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NTRK-rearranged spindle cell neoplasm is a group of tumors characterized by NTRK1/2/3 gene fusion. Recently, tumors with other kinase fusion genes were reported to exhibit similar morphologies. Herein, we discuss an adult-onset soft tissue tumor with similar histologic patterns as kinase gene fusion-related tumors but with BRAF and NRAS mutations. A female in her 40s had a 40 mm tumor with an unclear border in the soft tissue of her foot joint. Short spindle-shaped tumor cell proliferation with abundant capillaries and collagen fiber bundles were observed. The tumor infiltrated the subcutaneous adipose tissue, exhibiting a lipofibromatosis-like pattern. Immunohistochemically, the tumor cells coexpressed CD34, S-100, and BRAF V600E. Whole-exome sequencing revealed BRAF p.V600E and NRAS p.Q61K mutations. Since BRAF activation occurs in BRAF fusion gene tumors and BRAF mutations, they could share a similar mechanism in tumorigenesis. This case suggests the further expansion of kinase-related spindle cell tumors., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

This study aimed to investigate the prognostic relevance of cytogenetic risk in 9826 adults with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) during the first or second complete remission. The 5-year probabilities of overall survival (OS) were 66%, 61%, and 47% (P < 0.001), the cumulative incidences of relapse were 14%, 19%, and 32% (P < 0.001), and the cumulative incidences of non-relapse mortality (NRM) were 23%, 23%, and 25% (P = 0.208) in patients with favorable (n = 1418), intermediate (n = 6747), and poor cytogenetic risk (n = 1661), respectively. The significant effect of cytogenetic risk on OS was strong in all subgroups stratified by age, sex, performance status, disease status, donor type, conditioning intensity, graft-versus-host disease prophylaxis, and transplantation period (P < 0.001 for all). The evaluation of trends in posttransplant outcomes for patients in each cytogenetic risk category indicated that the risk of relapse declined in patients with favorable and intermediate cytogenetics and that the risk of NRM decreased in those with intermediate and poor cytogenetics. Therefore, patients with intermediate cytogenetics experienced the best OS improvement. These results confirm cytogenetic risk as a universal prognostic factor in patients with AML undergoing allogeneic HCT while highlighting the requirement for further improvements in posttransplant OS by reducing NRM in patients with favorable cytogenetics and by reducing relapse in patients with poor cytogenetics., Competing Interests: Declarations Ethical approval This study was approved by the institutional review board of the Aichi Medical University and was conducted in accordance with the Declaration of Helsinki. All patients provided informed consent for the use of their clinical information for research. Competing interests SM received research funding from Hayashikane Sangyo, and AT received research funding from Air Water, lecture fees from Novartis Pharmaceutical, and donated funds from Chugai Pharmaceutical, Kyowa Kirin, and Zenyaku Kogyo., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm with a poor prognosis. Most cases of SMARCA4-UT have extensive chest wall and mediastinum involvement. The efficacy of surgical resection has not been clearly established. Here, we report two surgical cases of SMARCA4-UT with chest wall invasion after chemoradiotherapy., Case Presentation: The first patient was a 40-year-old man with back pain. Computed tomography revealed a 6.8 cm mass in contact with the thoracic vertebrae near the intervertebral foramen, which was suspected to involve the third to fifth ribs. The patient was diagnosed with SMARCA4-UT with clinical T3N0M0 stage IIB. The tumor shrank after chemoradiotherapy, and conversion surgery combined with partial vertebrectomy was performed. Histopathological findings revealed 30% residual tumor in the tumor bed. Thirty-six days after surgery, the patient developed multiple liver metastases and peritoneal dissemination. Chemotherapy combined with immune checkpoint inhibitor treatment was performed, resulting in tumor shrinkage. However, peritoneal dissemination recurred within a short interval. The patient died 5 months postoperatively. The second patient was a 74-year-old man with chest pain. Computed tomography revealed a 7.4-cm mass in the left upper lobe with invasion of the third and fourth ribs. The patient was initially diagnosed with non-small cell lung cancer with clinical T4N1M0 stage IIIA. The tumor shrank after induction chemoradiotherapy, and a left upper lobectomy combined with the chest wall resection was performed. Based on histopathological findings, the patient was diagnosed with SMARCA4-UT. The residual tumor percentage was 3%. The patient was followed up for 12 months postoperatively without recurrence., Conclusions: We performed the complete resection of SMARCA4-UT following chemoradiotherapy. The two surgical cases had different postoperative courses. Radical surgery after chemoradiotherapy is effective for local control. However, its long-term prognostic efficacy remains unclear. Multidisciplinary approaches and further investigations of novel therapeutic options are required., (© 2024. The Author(s).)

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Background: Although the positive rate of preresection pleural lavage cytology (PLC) is low, it is an important indicator of poor prognosis for non-small-cell lung cancer patients with frequent pleural dissemination (PD) recurrence. Thin-section computed tomography (TSCT) can reveal relationships between a primary tumor and the pleura at 1 to 2 mm intervals, and this is associated with visceral pleural invasion (VPI). However, its association with PLC remains unclear. Therefore, we aimed to improve PLC efficiency and predict PD recurrence by understanding the relationship between PLC and preoperative TSCT findings., Patients and Methods: Between January 2014 and December 2018, we reviewed 978 patients with non-small-cell lung cancer who underwent PLC tests during complete resection surgery. Preoperative TSCT findings were evaluated, and factors with the highest specificity (proportion of patients with radiologically to pathologically diagnosed positive PLC) were investigated. We also evaluated their relationships with VPI and PD recurrence., Results: PLC positive was identified in 55 (5.6%) of the 978 patients. The two TSCT findings predicting PLC results, "the absence of pleural findings," ie, tumor not attached to pleura or without pleural tag, and "consolidation-to-tumor ratio ≤0.5", had a specificity of 100% (95% confidence interval: 90.4%-100%); additionally, all cases with these findings were VPI negative and had no PD recurrence. And 24% of the cohort had either of these findings., Conclusion: The absence of pleural findings and/or consolidation-to-tumor ratio ≤0.5 of primary tumor on preoperative TSCT can predict PLC negativity with very high probability; therefore, PLC can be omitted for such patients., Competing Interests: Disclosure The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Paroxysmal cold hemoglobinuria (PCH) is a rare disease in adults, and its concurrent presentation with warm-type autoimmune hemolytic anemia (AIHA) has not yet been reported. We encountered a 19-year-old woman with AIHA and a positive Donath-Landsteiner test result identified by a hemolytic attack during blood transfusion. She also showed positive results for the direct Coombs and Donath-Landsteiner antibody tests. After treatment with prednisolone followed by rituximab, the AIHA improved, and the Donath-Landsteiner antibody test result turned negative. Clinicians should be aware that patients may present with concurrent warm-type AIHA and PCH and consider rituximab for its treatment.

