Publications by authors named "Hiroyuki Ito"

547 Publications

The impact of pathological lymph node metastasis with lymphatic invasion on the survival of patients with clinically node-negative non-small cell lung cancer: A multicenter study.

Lung Cancer 2021 May 29;158:9-14. Epub 2021 May 29.

Department of Thoracic Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

Objectives: Lymphatic vessel invasion (Ly) plays a crucial role in pathological lymph node metastasis (pN), and we consider pN + Ly + disease to indicate a high affinity for the lymphatic system. This study evaluated the outcomes of patients with clinically node-negative (N0) non-small cell lung cancer (NSCLC) who presented with pN + with Ly+.

Materials And Methods: This retrospective study evaluated 1775 patients with clinically N0 stage I-III NSCLC who underwent R0 anatomical resection and systematic lymph node dissection at three institutions between January 2010 and December 2017. Patients were classified into four groups according to their pN and Ly statuses. Univariable and multivariable analyses were performed to identify factors associated with poor recurrence-free survival (RFS) and pN + Ly+.

Results: Kaplan-Meier curves revealed that the 5-year RFS rates were 90.8 % for pN-Ly- patients, 55.6 % for pN-Ly + patients, 63.4 % for pN + Ly- patients, and 41.3 % for pN + Ly + patients. Distant and lymph node recurrences were more common in the pN + Ly + group, relative to in the pN-Ly- and pN-Ly + groups (both p < 0.001). Multivariable analyses revealed that pN and Ly statuses were independently associated with RFS, while the solid tumor size and maximum standardized uptake value were independently associated with pN + Ly + status. The proportion of pN + Ly + disease was 17.2 % in patients with a solid-part size of > 1.80 cm and a SUVmax of > 3.55.

Conclusion: pN and Ly statuses were independent prognostic factors in patients with clinically N0 stage I-III NSCLC. Diseases presenting with pN + with Ly + were associated with increased rates of distant and lymph node recurrence.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.029DOI Listing
May 2021

Complex Segmentectomy for Hypermetabolic Clinical Stage IA Non-Small Cell Lung Cancer.

Ann Thorac Surg 2021 May 19. Epub 2021 May 19.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan. Electronic address:

Background: Due to its invasiveness, the indications for "complex segmentectomy" for radiologically hypermetabolic (high maximum standard uptake value [SUV max]) non-small cell lung cancer (NSCLC) remains controversial. This study compared the outcomes after complex segmentectomy and lobectomy in these patients.

Methods: We retrospectively reviewed 717 patients with radiologically hypermetabolic (SUV max ≥ 2.5), clinical Stage IA NSCLC who underwent complex segmentectomy (n = 61) or "location-adjusted" lobectomy (n = 656) at three institutions from 2010 to 2019. Postoperative outcomes were analyzed for all patients and their propensity score-matched pairs. Factors affecting oncologic outcomes were assessed by Kaplan-Meier estimates and Cox proportional hazards regression analyses.

Results: The prognosis of patients undergoing complex segmentectomy was not significantly different from that of patients undergoing lobectomy [5-year cancer specific survival (CSS) rate, 89.9% vs. 91.1%, P = 0.98 and 5-year recurrence-free interval (RFI) rates, 83.0% vs. 77.5%, P = 0.62] in non-adjusted cohort. In 55 propensity score-matched pairs, oncologic outcomes were not significantly different between patients undergoing complex segmentectomy (5-year CSS, 89.9%; 5-year RFI, 83.0%) and lobectomy (5-year CSS, 83.6%; 5-year RFI, 82.5%). Multivariable Cox regression analysis for RFI revealed no significant differences between oncologic outcomes associated with complex segmentectomy and lobectomy (hazard ratio, 0.84; 95% confidence interval, 0.25-2.14; P = 0.74).

Conclusions: Oncologic outcomes of complex segmentectomy and lobectomy were not significantly different in those with radiologically hypermetabolic, clinical Stage IA NSCLC patients. Complex segmentectomy can treat high SUV max, clinical Stage IA lung cancers without compromising oncologic results.
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.083DOI Listing
May 2021

Usefulness of monitoring intrapleural pressure with digital chest drainage system for the management of air leakage after lung resection.

Interact Cardiovasc Thorac Surg 2021 May 17. Epub 2021 May 17.

Department of Thoracic Surgery, Tokyo Medical University, Tokyo, Japan.

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Objectives: The objective of this study was to determine the variation in intrapleural pressure (IPP) with and without air leakage using a digital chest drainage system (DCS) for each pressure setting.

Methods: In this retrospective single-centre study, we analysed 49,553 h of air leakage after anatomical lung resection in 714 patients between 2018 and 2020. The transition of mean IPP and mean air leak flow was monitored using DCS, and the association between mean IPP and mean air leak flow was examined. The relationship between the transition of mean IPP and air leakage according to the varying suction pressures on DCS was also investigated.

Results: Overall, 272 patients (38.1%) showed air leakage after surgery. The mean IPP in patients without air leakage was -12.0 ± 2.9 cmH2O and maintained at about -12 cmH2O constantly, while the mean IPP in patients with air leakage was -8.3 ± 1.9 cmH2O, which changed to -12 cmH2O instantly if air leakage disappeared (P < 0.001). Among patients with air leakage, the mean IPP changed more distinctly in patients with mild suction management than in those with conventional suction management (-5.0 ± 2.6 to -11.5 ± 4.2 and -8.8 ± 1.3 to -12.1 ± 2.5 cmH2O, respectively; P < 0.001).

Conclusions: The change in IPP on a DCS is useful for detecting air leakage. Furthermore, management with a mild suction setting on DCS makes it easy to recognize the disappearance of postoperative air leakage.
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http://dx.doi.org/10.1093/icvts/ivab122DOI Listing
May 2021

Comprehensive molecular analysis of genomic profiles and PD-L1 expression in lung adenocarcinoma with a high-grade fetal adenocarcinoma component.

