fisher's exact test. Factors included age, gender, body-mass index, laterality, disease state, renal function, and comorbidity., Results: In 41 sides (82%) fluorescence from at least one PG was determined. There was no significant difference in the detection rates among the other clinical factors. A "White out" pattern in which the background was too bright to detect PGs was observed in 11 sides (22%), and a "Black out" pattern in which the background and PGs were dark was observed in 18 sides (36%). Malignant disease was statistically associated with a "White out" pattern. No factors were found to be related to the "Black out" pattern., Conclusion: In malignant disease, we should use this novel approach carefully.

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC 50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC 50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.

Cataracts have long been known, but a biomathematical model is still unavailable for cataratogenesis. There has been a renewed interest in ionizing radiation cataracts because the recent international recommendation of the reduced lens dose limit stimulated the discussion toward its regulatory implementation in various countries. Nevertheless, a relationship between radiation (dose and dose rate) and response (e.g., incidence, onset and progression) remains incompletely understood, raising the need for a risk-predictive mathematical model. We here report for the first time an in silico model for cataractogenesis. First, a simplified cell proliferation model was developed for human lens growth based on stem and progenitor cell proliferation as well as epithelial-fiber cell differentiation. Then, a model for spontaneous cataractogenesis was developed to reproduce the human data on a relationship between age and cataract incidence. Finally, a model for radiation cataractogenesis was developed that can reproduce the human data on a relationship between dose and cataract onset at various ages, which was further applied to estimate cataract incidence following chronic lifetime exposure. The model can serve as the foundation for further development of the risk-predictive model for cataractogenesis along with additional considerations of various biological mechanisms and epidemiological datasets., Competing Interests: The authors have declared that no competing interests exist.

Suicide prevention is an increasingly important issue, especially among older people. Recent work on improving its effectiveness has focused on developing a framework aligning interventions with key risk factors and stages of the suicide process. We have developed this further, by integrating psycho-behavioral components associated with suicide, existing guidelines for identifying critical points of intervention, and the previous preventive strategies framework. Our schematic diagram shows the relationship between the suicide process and prevention strategies, combined with initiatives for linking different types of strategies, from universal strategies at population level, through selective strategies focusing on groups at risk, to indicated strategies, aimed at specific high-risk individuals. We tested our framework using previous studies assessing the impact of suicide prevention interventions on suicide rates in older adults. It was possible to place all identified interventions within the framework. Examining effectiveness within the framework suggests that some interventions may be more successful in reducing suicide rates because they developed systematic linkages between universal, selective, and indicated prevention interventions. Other studies, however, show that interventions can be successful without these linkages, so other factors may also be important. The main weakness of our framework is a lack of evidence about critical intervention points within the suicide process, which may limit its practical application. However, the framework may help to improve the linkages between types of interventions, and support practitioners in developing a wide range of strategies across different areas and stages of the suicide process.

Radiation is widely used for biological applications and for ion-beam breeding, and among these methods, microbeam irradiation represents a powerful means of identifying radiosensitive sites in living organisms. This paper describes a series of on-chip immobilization methods developed for the targeted microbeam irradiation of live individuals of Caenorhabditis elegans. Notably, the treatment of the polydimethylsiloxane (PDMS) microfluidic chips that we previously developed to immobilize C. elegans individuals without the need for anesthesia is explained in detail. This chip, referred to as a worm sheet, is resilient to allow the microfluidic channels to be expanded, and the elasticity allows animals to be enveloped gently. Also, owing to the self-adsorption capacity of the PDMS, animals can be sealed in the channels by covering the surface of the worm sheet with a thin cover film, in which animals are not pushed into the channels for enclosure. By turning the cover film over, we can easily collect the animals. Furthermore, the worm sheet shows water retention and allows C. elegans individuals to be subjected to microscopic observation for long periods under live conditions. In addition, the sheet is only 300 µm thick, allowing heavy ions such as carbon ions to pass through the sheet enclosing the animals, thus allowing the ion particles to be detected and the applied radiation dose to be measured accurately. Because selection of the cover films used for enclosing the animals is very important for successful long-term immobilization, we conducted the selection of the suitable cover films and showed a recommended one among some films. As an application example of the chip, we introduced imaging observation of muscular activities of animals enclosing the microfluidic channel of the worm sheet, as well as the microbeam irradiation. These examples indicate that the worm sheets have greatly expanded the possibilities for biological experiments.