Niemann-Pick disease type C (NPC) is a lysosomal lipid storage disorder characterized by progressive neurodegeneration and hepatic dysfunction. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is currently under clinical investigation for NPC, but its adverse events remain problematic. We previously identified that a cyclic octasaccharide, 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), also ameliorated NPC manifestations with higher biocompatibility than HP-β-CD. However, preclinical studies describing the associations between the biodistribution and pharmacodynamics of these compounds, which are essential for clinical application, are still lacking. Here, we investigated these properties of HP-γ-CD by measuring its organ biodistribution and therapeutic effect after systemic and central administration. The effect of HP-γ-CD on disturbed cholesterol homeostasis appeared within several hours after exposure and persisted for several days in NPC model cells and mice. Tissue distribution indicated that only a small fraction of subcutaneously administered HP-γ-CD rapidly distributed to peripheral organs and contributed to disease amelioration. We found that a subcutaneous dose of HP-γ-CD negligibly ameliorated neurological characteristics because it has limited penetration of the blood-brain barrier; however, an intracerebroventricular microdose unexpectedly attenuated hepatic dysfunction without the detection of HP-γ-CD in the liver. These results demonstrate that central administration of HP-γ-CD can indirectly attenuate peripheral manifestations of NPC., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Two series of metallo-(Zn(II), Mg(II), and Ru(II)) and free-base phthalocyanines (Pcs) with a carboxyl anchoring group and well-established bulky peripheral substituents (either tert-butyl or bulky 2,6-diisopropylphenoxy) were synthesized and tested as sensitizers in dye-sensitized solar cells (DSSCs). The trend of photovoltaic efficiencies (PCEs) for free-base and metallo Pcs followed the order Zn(II)Pc>Mg(II)Pc≫H2Pc ≈ Ru(II)Pc regardless of the peripheral substitution. Higher efficiencies (4.95 versus 3.63 for the Zn(II) derivatives) were achieved with Pcs bearing the bulkier 2,6-diisopropylphenoxy group, indicating a lower aggregation and more suitable HOMO-LUMO levels. Furthermore, these derivatives showed a morelevant influence of the metal on the PCE values (from the highest 4.95 for the Zn(II)Pc to the lowest 0.23 for the Ru(II)Pc. In both series, the best PCEs observed with the Zn(II) derivatives were mainly due to their highest J sc values. The lowest efficiencies found for the free-bases and Ru(II) derivatives were attributed to a mismatch between their LUMO levels and the conduction band of the TiO 2 ,and lower light-harvesting capabilities, respectively. In conclusion, Zn(II) derivatives are still the best Pc candidates to use as sensitizers in molecular photovoltaics., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Allogeneic hematopoietic cell transplantation (HCT) is the last option for long-term survival for patients with chemotherapy-refractory acute myeloid leukemia (AML). By using the Japanese nationwide registry data, we analyzed 6927 adults with AML having undergone first allogeneic HCT while not in complete remission (CR) between 2001 and 2020. The 5-year overall survival (OS), relapse, and non-relapse mortality (NRM) rates were 23%, 53%, and 27%, respectively. Multivariate analysis identified several factors predictive of OS mainly through their effects on relapse (cytogenetics, percentage of blasts in the peripheral blood, and transplantation year) and NRM (age, sex, and performance status). As regards disease status, relapsed disease was associated with a higher risk of overall mortality than primary induction failure (PIF). The shorter duration of the first CR increased the risks of relapse and overall mortality for the relapsed group, and the longer time from diagnosis to transplantation did so for the PIF group. Our experience compiled over the past two decades demonstrated that >20% of patients still enjoy long-term survival with allogeneic HCT performed during non-CR and identified those less likely to benefit from allogeneic HCT. Future efforts are needed to reduce the risk of posttransplant relapse in these patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Although various companion diagnostic tests of ALK fusion gene-rearrangement are approved, few reports have assessed the concordance of ALK fusion gene-rearrangement in two companion diagnostic tests: next-generation sequencing (NGS) testing and immunohistochemistry (IHC)., Methods: The samples evaluated for gene alterations using NGS testing between May 2019 and November 2021 were included in this study. The inclusion criteria were as follows: samples were diagnosed with non-small cell lung cancer; the results of the NGS analysis were informative; and samples had residual specimens for IHC. We performed IHC on the residual specimens and retrospectively collected sample characteristics from medical records., Results: A total of 185 samples were analyzed using NGS. Twenty-six samples were excluded because of failure to analyze gene alterations using NGS, no residual samples, and inadequate IHC. We analyzed 159 samples. The major histological type was adenocarcinoma (115 samples). The number of surgical and transbronchial lung biopsy specimens was 59 and 56, respectively. ALK fusion gene-rearrangement was detected in four samples using NGS, and five were detected using IHC. The sensitivity and specificity of IHC referred to by NGS were 75.0% and 98.7%, respectively. The concordance rate between IHC and NGS was 98.1%. ALK rearrangement was detected in two patients using IHC but not using NGS. In addition, ALK rearrangement was detected in one patient using NGS but not using IHC., Conclusion: Our results suggest that IHC and NGS might be complementary tests. In patients suspected of harboring ALK fusion gene-rearrangement, it should be analyzed using another diagnostic method., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)-SCLC, to assess whether conventional NE markers are predictive of ICIs., Methods: Patients with untreated ED-SCLC who received first-line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first-line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI-chemo group) and with chemotherapy alone (chemo group)., Results: A total of 227 patients were included in the ICI-chemo and chemo groups, respectively. The progression-free survival (PFS) tended to be better in patients in the ICI-chemo group than those treated with chemotherapy alone in patients with NE marker-positive SCLC. In particular, it was statistically significant in patients with chromogranin A-positive SCLC (p = 0.036). In patients with NE marker-negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker., Conclusion: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker-negative SCLC., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Objective: Positive pleural lavage cytology (PLC +) is a poor prognostic factor for non-small cell lung cancer (NSCLC). However, data on the impact of intraoperative rapid diagnosis of PLC (rPLC) are lacking. Therefore, we evaluated the efficacy of rPLC before resection during surgery., Methods: A total of 1,838 patients who underwent rPLC for NSCLC between September 2002 and December 2014 were studied retrospectively. We assessed the clinicopathological factors between rPLC findings and the impact on survival of patients with curative resection., Results: The rPLC + status was observed in 96 (5.3%) among 1,838 patients. The rPLC + group had more unsuspected N2 (30%) than the rPLC- group (p < 0.001). The 5-year overall survival (OS) of patients who underwent lobectomy or more extensive resection with rPLC + , negative rPLC (rPLC-), and microscopic pleural dissemination (PD) and/or malignant pleural effusion (PE) were 67.3, 81.3, and 11.0%, respectively. In the rPLC + group, the prognosis of patients with pN2 was equal to that of pN0-1 (5-year OS: 77.9% vs. 63.4%, p = 0.263). Undetectable dissemination in the first evaluation immediately after starting surgery was found in 9% of rPLC + patients by additional evaluation of the thoracic cavity., Conclusions: Patients with rPLC + have more favorable survival than those with microscopic PD/PE after surgery. Curative resection should be performed in patients with rPLC + , even if N2 is detected during surgery. However, the rPLC + group often has N2 upstaging; therefore, systematic nodal dissection should be performed in rPLC + patients for exact staging. rPLC may contribute to preventing oversight PD by re-evaluation during surgery., (© 2023. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Introduction: The CD34 + CD38 - population in bone marrow includes hematopoietic stem/progenitor cells. Recently, in acute myeloid leukemia, the focus has shifted to flow cytometry analysis targeting CD34 + CD38 - leukemic cells due to their effectiveness in minimal/measurable residual disease detection and prognosis prediction. Nevertheless, the immunophenotype and cell frequency of these cells in the bone marrow, in the absence of leukemic cells, remains unknown. We aimed to evaluate detailed characteristics of CD34 + CD38 - cells in both normal and leukemic cells by flow cytometry., Methods: We compared the cell frequency and immunophenotype of the CD34 + CD38 - fraction in the following groups: patients with idiopathic thrombocytopenic purpura and malignant lymphoma as controls (n = 17), post-treatment patients without abnormal blasts (n = 35), and patients with myeloid malignancies (n = 86). The comparison was based on the presence or absence of CD45RA expression, a marker commonly used to prospectively isolate lymphoid-primed cell populations within the CD34 + CD38 - fraction., Results: The CD34 + CD38 - CD45RA + cell population exhibited a significant expansion in bone marrow without leukemic cells 1 month after cord blood transplantation and in various type of myeloid malignancies, compared to the control group (p < 0.01). Continuous CD45RA expression and notable expansion of the CD34 + CD38 - CD45RA - population were exclusively observed in myelodysplastic syndrome-related diseases. The CD34 + CD38 - CD45RA + population displayed frequent expression of various markers in both leukemic and non-leukemic cells, in contrast to the CD34 + CD38 - CD45RA - population., Conclusions: The CD34 + CD38 - fraction should be carefully evaluated considering the nature of normal hematopoietic precursor cells, their cell frequency and immunophenotype, including CD45RA expression pattern, for improving the accuracy of myeloid malignancy diagnosis., (© 2023 International Clinical Cytometry Society.)

