Publications by authors named "Hiroshi Nishihara"

389 Publications

ARID1A mutation/ARID1A loss is associated with a high immunogenic profile in clear cell ovarian cancer.

Gynecol Oncol 2021 Jul 13. Epub 2021 Jul 13.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Objectives: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer.

Methods: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases.

Results: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006).

Conclusions: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.
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http://dx.doi.org/10.1016/j.ygyno.2021.07.005DOI Listing
July 2021

Expansion of Photostable Luminescent Radical by Meta-Substitution.

Chem Asian J 2021 Jul 16. Epub 2021 Jul 16.

Ryukoku University: Ryukoku Daigaku, Department of Materials Chemistry, Faculty of Advanced Science and Technology, Seta, 520-2194, Otsu, JAPAN.

Polychlorinated pyridyldiphenylmethyl radicals having substituents meta to the position bearing the carbon-centered radical (α-carbon) are synthesized. All of them are stable in ambient conditions in solutions and fluorescent in cyclohexane. The fluorescence of the radicals with bromo, phenyl, 4-chlorophenyl, or pyridyl substituents are enhanced in chloroform, while the emission of the radicals with 2-thienyl or 2-furyl substituents are quenched in chloroform. DFT and TD-DFT calculations indicate that the first doublet excited states of the former are locally excited, while the first doublet excited states of the latter are charge transfer states from the π-electron-donating substituent to the accepting radical. The latter also show much higher photostability under 370-nm light irradiation compared with the first reported photostable fluorescent radical, (3,5-dichloro-4-pyridyl)bis(2,4,6-trichlorophenyl)methyl radical (PyBTM), with pronounced bathochromic shifts of the fluorescence.
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http://dx.doi.org/10.1002/asia.202100612DOI Listing
July 2021

Prominent response to platinum-based chemotherapy in a patient with mutant-neuroendocrine prostate cancer and amplification.

IJU Case Rep 2021 Jul 5;4(4):216-219. Epub 2021 May 5.

Department of Urology Keio University School of Medicine Tokyo Japan.

Introduction: Genomic profiling provides useful information for diagnosis, treatment, and prognosis, and detection of certain defects, such as DNA repair gene aberrations or microsatellite instability, can possibly lead to optimal treatment, but this testing has not been widely used to inform prostate cancer treatment.

Case Presentation: A 55-year-old man sequentially treated for prostate cancer was diagnosed as neuroendocrine prostate cancer from prostate specimens resected because of urinary retention. Subsequently, he received five cycles of platinum-based chemotherapy in total and responded well. We also performed next-generation sequencing of a sample from the prostate specimen and identified a mutation with amplification and loss of heterozygosity in .

Conclusion: We report a neuroendocrine prostate cancer patient with amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective, and one of the reasons for the good response might be the mutation.
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http://dx.doi.org/10.1002/iju5.12287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255288PMC
July 2021

A first Japanese case of and co-loss organ-confined prostate cancer successfully treated by radical prostatectomy.

Int Cancer Conf J 2021 Jul 27;10(3):170-173. Epub 2021 Mar 27.

Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan.

We report a rare case of localized prostate cancer with and co-loss, which is usually found at a more advanced stage with a poor prognosis. A 59-year-old male with prostate cancer was referred to our hospital for surgical treatment. He had schizophrenia that was well controlled by medicine. He had no family history of prostate cancer, breast cancer, or ovarian cancer. His initial PSA was 4.5 ng/mL, and Gleason score 3 + 4 adenocarcinoma was detected in one of 12 needle biopsy cores. Imaging studies demonstrated the clinical stage to be cT2aN0M0. Therefore, robot-assisted laparoscopic radical prostatectomy (RALP) with bilateral nerve sparing was performed. Based on histopathological analysis, the Gleason score was 4 + 3 and the pathological stage was pT2N0M0 with a negative surgical margin. Genetic sequencing identified and co-loss with limited loss of heterogeneity (LOH). At 12 months after surgery, his PSA level remained < 0.01 ng/mL. This case suggests the importance of early detection of prostate cancer and the possibility of cure for prostate cancer with high malignant potential.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-021-00469-z.
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http://dx.doi.org/10.1007/s13691-021-00469-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206394PMC
July 2021

A ground-state-dominated magnetic field effect on the luminescence of stable organic radicals.

