Publications by authors named "Kentaro Tanaka"

245 Publications

AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Am J Physiol Regul Integr Comp Physiol 2022 Jan 12. Epub 2022 Jan 12.

Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by the hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered in order to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal (i.p.) administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after i.p. administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after i.p. administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.
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http://dx.doi.org/10.1152/ajpregu.00107.2021DOI Listing
January 2022

Impact of directional coronary atherectomy followed by drug-coated balloon strategy to avoid the complex stenting for bifurcation lesions.

Heart Vessels 2022 Jan 4. Epub 2022 Jan 4.

Department of Cardiovascular Medicine, New Tokyo Hospital, Chiba, Wanagaya Matsudo, 1271270-2232, Japan.

Although the simple single stenting rather than complex double stenting is recommended on percutaneous coronary intervention (PCI) for bifurcation lesions, double stenting cannot always be avoided. We investigated the impact of directional coronary atherectomy (DCA), followed by drug-coated balloon (DCB) treatment to reduce the number of stents and avoid complex stenting in PCI for bifurcation lesions and short-term patency. DCA treatment without stents was attempted for 27 bifurcation lesions in 25 patients, of those, 26 bifurcation lesions in 24 patients were successfully treated and 3-month follow-up angiography and optical coherence tomography (OCT) were performed. Sixteen lesions (59.3%) were related to left main trunk distal bifurcations, and 7 (25.9%) were true bifurcation lesions. Among the true bifurcation lesions, 4 lesions (57.1%) needed 1 stent, and the other 3 lesions (42.9%) needed no stents. Among the non-true bifurcation lesions, 1 lesion (5.0%) needed bailout stent and other lesions (95.0%) needed no stents. According to DCA followed by DCB treatment, the angiographic mean diameter stenosis improved from 65.5 ± 15.0% to 7.8 ± 9.8%, and the mean plaque area in intravascular ultrasound improved from 80.4 ± 10.5% to 39.0 ± 11.5%, respectively. Angiographic and OCT late lumen loss values were 0.2 ± 0.6 mm and 1.4 ± 1.9 mm, respectively. No patient had in-hospital major adverse cardiac events (MACE) and 3-month MACE. In conclusion, compared with standard provisional side branch stenting strategy, DCA followed by DCB treatment might reduce the number of stents, avoid complex stenting for major bifurcation lesions and provide good short-term outcomes.
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http://dx.doi.org/10.1007/s00380-021-02000-zDOI Listing
January 2022

Construction of a prediction model for drug removal rate in hemodialysis based on chemical structures.

Mol Divers 2022 Jan 1. Epub 2022 Jan 1.

Department of Medical Molecular Informatics, Meiji Pharmaceutical University, 2-522-1Kiyose-shi, Tokyo, Noshio, 204-858, Japan.

In designing drug dosing for hemodialysis patients, the removal rate (RR) of the drug by hemodialysis is important. However, acquiring the RR is difficult, and there is a need for an estimation method that can be used in clinical settings. In this study, the RR predictive model was constructed using the RR of known drugs by quantitative structure-activity relationship (QSAR) analysis. Drugs were divided into a model construction drug set (75%) and a model validation drug set (25%). The RR was collected from 143 medicines. The objective variable (RR) and chemical structural characteristics (descriptors) of the drug (explanatory variable) were used to construct a prediction model using partial least squares (PLS) regression and artificial neural network (ANN) analyses. The determination coefficients in the PLS and ANN methods were 0.586 and 0.721 for the model validation drug set, respectively. QSAR analysis successfully constructed dialysis RR prediction models that were comparable or superior to those using pharmacokinetic parameters. Considering that the RR dataset contains potential errors, we believe that this study has achieved the most reliable RR prediction accuracy currently available. These predictive RR models can be achieved using only the chemical structure of the drug. This model is expected to be applied at the time of hemodialysis.
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http://dx.doi.org/10.1007/s11030-021-10348-7DOI Listing
January 2022

Optically Active Cyclic Oligomers Based on Planar Chiral [2.2]Paracyclophane.

Chem Asian J 2022 Jan 18;17(2):e202101267. Epub 2021 Dec 18.

Department of Applied Chemistry for Environment, School of Biological and Environmental Sciences, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo, 669-1337, Japan.

Optically active cyclic dimer, trimer, and tetramer, in which the p-arylene-ethynylenes were stacked, were prepared using enantiopure 4,7,12,15-tetrasubstituted [2.2]paracyclophane as the chiral building block. All molecules exhibited clear Cotton effects in their absorption bands with mirror image spectra, and the signals of the longest wavelengths of the (R )- and (S )-isomers were positive and negative, respectively. Their circularly polarized luminescence (CPL) signs corresponded with the those of the first Cotton effect. For all molecules, molecular orbitals were localized in one of the stacked p-arylene-ethynylenes in the excited states, resulting in a similar photoluminescence behavior. Although the cyclic dimer did not emit CPL, the cyclic trimer and tetramer exhibited intense CPL emissions with a relatively high dissymmetry factor in the order of 10 . Their optical and chiroptical properties were reproduced by time-dependent density functional theory calculations.
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http://dx.doi.org/10.1002/asia.202101267DOI Listing
January 2022

Clusterin and Related Scoring Index as Potential Early Predictors of Response to Sorafenib in Hepatocellular Carcinoma.

