Publications by authors named "Hiroyuki Amano"

37 Publications

Pembrolizumab for Previously Untreated Patients with Advanced Non-small-cell Lung Cancer and Preexisting Interstitial Lung Disease.

Intern Med 2020 Aug 8;59(16):1939-1945. Epub 2020 May 8.

Department of Respirology, Funabashi Municipal Medical Center, Japan.

Objective Pembrolizumab has benefited patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death-ligand (PD-L) 1 high expression, but little information is available regarding its safety for patients with interstitial lung disease (ILD). The aim of this study was to assess the efficacy and tolerability of pembrolizumab for patients with advanced NSCLC and preexisting ILD. Methods We retrospectively reviewed the medical records of five patients with advanced NSCLC and preexisting ILD who received pembrolizumab monotherapy in a first-line setting. Patients All patients had mild ILD and pulmonary emphysema with a forced vital capacity within the normal range. Pembrolizumab was administered at a dose of 200 mg/body on day 1 every 3 weeks. Results The overall response rate was 60%. Four patients developed pembrolizumab-induced lung injury, which was improved in all cases by corticosteroid therapy. One patient received pembrolizumab for two years, did not experience lung injury and achieved a complete response. Conclusion Pembrolizumab has a high risk of inducing lung injury in patients with preexisting ILD, although it may be very effective in NSCLC patients with a high PD-L1 expression, even concurrent with preexisting ILD. Further large-scale studies are needed to determine risk factors of pembrolizumab-induced lung injury in such patients.
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http://dx.doi.org/10.2169/internalmedicine.4552-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492129PMC
August 2020

Rapidly declining trend of signet ring cell cancer of the stomach may parallel the infection rate of Helicobacter pylori.

BMC Gastroenterol 2019 Nov 8;19(1):178. Epub 2019 Nov 8.

Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan.

Background: Studies indicate that gastric cancer (GC) incidence has decreased, whereas signet ring cell carcinoma (SRC) incidence has increased. However, recent trends in GC incidence are unclear. We used our hospital cancer registry to evaluate the changes in the incidence of GC, SRC, and non-SRC (NSRC) over time in comparison to changes in the H. pylori infection rates over time.

Methods: We identified 2532 patients with GC enrolled in our registry between January 2007 and December 2018 and statistically analyzed SRC and NSRC incidence. The H. pylori infection rate in patients with SRC was determined by serum anti-H. pylori antibody testing, urea breath test, biopsy specimen culture, and immunohistochemical analysis (IHC) of gastric tissue. Additionally, genomic detection of H. pylori was performed in SRCs by extracting DNA from formalin-fixed paraffin-embedded gastric tissue and targeting 16S ribosomal RNA of H. pylori.

Results: Overall, 211 patients had SRC (8.3%). Compared with patients with NSRC, those with SRC were younger (P <  0.001) and more likely to be female (P <  0.001). Time series analysis using an autoregressive integrated moving average model revealed a significant decrease in SRC (P <  0.001) incidence; NSRC incidence showed no decline. There was no difference in H. pylori infection prevalence between the SRC and NSRC groups. IHC and genomic methods detected H. pylori in 30 of 37 (81.1%) SRCs.

Conclusions: Reduction in H. pylori infection prevalence may be associated with the decrease in the incidence of SRC, which was higher than that of NSRC.
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http://dx.doi.org/10.1186/s12876-019-1094-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842265PMC
November 2019

Pemetrexed Plus Platinum for Patients With Advanced Non-small Cell Lung Cancer and Interstitial Lung Disease.

In Vivo 2019 Nov-Dec;33(6):2059-2064

Department of Respirology, Funabashi Municipal Medical Center, Kanasugi, Japan.

Background/aim: Pemetrexed plus platinum followed by pemetrexed maintenance has been one of the standard first-line treatments in advanced nonsquamous non-small cell lung cancer (NSCLC), but little is known regarding its safety and efficacy for patients with interstitial lung disease (ILD).

Patients And Methods: The medical records of 24 patients with advanced nonsquamous NSCLC and preexisting ILD who received pemetrexed and platinum doublet therapy with and without pemetrexed maintenance in the first-line setting between December 2009 and June 2016, were retrospectively reviewed.

Results: The median progression-free survival time was 4.7 months, and the median overall survival time was 9.5 months. Of the 24 patients analyzed, six received pemetrexed maintenance. Acute exacerbation of ILD (AE-ILD) occurred in five (20.8 %) of 24 patients, including two fatal cases.

Conclusion: The treatment with pemetrexed plus platinum has a high risk of AE-ILD in patients with advanced nonsquamous NSCLC and preexisting ILD.
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http://dx.doi.org/10.21873/invivo.11704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899148PMC
March 2020

Pembrolizumab-induced interstitial lung disease following thoracic surgery in a patient with non-small cell lung cancer.

Thorac Cancer 2019 11 11;10(11):2179-2182. Epub 2019 Sep 11.

Department of Respirology, Funabashi Municipal Medical Center, Chiba, Japan.