Background: Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet., Methods: We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE)., Findings: We identified 14 lorlatinib-resistant ALK-compound mutants, including several mutants that were recently discovered in lorlatinib-resistant patients. Some of these compound mutants were found to be sensitive to early generation ALK-TKIs and several BCR-ABL inhibitors. Using our original computational simulation, we succeeded in demonstrating a clear linear correlation between binding free energy and in vitro experimental IC 50 value of several ALK-TKIs to single- or compound-mutated EML4-ALK expressing Ba/F3 cells and in recapitulating the tendency of the binding affinity reduction by double mutations found in this study. Computational simulation revealed that ALK-L1256F single mutant conferred resistance to lorlatinib but increased the sensitivity to alectinib., Interpretation: We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Targeted α-particle therapy is a promising option for patients with malignant pheochromocytoma. Recent observations regarding meta - 211 At-astato-benzylguanidine ( 211 At-MABG) in a pheochromocytoma mouse model showed a strong anti-tumor effect, though the molecular mechanism remains elusive. Here, we present the first comprehensive RNA-sequencing (RNA-seq) data for pheochromocytoma cells based on in vitro 211 At-MABG administration experiments. Key genes and pathways in the tumor α-particle radiation response are also examined to obtain potential response biomarkers. Methods: We evaluated genome-wide transcriptional alterations in the rat pheochromocytoma cell line PC12 at 3, 6, and 12 h after 211 At-MABG treatment; a control experiment using 60 Co γ-ray irradiation was carried out to highlight 211 At-MABG-specific gene expression. For comparisons, 10% and 80% iso-survival doses (0.8 and 0.1 kBq/mL for 211 At-MABG and 10 and 1 Gy for 60 Co γ-rays) were used. Results: Enrichment analysis of differentially expressed genes (DEGs) and analysis of the gene expression profiles of cell cycle checkpoints revealed similar modes of cell death via the p53-p21 signaling pathway after 211 At-MABG treatment and γ-ray irradiation. The top list of ranked DEGs demonstrated the expression of key genes on the decrease in the survival following 211 At-MABG exposure, and four potential genes ( Mien1 , Otub1 , Vdac1 and Vegfa genes) of 211 At-MABG therapy. Western blot analysis indicated increased expression of TSPO in 211 At-MABG-treated cells, suggesting its potential as a PET imaging probe. Conclusion: Comprehensive RNA-seq revealed contrasting cellular responses to γ-ray and α-particle therapy, leading to the identification of four potential candidate genes that may serve as molecular imaging and 211 At-MABG therapy targets., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The purpose was to compare survival differences between patients with external auditory canal (EAC) cancer treated according to the University of Pittsburgh modified TNM staging system and those treated in accordance with the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual on the TNM staging system for cutaneous cancers of the head and neck., Methods: We performed a retrospective, single-institution review of 60 patients with EAC cancer treated with curative intent between September 2002 and March 2018. Survival outcomes were measured on the basis of the two staging systems., Results: The C-index values for the overall survival (OS) rate revealed that the University of Pittsburgh staging system had higher prognostic accuracy than the 8th edition of the AJCC staging system. Univariable and multivariable analysis showed that T classification according to the University of Pittsburgh staging system was an independent predictor of the OS rate (hazard ratio 5.25; 95% confidence interval 1.38-24.9; P = 0.015). Meanwhile, the AJCC staging system could not differentiate T2 from T3-4 cancers., Conclusion: The University of Pittsburgh staging system for patients with EAC cancer is a valuable tool for use in clinical decision-making and predicting survival outcome.