Chem Sci 2021 Jan 5;12(6):2025-2029. Epub 2021 Jan 5.

Department of Life and Coordination-Complex Molecular Science, Institute for Molecular Science 5-1 Higashiyama, Myodaiji Okazaki Aichi 444-8787 Japan

Organic radicals are an emerging class of luminophores possessing multiplet spin states and potentially showing spin-luminescence correlated properties. We investigated the mechanism of recently reported magnetic field sensitivity in the emission of a photostable luminescent radical, (3,5-dichloro-4-pyridyl)bis(2,4,6-trichlorophenyl)methyl radical (PyBTM) doped into host -PyBTM molecular crystals. The magnetic field (0-14 T), temperature (4.2-20 K), and the doping concentration (0.1, 4, 10, and 22 wt%) dependence on the time-resolved emission were examined by measuring emission decays of the monomer and excimer. Quantum mechanical simulations on the decay curves disclosed the role of the magnetic field; it dominantly affects the spin sublevel population of radical dimers in the ground states. This situation is distinctly different from that in conventional closed-shell luminophores, where the magnetic field modulates their excited-state spin multiplicity. Namely, the spin degree of freedom of ground-state open-shell molecules is a new key for achieving magnetic-field-controlled molecular photofunctions.
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http://dx.doi.org/10.1039/d0sc05965jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179284PMC
January 2021

Sclerosing Polycystic Adenosis Arising in the Parotid Gland Without PI3K Pathway Mutations.

Head Neck Pathol 2021 Jun 2. Epub 2021 Jun 2.

Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center At Shreveport, 1501 Kings Highway, Shreveport, LA, 71103, USA.

A 15-year-old old Japanese male with a 2-month history of swelling of his left subauricular area was admitted to our department. A thumb-sized, hard mass with mild tenderness was palpated on the left parotid gland. Ultrasonography revealed a well-circumscribed, hypoechoic mass exhibiting heterogeneity in the left parotid gland measuring 1.7 × 1.5 × 1.3 cm. Computed tomography scan revealed a well-circumscribed, solid mass exhibiting slight peripheral enhancement in the left parotid gland. Magnetic resonance imaging revealed a hypointense mass in the left parotid gland on both T1- and T2-weighted images. Clinicoradiologic findings suggested a benign or low-grade malignant parotid tumor. The patient underwent left superficial parotidectomy with adequate safety margins. The facial nerve was identified and preserved. Neither facial paralysis nor tumor recurrence was observed as of 1 year postoperatively. Histologically, the nodule consisted of a vaguely nodular arrangement of variably sized ducts and acini in a hyalinized fibrous background with focal myxoid changes. The ductal/acinar component exhibited a bilayered arrangement of cuboidal luminal and flattened abluminal cells exhibiting a variety of epithelial proliferative patterns, including micropapillary and cribriform. Areas of oncocyte-like changes with intracellular coarse eosinophilic granules, apocrine-like feature, foamy/vacuolated changes, and clear cells were noted in the proliferating epithelium. Immunohistologically, the luminal cells were positive for gross cystic disease fluid protein-15. The Ki-67 labeling index was 2-3%. The histologic features and immunohistologic profile were consistent with sclerosing polycystic adenosis. Targeted next-generation sequencing of 160 cancer-related genes using the surgical specimen revealed no mutations, including known significant mutations in PTEN, PIK3CA, or PIK3R1.
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http://dx.doi.org/10.1007/s12105-021-01339-zDOI Listing
June 2021

Determination of Brain Tumor Recurrence using C-methionine Positron Emission Tomography after Radiotherapy.

Cancer Sci 2021 Jun 1. Epub 2021 Jun 1.

Department of Nuclear Medicine, Hokkaido University Hospital, Sapporo, Japan.