Hepatol Commun 2021 Nov 27. Epub 2021 Nov 27.

Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Advanced hepatocellular carcinoma (HCC) remains a highly lethal malignancy, although several systemic therapeutic options are available, including sorafenib (SFN), which has been one of the standard treatment agents for almost a decade. As early prediction of response to SFN remains challenging, biomarkers that enable early prediction using a clinically feasible method are needed. Here, we report that the serum secretory form of clusterin (sCLU) protein and its related predictive index are potential beneficial biomarkers for early prediction of SFN response. Using high-throughput screening and subsequent multivariate analysis in the derivation cohort, we found that changes in the concentrations of CLU, vascular cell adhesion molecule-1 (VCAM1), and α-fetoprotein were significantly associated with response to SFN. Furthermore, we confirmed that an increase in CLU serum level 1 month after treatment initiation was significantly associated with shorter progression-free survival. In addition, "NR-index," which comprises these proteins, was evaluated as a tool for accurately predicting the efficacy of SFN and confirmed in the validation cohort. We also established SFN-resistant HepG2 cells (HepG2-SR) and found that sCLU significantly increased in HepG2-SR cells compared with normal HepG2 cells, and confirmed that HepG2-SR cells treated with SFN were resistant to apoptosis. The mechanism underlying activation of sCLU expression in acquired SFN resistance involves aberrant signaling and expression of Akt, mammalian target of rapamycin (mTOR), and a nutrient-related transcription factor, sterol regulatory element binding protein 1c (SREBP-1c). Furthermore, the PI3K and mTOR inhibitor BEZ235 markedly decreased sCLU expression in HepG2-SR cells. Conclusion: These results suggest that measurement of sCLU serum levels and the sCLU-related NR-index are promising clinical tools for the early prediction of SFN response in HCC. Additionally, sCLU-overexpressing HCC might be susceptible to mTOR inhibition.
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http://dx.doi.org/10.1002/hep4.1872DOI Listing
November 2021

A Multicenter, Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non-Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study).

Clin Lung Cancer 2021 Oct 25. Epub 2021 Oct 25.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan. Electronic address:

Background: First-line treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death-1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte-associated protein-4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC.

Patients And Methods: Chemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events.

Conclusion: If the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2021.10.012DOI Listing
October 2021

Standard therapy-resistant small cell lung cancer showing dynamic transition of neuroendocrine fate during the cancer trajectory: A case report.

Mol Clin Oncol 2021 Dec 20;15(6):261. Epub 2021 Oct 20.

Department of Medicine, Keiyu Hospital, Yokohama, Kanagawa 220-8521, Japan.

While small cell lung cancer (SCLC) has been treated as a single disease historically, recent studies have suggested that SCLC can be classified into molecular subtypes based on the expression of lineage transcription factors such as achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU domain class 2 transcription factor 3 (POU2F3) and transcriptional coactivator YAP1 (YAP1). These transcription factor-based subtypes may be specifically targeted in therapy, and recent studies have suggested that the SCLC subtypes represent different stages of dynamic evolution of SCLC rather than independent diseases. Nevertheless, evidence of shift in neuroendocrine differentiation during SCLC evolution has been lacking in the clinical setting. In the present study, a 60-year-old male was diagnosed with extensive SCLC. The tumor responded not to the standard SCLC regimen of carboplatin, etoposide and atezolizumab, but to the non-SCLC regimen of carboplatin, nab-paclitaxel and pembrolizumab. The patient succumbed 5 months after the initial diagnosis and a pathological autopsy was performed. The tumor was originally negative for all four transcription factors, ASCL1, NEUROD1, POU2F3 and YAP1, in the biopsy specimens at diagnosis. Loss of synaptophysin expression and emergence of Myc proto-oncogene protein and YAP1 expression was recorded in the autopsy specimens, suggesting the transition to a decreased neuroendocrine fate during the disease trajectory. This case provides clinical evidence of dynamic transition of neuroendocrine fate during SCLC evolution. In light of SCLC heterogeneity and plasticity, development of precision medicine is required.
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http://dx.doi.org/10.3892/mco.2021.2423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591693PMC
December 2021

Synthesis of a monocationic μ-nitrido-bridged iron porphycene dimer and its methane oxidation activity.

Dalton Trans 2021 Nov 23;50(45):16775-16781. Epub 2021 Nov 23.

Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.

Herein, we report the synthesis of a monocationic μ-nitrido-bridged iron porphycene dimer, a structural analogue of a monocationic μ-nitrido-bridged iron phthalocyanine dimer, which is known to be one of the most potent molecule-based catalysts for methane oxidation. H-NMR and single-crystal X-ray structural analyses showed that the porphycene complex includes two Fe(IV) ions, and the structure around the Fe-NFe core is quite similar to that of the monocationic μ-nitrido-bridged iron phthalocyanine dimer. Although methane was oxidized into MeOH, HCHO, and HCOOH in the presence of a silica-supported catalyst of this monocationic μ-nitrido-bridged iron porphycene dimer in an acidic aqueous solution containing excess HO, its reactive intermediate was not a high-valence iron-oxo species, as in the case of a monocationic μ-nitrido-bridged iron phthalocyanine dimer, but ˙OH. It is suggested that the high-valent iron-oxo species of the μ-nitrido-bridged iron porphycene dimer was gradually decomposed under these reaction conditions, and the decomposed compound catalyzed a Fenton-type reaction. This result indicates that the stability of the oxo-species is indispensable for achieving high catalytic methane oxidation activity using a μ-nitrido-bridged iron porphyrinoid dimer with an Fe-NFe core as a catalyst.
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http://dx.doi.org/10.1039/d1dt02922cDOI Listing
November 2021

Comparative Blink Analysis in Patients With Established Facial Paralysis Using High-Speed Video Analysis.