Transl Lung Cancer Res 2021 Mar;10(3):1292-1304

Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.

Background: Fetal adenocarcinoma of the lung is a rare variant of lung adenocarcinoma and is subcategorized into low-grade and high-grade (H-FLAC) fetal adenocarcinoma. We previously reported poor prognosis in pulmonary adenocarcinomas with an H-FLAC component; however, the genetic abnormalities involved in H-FLAC remain unclear. Therefore, this study aimed to elucidate molecular abnormalities as potential therapeutic targets for H-FLACs.

Methods: We performed immunohistochemical analysis and comprehensive genetic analyses using whole-exome sequencing in 16 lung cancer samples with an H-FLAC component. DNA was extracted from formalin-fixed paraffin-embedded tissues after macrodissection of the H-FLAC component.

Results: Cancer-related mutations were identified in (7/16 cases), (6/16 cases), (4/16 cases), (3/16 cases), (3/16 cases), (2/16 cases), and (1/16 cases). A high tumor mutation burden of ≥10 mutations per megabase was observed in 3/16 cases. A high microsatellite instability was not detected in any case. Based on the cosine similarity with the Catalogue of Somatic Mutations in Cancer mutational signatures, H-FLACs were hierarchically clustered into three types: common adenocarcinoma-like (five cases), surfactant-deficient (ten cases), and signatures 2 and 13-related (one case). All common adenocarcinoma-like cases presented thyroid transcription factor-1 (TTF-1) expression, whereas surfactant-deficient cases often presented loss of TTF-1 and surfactant protein expression and included cases with mutations in the surfactant system genes and . H-FLACs displayed low programmed death ligand-1 (PD-L1) expression (1-49% of tumor cells) in 5/16 cases, and no case displayed high PD-L1 expression (≥50% of tumor cells).

Conclusions: This study indicates that lung cancers with an H-FLAC component rarely harbor currently targetable driver gene mutations for lung cancer but display a high frequency of mutations. The microsatellite instability, tumor mutation burden, and PD-L1 expression status suggest a poor response to immune checkpoint therapy.
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http://dx.doi.org/10.21037/tlcr-20-1158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044470PMC
March 2021

Detection of EGFR mutation of pulmonary adenocarcinoma in sputum using droplet digital PCR.

BMC Pulm Med 2021 Mar 23;21(1):100. Epub 2021 Mar 23.

Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama, Kanagawa, 236-0004, Japan.

Background: It is still unclear whether epidermal growth factor receptor (EGFR) mutation of primary lung adenocarcinoma can be detected on sputum samples. This study aimed to examine EGFR mutations of primary lung adenocarcinoma in sputum samples using droplet digital polymerase chain reaction (ddPCR) and compare it with an EGFR mutation in surgically resected lung cancer.

Methods: Sputum was prospectively collected from the patients before complete resection of the primary lung cancer at Kanagawa Cancer Center from September 2014 to May 2016. ddPCR was performed to detect EGFR exon 21 L858R point mutation (Ex21) and EGFR exon 19 deletion mutation (Ex19) in sputum samples from patients with lung adenocarcinoma. The concordance of EGFR mutation status in sputum samples and tumors in surgically resected specimen was evaluated for each positive and negative cytology group.

Results: One hundred and eighteen patients with primary lung adenocarcinoma provided sputum samples. Sputum cytology was positive in 13 patients (11.0%). ddPCR detected two cases of Ex21 and two cases of Ex19 in sputum cytology positive cases. Compared to surgically resected specimens, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 80.0%, 100%, and 100%, respectively, in sputum cytology positive cases. In contrast, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 3.1%, 100%, and 100%, respectively, in sputum cytology negative cases.

Conclusions: EGFR mutations in primary lung adenocarcinoma can be detected with high sensitivity in sputum samples if sputum cytology is positive.
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http://dx.doi.org/10.1186/s12890-021-01468-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988937PMC
March 2021

Preoperative nivolumab to evaluate pathological response in patients with stage I non-small cell lung cancer: a study protocol of phase II trial (POTENTIAL).

BMJ Open 2021 03 17;11(3):e043234. Epub 2021 Mar 17.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan.

Introduction: Recently, inhibition of programmed cell death 1 or its ligand has shown therapeutic effects on non-small cell lung cancer (NSCLC). However, the effectiveness of preoperative nivolumab monotherapy for stage I NSCLC remains unknown. The present study aimed to investigate the pathological response of preoperative treatment with nivolumab for clinically node negative but having a high risk of NSCLC recurrence.

Methods And Analysis: The Preoperative Nivolumab (Opdivo) to evaluate pathologic response in patients with stage I non-small cell lung cancer: a phase 2 trial (POTENTIAL) study is a multicentre phase II trial investigating efficacy of preoperative nivolumab for clinical stage I patients at high risk of recurrence. This study includes histologically or cytologically confirmed NSCLC patients with clinical N0 who were found on preoperative high-resolution CT to have a pure solid tumour without a ground-glass opacity component (clinical T1b, T1c or T2a) or a solid component measuring 2-4 cm in size (clinical T1c or T2a). Patients with epidermal growth factor receptor (EGFR) mutation (deletion of exon 19 or point mutation on exon21, L858R), anaplastic lymphoma kinase (ALK) translocation or c-ros oncogene 1 (ROS-1) translocation are excluded from this study. Nivolumab (240 mg/body) is administrated intravenously as preoperative therapy every 2 weeks for three cycles. Afterward, lobectomy and mediastinal lymph node dissection (ND 2a-1 or ND 2a-2) are performed. The primary endpoint is a pathological complete response in the resected specimens. The secondary endpoints are safety, response rates and major pathological response. The planed sample size is 50 patients. Patients have been enrolled since April 2019.

