Publications by authors named "Norihiro Kikuchi"

61 Publications

Treatment of Patients With Non-small-cell Lung Cancer With Uncommon Mutations in Clinical Practice.

Anticancer Res 2020 Oct;40(10):5757-5764

Respiratory Center, Ibaraki Prefectural Central Hospital and Cancer Center, Kasama, Japan.

Background/aim: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations.

Materials And Methods: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019.

Results: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious.

Conclusion: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.
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http://dx.doi.org/10.21873/anticanres.14592DOI Listing
October 2020

Serum CEA and CYFRA Levels in ALK-rearranged NSCLC Patients: Correlation With Distant Metastasis.

In Vivo 2020 Jul-Aug;34(4):2095-2100

Division of Respiratory Medicine, JA Toride Medical Center Hospital, Toride, Japan.

Aim: To clarify the correlation between serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) and metastasis and survival in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients.

Patients And Methods: CEA and CYFRA levels in 131 ALK-rearranged NSCLC patients were determined using fluorescence in situ hybridization (FISH), real time-reverse transcription polymerase chain reaction, and immunohistochemistry, using biopsy specimens, cytology specimens, and plasma specimens. Cut-off value of each marker was determined as 10 ng/ml.

Results: In logistic regression analysis, higher levels of both markers had a positive relationship with bone metastases, and higher levels of CYFRA was relevant to liver metastases, and multiple-organ metastases. However, these markers were not proven to be poor prognostic factors in Cox's proportional model analysis.

Conclusion: Elevated serum CEA and CYFRA levels seem to provide useful clinical information about presence of bone and liver metastasis and multiple-organ metastases, although they were not a powerful indicator of prognosis. These two markers may suggest the extension of metastasis and would be helpful in considering treatment options.
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http://dx.doi.org/10.21873/invivo.12013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439905PMC
March 2020

Clinicopathological Features in Elderly ALK-rearranged Non-small Cell Lung Cancer Patients.

In Vivo 2020 Jul-Aug;34(4):2001-2007

Division of Respiratory Medicine, JA Toride Medical Center Hospital, Toride, Japan.

Aim: To clarify the clinicopathological features in elderly anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) patients.

Patients And Methods: A retrospective study was performed in 129 ALK rearranged NSCLC patients diagnosed between April 2008 and March 2019 in fifteen Institutions of the Ibaraki prefecture, Japan.

Results: Median age of patients was 63 years. In 59 patients aged 65 and older, the proportions of patients with advanced stage and those treated with ALK-tyrosine kinase inhibitor (TKI) were lower than those younger than 65 years. There was no difference in overall survival (OS) between the two age groups. Among the elderly patients, no difference was observed in OS between the patients aged 65-69 and those aged 70 and older. In 89 patients treated with TKI, no significant differences were observed in the progression-free survival of TKIs and OS between patients aged 65 and older and those younger than 65, respectively.

Conclusion: Evaluation of ALK gene status and TKI treatment are desirable even for elderly patients.
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http://dx.doi.org/10.21873/invivo.11998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439864PMC
March 2020

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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http://dx.doi.org/10.1001/jamaoncol.2020.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226294PMC
July 2020

Real Clinical Practice in ALK-rearranged NSCLC Patients: A Retrospective Observational Study.

Anticancer Res 2020 Feb;40(2):957-964

Division of Respiratory Medicine, Seinan Medical Center, Sakai-machi, Japan.

Background/aim: To describe real clinical outcomes when using systemic therapy to treat non-small cell lung cancer (NSCLC) patients who have anaplastic lymphoma kinase (ALK) fusion gene mutation.

Patients And Methods: We performed a retrospective chart review from April 2008 to March 2019 sourced from 16 medical institutes that cover a population of three million people.

Results: There were 129 ALK rearranged NSCLC patients. Among them, 103 patients including 40 recurrent disease cases received ALK-tyrosine kinase inhibitors (TKI) and chemotherapy. Our treatment results were comparable to previously reported clinical trials and clinical practice studies. First-line alectinib, treatment sequence of ALK-TKI followed by another ALK-TKI, and pemetrexed-containing chemotherapy contributed to the outcome of treatment.