Introduction: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors., Materials and Methods: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle., Results: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease., Conclusions: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown., Trial Registration: ClinicalTrials.gov, NCT04462952., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S Kondo has received research funding from AstraZeneca, Chugai, Astellas, AbbVie, Eisai, and Incyte. Y Katsuya has no conflicts of interest to disclose. K Yonemori has received honoraria from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR Pharma, MSD, Boehringer Ingelheim, Ono, Daiichi-Sankyo, Bayer, Jansen, and Sanofi; and research funding from MSD, Daiichi-Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe. N Yamamoto has a leadership/advisory role in Healios; has received honoraria from Chugai; and has received research funding from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono, Janssen Pharma, MSD, MERCK, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio, and Rakuten Medical. K Komuro, M Sugeno, T Kawata, D Ghiorghiu, and D Meulendijks are employees of AstraZeneca and may own stock in AstraZeneca., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a group of diseases classified by left ventricular (LV) EF, a measure of pump function. However, LVEF does not reflect LV contractility. Previous studies have shown that tissue Doppler-derived LV isovolumic contraction velocity (IVCv) correlates well with the LV peak dP/dt, an index of LV contractility. We explored whether LV IVCv is associated with 1-year post-discharge outcomes in HFpEF., Methods: We enrolled 113 patients (median age, 86 years, 45 male) with HFpEF (EF on admission ≥ 50%) who were admitted to our hospital for the treatment of acute HF. Clinical characteristics including echocardiographic data were obtained before discharge. IVCv was obtained from the tissue Doppler waveforms of both the septal and lateral mitral annulus of the apical 4-chamber view and averaged data were used. Primary outcomes were all-cause death or unplanned hospitalization due to HF within the first year., Results: Among all patients, median LVEF was 61%, left atrial diameter was 47 mm, E/e' was 17.5, and IVCv was 4.5 cm/sec; mean tricuspid regurgitation velocity was 2.6 m/sec. Regarding laboratory data, the median plasma B-type natriuretic peptide level was 185 pg/mL. Thirty-four events occurred (15 deaths, 19 unplanned hospitalizations due to HF) within the first year. In multivariate Cox proportional hazards analyses, IVCv was significantly associated with outcomes (hazard ratio .68, 95% confidence interval .50-.89, p = .0095), independent of general characteristics, echocardiographic measures and pertinent laboratory parameters., Conclusion: LV IVCv was independently associated with 1-year outcomes in patients with HFpEF., (© 2024 Wiley Periodicals LLC.)

