Publications by authors named "Nobuhiko Seki"

93 Publications

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.

Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama-City, Hiroshima, 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

Pretreatment neutrophil-to-lymphocyte ratio predicts treatment efficacy and prognosis of cytotoxic anticancer drugs, molecular targeted drugs, and immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

Transl Lung Cancer Res 2021 Jan;10(1):221-232

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo, Japan.

Background: Neutrophil-to-lymphocyte ratio (NLR) has recently attracted attention as a prognostic predictor in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors (ICIs). However, the utility of NLR in relation to cytotoxic anticancer drugs or molecular targeted drugs remains unclear. We determined if NLR could predict the treatment efficacy and prognosis in NSCLC patients who receive cytotoxic anticancer drugs or molecular targeted drugs, as well as ICIs, in a cross-sectional manner.

Methods: Of 658 patients with advanced NSCLC who received first-line systemic treatment in our hospital between 2008 and 2019, 312 who met the analytical criteria were included in the study. We retrospectively analyzed the ability of NLR with a cut-off value of 5 to predict time to treatment failure (TTF) and overall survival (OS) in patients who received the following treatments: first-line treatment with molecular targeted drugs (mt group, n=100); first-line treatment with cytotoxic anticancer drugs (wt group, n=212); and first-line treatment with cytotoxic anticancer drugs followed by ICIs (ICI group, n=58).

Results: In the high- and low-NLR mt subgroups, median TTFs were 6.7 and 14.9 months (P<0.01), respectively, and median survival times (MSTs) were 17.8 and 39.1 months (P<0.01), respectively. In the high- and low-NLR wt subgroups, median TTFs were 1.5 and 5.8 months (P<0.01), and MSTs were 6.3 and 20.7 months (P<0.01), respectively. In the high- and low-NLR ICI subgroups, median TTFs were 1.3 and 6.8 months (P<0.01), and MSTs were 9.2 and 25.8 months (P<0.01), respectively. Multivariate analysis identified NLR as a significant independent predictor of TTF [hazard ratio (HR) 1.89, P=0.01; HR 2.51, P<0.01; and HR 5.06, P<0.01 in the mt, wt, and ICI groups, respectively) and OS (HR 3.81, P<0.01; HR 2.59, P<0.01; and HR 2.48, P<0.01, respectively).

Conclusions: This study showed that NLR might be a predictor of treatment efficacy and prognosis in advanced NSCLC patients who receive various systemic treatments. This finding of consistent applicability of NLR to a wide variety of systemic treatments is of great significance.
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http://dx.doi.org/10.21037/tlcr-20-777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867774PMC
January 2021

Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study).

Ther Adv Med Oncol 2020 31;12:1758835920967254. Epub 2020 Oct 31.

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

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82-2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients.

Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up.

Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221.
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http://dx.doi.org/10.1177/1758835920967254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607717PMC
October 2020

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Invest New Drugs 2021 Apr 7;39(2):530-536. Epub 2020 Nov 7.

Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0375, Japan.

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (C) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the C of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.
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http://dx.doi.org/10.1007/s10637-020-01031-zDOI Listing
April 2021

Phase I/II study of erlotinib plus S-1 for patients with previously treated non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0808/0913.

Invest New Drugs 2021 Feb 15;39(1):202-209. Epub 2020 Aug 15.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan.