Background: The revised 8th edition of the AJCC/UICC staging system was released in January 2017, and depth of invasion (DOI) was added to the new criteria for T classification in oral cavity cancer. In this study, we evaluated whether the 8th edition presents the prognosis and risk of nodal metastasis in patients with squamous cell carcinoma of tongue more accurately than did the 7th edition., Methods: The data for 112 patients were obtained and reclassified based on the criteria presented in the 8th edition., Results: Seven patients previously staged as T1 based on the criteria in the 7th edition were reclassified as T2 based on the 8th edition, while 19 T2 patients were reclassified as T3, and 9 T4a patients were reclassified as T3. T3 in the 8th edition represents a homogenous population showing the same prognosis, while T2 in the 8th edition represents a heterogenous population. Nodal metastasis was significantly correlated with T classification in both editions and DOI. However, neither the T classification in the 7th or 8th edition, nor DOI could predict the probability of potential nodal metastasis in patients with cN0 disease., Conclusions: The classification on T3 in the 8th edition can be seen as reasonable with regard to prognosis. Nodal metastasis was significantly correlated with T classification and DOI; however, the probability of subsequent nodal metastasis in patients with T2N0 was almost same for the criteria in the 7th and 8th editions, therefore, the same careful management as before is required for patients with N0 disease.

Objective: Although elevated anti-mumps IgM antibody levels were reported in 5.7%-7.2% of Japanese patients with sudden sensorineural hearing loss (SSNHL), there were several reports of false-positive cases, such as the continually IgM positive case and the IgM positive case in normal adults. To improve specificity, the new enzyme immuno assay (EIA) anti-mumps IgM antibody measurement kit was introduced in December 2009. This study re-examined the frequency of anti-mumps IgM antibody test positivity with SSNHL using the new measurement kit and compared the results with those from a previous report that used old kit., Methods: This is a retrospective multi-institutional study involving patients diagnosed with SSNHL who exhibited the anti-mumps IgM antibody. We compared the positive rate of anti-mumps IgM antibody and the annual average number of mumps cases per sentinel in Hokkaido between the patients in the present study and patients previously evaluated., Results: Overall, 100 patients with SSNHL were enrolled. One case (1.0%) was positive for anti-mumps IgM antibody. Of the 69 patients evaluated in the previous study, 5 cases (7.2%) were positive for anti-mumps IgM antibody. The positive rate of the anti-mumps IgM antibody in the present cases was significantly lower than that previously reported (p=0.042). The annual average number of mumps cases per sentinel in Hokkaido of the present and previous surveillance period was 34.47 and 42.77, respectively; no significant difference was seen in these data (p=0.4519)., Conclusion: The present study revealed that 1.0% of SSNHL was positive for the anti-mumps IgM antibody using the new EIA-IgM measurement kit. After the introduction of the new EIA-IgM measurement kit, anti-mumps IgM antibody positive rate with SSNHL significantly decreased, indicating that the proportion of asymptomatic mumps among etiology of SSNHL may be lower than those previously reported., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Targeted microbeam irradiation of Caenorhabditis elegans allows the effective