The safety of treatment with immune-checkpoint inhibitors prior to thoracic surgery in patients with non-small cell lung cancer (NSCLC) remains unclear. Here, we describe the case of a 62-year-old woman with NSCLC with programmed death ligand 1 expression on 85% of tumor cells. The patient was initially considered to have unresectable stage IIIB disease and received pembrolizumab monotherapy. After 12 cycles of pembrolizumab, the primary tumor was reduced, but a small lung nodule in another lobe was unchanged. Based on the course of image findings, the nodule was considered to be an old inflammatory change. The clinical stage was changed to stage IB and partial resection was performed. Three days after thoracic surgery, the patient began to complain of coughing and shortness of breath. A CT of the chest revealed ground-glass opacity in the bilateral lung fields, suggesting interstitial lung disease (ILD) associated with pembrolizumab. Corticosteroid therapy was started and a chest X-ray showed a reduction in the opacity with improved oxygenation. This is the first case of immune-checkpoint inhibitor-related ILD triggered by thoracic surgery following long-term immune-checkpoint therapy.
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http://dx.doi.org/10.1111/1759-7714.13194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825914PMC
November 2019

Hematobium schistosomiasis control for health management of labor force generation at Nkhotakota and Lilongwe in the Republic of Malawi-assumed to be related to occupational risk.

Trop Med Health 2019 2;47:28. Epub 2019 May 2.

1Department of Hygiene and Public Health, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, 573-1010 Japan.

Background: In Malawi, hematobium schistosomiasis is highly endemic. According to previous studies, countermeasures have been conducted mainly in school-aged children. In this study, we focused on the age groups, which are assumed to be major labor force generation. Hematobium schistosomiasis is supposed to be related to occupational activities in schistosome-endemic countries because of its infectious route. We chronologically followed the transition of schistosome egg-positive prevalence before and after mass drug administration of praziquantel (MDA) by using a urine filtering examination. We also analyzed the effectiveness of urine reagent strips from the cost perspective.

Results: The egg-positive prevalence was 34.3% (95% CI 28.5-40.5) just before MDA in June 2010 and the highest prevalence was in the age of twenties. The egg-positive prevalence reduced to 12.7% (95% CI 9.2-17.3,  < 0.01) 8 weeks after the first MDA and the prevalence reduced to 6.9% (95% CI 4.6-10.0,  < 0.01) after the second MDA in August 2011. The egg-positive prevalence after MDA in 2013 was reduced from 3.8% (95% CI 2.1-6.9) to 0.9% (95% CI 0.3-3.4) and value was 0.050. Using urine reagent strips after MDA, the positive predictive value decreased, but the negative predictive value remained high. The cost of one urine reagent strip and one tablet of praziquantel were US$0.06 and US$0.125 in 2013 in Malawi. If the egg-positive prevalence is 40%, screening subjects for MDA using urine reagent strips, the cost reduction can be estimated to be about 24%, showing an overall cost reduction.

Conclusions: MDA of praziquantel can assuredly reduce schistosome egg-positive prevalence. The combination of MDA and urine reagent strips could be both a practical and cost-effective countermeasure for hematobium schistosomiasis. It is key to recognize that hematobium schistosomiasis could be considered a disease that is assumed to have some concern with occupational risk at Nkhotakota and Lilongwe in Malawi. From this point of view, it is very important to manage workers' health; the sound labor force generation is vital for economic growth and development in these areas and countries.
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http://dx.doi.org/10.1186/s41182-019-0155-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498665PMC
May 2019

Deficiency of mismatch repair genes is less frequently observed in signet ring cell compared with non-signet ring cell gastric cancer.

Med Oncol 2019 Jan 29;36(3):23. Epub 2019 Jan 29.

Genome Analysis Center, Yamanashi Central Hospital, 1-1-1, Fujimi, Kofu, Yamanashi, Japan.

Signet ring cell (SRC) gastric cancer at advanced stage has poor prognosis. While a recent study reported nearly one-third of SRC cases contain tumors with deficient mismatch repair (MMR) genes, other studies in SRC have been inconclusive. To re-analyze the results, we performed immunohistochemical staining of MLH1, MSH2, MSH6 and PMS2 proteins in 38 SRC gastric tumors compared with 109 non-SRC (NSRC) tumors from 94 patients. In contrast to the previous study, all SRC gastric tumors normally expressed MMR proteins, whereas 22 of 109 of NSRC (20%) showed deficient MMR proteins. To reinforce our results, we referred to the Cancer Genome Atlas (TCGA) genomic database and found that only 6 (6%) of 99 samples with diffuse gastric tumors showed deficient MMR, whereas 64 (21%) of 304 in intestinal gastric tumors showed deficient MMR. Our results as well as the TCGA database indicated that MMR genes are infrequently inactivated in SRC gastric cancer. These findings indicate that SRC patients may not be the best candidates for immuno-oncology therapy.
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http://dx.doi.org/10.1007/s12032-019-1246-4DOI Listing
January 2019

The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.

Hepatol Int 2019 Mar 22;13(2):199-204. Epub 2019 Jan 22.

Department of Gastroenterology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, 400-8506, Yamanashi, Japan.

Background/purpose: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting.

Methods: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0.

Results: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%.

