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Naoko Katsurada,1 Motoko Tachihara,1 Yukihisa Hatakeyama,1 Kiyoko Koyama,1 Masako Yumura,1 Tatsunori Kiriu,1 Ryota Dokuni,1 Daisuke Hazama,1 Shuntaro Tokunaga,1 Daisuke Tamura,1 Kyosuke Nakata,1 Masatsugu Yamamoto,1 Hiroshi Kamiryo,1 Kazuyuki Kobayashi,1 Yugo Tanaka,2 Yoshimasa Maniwa,2 Yoshihiro Nishimura1 1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; 2Division of General Theocratic Surgery, Kobe University Graduate School of Medicine, Kobe, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpPurpose: Adjuvant chemotherapy with cisplatin (CDDP) plus vinorelbine is the standard regimen for the treatment of non-small cell lung cancer (NSCLC). However, CDDP elicits severe toxic effects, including emesis, neurotoxicity, and renal damage; carboplatin (CBDCA) may be a feasible alternative for CDDP-unfit patients. CBDCA plus paclitaxel (PTX) adjuvant chemotherapy showed a survival benefit for patients with stage IB tumors > 4 cm in size, while CBDCA plus nanoparticle albumin-bound (nab)-PTX showed greater efficacy and lower neurotoxicity than CBDCA plus PTX in advanced NSCLC. Here, we investigated the feasibility of using CBDCA plus nab-PTX as adjuvant chemotherapy for NSCLC.Patients and Methods: Patients with completely resected stage II or III NSCLC, with an Eastern Cooperative Oncology Group performance status of 0– 1 and adequate kidney function, received four cycles of postoperative adjuvant chemotherapy with CBDCA (AUC=5 mg/mL/min, on day 1) and nab-PTX (100 mg/m2, on days 1, 8, and 15) administered every 4 weeks within 8 weeks after surgery. The study was designed as a prospective, single-center, Phase II study. The primary endpoint was the completion rate of chemotherapy; secondary endpoints were two-year relapse-free survival (RFS) and safety. The expected completion rate was 80%, with a 50% lower limit.Results: Of 21 enrolled patients, 18 (85.7%) were CDDP-unfit owing to age (≥ 75 years old [n=11, 52.4%]) or mild renal impairment (n=7, 33.3%). Nineteen of the 21 enrolled patients were assigned to the intervention. The most common grade 3 or 4 adverse events were neutropenia (n=15, 78.9%) and anemia (n=3, 15.8%). The completion rate for the four cycles was 63.2% (95% CI, 38.4– 83.7). Two-year RFS was 56.8% (95% CI, 29.7– 76.9).Conclusion: The completion rate for CBDCA plus nab-PTX as adjuvant chemotherapy for CDDP-unfit NSCLC patients did not reach treatment feasibility. Further dose modifications may be required in future studies.Keywords: nab-paclitaxel, carboplatin, adjuvant chemotherapy, non-small cell cancer

Motoko Tachihara,1 Tatsunori Kiriu,1 Akito Hata,2 Yukihisa Hatakeyama,3 Kyosuke Nakata,1 Tatsuya Nagano,1 Masatsugu Yamamoto,1 Kazuyuki Kobayashi,1 Hisashi Ohnishi,3 Nobuyuki Katakami,2 Yoshihiro Nishimura11Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan; 2Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Hyogo 650-0047, Japan; 3Department of Respiratory Medicine, Akashi Medical Center, Akashi, Hyogo 674-0063, JapanBackground: Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.Methods: Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) + GEM (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS).Results: Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47–79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1–10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6–4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%).Conclusion: The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.Keywords: nab-paclitaxel, gemcitabine, non-small-cell lung cancer

Wiwin Is Effendi,1,2 Tatsuya Nagano,1 Motoko Tachihara,1 Kanoko Umezawa,1 Tatsunori Kiriu,1 Ryota Dokuni,1 Masahiro Katsurada,1 Masatsugu Yamamoto,1 Kazuyuki Kobayashi,1 Yoshihiro Nishimura11Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; 2Department of Pulmonology and Respiratory Medicine, Airlangga University Medical Faculty, Surabaya 60131, IndonesiaBackground: The combination of gemcitabine (GEM) and paclitaxel (PTX) was appealing for clinical exploration due to different mechanisms of action and partially non-overlapping toxicities.Purpose: The aim of this study was to elucidate a potential effect of this combination on the proliferation of two non-small cell lung cancer (NSCLC) cell lines, A549 and H520.Materials and methods: Cell lines were treated with GEM and PTX for 48 hours to evaluate the half maximal inhibitory concentration (IC50). To determine the combination index (CI), cell lines were exposed to GEM and PTX, in a constant ratio of IC50, by various combination treatments. GEM`s effect on tubulin was assessed by western blotting and immunofluorescent staining. GEM was combined with nanoparticle albumin-bound-paclitaxel (NP) in evaluating tumor growth inhibition.Results: The IC50 of GEM and PTX in A549 and H520 were 6.6 nM and 46.1 nM, and 1.35 nM and 7.59 nM, respectively. Among the sequences explored (GEM→PTX, PTX→GEM, and GEM plus PTX simultaneously [GEM+PTX]), GEM→PTX produced a mean CI