Introduction In preclinical data, the combination therapy with S-1 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had a synergistic antitumor effect on non-small cell lung cancer (NSCLC), regardless of the EGFR mutation status. Patients and Methods Patients with previously treated NSCLC and adequate organ function regardless of EGFR mutation status were eligible for the phase I study, with wild-type EGFR were eligible for the phase II study. Treatment consisted of erlotinib 150 mg/body orally once every day and S-1 60 mg/m, 70 mg/m, or 80 mg/m (level 0, level 1, or level 2) orally on days 1-14 every three weeks. The primary endpoint for the phase I study was the determination of the recommended dose (RD), the phase II study was the overall response rate (ORR). Results A total of 7 patients with performance-status (PS) 0 or 1 were enrolled as subjects in phase I. Five of these subjects were EGFR-mutation positive. Four subjects were enrolled at S-1 dose level 1 and 3 were enrolled at S-1 dose level 2. No dose-limiting toxicities were observed in these subjects. The RD was decided as erlotinib 150 mg/body and S-1 80 mg/m. In phase I, 5 subjects achieved partial response, and the ORR was 71.4%. A total of 10 patients with PS 0, 1, or 2 EGFR-wild type NSCLC were enrolled in phase II. In phase II, the ORR was 10.0%, and the disease control rate (DCR) was 40.0%. After the enrollment of 10 subjects, enrollment was stopped based on two treatment-related deaths. Conclusion The combination therapy of erlotinib plus S-1 was not feasible in the EGFR wild-type NSCLC at least and early stopped. Trial registration: UMIN-CTR Identifier: 000003421 (2010/03/31, phase I), 000003422 (2010/03/31, Phase II).
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http://dx.doi.org/10.1007/s10637-020-00985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851018PMC
February 2021

Open-label, multicenter, randomized phase II study on docetaxel plus bevacizumab or pemetrexed plus bevacizumab for treatment of elderly (aged ≥75 years) patients with previously untreated advanced non-squamous non-small cell lung cancer: TORG1323.

Transl Lung Cancer Res 2020 Jun;9(3):459-470

Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan.

Background: The effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored.

Methods: Untreated patients (≥75 years; performance status 0-1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor () mutation or anaplastic lymphoma kinase () gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m) (DB) or pemetrexed (500 mg/m) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity.

Results: Overall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75-88] and 79 [75-94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66-1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% . 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm.

Conclusions: In previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).
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http://dx.doi.org/10.21037/tlcr.2020.03.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354128PMC
June 2020

Phase I/II study of carboplatin plus weekly nab-paclitaxel in patients aged ≥75 years with squamous-cell lung cancer: TORG1322.

Lung Cancer 2020 08 19;146:182-188. Epub 2020 May 19.

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

Objectives: This phase I/II study assessed the efficacy and safety of combination therapy with carboplatin (CBDCA) and nab-paclitaxel (nab-PTX) in advanced elderly patients (aged ≥75 years) with advanced squamous cell lung cancer (SqCLC).

Materials And Methods: In this phase I study, the doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL/min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m) on days 1, 8, and 15 every 4 weeks for up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6 m PFS) rate.

Results: A total of 46 patients were enrolled in this study. Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia; at dose level 2, 1/3 patient exhibited grade 3 anorexia as a DLT. The recommended dose was determined to be level 2. Efficacy was then evaluated in 39 patients enrolled in a phase II study. The median number of cycles was 4 (range, 1-6), and the median follow-up time was 17.5 months (range, 5.6-28.9 months). The 6 m PFS rate was 59.4% (90% confidence interval [CI], 44.8%-71.4%), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6-35.4), and the median PFS was 6.8 months (95% CI, 5.4-9.1). The response rate was 54%, and the disease control rate was 92%. Sixteen patients (41%) received immune checkpoint inhibitors post-study. Common grade 3 or 4 toxicities were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%).

Conclusion: Combination chemotherapy consisting of CBDCA with weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly patients (aged ≥75 years) with advanced SqCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.005DOI Listing
August 2020

Importance and Difficulty of Differentiating BMA-induced AFF Prodromal Symptoms from Hormonal Therapy-related Femoral Pain.

Intern Med 2020 Mar 22;59(6):855-857. Epub 2019 Nov 22.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Japan.