knockdown of specific regions, thus helping to identify their roles in processes such as locomotion. We previously employed on-chip immobilization of individuals without anesthesia; however, this method was limited by the thickness of the chip, which prevented the detection of ions passing through the animal, and by dehydration of the animals after prolonged immobilization., New Method: We developed ultra-thin, ion-penetrable, polydimethylsiloxane microfluidic chips, referred to as Worm Sheets, with and without wettability (hydrophilicity/hydrophobicity), and identified suitable buffer conditions for maintaining moisture in the microfluidic channels., Results: Using a collimating microbeam system, we demonstrated that carbon ions (with a range of ∼1 mm) could pass through the chip, thus allowing the ions to be detected and the applied radiation dose to therefore by measured accurately. We also examined the locomotion of C. elegans following on-chip immobilization in different buffers. Locomotion was decreased in certain buffers on unwettable chips as a result of dehydration due to evaporation, but not on wettable chips. However, locomotion was unaffected on either chip in the presence of a gelatin-based wash buffer., Comparison With Existing Method(s): We developed 300-μm-ultra-thin, wettable, ion-penetrable chips for immobilizing C. elegans and provided initial guidance regarding suitable buffer solutions to maintain moisture in microfluidic channels., Conclusions: This improved, wettable chip, together with the identification of suitable buffer conditions, will become a powerful tool for prolonged immobilizing C. elegans, and is widely applicable not only to microbeam irradiation but also to neurobiological assays., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Therapeutic options for patients with malignant pheochromocytoma are currently limited, and therefore new treatment approaches are being sought. Targeted radionuclide therapy provides tumor-specific systemic treatments. The β-emitting radiopharmaceutical meta- 131 I-iodo-benzylguanidine ( 131 I-MIBG) provides limited survival benefits and has adverse effects. A new generation of radionuclides for therapy using α-particles including meta- 211 At-astato-benzylguanidine ( 211 At-MABG) are expected to have strong therapeutic effects with minimal side effects. However, this possibility has not been evaluated in an animal model of pheochromocytoma. We aimed to evaluate the therapeutic effects of the α-emitter 211 At-MABG in a pheochromocytoma model., Methods: We evaluated tumor volume-reducing effects of 211 At-MABG using rat pheochromocytoma cell line PC12 tumor-bearing mice. PC12 tumor-bearing mice received intravenous injections of 211 At-MABG (0.28, 0.56, 1.11, 1.85, 3.70 and 5.55 MBq; five mice per group). Tumor volumes were evaluated for 8 weeks after 211 At-MABG administration. The control group of ten mice received phosphate-buffered saline., Results: The 211 At-MABG-treated mice showed significantly lower relative tumor growth during the first 38 days than the control mice. The relative tumor volumes on day 21 were 509.2% ± 169.1% in the control mice and 9.6% ± 5.5% in the mice receiving 0.56 MBq (p < 0.01). In addition, the mice treated with 0.28, 0.56 and 1.11 MBq of 211 At-MABG showed only a temporary weight reduction, with recovery in weight by day 10., Conclusion: 211 At-MABG exhibited a strong tumor volume-reducing effect in a mouse model of pheochromocytoma without weight reduction. Therefore, 211 At-MABG might be an effective therapeutic agent for the treatment of malignant pheochromocytoma.