Conclusion: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.
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http://dx.doi.org/10.1007/s12072-019-09929-4DOI Listing
March 2019

The Antemortem Diagnosis of Primary Malignant Pericardial Mesothelioma: A Multidisciplinary Evaluation.

Intern Med 2018 Sep 27;57(17):2559-2562. Epub 2018 Apr 27.

Department of Pathology, Funabashi Municipal Medical Center, Japan.

A 64-year-old woman complaining of progressive dyspnea was admitted with recurrence of massive pericardial effusion. The patient had been diagnosed with radiation pericarditis based on a previous case of pericardiocentesis. To make a diagnosis and improve her symptoms, imaging examinations and pericardial fenestration were performed. Because of difficulty making a diagnosis, after some months, pericardiotomy and incision of the epicardium were performed. The patient was ultimately diagnosed with primary malignant pericardial mesothelioma of the epithelioid type. Primary malignant pericardial mesothelioma is a rare tumor that is difficult to diagnose. An antemortem diagnosis can be made by a multidisciplinary evaluation.
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http://dx.doi.org/10.2169/internalmedicine.0355-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172541PMC
September 2018

Metastatic Recurrence of Typical Pulmonary Carcinoid Accompanied by Carcinoid Syndrome, Successfully Treated with Octreotide LAR.

Case Rep Oncol Med 2017 28;2017:1564819. Epub 2017 Dec 28.

Department of Respiratory Medicine, Funabashi Municipal Medical Center, Chiba, Japan.

We present a case of metastatic recurrence of carcinoid tumor accompanied by carcinoid syndrome in a 68-year-old Japanese man, 12 years after resection of typical pulmonary carcinoid. Histopathologic examination from percutaneous liver biopsy revealed metastatic typical carcinoid. Clinical symptoms gradually improved after administration of octreotide LAR. Two years after starting treatment, the disease remains well controlled. This case report illustrates the possibility of antiproliferative effects of octreotide LAR on typical pulmonary carcinoid.
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http://dx.doi.org/10.1155/2017/1564819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763055PMC
December 2017

The Safety and Efficacy of Treatment with Nab-paclitaxel and Carboplatin for Patients with Advanced Squamous Non-small Cell Lung Cancer Concurrent with Idiopathic Interstitial Pneumonias.

Intern Med 2018 Jul 9;57(13):1827-1832. Epub 2018 Feb 9.

Department of Respirology, Funabashi Municipal Medical Center, Japan.

Objective Although lung squamous cell carcinoma (SCC) accounts for 20-30% of lung cancer cases, new treatment options are limited. The CA031 study showed that nanoparticle albumin-bound-paclitaxel (nab-PTX) plus carboplatin produced a significantly higher overall response rate (41%) than solvent-based paclitaxel plus carboplatin in patients with lung SCC. However, the safety and efficacy of combination chemotherapy of nab-PTX and carboplatin has not yet been established for patients with concurrent lung SCC and idiopathic interstitial pneumonias (IIPs). The aim of this study was to assess the safety and efficacy profiles of nab-PTX and carboplatin in patients with lung SCC and concurrent IIPs. Methods Eight patients with inoperable-stage lung SCC and IIPs were treated with nab-PTX plus carboplatin in a first-line setting between June 2013 and December 2016. One of the eight was a woman, and the median age was 77 (range=72-80) years. Their clinical outcomes, including chemotherapy-associated acute exacerbation of IIPs, were retrospectively investigated. Results The overall response rate was 50%, the median progression-free survival time was 5.6 months, and the median overall survival time was 8.1 months. No patients experienced chemotherapy-related exacerbation of IIPs in the first-line treatment with nab-PTX plus carboplatin. However, IIPs worsened in two of four patients who received second-line chemotherapy. Conclusion Combination chemotherapy of nab-PTX and carboplatin may be an effective and safe treatment option for patients with inoperable lung SCC with IIPs. To confirm this, a large-scale prospective study is needed.
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http://dx.doi.org/10.2169/internalmedicine.0404-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064686PMC
July 2018

Crizotinib-induced Rectal Perforation with Abscess.

Intern Med 2017 Dec 11;56(23):3211-3213. Epub 2017 Oct 11.

Department of Respiratory Medicine, Funabashi Municipal Medical Center, Japan.

An 86-year-old Japanese man was diagnosed with stage IV lung adenocarcinoma. The patient was treated with crizotinib after echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement was detected from his pleural effusion. He subsequently developed abdominal pain and rebound tenderness in the right lower abdomen. Contrast-enhanced abdominal CT showed a low-density area in the abdominal cavity. The size of the abscess was decreased by drainage and the administration of antibiotics. Fistulography revealed a fistula from the rectum to the abscess, and a diagnosis of lower intestinal tract perforation with abscess formation was made. Crizotinib was discontinued and treatment with alectinib was initiated. The patient remains under treatment as an outpatient at our department without adverse effects.
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http://dx.doi.org/10.2169/internalmedicine.8214-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742395PMC
December 2017

Robotic Renal Autotransplantation: First Case Outside of North America.