J Craniofac Surg 2021 Nov 5. Epub 2021 Nov 5.

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, The University of Tokyo Department of Plastic and Reconstructive Surgery, Graduate School of Science Research Administration Divisions, Research University Promotion Organization, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract: This study analyzed the blink characteristics of patients with incomplete and complete facial paralysis. The authors measured and compared the palpebral distance, eyelid movement distance, and the eye-closing ratio of blinks in 55 patients with Bell's palsy or Ramsay Hunt syndrome (Bell & Hunt group) and 14 with complete paralysis (Complete Paralysis group). In the Bell & Hunt group, the palpebral distance (7.94 mm) was smaller on the paralyzed side than on the non-paralyzed side (9.61 mm). The eye-closing ratio and the upper eyelid movement were reduced on the paralyzed side (65.3% versus 93.7%, 4.61 versus 7.97 mm) and in the Complete Paralysis group (25.3% versus 94.7%, 2.10 versus 8.49 mm). In the Bell & Hunt group, movement of the upper eyelid on the paralyzed side was weakened despite palpebral contracture. The Complete Paralysis group exhibited highly reduced movement in both the upper and lower eyelids.
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http://dx.doi.org/10.1097/SCS.0000000000008326DOI Listing
November 2021

A Concept of "Boundary Determination" by the Combination of a Local Flap and Free Tissue Transfer Useful for the Prevention of Postoperative Complications After Complex and Widespread Skull Base Reconstruction.

J Craniofac Surg 2021 Nov-Dec 01;32(8):e820-e822

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Abstract: The transplanted tissue is sutured to the stumps of the bones in skull base reconstruction. Concerning reconstruction by free tissue transfer, it is difficult that the tissue is accurately sutured/fixed to a complex three-dimensional structure. The authors devised a technique in which free tissue transfer is combined with a local flap. A pericranial flap is sutured/fixed onto the irregular border between the cranial and nasal cavities. A free tissue graft is transplanted cranial or caudal to the determined border. Clinical presentation 1 is a patient with carcinoma of the frontal sinus (T4bN0M0). Resection of the frontal bone/nasal bone/medial and superior walls of the orbit, frontal lobectomy was performed. Clinical presentation 2 is a patient with carcinoma of the maxillary sinus (T4aN0M0). Extended total maxillectomy, simultaneous resection of the facial skin/temporal muscle were performed. There were no serious postoperative complications related to compression or occlusion of the cerebral parenchyma or paranasal sinus.
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http://dx.doi.org/10.1097/SCS.0000000000007889DOI Listing
November 2021

Influence of Marker Number and Position on Accuracy of Breast Measurement With Three-Dimensional Camera.

Aesthetic Plast Surg 2021 Oct 26. Epub 2021 Oct 26.

Plastic and Reconstructive Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.

Background: The VECTRA H1 three-dimensional (3D) imaging system (Canfield Scientific, Parsippany, NJ) enables easy 3D image construction and measurement. Although the number and positions of markers on the skin for image synthesis might affect accuracy of measurements, few studies have mentioned the possibility. This study investigated the accuracy and reproducibility of distance measurements using VECTRA H1, focusing on the number and positions of markers.

Methods: A total of 3, 5, or 7 markers were attached to a female breast model including lateral markers 6 cm from the midline and photographed with VECTRA. Five markers were configured in more two ways, with the lateral markers either positioned 3 cm outside the midline (narrow interval) or 9 cm outside the midline (wide interval). 3D models were created three times under each condition, for a total of 15 models. Differences (measurement error) between measured values on 3D models and actual measured values were verified for six distances, such as distance between the nipples.

Results: The average difference was 11.1 mm with 3 markers (95% confidence interval (CI), 4.38-17.7 mm, p = 0.0028). In comparison, average difference was -0.395 mm (-0.866 to 0.0763 mm, p = 0.095) with 5 markers, and 0.139 mm (-0186 to 0.465 mm, p = 0.379) with 7 markers, all less than 1 mm. Average difference with narrow interval 5 markers was larger than one with wide interval.

Conclusions: In 3D imaging of the breast using VECTRA H1, distance measurements offering clinically satisfactory accuracy can be made by setting appropriate marker conditions.

Level Of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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http://dx.doi.org/10.1007/s00266-021-02629-1DOI Listing
October 2021

Optimal management of lenvatinib therapy for patients with unresectable hepatocellular carcinoma by balancing the therapeutic effect with the relative dose intensity.

Hepatol Res 2022 Jan 22;52(1):105-119. Epub 2021 Oct 22.

Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Aims: We aimed to assess the optimal management of first or later-line lenvatinib therapy (LEN) for patients with unresectable hepatocellular carcinoma (uHCC), by clarifying the difference of degree between relative dose intensity (RDI) to achieve objective response (OR) and disease control (DC) by aiming at stable disease (SD), taking dose modifications into consideration.

Methods: One hundred uHCC patients who received LEN in first- or later-line settings, between April 2018 and December 2020 in our hospital were analyzed retrospectively. The factors associated with overall survival (OS), time to progression (TTP), OR and DC were assessed. The optimal cut-off values of RDI 4 weeks after initiation of LEN (RDI during cycle 1) and total RDI (RDI during all cycles) to predict achievement of OR and DC by aiming at SD were determined by receiver operator curve analysis.

Results: Achievement of OR and SD were favorable factors for OS (HR, 0.080 and 0.20) and TTP (HR, 0.052 and 0.073), with progressive disease defined as the reference. RDI ≥ 0.8 during cycle 1 and RDI ≥ 0.4 during cycle 1 contributed to achievement of OR (odds ratio, 3.28) and DC (odds ratio, 4.85), respectively. Experience of dose interruption was associated with a favorable TTP (HR, 0.58). The therapeutic line of LEN did not contribute to OS, TTP or best response.

Conclusions: To achieve OR and SD for a favorable outcome of first- or later-line LEN, high and moderate early-phase RDI are required, respectively. The degree of RDI during LEN and tolerance need compatible by dose modifications.
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http://dx.doi.org/10.1111/hepr.13720DOI Listing
January 2022

Influence of normal tide and the Great Tsunami as recorded through hourly-resolution micro-analysis of a mussel shell.

Sci Rep 2021 10 6;11(1):19874. Epub 2021 Oct 6.

Atmosphere and Ocean Research Institute, University of Tokyo, Chiba, Japan.

We report here hourly variations of Mg/Ca, Sr/Ca, and Ba/Ca ratios in a Mediterranean mussel shell (Mytilus galloprovincialis) collected at the Otsuchi bay, on the Pacific coast of northeastern Japan. This bivalve was living in the intertidal zone, where such organisms are known to form a daily or bidaily growth line comprised of abundant organic matter. Mg/Ca ratios of the inner surface of the outer shell layer, corresponding to the most recent date, show cyclic changes at 25-90 μm intervals, while no interpretable variations are observed in Sr/Ca and Ba/Ca ratios. High Mg/Ca ratios were probably established by (1) cessation of the external supply of Ca and organic layer forming when the shell is closed at low tide, and (2) the strong binding of Mg to the organic layer, but not of Sr and Ba. Immediately following the great tsunami induced by the 2011 Tohoku earthquake, Mg/Ca enrichment occurred, up to 10 times that of normal low tide, while apparent Ba/Ca enrichment was observed for only a few days following the event, therefore serving a proxy of the past tsunami. Following the tsunami, periodic peaks and troughs in Mg/Ca continued, perhaps due to a biological memory effect as an endogenous clock.
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http://dx.doi.org/10.1038/s41598-021-99361-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494904PMC
October 2021

High Incidence of C797S Mutation in Patients With Long Treatment History of EGFR Tyrosine Kinase Inhibitors Including Osimertinib.

JTO Clin Res Rep 2021 Jul 14;2(7):100191. Epub 2021 May 14.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Yufu, Japan.

Introduction: Although treatment with osimertinib confers survival benefits in patients with lung cancer with the T790M mutation, the mechanism of acquired resistance to osimertinib remains poorly understood. We conducted a prospective observational study to identify the mechanism on the basis of repeated tissue biopsies.

Methods: Patients with -mutated advanced lung cancer with a T790M mutation detected on a tissue biopsy underwent a rebiopsy after developing acquired resistance to osimertinib. Nucleic acids extracted from the biopsy samples were subjected to targeted resequencing (Oncomine Comprehensive Assay), and circulating cell-free DNA (ccfDNA) was analyzed by CAncer Personalized Profiling by deep Sequencing (AVENIO ctDNA Surveillance Kit).

Results: Between November 2016 and March 2020, a total of 87 patients were screened. Among them, 44 developed acquired resistance. Of these, 19 samples from rebiopsies and 12 from preosimertinib biopsies were able to be analyzed by an Oncomine Comprehensive Assay. A ccfDNA analysis was performed in 16 patients. Regarding the mechanisms of acquired resistance, structural change in EGFR, namely, C797S, G796S, or L792V, was the most frequent alteration, being observed in 57.9% of the cases. gain was observed in 31.6% of the cases, and gains in cell cycle genes were observed in 26.3% of the cases. In addition, we identified gain and an mutation in a patient with small-cell transformation and a V600E mutation in a patient with oligoprogressive disease.

Conclusions: A repeated tissue biopsy and a ccfDNA analysis were useful in analyzing the mechanisms underlying acquired resistance. A long treatment history of EGFR TKIs may result in a high percentage of EGFR structural change.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474195PMC
July 2021

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With Mutations.

JTO Clin Res Rep 2021 Jan 12;2(1):100107. Epub 2020 Oct 12.

Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.

Patients with NSCLC in East Asia, including Japan, frequently contain mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent -mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring -activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474490PMC
January 2021

The C29-C34 parts of antitumor macrolide aplyronine A serve as versatile actin-affinity tags.