Background: A methodology to assess the immune microenvironment (IME) of non-small cell lung cancer (NSCLC) has not been established, and the prognostic impact of IME factors is not yet clear., Aims: This study aimed to assess the IME factors and evaluate their prognostic values., Methods and Results: We assessed CD8 + tumor-infiltrating lymphocyte (TIL) density, forkhead box protein P3 + (Foxp3 + ) TIL density, and programmed death receptor ligand-1 (PD-L1) tumor proportion score (TPS) using a machine-learning algorithm in whole-slide imaging (WSI). We dichotomized patients according to TIL density or TPS and compared their clinical outcomes. Between September 2014 and September 2015, 165 patients with NSCLC were enrolled in the study. We assessed IME factors in the epithelium, stroma, and their combination. An improvement in disease-free survival (DFS) was observed in the high CD8 + TIL density group in the epithelium, stroma, and the combination of both. Moreover, the group with high PD-L1 TPS in the epithelium showed better DFS than that with low PD-L1 TPS. In the multivariate analysis, the CD8 + TIL density in the combination of epithelium and stroma and PD-L1 TPS in the epithelium were independent prognostic factors (hazard ratio [HR] = 0.43; 95% confidence interval [CI] = 0.26-0.72; p = .001, HR = 0.49; 95% CI = 0.30-0.81; p = .005, respectively)., Conclusion: Our approach demonstrated that the IME factors are related to survival in patients with NSCLC. The quantitative assessment of IME factors enables to discriminate patients with high risk of recurrence, who can be the candidates for adjuvant therapy. Assessing the CD8 + TIL density in the combination of epithelium and stroma might be more useful than their individual assessment because it is a simple and time-saving analysis of TILs in WSI., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: This study aimed to evaluate the efficacy and safety of dentin hypersensitivity (DH) treatment using a newly developed device based on a powder jet deposition (PJD) technique that creates a hydroxyapatite (HAP) layer on the dentin surface, thereby alleviating the hypersensitivity. The effect of the PJD treatment was compared with that of conventional treatment using Teethmate Desensitizer (TMD; calcium-phosphate containing material with TTCP (Ca 4 (PO 4 ) 2 O) and DCPA (CaHPO 4 )), which has been used clinically in Japan with well-confirmed effectiveness., Materials and Methods: A randomized controlled trial was conducted including 35 patients who had symptoms of DH in two or more quadrants. Two test teeth were selected per patient (70 teeth in total) and randomly assigned to PJD or TMD treatment. The efficacy was evaluated using the improvement rate for air and scratch pain according to the scores obtained via visual analog scale 12 weeks after treatment. The safety assessment was performed focusing on gingival index (GI) and spontaneous pain. The t-test was used to analyze the non-inferiority of PJD treatment compared to TMD treatment., Results: The improvement rate of air pain was 69.0% for PJD and 69.7% for TMD. The improvement rate of scratch pain was 80.8% for PJD and 81.7% for TMD. Non-inferiority with a margin of 10% was not observed for both air and scratch pain. No change was observed in GI from baseline and the improvement rate of spontaneous pain for PJD was higher than that for TMD., Conclusion: Non-inferiority of PJD to TMD treatment was not observed in this study; however, it was not statistically demonstrated, and the results were thus interpreted as inconclusive. PJD did improve the DH symptoms, as did TMD. PJD's therapeutic effect was most likely attributable to the deposition of a HAP layer on the tooth surface, which would alleviate hypersensitivity for at least 12 weeks without causing severe adverse events., Trial Registration: UMIN-CTR. ID: UMIN000025022. date: 02/12/2016., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Appropriate load distribution among the supporting elements is essential for the long-term success of implant-assisted removable partial dentures; however, there is little information available on load distribution., Purpose: This study aimed to evaluate the effect of implant location on load distribution in implant-assisted removable partial dentures by reviewing in vitro models and finite-element analysis studies., Materials and Methods: English-language studies which examined the load distribution of implant-assisted removable partial dentures and were published between January 2001 and October 2022 were extracted from PubMed, ScienceDirect, and Scopus online databases, and manual searching. Two reviewers selected the articles based on the predetermined inclusion and exclusion criteria, followed by data extraction and analysis., Results: Forty-seven studies were selected after evaluating the titles and abstracts of 264 articles; two were identified manually. After screening the text, 12 studies were included: six in vitro model experiments and six finite-element analysis studies. All included studies used a mandibular free-end missing model (Kennedy Class I or II). The influence of implant location on load distribution to the abutment tooth, implant, and mucosa under the denture base was summarized in three cases: implant at the premolar, first molar, and second molar region. Due to differences in the measurement method of load distribution and loading condition to the denture, the results differed among the studies., Conclusions: The implant location in implant-assisted removable partial dentures can affect load distribution to the supporting elements, such as the abutment tooth, implant, and mucosa under the denture base., (© 2023. Deutsche Gesellschaft für Implantologie im Zahn‐, Mund‐ und Kieferbereich e.V., Japanese Society of Oral Implantology.)