We herein report a case of breast cancer in a 74-year-old woman treated with exemestane as fourth-line hormonal therapy and bone-modifying agents for long time. She suddenly developed a right femoral shaft fracture during treatment. Her femoral fracture had a beaking sign on radiogram. Given this finding, her fracture was ultimately diagnosed as atypical femoral fracture (AFF). In this case, it was difficult to recognize the difference between groin pain as a prodromal symptom of AFF and that due to an adverse reaction to hormonal therapy. Therefore, clinicians should recognize the difficulty of this differentiation and consider the situation with caution.
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http://dx.doi.org/10.2169/internalmedicine.3157-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118384PMC
March 2020

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Mol Clin Oncol 2019 Oct 23;11(4):349-353. Epub 2019 Jul 23.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa 240-8555, Japan.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20-30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92-133 days], and the median number of ZA administrations was 4 (range, 2-41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156-264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.
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http://dx.doi.org/10.3892/mco.2019.1903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713944PMC
October 2019

Promising Combination Therapy with Bevacizumab and Erlotinib in an EGFR-Mutated NSCLC Patient with MET Amplification Who Showed Intrinsic Resistance to Initial EGFR-TKI Therapy.

Case Rep Oncol 2019 Jan-Apr;12(1):91-97. Epub 2019 Jan 21.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

In lung cancer, several potential mechanisms of intrinsic and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been explored, including mesenchymal-epithelial transition factor (MET) signaling pathway activation. On the other hand, vascular endothelial growth factor (VEGF) production of EGFR-mutated lung cancer cells is stimulated by predominantly activated MET signaling pathway. Therefore, the inhibition of VEGF axis as the downstream target of MET signaling pathway seems promising. Here, for the first time, we report the potential efficacy of combination therapy with bevacizumab and erlotinib in an EGFR-mutated NSCLC patient with MET amplification who showed intrinsic resistance to initial EGFR-TKI therapy. The patient was a 60-year-old male smoker, showing performance status (PS) 2, who presented with stage IV lung adenocarcinoma (cT4N2M1a) harboring the EGFR exon 19 deletion mutation. He was started on gefitinib at 250 mg/day. However, by 28 days, his symptoms further deteriorated along with the increased tumor size, resulting in PS 3. Then, repeat biopsy was performed, showing the positive MET amplification and the preserved EGFR exon 19 deletion mutation. Therefore, on the basis of the potential efficacy for activated MET signaling pathway as well as the confirmed safety by the known phase II trial for EGFR-mutated patients, the patient was started on combination therapy with bevacizumab at 15 mg/kg every 3 weeks plus erlotinib at 150 mg/day. By 21 days, his symptoms gradually improved along with the decreased tumor size, resulting in better PS with no severe toxicities.
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http://dx.doi.org/10.1159/000493088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381877PMC
January 2019

Need for Flexible Adjustment of the Treatment Schedule for Aprepitant Administration against Erlotinib-Induced Refractory Pruritus and Skin Rush.

Case Rep Oncol 2019 Jan-Apr;12(1):84-90. Epub 2019 Jan 21.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Common dermatological side-effects associated with erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), include pruritus and skin rash, which are mediated by substance P, leading to the occasional discontinuation of cancer treatment. Aprepitant is an antagonist of neurokinin-1 receptor, through which substance P activates the pruritogens. Thus, aprepitant is expected to offer a promising option for the treatment of erlotinib-induced pruritus. However, the appropriate treatment schedule for aprepitant administration is under consideration. Here, we discuss the need for flexible adjustment of the treatment schedule for aprepitant administration against erlotinib-induced refractory pruritus and skin rush. A 71-year-old female smoker presented with stage IV EGFR-mutated lung adenocarcinoma. She was started on erlotinib at 150 mg/day. However, by 28 days, severe pruritus and acneiform skin rush resistant to standard therapies occurred, resulting in the interruption of erlotinib therapy. After recovery, she was restarted on erlotinib at 100 mg/day. However, severe pruritus and skin rush developed again within 2 weeks. Then, we started the first 3-day dose of aprepitant (125 mg on day 1, 80 mg on day 3, and 80 mg on day 5) based on the results of the previous prospective study, which showed the success rate of 100% with at least the second dose of aprepitant. However, the pruritus and skin rush exacerbated again within 4 weeks. Therefore, we started the second 3-day dose of aprepitant, but in vain. At this point, as the patient-centered medicine, bi-weekly schedule of the 3-day dose of aprepitant was considered and, then, adopted. As the results, the pruritus and skin rush remained well-controlled throughout the subsequent treatment with erlotinib.
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http://dx.doi.org/10.1159/000493256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381921PMC
January 2019

Significance of Earlier Initiation of Chemotherapy for Lung Cancer Complicated with Primary or Secondary Nephrotic Syndrome following Its Appropriate Differential Diagnosis.