Conclusion: By arrangement of treatment such as treatment sequence of ALK-TKI and chemotherapy regimen, it might be possible to obtain a treatment outcome almost equivalent to those of clinical trials even in real clinical practice.
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http://dx.doi.org/10.21873/anticanres.14029DOI Listing
February 2020

Pneumonitis Due to Oren-gedoku-to (Coptis Detoxifying Decoction).

Intern Med 2019 15;58(20):3019-3023. Epub 2019 Oct 15.

Department of Respiratory Medicine, National Hospital Organization Kasumigaura Medical Center, Japan.

A 54-year-old man started to take oren-gedoku-to (coptis detoxifying decoction) because he was experiencing chronic hot flashes, night sweats and insomnia. He developed a high fever from the day of intake. At day 17, he stopped taking oren-gedoku-to because of malaise and chills, and he was admitted to our hospital. Drug-induced pneumonitis was suspected, and all drugs were stopped. Consequently, his symptoms, laboratory data and chest X-ray findings markedly improved. The results of a lymphocyte stimulation test were positive for oren-gedoku-to and one of its components, ougon (Baikal skullcap). Based on these findings, we diagnosed him with pneumonitis caused by ougon.
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http://dx.doi.org/10.2169/internalmedicine.2586-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859392PMC
January 2020

Real Clinical Practice of Using Afatinib Therapy in NSCLC Patients with an Acquired T790M Mutation.

Anticancer Res 2018 Sep;38(9):5409-5415

Faculty of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.

Background/aim: To describe real clinical outcomes when using afatinib therapy to treat non-small cell lung cancer patients who have an acquired EGFR T790M mutation.

Materials And Methods: A retrospective chart review was conducted from January 2013 to November 2017 sourced from 15 medical institutes that cover a population of three million people.

Results: There were 74 patients who met the above-mentioned criteria. Treatment outcomes with afatinib, in patients with or without tyrosine kinase inhibitor (TKI) therapy prior to afatinib, were similar to previously reported clinical trials. Stratification of patients by the presence or absence of TKI pretreatment before afatinib, and the presence or absence of an acquired T790M mutation found no statistical difference in overall survival.

Conclusion: This population-based study found that the disadvantages of pretreatment before afatinib, and absence of an acquired T790M EGFR mutation, could be overcome by an appropriate treatment strategy in clinical practice.
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http://dx.doi.org/10.21873/anticanres.12871DOI Listing
September 2018

Acquired T790M Mutation After Relapse Following EGFR-TKI Therapy: A Population-based Multi-institutional Study.

Anticancer Res 2018 05;38(5):3145-3150

Divisions of Respiratory Medicine and Thoracic Surgery, Ibaraki Seinan Medical Center Hospital, Sakai-machi, Japan.

Aim: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting.

Materials And Methods: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people.

Results: We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42.5%) patients had acquired T790M mutations in EGFR. Patients ≥75 years old and patients with an exon 19 deletion had higher rates of acquired T790M mutation than did younger patients and those with an exon 21 L858R mutation. In 75 patients treated with afatinib, 34 (45.3%) patients had acquired T790M mutation. The sensitivity of T790M mutation detection was lower in plasma specimens than in biopsy specimens.

Conclusion: This population-based study confirms previous studies and highlights potential determinants of acquired T790M mutation to be considered in clinical practice.
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http://dx.doi.org/10.21873/anticanres.12577DOI Listing
May 2018

S-1-containing chemotherapy for patients with non-small-cell lung cancer: A population-based observational study by the Ibaraki thoracic integrative (POSITIVE) research group.

Mol Clin Oncol 2016 Jun 21;4(6):1025-1030. Epub 2016 Mar 21.

Tokyo Medical University, Ibaraki Medical Center Hospital, Ami, Ibaraki 300-0395, Japan.