Background: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear., Methods: We estimated CD-UC complexation for nine CD derivatives derived from native α-, β-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models., Findings: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability., Conclusions: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague-Dawley rats fed a high-phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups-baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers., (© 2023 Federation of American Societies for Experimental Biology.)

Purpose: To evaluate the effect of different abutment screw retightening procedures on the screw stability between the abutment and implant., Materials and Methods: External hexagon connection (EHC) and internal trichannel connection (ITC) implants were employed in this study. Each abutment screw was used for the following specific applications (n = 5 for each group): group 0 = abutment was tightened and retightened with a 10-minute interval; group 1 = abutment was tightened and retightened with a 10-minute interval, then loaded for 500,000 cycles; group 2 = abutment was loaded for 83,000 cycles during tightening and retightening, then loaded for 500,000 cycles; group 3 = abutment was loaded for 167,000 cycles during tightening and retightening, then loaded for 500,000 cycles; and group 4 = abutment was loaded for 250,000 cycles during tightening and retightening, then loaded for 500,000 cycles. Both tightening and retightening torques were set at 35 Ncm, and dynamic oblique loading between 0 N and 200 N was applied on the abutment in all groups. The settling values of the abutments after retightening and the abutment removal torque values (RTVs) after testing were measured., Results: No significant differences in settling values were found between EHC and ITC. There were significant differences in the RTVs of EHC implants, but ITC implants showed no difference in RTV with different prosthetic retightening applications., Conclusion: The retightening application affected the joint stability of EHC implants but did not affect the settlement and joint stability of ITC implants. Int J Prosthodont 2023;36:181-188. doi: 10.11607/ijp.6863.

Aims/introduction: We carried out a cross-sectional study of people with type 2 diabetes mellitus to elucidate the association between sleep duration and food intake., Materials and Methods: Overall, 2,887 participants with type 2 diabetes mellitus (mean age 63.0 years; 61.1% men; mean glycated hemoglobin level 7.5%) were included in this study. The participants' self-reported dietary habits and sleep duration were evaluated using a brief self-administered dietary history questionnaire and Pittsburgh Sleep Quality Index, respectively. The participants were categorized into the following four groups based on sleep duration: <6, 6-6.9, 7-7.9 (reference) and ≥8 h., Results: No significant differences were observed between the groups regarding energy intake (kcal/day), absolute intake (g/day) or relative intake (% energy) of carbohydrates, total fat, proteins and fibers. However, confectionery intake was higher in the <6 h group and lower in the ≥8 h group than in the reference group after adjustment for confounding factors. In multivariate analysis, sleep durations <6 h and ≥8 h significantly correlated with increased (95% confidence interval 0.55 to 3.6; P = 0.0078) and decreased (95% confidence interval -4.0 to -0.32; P = 0.021) confectionery intake, respectively. Confectionery intake was positively correlated with female sex, glycated hemoglobin level and dyslipidemia, whereas it was negatively correlated with alcohol consumption and current smoking status., Conclusions: Short sleep duration is associated with high confectionery intake in people with type 2 diabetes mellitus; this might disturb their glycemic control. Therefore, short sleepers with type 2 diabetes mellitus could improve their glycemic control by avoiding confectionery intake and maintaining adequate sleep duration., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Pathological N2 (pN2) non-small cell lung cancer (NSCLC) is diverse; its treatment depends on the clinical N (cN) status. We aimed to determine the efficacy of upfront surgery for cN2pN2 NSCLC., Methods: The study included 43 cN2pN2 NSCLC patients who underwent upfront surgery at the Shizuoka Cancer Center between 2002 and 2017. Survival outcome, focusing on cN2 status, was retrospectively investigated. Mediastinal lymph nodes were pre-operatively evaluated using computed tomography and positron emission tomography. Surgical eligibility criteria included single-station cN2. N2 with N1 and skip N2 were defined as N2 with and without ipsilateral hilar lymph node metastasis, respectively. A platinum-doublet regimen was used for adjuvant chemotherapy. Survival curves were analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model., Results: Clinical-skip N2 and cN2 with N1 cases included 22 and 21 patients, respectively. Twenty-three patients received adjuvant chemotherapy. The median follow-up duration was 73 months. Clinical-skip N2 had a significantly better 5-year recurrence-free survival (RFS) than cN2 with N1 (58.3 vs 28.6%, P = 0.038) and was an independent favorable RFS predictor. Recurrence within 18 months occurred in 71% of cN2 with N1 cases. Five-year overall survival and RFS rates in patients receiving adjuvant chemotherapy vs those without adjuvant chemotherapy were 82.2 vs 41.9% (P = 0.019) and 56.5 vs 28.0% (P = 0.049), respectively., Conclusions: Clinical-skip N2 had an excellent prognosis, and upfront surgery was acceptable. Conversely, upfront surgery followed by chemotherapy is not recommended for cN2 with N1 patients because of early recurrence., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0-3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: Alcohol use disorder (AUD) is frequently accompanied by comorbid attention-deficit hyperactivity disorder (ADHD). Comorbid ADHD has been reported to increase the severity of AUD. We investigated whether ADHD severity also influences AUD relapse risk at baseline and after inpatient treatment., Methods: In this study, 187 AUD patients admitted to Narimasu Kosei Hospital from October 2019 to March 2021 were included in the analysis. According to the Adult ADHD Self-Report Scale (ASRS), participants were divided into two groups: ASRS+ with ADHD characteristics (n = 43) and ASRS- with low/no ADHD characteristics (n = 144). Groups were compared for AUD relapse risk at the start of treatment (baseline) and before hospital discharge using the multidimensional Alcohol Relapse Risk Scale (ARRS). The change in relapse risk during hospitalization was also compared by assessment of the interaction between groups (ASRS+ vs. ASRS-) and time (at discharge vs. baseline)., Results: The total ARRS score and dimension subscores for stimulus-induced vulnerability and emotionality problems were significantly higher in the ASRS+ group at baseline and before discharge compared to the ASRS- group. There was a significant group × time interaction indicating less improvement of stimulus-induced vulnerability during inpatient treatment among the ASRS+ group compared to the ASRS- group., Conclusions: Our findings suggest that AUD patients with ADHD characteristics have a higher risk of relapse both at baseline and after inpatient treatment. Stimulus-induced vulnerability to relapse is less likely to improve with treatment in patients with ADHD characteristics., (© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