Ethics And Dissemination: This trial was approved by the Institutional Review Board of Hiroshima University Hospital and other participating institutions. This trial will help examine the efficacy of preoperative nivolumab therapy for clinical stage I NSCLC.

Trial Registration Number: jRCT2061180016.
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http://dx.doi.org/10.1136/bmjopen-2020-043234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978092PMC
March 2021

Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: A retrospective study during 12 months before and after initiation.

PLoS One 2021 15;16(3):e0248577. Epub 2021 Mar 15.

Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan.

Aims: The safety and efficacy, particularly, the factors associated with the renal prognosis, were assessed over 12 months after the initiation of luseogliflozin therapy in Japanese patients with type 2 diabetes and renal impairment.

Methods: In total, 238 patients treated with luseogliflozin (2.5 mg, once daily) were studied as the safety analysis set. Two hundred and two subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into 3 groups based on the estimated glomerular filtration rate (eGFR): high eGFR (n = 49), normal eGFR (n = 116) and low eGFR (n = 37) groups.

Results: The body weight, systolic blood pressure, HbA1c and urinary protein excretion gradually decreased from baseline in all eGFR groups. While the eGFR was significantly reduced from baseline in the high and normal eGFR groups, the eGFR did not significantly differ over time in the low eGFR group. There was no marked difference in the frequency of adverse events that were specific for SGLT2 inhibitors among the 3 groups in the safety analysis set.

Conclusions: Luseogliflozin can preserve the renal function in the medium term in patients with type 2 diabetes and renal impairment without an increase in specific adverse events.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959360PMC
March 2021

Author Correction: Cigarette smoke induces endoplasmic reticulum stress and suppresses efferocytosis through the activation of RhoA.

Sci Rep 2021 Mar 8;11(1):5866. Epub 2021 Mar 8.

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki City, Nagasaki, 852-8523, Japan.

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http://dx.doi.org/10.1038/s41598-021-85556-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940424PMC
March 2021

A novel rice dull gene, LowAC1, encodes an RNA recognition motif protein affecting Waxy pre-mRNA splicing.

Plant Physiol Biochem 2021 May 26;162:100-109. Epub 2021 Feb 26.

Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori, 036-8561, Japan. Electronic address:

A new dull grain rice mutant with low amylose content, designated lowac1, has been isolated and characterized. To identify the causal mutation site, resequencing of the whole genome and analysis of a cleaved amplified polymorphic sequence (CAPS) marker were performed. Genotypes using the CAPS marker of the identified LowAC1 gene encoding an RNA recognition motif (RRM) protein were entirely consistent with low amylose phenotypes in BCF progeny. Moreover, the segregation of BCF population indicated that the low amylose phenotype was controlled by a single recessive gene. lowac1 involves a single-nucleotide polymorphism from G to A within the gene, resulting in the stop codon generation. The RRM protein deletion in the mutant seed specifically affected the splicing efficiency of Waxy (Wx) in the 5' splice site of intron 1, resulting in decreased protein levels of granule-bound starch synthase I (GBSSI) encoded by Wx. Whereas, the RRM protein did not affect amylose content in Wx of indica variety. Also, the mutation induced a little variation in the expression levels of some genes involved in starch biosynthesis. Particularly, expression levels of SBEIIb, PUL, and AGPL2 mRNAs in lowac1 mutant were approximately two times higher compared to the corresponding wild type (WT) genes. Aside from low amylose content, lowac1 seeds included an amylopectin structure reducing short chains compared to that of WT seeds. Overall, our data suggest that LowAC1 is a novel regulatory factor for starch synthesis in rice.
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http://dx.doi.org/10.1016/j.plaphy.2021.02.035DOI Listing
May 2021

Neurotoxicity studies with a tropomyosin-related kinase A inhibitor, ASP7962, on the sympathetic and sensory nervous systems in rats.

Toxicol Lett 2021 Jun 2;344:34-45. Epub 2021 Mar 2.

Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.

ASP7962 is a small molecule inhibitor for the nerve growth factor (NGF) receptor, tropomyosin-related kinase A (TrkA). NGF contributes to the survival of sensory and sympathetic neurons through TrkA receptor activation. Gross, microscopic, and quantitative effects to the nervous system were evaluated following oral ASP7962 administration to Sprague Dawley rats for 4 weeks and 13 weeks and after a recovery period. Histopathological findings included reversible neuronal atrophy but no neuronal death in the sympathetic ganglia (cervicothoracic ganglion, cranial mesenteric ganglion or superior [cranial] cervical ganglion). Stereological analysis showed reversible decreased ganglion volume and/or decreased neuron size in the superior (cranial) cervical ganglion in both the 4-week and the 13-week repeated dose studies. There were no test article related changes in the brain, dorsal root ganglia with spinal nerve roots or trigeminal ganglia and no functional deficits. ASP7962 did not cause any detectable dysfunction of the sympathetic and sensory nervous system in either study.
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http://dx.doi.org/10.1016/j.toxlet.2021.02.018DOI Listing
June 2021

Procedure-Related Complications and Survival after Gastrostomy: Results from a Japanese Cohort.

Ann Nutr Metab 2020 24;76(6):413-421. Epub 2021 Feb 24.

Department of Gastroenterology and Hepatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Introduction: In 2010, a large-scale multi-institutional study in Japan showed a good prognosis for percutaneous endoscopic gastrostomy (PEG). However, the function and efficacy of PEG are not fully understood by patients, families, and health-care professionals; thus, the number of PEG treatments in Japan has declined. Therefore, we aimed to investigate the safety of the PEG procedure and subsequent survival after PEG.

Methods: In total, 249 PEGs were performed at Juzenkai Hospital from 2005 to 2017. PEG was originally performed using the pull method and then by a modified introducer method from mid-2011. We examined procedure-related complications and survival rates after PEG.