Acta Med Okayama 2017 Aug;71(4):351-355

Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558,

A 38-year-old woman with a 2.7-cm left ureteral stenosis requiring chronic ureteral stent exchange elected to undergo robotic renal autotransplantation. Left ureteropelvic junction obstruction (UPJO) was also suspected. Robotic donor nephrectomy contributed to the fine dissection for desmoplastic changes. The kidney was removed through a Gelport and examined on ice. UPJO was not seen. An end-to-side robotic anastomosis was created between the renal and external iliac vessels. The console time was 507 min, and the warm ischemia time was 4 min 5 sec. She became stent-free. Robotic renal autotransplantation is a new, minimally invasive approach to renal preservation.
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http://dx.doi.org/10.18926/AMO/55313DOI Listing
August 2017

Discriminatory Power of Superficial Vessel Density and Prelaminar Vascular Flow Index in Eyes With Glaucoma and Ocular Hypertension and Normal Eyes.

Invest Ophthalmol Vis Sci 2017 01;58(1):690-697

Department of Ophthalmology, Kansai Medical University, Hirakata, Osaka, Japan.

Purpose: We evaluate the ability of optical coherence tomography angiography parameters, such as the peripapillary vessel density of the superficial retina and prelaminar flow index of the optic disc (PLFI), to differentiate primary open-angle glaucoma (POAG) and ocular hypertension (OH) from normal eyes.

Methods: The vessel density, PLFI, mean deviation of the visual field, circumpapillary retinal nerve fiber layer thickness (cpNFLT), and global loss volume of the ganglion cell complex were evaluated in one eye of 105 subjects with POAG and OH and normal eyes. The discriminatory powers of these parameters were evaluated based on the area under the curve (AUC) of the receiver operation characteristic curve and multiple comparisons.

Results: The vessel density (P < 0.001) and PLFI/unit area (PLFI/UA; P = 0.020) in eyes with POAG were significantly less than in normal eyes. The vessel density in eyes with OH was significantly (P = 0.018) reduced, whereas the PLFI/UA, global loss volume and cpNFLT were unaffected. The AUCs of the vessel density to discriminate glaucoma and OH from normal eyes were 0.832 and 0.724, respectively, and were significantly better than the PLFI/UA, in which the AUCs were 0.662 (P = 0.002) and 0.569 (P = 0.038), respectively. The powers of the vessel density and PLFI/UA to discriminate POAG from normal eyes were inferior to the global loss volume (P = 0.006 and <0.0001) and cpNFLT (P = 0.055 and P < 0.0001, respectively).

Conclusions: The vessel density and PLFI/UA decreased significantly in glaucomatous eyes. The vessel density was more efficient than the PLFI/UA for differentiating glaucoma and OH from normal eyes.
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http://dx.doi.org/10.1167/iovs.16-20709DOI Listing
January 2017

Quantitative Retinal Optical Coherence Tomography Angiography in Patients With Diabetes Without Diabetic Retinopathy.

Invest Ophthalmol Vis Sci 2017 01;58(1):190-196

Sensho-kai Eye Institute, Iseda, Uji, Kyoto, Japan.

Purpose: To compare optical coherence tomography (OCT) angiographic parameters in retina and choriocapillaris between control subjects and diabetic patients without diabetic retinopathy (NDR). Correlations were studied between OCT angiography parameters, retinal structure parameters, and systemic characteristics in all subjects.

Methods: Sixty-two patients were included in the study: control subjects (n = 33) and patients with NDR (n = 29). Optical coherence topography angiographic parameters were as follows: vessel density (%) (in superficial, deep retinal vessel plexus and in choriocapillary layer) and foveal avascular zone (FAZ) area (mm2) in superficial and deep retinal vessel plexus of parafovea. Split-spectrum amplitude decorrelation angiography (SSADA) software algorithm was used for evaluation of vessel density and FAZ area (nonflow area tool). Spectral-domain OCT was used to assess full, inner, and outer retinal thickness and volume in parafovea.

Results: In superficial and deep retina, vessel densities in NDR (44.35% ± 13.31% and 31.03% ± 16.33%) were decreased as compared to control subjects (51.39% ± 13.05%, P = 0.04; and 41.53% ± 14.08%, P < 0.01). Foveal avascular zone in superficial retina of NDR patients (0.37 ± 0.11 mm2) was greater than in controls (0.31 ± 0.10 mm2, P = 0.02). Superficial vessel density significantly correlated with full retinal thickness and volume in parafovea (r = 0.43, P = 0.01; r = 0.43, P = 0.01) and with outer retinal volume in parafovea (r = 0.35, P < 0.05) of healthy subjects. Systolic blood pressure and ocular perfusion pressure significantly correlated with deep vessel density in NDR (r = -0.45, P = 0.02; r = -0.46, P = 0.01), but not in controls.

Conclusions: Superficial and deep retinal vessel density in parafovea of diabetic patients without diabetic retinopathy are both decreased compared to healthy subjects. The associations between vessel density with retinal tissue thickness and with subject's clinical characteristics differ between healthy subjects and patients with NDR.
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http://dx.doi.org/10.1167/iovs.16-20531DOI Listing
January 2017

A prospective, multicenter phase II trial of low-dose erlotinib as maintenance treatment after platinum doublet chemotherapy for advanced non-small cell lung cancer harboring EGFR mutation.