To elucidate the effect of evocalcet, a new oral calcimimetic to bone of secondary hyperparathyroidism (SHPT) with chronic kidney disease (CKD), the rats were 5/6 nephrectomized and fed on a high-phosphate diet. The treated rats were then divided into vehicle groups and evocalcet administered groups. The rats in the vehicle groups exhibited increased levels of serum PTH and inorganic phosphate (Pi) levels, high bone turnover, and severe cortical porosity, mimicking SHPT (CKD-SHPT rats). The cortical bone of the CKD-SHPT rats showed broad demineralization around the osteocytes, suppression of Phex/small integrin-binding ligand N-linked glycoprotein-mediated mineralization in the periphery of the osteocytic lacunae, and increased levels of osteocytic cell death, all of which were considered as the first steps of cortical porosity. In contrast, evocalcet ameliorated the increased serum PTH levels, the enlarged osteocytic lacunae, and the cortical porosity of the CKD-SHPT rats. Osteocytes of CKD-SHPT rats strongly expressed PTH receptor and Pit1/Pit2, which sense extracellular Pi, indicating that PTH and Pi affected these osteocytes. Cell death of cultured osteocytes increased in a Pi concentration-dependent manner, and PTH administration rapidly elevated Pit1 expression and enhanced osteocytic death, indicating the possibility that the highly concentrated serum PTH and Pi cause severe perilacunar osteolysis and osteocytic cell death. It is likely therefore that evocalcet not only decreases serum PTH but also reduces the exacerbation combined with PTH and Pi to the demineralization of osteocytic lacunae and osteocytic cell death, thereby protecting cortical porosity in CKD-SHPT rats., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

STATa is a pivotal transcription factor for Dictyostelium development. dutA is the most abundant RNA transcribed by RNA polymerase II in Dictyostelium, and its functional interplay with STATa has been suggested. This study demonstrates that dutA RNA molecules are distributed as spot-like structures in the cytoplasm, and that its cell type-specific expression changes dramatically during development. dutA RNA was exclusively detectable in the prespore region of slugs and then predominantly localized in prestalk cells, including the organizer region, at the Mexican hat stage before most dutA transcripts, excluding those in prestalk O cells, disappeared as culmination proceeded. dutA RNA was not translated into small peptides from any potential open reading frame, which confirmed that it is a cytoplasmic lncRNA. Ectopic expression of dutA RNA in the organizer region of slugs caused a prolonged slug migration period. In addition, buffered suspension-cultured cells of the strain displayed reduced STATa nuclear translocation and phosphorylation on Tyr702. Analysis of gene expression in various dutA mutants revealed changes in the levels of several STATa-regulated genes, such as the transcription factors mybC and gtaG, which might affect the phenotype. dutA RNA may regulate several mRNA species, thereby playing an indirect role in STATa activation., (© 2022 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background: The importance of the stromal components in tumour progression has been discussed widely, but their prognostic role in small size tumours with lepidic components is not fully understood. Applying digital tissue image analysis to whole-slide imaging may enhance the accuracy and reproducibility of pathological assessment. This study aimed to evaluate the prognostic value of tumour components of lung adenocarcinoma by measuring the dimensions of the tumour consisting elements separately, using a machine learning algorithm., Methods: Between September 2002 and December 2016, 317 patients with surgically resected, pathological stage IA adenocarcinoma with lepidic components were analysed. We assessed the whole tumour area, including the lepidic components, and measured the epithelium, collagen, elastin areas and alveolar air space. We analysed the prognostic impact of each tumour component., Results: The dimensions of the epithelium and collagen areas were independent significant risk factors for recurrence-free survival (hazard ratio, 8.38; 95% confidence interval, 1.14-61.88; P = 0.037, and hazard ratio, 2.58; 95% confidence interval, 1.14-5.83; P = 0.022, respectively). According to the subgroup analysis when combining the epithelium and collagen areas as risk factors, patients with tumours consisting of both large epithelium and collagen areas showed significantly poor prognoses (P = 0.002)., Conclusions: We assessed tumour components using a machine learning algorithm to stratify the post-operative prognosis of surgically resected stage IA adenocarcinomas. This method might guide the selection of patients with a high risk of recurrence., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The contribution ratio of metabolic enzymes such as cytochrome P450 to in vivo clearance (fraction metabolized: fm) is a pharmacokinetic index that is particularly important for the quantitative evaluation of drug-drug interactions. Since obtaining experimental in vivo fm values is challenging, those derived from in vitro experiments have often been used alternatively. This study aimed to explore the possibility of constructing machine learning models for predicting in vivo fm using chemical structure information alone. We collected in vivo fm values and chemical structures of 319 compounds from a public database with careful manual curation and constructed predictive models using several machine learning methods. The results showed that in vivo fm values can be obtained from structural information alone with a performance comparable to that based on in vitro experimental values and that the prediction accuracy for the compounds involved in CYP induction or inhibition is significantly higher than that by using in vitro values. Our new approach to predicting in vivo fm values in the early stages of drug discovery should help improve the efficiency of the drug optimization process.