Background: We are currently undertaking a multi-institutional prospective trial of the superselective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy for patients with T4aN0M0 or T4bN0M0 locally advanced maxillary sinus squamous cell carcinomas (SCC). We herein report the results of the dose-finding phase., Methods: The dose-finding phase sought to evaluate the incidence of dose-limiting toxicities and determine the recommended number of cycles of the intra-arterial infusion of cisplatin. In this phase, 100 mg/m 2 of cisplatin was administered intra-arterially weekly for 7 weeks with concomitant radiotherapy (70 Gy)., Results: All 18 patients received a full dose of radiotherapy. The number of cycles of cisplatin was 7 in 13 patients and 6 in 5 patients. The dose-limiting toxicities were observed in 5 patients., Conclusion: These results indicated that this therapy is safe and well-tolerated at 7 cycles of cisplatin, which was determined to be the recommended number of cycles for locally advanced maxillary sinus SCC., (© 2017 Wiley Periodicals, Inc.)

Objective: Radionuclide therapy with low-energy auger electron emitters may provide high antitumor efficacy while keeping the toxicity to normal organs low. Here we evaluated the usefulness of an auger electron emitter and compared it with that of a beta emitter for tumor treatment in in vitro models and conducted a dosimetry simulation using radioiodine-labeled metaiodobenzylguanidine (MIBG) as a model compound., Methods: We evaluated the cellular uptake of 125 I-MIBG and the therapeutic effects of 125 I- and 131 I-MIBG in 2D and 3D PC-12 cell culture models. We used a Monte Carlo simulation code (PHITS) to calculate the absorbed radiation dose of 125 I or 131 I in computer simulation models for 2D and 3D cell cultures. In the dosimetry calculation for the 3D model, several distribution patterns of radionuclide were applied., Results: A higher cumulative dose was observed in the 3D model due to the prolonged retention of MIBG compared to the 2D model. However, 125 I-MIBG showed a greater therapeutic effect in the 2D model compared to the 3D model (respective EC 50 values in the 2D and 3D models: 86.9 and 303.9 MBq/cell), whereas 131 I-MIBG showed the opposite result (respective EC 50 values in the 2D and 3D models: 49.4 and 30.2 MBq/cell). The therapeutic effect of 125 I-MIBG was lower than that of 131 I-MIBG in both models, but the radionuclide-derived difference was smaller in the 2D model. The dosimetry simulation with PHITS revealed the influence of the radiation quality, the crossfire effect, radionuclide distribution, and tumor shape on the absorbed dose. Application of the heterogeneous distribution series dramatically changed the radiation dose distribution of 125 I-MIBG, and mitigated the difference between the estimated and measured therapeutic effects of 125 I-MIBG., Conclusions: The therapeutic effect of 125 I-MIBG was comparable to that of 131 I-MIBG in the 2D model, but the efficacy was inferior to that of 131 I-MIBG in the 3D model, since the crossfire effect is negligible and the homogeneous distribution of radionuclides was insufficient. Thus, auger electrons would be suitable for treating small-sized tumors. The design of radiopharmaceuticals with auger electron emitters requires particularly careful consideration of achieving a homogeneous distribution of the compound in the tumor.

Purpose: To evaluate the diagnostic power of hybrid intravoxel incoherent motion (IVIM)-diffusion kurtosis imaging (DKI) model parameters in pretreatment for the prediction of future distant metastasis in head and neck squamous cell carcinoma (HNSCC) patients., Materials and Methods: We retrospectively evaluated 49 HNSCC patients who underwent curative chemoradiation therapy. Diffusion-weighted image (DWI) acquired by single-shot spin-echo echo-planar imaging with 12 b-values (0-2000) was performed in all patients before any treatment. We calculated the IVIM-DKI parameters and the conventional apparent diffusion coefficient (ADC) in the ROI placed on the primary lesion. The presence of future distant metastasis was determined by histological findings or clinical follow-up., Results: A univariate analysis revealed significant differences between the patients with distant metastasis and those without in slow diffusion coefficient (D) and kurtosis value (K). Highest diagnostic accuracy was obtained by the D value. In addition, a multivariate analysis revealed that the D value was an independent predictor of future distant metastasis., Conclusion: The D and K values obtained by this hybrid IVIM-DKI model can be one of the diagnostic tools for the prediction of future distant metastasis in HNSCC patients.