Chin Clin Oncol 2016 Dec;5(6):77

Department of Respiratory Medicine, National Center for Global Health and Medicine, 1-11-1 Toyama, Tokyo 162-0056, Japan.

Background: Maintenance therapy with full-dose erlotinib for patients with advanced non-small cell lung cancer (NSCLC) has demonstrated a significant overall survival (OS) benefit. However, 150 mg/day of erlotinib seems too toxic as maintenance therapy. This study aimed to evaluate the efficacy and safety of low-dose erlotinib (25 mg/day) as maintenance treatment after platinum doublet chemotherapy in NSCLC harboring epidermal growth factor receptor (EGFR) mutation.

Methods: Activated EGFR-mutation-positive NSCLC patients who did not progress after first-line platinum-doublet chemotherapy, ≥20 and ≤85 years old, with performance status (PS) 0-3 were included in this study. Low-dose erlotinib (25 mg/day) was administered until disease progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), OS, and safety. The required sample size was 40 patients.

Results: The study was stopped early, after achieving only 28% of planned enrollment, due to poor accrual. Between April 2011 and May 2014, 11 patients (male/female, 5/6; median age, 72 years; PS 0/1, 8/3; stage IV/relapse after surgery, 9/2; exon 19 deletions/L858R, 7/4) were enrolled and accessible in this study. Partial response (PR) was observed in 6 patients (56%). Median PFS was 14.9 months [95% confidence interval (CI), 2.7-27.1 months] and median OS was not calculable. Toxicities were generally mild. Only one patient developed grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation. Eight patients developed grade 1 skin rash. No treatment-related deaths were observed. Eight patients progressed, and recurrences included brain metastases (n=3), local recurrence (n=2), local recurrence plus brain metastasis (n=1), bone metastasis (n=1), and pulmonary metastasis (n=1).

Conclusions: The study was stopped early due to poor accrual. However, our study suggests that maintenance therapy with low-dose erlotinib might be useful and tolerable in selected NSCLC patients harboring EGFR mutation.
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http://dx.doi.org/10.21037/cco.2016.11.02DOI Listing
December 2016

Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis.

Respir Res 2015 Aug 20;16:99. Epub 2015 Aug 20.

Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Various signals are known to participate in the pathogenesis of lung fibrosis. Our aim was to determine which signal is predominantly mobilized in the early inflammatory phase and thereafter modulates the development of lung fibrosis.

Methods: Mice received a single dose of 3 mg/kg body weight of bleomycin (BLM) and were sacrificed at designated days post-instillation (dpi). Lung homogenates and sections from mice in the early inflammatory phase were subjected to phospho-protein array analysis and immunofluorescence studies, respectively. Bronchoalveolar lavage fluid (BALF) from mice was subjected to an enzyme-linked immunosorbent assay (EIA) for interleukin (IL)-6 and evaluation of infiltrated cell populations. The effects of endogenous and exogenous IL-6 on the BLM-induced apoptotic signal in A549 cells and type 2 pneumocytes were elucidated. In addition, the effect of IL-6-neutralizing antibody on BLM-induced lung injury was evaluated.

Results: Phospho-protein array revealed that BLM induced phosphorylation of molecules downstream of the IL-6 receptor such as Stat3 and Akt in the lung at 3 dpi. At 3 dpi, immunofluorescence studies showed that signals of phospho-Stat3 and -Akt were localized in type 2 pneumocytes, and that BLM-induced IL-6-like immunoreactivity was predominantly observed in type 2 pneumocytes. Activation of caspases in BLM-treated A549 cells and type 2 pneumocytes was augmented by application of IL-6-neutralizing antibody, a PI3K inhibitor or a Stat3 inhibitor. EIA revealed that BLM-induced IL-6 in BALF was biphasic, with the first increase from 0.5 to 3 dpi followed by the second increase from 8 to 10 dpi. Blockade of the first increase of IL-6 by IL-6-neutralizing antibody enhanced apoptosis of type 2 pneumocytes and neutrophilic infiltration and markedly accelerated fibrosis in the lung. In contrast, blockade of the second increase of IL-6 by IL-6-neutralizing antibody ameliorated lung fibrosis.

Conclusions: The present study demonstrated that IL-6 could play a bidirectional role in the pathogenesis of lung fibrosis. In particular, upregulation of IL-6 at the early inflammatory stage of BLM-injured lung has antifibrotic activity through regulating the cell fate of type 2 pneumocytes in an autocrine/paracrine manner.
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http://dx.doi.org/10.1186/s12931-015-0261-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546032PMC
August 2015

[IgG4-related kidney disease: a long-term follow up case of pseudotumor of the renal pelvis].