Primary tracheal diffuse large B-cell lymphoma (DLBCL) is a rare, aggressive, but potentially curable malignancy that is difficult to diagnose and treat. We herein report a 93-year-old Japanese man diagnosed with primary tracheal DLBCL after presenting with progressive dyspnea due to severe upper tracheal stenosis during follow-up for pulmonary amyloidosis. Following the diagnosis, the patient was treated with corticosteroids, followed by R-CHOP chemotherapy, resulting in a therapeutic response. The patient's history of pulmonary amyloidosis may have contributed to the development of tracheal DLBCL. An evaluation of the risks and benefits of various therapeutic interventions is crucial for providing optimal patient-specific care.

Objectives: We introduced the critical pathway (CP) for follow-up on patients with postoperative lung cancer to the staff of the Hyogo Prefectural Awaji Medical Center and regional medical institutions in Japan, in 2010., Methods and Results: We raised awareness within our hospital and collaborating medical institutes and trained our staff on the CP before introducing it. From May 2013 through October 2023, lung cancer surgery was performed on 460 patients. Our CP was applied to 71.7% of these patients. Reasons for non-application included the high risk of recurrence due to advanced cancer stages( 39.2%) and the treatment for other types of cancer was needed in our hospital (26.2%). We reviewed the outcome of our CP., Conclusion: The high application rate was facilitated by preparatory actions, including training our hospital staff and collaborating medical institutions. An even higher application rate can be achieved by continuing to raise awareness and strengthening cooperation between concerned medical institutions that treat advanced lung cancer.

Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral angioedema (CholU-PA), 3) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd); 1) and 2) include SAT based on pathogenesis. There have been no studies on differences in the prevalence of bronchial asthma among the subtypes. We analyzed bronchial responsiveness using the methacholine dose indicator D min , respiratory symptoms, and exhaled nitric oxide (FeNO). Median log10 D min (interquartile range) of patients with conventional SAT-CholU (n = 11), CholU-PA (n = 11), and CholU-Anhd (n = 11) was 0.381 (- 0.829, 1.079), 0.717 (0.249, 0.787), and 1.318 (0.121, 1.699), respectively (p = 0.516). Respiratory symptoms were less frequently observed in CholU-Anhd than in conventional SAT-CholU or CholU-PA. FeNO of patients with conventional SAT-CholU, CholU-PA, and CholU-Anhd was 23 (18.5, 65.0), 39 (32.0, 59.5), and 25 (19.0, 33.0) ppb, respectively (p = 0.237). Nine% of conventional SAT-CholU patients and more than half of CholU-PA patients required treatment for asthma. Log D min tended to be lower in patients with SAT-CholU than in those with CholU-Anhd. CholU-PA might be associated with asthma., (© 2022. The Author(s).)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant omicron is now under investigation. We evaluated cross-neutralizing activity against omicron in coronavirus disease 2019 (COVID-19) convalescent patients (n = 23) who had received 2 doses of an mRNA vaccination (BNT162b2 or mRNA-1273). Intriguingly, after the second vaccination, the neutralizing antibody titers of subjects against SARS-CoV-2 variants, including omicron, all became seropositive, and significant fold-increases (21.1-52.0) were seen regardless of the disease severity. Our findings thus demonstrate that 2 doses of mRNA vaccination to SARS-CoV-2 convalescent patients can induce cross-neutralizing activity against omicron., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Bronchoscopy can be a distress for the patient. There have been few studies on the combination of sedatives and opioids. The aim of this study was to demonstrate the usefulness and safety of administration of the combination of midazolam and pethidine during bronchoscopy., Methods: In this prospective randomized single (patient)-blind study, we randomly assigned 100 patients who were scheduled to undergo bronchoscopy biopsy to receive treatment with either the midazolam/pethidine combination (combination group) or midazolam alone (midazolam group) during examinations. After the end of bronchoscopy, patients completed a questionnaire and the visual analogue scale was measured. The primary outcome was the patients' acceptance of re-examination assessed by visual analogue scale. We also assessed pain levels, vital signs, midazolam use, xylocaine use, and adverse events. Univariate analyses were performed using Fisher's exact test for categorical data, and the t-test or Mann-Whitney test was carried out for analysis of numeric data. All P-values were two-sided, and values < 0.05 were considered statistically significant., Results: We analyzed 47 patients in the combination group and 49 patients in the midazolam group. The primary outcome was a good trend in the combination group, but not significantly different (3.82 ± 2.3 in combination group versus 4.17 ± 2.75 in midazolam alone, P = 0.400). In the combination group, the visual analog scale score for pain during bronchoscopy was significantly lower (1.10 ± 1.88 versus 2.13 ± 2.42, P = 0.022), and the sedation level score per the modified observer's assessment of alertness/sedation scale was significantly deeper (3.49 ± 0.98 versus 3.94 ± 1.03, P = 0.031). Maximal systolic blood pressure during testing was significantly lower (162.39 ± 23.45 mmHg versus 178.24 ± 30.24 mmHg, P = 0.005), and the number of additional administrations of midazolam was significantly lower (2.06 ± 1.45 versus 2.63 ± 1.35, P = 0.049). There were also significantly fewer adverse events (30 versus 41, P = 0.036)., Conclusions: The combination uses of midazolam and pethidine for sedation resulted in significant improvements in the pain, blood pressure, additional use of midazolam, and safety during bronchoscopy among patients., Trial Registration: This study was registered in the University Medical Hospital Information Network in Japan (UMINCTR Registration number: UMIN000032230 , Registered: 13/April/2018)., (© 2022. The Author(s).)