We conducted a prospective multicenter trial to compare the usefulness of C-methioinine (MET) and F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for identifying tumor recurrence. Patients with clinically suspected tumor recurrence after radiotherapy underwent both C-MET and F-FDG PET. When a lesion showed a visually detected uptake of either tracer, it was surgically resected for histopathological analysis. Patients with a lesion negative to both tracers were revaluated by magnetic resonance imaging (MRI) at three months after the PET studies. The primary outcome measure was the sensitivity of each tracer in cases with histopathologically confirmed recurrence, as determined by the McNemar test. Sixty-one cases were enrolled, and 56 cases could be evaluated. The 38 cases where the lesions showed uptake of either C-MET or F-FDG underwent surgery; and 32 of these cases were confirmed to be subject to recurrence. Eighteen cases where the lesions showed uptake of neither tracer received follow-up MRI; the lesion size increased in 1 of these cases. Among the cases with histologically confirmed recurrence, the sensitivities of C-MET PET and F-FDG PET were 0.97 (32/33, 95% CI: 0.85-0.99) and 0.48 (16/33, 95% CI: 0.33-0.65), respectively, and the difference was statistically significant (p<0.0001). The diagnostic accuracy of C-MET PET was significantly better than that of F-FDG PET (87.5% vs. 69.6%, p=0.033). No examination-related adverse events were observed. The results of the study demonstrated that C-MET PET was superior to F-FDG PET for discriminating between tumor recurrence and radiation-induced necrosis.
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http://dx.doi.org/10.1111/cas.15001DOI Listing
June 2021

Germline mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy.

Asian J Androl 2021 May 21. Epub 2021 May 21.

Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

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http://dx.doi.org/10.4103/aja.aja_37_21DOI Listing
May 2021

Two-Dimensional π-Conjugated Frameworks as a Model System to Unveil a Multielectron-Transfer-Based Energy Storage Mechanism.

Acc Chem Res 2021 May 15. Epub 2021 May 15.

Research Center for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

ConspectusAlthough electrochemical energy storage is commonplace in our society, further advancements in this technology are indispensable for the transition to a low-carbon society. Recent intensive research has expanded concepts in this field; however, finding one suitable material to obtain a high energy density accomplishing the criteria of next-generation batteries is still a conundrum. To solve this issue, material investigations based on big data combined with artificial intelligence are a present trend. On the contrary, this Account focuses on an alternative approach, i.e., fundamental research to shed light on key basic principles to design new electrode materials and new principles achieving multielectron transfer, which is a key to improve a specific capacity. In addition to the cation-redox mechanism, materials showing the multielectron-transfer mechanism based on cation-/anion-redox can enrich material choices with high theoretical energy densities. The challenge in this mechanism is that a rational design of electrode materials based on microscopic understanding of underlying electrode processes has not been fully achieved so far. This is a key bottleneck in machine-learning approaches as well because the reliability of outputs from an algorithm is dependent on the reliability of data from a corresponding microscopic electrode process. Therefore, uncovering fundamental mechanisms in electrochemical energy storage remains one of the primary goals for the present research. In our series of investigations, we developed concepts for replacing complex practical electrode materials, such as polyanion or Li-rich layered oxides, by simplified model systems based on two-dimensional (2D) π-conjugated frameworks, which are based on purely organic aromatic systems and metal-containing coordination polymers. These materials are relatively simple, but it is still possible to control their complexity of systems in order to mimic certain aspects of structure-property relations in practical electrode materials. In particular, recent studies have shown that we can tune electronic structures of 2D π-conjugated frameworks, which is a key feature to investigate electron-transfer mechanisms, along with the concept of the threefold correlation approach, i.e., the relations in chemical structures, electronic structures, and electrochemical reactions. In this Account, several model studies focusing on microscopic understandings of structure-electrochemical energy storage functions are presented in which we investigate how the structural periodicity and nature of the coordination environment affect their electronic properties and the electrochemical reactions. In particular, we investigate the effects of combinations of linkers and metal ions toward the mechanism of the electrochemical energy storage reaction. We identified few major factors determining the energy storage mechanism of 2D π-conjugated frameworks. Local configurations of coordinate covalent bonding and organic linkers interact with each other, and these effects provide unique electronic states. These electronic states are projections of intriguing electrochemical features in this materials system, such as cation/anion co-redox mechanism, anion-insertion mechanism, or inductive effect. This Account indicates that 2D π-conjugated frameworks can be applied as models to extract fundamental/microscopic principles in the complicated electrode processes, which is linked to practical electrode materials, such as oxides. Therefore, the approach shown here is a powerful tool to unveil microscopic electrochemical energy storage mechanisms, which is indispensable to advance clean energy technology and accelerate decarbonization.
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http://dx.doi.org/10.1021/acs.accounts.1c00172DOI Listing
May 2021

First case of ductal adenocarcinoma of the prostate with MAP3K1 homozygous deletion.

