Publications by authors named "Kei Kusaka"

13 Publications

  • Page 1 of 1

A phase II study of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small-cell lung cancer in Japan (SAMURAI study).

Ther Adv Med Oncol 2021 27;13:1758835921998588. Epub 2021 Feb 27.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606, Japan.

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study.

Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate.

Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127.
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http://dx.doi.org/10.1177/1758835921998588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917867PMC
February 2021

Multi-Institutional Prospective Cohort Study of Patients With Pulmonary Hypertension Associated With Respiratory Diseases.

Circ J 2021 Mar 2;85(4):333-342. Epub 2021 Feb 2.

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

Background: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis.Methods and Results:Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI.

Conclusions: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.
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http://dx.doi.org/10.1253/circj.CJ-20-0939DOI Listing
March 2021

An autopsy case report of yellow nail syndrome coincided with primary biliary cholangitis.

Respir Med Case Rep 2021 31;32:101332. Epub 2020 Dec 31.

Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan.

Yellow nail syndrome (YNS) is a rare entity characterized by thickened yellowish nails, lymphedema and respiratory manifestations such as pleural effusion. Lymphatic dysfunction is considered as a cause of YNS. However, evidence of systemic dilatation/hyperplasia of lymphatics based on autopsy in YNS is not available. In this report, autopsy revealed dilatation and hyperplasia of lymphatic vessels in lungs, visceral and parietal pleurae, and intestines. We identified the direct opening of lymphatic vessels of the visceral pleura to the pleural cavity, which indicated the pathophysiology of uncontrollable pleural effusion in YNS. The current case was compromised with primary biliary cholangitis (PBC). The onset of PBC seemed to be related with the progression of YNS.
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http://dx.doi.org/10.1016/j.rmcr.2020.101332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817504PMC
December 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

Improvement of pulmonary arterial compliance by pulmonary vasodilator in pulmonary hypertension from combined pulmonary fibrosis and emphysema.

Respir Med Case Rep 2019 27;28:100940. Epub 2019 Sep 27.

Center for Pulmonary Diseases, Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-shi, Tokyo, 204-8585, Japan.

Combined pulmonary fibrosis and emphysema (CPFE) is a common but under-recognized syndrome characterized with distinct profiles of both pulmonary fibrosis and emphysema. Pulmonary hypertension (PH) is particularly prone to develop as a common complication, leading to exercise limitation and worse prognosis of CPFE. Although the therapy of patients with PH from CPFE cannot be endorsed, an individual treatment may be considerable when accompanying severe PH. We report a case of a 71-year-old male with PH from CPFE, who improved pulmonary arterial compliance (PAC) and exercise capacity in response to pulmonary vasodilator.
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http://dx.doi.org/10.1016/j.rmcr.2019.100940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812224PMC
September 2019

A successful pembrolizumab treatment case of lung adenocarcinoma after becoming resistant to ALK-TKI treatment due to G1202R mutation.

Respir Investig 2018 Jul 2;56(4):365-368. Epub 2018 Jul 2.

Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, Tokyo 204-8585, Japan. Electronic address:

Background: In current guidelines, the role of immune checkpoint inhibitors is not yet determined in the treatment strategy for NSCLC harboring ALK translocations.

Case: A 51-year-old woman with lung adenocarcinoma harboring ALK translocation was treated with alectinib until PD. After the second (CDDP/PEM) and third (crizotinib) line treatment, a second biopsy was performed, revealing PD-L1 tumor proportion score of 70-80% and G1202R mutation of ALK. Pembrolizumab was selected for the fourth line, leading to PR for more than 6 months.

Conclusions: While alectinib might induce resistance to ALK-TKI, it could increase PD-L1 positive cells to become sensitive to PD-1/PD-L1 inhibitors.
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http://dx.doi.org/10.1016/j.resinv.2018.04.004DOI Listing
July 2018

Pulmonary Adenocarcinoma, Harboring Both an EGFR Mutation and ALK Rearrangement, Presenting a Stable Disease to Erlotinib and a Partial Response to Alectinib.

Intern Med 2018 Aug 9;57(16):2377-2382. Epub 2018 Mar 9.

Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Japan.

A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor (EGFR) mutation and an anaplastic lymphoma kinase (ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents.
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http://dx.doi.org/10.2169/internalmedicine.0383-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148164PMC
August 2018

Relationship Between Lung Cancer and Mycobacterium Avium Complex Isolated Using Bronchoscopy.

Open Respir Med J 2016 12;10:20-8. Epub 2016 May 12.

Clinical Research, Innovation and Education Center, Tohoku University Hospital, Sendai, Miyagi 980-8574, Japan.