Background/aim: Annexin A10 (ANXA10) is a member of the annexin family and a calcium-dependent phospholipid-binding protein. The aim of this study was to clarify the clinical significance of ANXA10 expression in lung adenocarcinoma., Materials and Methods: ANXA10 expression was immunohistochemically examined in surgical specimens of lung adenocarcinoma obtained from 74 consecutive patients who underwent complete resection from January 2014 to December 2014. Expression of ANXA10 was down-regulated in A549 cells via siRNA transfection and the effect of ANXA10 on cell migration was assessed by the wound healing assay. Expression of ANXA10 was examined by immunocytochemistry and polymerase chain reaction., Results: High ANXA10 expression was significantly correlated with poor overall survival (p=0.00705). Multivariate analysis with the Cox proportional hazard model demonstrated that ANXA10 expression was an independent prognostic factor. Cell migration was suppressed in ANXA10-down-regulated A549 cell lines., Conclusion: ANXA10 has a role in cancer cell migration and high ANXA10 expression is a novel prognostic marker in lung adenocarcinoma., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. The emergence of variants of concern (VOCs) has become one of the most pressing issues in public health. To control VOCs, it is important to know which COVID-19 convalescent sera have cross-neutralizing activity against VOCs and how long the sera maintain this protective activity., Methods: Sera of patients infected with SARS-CoV-2 from March 2020 to January 2021 and admitted to Hyogo Prefectural Kakogawa Medical Center were selected. Blood was drawn from patients at 1-3, 3-6, and 6-8 months post onset. Then, a virus neutralization assay against SARS-CoV-2 variants (D614G mutation as conventional strain; B.1.1.7, P.1, and B.1.351 as VOCs) was performed using authentic viruses., Results: We assessed 97 sera from 42 patients. Sera from 28 patients showed neutralizing activity that was sustained for 3-8 months post onset. The neutralizing antibody titer against D614G significantly decreased in sera of 6-8 months post onset compared to those of 1-3 months post onset. However, the neutralizing antibody titers against the three VOCs were not significantly different among 1-3, 3-6, and 6-8 months post onset., Discussion: Our results indicate that neutralizing antibodies that recognize the common epitope for several variants may be maintained for a long time, while neutralizing antibodies having specific epitopes for a variant, produced in large quantities immediately after infection, may decrease quite rapidly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kurahashi, Sutandhio, Furukawa, Tjan, Iwata, Sano, Tohma, Ohkita, Nakamura, Nishimura, Arii, Kiriu, Yamamoto, Nagano, Nishimura and Mori.)