Nihon Hinyokika Gakkai Zasshi 2014 Apr;105(2):51-5

A 69-year-old man had undergone left ureteronephrectomy because of a left renal pelvic tumor, however the pathological diagnosis was inflammatory pseudotumor. About 1 year later, computed tomography showed a mass at the right kidney near the hilar. Ureterorenoscopy and urine cytology were performed, and their results showed no evidence of malignancy. He had been followed closely without therapy. The mass increased in size during follow-up, and we reviewed the surgical specimen of the left ureteronephrectomy. Immunohistochemical studies revealed diffuse infiltration by IgG4 positive plasma cell. His serum IgG4 was high. We diagnosed him as IgG4-related kidney disease. In response to treatment with corticosteroid, the size of the tumor and serum IgG4 levels decreased. Most reported cases of IgG4-related disease involving kidney have a history of prior pancreatic involvement. We report a rare long term follow-up case of IgG4-related kidney disease without pancreatic involvement.
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http://dx.doi.org/10.5980/jpnjurol.105.51DOI Listing
April 2014

p38 Mitogen-activated protein kinase accelerates emphysema in mouse model of chronic obstructive pulmonary disease.

J Recept Signal Transduct Res 2014 Aug 5;34(4):299-306. Epub 2014 Mar 5.

Department of Biochemistry and Molecular Pharmacology .

Context: There are few short-term mouse models of chronic obstructive pulmonary disease (COPD) mimicking the human disease. In addition, p38 is recently recognized as a target for the treatment of COPD. However, the precise mechanism how p38 contributes to the pathogenesis of COPD is still unknown.

Objective: We attempted to create a new mouse model for COPD by intra-tracheal administration of a mixture of lipopolysaccharide (LPS) and cigarette smoke solution (CSS), and investigated the importance of the p38 mitogen-activated protein kinase (p38) pathway in the pathogenesis of COPD.

Methods: Mice were administered LPS + CSS once a day on days 0-4 and 7-11. Thereafter, CSS alone was administered to mice once a day on days 14-18. On day 28, histopathological changes of the lung were evaluated, and bronchoalveolar lavage fluid (BALF) was subjected to western blot array for cytokines. Transgenic (TG) mice expressing a constitutive-active form of MKK6, a p38-specific activator in the lung, were subjected to our experimental protocol of COPD model.

Results: LPS + CSS administration induced enlargement of alveolar air spaces and destruction of lung parenchyma. BALF analyses of the LPS + CSS group revealed an increase in expression levels of several cytokines involved in the pathogenesis of human COPD. These results suggest that our experimental protocol can induce COPD in mice. Likewise, histopathological findings of the lung and induction of cytokines in BALF from MKK6 c.a.-TG mice were more marked than those in WT mice.

Conclusion: In a new experimental COPD mouse model, p38 accelerates the development of emphysema.
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http://dx.doi.org/10.3109/10799893.2014.896380DOI Listing
August 2014

Association of deep vein thrombosis type with clinical phenotype of chronic thromboembolic pulmonary hypertension.

Int J Cardiol 2013 May 17;165(3):474-7. Epub 2011 Sep 17.

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) has been considered to be caused by single or recurrent pulmonary embolism (PE) arising from deep vein thrombosis (DVT). In Japan, female predominance and association of HLA-B*5201 with CTEPH unrelated to DVT were reported. In acute PE residual proximal DVT is associated with larger obstruction of pulmonary arteries. However, it remains uncertain whether DVT and the type of DVT are associated with clinical phenotype of CTEPH.

Purpose: To clarify the association of DVT and DVT type with clinical phenotype of CTEPH.

Methods: Among 98 consecutive patients who underwent 16 or 64-slice multidetector CT angiography and indirect venography, 91 patients (66% female, age: 56±3 years) with adequate images were enrolled. The associations of DVT and DVT type with pulmonary hemodynamics, CT obstruction index and other clinical parameters were analyzed.

Results: DVT was found in 45 patients (49.5%) (distal: 12, proximal: 33), and was significantly associated with male gender and recurrent type. Furthermore, it was more frequent in HLA-B*5201-negative, and d-dimer positive patients. Compared with distal DVT, proximal DVT was associated with male gender, larger CT obstruction index (48.6±13.0 vs. 34.1±13.2%, p=0.004), and higher mean pulmonary arterial pressure (48.2±12.8 vs. 40.8±7.9 mmHg, p=0.03). Proximal DVT was significantly associated with the central type of CTEPH only in HLA-B*5201-negative patients.

Conclusions: The existence and type of DVT were associated with clinical phenotype of CTEPH, and proximal DVT might contribute to the central type of CTEPH in only HLA-B*5201-negative patients.
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http://dx.doi.org/10.1016/j.ijcard.2011.08.851DOI Listing
May 2013

[A case of small-cell lung carcinoma accompanied by the syndrome of inappropriate secretion of antidiuretic hormone and Lambert-Eaton myasthenic syndrome].

Nihon Kokyuki Gakkai Zasshi 2011 Mar;49(3):197-202

Department of Respirology, Graduate School of Medicine, Chiba University.

Although the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS) are often individually accompanied by small-cell lung carcinoma, simultaneous occurrence of the 2 syndromes is rare. A 61-year-old man was admitted to our hospital because of fatigue and myasthenia in the extremities, and small-cell lung carcinoma with pulmonary metastasis was diagnosed, together with SIADH and LEMS. These syndromes markedly ameliorated following tumor shrinkage, with 4 cycles of chemotherapy consisting of carboplatin and etoposide. On progression of the tumor thereafter, neither syndrome recurred. A literature review disclosed that these syndromes frequently resolve with tumor shrinkage.
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March 2011

[Case of thymic carcinoid associated with multiple endocrine neoplasia type I treated effectively with chemotherapy].