Radiation may affect essential functions and behaviors such as locomotion, feeding, learning and memory. Although whole-body irradiation has been shown to reduce motility in the nematode Caenorhabditis elegans, the detailed mechanism responsible for this effect remains unknown. Targeted irradiation of the nerve ring responsible for sensory integration and information processing would allow us to determine whether the reduction of motility following whole-body irradiation reflects effects on the central nervous system or on the muscle cells themselves. We therefore addressed this issue using a collimating microbeam system. However, radiation targeting requires the animal to be immobilized, and previous studies have anesthetized animals to prevent their movement, thus making it impossible to assess their locomotion immediately after irradiation. We developed a method in which the animal was enclosed in a straight, microfluidic channel in a polydimethylsiloxane chip to inhibit free motion during irradiation, thus allowing locomotion to be observed immediately after irradiation. The head region (including the central nervous system), mid region around the intestine and uterus, and tail region were targeted independently. Each region was irradiated with 12 000 carbon ions (12C; 18.3 MeV/u; linear energy transfer = 106.4 keV/μm), corresponding to 500 Gy at a φ20 μm region. Motility was significantly decreased by whole-body irradiation, but not by irradiation of any of the individual regions, including the central nervous system. This suggests that radiation inhibits locomotion by a whole-body mechanism, potentially involving motoneurons and/or body-wall muscle cells, rather than affecting motor control via the central nervous system and the stimulation response., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Several studies have demonstrated that the seventh edition of the American Joint Committee on Cancer/American Joint Committee on Cancer (AJCC/UICC) TNM staging system does not consistently distinguish between prognostic subgroups for human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma (OPSCC). The eighth edition of the AJCC/UICC TNM staging system came into effect for use with HPV-mediated OPSCC on or after 1 January 2017. This study confirms that the eighth edition of the AJCC/UICC TNM staging system for HPV-mediated OPSCC accurately reflects disease outcomes., Patients and Methods: We retrospectively analyzed 195 patients with OPSCC treated at Hokkaido University Hospital, Sapporo, Japan between 1998 and 2015. HPV status was evaluated by immunohistochemical analysis of p16., Results: Of the 195 OPSCC patients evaluated, 111 (56.9%) were p16 positive and 84 (43.1%) were p16 negative. The 3-year overall survival rate (OS) was significantly lower in the p16-negative patients with stage III-IV in comparison with those with stage I-II (55.0 vs. 93.1%, respectively; p < 0.01). The 3-year OS did not differ significantly between stage I-II and stage III-IV in the p16-positive patients (86.7 vs 87.7%). According to the eighth edition of the AJCC/UICC TNM staging system, stage I-II and stage III can be differentiated on the basis of the 3-year OS in the p16-positive patients (90.9 vs 70.2%, respectively; p < 0.01)., Conclusions: The seventh edition of the AJCC/UICC TNM staging system is suitable for use with p16-negative patients; however, it does not effectively discriminate between p16-positive patients. Therefore, the eighth edition of the AJCC/UICC TNM staging system is more suitable for HPV-mediated OPSCC in Japan.

Background: Osteoradionecrosis (ORN) of the hyoid bone sometimes induces severe front neck infection and can cause laryngeal stenosis and carotid rupture. Although ORN of the hyoid bone is known to be a complication of chemoradiotherapy for head and neck cancer, there has been no basis for its evaluation. Our purpose is to present the clinical and MR imaging features of ORN of the hyoid bone., Methods: The study group comprised patients with advanced oropharyngeal cancer treated with targeted intra-arterial cisplatin infusion with concomitant radiotherapy. ORN of the hyoid bone was identified on the basis of decreased signal intensity of the bone marrow on T1WI images. Signal intensity on T2WI images was used to distinguish between inflammation and fibrosis., Results: A total of 39 pre-treatment MR images and follow-up MR images were reviewed. ORN of the hyoid bone were detected in 30% of patients after treatment, with 23% of them showing inflammation and 7.7% fibrosis. Two patients developed severe neck infection and received antibiotics and underwent surgical intervention by tracheostomy and resection of the hyoid bone., Conclusion: Our MR imaging study showed that ORN of the hyoid bone is not particularly rare in patients with oropharyngeal cancer treated with chemoradiotherapy. Clinicians should evaluate images carefully to prevent the development of severe complication due to infection associated with ORN of the hyoid bone.

Inverted papilloma (IP) is a benign tumor occurring in the nasal cavity and paranasal sinuses. It is reported that 5-15% of IPs undergo malignant transformation into squamous cell carcinoma (SCC), and the role of microRNAs (miRNA/miR) in this process remains to be elucidated. In the present study, whole miRNA profiles using samples of IP and SCC were investigated, in order to detect the function of miRNA in the carcinogenesis of IP. Samples from IPs (n=5) and SCC lesions (n=5), which arose from IPs, were used for miRNA analysis. A total of 200 miRNAs exhibited a >2-fold differential expression between IP and SCC. miR-296-3p was markedly upregulated in SCC with a 23-fold difference. Computational analysis indicated that miR-296-3p targeted PTEN, which regulates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and PTEN is involved in the carcinogenesis of SCC. miR-296-3p directly regulated PTEN expression in head and neck cancer cells, with PTEN protein levels decreased in 4/19 the SCCs (21.0%), as compared with those in the IPs (76.4%). Positive p21 staining was observed in 64.7% of IPs; this was a significantly increased rate compared with that for SCCs (26.3%, P=0.0086). The results of the present study indicated that there were marked changes in the miRNA expression signature during the malignant transition. miR-296-3p may serve an important role in the malignant transformation of IPs via the regulation of PTEN, combined with the subsequent inhibition of the PI3K/Akt signaling pathway, and may be a novel agent for cancer prevention.