Chem Commun (Camb) 2021 Oct 12;57(81):10540-10543. Epub 2021 Oct 12.

Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.

Anticancer drug development inspired by natural products based on protein-protein interactions (PPI) is a promising strategy. We developed structurally-simplified C29-C34 side-chain analogs of aplyronine A (ApA), an antitumor marine macrolide. Among them, the analog possessing the C23 acyloxy group, the C29 ,-dimethyl-L-alanine ester and the C34 -methyl enamide showed potent actin-depolymerizing activity. Binding kinetics, molecular docking, and affinity-purification experiments revealed that they are versatile actin-affinity tags to accelerate studies on the mode of action related to cytoskeletal dynamics and the development of PPI-based drug leads.
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http://dx.doi.org/10.1039/d1cc04259aDOI Listing
October 2021

The different concepts of surgical managements between anterior and lateral skull base reconstructions based on surgical purposes.

Auris Nasus Larynx 2021 Aug 27. Epub 2021 Aug 27.

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objective: Anterior and middle cranial fossa defects require different strategies, depending on their anatomical location. The aim of this study was to elucidate the surgical managements for the defects based on surgical purposes and to clarify the conceptional differences relating to anterior and lateral skull base reconstructions.

Methods: This study included patients who had undergone reconstructive surgery for anterior or middle cranial fossa defects in our institution between July 2008 and June 2019. It consisted of 66 patients who had been subject to anterior skull base reconstructions, and 84 patients who had experienced lateral skull base reconstructions. The medical records were examined retrospectively, and the surgical purposes and procedures performed were reviewed. The surgical purposes were divided into four groups: Separation, Restoration, Augmentation, and Coverage.

Results: Regarding anterior skull base reconstructions, the Separation group included 65 patients, who represented 98% of this category. There were 26 cases in the Separation-only group, 20 of which were reconstructed with locoregional flaps, and 6 of which with free tissue transfers. A Combination group, which consisted of Separation and Other purposes, consisted of 40 cases. Within this group, 5 cases were reconstructed with locoregional flaps, and 35 with free tissue transfers. Regarding lateral skull base reconstructions, the Separation group included 34 patients, who represented 40% of this category. The rate of the Other purposes represented the majority. In the Separation-only group of 24 patients, 16 cases were reconstructed with locoregional flaps and 8 cases with free tissue transfers. In the Combination group of 10 patients, 2 cases were reconstructed with locoregional flaps and 8 cases with free tissue transfers. In groups other than the Separation group, 27 cases were reconstructed with locoregional flaps and 23 cases with free tissue transfers.

Conclusion: In most anterior cranial fossa defect cases, the surgical purpose is separation. In middle cranial fossa defect cases, there are many cases in which the surgical purpose is not separation. In the Separation groups, relating to both anterior and lateral skull base reconstructions, the use of locoregional flaps was an effective measure. Free tissue transfers were required in many cases of the Combination group. Outside of the Separation group associated with lateral skull base reconstructions, the use of locoregional flaps and free tissue transfers were almost equal in proportion, and the selection of reconstructive procedures tended to change from locoregional flaps to large free flaps with increase in the numbers of surgical purposes.
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http://dx.doi.org/10.1016/j.anl.2021.08.005DOI Listing
August 2021

A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L).

J Thorac Oncol 2021 12 19;16(12):2121-2132. Epub 2021 Aug 19.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Lung Oncology Group in Kyushu (LOGiK), Fukuoka, Japan.

Objectives: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC.

Methods: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA.

Results: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively.

Conclusions: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
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http://dx.doi.org/10.1016/j.jtho.2021.07.026DOI Listing
December 2021

Increased plasma levels of damage-associated molecular patterns during systemic anticancer therapy in patients with advanced lung cancer.

Transl Lung Cancer Res 2021 Jun;10(6):2475-2486

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Immunogenic cell death (ICD) characterized by the release of damage-associated molecular patterns (DAMPs) from dying cancer cells may contribute to the synergistic antitumor effect of cytotoxic chemotherapy combined with an immune checkpoint inhibitor. The kinetics of circulating DAMP levels in cancer patients have remained largely uncharacterized, however.

Methods: We evaluated the possible effects of various systemic anticancer therapy modalities on the kinetics of plasma DAMP concentrations in a prospective observational study of patients with advanced lung cancer. The plasma concentrations of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), annexin A1, and histone H3 were thus determined in 121 such patients at four time points during the first cycle of treatment.

Results: The mean of the maximum fold change in HMGB1, HSP70, or annexin A1 concentration observed during treatment was significantly greater than the corresponding baseline value (P<0.005). The maximum fold changes in HMGB1 and CRT concentrations tended to be associated with clinical response as evaluated by RECIST criteria, although the changes in the levels of these two DAMPs were not correlated, suggestive of differential induction mechanisms. Among the various treatment modalities administered, platinum-based combination or single-agent chemotherapy tended to elicit robust increases in the concentrations of HMGB1 and CRT.

Conclusions: Serial monitoring of plasma revealed that systemic anticancer therapy increased the circulating levels of HMGB1 and CRT and that these changes tended to be associated with clinical response, suggesting that agents capable of releasing these DAMPs into plasma might induce ICD in advanced lung cancer patients.
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http://dx.doi.org/10.21037/tlcr-21-92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264341PMC
June 2021

Decline in renal function associated with cardiovascular autonomic neuropathy positively coordinated with proteinuria in patients with type 2 diabetes.