Nihon Kokyuki Gakkai Zasshi 2010 Nov;48(11):855-9

Department of Respirology, Graduate School of Medicine, Chiba University.

A 53-year-old man was referred to our hospital due to a mediastinal mass found during a medical checkup in July 2009. He had a past history of hyperparathyroidism, for which he underwent surgery in 1994, and also had a family history in that his sister had multiple endocrine neoplasia type 1 (MEN1). He was given a diagnosis of MEN I on genetic testing. Chest CT revealed a mediastinal mass 4 cm in maximum dimension, and an atypical carcinoid was diagnosed according to mediastinal biopsy findings. Bone metastasis was detected and he was given cisplatin and etoposide. The tumor decreased in size by 30%, and was evaluated as showing partial response. Although there are some cases of MEN-related thymoma treated by surgery, a case which successfully responded to chemotherapy alone is thought to be extremely rare.
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November 2010

A case of isolated peripheral pulmonary artery branch stenosis associated with multiple pulmonary artery aneurysms.

Intern Med 2010 1;49(17):1895-9. Epub 2010 Sep 1.

Department of Respirology, Chiba University, Chiba, Japan.

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.
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http://dx.doi.org/10.2169/internalmedicine.49.3815DOI Listing
January 2011

Contralateral metachronous tumor occurrence is more frequently associated with distant metastases or postoperative intrarenal recurrence in renal cell carcinoma patients.

Int J Urol 2010 Jul 7;17(7):615-22. Epub 2010 May 7.

Department of Urology, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.

Objective: To analyze the prognosis of patients with sporadic bilateral renal cell carcinoma (RCC).

Methods: From January 1979 to December 2007, 984 patients with sporadic RCC underwent surgery at our department. Of these, 53 patients (5.7%) presenting with bilateral RCC were included in this retrospective analysis.

Results: Thirty-one of the 53 bilateral RCC patients had synchronous RCC, and 22 had metachronous RCC. Distant metastases by the time of the bilateral tumor occurrence were found in four patients (13%) in the synchronous group and in 10 patients (48%) in the metachronous group. No difference was found between the two groups in terms of overall survival. In contrast, survival after the second surgery in the metachronous group was significantly lower than that after the first surgery (P < 0.001) in the synchronous group (P = 0.02). In addition, the incidence of local recurrence after partial nephrectomy was higher in the metachronous group (26%) compared to the synchronous group (4%, P = 0.04) or the unilateral RCC patients (0.4%, P < 0.01).

Conclusions: Metachronous occurrence of RCC in the contralateral kidney is associated with an unfavorable prognosis, suggesting that metachronous contralateral tumors might be metastasis of the original tumors. A stricter follow-up schedule is advisable for metachronous bilateral RCC patients.
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http://dx.doi.org/10.1111/j.1442-2042.2010.02541.xDOI Listing
July 2010

New-onset diabetes after transplantation in tacrolimus-treated, living kidney transplantation: long-term impact and utility of the pre-transplant OGTT.

Int Urol Nephrol 2010 Dec 19;42(4):935-45. Epub 2010 Feb 19.

Section of Renal Transplantation/Renovascular Surgery, Tokyo Women's Medical University, Tokyo, Japan.

Background: To evaluate the role of the oral glucose tolerance test (OGTT) before transplantation and to examine the risk factors for new-onset diabetes after transplantation (NODAT) during long-term follow-up of renal transplant recipients receiving FK-based therapy.

Methods: The study evaluated 378 patients pre-transplantation using the OGTT and assigned them to one of three groups: Group 1, normal pattern; Group 2, impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) pattern (IFG/IGT); and Group 3, DM pattern.

Results: Although the incidence of NODAT was higher in Group 3 than in groups 1 and 2, no significant difference was found between the three groups with regard to graft survival during long-term follow-up. Multivariate analysis showed that only a family history of diabetes was a significant factor determining NODAT progression.

Conclusions: Impaired glucose tolerance appears to be a threshold influencing NODAT; however, it was not a significant factor in graft survival. Careful monitoring and management based on the result of the pre-transplantation OGTT appear to prevent the deterioration of impaired glucose tolerance in renal transplant recipients receiving FK-based therapy, even when a pre-operative OGTT shows impaired glycemic control.
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http://dx.doi.org/10.1007/s11255-010-9712-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995209PMC
December 2010

[A case of sternoclavicular joint tuberculosis with renal failure due to rifampicin].

Kekkaku 2009 Aug;84(8):591-5

Department of Pulmonary Medicine, Tokyo Metropolitan Fuchu Hospital, Tokyo, Japan.