To evaluate the efficacy and safety of S-1 monotherapy, S-1-containing combined chemotherapy and S-1 containing chemoradiotherapy for non-small cell lung cancer (NSCLC), a population-based observational study was performed. The efficacy and safety of the chemotherapies were evaluated at 13 institutes in a prefecture of Japan between April 2011 and March 2015. Datasets were obtained from 282 patients with NSCLC. For either wild-type or mutated epidermal growth factor receptor (EGFR), these three therapy groups generated almost identical response results and toxicity profiles as those in previously reported clinical trials, although the present study appeared to have slightly lower survival rates compared with those in the previous clinical trials. This may be due to the inclusion of patients in poor condition, and S-1 therapy being administered in the second, or later, line of therapy. In conclusion, the present study has confirmed that S-1-containing chemotherapy is effective against wild- and mutated-type EGFR NSCLC, and it is also tolerable in clinical practice.
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http://dx.doi.org/10.3892/mco.2016.826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887806PMC
June 2016

Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10 induced modulation of phagocyte antifungal activity.

Eur J Immunol 2016 07 27;46(7):1691-703. Epub 2016 May 27.

Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan.

Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune-modulating cytokines. Here, we investigated the role of iNKT cells in host defense against candidiasis using Jα18-deficient mice (Jα18(-/-) ), which lack iNKT cells. Jα18(-/-) mice were more resistant to the development of lethal candidiasis than wild-type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α-galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL-10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL-10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL-1β and IL-18, and caspase-1 activity were also significantly elevated in Jα18(-/-) mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL-10 into Jα18(-/-) reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL-10 induced modulation of macrophage antifungal activity.
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http://dx.doi.org/10.1002/eji.201545987DOI Listing
July 2016

[Use of Transdermal Fentanyl in a Hospital].

Gan To Kagaku Ryoho 2016 Mar;43(3):341-4

Dept. of Pharmacy, National Hospital Organization Kasumigaura Medical Center.

Recently, the use of transdermal fentanyl (TDF) has been increasing at our hospital owing to its convenience. Furthermore, TDF tends to be increasingly used for patients who have never used opioids. However, the appropriate criteria for indicating TDF have not been established yet. Therefore, we examined how TDF was prescribed in practice and determined its effective dosage. In 43 cases, the reasons, effects, and side effects of TDF were investigated retrospectively. Of the patients, 60% continued using TDF for 30 days. Meanwhile, approximately 25% of them terminated TDF therapy within 8 days. Of those who discontinued TDF therapy, some entirely stopped taking TDF and others chose other opioids instead because of poor pain control. Before receiving TDF therapy, 17 patients (45%) used oxycodone and 14 (37%) never used opioids. In addition, the main reason for starting TDF in opioid-naive patients was gastrointestinal condition. Between opioid-naive and opioid-using groups, no significant differences were observed in usage duration and incidence of side effects. The side effects included somnolence in 6 patients, delirium in 2 patients, and nausea and vomiting, constipation, and breathing restraint in 1 patient each. TDF was considered as an effective treatment regardless of the previous use of opioids. Nonetheless, careful deliberation is necessary because of the slow effects and difficulty with dosage adjustment.
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March 2016

Efficacy of first-line erlotinib in non-small cell lung cancer patients undergoing dose reduction and those with a low body surface area: A population-based observational study by the Ibaraki Thoracic Integrative (POSITIVE) Research Group.

Mol Clin Oncol 2016 Mar 21;4(3):425-428. Epub 2015 Dec 21.

Divisions of Thoracic Surgery and Respiratory Medicine, Tokyo Medical University, Ibaraki Medical Center Hospital, Ami, Ibaraki 300-0395, Japan.

The aim of the present study was to evaluate the efficacy of erlotinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), in patients undergoing dose reduction and in those with a low body surface area (BSA). The association between dose reduction, low BSA and efficacy, including response rate, disease control rate, time to treatment failure and overall survival, were evaluated in patients prescribed first-line erlotinib for EGFR mutated non-small cell lung cancer patients between April 2012 and March 2015. A total of 22 patients received first-line erlotinib during the study period. A dose reduction of erlotinib for the reason of low BSA and poor performance status occurred in 14 (63.6%) of the patients: 6 (27.3%) had initial dose reduction, 6 (27.3%) had dose reduction in their clinical courses, and 2 (9.1%) had both. Dose reduction of erlotinib with the initial dose of erlotinib/BSA was >80 mg/m, and longest-term prescribed dose of erlotinib/BSA was >50 mg/m, which may have no association with a survival disadvantage. Dose-reduction estimation studies for TKIs may be crucial, particularly for patients with a low BSA. Future prospective studies and confirmation of these results in population-based retrospective ones investigating the incidence of dose reduction in patients with AEs and those with low BSA may be required for the efficient use of erlotinib in common clinical practice.
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http://dx.doi.org/10.3892/mco.2015.720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774513PMC
March 2016