J Diabetes Investig 2022 Jan 27;13(1):102-111. Epub 2021 Jul 27.

Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose City, Japan.

Aims/introduction: To investigate the association between cardiovascular autonomic neuropathy (CAN) assessed by the coefficient of variation of the R-R interval and the reduction in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.

Materials And Methods: This retrospective observational cohort study enrolled type 2 diabetes patients who had their coefficient of variation of the R-R interval measured on an electrocardiogram from January 2005 to December 2018. CAN was defined using the reference coefficient of variation of the R-R interval value based on age and sex. The primary outcome was set as a 40% eGFR decline from baseline. Regression analyses using the Cox proportional hazards model were carried out to evaluate the association.

Results: Of the 831 patients, 118 (14.2%) were diagnosed with CAN. In the analysis of the primary outcome, the median follow-up period was 5.3 years, and 25 (21.2%) patients with CAN and 78 (10.9%) patients without CAN developed a 40% eGFR decline. In the univariate regression analysis, CAN was significantly associated with a 40% eGFR decline (hazard ratio 2.42, 95% confidence interval 1.54-3.80). In the multivariate analysis, CAN remained almost significant after adjusting for the prognostic risk factors for CAN and the decline in the renal function, and an interaction with proteinuria was found. In analyses for the interaction effect between CAN and proteinuria, the presence of CAN synergistically increased the risk of an eGFR decline in patients with macroproteinuria.

Conclusions: CAN strongly increased the risk of a 40% eGFR decline from baseline, especially in type 2 diabetes patients with macroproteinuria.
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http://dx.doi.org/10.1111/jdi.13625DOI Listing
January 2022

Reliability of Temporal Vascular Anastomosis and Techniques for Better Outcomes.

J Reconstr Microsurg 2022 Jan 29;38(1):41-46. Epub 2021 Jun 29.

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background:  Although there are several potential recipient vessels in the neck, those in the temporal region are limited. In skull base reconstruction, there are difficulties associated with the anastomosing recipient vessels in the neck region since long nutrient vessels are needed in the flap. We evaluated the reliability of temporal vascular anastomosis by comparing surgical outcomes between reconstructive methods and examined which surgical procedures may achieve better results.

Methods:  We examined the medical records of free tissue transfer cases between April 2007 and March 2018. Seventy-three surgeries were performed in the temporal region, including skull base reconstruction in 48, head and neck reconstruction (without skull base) in 16, and secondary surgery for head deformities in nine cases. In total, 445 neck surgeries were performed. Postoperative complications were retrospectively analyzed.

Results:  The postoperative complication rates were 8.2 and 2.7% for all temporal and neck surgeries, respectively. There were no arterial complications in the temporal region and all of the six postoperative anastomotic complications were due to venous thrombosis. In contrast, there were 12 cases of vascular anastomotic complications, with six cases each of arterial and venous thrombosis in the neck. In the temporal region, the complication rate was 2.1% for skull base reconstruction, 11% for secondary revision, and 25% in head and neck reconstruction. The corresponding values for middle temporal vein (MTV) usage rates were 54, 22, and 25%. In skull base reconstruction, a coronal incision was made in all cases. A more frequent use of the MTV was associated with a reduced complication rate.

Conclusion:  The low complication rate in the temporal region was attributed to the wide surgical field and low tension of anastomotic vessels. Multiple venous anastomoses, including those of the MTV, are recommended to prevent complications.
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http://dx.doi.org/10.1055/s-0041-1729883DOI Listing
January 2022

Paired analysis of tumor mutation burden for lung adenocarcinoma and associated idiopathic pulmonary fibrosis.

Sci Rep 2021 06 17;11(1):12732. Epub 2021 Jun 17.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.
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http://dx.doi.org/10.1038/s41598-021-92098-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211684PMC
June 2021

Quantification of HER family dimers by proximity ligation assay and its clinical evaluation in non-small cell lung cancer patients treated with osimertinib.

Lung Cancer 2021 08 25;158:156-161. Epub 2021 May 25.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objectives: The epidermal growth factor receptor (EGFR, also known as Her1) is a member of the human epidermal growth factor receptor (HER) family of proteins and a target of tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) positive for activating mutations ofEGFR. Signal transduction by HER family proteins is dependent on their homo- or heterodimerization, but little is known of the relation between the relative proportions of such dimers of Her1 and sensitivity to EGFR-TKIs. We here investigated the feasibility of assessing this relation with the in situ proximity ligation assay (PLA) technique, which is able to detect the interaction of two proteins of interest when they are in close proximity.

Materials And Methods: In situ PLA was applied to detect Her1 homodimers and Her1 heterodimers in NSCLC cell lines and tissue specimens positive for EGFR activating mutations.

Results: In situ PLA allowed visualization and quantitative assessment of Her1 homodimers as well as of Her1 heterodimers with Her2, Her3, or Her4 not only in NSCLC cell lines but also in NSCLC tissue specimens obtained from various anatomic sites and by different collection methods. Treatment of NSCLC cell lines with EGFR-TKIs resulted in a decrease in the number of Her1 dimers, with the effect on homodimers being greater than that on heterodimers. A high ratio of Her1 heterodimers to homodimers was associated with poor progression-free survival in NSCLC patients treated with osimertinib.