Background/aim: Chloride intracellular channel 1 (CLIC1) is a member of the chloride channel protein family. The aim of this study was to clarify the role of CLIC1 in lung adenocarcinoma., Patients and Methods: The expression levels of CLIC1 in 74 patients with completely resected lung adenocarcinoma were analyzed by immunohistochemistry. Overall survival was assessed in relation to the expression level of CLIC1. Moreover, in the lung cancer cell lines A549 and PC9, CLIC1 expression was inhibited by small interfering RNA. The function of CLIC1 was analyzed in these cell lines., Results: High expression of CLIC1 was associated with short overall survival compared to low expression (p=0.0327). Multivariate analysis revealed that CLIC1 expression was an independent prognostic factor. Knockdown of CLIC1 inhibited cell proliferation and migration through suppression of the p38 MAPK signaling pathway in A549 and PC9 cells., Conclusion: CLIC1 may be a useful prognostic factor in lung adenocarcinoma., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Adequate tumor tissue is required to make the best treatment choice for non-small cell lung cancer (NSCLC). Transbronchial biopsy (TBB) by endobronchial ultrasonography with a guide sheath (EBUS-GS) is useful to diagnose peripheral lung lesions. The data of tumor cell numbers obtained by two different sizes of GSs is limited. We conducted this study to investigate the utility of a large GS kit to obtain many tumor cells in patients with NSCLC., Methods: Patients with a peripheral lung lesion and suspected of NSCLC were prospectively enrolled. They underwent TBB with a 5.9-mm diameter bronchoscope with a large GS. When the lesion was invisible in EBUS, we changed to a thinner bronchoscope and TBB was performed with a small GS. We compared the tumor cell number prospectively obtained with a large GS (prospective large GS group) and those previously obtained with a small GS (small GS cohort). The primary endpoint was the tumor cell number per sample, and we assessed characteristics of lesions that could be obtained by TBB with large GS., Results: Biopsy with large GS was performed in 55 of 87 patients (63.2%), and 37 were diagnosed with NSCLC based on histological samples. The number of tumor cells per sample was not different between two groups (658±553 vs. 532±526, estimated difference between two groups with 95% confidence interval (CI); 125 (-125-376), p = 0.32). The sample size of the large GS group was significantly larger than that of the small GS cohort (1.75 mm2 vs. 0.83 mm2, estimated difference with 95% CI; 0.92 (0.60-1.23) mm2, p = 0.00000019). The lesion involving a third or less bronchus generation was predictive factors using large GS., Conclusions: The sample size obtained with large GS was significantly larger compared to that obtained with small GS, but there was no significant difference in tumor cell number. The 5.9-mm diameter bronchoscope with large GS can be used for lesions involving a third or less bronchus generation., Competing Interests: The authors have declared that no competing interests exist.

Background: As of March 2021, Japan is facing a fourth wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To prevent further spread of infection, sera cross-neutralizing activity of patients previously infected with conventional SARS-CoV-2 against novel variants is important but has not been firmly established., Methods: We investigated the neutralizing potency of 81 coronavirus disease 2019 (COVID-19) patients' sera from the first to fourth waves of the pandemic against SARS-CoV-2 D614G, B.1.1.7, P.1, and B.1.351 variants using their authentic viruses., Results: Most sera had neutralizing activity against all variants, showing similar activity against B.1.1.7 and D614G, but lower activity especially against B.1.351. In the fourth wave, sera-neutralizing activity against B.1.1.7 was significantly higher than that against any other variants, including D614G. The sera-neutralizing activity in less severe patients was lower than that of more severe patients for all variants., Conclusions: The cross-neutralizing activity of convalescent sera was effective against all variants but was potentially weaker for B.1.351. The high neutralizing activity specific to B.1.1.7 in the fourth wave suggests that mutations in the virus might cause conformational change of its spike protein, which affects immune recognition of D614G. Our results indicate that individuals who recover from COVID-19 could be protected from the severity caused by infection with newly emerging variants., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We herein report a fatal case of coronavirus disease 2019 (COVID-19) pneumonia with rapid progression of respiratory failure and lymphopenia. Excessive recruitment and sequestration of lymphocytes in the lung were suggested as the pathophysiology underlying COVID-19-associated lymphopenia. Interestingly, the autopsy in this case revealed lymphocytic infiltration in the lungs even at sites that appeared normal on autopsy imaging. These findings suggest that in COVID-19 cases with risk factors of severe exacerbation, early glucocorticoid administration should be considered, especially if lymphopenia is present, even if the imaging findings show only mild abnormalities.