Results: Fifty-one (20.5%) procedure-related complications occurred; emergency surgery was required in 4 cases. Infections accounted for 76.5% (39/51) of complications. More infections occurred with the pull method than with the modified introducer method. The 1-year survival rate was 66.8%; the median survival time was 678 days. Nine patients (3.6%) died within 30 days; no deaths were directly related to PEG. Sex, age, and albumin level before surgery significantly influenced the prognosis.

Conclusion: Due to changes in the PEG insertion method and other factors, PEG has become a safer treatment method. Additionally, PEG-based nutritional supplementation is associated with adequate survival.
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http://dx.doi.org/10.1159/000513616DOI Listing
February 2021

A Cube Version of the Square-Diamond Illusion.

Iperception 2021 Jan-Feb;12(1):2041669520986574. Epub 2021 Jan 20.

Department of Visual Communication Design, Kyushu University, Minami-ku, Fukuoka, Japan.

The square-diamond illusion is often referred to as a type of size illusion. However, the 45-degree tilting of a square remarkably affects perceived corner angles when a cube version of the figure is used. This illusion is measured and discussed in relation to anisotropy in shape interpretation.
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http://dx.doi.org/10.1177/2041669520986574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829539PMC
January 2021

Safety and feasibility of lung biopsy in diagnosis of acute respiratory distress syndrome: protocol for a systematic review and meta-analysis.

BMJ Open 2021 02 12;11(2):e043600. Epub 2021 Feb 12.

Primary Care and Emergency Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Introduction: Acute respiratory distress syndrome (ARDS) is a type of acute respiratory failure characterised by non-cardiac pulmonary oedema caused by various underlying conditions. ARDS is often pathologically characterised by diffuse alveolar damage, and its pathological findings have been reported to be associated with prognosis, although the adverse effects of lung biopsies to obtain pathological findings are still unclear. The purpose of this systematic review and meta-analysis is to reveal the safety and feasibility of lung biopsy in the diagnosis of ARDS.

Methods And Analysis: We will include studies that were published in MEDLINE and Cochrane Central Register of Controlled Trials until 1 June 2020. We will include the reports for critically ill patients in an intensive care unit or emergency department who undergo lung biopsy and require a mechanical ventilation. Two review authors will independently scan titles and abstracts of all identified studies. Furthermore, these two authors will read and assess the full text of study reports to identify trials that appeared broadly to address the subject of the review. We will perform a risk of bias assessment using the McMaster Quality Assessment Scale of Harms.

Ethics And Dissemination: This study will be based on the published data, therefore, it does not require ethical approval. The final results of the study will be published in a peer-reviewed journal.

Trial Registration Number: UMIN000040650.
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http://dx.doi.org/10.1136/bmjopen-2020-043600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883844PMC
February 2021

Fine and gross motor skills predict later psychosocial maladaptation and academic achievement.

Brain Dev 2021 May 6;43(5):605-615. Epub 2021 Feb 6.

School of Contemporary Sociology, Chukyo University, Japan.

Background: Difficulties in fine and gross motor skills are often overlooked as developmental problems, although approximately 6-13% of all school-age children have poor motor coordination. Understanding motor coordination is important from the perspective of school adaptation. This longitudinal cohort study aimed to determine whether fine and gross motor skills in preschool children predict later academic achievement and psychosocial maladaptation.

Methods & Procedures: Participants were 2,501 children from nursery and elementary schools (5-13 years old). The motor skills of preschool children were assessed by their nursery teacher immediately before entering elementary school. The Strengths and Difficulties Questionnaire and a standardized Japanese test were administered annually throughout elementary school.

Results: Early motor difficulties in preschool children had significant effects on their academic achievement and psychosocial maladaptation up until the sixth grade. Gross motor difficulties in preschool were associated with the later peer problems and worsened emotional symptoms.

Conclusions: Motor skills in preschool children are useful as a predictor of later psychosocial maladaptation and academic achievement.
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http://dx.doi.org/10.1016/j.braindev.2021.01.003DOI Listing
May 2021

Surgical challenges in multimodal treatment of N2-stage IIIA non-small cell lung cancer.

Jpn J Clin Oncol 2021 Mar;51(3):333-344

Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

Locally advanced non-small cell lung cancer, especially mediastinal lymph node metastasis-positive stage IIIA-N2 cancer, is a heterogeneous disease state characterized by anatomically locally advanced disease with latent micrometastases. Thus, surgical resection or radiotherapy alone has historically failed to cure this disease. During the last three decades, persistent efforts have been made to develop a suitable treatment modality to overcome these problems using chemotherapy and/or radiotherapy with surgical resection. However, the role of surgical resection remains unclear, and the standard treatment for stage IIIA-N2 disease is concurrent chemoradiotherapy. In general, adjuvant chemotherapy is indicated for completely resected pathological stage IB disease or lymph node metastasis-positive pathological stage II or IIIA disease. Platinum-based doublet cytotoxic chemotherapy is currently the standard regimen. Additionally, post-operative radiotherapy might be indicated for post-operatively proven mediastinal lymph node metastasis; i.e. clinical N0-1 and pathological N2 disease. With the remarkable progression that has recently been made in the field of chemotherapy, such as advances in molecular targeting agents and immune checkpoint inhibitors, the basic policy of chemotherapy has been shifting to personalized treatment based on the individual patient's oncogene driver mutation status, immune status and other parameters. The same trend is being seen in the treatment of stage IIIA-N2 disease. We should consider the past and upcoming results of several clinical trials to optimize the coming era of personalized treatment.
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http://dx.doi.org/10.1093/jjco/hyaa249DOI Listing
March 2021

Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II-Renin Feedback in Hypertensive Patients.