Ventilatory Response to Hypercapnia Predicts Dementia with Lewy Bodies in Late-Onset Major Depressive Disorder.

J Alzheimers Dis 2016 ;50(3):751-8

Tokyo Medical and Dental University, Tokyo, Japan.

Background: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB.

Objective: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD.

Methods: Participants were 35 consecutive patients with first onset MDD at 50 years or older with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123I-meta-iodobenzylguanidine scintigraphy.

Results: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters.

Conclusion: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB.
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http://dx.doi.org/10.3233/JAD-150507DOI Listing
October 2016

T-cell-restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung.

Blood 2015 Jan 27;125(2):370-82. Epub 2014 Oct 27.

Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan;

Although overexpression of T-bet, a master transcription factor in type-1 helper T lymphocytes, has been reported in several hematologic and immune diseases, its role in their pathogenesis is not fully understood. In the present study, we used transgenic model mice (T-bet(tg/wt) and T-bet(tg/tg)) to investigate the effects of T-bet overexpression selectively in T lymphocytes on the development of hematologic and immune diseases. The results showed that T-bet overexpression in T cells spontaneously induced maturation arrest in the mononuclear phagocyte lineage, as well as spontaneous dermatitis and pulmonary alveolar proteinosis (PAP)-like disease in T-bet(tg/wt) and T-bet(tg/tg) mice, respectively. T-bet(tg/tg) alveoli with the PAP phenotype showed remarkable reorganization of alveolar mononuclear phagocyte subpopulations and impaired function, in addition to augmented T-cell infiltration. In addition, PAP development in T-bet(tg/tg) mice was found to be associated with increased migration of myeloid cells from the bone marrow into the peripheral blood. These findings reveal an unexpected link between T-bet overexpression in T lymphocytes and the development of PAP caused by reorganization of mononuclear phagocytes in the lung, and provide new insight into the molecular pathogenesis of secondary PAP accompanied by hematologic disorders.
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http://dx.doi.org/10.1182/blood-2014-05-575225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300389PMC
January 2015

Cryptogenic organising pneumonia after radiotherapy.

BMJ Case Rep 2014 Oct 15;2014. Epub 2014 Oct 15.

Department of Radiology, Tokyo Medical University, Tokyo, Japan.

A patient with cryptogenic organising pneumonia after radiotherapy in the thorax was dramatically dissolved by administration of corticosteroid.
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http://dx.doi.org/10.1136/bcr-2014-205812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202072PMC
October 2014

[Effectiveness of switching opioids from fentanyl patch to morphine injection].

Gan To Kagaku Ryoho 2013 Apr;40(4):541-5

Dept. of Pharmacy, National Hospital Organization Kasumigaura Medical Center.

Patients endure the switching of opioids from fentanyl patch to morphine injection to improve inadequate pain relief. We retrospectively examined the differences between the maintenance dose of morphine injection after switching, its estimated dose prior to switching, and some other factors. As a result, 8 out of 9 patients had pain control after switching. Also, patients who increased the dose of the fentanyl patch more than twice in a month before switching required a significantly lower maintenance dose for the estimated dose after switching (p < 0.05) than those who took less. In conclusion, switching opioids to morphine injection is very effective, both from the viewpoint of pain control and the reduction of the amount of opioids used for patients with poor pain control, who frequently increase their use of the fentanyl patch.
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April 2013

[Syndrome of inappropriate secretion of ADH following chemoradiation therapy].

Gan To Kagaku Ryoho 2012 Nov;39(11):1711-4

Dept. of Pulmonary Medicine, Kasumigaura Medical Center.