We assessed parameters of advanced diffusion weighted imaging (DWI) models for the prediction of the tumor growth rate in 55 head and neck squamous cell carcinoma (HNSCC) patients. The DWI acquisition used single-shot spin-echo echo-planar imaging with 12 b-values (0-2000). We calculated 14 DWI parameters using mono-exponential, bi-exponential, tri-exponential, stretched exponential and diffusion kurtosis imaging models. We directly measured the tumor growth rate from two sets of different-date imaging data. We divided the patients into a discovery group (n = 40) and validation group (n = 15) based on their MR acquisition dates. In the discovery group, we performed univariate and multivariate regression analyses to establish the multiple regression equation for the prediction of the tumor growth rate using diffusion parameters. The equation obtained with the discovery group was applied to the validation group for the confirmation of the equation's accuracy. After the univariate and multivariate regression analyses in the discovery-group patients, the estimated tumor growth rate equation was established by using the significant parameters of intermediate diffusion coefficient D2 and slow diffusion coefficient D3 obtained by the tri-exponential model. The discovery group's correlation coefficient between the estimated and directly measured tumor growth rates was 0.74. In the validation group, the correlation coefficient (r = 0.66) and intra-class correlation coefficient (0.65) between the estimated and directly measured tumor growth rates were respectively good. In conclusion, advanced DWI model parameters can be a predictor for determining HNSCC patients' tumor growth rate.