Int J Hypertens 2020 22;2020:6653851. Epub 2020 Dec 22.

Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.

Objectives: Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS.

Methods: A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine ( = 12) or amlodipine ( = 13) group. The effects of cilnidipine on proteinuria and angiotensin II-renin feedback were assessed.

Results: After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group ( < 0.05) than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels ( < 0.05), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1-7) (Ang-(1-7)) to angiotensin II in plasma than the amlodipine group ( < 0.05).

Conclusions: The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1-7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.
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http://dx.doi.org/10.1155/2020/6653851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803135PMC
December 2020

Prediction of Unexpected N2 Disease Associated With Clinical T1-2N0-1M0 Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2021 Mar 27;22(2):120-126.e3. Epub 2020 Dec 27.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan. Electronic address:

Background: Despite the recent development of radiologic mediastinal staging modality, unexpected mediastinal lymph node metastasis still occurs. Preoperative accurate nodal staging is important to determine the optimal treatment. Therefore, this study aimed to identify predictors of unexpected N2 disease in non-small-cell lung cancer (NSCLC).

Patients And Methods: Data from a multicenter database of 2802 patients with clinical T1-2N0-1M0 NSCLC who underwent anatomical segmentectomy or lobectomy were retrospectively analyzed. Unexpected N2 disease was defined as pathologic N2 disease with clinical N0 or N1. The predictive criteria of unexpected N2 disease were established on the basis of the multivariable analysis results of a derivation cohort of 2019 patients, and the criteria were further tested in a validation cohort of 783 patients.

Results: In multivariable analyses, maximum standardized uptake value (SUV) of the primary tumor on 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (odds ratio, 1.072; 95% confidence interval, 1.018-1.129; P = .008) and clinical N1 (vs. clinical N0) disease (odds ratio, 5.40; 95% confidence interval, 1.829-15.94; P = .002) were independent predictors of unexpected N2 disease. The predictive criteria of unexpected N2 disease was defined as tumors with SUV of ≥ 3.1, determined by receiver operating characteristic curves, and clinical N1 disease. This criterion showed diagnostic accuracy of 90.6% (sensitivity 32.0%, specificity 94.5%) in the derivation cohort and 91.3% (sensitivity 32.6%, specificity 94.7%) in the validation cohort.

Conclusion: The predictive criteria of unexpected N2 disease (tumors with SUV of ≥ 3.1 and clinical N1) can be used to select candidates for preoperative invasive mediastinal staging in patients with clinical T1-2N0-1M0 NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.12.010DOI Listing
March 2021

Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment.

Lung Cancer 2021 03 10;153:108-116. Epub 2021 Jan 10.

Department of General Thoracic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan.

Objectives: The prognostic impact of surgical intervention for recurrent or residual non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement after tyrosine-kinase inhibitor (TKI) treatment remains unclear. We aimed to describe the characteristics and outcomes of patients undergoing salvage surgery in this setting.

Methods: We retrospectively collected and analyzed nationwide Japanese data on perioperative and postoperative outcomes of patients who underwent salvage surgery after EGFR or ALK-TKI during 2010-2015. The primary endpoint was a 3-year overall survival (OS) rate and secondary endpoints were the rate of adverse events, perioperative mortality rate, 3-year recurrence-free survival (RFS) rate, and median survival time after salvage lung resection. Univariate and multivariate analyses were performed to identify independent prognostic factors of OS and RFS.

Results: Thirty-six patients were included (EGFR-TKI: 33, ALK-TKI: 3). The 3-year OS and RFS after the surgery were 75.1 % (95 % confidence interval [CI] 55.9-86.9 %) and 22.2 % (95 % CI 8.6-39.7 %), respectively. Of clinicopathological factors, the progression of disease while on TKI and preoperative carcinoembryonic antigen (CEA) levels (≥5 ng/mL) were shown to be worse independent prognosticators of OS (hazard ratio [HR] 9.38, 95 % CI 1.57-55.88, P = .014; HR 4.84, 95 % CI 1.62-14.46, P = .005, respectively). Older age at initial treatment (≥70 years) and advanced pathological T stage (T2-T4) were the worse prognosticators for RFS (HR 12.58, 95 % CI 2.51-62.97, P = .002; HR 3.06, 95 % CI 1.04-9.03, P = .043, respectively). Grade 3 adverse events occurred in 5.6 % (2/36) patients, but no deaths were reported within 90 days after surgery.

Conclusion: Our study showed that salvage surgery after TKI treatment was safe and feasible and may contribute to prolonged OS time by reducing the local tumor burden.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.037DOI Listing
March 2021

Eosinophilic Cholecystitis Associated with Eosinophilic Granulomatosis with Polyangiitis.

Case Rep Gastroenterol 2020 Sep-Dec;14(3):668-674. Epub 2020 Dec 11.

Department of Gastroenterology, Tokai University Hachioji Hospital, Tokyo, Japan.

We report a case of eosinophilic cholecystitis associated with eosinophilic granulomatosis with polyangiitis (EGPA) complicated by cerebral hemorrhage. A 60-year-old man presented to a local hospital with a diagnosis of acute cholecystitis, with persistent fever and epigastric pain for 2 weeks. His symptoms persisted despite 3-week hospitalization; therefore, he was transferred to our hospital for further evaluation. Laboratory investigations upon admission showed white blood cells 26,300/µL and significant eosinophilia (eosinophils 61%). Abdominal computed tomography revealed no gallbladder enlargement but a circumferentially edematous gallbladder wall. Additional blood test results were negative for antineutrophil cytoplasmic and perinuclear antineutrophil cytoplasmic antibodies; however, immunoglobulin (Ig)G and IgE levels were high at 1,953 mg/dL and 3,040/IU/mL, respectively. He improved following endoscopic transnasal gallbladder drainage for cholecystitis and was diagnosed with EGPA and received corticosteroid and immunosuppressant combination therapy. The eosinophil count decreased immediately after treatment, and abdominal pain and numbness resolved. He returned with left-sided suboccipital hemorrhage likely attributed to EGPA 6 months after discharge. EGPA is characterized by inflammation of small blood vessels and clinically manifests with an allergic presentation of bronchial asthma, as well as renal dysfunction, interstitial pneumonia, enteritis, and cerebral hemorrhage. Few reports have described cholecystitis as a presenting symptom of EGPA. We report a rare case of such a presentation with added considerations.
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http://dx.doi.org/10.1159/000511863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772830PMC
December 2020

[Self-made Bovine Pericardial Roll Graft Replacement of Infected Aneurysm Following Thoracic Endovascular Aortic Repair;Report of a Case].