Conclusion: In situ PLA allows the detection of HER family dimers in NSCLC tissue, and quantitative assessment of Her1 homo- and heterodimers may prove informative for prediction of the response of NSCLC patients to EGFR-TKI treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.023DOI Listing
August 2021

Quantitative sonographic assessment of quadriceps muscle thickness for fall injury prediction in patients undergoing maintenance hemodialysis: an observational cohort study.

BMC Nephrol 2021 05 22;22(1):191. Epub 2021 May 22.

Kodaira Kitaguchi Clinic, Tokyo, Japan.

Background: Accidental fall risk is high in patients undergoing maintenance hemodialysis. Falls are associated with fatal injury, comorbidities, and mortality. Risk assessment should be a primary component of fall prevention. This study investigated whether quadriceps muscle thickness measured using ultrasonography can predict fall injury among dialysis patients.

Methods: Using an observational cohort study design, 180 ambulatory hemodialysis patients were recruited from 2015 to 2016 from four dialysis clinics. The sum of the maximum quadriceps muscle thickness on both sides and the average of the maximum thigh circumference and handgrip strength after hemodialysis were calculated. Patients were stratified according to tertiles of quadriceps muscle thickness. Fall injury was surveyed according to the patient's self-report during the one-year period.

Results: Among the 180 hemodialysis patients, 44 (24.4%) had fall injuries during the 12-month follow-up period. When the quadriceps muscle thickness levels were stratified into sex-specific tertiles, patients in the lowest tertile were more likely to have a higher incidence of fall injury than those in the higher two tertiles (0.52 vs. 0.19 and 0.17 fall injuries/person-year). After adjusting for covariates, lower quadriceps muscle thickness was found to be an independent predictor of fall injury (hazard ratio [95% confidence interval], 2.33 [1.22-4.52], P < 0.05). Receiver operating characteristic curves were constructed to determine the optimal cutoffs of quadriceps muscle thickness, thigh circumference, and handgrip strength that best predicted fall injury (quadriceps muscle thickness, 3.37 cm and 3.54 cm in men and women; thigh circumference, 44.6 cm and 37.2 cm in men and women; and handgrip strength, 23.3 kg and 16.5 kg in men and women). Using these cutoff values, the areas under the curve were 0.662 (95% CI, 0.576-0.738), 0.625 (95% CI, 0.545-0.699), and 0.701 (95% CI, 0.617-0.774), for quadriceps muscle thickness, thigh circumference, and handgrip strength, respectively. Quadriceps muscle thickness was a more precise predictor of fall injury than thigh circumference and had similar diagnostic performance as handgrip strength tests in dialysis patients.

Conclusions: Quadriceps muscle thickness can be measured easily at the bedside using ultrasonography and is a precise predictor of fall injury in patients undergoing maintenance hemodialysis.
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http://dx.doi.org/10.1186/s12882-021-02347-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140437PMC
May 2021

High catalytic methane oxidation activity of monocationic μ-nitrido-bridged iron phthalocyanine dimer with sixteen methyl groups.

Dalton Trans 2021 May;50(19):6718-6724

Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan.

Herein, we report the highly potent catalytic methane oxidation activity of a monocationic μ-nitrido-bridged iron phthalocyanine dimer with 16 peripheral methyl groups. It was confirmed that this complex oxidized methane stably into MeOH, HCHO, and HCOOH in a catalytic manner in an acidic aqueous solution containing excess H2O2 at 60 °C. The total turnover number of the reaction reached 135 after 12 h, which is almost seven times higher than that of a monocatinoic μ-nitrido-bridged iron phthalocyanine dimer with no peripheral substituents. This suggests that the increased number of peripheral electron-donating substituents could have facilitated the generation of a reactive high-valent iron-oxo species as well as hydrogen abstraction from methane by the reactive iron-oxo species.
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http://dx.doi.org/10.1039/d1dt00941aDOI Listing
May 2021

Chimeric Latissimus Dorsi Flap in One-Stage Reconstruction of Depressor Muscle Dysfunction and Depression Deformity in the Perimandibular Area.

J Craniofac Surg 2021 Oct;32(7):2512-2515

Department of Plastic and Reconstructive Surgery, Graduate School of Science, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Depression deformity and paralysis of depressor muscles (DMs) may occur following tumor resection in the perimandibular region. Obtaining satisfactory results is challenging. The authors report 3 cases of 1-stage reconstruction by transferring neurovascular chimeric latissimus dorsi (LD) musculo-adipose flaps, with satisfactory results.

Methods: Three patients with depression deformity and DMs dysfunction after tumor resection in the perimandibular region underwent chimeric LD flap transfer. The flap comprised 1 portion with adipose tissue for augmentation, and the other contained muscle bellies with 1 or 2 neural pedicle (s) for DM reanimation. In case 1, the neural pedicle was sutured to the contralateral marginal mandibular branch. In case 2, the neural pedicle was sutured to the ipsilateral marginal mandibular branch. In case 3, the neural pedicle was sutured to both branches of the facial nerve.