IJU Case Rep 2021 May 17;4(3):176-179. Epub 2021 Mar 17.

Department of Urology Keio University School of Medicine Tokyo Japan.

Introduction: Ductal adenocarcinoma of the prostate is a rare prostate cancer variant and associated with higher stage and greater risk of mortality. Optimal systemic therapy for metastatic ductal adenocarcinoma is not known.

Case Presentation: A 67-year-old man presented with ductal adenocarcinoma of the prostate accompanied by multiple lung metastases and advanced bone metastases. We performed channel transurethral resection of the prostate and confirmed the diagnosis of ductal adenocarcinoma of the prostate. DNA sequencing identified a TP53 somatic point mutation (p.Gly245Ser) as the pathogenic variant. Furthermore, a homozygous deletion was observed in mitogen-activated protein kinase kinase kinase 1. The patient received enzalutamide but deceased 5 months after presenting to our institution.

Conclusion: To our knowledge, this is the first report of ductal adenocarcinoma of the prostate with a mitogen-activated protein kinase kinase kinase 1 homozygous deletion. Accumulation of whole-exome sequencing data is expected to inform future advances in therapy development.
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http://dx.doi.org/10.1002/iju5.12274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088887PMC
May 2021

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer.

Sci Rep 2021 Apr 14;11(1):8109. Epub 2021 Apr 14.

Department of Breast Surgery, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, 060-8648, Japan.

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.
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http://dx.doi.org/10.1038/s41598-021-87645-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047009PMC
April 2021

Radical-Based Coordination Polymers as a Platform for Magnetoluminescence.

J Am Chem Soc 2021 Apr 7;143(15):5610-5615. Epub 2021 Apr 7.

Institute for Molecular Science, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.

Spin-correlated electronic and magnetic properties of organic radicals have been developed, but luminescence properties, based on interplay with spins, have rarely been reported. The effect of magnetic fields on luminescence (i.e., magnetoluminescence) is a rare example of such properties, observed to date only in radicals dispersed in host matrices. We now report a novel method for achieving radical magnetoluminescence involving radical-based coordination polymers (CPs). The luminescence properties of the bis(3,5-dichloro-4-pyridyl)(2,4,6-trichlorophenyl)methyl (bisPyTM) and tris(3,5-dichloro-4-pyridyl)methyl (trisPyM) radicals and their 1D and 2D Zn CPs were investigated. Although solid-state emissions of bisPyTM and trisPyM were not affected significantly by external magnetic fields at 4.2 K, those of CPs were greatly modulated. Studies of the crystal structures, magnetic properties, and the temperature-dependence and time-resolved properties of the magnetoluminescence indicate that the reduction of radical-radical interactions in CPs would be a key method for achieving magnetoluminescence.
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http://dx.doi.org/10.1021/jacs.1c00661DOI Listing
April 2021

Diffuse-Type Tenosynovial Giant Cell Tumor Arising in the Temporomandibular Joint Extending to the External Auditory Canal: A Case Report and Literature Review.

Ear Nose Throat J 2021 Mar 23:1455613211002954. Epub 2021 Mar 23.

Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Japan.

A 74-year-old Japanese woman with a 1-year history of right preauricular pain and a 2-month history of bleeding from the right ear was admitted to our department. Tumor was observed in the anterior wall in the right external auditory canal. Bony swelling of the right preauricular area was palpated. Computed tomography revealed an ill-defined, osteogenic tumor around the mandibular condyle with a destructive bony lesion involving the temporal bone. Magnetic resonance imaging revealed a 2.0 × 1.5 × 1.3-cm solid tumor around the mandibular condyle, exhibiting a low-intensity signal on T1-weighted imaging and an isointense central area surrounded by low-signal intensity on T2-weighted imaging. Histological examination of biopsy specimens revealed diffuse-type tenosynovial giant cell tumor (D-TGCT). After the feeding arteries for the tumor were embolized, the patient underwent surgery with combined temporal craniotomy and mandibular condylectomy. The soft and cystic tumor with calcification located in the extradural space was totally resected along with the mandibular condyle. No facial paralysis or recurrence was evident as of 6 months postoperatively. To date, only 23 cases of D-TGCT arising in the temporomandibular joint (TMJ) with ear involvement have been reported since 2011. We report successful resection of a rare case of D-TGCT arising in the TMJ.
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http://dx.doi.org/10.1177/01455613211002954DOI Listing
March 2021

RT-PCR Screening Tests for SARS-CoV-2 with Saliva Samples in Asymptomatic People: Strategy to Maintain Social and Economic Activities while Reducing the Risk of Spreading the Virus.