Kyobu Geka 2020 Dec;73(13):1085-1089

Department of Cardiovascular Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan.

A 72 years-old man was admitted with fever and cough. He had undergone aortic arch graft replacement with elephant trunk and endovascular stent graft for distal arch aortic aneurysm 1 year ago. Additionally, he had treated type I endoleak with an endovascular stent graft 3 month previously. Computed tomography showed soft tissue around the aneurysm and visible gas bubble within intramural thrombus, and he was diagnosed with stent graft infection. The stent graft was removed and aortic reconstruction was performed using bovine pericardial roll grafts. The grafts were covered with the greater omentum. He was discharged on the 48th postoperative day, and was alive and well 4 years after the operation.
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December 2020

Early Improvement of Non-islet Cell Tumor Hypoglycemia by Chemotherapy Using Lenvatinib in a Case with Type 2 Diabetes and Hepatocellular Carcinoma Producing Big IGF-II.

Intern Med 2021 May 30;60(9):1427-1432. Epub 2020 Nov 30.

Department of Oncology and Hematology, Edogawa Hospital, Japan.

A 77-year-old man was treated with a DPP-4 inhibitor for type 2 diabetes. Hypoglycemia occurred frequently, and an examination revealed a tumor with a maximum diameter of 140 mm in both lobes of the liver. Western immunoblotting detected a high-molecular-weight form of insulin-like growth factor-II, and non-islet cell tumor hypoglycemia was diagnosed. Although prednisolone 40 mg was started, hypoglycemia continued to occur frequently. Surgical tumor removal was not indicated, so lenvatinib was initiated. Hypoglycemia improved quickly, and the tumor shrank until it had partially disappeared. His condition continued to improve, and he was discharged.
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http://dx.doi.org/10.2169/internalmedicine.5328-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170237PMC
May 2021

Salvage surgery for non-small-cell lung cancer after definitive radiotherapy.

Ann Thorac Surg 2020 Nov 26. Epub 2020 Nov 26.

Department of General Thoracic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan.

Background: The aim of this study is to describe the characteristics and outcomes of patients with non-small-cell lung cancer undergoing salvage surgery after chemoradiotherapy, conventional external beam, stereotactic body radiotherapy (SBRT), and ion beam radiotherapy.

Methods: We retrospectively evaluated patients who underwent salvage surgery between 2010 and 2016. Data on perioperative morbidity and mortality and patient outcomes were analyzed.

Results: In total, 156 patients were included; of them, 110 and 46 were categorized into Category 1: chemoradiotherapy or conventional external beam and Category 2: SBRT or ion beam radiotherapy, respectively. The 3-year overall survival (OS) and recurrence free survival (RFS) rates in Category 1 was 67.3% and 49.8%, respectively. In Category 1, pathological nodal stage was an independent prognosticator of both OS (hazard ratio [HR]: 3.53, 95% CI: 1.05-11.83) and RFS (HR: 4.32, 95% CI: 1.32-14.14). In Category 2, the 3-year OS and RFS rates were 57.7% and 46.4%, respectively. Age ≥70 years at initial treatment was the only independent prognosticator of OS (HR: 5.61, 95% CI: 1.44-21.87), while age at initial treatment (HR: 6.13, 95% CI 1.38-27.12) and pathological nodal metastasis (HR: 3.84, 95% CI: 1.40-10.57) were independent prognosticators for RFS. The overall 30- and 90-day mortality rates were 0% and 0.9% in Category 1 and 0% and 4.3% in Category 2, respectively.

Conclusions: Patients who undergo salvage surgery can have reasonable outcomes, and salvage surgery can be considered in selected patients.
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http://dx.doi.org/10.1016/j.athoracsur.2020.10.035DOI Listing
November 2020

Examining simultaneous associations of four emotion regulation strategies with abnormal eating behaviors/attitudes in early adolescents.

Eat Behav 2021 01 13;40:101449. Epub 2020 Nov 13.

School of Contemporary Sociology, Chukyo University, Toyota, Japan; Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Previous research has suggested that emotion regulation strategies (ERSs) are associated with abnormal eating behaviors and attitudes (AEBs). Available data have demonstrated that frequent rumination, a major maladaptive ERS, is associated with elevated AEBs, whereas adaptive ERSs, such as problem-solving and cognitive reappraisal, showed negative associations with AEBs. Most previous studies examined the association of a single ERS with AEBs. Therefore, any significant associations between an individual ERS and AEB reported in previous research might stem from spurious correlations. The current cross-sectional study sought to examine simultaneous associations of four ERSs (rumination, problem-solving, distraction, and cognitive reappraisal) with two categories of ED symptoms (i.e., drive for thinness and bulimic symptoms) in early adolescents in Japan (ages 10-15, N = 5301). Participants self-reported their use of the different ERSs and the ED symptoms. We found certain ERSs were uniquely associated with levels of drive for thinness and bulimic symptoms even after controlling for body mass index, depression, and socioeconomic status. Particularly, frequent rumination in both boys and girls was associated with a severe drive for thinness and bulimic symptoms. Regarding adaptive strategies, frequent uses of problem-solving was associated with decreased bulimic symptoms only in girls, with the effect size being small. In addition, contrary to our expectation, greater use of distraction was associated with elevated AEBs, except the association with drive for thinness in boys. Although this study extended findings of previous research, prospective studies are required to clarify the causal relationship between ERSs and eating pathology.
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http://dx.doi.org/10.1016/j.eatbeh.2020.101449DOI Listing
January 2021

Clinical features and outcomes of patients with stage I multiple primary lung cancers.