Case Rep Oncol 2019 Jan-Apr;12(1):53-58. Epub 2019 Jan 11.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

We encountered a case of primary lung cancer complicated with membranous nephropathy as primary nephrotic syndrome. Because treatment approaches vary greatly for primary and secondary nephrotic syndrome, a renal biopsy was performed for diagnosis. Much time was required to make a definitive diagnosis of primary nephrotic syndrome, as opposed to paraneoplastic nephrotic syndrome. Consequently, the subsequent chemotherapy was ineffective and caused significant toxicity due to reduced performance status (PS) and progression of hypoalbuminemia. Therefore, it is imperative that a diagnosis be made and treatment be initiated without delay before PS declines and hypoalbuminemia progresses.
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http://dx.doi.org/10.1159/000493851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381920PMC
January 2019

Successful Treatment with Taxane-Based Chemotherapy in Advanced Sebaceous Carcinoma: A Case Report and Literature Review.

Case Rep Oncol 2019 Jan-Apr;12(1):47-52. Epub 2019 Jan 11.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.
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http://dx.doi.org/10.1159/000493850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381883PMC
January 2019

Benefits of a Nationwide Palliative Care Education Program on Lung Cancer Physicians.

Intern Med 2019 May 1;58(10):1399-1403. Epub 2019 Feb 1.

Division of Pulmonary Medicine, Department of Internal Medicine, Jichi Medical University, Japan.

Objective The early integration of palliative care into standard cancer treatment has become a global standard. The Palliative care Emphasis program on symptom management and Assessment for Continuous medical Education (PEACE) has been conducted in Japan, and previous studies have reported that the PEACE workshop was able to improve various palliative care skills of participants. However, whether or not the effects of the program are long-lasting and if the program consequently changed physicians' practice with regard to lung cancer patients have been unclear. Methods Web-based surveys, including the palliative care knowledge test (PEACE-Q), the Palliative Care self-reported Practice Scale (PCPS), and the Palliative Care Difficulties Scale (PCDS), were conducted among lung cancer physicians in Japan. The differences in the survey results between participants and non-participants of the PEACE workshop were examined. Results Among 923 respondents (455 respiratory physicians, 345 pulmonary surgeons, and 123 others), 519 had participated in the PEACE workshop. The total PEACE-Q score was significantly higher in the PEACE workshop participants than in non-participants (28.0 versus 24.5, p<0.0001). The score was significantly higher in respiratory physicians than in pulmonary surgeons (27.4 versus 25.5). The total PCPS and PCDS scores were also significantly better in workshop participants than in non-participants (71.8 versus 67.1 and 34.3 versus 36.9, respectively), although some domains of PCDS were similar between the groups. Conclusion The PEACE program improved the knowledge and practices with regard to palliative care and resolved difficulties associated therewith among lung cancer physicians. In regions where palliative care specialists are insufficient, such educational programs may be effective.
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http://dx.doi.org/10.2169/internalmedicine.0872-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548920PMC
May 2019

Effect of preoperative pregabalin in video-assisted thoracoscopic surgery.

J Thorac Dis 2018 Nov;10(Suppl 33):S4028-S4030

Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.21037/jtd.2018.09.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297520PMC
November 2018

Economic analysis of palonosetron versus granisetron in the standard triplet regimen for preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy in Japan (TRIPLE phase III trial).

J Pharm Health Care Sci 2018 10;4:31. Epub 2018 Dec 10.

1Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan.

Background: We conducted an economic assessment using test data from the phase III TRIPLE study, which examined the efficacy of a 5-hydroxytryptamine 3 receptor antagonist as part of a standard triplet antiemetic regimen including aprepitant and dexamethasone in preventing chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy (HEC).