Keio J Med 2021 Jun 19;70(2):35-43. Epub 2021 Mar 19.

Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.

The year 2020 will be remembered for the coronavirus disease 2019 (COVID-19) pandemic, which continues to affect the whole world. Early and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to combat the disease. Among the current diagnostic tests, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) is the most reliable and frequently used method. Herein, we discuss the interpretation of RT-qPCR results relative to viral infectivity. Although nasopharyngeal swab samples are often used for RT-qPCR testing, they require collection by trained medical staff. Saliva samples are emerging as an inexpensive and efficient alternative for large-scale screening. Pooled-sample testing of saliva has been applied for mass screening of SARS-CoV-2 infection. Current policies recommend isolating people with borderline cycle threshold (Ct) values (35
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http://dx.doi.org/10.2302/kjm.2021-0003-OADOI Listing
June 2021

An Open-shell, Luminescent, Two-Dimensional Coordination Polymer with a Honeycomb Lattice and Triangular Organic Radical.

J Am Chem Soc 2021 Mar 15;143(11):4329-4338. Epub 2021 Mar 15.

Institute for Molecular Science, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.

The use of organic radicals as building blocks is an effective approach to the production of open-shell coordination polymers (CPs). Two-dimensional (2D) CPs with honeycomb spin-lattices have attracted attention because of the unique electronic structures and physical properties afforded by their structural topology. However, radical-based CPs with honeycomb spin-lattices tend to have low chemical stability or poor crystallinity, and thus novel systems with high crystallinity and persistence are in strong demand. In this study, a novel triangular organic radical possessing three pyridyl groups, tris(3,5-dichloro-4-pyridyl)methyl radical (trisPyM) was prepared. It exhibits luminescence, high photostability, and a coordination ability, allowing formation of defined and persistent 2D CPs. Optical measurements confirmed the luminescence of trisPyM both in solution and in the solid state, with emission wavelengths, λ, of 665 and 700 nm, respectively. trisPyM exhibits better chemical stability under photoirradiation than other luminescent radicals: the half-life of trisPyM in CHCl was 10 000 times that of the tris(2,4,6-trichlorophenyl)methyl radical (TTM), a conventional luminescent radical. Complexation between trisPyM and Zn(hfac) yielded a single crystal of a 2D CP , possessing a honeycomb lattice with graphene-like spin topology. The coordination structure of is stable under evacuation at 60 °C. Moreover, exhibits luminescence at 79 K, with λ = 695 nm, and is a rare example of a luminescent material among 2D radical-based CPs. Our results indicate that trisPyM may be a promising building block in the construction of a new class of 2D honeycomb CPs with novel properties, including luminescence.
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http://dx.doi.org/10.1021/jacs.0c13310DOI Listing
March 2021

Estimating copy number using next-generation sequencing to determine ERBB2 amplification status.

Med Oncol 2021 Mar 12;38(4):36. Epub 2021 Mar 12.

Genomics Unit, Keio Cancer Center, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.

Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as "equivocal", which means that some ERBB2 amplification cases diagnosed as "HER2 negative" might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.
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http://dx.doi.org/10.1007/s12032-021-01482-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954749PMC
March 2021

Biglycan, tumor endothelial cell secreting proteoglycan, as possible biomarker for lung cancer.

Thorac Cancer 2021 05 11;12(9):1347-1357. Epub 2021 Mar 11.

Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan.

Objectives: In lung cancer, surgery remains the most curative treatment and limited resection is beneficial for patients with low cardiopulmonary function and low malignancy tumors. However, there are no biomarkers of low malignancy to select candidates for limited resection without compromising the outcome of treatments. Recently we identified biglycan (BGN) as a tumor endothelial cell (TEC) marker that is associated with tumor progression in various cancers. In this study, we analyzed the association between BGN expression in TECs in lung cancer and cancer progression in patients.