Cancer Sci 2021 May 9;112(5):1924-1935. Epub 2021 Mar 9.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18 978 registered cases, 9689 patients with clinical stage I non-small-cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was carried out within 2 years after the initial surgery; metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Female sex, nonsmoker, low consolidation-tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, whereas patients with metachronous MPLC had higher frequencies of male sex, smoker, chronic obstructive pulmonary disease (COPD), and nonadenocarcinoma. There was no significant difference in survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC. Logistic regression analysis showed that female sex, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings could have major implications regarding MPLC diagnosis and identification of independent prognostic factors, and provide valuable information for postoperative management of patients with MPLC.
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http://dx.doi.org/10.1111/cas.14748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088915PMC
May 2021

Anti-CD71 antibody immunohistochemistry in the diagnosis of acute myeloid leukemia, subtype acute erythroid leukemia with erythroid dominance (AML M6-Er), in a retrovirus-negative cat.

J Vet Diagn Invest 2021 Jan 22;33(1):87-94. Epub 2020 Nov 22.

Koto General Hospital, Kariya Animal Hospital Group, Koto, Tokyo, Japan.

CD71 is an immunohistochemical marker used in diagnosing acute myeloid leukemia (AML) M6-Er in humans; however, to our knowledge, it has not been reportedly used for immunohistochemistry in veterinary medicine. We evaluated the pathologic features of AML M6-Er in a retrovirus-negative cat and used CD71 to support the diagnosis. A 4-y-old spayed female Scottish Fold cat was presented with lethargy, anorexia, and fever. Whole-blood PCR assay results for pro feline leukemia virus/pro feline immunodeficiency virus and feline vector-borne diseases were negative. Early erythroid precursors were observed in the peripheral blood smear. Fine-needle aspiration of the enlarged spleen and splenic lymph node showed many early erythroid precursors. Bone marrow aspirate smears revealed erythroid hyperplasia with 68.4% erythroid lineage and 3.6% rubriblasts. Dysplastic cells infiltrated other organs. The patient was diagnosed with myelodysplastic syndrome, progressing to the early phase of AML M6-Er. The patient died on day 121 despite multidrug treatments. Postmortem examination revealed neoplastic erythroblasts infiltrating the bone marrow and other organs. Neoplastic cells were immunopositive for CD71 but immunonegative for CD3, CD20, granzyme B, von Willebrand factor, CD61, myeloperoxidase, and Iba-1. Although further studies are necessary for the application of CD71, our results supported the morphologic diagnosis of AML M6-Er.
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http://dx.doi.org/10.1177/1040638720973403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758705PMC
January 2021

Comparison of cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer.

J Thorac Cardiovasc Surg 2020 Oct 22. Epub 2020 Oct 22.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan. Electronic address:

Objective: The study objective was to compare cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer.

Methods: Between 2010 and 2015, 457 patients with clinical stage IA (8th edition) non-small cell lung cancer undergoing wedge resection or segmentectomy were identified at 3 institutions. Propensity scores were calculated on the basis of the extent of resection (wedge resection or segmentectomy) and included adjustment for confounding variables, such as age, sex, smoking status, pulmonary functions, laterality, tumor size, maximum standardized uptake value on F-fluorodeoxyglucose positron emission tomography, presence of ground-glass opacity on high-resolution computed tomography, histology, and visceral pleural invasion for multivariable analysis and matching. The primary end point was cumulative incidence of recurrence.

Results: In all cohorts, postoperative recurrence occurred in 36 of 195 patients (18.5%) undergoing wedge resection and 14 of 262 patients (5.3%) undergoing segmentectomy. Cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 5.3%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 19.1%; P < .001). In propensity score-adjusted multivariable analysis, segmentectomy was identified as an independent favorable prognostic factor for cumulative incidence of recurrence (hazard ratio, 0.47; 95% confidence interval, 0.24-0.90; P = .022). In propensity score matching of 163 pairs, cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 6.6%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 13.2%; P = .041).

Conclusions: Cancer control was better in segmentectomy than in wedge resection. Segmentectomy is the preferred oncologic procedure as sublobar resection to treat clinical stage IA non-small cell lung cancer.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.024DOI Listing
October 2020

Appropriate Extent of Lymphadenectomy in Segmentectomy: A Multicenter Study.

Jpn J Clin Oncol 2021 Mar;51(3):451-458

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan.

Background: The significance of lymphadenectomy is yet to be fully examined in segmentectomy. We compared the oncological outcomes of mediastinal lymph node dissection (LND) and hilar LND for lung cancer treated with segmentectomy via a multicenter database using propensity score-matched analysis.

Methods: We reviewed 357 clinical stage IA radiologically solid-dominant lung cancer patients who underwent segmentectomy with lymphadenectomy. The extent of LND was classified into systematic/lobe-specific mediastinal LND and hilar LND only groups. Postoperative results after segmentectomy with mediastinal LND (n = 179) and hilar LND (n = 178) were analyzed for all patients and their propensity score-matched pairs.