Introduction: The incidence of Mycobacterium avium complex (MAC)-positive respiratory specimen cultures and MAC lung disease (MACLD) is increasing worldwide. This retrospective study aimed to assess the association between MAC culture-positive bronchoscopy specimens and lung cancer.

Materials And Methods: The medical records of 1382 untreated lung cancer patients between 2003 and 2011 were collected using our hospital database. Of them, records for 1258 that had undergone bronchoscopy together with sampling for mycobacterial culture were reviewed. Patient characteristics were compared between those with MAC-positive/other nontuberculous mycobacteria (NTM)-negative bronchial washings and those with MAC-negative/other NTM-negative bronchial washings. Patients with MAC-positive lung cancer were cross-sectionally divided into MACLD and non-MACLD groups, and their features were assessed. Follow-up data for patients with lung cancer but without MACLD were reviewed for subsequent development of MACLD.

Results: Of the 1258 patients with lung cancer, 25 (2.0%) had MAC-positive/other NTM-negative bronchial washings. The proportion of women (52% vs 30%; P = 0.0274) and patient age (72 years vs 69 years; P = 0.0380) were significantly higher in the MAC-positive/other NTM-negative lung cancer group (n = 25) than in the MAC-negative/other NTM-negative lung cancer group (n = 1223). There were 10 patients with lung cancer and MACLD and 15 without MACLD; significant differences in patient characteristics were not found between the two groups, and none of the 15 patients without MACLD subsequently developed MACLD.

Conclusion: MAC culture-positive bronchial washing is positively associated with lung cancer. Female sex and advanced age, but not lung cancer characteristics, were found to be associated with MAC infection in patients with lung cancer.
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http://dx.doi.org/10.2174/1874306401610010020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892172PMC
June 2016

[Evaluation of the Efficacy and Safety of Platinum Doublet Re-Challenge Chemotherapy in Patients with Recurrent Advanced Non-Small Cell Lung Cancer].

Gan To Kagaku Ryoho 2016 Jun;43(6):723-6

Dept. of Respirology, National Hospital Organization Tokyo National Hospital.

Background: Docetaxel or pemetrexed is the standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Until now, combination chemotherapy has failed to demonstrate superiority in patients with recurrent advanced NSCLC, compared to single-agent chemotherapy. The aim of the present study was to assess the efficacy and safety of platinum doublet re-challenge chemotherapy in patients with recurrent advanced NSCLC.

Methods: Fifty-eight patients with recurrent advanced NSCLC who underwent platinum doublet re-challenge chemotherapy were retrospectively analyzed.

Results: The response rate was 6.9%(95%CI: 1.9-16.7%), the disease control rate was 70.7% (95%CI: 57.3-81.9%), the median progression-free survival (PFS) was 123 days, and the median survival time (MST) after re-challenge chemotherapy was 470 days. The disease control rate and the PFS were significantly better in patients who achieved a partial response to first-line chemotherapy than in patients who had stable or progressive disease. In addition, the PFS and MST were significantly longer in patients whose treatment-free interval was more than 90 days. Toxicities were tolerable in most patients, except for 1 patient who showed drug-induced pneumonia.

Conclusion: Platinum doublet re-challenge chemotherapy is a treatment option for patients with advanced NSCLC who achieved a partial response to first-line chemotherapy or for patients whose treatment-free interval lasted longer than 90 days.
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June 2016

Six Cases of Pulmonary Mycobacterium shinjukuense Infection at a Single Hospital.

Intern Med 2016 1;55(7):787-91. Epub 2016 Apr 1.

Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Japan.

Mycobacterium shinjukuense lung disease was diagnosed in 3 men and 3 women [mean age: 77.0±12.2 (57-93) years]. On imaging, 3 patients with previous pulmonary tuberculosis exhibited a fibrocavitary pattern, while the other 3 patients showed nodular bronchiectasis. A test with a tuberculosis rRNA identification kit (TRC Rapid(®) M. TB) was falsely positive for M. tuberculosis due to DNA sequence similarity in 16SrRNA. M. shinjukuense was identified by the gene sequences of rpoB, 16S rRNA, and hsp65. The symptoms and imaging findings of most of the patients have improved with chemotherapy with low minimum inhibitory concentrations of anti-tuberculosis drugs.
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http://dx.doi.org/10.2169/internalmedicine.55.5460DOI Listing
October 2016

A family of distal arthrogryposis type 5 due to a novel PIEZO2 mutation.

Am J Med Genet A 2015 May 25;167A(5):1100-6. Epub 2015 Feb 25.