Materials And Methods: First, we performed immunohistochemistry of BGN with resected lung tumor tissues of 155 patients who had undergone thoracic surgery and analyzed the correlation between BGN-positive vessel density in primary lung tumors and clinicopathological factors. Second, we measured the BGN levels in preoperative serum of other 46 patients with lung cancer by ELISA, and analyzed the correlation between BGN expression in tumor tissues and blood BGN levels.

Results: High BGN expression in the TECs was significantly associated with T factor, and was a significant negative predictor. BGN levels in preoperative serum of 46 patients with lung cancer was significantly correlated with BGN expression in the TECs. Preoperative serum BGN level was significantly lower in healthy volunteers and less invasive adenocarcinoma than in invasive adenocarcinoma and other lung carcinomas. These results suggest that low BGN level in preoperative serum in patients with lung cancer might indicate low malignancy.

Conclusions: BGN can be a potential biomarker for lung cancer.
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http://dx.doi.org/10.1111/1759-7714.13907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088962PMC
May 2021

Genetic Profiling of Malignant Melanoma Arising from an Ovarian Mature Cystic Teratoma: A Case Report.

Int J Mol Sci 2021 Feb 28;22(5). Epub 2021 Feb 28.

Genomics Unit, Keio Cancer Center, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan.

Ovarian mature cystic teratomas comprise tissues derived from all three germ layers. In rare cases, malignant tumors arise from ovarian mature cystic teratoma. A variety of tumors can arise from mature cystic teratoma, among which primary malignant melanoma (MM), for which no molecular analyses such as genomic sequencing have been reported to date, is exceedingly rare, thereby limiting possible therapeutic options using precision medicine. We used targeted gene sequencing to analyze the status of 160 cancer-related genes in a patient with MM arising from an ovarian mature cystic teratoma (MM-MCT). amplification and homozygous deletion in and were detected in tumor samples collected from the patient. No amplification has been previously reported in cutaneous MM, indicating that the carcinogenesis of MM-MCT differs from that of primary cutaneous melanomas. A better understanding of the underlying genetic mechanisms will help clarify the carcinogenesis of MM-MCT. In turn, this will enable treatment with novel targeting agents as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.
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http://dx.doi.org/10.3390/ijms22052436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957566PMC
February 2021

Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004).

Lung Cancer 2021 03 14;153:134-142. Epub 2021 Jan 14.

Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan.

Objectives: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT).

Methods: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (I) -labeled anti-DLK1 antibody, knowing that I can be replaced with the alpha-particle-emitter astatine-211 (At).

Results: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model.

Conclusion: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.014DOI Listing
March 2021

Pulmonary metastasis secondary to abiraterone-resistant prostate cancer with homozygous deletions of BRCA2: First Japanese case.

IJU Case Rep 2021 Jan 15;4(1):14-17. Epub 2020 Oct 15.

Department of Urology Keio University School of Medicine Tokyo Japan.

Introduction: Most metastatic prostate cancers acquire the capacity for androgen-independent growth and become resistant to androgen deprivation therapy. A patient-focused treatment strategy is needed for aggressive castration-resistant prostate cancer.

Case Presentation: We report the case of a 62-year-old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first-line therapy, he was diagnosed with multiple metastatic castration-resistant prostate cancer in the lung. Second-line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next-generation sequencing of the specimens demonstrated homozygous loss of . We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic deletions.

Conclusions: We present the first Japanese case of a metastatic abiraterone acetate-resistant castration-resistant prostate cancer accompanied by BRCA2 mutation.
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http://dx.doi.org/10.1002/iju5.12224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784740PMC
January 2021

Multiple squamous cell carcinomas arising on an epidermal nevus harboring HRAS p.G13R mutation.

J Dermatol 2021 Feb 8;48(2):e92-e93. Epub 2020 Nov 8.

Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15682DOI Listing
February 2021

Spiradenoma of the breast: a rare diagnostic pitfall in the evaluation of solid-basaloid breast lesions with a dual cell population.

Virchows Arch 2020 Nov 5. Epub 2020 Nov 5.

Department of Pathology, Japanese Red Cross Okinawa Hospital, Okinawa, Japan.