Results: Cancer-specific survival (CSS) and recurrence-free interval (RFI) rates for the mediastinal LND group were determined to be not significantly different compared with the hilar LND group in all non-adjusted cohorts. In the propensity score-matched cohort (129 pairs), mediastinal LND harvested more lymph nodes compared with hilar LND, and both groups had significantly different pathological stages (P = 0.015). Adjuvant chemotherapy was performed in 10 (7.8%) patients in the mediastinal LND group and 4 (3.1%) in the hilar LND group. The mediastinal LND group tended to have better prognosis than the hilar LND group (5-year CSS rates, 97.4% vs 93.2%; 5-year RFI rates, 93.5% vs 88.5%).

Conclusions: Mediastinal LND was found to provide more appropriate pathological staging compared with hilar LND in patients with segmentectomy by harvesting more lymph nodes. In addition, mediastinal LND might lead to better oncological outcome than hilar LND in segmentectomy.
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http://dx.doi.org/10.1093/jjco/hyaa199DOI Listing
March 2021

Tissue surface area and tumor cell count affect the success rate of the Oncomine Dx Target Test in the analysis of biopsy tissue samples.

Thorac Cancer 2021 01 13;12(2):194-200. Epub 2020 Nov 13.

Department of Surgery, Yokohama City University, Yokohama, Japan.

Background: The Oncomine Dx Target Test (ODxTT) is a next-generation sequencing-based companion diagnostic test which has been recently developed; however, its analysis success rate could be improved, especially for small samples. The aim of this study was to identify the pathological factors associated with biopsy specimens that affect the analysis success rate of ODxTT.

Methods: We retrospectively investigated 119 cases subjected to ODxTT at Kanagawa Cancer Center. Data pertaining to the results of BRAF V600E mutation analysis in ODxTT and pathological factors based on microscope slides were collected. Pathological factors including tissue surface area, tumor cell count, and tumor content rate were assessed. We constructed receiver operating characteristic curves and determined the optimal cutoff values of each pathological factor. Multivariate logistic analysis was used to identify significant factors.

Results: A total of 98 of 119 samples were successfully analyzed (75.6%). The tissue surface area and tumor cell count were significantly higher in the group associated with analysis success (P < 0.001 and P = 0.011, respectively), and their optimal cutoff values were 1.04 mm and 375 cells, respectively. A tissue surface area > 1.04 mm and tumor cell count >375 cells had a positive effect on the analysis success rate of ODxTT (odds ratio [OR] 0.10; 95% confidence interval [CI]: 0.03-0.35; P < 0.001 and OR 0.25; 95% CI: 0.07-0.90; P = 0.033, respectively).

Conclusions: Selecting samples with a tissue surface area > 1.04 mm and a tumor cell count >375 cells might improve the analysis success rate of ODxTT.

Key Points: Significant findings of the study: We found that a tissue surface area > 1.04 mm and tumor cell count >375 cells had a positive effect on the analysis success rate of ODxTT in the analysis of biopsy tissue samples.

What This Study Adds: It is sometimes necessary to assess genetic alterations with a small biopsy sample in daily practice. The criteria mentioned above will help to determine which tests should be performed, ODxTT or multiple single-gene testing.
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http://dx.doi.org/10.1111/1759-7714.13743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812068PMC
January 2021

Chronic treatment with the (iso-)glutaminyl cyclase inhibitor PQ529 is a novel and effective approach for glomerulonephritis in chronic kidney disease.

Naunyn Schmiedebergs Arch Pharmacol 2021 04 29;394(4):751-761. Epub 2021 Mar 29.

Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, 305-8585, Japan.

Glomeruli and renal tubule injury in chronic kidney disease (CKD) is reported to involve induction of macrophage activation through the CCL2/CCR2 axis. The effects of inhibitors of the CCL2/CCR2 axis, such as anti-CCL2 antibody and CCR2 antagonist, on kidney function in animal models or humans with kidney dysfunction have been demonstrated. The N-terminal glutamine on immature CCL2 is replaced with pyroglutamate (pE) by glutaminyl cyclase (QC) and isoQC. pE-CCL2 is stable and resistant to peptidases. We hypothesized that inhibiting QC/isoQC activity would lead to the degradation of CCL2, thereby ameliorating CKD and reducing kidney inflammation. To test this hypothesis, we investigated the renoprotective properties of the QC/isoQC inhibitor PQ529 in anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis Wistar Kyoto (WKY) rats. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. Correlations between the urinary protein level and serum or urinary CCL2 levels were confirmed in tested animals. Repeated administration of PQ529 significantly reduced the expression of CD68, a macrophage marker, in the kidney cortex and mononuclear infiltration into the tubulointerstitium. In addition, decreased levels of urinary KIM-1, β2 microglobulin, and clusterin were detected, suggesting the inhibition of inflammation in both the proximal and distal tubules. These results suggest that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients.
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http://dx.doi.org/10.1007/s00210-020-02013-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007495PMC
April 2021

Cardiogenic cerebral embolism caused by a severe hypoglycemic attack : a case report.

J Med Invest 2020 ;67(3.4):362-364

Department of Neurosurgery, Kawasaki medical school hopsptal, Okayama, Japan.

The direct relationship between a hypoglycemic attack and cerebral infarction remains unknown. It has been reported that a hypoglycemic attack can result in takotsubo syndrome, leading to cerebral infarction. We report a case of a cardiogenic cerebral embolism caused by a hypoglycemic attack, with additional literature review. A 71-year-old woman was admitted to our hospital in a semi-comatose state due to a severe hypoglycemic attack ; she developed hemiplegia one day after admission. Magnetic resonance imaging revealed cerebral infarction in the area supplied by the left middle cerebral artery. Takotsubo syndrome was suspected based on echocardiography. We diagnosed cerebral embolism due to takotsubo syndrome, caused by the hypoglycemic attack. J. Med. Invest. 67 : 362-364, August, 2020.
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http://dx.doi.org/10.2152/jmi.67.362DOI Listing
January 2020