Results: All patients were satisfied with the deformity corrections. However, contractions of the transferred muscles varied. Case 1 showed insufficient contraction. Case 2 had excessive muscle contraction. In case 3, the muscle had double innervation, and well-balanced contraction was maintained for 3 years.

Conclusions: Neurovascular chimeric LD flaps are versatile and useful for secondary reconstruction after tumor resection for functional loss of mimetic muscles. The ipsilateral facial nerve may be an effective motor source.
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http://dx.doi.org/10.1097/SCS.0000000000007652DOI Listing
October 2021

Osimertinib-induced Syndrome of Inappropriate Secretion of Antidiuretic Hormone.

Clin Lung Cancer 2021 09 16;22(5):e784-e785. Epub 2021 Mar 16.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2021.03.003DOI Listing
September 2021

Cytotoxic chemotherapeutic agents and the EGFR-TKI osimertinib induce calreticulin exposure in non-small cell lung cancer.

Lung Cancer 2021 05 26;155:144-150. Epub 2021 Mar 26.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Objectives: Synergistic anticancer efficacy of combination treatment with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) may be attributable in part to the phenomenon of immunogenic cell death (ICD), which is characterized by the release of damage-associated molecular patterns (DAMPs) from dying tumor cells. The ability of cytotoxic chemotherapeutic agents and molecularly targeted drugs such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to induce DAMPs during the treatment of NSCLC has remained unclear, however.

Materials And Methods: We investigated the ability of seven cytotoxic chemotherapeutic agents and the third-generation EGFR-TKI osimertinib to induce translocation of the DAMP calreticulin to the cell surface in multiple NSCLC cell lines. The plasma concentration of soluble CRT in advanced NSCLC patients treated with cytotoxic chemotherapy or osimertinib was measured.

Results: Antimetabolites and microtubule inhibitors induced expression of CRT at the cell surface (ecto-CRT) to a greater extent than did platinum agents in six NSCLC cell lines, exhibiting higher up-regulation of phosphorylation of eukaryotic initiation factor-2α (eIF2α). Ecto-CRT expression was positively correlated with apoptosis induction in NSCLC cells treated with these various chemotherapeutic agents. The drug-induced up-regulation of ecto-CRT in NSCLC cells was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Osimertinib similarly increased ecto-CRT expression in association with apoptosis induction in five EGFR-mutated NSCLC cell lines. Furthermore, the plasma concentration of soluble CRT in 16 NSCLC patients treated with single-agent pemetrexed or docetaxel and in nine EGFR-mutated NSCLC patients treated with osimertinib was increased after treatment onset.

Conclusion: Our findings indicate that antimetabolites, microtubule inhibitors, and osimertinib are effective inducers both of CRT exposure in NSCLC cell lines and of soluble CRT release in patients with advanced NSCLC, suggesting that these agents might prove effective for promotion of antitumor immunity in combination immunotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2021.03.018DOI Listing
May 2021

Successful daptomycin therapy for a premature neonate with left-sided infective endocarditis caused by Staphylococcus epidermidis.

Pediatr Neonatol 2021 07 19;62(4):456-457. Epub 2021 Mar 19.

Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Japan.

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http://dx.doi.org/10.1016/j.pedneo.2021.03.007DOI Listing
July 2021

Osimertinib versus osimertinib plus chemotherapy for non-small cell lung cancer with EGFR (T790M)-associated resistance to initial EGFR inhibitor treatment: An open-label, randomised phase 2 clinical trial.

Eur J Cancer 2021 05 1;149:14-22. Epub 2021 Apr 1.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

Background: Osimertinib is now a standard treatment for patients with previously untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC). We here investigated whether the combination of osimertinib with cytotoxic chemotherapy might hold additive efficacy, as well as tolerability.

Patients And Methods: We conducted an open-label randomised phase 2 study to evaluate osimertinib and carboplatin-pemetrexed combination in comparison with osimertinib monotherapy in EGFR mutation-positive NSCLC patients who experienced disease progression associated with the emergence of the T790M resistance mutation of EGFR during first-line EGFR-TKI therapy. The primary endpoint was PFS, with secondary endpoints, including OS, response, and safety. Given that osimertinib was approved as a first-line treatment during the study, patient accrual was discontinued, and a final analysis was performed for the 62 enrolled patients.

Results: Median PFS was 15.8 months for the osimertinib monotherapy group and 14.6 months for the combination therapy group (hazard ratio of 1.09, with a 95% confidence interval of 0.51-2.32; P = .83). Median OS was not reached in either group. The overall response rate was 71.4% in the osimertinib monotherapy group and 53.6% in the combination group. The frequency or severity of known adverse events in the combination group was comparable to those with carboplatin and pemetrexed previously reported, and novel adverse events were not observed in this study.

Conclusion: This is the first randomised study to investigate the efficacy and safety of the combination of osimertinib and cytotoxic chemotherapy for EGFR-mutated NSCLC. The addition of chemotherapy to osimertinib as a second-line treatment did not prolong survival, while it was found to be generally tolerable. This combination strategy will be further validated in the first-line setting.

Trial Registration: Japan Registry of Clinical Trials (jRCT) identifier: jRCTs071180062.
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http://dx.doi.org/10.1016/j.ejca.2021.02.019DOI Listing
May 2021
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