Breast spiradenoma is extremely rare, with only 4 cases reported previously. We describe an instructive case of breast spiradenoma resembling adenoid cystic carcinoma (AdCC). A 71-year-old woman underwent excisional biopsy of a breast mass after a conclusive diagnosis was unable to be obtained from core needle biopsy showing an AdCC-like pattern. Histopathologically, the lesion demonstrated solid and cribriform foci comprising basaloid cells, luminal cells, and eosinophilic hyaline material, reminiscent of solid-basaloid AdCC, alongside convoluted lumens, stromal edema, lymphocytic infiltration, and c-kit negativity. On molecular analysis, neither MYB fusion genes nor CYLD gene abnormalities were identified. These results were supportive of spiradenoma. Salivary gland- and skin adnexal-type tumors are challenging to diagnose due to morphological overlaps. This case, highlighting histopathological and molecular features, shows that breast spiradenoma can be a diagnostic pitfall among the differential diagnoses of AdCC.
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http://dx.doi.org/10.1007/s00428-020-02958-7DOI Listing
November 2020

CDK12 and HER2 coamplification in two urothelial carcinomas with rapid and aggressive clinical progression.

Cancer Sci 2020 Dec 23;111(12):4652-4655. Epub 2020 Oct 23.

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2). In this report, CDK12 and ERBB2 coamplification was detected by targeted next-generation sequencing in two urothelial carcinomas. The staining intensity of the CDK12 and human epidermal growth factor receptor-2 proteins was associated with the prognosis of each urothelial carcinoma case. Our results suggest that CDK12 coamplification with ERBB2 might be associated with tumor aggressiveness and contribution to cancer pathogenesis. Therapies targeting CDK12 should be developed for these patients.
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http://dx.doi.org/10.1111/cas.14672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734002PMC
December 2020

Excimer emission and magnetoluminescence of radical-based zinc(II) complexes doped in host crystals.

Chem Commun (Camb) 2020 Sep;56(76):11195-11198

Institute for Molecular Science, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.

A ZnII complex based on a luminescent organic radical was doped into host molecular crystals. The 5, 10, and 20 wt%-doped crystals showed excimer emissions and their luminescent behaviours were significantly modulated by an external magnetic field. These are the first examples showing excimer emissions and magnetic-field-sensitive luminescent properties for complexes based on luminescent radicals. The excimer species contributing to magnetoluminescence was determined by analyzing the emission spectra and their magnetic-field dependencies. These results suggest the general nature of magnetic field effects on the luminescence of radicals as well as the importance of the type of interaction between radicals.
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http://dx.doi.org/10.1039/d0cc04830eDOI Listing
September 2020

[Management of Cancer Genomic Board and Preparation of Genomic Report].

Gan To Kagaku Ryoho 2020 Aug;47(8):1141-1148

Genomics Unit, Keio Cancer Center, Keio University School of Medicine.

The accumulation of gene alteration is the major pathogenicity of any types of cancer. The concept of precision cancer medicine is therefore the individualized treatment based on the driver gene alteration in each case. The cancer gene profiling (CGP) test, so called gene panel test, will be the major clinical examination to identify the driver gene alteration usually using the FFPE tissue from the surgically resected pathological archives, and government insurance system will cover the examination fee for limited number of cancer patients since 2019 in Japan. Although genetic profiling of tumors is a potentially powerful tool to predict drug sensitivity and resistance, its routine use has been limited because physicians are often unfamiliar with interpretation and incorporation of the information into practice. We established a molecular tumor board (MTB)and clinical tumor board(CTB)system to interpret individual patients' tumor genetic profiles and provide treatment recommendations upon the molecular report.
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August 2020

Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors.

Cancer Med 2020 10 19;9(20):7407-7417. Epub 2020 Aug 19.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. Actionable BRCA1 and BRCA2 variants were found in 4.5% of each of the cases. ERBB2 amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden ≥ 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P < .005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P < .05) and worse survival (P < .01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P < .05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.
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http://dx.doi.org/10.1002/cam4.3383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571820PMC
October 2020

Association of Epstein-Barr virus with regression after withdrawal of immunosuppressive drugs and subsequent progression of iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with autoimmune diseases.

Hematol Oncol 2020 Dec 21;38(5):799-807. Epub 2020 Aug 21.

Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan.