Most patients with coronavirus disease 2019 (COVID-19) experience asymptomatic disease or mild symptoms, but some have critical symptoms requiring intensive care. It is important to determine how patients with asymptomatic or mild COVID-19 react to severe acute respiratory syndrome coronavirus 2 infection and suppress virus spread. Innate immunity is important for evasion from the first virus attack, and it may play an important role in the pathogenesis in these patients. We measured serum cytokine levels in 95 patients with COVID-19 during the infection's acute phase and report that significantly higher interleukin 12 and 2 levels were induced in patients with asymptomatic or mild disease than in those with moderate or severe disease, indicating the key roles of these cytokines in the pathogenesis of asymptomatic or mild COVID-19., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Recent studies have revealed that serpin peptidase inhibitor clade E member 2 (SERPINE2) is associated with tumorigenesis. However, SERPINE2 expression and its role in lung adenocarcinomas are still unknown., Methods: The expression levels of SERPINE2 in 74 consecutively resected lung adenocarcinomas were analyzed by using immunostaining. Inhibition of SERPINE2 expression by small interfering RNA (siRNA) was detected by quantitative PCR. Cell number assays and cell apoptosis assays were performed to clarify the cell-autonomous function of SERPINE2 in A549 and PC9 lung cancer cells., Results: The overall survival of patients with high SERPINE2 expression was significantly worse than that of patients with low SERPINE2 expression (P = 0.0172). Multivariate analysis revealed that SERPINE2 expression was an independent factor associated with poor prognosis (P = 0.03237). The interference of SERPINE2 decreased cell number and increased apoptosis in A549 and PC9 cells CONCLUSION: These results suggest that SERPINE2 can be used as a novel prognostic marker of lung adenocarcinoma.

Multiple thymic carcinoids are rare, and giant cell arteritis (GCA) is one of the less recognized paraneoplastic diseases. The co-occurrence of these two diseases is therefore extremely rare. We report herein a patient with multiple atypical thymic carcinoids and asymptomatic paraneoplastic GCA. All the thymic carcinoids were diagnosed histopathologically as atypical thymic carcinoids with an intrathymic metastasis. Treatment consisted of a complete tumor resection followed by observation of the GCA without any adjuvant therapy. Subsequent positron emission tomography revealed a decrease in F-fludeoxyglucose accumulation in the systemic arteries. Based on these findings, paraneoplastic GCA was diagnosed. Thymic carcinoids rarely involve intrathymic metastasis or cause neopleonastic GCA. However, when they do, a complete tumor resection is the best option for management.

Histologic transformation has been described as an acquired mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We herein report the case of a woman with stage IV lung adenocarcinoma harboring EGFR exon 19 deletions who was initially treated with EGFR-TKIs; several cytotoxic chemotherapeutic regimens were used when resistance developed. A lymph node re-biopsy revealed histologic transformation of the tumor to combined small-cell lung cancer and squamous cell carcinoma with retained EGFR exon 19 deletions. Following sequential chemotherapy appropriate for transformed histology, a clinical response was achieved.

Objective: To investigate the relationship between the precursors of high grade serous ovarian cancer (HGSOC) and the characteristics of patients with a low HGSOC risk in terms of the effects of pregnancy., Methods: We prospectively examined consecutive cases in which the bilateral fallopian tubes were removed during benign gynecological or obstetric surgery and assessed the relationship between the patient characteristics, including parity and pregnancy, and the incidence of HGSOC precursors. All the fallopian tubes were examined by applying the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) Protocol., Results: Of the 113 patients enrolled, 67 were gynecological and 46 were obstetric. The p53 signature was identified in 21 patients. No other precursors were identified. In a comparison of the p53 signature-positive and negative groups, parous women and pregnant women were significantly fewer in the p53 signature-positive group (53% vs. 86%, p=0.002, 10% vs. 47%, p=0.001, respectively). Current pregnancy was also associated with a significantly lower incidence of the p53 signature after multivariate adjustment (odds ratio [OR]=0.112; 95% confidence interval [95% CI]=0.017-0.731; p=0.022). Among gynecological patients, parous women were fewer in the p53 signature-positive group on univariate (47% vs. 73%, p=0.047) and multivariate analysis (OR=0.252; 95% CI=0.069-0.911; p=0.036). No other characteristics were associated with p53 signature positivity., Conclusions: The incidence of the p53 signature was significantly lower in parous women and pregnant women. This decreased incidence of early phase serous carcinogenesis may be one of the possible mechanisms underlying HGSOC risk reduction among parous women., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.