We report a 69-year-old female patient with pulmonary adenocarcinoma complicated by the syndrome of inappropriate secretion of antidiuretic hormone(SIADH)following systemic chemotherapy with cisplatin(CDDP)and vinorelbine(VNR). She was admitted to our hospital for chemo-radiotherapy for advanced lung cancer, and became restless 4 hours after the administration of CDDP and VNR. Symptoms such as restlessness and incontinence were worsening despite the massive infusion that was completed. Laboratory examinations on day 6 after chemotherapy showed severe hyponatremia(107mEq/L)with decreased serum osmolarity(227mOsm/L)and increased urine osmolarity(452mOsm/L). The serum anti-diuretic hormone(ADH)level was elevated to 16. 7 pg/mL despite severe hyponatremia. She was diagnosed with SIADH and was treated with hypertonic saline infusion and fluid restriction. Her restlessness and other psychiatric symptoms were improved. The use of carboplatin and VNR in the subsequent course did not develop SIADH, indicating that the SIADH was induced by CDDP. Although SIADH following CDDP administration is rare, the electrolyte balance should be carefully monitored throughout the clinical course of chemo-radiation therapy, when psychiatric symptoms are found in patients with lung cancer.
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November 2012

Aggravation of bleomycin-induced pulmonary inflammation and fibrosis in mice lacking peroxiredoxin I.

Am J Respir Cell Mol Biol 2011 Sep 14;45(3):600-9. Epub 2011 Jan 14.

Department of Respiratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.

Oxidative stress plays an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. Peroxiredoxin (Prx) I is a cellular antioxidant enzyme induced under stress conditions. In the present study, the protective effects of Prx I on the development of bleomycin-induced acute pulmonary inflammation and pulmonary fibrosis were investigated using Prx I-deficient mice. Survival of Prx I-deficient mice after bleomycin administration was significantly lower than that of wild-type mice, corresponding with enhanced acute pulmonary inflammation and fibrosis. The level of inflammatory cytokines and chemokines, such as TNF-α, macrophage inflammatory protein-2, and monocyte chemotactic protein-1, was significantly elevated in the bronchoalveolar lavage fluid of Prx I-deficient mice after bleomycin administration. Furthermore, the level of 8-isoprostane, an oxidative stress marker, and the concentration and alveolar macrophage expression of macrophage migration inhibitory factor were elevated in the lungs of Prx I-deficient mice after bleomycin administration. The exacerbation of bleomycin-induced pulmonary inflammation and fibrosis in Prx I-deficient mice was inhibited by treatment with N-acetyl-L-cysteine, a radical scavenger, or with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, a tautomerase inhibitor of macrophage migration inhibitory factor. These findings suggest that mice lacking Prx I are highly susceptible to bleomycin-induced pulmonary inflammation and fibrosis because of increases in pulmonary oxidant levels and macrophage migration inhibitory factor activity in response to bleomycin.
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http://dx.doi.org/10.1165/rcmb.2010-0137OCDOI Listing
September 2011

Upper lobe-dominant pulmonary fibrosis showing deposits of hard metal component in the fibrotic lesions.

Intern Med 2010 1;49(19):2143-5. Epub 2010 Oct 1.

Department of Respiratory Medicine, University of Tsukuba.

We present a 54-year-old man employed in the field of hard metal manufacturing who complained of progressive dyspnea and weight loss. His chest radiograph showed bilateral fibrosis predominantly distributed in the upper lobes with bilateral pleural effusions, and a strong reduction in lung volume. Lung histopathology showed apical cap-like fibrosis but no giant cell interstitial pneumonia. Electron probe microanalysis detected tungsten deposits in the fibrotic region: we therefore considered this to be a case of hard metal disease. Hard metal disease should be considered as one possibility in the differential diagnosis of upper lobe-dominant pulmonary fibrosis.
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http://dx.doi.org/10.2169/internalmedicine.49.3801DOI Listing
February 2011

[A case of Henoch-Schönlein purpura which was difficult to distinguish from a skin rash associated with gefitinib].