Methods: We retrospectively investigated all medicines prescribed for antiemetic purposes within 120 h after the initiation of cisplatin administration during hospitalization. In the TRIPLE study, patients were assigned to treatment with granisetron (GRA) 1 mg ( = 413) or palonosetron (PALO) 0.75 mg ( = 414). The evaluation measure was the cost-effectiveness ratio (CER) assessed as the cost per complete response (CR; no vomiting/retching and no rescue medication). The analysis was conducted from the public healthcare payer's perspective.

Results: The CR rates were 59.1% in the GRA group and 65.7% in the PALO group ( = 0.0539), and the total frequencies of rescue medication use for these groups were 717 (153/413 patients) and 573 (123/414 patients), respectively. In both groups, drugs with antidopaminergic effects were chosen as rescue medication in 86% of patients. The costs of including GRA and PALO in the standard triplet antiemetic regimen were 15,342.8 and 27,863.8 Japanese yen (JPY), respectively. In addition, the total costs of rescue medication use were 73,883.8 (range, 71,106.4-79,017.1) JPY for the GRA group and 59,292.7 (range, 57,707.5-60,972.8) JPY for the PALO group. The CERs (JPY/CR) were 26,263.4 and 42,628.6 for the GRA and PALO groups, respectively, and the incremental cost-effectiveness ratio (ICER) between the groups was 189,171.6 (189,044.8-189,215.5) JPY/CR.

Conclusions: We found that PALO was more expensive than GRA in patients who received a cisplatin-based HEC regimen.
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http://dx.doi.org/10.1186/s40780-018-0128-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287343PMC
December 2018

Prospective exosome-focused translational research for afatinib study of non-small cell lung cancer patients expressing EGFR (EXTRA study).

Thorac Cancer 2019 02 8;10(2):395-400. Epub 2018 Dec 8.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) exhibit resistance to EGFR-tyrosine kinase inhibitors (TKIs) within 9-14 months of therapy. Recently, EGFR-mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression-free and overall survival and other parameters affecting EGFR-TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome-focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four "OMICs" (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib. This study aims to: (i) conduct comprehensive multi-OMIC analyses in a prospective clinical trial, and (ii) focus on both sera/plasma and exosome as a source for OMIC analyses to identify a novel predictor of the efficacy of a specific drug. To eliminate the carryover bias of prior treatment, systemic treatment-naïve patients were enrolled. The candidates to be screened for biomarkers comprise a discovery cohort of 60 patients and an independent validation cohort of 40 patients. The EXTRA study is the first trial to screen novel biomarkers of longer treatment efficacy of EGFR-TKIs using four-OMICs analyses, focusing on both "naked or free" molecules and "capsulated" exosomal components in serially collected peripheral blood.
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http://dx.doi.org/10.1111/1759-7714.12923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360199PMC
February 2019

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

Oncologist 2019 03 13;24(3):327-337. Epub 2018 Nov 13.

Department of Biostatistics, Yokohama City University School of Medicine, Japan.

Background: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC.

Materials And Methods: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG).

Results: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, = .134 for RR; interaction test, = .102 for PFS and = .003 for OS) and 8q24.2 (Fisher's exact test, = .179 for RR; interaction test, = .144 for PFS and = .002 for OS).

Conclusion: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC.

Implications For Practice: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.
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http://dx.doi.org/10.1634/theoncologist.2018-0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519767PMC
March 2019

Risk factors associated with chemotherapy-induced nausea and vomiting in the triplet antiemetic regimen including palonosetron or granisetron for cisplatin-based chemotherapy: analysis of a randomized, double-blind controlled trial.

Support Care Cancer 2019 Mar 10;27(3):1139-1147. Epub 2018 Aug 10.

Department of Clinical Pharmacology & Genetics, University of Shizuoka, 52-1, Yada, Surugaku, Shizuoka, 422-8526, Japan.