The covalent linkage of phenanthrene units at 9 and 10 positions resulted in a broadening of the absorption band and a red-shift of the fluorescence band in ethanol compared with its monomer. Spatial stacking of phenanthrene units also altered the spectral shape of phosphorescence emission, and the oligomer film emitted phosphorescence at room temperature.

Background: For biomechanical consideration of dental implants, an understanding of the three-dimensional (3D) load exerted on the implant is essential, but little information is available on the in vivo load, including the measuring devices., Purpose: This review aimed to evaluate studies that used specific load-measuring devices that could be mounted on an implant to measure the functional load in vivo., Materials and Methods: An electronic search utilizing the internet research databases PubMed, Google Scholar, and Scopus was performed. The articles were chosen by two authors based on the inclusion and exclusion criteria., Results: In all, 132 studies were selected from the database search, and 16 were selected from a manual search. Twenty-three studies were finally included in this review after a complete full-text evaluation. Eleven studies were related to the force measurements using the strain gauges, and 12 were related to the piezoelectric force transducer. The principles of the two types of devices were completely different, but the devices produced comparable outcomes. The dynamics of the load magnitude and direction on the implant during function were clarified, although the number of participants in each study was small., Conclusions: The load exerted on the implant during function was precisely measured in vivo using specific measuring devices, such as strain gauges or piezoelectric force transducers. The in vivo load data enable us to determine the actual biomechanical status in more detail, which might be useful for optimization of the implant prosthetic design and development of related materials. Due to the limited data and difficulty of in vivo measurements, the development of a new, simpler force measurement device and method might be necessary., (© 2022. The Author(s).)

Objective: Lobe-specific nodal dissection (LND) is increasingly used for non-small cell lung cancer (NSCLC) in Japan; however, its treatment validity remains unclarified. Since 2013, LND has been used as a standard procedure for clinical stage-I (c-stage-I) NSCLC at our institution. We aimed to evaluate its validity using intraoperative frozen section analysis (FSA) for c-stage-I NSCLC., Methods: The participants comprised patients with NSCLC who underwent LND between 2013 and 2016 (n = 307) or systematic nodal dissection (SND) between 2002 and 2013 (n = 367) for c-stage-I disease. FSA was routinely performed in LND to examine at least three stations. Outcomes were compared between the LND and SND groups. Patients in whom LND was converted to SND due to metastasis on FSA of the sampled lymph node were still categorized into the LND group, i.e., intention-to-treat analysis. The prognostic impact was compared using propensity score matching., Results: The rate of conversion from LND to SND was 10.4%. Of the patients converted to SND, 12.5% had metastases outside the LND area. False-negative N2 results were detected in only 0.7% of the LND group patients after FSA. After matching, each group had 220 patients. There were no significant between-group differences in the lymph-node recurrence rate (7% vs. 6%), 5-year recurrence-free survival (80.1% vs. 79.0%), and overall survival (90.4% vs. 90.3%)., Conclusions: LND with intraoperative FSA is a valid modality that could serve as a standard surgical procedure for c-stage-I NSCLC. Intraoperative FSA may lower the residual lymph-node metastasis risk in LND., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Purpose: Several studies reported the possibility of predicting genetic abnormalities in non-small-cell lung cancer by deep learning (DL). However, there are no data of predicting ALK gene rearrangement ( ALKr ) using DL. We evaluated the ALKr predictability using the DL platform., Materials and Methods: We selected 66 ALKr -positive cases and 142 ALKr -negative cases, which were diagnosed by ALKr immunohistochemical staining in our institution from January 2009 to March 2019. We generated virtual slide of 300 slides (150 ALKr -positive slides and 150 ALKr -negative slides) using NanoZoomer. HALO-AI was used to analyze the whole-slide imaging data, and the DenseNet network was used to build the learning model. Of the 300 slides, we randomly assigned 172 slides to the training cohort and 128 slides to the test cohort to ensure no duplication of cases. In four resolutions (16.0/4.0/1.0/0.25 μm/pix), ALKr prediction models were built in the training cohort and ALKr prediction performance was evaluated in the test cohort. We evaluated the diagnostic probability of ALKr by receiver operating characteristic analysis in each ALKr probability threshold (50%, 60%, 70%, 80%, 90%, and 95%). We expected the area under the curve to be 0.64-0.85 in the model of a previous study. Furthermore, in the test cohort data, an expert pathologist also evaluated the presence of ALKr by hematoxylin and eosin staining on whole-slide imaging., Results: The maximum area under the curve was 0.73 (50% threshold: 95% CI, 0.65 to 0.82) in the resolution of 1.0 μm/pix. In this resolution, with an ALKr probability of 50% threshold, the sensitivity and specificity were 73% and 73%, respectively. The expert pathologist's sensitivity and specificity in the same test cohort were 13% and 94%., Conclusion: The ALKr prediction by DL was feasible. Further study should be addressed to improve accuracy of ALKr prediction., Competing Interests: Akira OnoHonoraria: Chugai Pharma, Ono Pharmaceutical, AstraZeneca, Bristol Myers SquibbResearch Funding: AstraZeneca (Inst), Janssen Research & Development (Inst) Toru ImaiSpeakers' Bureau: Boehringer Ingelheim Toshiaki TakahashiHonoraria: AstraZeneca Japan, Chugai Pharma, Lilly Japan, Ono Pharmaceutical, MSD K.K, Pfizer, Boehringer Ingelheim, Roche, Takeda, Yakult HonshaResearch Funding: AstraZeneca Japan (Inst), Lilly Japan (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), MSD K.K (Inst), Pfizer (Inst), Amgen (Inst), Boehringer Ingelheim Japan (Inst), Merck (Inst)No other potential conflicts of interest were reported.