Nihon Kokyuki Gakkai Zasshi 2010 Jul;48(7):529-34

Department of Pulmonary Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba.

A 52-year-old woman with advanced non-small cell lung cancer was admitted to our hospital with melena and palpable purpura which appeared on her lower legs. She had been taking gefitinib for about 2 months before admission. A skin biopsy revealed leukocytoclastic vasculitis in the superficial dermis and immunofluorescence also showed the presence of C3 depositions within the blood vessel walls, which led to a diagnosis of Henoch-Schönlein purpura. The purpura gradually improved with topical steroids and bed rest; however, gefitinib had to be discontinued because of a growing papulopustular rash with intense itching, and as a result of the discontinuation, both types of skin lesions resolved. Two months later, she resumed gefitinib treatment since her level of CEA began to rise. Even though the papulopustular rash developed after the readministration of gefitinib, there had been no evidence of Henoch-Schönlein purpura recurrence during 2.5 years follow-up. It has been reported that adult onset Henoch-Schönlein purpura is often associated with malignancy. This case, however, suggests that not only drug eruption but also paraneoplastic vasculitis should be considered in the differential diagnosis of palpable purpura in patients with non-small cell lung cancer receiving treatment with gefitinib.
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July 2010

Payao: a community platform for SBML pathway model curation.

Bioinformatics 2010 May 5;26(10):1381-3. Epub 2010 Apr 5.

The Systems Biology Institute, Tokyo, Japan.

Summary: Payao is a community-based, collaborative web service platform for gene-regulatory and biochemical pathway model curation. The system combines Web 2.0 technologies and online model visualization functions to enable a collaborative community to annotate and curate biological models. Payao reads the models in Systems Biology Markup Language format, displays them with CellDesigner, a process diagram editor, which complies with the Systems Biology Graphical Notation, and provides an interface for model enrichment (adding tags and comments to the models) for the access-controlled community members.

Availability And Implementation: Freely available for model curation service at http://www.payaologue.org. Web site implemented in Seaser Framework 2.0 with S2Flex2, MySQL 5.0 and Tomcat 5.5, with all major browsers supported.

Contact: kitano@sbi.jp
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http://dx.doi.org/10.1093/bioinformatics/btq143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865864PMC
May 2010

Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and Th1/Th2 balance.

Respir Res 2010 Mar 18;11:31. Epub 2010 Mar 18.

Department of Respiratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.

Background: Pulmonary fibrosis is a progressive and lethal disorder. Although the precise mechanisms of pulmonary fibrosis are not fully understood, oxidant/antioxidant and Th1/Th2 balances may play an important role in many of the processes of inflammation and fibrosis. The transcription factor Nrf2 acts as a critical regulator for various inflammatory and immune responses by controlling oxidative stress. We therefore investigated the protective role of Nrf2 against the development of pulmonary fibrosis.

Methods: To generate pulmonary fibrosis, both wild-type C57BL/6 mice and Nrf2-deficient mice of the same background were administered bleomycin intratracheally.

Results: The survival of Nrf2-deficient mice after bleomycin administration was significantly lower than that of wild-type mice. The degree of bleomycin-induced initial pulmonary inflammation and pulmonary fibrosis was much more severe in Nrf2-deficient mice than in wild-type mice. The expression of antioxidant enzymes and phase II detoxifying enzymes was significantly reduced in the lungs of Nrf2-deficient mice, concomitant with an elevation of lung 8-isoprostane level, compared with wild-type mice. The expression of Th2 cytokines, such as interleukin-4 and interleukin-13, was significantly elevated in the lungs of Nrf2-deficient mice with an increase in the number of Th2 cells that express GATA-binding protein 3.

Conclusions: The results indicated that Nrf2 protects against the development of pulmonary fibrosis by regulating the cellular redox level and lung Th1/Th2 balance. Thus, Nrf2 might be an important genetic factor in the determination of susceptibility to pulmonary fibrosis.
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http://dx.doi.org/10.1186/1465-9921-11-31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846897PMC
March 2010

Impairment of host defense against disseminated candidiasis in mice overexpressing GATA-3.

Infect Immun 2010 May 15;78(5):2302-11. Epub 2010 Mar 15.