Purpose: The triplet antiemetic regimen is recommended for cisplatin-based highly emetogenic chemotherapy, in the current guidelines for antiemetic prophylaxis. Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by several prior studies, there are only few studies evaluating risk factors associated with the prophylactic triplet antiemetic therapy, particularly in palonosetron use. The present study aimed to reveal the risk factors related to CINV development in patients receiving cisplatin and to compare CINV risk factors between palonosetron and granisetron use.

Methods: In total, 825 patients in a phase III trial receiving palonosetron with graniestron were evaluated. Multivariate logistic regression models were used to predict risk factors associated with CINV development. Additionally, risk factors associated with CINV development were separately evaluated in each treatment group.

Results: Multivariate analysis of the entire study group revealed that sex, age, cisplatin dose, and granisetron use were significant and independent factors affecting CINV development in the overall phase. Similarly, sex and age were risk factors for CINV in both treatment groups. Kaplan-Meier curves classified by each treatment group showed no significant difference between the groups among patients without any risk factors for CINV (P = 0.353). Conversely, complete response rates for patients with at least one risk factor were higher in patients receiving palonosetron (P = 0.049).

Conclusions: This analysis revealed the importance of previously reported CINV risk factors when using triplet antiemetics. Palonosetron might be preferred for patients with at least one risk factor.
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http://dx.doi.org/10.1007/s00520-018-4403-yDOI Listing
March 2019

Postoperative empyema following lung cancer surgery.

Oncotarget 2018 Jul 3;9(51):29810-29819. Epub 2018 Jul 3.

Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.

Postoperative empyema following lung cancer surgery is a serious complication. Occurrence rate of postoperative empyema following lung cancer surgery, patient background, surgical procedures, date of empyema onset, treatment, and prognosis of 4772 patients who underwent lung cancer surgery between 2008 and 2012 were investigated. Postoperative empyema following lung cancer surgery was found in 43 patients (0.9%). The occurrence rate of postoperative empyema was significantly higher in patients with the following factors: male gender, extended surgery such as pneumonectomy, bi-lobectomy and thoracotomy, squamous cell carcinoma, and an advanced pathologic stage of II and above. Chest drainage, video-assisted thoracic surgery debridement, fenestration, and thoracoplasy were performed, where 29 patients were cured (67.5%) and 5 patients (11.6%) died from thoracic empyema-related complications. Nine patients were not cured and died due to cancer or other diseases during treatment. When comparing cured and non-cured patients, it is indicated that squamous cell carcinoma, administration of steroids, history of interstitial pneumonia, presence of bronchial stump fistula, exacerbation of interstitial pneumonia and presence of non-fermenting Gram-negative bacilli led to a significantly low prognosis. The five-year overall survival rate was 34.9%.
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http://dx.doi.org/10.18632/oncotarget.25629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049863PMC
July 2018

Factors Influencing Cancer Patients' Choice of End-of-Life Care Place.

J Palliat Med 2018 06 22;21(6):751-765. Epub 2018 Mar 22.

1 Department of Medicine, Teikyo University School of Medicine , Tokyo, Japan .

Background: It is important for cancer patients to receive end-of-life care at the desired place.

Objective: To identify issues in selection of place for end-of-life care of cancer patients to realize their optimal survivorship.

Design And Setting: Between September 2015 and January 2016, a questionnaire consisting of 33 items, including end-of-life care place preferences, was administered to cancer patients who attended three university hospitals in Japan.

Results: A total of 971 questionnaires were collected (response rate, 88.4%). Fifty-eight percent of patients preferred to stay at home to receive end-of-life care. In contrast, more than 80% of patients did not know the details of healthcare services. The factors significantly associated with patients' choice for place of end-of-life care at home were "male gender" (odds ratio [OR] = 1.43, p = 0.030), "living in a one-person household" (OR = 0.21, p < 0.001), "feeling close to friends" (OR = 0.94, p = 0.049), "thinking that the family is burdened" (OR = 0.55, p < 0.001), "thinking that pain is controllable at home" (OR = 1.39, p < 0.001), and "thinking that society should establish a system of home palliative care" (OR = 1.93, p < 0.001).