Patients with autoimmune diseases (AIDs) may develop lymphoproliferative disorders (LPDs) during treatment with immunosuppressive agents (IS) such as methotrexate (MTX), biological agents, or tacrolimus. Some LPDs in patients with AIDs (AID-LPDs) regress after withdrawal of IS, and a high incidence of Epstein-Barr virus (EBV) positivity in such patients has been reported. To identify characteristics and factors predictive of the response to treatment and disease progression, we retrospectively analyzed clinical and histopathological data for 81 patients with AID-LPDs. Almost all of them (96%) had been treated with MTX. Diffuse large B cell lymphoma was the most common LPD type (61%) and seven patients (9%) had classical Hodgkin lymphoma (CHL). EBV was detected by in situ hybridization with an EBV-encoded small RNA (EBER) probe in 43% of the examined cases. In 59 patients, IS was discontinued as the initial treatment, resulting in regression of LPDs in 69% of them, and multivariate analysis showed that EBER positivity was an independent factor predictive of such regression (p = 0.022). Two-year progression-free survival (PFS) and overall survival for the patients overall were 63% and 83%, respectively. Poor PFS was associated with advanced stage (p = 0.024), worse performance status (PS, p = 0.031), CHL histology (p = 0.013), and reactivation of EBV-related antibodies (p = 0.029). In conclusion, EBV positivity demonstrated using an EBER probe is useful for prediction of successful regression after withdrawal of IS in patients with AID-LPDs. Patients with advanced stage disease, worse PS, CHL histology, or reactivation of EBV-related antibodies should be closely monitored after initial treatment.
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http://dx.doi.org/10.1002/hon.2790DOI Listing
December 2020

Redox-active, luminescent coordination nanosheet capsules containing magnetite.

Sci Rep 2020 08 14;10(1):13818. Epub 2020 Aug 14.

Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Two-dimensional coordination nanosheets (CONASHs) are grown at the spherical liquid-liquid interface of a dichloromethane droplet in water to form zero-dimensional nano- and micro-capsules using a simple dropping method, a syringe-pump method, and an emulsion method. Reaction of 1,3,5-tris[4-(4'-2,2':6',2″-terpyridyl)phenyl]benzene (1) with Fe(BF) affords electrochromic Fe(tpy) CONASH capsules and that of ligand 1 with ZnSO does photoluminescent Zn(μ-OSO)(tpy) CONASH capsules. Fe(tpy) CONASH capsules containing magnetite particles were produced by the syringe-pump method by adding magnetite to the aqueous phase, with the assembly and dispersion of the magnetite-containing CONASH capsules being easily controlled with a magnet. This indicates that physicochemically functional CONASH capsules are suitable for incorporating other functional materials to develop hybrid systems.
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http://dx.doi.org/10.1038/s41598-020-70715-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429495PMC
August 2020

Clinical impact of a cancer genomic profiling test using an in-house comprehensive targeted sequencing system.

Cancer Sci 2020 Oct 6;111(10):3926-3937. Epub 2020 Sep 6.

Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan.

Precision medicine is a promising strategy for cancer treatment. In this study, we developed an in-house clinical sequencing system to perform a comprehensive cancer genomic profiling test as a clinical examination and analyzed the utility of this system. Genomic DNA was extracted from tumor tissues and peripheral blood cells collected from 161 patients with different stages and types of cancer. A comprehensive targeted amplicon exome sequencing for 160 cancer-related genes was performed using next-generation sequencing (NGS). The sequencing data were analyzed using an original bioinformatics pipeline, and multiple cancer-specific gene alterations were identified. The success rate of our test was 99% (160/161), while re-biopsy was required for 24% (39/161) of the cases. Potentially actionable and actionable gene alterations were detected in 91% (145/160) and 46% (73/160) of the patients, respectively. The actionable gene alterations were frequently detected in PIK3CA (9%), ERBB2 (8%), and EGFR (4%). High tumor mutation burden (TMB) (≥10 mut/Mb) was observed in 12% (19/160) of the patients. The secondary findings in germline variants considered to be associated with hereditary tumors were detected in 9% (15/160) of the patients. Seventeen patients (11%, 17/160) were treated with genotype-matched therapeutic agents, and the response rate was 47% (8/17). The median turnaround time for physicians was 20 days, and the median survival time after the initial visit was 8.7 months. The results of the present study prove the feasibility of implementing in-house clinical sequencing as a promising laboratory examination technique for precision cancer medicine.
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http://dx.doi.org/10.1111/cas.14608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540994PMC
October 2020