Department of Respiratory Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan.

Candida species are the most common source of nosocomial invasive fungal infections. Previous studies have indicated that T-helper immune response is the critical host factor for susceptibility to Candida infection. The transcription factor GATA-3 is known as the master regulator for T-helper type 2 (Th2) differentiation. We therefore investigated the role of GATA-3 in the host defense against systemic Candida infection using GATA-3-overexpressing transgenic mice. The survival of GATA-3-overexpressing mice after Candida infection was significantly lower than that of wild-type mice. Candida outgrowth was significantly increased in the kidneys of GATA-3-overexpressing mice, compared with wild-type mice. The levels of various Th2 cytokines, including interleukin-4 (IL-4), IL-5, and IL-13, were significantly higher while the level of Th1 cytokine gamma interferon was significantly lower in the splenocytes of GATA-3-overexpressing mice after Candida infection. Recruitment of macrophages into the peritoneal cavity in response to Candida infection and their phagocytic activity were significantly lower in GATA-3-overexpressing mice than in wild-type mice. Exogenous administration of gamma interferon to GATA-3-overexpressing mice significantly reduced Candida outgrowth in the kidney and thus increased the survival rate. Administration of gamma interferon also increased the recruitment of macrophages into the peritoneal cavity in response to Candida infection. These results indicate that overexpression of GATA-3 modulates macrophage antifungal activity and thus enhances the susceptibility to systemic Candida infection, possibly by reducing the production of gamma interferon in response to Candida infection.
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http://dx.doi.org/10.1128/IAI.01398-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863530PMC
May 2010

Small large-cell neuroendocrine carcinoma in a patient with pulmonary emphysema.

Tuberk Toraks 2009 ;57(1):77-80

Divisions of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-city, Ibaraki, Japan.

Large-cell neuroendocrine carcinomas (LCNECs) are relatively rare, and most reported occurrences tend to involve relatively large tumors. We report a small LCNEC in a 63-year-old male patient with pulmonary emphysema. The peripheral pulmonary nodule did not have lobulation and spiculation, and it was difficult to establish correct diagnosis before surgery because of its small size and effect of surrounding emphysematous change.
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October 2009

Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer.

Clin Cancer Res 2009 May 5;15(10):3423-32. Epub 2009 May 5.

Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan.

Purpose: NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated.

Experimental Design: We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions.

Result: A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G(1) phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells.

Conclusion: These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-2822DOI Listing
May 2009

Metacarpal bone metastasis from lung cancer.

Onkologie 2009 Apr 6;32(4):216-7. Epub 2009 Mar 6.

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http://dx.doi.org/10.1159/000203347DOI Listing
April 2009

Anticlockwise migrating infiltration in both lungs.

Tuberk Toraks 2008 ;56(4):462-3

Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, and Nishimagi Hospital, Tsukuba, Japan.

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April 2009

Hypointense gallbladder on MR cholangiopancreatography.

Hepatogastroenterology 2008 Mar-Apr;55(82-83):333

Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-city 305-8575, Ibaraki, Japan.

A few patients show a gallbladder of poor visibility on magnetic resonance cholangiopancreatography (MRCP) images due to various reasons. A 45-year-old man was referred with abdominal pain and fever. In contrast enhanced computed tomography, several calcified gallstones were observed in the gallbladder. Although a solitary calcified stone was seen in the neck of the gallbladder, neither stones in the common bile duct (CBD) nor dilatation of CBD were observed. On MRCP, hypointense gallbladder with no filling defect in the CBD was observed. Histopathological analysis of the gallbladder, which was obtained by laparoscopic cholecystectomy, confirmed severe chronic cholecystitis with several calcified gallstones up to 0.5 cm in diameter. In conclusion, the finding of hypointense gallbladder on MRCP in patients with cholecystitis and its underlying condition, though rare, should be kept in mind.
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December 2008

Prolonged response to gefitinib in bone metastasis.

Med Oncol 2009 8;26(1):101-2. Epub 2008 Jul 8.

Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan.

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http://dx.doi.org/10.1007/s12032-008-9082-yDOI Listing
May 2009