Background/aim: Immune checkpoint inhibitors (ICI) are a novel medication for non-small cell lung cancer (NSCLC). Recent reports indicated that baseline tumor size (BTS) relates to the efficacy of ICI therapy for melanoma, but no study exists for NSCLC. This study aimed to evaluate the utility of BTS for ICI therapy., Patients and Methods: Data from 58 patients diagnosed with NSCLC who underwent ICI monotherapy, were retrospectively analyzed. Patients were divided into two groups according to BTS (below 101 mm, above 101 mm). The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS)., Results: PFS of patients with a large BTS was significantly shorter than that of those with a small BTS (median; 2.07 [95% confidence interval [CI]=0.99-6.77] months versus 6.39 [95%CI=4.17-11.50] months) (p=0.044). OS of patients with large BTS was also significantly shorter (p<0.01)., Conclusion: BTS is a predictive and prognostic negative factor of ICI therapy for NSCLC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Red cell distribution width (RDW) has been reported to reflect the inflammation and nutrition status and predict prognosis of non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1 (PD-1) antibody. The aim of this study was to analyze the correlation between RDW and prognosis of NSCLC patients., Patients and Methods: We collected retrospective data on consecutive NSCLC patients treated with anti-PD-1 antibody from December 2015 to April 2018 at the Kobe University Hospital, Japan., Results: Forty-seven patients were treated. Patients with RDW ≥16% had a significantly shorter OS (p=0.010) compared to those with RDW <16%. In multivariate analysis, RDW ≥16% was an independent factor predicting poor prognosis (p=0.019)., Conclusion: Pre-treatment RDW ≥16% is an indicator of poor prognosis. RDW is an inexpensive, convenient, and routinely available marker of prognosis., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 43-year-old woman presented with worsening shortness of breath and lower-extremity edema. Echocardiography and computed tomography showed obstruction of blood flow due to a mass filling the right atrium. Emergency surgery was performed for circulatory failure. Primary cardiac rhabdomyosarcoma was diagnosed based on a histological examination. The patient died about two months after the diagnosis despite surgical excision and radiation therapy. The poor prognosis may have resulted from the grossly incomplete removal of the tumor and chemotherapy intolerance. We herein report a case of primary cardiac rhabdomyosarcoma filling the right atrium and offer possible reasons for the poor prognosis.

Objective: Endobronchial ultrasonography and guide sheath (EBUS-GS) technique has high diagnostic yield in lung nodules. Virtual bronchoscopic navigation (VBN) can lead bronchoscope to the target bronchi. The aim of this prospective study was to compare the diagnostic yield of two bronchoscopic procedures: bronchoscopy under EBUS-GS and VBN with or without x-ray fluoroscopy in small peripheral pulmonary lesions (PPLs, ≤30mm) with apparent CT-bronchus sign., Methods: 31 patients with PPLs which had apparent CT-bronchus sign were randomly assigned to the X-ray or the non-X-ray groups (18 with and 13 without fluoroscopy) between September 1, 2012, and September 30, 2015. A bronchoscope was introduced into the target bronchus using the VBN system. Sites of specimen sampling were verified using EBUS-GS with or without fluoroscopy., Results: The overall diagnostic yield was 83.3% in the X-ray and 69.2% in the non-X-ray group. The diagnostic yield of malignancy was 88.2% and 81.8%, respectively. The duration of the examination and time elapsed until the first EBUS visualization were similar in the X-ray and the non-X-ray group (9.0 (5.8-20.) min vs 11.0 (5.3-17.3) min, and 2.5 (1.3-14.2) min vs 4.1 (1.4-8.1) min, respectively). The fluoroscopy exposure time was 3.7 (2.9-10.56) min. The only adverse event was mild pneumothorax in a patient from the non-X-ray group, who had consequent TBB under fluoroscopy., Conclusions: There was a possibility that VBN-guided EBUS-transbronchial diagnosis without fluoroscopy might be equivalent to that under fluoroscopy. Further multi-center randomized study may be desired. (UMIN000008592).

Background: Nivolumab improves the survival of advanced non-small cell lung cancer (NSCLC), but a significant number of patients still fail to benefit from this treatment. In this study, we evaluated the efficacy of the time-series behavior of neutrophil-to-lymphocyte ratio (NLR) in a complete blood count from advanced NSCLC patients as a predictive marker of the anticancer effect of nivolumab., Methods: We performed a retrospective review of medical records and collected data on patients with advanced NSCLC treated with nivolumab as second- and further-line treatments from December 2015 to March 2017. The NLRs were calculated before each treatment cycle for four cycles. These parameters were tested for its association with the overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF)., Results: Nineteen patients were treated with nivolumab. Stratified by the response to nivolumab, the median OS was 2.8 months in progressive disease (PD) and 14.0 months in non-PD (p = 0.002). Before discontinuation of PD or toxicity, an NLR is rising from baseline in 5 out of 7 patients with PD and all of 4 patients with discontinuation due to toxicity. Patients with an >30% increase in NLR were associated with a significantly shorter TTF compared with those with stable or decrease in NLR both after first cycle (p = 0.014) and second cycle (p < 0.001)., Conclusions: The NLR is suggested to be useful not only as a prognostic marker but also as a predictive marker for treatment with nivolumab. Further prospective study is warranted to develop a predictive algorithm to detect PD cases as early as possible by focusing the time-series behavior of NLR.