Conclusions: This study identified six factors influencing the selection of a place for end-of-life care. Most patients have a desire for a social system that allows end-of-life care at home where they can live with their family, but have anxiety about treatment to deal with symptom change, with concern about burden on their family. These issues should be addressed in the future.
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http://dx.doi.org/10.1089/jpm.2017.0481DOI Listing
June 2018

A Patient with Advanced Gastric Cancer Who Achieved a Long-Term Prognosis by Early Diagnosis of Sister Mary Joseph's Nodule.

Case Rep Oncol 2018 Jan-Apr;11(1):11-16. Epub 2018 Jan 4.

aDivision of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

The patient was a 66-year-old woman. An induration of approximately 15 mm in size that accompanied redness was palpable in the umbilical fossa. She did not respond to 1-month antibiotic treatment provided by the previous physician. For this reason, a biopsy of the site was performed with the possibility of neoplastic disease in mind, resulting in the detection of adenocarcinoma. Subsequent detailed whole-body examination revealed advanced gastric cancer and peritoneal dissemination, and the induration in the umbilical fossa was diagnosed as a direct infiltration from the peritoneal dissemination. Metastasis or infiltration of malignant tumor to the umbilicus is called Sister Mary Joseph's nodule (SMJN), and considered as a sign of poor prognosis. However, this case was successfully treated and achieved a long-term prognosis by the early diagnosis of SMJN. In routine clinical practice, it is considered necessary to examine patients carefully, as not to overlook SMJN.
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http://dx.doi.org/10.1159/000484976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836228PMC
January 2018

A Case of Lung Adenocarcinoma with Marked Improvement of Pulmonary Lymphangitic Carcinomatosis by Adding Bevacizumab to Cisplatin and Pemetrexed.

Case Rep Oncol 2017 Sep-Dec;10(3):1065-1069. Epub 2017 Nov 27.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

A 40-year-old man with a diagnosis of lung adenocarcinoma (cT4N3M1c, stage IVB) experienced worsening of lymphangitic carcinomatosis in the right lung and right pleural effusion after receiving 1 cycle of first-line chemotherapy consisting of cisplatin and pemetrexed. Bevacizumab was thus added from the second cycle of the cisplatin-pemetrexed regimen, leading to a marked improvement in pulmonary lymphangitic carcinomatosis and a decrease in pleural effusion. Subsequently, maintenance therapy consisting of pemetrexed and bevacizumab was continued, successfully leading to long-term progression-free survival. Generally, pulmonary lymphangitic carcinomatosis shows poor prognosis because of poor response to chemotherapy. However, recent studies have been elucidating the role of the vascular endothelial growth factor A (VEGF-A)/VEGF receptor-2 pathway in pulmonary lymphangitic carcinomatosis. Therefore, bevacizumab is expected to be beneficial in the treatment of this pathological condition.
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http://dx.doi.org/10.1159/000484662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836232PMC
November 2017

A Case of Paraneoplastic Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Improved by Chemotherapy.

Case Rep Oncol 2017 Sep-Dec;10(3):1131-1137. Epub 2017 Dec 20.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

The patient was a 69-year-old male who had started experiencing acute-onset pain in both shoulder joints and edema of both hands and feet. His symptoms progressively worsened within 1 month. Laboratory data indicated elevated CRP and erythrocyte sedimentation rate despite the normal range of antinuclear antibodies and rheumatoid factor and normal organ function. Furthermore, imaging data of the hand indicated synovitis without bone erosions. Meanwhile, chest CT revealed a lung tumor, leading to a diagnosis of primary lung adenocarcinoma with EGFR mutation (cT2aN3M0, stage IIIB). Based on these findings, he was diagnosed as suffering from paraneoplastic remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Thereafter, his symptoms disappeared as the tumor size was rapidly decreased by gefitinib therapy for lung adenocarcinoma. Currently, RS3PE syndrome can be classified as a vascular endothelial growth factor (VEGF)-associated disorder. Given that his symptoms improved by chemotherapy, the present case further supported the possible hypothesis that paraneoplastic RS3PE syndrome might be caused by tumor-induced VEGF. Therefore, the present case suggested that the symptoms of acute-onset joint pain accompanied by pitting edema in elderly patients should be considered suspicious for a malignant tumor, thereby warranting a detailed full-body examination.
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http://dx.doi.org/10.1159/000484977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803715PMC
December 2017

A Case of Advanced Submandibular Gland Cancer in Which Increased Prostate-Specific Antigen and Multiple Bone Metastases Wrongly Suggested Concurrent Prostate Cancer.