Purpose: To evaluate the detectability of the residual tumour in post-treatment granulation tissue using parameters obtained with an advanced diffusion model in patients with head and neck squamous cell carcinoma (HNSCC) treated by chemoradiation therapy., Materials and Methods: We retrospectively evaluated 23 patients with HNSCC after the full course of chemoradiation therapy. The diffusion-weighted image (DWI) acquisition used single-shot spin-echo echo-planar imaging with 11 b-values (0-1000). We calculated 10 DWI parameters using a mono-exponential model, a bi-exponential model, a stretched exponential model (SEM), a diffusion kurtosis imaging (DKI) model and a statistical diffusion model (SDM) in the region of interest (ROI) placed on the post-treatment granulation tissue. The presence of residual tumour was determined by histological findings or clinical follow-up., Results: Among the 23 patients, seven patients were revealed to have residual tumour. The univariate analysis revealed significant differences in six parameters between the patients with and without residual tumour. From the receiver operating characteristic curve analysis, the highest area under curve was detected in the center of the Gaussian distribution of diffusion coefficient (D s ) obtained by the SDM. The multivariate analysis revealed that the D s and diffusion heterogeneity (α) obtained by the SEM were predictors for the presence of residual tumour., Conclusion: DWI parameters obtained by advanced fitting models will be one of the diagnostic tools for the detection of residual tumour., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Activated factor X (FXa) plays an important role in thrombin generation and inflammation. Factor X is not converted constitutively to FXa, but only after intrinsic clotting factors are activated and/or cellular injury occurs. Although rivaroxaban is one of direct FXa inhibitors, its function in the inactivated coagulation cascade is unclear. In human umbilical vein endothelial cells that natively express protease-activated receptor-1 and -2, high dose rivaroxaban did not alter gene transcripts including pro-inflammatory genes in DNA microarray. Upon FXa stimulation, the expressions of pro-inflammatory genes such as monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1, and interleukin-8 were maximally increased at 4 h after stimulation, and were suppressed by rivaroxaban. To confirm these results, quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) for MCP-1 were performed. FXa evoked the expression of MCP-1 maximally at 4 h after stimulation, whereas MCP-1 displayed a different temporal activation in ELISA. Interestingly, rivaroxaban inhibited both time courses of MCP-1 expression. These results suggest that rivaroxaban may not influence gene modulation in the inactivated coagulation state, but can attenuate the endothelial damage evoked by FXa and pro-inflammatory cytokine genes., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the diagnostic value of intravoxel incoherent motion (IVIM) and diffusional kurtosis imaging (DKI) parameters in nasal or sinonasal squamous cell carcinoma (SCC) patients to determine local control/failure., Methods: Twenty-eight patients were evaluated. MR acquisition used single-shot spin-echo EPI with 12 b-values. Quantitative parameters (mean value, 25th, 50th and 75th percentiles) of IVIM (perfusion fraction f, pseudo-diffusion coefficient D*, and true-diffusion coefficient D), DKI (kurtosis value K, kurtosis corrected diffusion coefficient D k ) and apparent diffusion coefficient (ADC) were calculated. Parameter values at both the pretreatment and early-treatment period, and the percentage change between these two periods were obtained., Results: Multivariate logistic regression analysis: the percentage changes of D (mean, 25th, 50th, 75th), K (mean, 50th, 75th), Dk (mean, 25th, 50th), and ADC (mean, 25th, 50th) were predictors of local control. ROC curve analysis: the parameter with the highest accuracy = the percentage change of D value with the histogram 25th percentile (0.93 diagnostic accuracy). Multivariate Cox regression analyses: the percentage changes of D (mean, 25th, 50th), K (mean, 50th, 75th), Dk (mean, 25th, 50th) and ADC (mean, 25th, 50th) are predictors., Conclusions: IVIM and DKI parameters, especially the D-value's histogram 25th percentile, are useful for predicting local control., Key Points: • Noninvasive assessment of treatment outcome in SCC patients was achieved using IVIM/DKI. • Several IVIM and DKI parameters can predict the local control. • Especially, the D-value's histogram 25th percentile has high diagnostic accuracy.

Purpose: We assessed advanced fitting models of diffusion weighted imaging (DWI) in head/neck squamous cell carcinoma (HNSCC) patients to determine the best goodness of fit and correlations among diffusion parameters. We compared these results with those of dynamic contrast-enhanced (DCE) perfusion parameters., Materials and Methods: We retrospectively evaluated 32 HNSCC patients (12 sinonasal, 20 pharynx/oral cavity). The DWI acquisition used single-shot spin-echo echo-planar imaging (EPI) with 12 b-values (0-2000). We calculated 14 DWI parameters using mono-exponential, bi-exponential, and tri-exponential models, stretched exponential model (SEM) and diffusion kurtosis imaging (DKI) models. We compared each model's goodness of fit using the residual sum of squares (RSS), Akaike Information Criterion (AIC) and Bayesian information criterion (BIC) value. We determined the correlation between each pair of DWI parameters and between each DWI parameter and DCE perfusion parameter., Results: The tri-exponential fit's RSS, AIC and BIC values were significantly smaller than those for bi-exponential fit. The RSS, AIC and BIC values of the SEM fit and DKI fit were significantly smaller than mono-exponential model. Significant correlations were observed in 30 pairs (sinonasal cavity) and 31 (sinonasal cavity group) among 91 DWI parameter combinations. Significant correlations were also observed in nine pairs (both sinonasal cavity and pharynx/oral cavity group) among 64 DWI/DCE perfusion parameter pairs, in particular, high positive correlations between the tri-exponential model's intermediate diffusion fraction (f 2 ) and the volume of the extracellular extravascular space per unit volume of tissue (v e ) were observed in both patient groups., Conclusion: We identified several correlations between DWI parameters by advanced fitting models and correlations between DWI and DCE parameters. These will help determine HNSCC patients' detailed tissue structures., (Copyright © 2016 Elsevier Inc. All rights reserved.)