A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the Epidermal growth factor receptor (EGFR) was treated with EGFR-tyrosine kinase inhibitors (TKIs) and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone. The patient showed neither disease progression nor a recurrence of ILD at 5 months. In situations in which no alternative treatment is available, osimertinib rechallenge should thus be considered as an alternative treatment.

In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor-tyrosine kinase inhibitor-induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR-mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell-related markers by quantitative RT-PCR and the expression of the cellular senescence-associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem-like cell targeting drug, withaferin A. Drug-tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem-like cells (CSCs) and the other with the properties of therapy-induced senescent (TIS) cells. The CD133 high cell population had CSC properties and the CD133 low cell population had TIS properties. The CD133 low cell population containing TIS cells showed a senescence-associated secretory phenotype that supported the emergence of the CD133 high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133 low cell population. Withaferin A effectively eliminated the CD133 high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib-resistant tumor growth., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Concurrent chemoradiotherapy (CCRT) is the preferred treatment for stage III unresectable non-small cell lung cancer (NSCLC). However, there have been few reports on combination chemotherapy with radiation for second- and third-generation antitumor drugs, although clinical guidelines have recommended the use of these drugs along with platinum agents., Methods: We retrospectively analyzed the efficacy and toxicity of cisplatin and either S-1 or vinorelbine for treating stage III unresectable NSCLC patients who were treated with CCRT., Results: Between September 2006 and May 2014, 56 patients with unresectable stage III NSCLC were treated with CCRT with S-1 and cisplatin (median age: 63 years) and 58 patients were treated with CCRT with vinorelbine and cisplatin (median age: 61 years). The median follow-up time was 14.6 months in the S-1 arm and 28.0 months in the vinorelbine arm. We found no significant difference in progression-free survival (15.8 months vs. 10.1 months; p=0.15) and overall survival (33.7 months vs. 31.1 months; p=0.63) between the S-1 and vinorelbine arms, respectively. Severe (more than grade 3) leukopenia (35.7% vs. 98.2%; p<0.01), neutropenia (44.6% vs. 98.2%; p<0.01), and febrile neutropenia (1.8% vs. 46.6%, p<0.01) were significantly less frequent in the S-1 arm than in the vinorelbine arm. Treatment-related deaths were not observed in either arm., Conclusions: CCRT with both S-1 or vinorelbine with cisplatin appears feasible based on their efficacy and toxicity profiles. Both treatments may be recommended as treatment options for patients with stage III unresectable NSCLC., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

A 62-year-old man with myelodysplastic syndrome (MDS) presented to our hospital with a high fever. Although treatment with broad-spectrum antibiotics was initiated, his respiratory status worsened to the point that he required mechanical ventilation. However, he was successfully treated with a corticosteroid without immunosuppression. Sequential transbronchial lung biopsies revealed abundant fibrin exudate in the alveolar spaces, which was subsequently replaced by fibroblasts, showing that acute fibrinous and organizing pneumonia (AFOP) gradually changes into organizing pneumonia. Our case demonstrated both the efficacy of corticosteroid-monotherapy and the histological course of AFOP.