A 79-year-old man was admitted to a previous hospital complaining of left precordial swelling. Chest CT scan showed destruction of left sternoclavicular joint and a mass of 5 cm in diameter. Needle biopsy was performed and the diagnosis of sternoclavicular joint tuberculosis was made on the basis of presence of M. tuberculosis in the specimen. The patient was treated with isoniazid, ethambutol, rifampicin, and pyrazinamid but he developed renal failure. Then, he was transferred to our hospital. All medications were suspended because of the possibility of the side effect of drugs. We performed renal biopsy and histopathological examination revealed interstitial nephritis and minimal-change glomerulonephritis. From the result of examination, we considered interstitial nephritis was due to rifamicin. The treatment with 50 mg/day of prednisolone and isoniazid, ethambutol, and levofloxacin was administrated and renal failure and precordial mass were improved. Tuberculous arthritis usually affect hip and knee joint and sternoclavicular joint involvement is very rare.
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August 2009

Cytomegalovirus infection following renal transplantation in patients administered low-dose rituximab induction therapy.

Transpl Int 2009 Oct 10;22(10):961-9. Epub 2009 Jul 10.

Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.

Anti-CD20 antibody (rituximab) is recently being used as a B cell-depleting agent in renal transplantation (RTx). However, the incidence of infectious complications associated with rituximab therapy remains uncertain. We evaluated the incidence of cytomegalovirus (CMV) infection associated with rituximab therapy in RTx. A total of 83 patients were enrolled. The immunosuppressive regimen consisted of tacrolimus or cyclosporin, mycophenolate mofetil, methylprednisolone and basiliximab. In 54 patients, only one dose of rituximab (200 or 500 mg/kg body weight) was given before RTx. A total of 25 of 43 (58.1%) recipients who were CMV seropositive prior to RTx and who received rituximab induction therapy developed CMV infection, compared to 18 of 24 (75%) CMV seropositive recipients who did not receive rituximab therapy (P = 0.1676). A total of 8 of 11 patients who were CMV seronegative prior to RTx and who received rituximab developed CMV infection. However, CMV seroconversion was seen in all 8 of these infected patients. Low-dose rituximab induction therapy in renal transplant recipients appears to have no influence on the incidence of CMV infection and CMV seroconversion. However, we have to consider anti-CMV prophylaxis therapy, because of high incidents of CMV infection, especially for CMV seronegative recipients who received rituximab.
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http://dx.doi.org/10.1111/j.1432-2277.2009.00903.xDOI Listing
October 2009

Monokine induced by interferon-gamma (MIG/CXCL9) is derived from both donor and recipient sources during rejection of class II major histocompatibility complex disparate skin allografts.

Am J Pathol 2009 Jun 23;174(6):2172-81. Epub 2009 Apr 23.

NB3-59, Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195-0001, USA.

Chemokines, including monokine induced by interferon-gamma (Mig/CXCL9), are produced both in allografts and during the direct T-cell infiltration that mediates graft rejection. Neither the specific production nor contribution of allograft donor versus recipient Mig in allograft rejection is currently known. C57BL/6 mice with a targeted deletion in the Mig gene were used as both skin allograft donors and recipients in a class II major histocompatibility complex-mismatched graft model to test the requirement for donor- versus recipient-derived Mig for acute rejection. B6.Mig(-/-) allografts had a 10-day prolonged survival in B6.H-2(bm12) recipients when compared with wild-type C57BL/6 allograft donors, and B6.H-2(bm12) skin allografts had a 5-day prolonged survival in B6.Mig(-/-) versus wild-type recipients. Transplantation of B6.Mig(-/-) skin grafts onto B6.H-2(bm12).Mig(-/-) recipients resulted in further prolonged allograft survival with more than 30% of the grafts surviving longer than 60 days. Prolonged allograft survival was also associated with delayed cellular infiltration into grafts but not with altered T-cell proliferative responses to donor stimulators. Immunohistochemical staining of allograft sections indicated that Mig is produced by both donor- and recipient-derived sources, but Mig from each of these sources appeared in different areas of the allograft tissue. These results therefore demonstrate the synergy of donor- and recipient-derived Mig in promoting T-cell infiltration into allografts.
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http://dx.doi.org/10.2353/ajpath.2009.080516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684182PMC
June 2009

[A cluster of paragonimiasis westermani infections in Thai immigrants].

Nihon Kokyuki Gakkai Zasshi 2009 Mar;47(3):249-53

Department of Emergency Medicine, Tokyo Metropolitan Fuchu Hospital.

We report a cluster of infections in four female Thai immigrants aged between 35 and 49 years who developed paragonimiasis westermani within 16 months of ingesting freshwater crabs purchased from a market in Japan. Their symptoms included cough, bloody sputum, chest pain, and dyspnea. Radiographic and CT findings comprised pleural effusion, pneumothorax, air-space consolidation, and nodular opacities. Paragonimus eggs were identified in the feces of one patient, and in the pleural effusion and the bronchoalveolar lavage fluid (BALF) of another. All diagnoses of paragonimiasis westermani were established by enzyme-linked immunosorbent assay (ELISA) of their serum. Paragonimiasis is a re-emerging disease in Japan. Moreover, since the number of immigrant patients is increasing, it is necessary to pay attention to infectious diseases resulting from their eating habits as well as imported diseases.
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March 2009