Department of Child Neurology, National Center of Neurology and Psychiatry, Japan.

Distal arthrogryposis (DA) encompasses a heterogeneous group of hereditary disorders with multiple congenital contractures predominant in the distal extremities. A total of 10 subtypes are proposed based on the pattern of contractures and association with extraarticular symptoms. DA5 is defined as a subtype with ptosis/oculomotor limitation. However, affected individuals have a variety of non-ocular features as well. We report on a two-generation family, including four affected individuals who all had congenital contractures of the distal joints, ptosis, restricted ocular movements, distinct facial appearance with deep-set eyes, and shortening of the 1st and 5th toes. The proband and her affected mother had restrictive lung disease, a recently recognized syndromic component of DA5, while younger patients did not. The proband had metacarpal and metatarsal synostosis, and the mother showed excavation of the optic disk. Whole-exome sequencing revealed a novel heterozygous mutation c.4456G>C (p.A1486P) of PIEZO2. PIEZO2 encodes a mechanosensitive ion channel, malfunction of which provides pleiotropic effects on joints, ocular muscles, lung function, and bone development.
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http://dx.doi.org/10.1002/ajmg.a.36881DOI Listing
May 2015

Doctor's delay in endobronchial tuberculosis.

Kekkaku 2013 Jan;88(1):9-13

Department of Respiratory Diseases, National Hospital Organization Tokyo National Hospital, Tokyo, Japan.

Objective: The aim of this study was to investigate the current status of doctor's delay in diagnosing endobronchial tuberculosis (EBTB) and to elucidate the risk factors contributing to the delay.

Methods: Retrospective clinicopathological analysis.

Patients: Sixty-two patients with EBTB were admitted at our hospital between 1999 and 2010. Their backgrounds, symptoms, diagnoses at initial consultation, delay in diagnosis, and clinical examination results were analyzed.

Results: Of the 62 patients, 59 had acid-fast, bacillipositive sputum smear test results at admission. Among the 40 patients with total diagnostic delay of more than 2 months, only 11 experienced long patient's delay exceeding 2 months. However, 22 patients experienced long doctor's delay of more than 2 months (28% vs. 55%, respectively, p < 0.05), suggesting that doctor's delay contributes more to total delay than patient's delay. Fever was less frequent in patients with long doctor's delays than in those without (0% vs. 18%, respectively), at the initial consultation. In addition, radiographs showed that patients with long doctor's delays more frequently presented with shadows in the lower lung field (50% vs. 23%, p < 0.05), and most of these patients had noncavitary shadows on admission. All 7 patients diagnosed with bronchial asthma at the initial consultation had long doctor's delays.

Conclusion: These findings demonstrate that long doctor's delays in diagnosing EBTB remain an issue. The clinical features of EBTB with long doctor's delays were confirmed to be quite different from those of pulmonary tuberculosis.
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January 2013

[A case of tuberculous pleurisy developing contralateral effusion during anti-tuberculosis chemotherapy].

Kekkaku 2011 Jul;86(7):723-7

Department of Respiratory Medicine, Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital, Japan.

A 55-year-old woman was admitted to our hospital because of chest pain, fever, and right pleural effusion that was exudative and lymphocyte-dominant with a high level of adenosine deaminase (ADA). Since her blood QuantiFERON-TB 3G test (QFT) was positive, she was diagnosed with tuberculous pleurisy. After initiation of anti-tuberculosis chemotherapy with isoniazid, rifampicin, ethambutol, and pyrazinamide, her symptoms improved. Later, liquid culture of the pleural effusion turned positive for Mycobacterium tuberculosis. On the 18th day of treatment, her chest X-ray and computed tomography exhibited pleural effusion in a moderate amount in the left thorax, with subsiding pleural effusion in the right thorax. Thoracocentesis demonstrated that the left thorax effusion was also exudative and lymphocyte-dominant, with elevated QFT response and high ADA concentration, suggesting tuberculous pleurisy. Mycobacterium tuberculosis was detected in the culture of a left pleural biopsy specimen obtained by thoracoscopy. We assumed that the left pleural effusion was due to paradoxical worsening because (1) on admission no effusion or lung parenchymal lesion was detected in the left hemithorax, (2) on the 14th day of treatment she was afebrile without pleural effusion on both sides, and (3) the bacilli were sensitive to the drugs she had been taking regularly. We performed drainage of the left effusion and continued the same anti-tuberculosis drugs, which led to the elimination of all her symptoms and of the pleural effusion on both sides. In conclusion, paradoxical worsening should be included in the differential diagnosis when contralateral pleural effusion is detected during the treatment of tuberculosis.
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July 2011