A Peutz-Jeghers polyp (PJP) is a hamartomatous lesion characterized by arborescent smooth muscle bundles covered with mucosa native to the site of involvement. PJPs in the small intestine may represent misplacement of non-neoplastic epithelium into the submucosa, muscularis propria and subserosa. Although epithelial misplacement in PJPs is a well-documented phenomenon, pseudoinvasion even into the vascular space in PJPs has not previously been reported. We report a case of a 22-year-old Japanese woman with a solitary PJP in the ileum. The ileal PJP in this patient showed epithelial herniation even into the vascular space. All the herniated epithelium, including the epithelial components invaginated into the vascular space, demonstrated features of pseudoinvasion, that is, presence of normal small intestinal type mucosa accompanied by the lamina propria, absence of any stromal desmoplastic reaction, and retention of the basal-luminal gradient. Pathologists must be aware of the possibility of vascular pseudoinvasion in small intestinal PJPs to avoid overdiagnosis of carcinoma and resulting unnecessary major surgery., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background and Aims: This study was undertaken to determine the incidence of and risk factors for anal incontinence after fistulotomy for intersphincteric fistula-in-ano. We also evaluated the role of anal manometry in preoperative assessment of intersphincteric fistula., Materials and Methods: A prospective, observational study was undertaken in 148 patients who underwent fistulotomy for intersphincteric fistula between January and December 2004. Functional results were assessed by standard questionnaire and anal manometry. Possible factors predicting postoperative incontinence were examined by univariate and multivariate regression analyses., Results: The mean follow-up period was 12 months. Postoperative anal incontinence occurred in 30 patients (20.3%), i.e., soiling in 6, incontinence for flatus in 27, and incontinence for liquid stool in 4. Fistulotomy significantly decreased maximum resting pressure (85.9 +/- 20.4 to 60.2 +/- 18.4 mmHg, P < 0.0001) and length of the high pressure zone (3.92 +/- 0.69 to 3.82 +/- 0.77 cm, P = 0.035), but it did not affect voluntary contraction pressure (164.7 +/- 85.2 to 160.3 +/- 84.8 mmHg, P = 0.2792). Multivariate analysis showed low voluntary contraction pressure and multiple previous drainage surgeries to be independent risk factors for postoperative incontinence., Conclusion: Fistulotomy produces a satisfactory outcome in terms of eradicating sepsis and preserving function in the vast majority of patients with intersphincteric fistula with intact sphincters. However, sphincter-preserving treatment may be advocated for patients with low preoperative voluntary contraction pressure or those who have undergone multiple drainage surgeries. Preoperative anal manometry is useful in determining the proper surgical procedure.

The copper and iron status in the liver of non-tumor bearing Long-Evans Cinnamon (LEC) rats (average age 17 months) was investigated. A direct quantitation of loosely-bound copper and iron was also investigated by using a chelating agent, nitrilotriacetic acid (NTA-chelatable free copper and iron). Besides the total copper and iron contents, the level of NTA-chelatable free copper was also higher in LEC rats than in LEA rats (P<0.05). But for the free iron level there was no significant difference between the two rat groups (P>0.05). The formation of thiobarbituric acid-reactive substances was higher in LEC rats than in LEA rats (P<0.01). The 4-hydroxy-2-nonenal (HNE)-modified proteins were also clearly demonstrated in LEC rat liver. The copper and iron which produced the most important effect in the process of oxidative damage in LEC rats could not be distinguished. Even though free copper, which could induce free radical injuries, was increased in LEC rats, neither tumor-induction nor preneoplastic lesions in the experimental LEC rats were observed. Therefore it is speculated that the elevation of a free iron is another important factor. Copper and iron, both important transition metals in the body, may participate in the induction of DNA damage and oncogenesis.

This report describes a slight difference in the rate of decrease of serum paraquat and diquat concentrations in eight human cases of poisoning by the herbicide PreegloxL (containing paraquatCl2, 5% and diquatBr2, 7%) and the distribution of each in three autopsied cases. There was no variation between the serum concentrations of paraquat and diquat within 24 h after ingestion, but paraquat remained at a slightly higher concentration than diquat after more than 24 h. The decrease of urinary paraquat and diquat concentrations was almost the same during the 24-h determination period. In three autopsied cases, diquat concentrations in the tissues were relatively lower than those of paraquat, except in bile. Paraquat and diquat were unevenly distributed in various tissues and fluids, but the distribution patterns of each in any particular tissues were quite similar. As no difference was observed in the decrease of urinary paraquat and diquat, the much higher concentration of diquat in bile indicates that bile may be one of the effective factors in lowering the concentration of diquat in serum and in tissues of the human body long after ingestion.

In Japan, an average of 37 fatalities per year related to bee or wasp stings were reported during the years 1979-1988. To confirm fatal anaphylaxis serologically, we measured bee or wasp venom specific IgE (sIgE) and IgG4 (sIgG4) antibodies in the sera of 22 patients who visited hospitals with either allergic or anaphylactic reactions after bee or wasp stings by using Enzyme-Linked Immunosorbent Assay. Specific IgE or IgG4 antibodies against Polistes apachus (Paper wasp) and/or a mixture of Polistes annularis, P. exceramans, P. fuscatus, and P. metricus venoms of Polistes genus were detected in 11 patients and the detection frequencies were the highest among positive antibodies against bee or wasp venoms. The severity of allergic reactions was graded from 0-4 according to Mueller. The detection frequencies of sIgE in Mueller grade 0-3 patients were in the range of 33% to 67%, and in grade 4 were 100%. Whereas, the detection frequency of sIgG4 was high (67-100%) in grade 2-4 patients. Especially high levels of sIgE and sIgG4 were detected in patients experiencing the most severe clinical reactions. The detection of venom specific IgE and IgG4 antibodies appears to be useful when determining bee or wasp stings as the cause of fatalities.