Background: Trophoblast cell-surface antigen 2 (TROP2) is expressed on the surface of trophoblast cells and many malignant tumor cells. However, data on TROP2 expression in advanced lung cancer are insufficient, and its changes have not been fully evaluated., Methods: We assessed the prevalence and changes in TROP2 expression in patients with lung cancer who received anti-cancer treatments using immunohistochemical (IHC) analysis with an anti-TROP2 antibody (clone: SP295). IHC scores were graded from 0 to 3; grade ≥ 2 was considered positive for TROP2 expression. We defined a difference in IHC score, before and after anti-cancer treatments, as the change in TROP2 expression., Results: Before anti-cancer treatment, TROP2 expression was observed in 89% (143/160) of the patients and was significantly more common in adenocarcinoma and squamous cell carcinoma than in neuroendocrine carcinoma (P < 0.001). After anti-cancer treatment, TROP2 expression was observed in 87% (139/160) of the patients. The distribution of TROP2 expression in post-treatment samples was analogous to that in pre-treatment samples when compared using the Wilcoxon signed-rank test (P = 0.509). However, an increase in TROP2 expression was seen in 19 (12%), and a decrease in 20 (13%) patients. Patients treated with targeted therapy showed significantly higher changes in TROP2 expression (P = 0.019) and thoracic radiotherapy was more likely to increase TROP2 expression than chemotherapy alone., Conclusion: Although some anti-cancer treatments might alter the TROP2 expression, TROP2 was expressed in most lung cancer specimens before and after anti-cancer treatments. These results support the development of TROP2-directed therapy against advanced lung cancer in various treatment lines., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Ultrasound assessment of inferior vena cava (IVC) diameter and its respiratory variation is widely used to estimate right atrial pressure (RAP). Generally, the IVC distends as the RAP rises; however, there may be discrepancies between the values. Therefore, it is critical to recognize clinical factors other than RAP that may influence IVC measurements., Methods: We obtained the IVC maximum diameter and IVC collapsibility index (IVCCI) simultaneously during right-heart catheterization in 71 consecutive patients. Then, we assessed various clinical and hemodynamic factors to elucidate the independent determinants of IVC measurements. Moreover, we tried to generate the regression equation to estimate mean RAP from the IVC maximum diameter and IVCCI., Results: The mean IVC maximum diameter and IVCCI were 15 ± 4 mm and 51 ± 15%, respectively. In stepwise multivariate analysis, the higher mean RAP (β = 0.52; p < 0.0001), the presence of significant tricuspid regurgitation (β = 0.31; p = 0.0005), a larger body surface area (β = 0.22; p = 0.0017), and younger age (β = -0.18; p = 0.049) were independently associated with the IVC maximum diameter. Only the mean RAP was independently associated with the IVCCI (β = -0.45; p < 0.0001). The regression equation (R 2  = 0.43, p < 0.0001) was as follows: estimated mean RAP = 3.7 + 0.62 × maximum IVC diameter / BSA - 0.07 × IVCCI., Conclusion: Distension of the IVC mainly occurs with elevated RAP. However, the presence of significant tricuspid regurgitation, a larger body surface area, and younger age are associated with the IVC maximum diameter, independently of RAP. Interestingly, IVCCI is influenced only by RAP., Competing Interests: Conflict of interest Nothing to Disclose, (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The lung is a major target organ of metastasis in several cancers. To distinguish primary lung cancer from pulmonary metastases is a clinical challenge. Small pulmonary nodules (PNs) are frequently diagnosed by frozen section diagnosis (FSD) intraoperatively after resection. Intraoperative FSD is very important to determine the extent of subsequent surgical procedures. This study aimed to know the validity of surgical decision based on FSD for preoperatively unconfirmed PN with previous malignancy., Methods: We retrospectively evaluated 96 patients with suspected malignant PN who underwent intraoperative FSD between 2018 and 2020. Intraoperative FSD, final diagnosis, and surgical procedure data were examined., Results: Surgical procedure adequacy, based on FSD for preoperatively unconfirmed PN with previous malignancy, was 91% (88/96). The overall diagnostic accuracy of FSD was 83.3% (80/96). Discrepancy was noted in two cases (2.1%), and conclusive diagnosis could not be reached intraoperatively in 14 cases (14.6%). A second surgery was required in three patients and no additional excision for primary lung cancer was performed in three patients. Conversely, there were three cases of over-surgery, namely, lobectomy for pulmonary metastasis., Conclusions: Surgical decision-making based on FSD for preoperatively unconfirmed PN in patients with previous malignancy was generally adequate. However, there were inadequate or excessive surgical procedures due to limitations in the accuracy of intraoperative FSD. Improving the accuracy of intraoperative FSD is a necessary step for obtaining adequate surgical decision-making and precision medicine., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

This study aimed to reveal the relationship between quality of life (QOL) and sleep quality in patients with type 1 diabetes mellitus (T1DM). Overall, 202 patients with T1DM were registered in our study, and 192 were eligible for analysis. Baseline characteristics and laboratory values were determined. Patients completed the Japanese versions of the Pittsburgh Sleep Quality Index (PSQI) and Diabetes Therapy-Related QOL (DTR-QOL) questionnaires. We investigated the relationship between the global PSQI and DTR-QOL total scores by using linear regression analysis. In univariate regression analysis, DTR-QOL total scores were associated with body mass index, alcohol consumption, hypertension, hemoglobin A1c (HbA1c), and global PSQI score (all p-value <0.05) but not with sleep duration. When the association between PSQI subscales and DTR-QOL total scores was examined, DTR-QOL total scores were significantly related to subjective sleep quality and daytime dysfunction. In a multivariate regression analysis, the global PSQI score was negatively related to DTR-QOL total scores. Patients with an HbA1c concentration ≥8.0% had significantly lower DTR-QOL total scores. We revealed a relationship between QOL and sleep quality in T1DM patients and showed that the relationship between QOL and PSQI subscales in T1DM patients may be different from that in patients with type 2 diabetes mellitus. Assessing and managing sleep quality may be necessary for patients with diabetes to improve QOL.