Case Rep Oncol 2017 Sep-Dec;10(3):1127-1130. Epub 2017 Dec 20.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

A 73-year-old man, followed for prostatic hyperplasia, developed submandibular gland cancer. Initially, because of the concurrent presence of elevated serum prostate-specific antigen (PSA) and multiple bone metastases, he was clinically determined as having stage IV prostate cancer in addition to stage II submandibular gland cancer, and radical surgery for his submandibular gland cancer was performed first. However, subsequent detailed examinations of the prostate gland showed no prostate cancer, and a diagnosis of advanced submandibular gland cancer with increased PSA and multiple bone metastases was established. Serum PSA is highly specific for prostate diseases and is widely used as a tumor marker of prostate cancer. However, clinicians should be aware that, in patients with non-prostate cancer, the detection of increased PSA and multiple bone metastases does not necessarily indicate the concurrent presence of prostate cancer.
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http://dx.doi.org/10.1159/000484975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803733PMC
December 2017

Paraneoplastic IgA Vasculitis in an Adult with Lung Adenocarcinoma.

Intern Med 2018 May 27;57(9):1273-1276. Epub 2017 Dec 27.

Division of Medical Oncology, Teikyo University School of Medicine, Japan.

A 50-year-old man with lung adenocarcinoma (c-T1aN2M1b) experienced reddish purpura mainly on the lower legs after receiving 12 cycles of second-line chemotherapy with docetaxel. There was tumor enlargement on computed tomography performed to assess the therapeutic response, so paraneoplastic IgA vasculitis was considered. IgA vasculitis was diagnosed based on a biopsy of the skin lesion and histology of an upper gastrointestinal hemorrhagic mucosal erosion. As IgA vasculitis can lead to serious gastrointestinal or systemic complications, IgA vasculitis should be considered as a differential diagnosis for rashes in patients with malignancy.
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http://dx.doi.org/10.2169/internalmedicine.9651-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980809PMC
May 2018

Nivolumab-Induced Myocarditis Concomitant with Myasthenia Gravis.

Case Rep Oncol 2017 Sep-Dec;10(3):809-812. Epub 2017 Sep 6.

Department of Medical Oncology, Teikyo University School of Medicine, Tokyo, Japan.

We report a 69-year-old female patient with advanced lung cancer who developed myocarditis concomitant with myasthenia gravis (MG), also known as "Herzmyasthenie," after 3 cycles of nivolumab administration. Her initial symptoms were general malaise and double vision. However, her myocarditis deteriorated rapidly the following day, necessitating a temporary pacemaker and noninvasive positive pressure ventilation in the intensive care unit. Immunohistochemical examination of a myocardial biopsy suggested an immune response on the basis of associations. The patient also developed impaired adduction of her left eye and elevated serum levels of acetylcholine receptor antibody, suggesting the onset of MG. Her condition gradually improved after immediate methylprednisolone pulse therapy. This case of nivolumab-induced "Herzmyasthenie" highlights the need to be aware that fulminant myocarditis might occur at the same time as MG during treatment with anti-programmed cell death-1 monoclonal antibodies.
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http://dx.doi.org/10.1159/000479958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649238PMC
September 2017

A Symptomatic Case of Adenomatous Ductal Proliferation/Hyperplasia with a Large Cystic Lesion.

Case Rep Oncol 2017 May-Aug;10(2):676-682. Epub 2017 Jul 27.

Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Adenomatous ductal proliferation/hyperplasia (ADP/H) of the salivary gland, a rare asymptomatic nonneoplastic lesion that histopathologically resembles basal cell adenoma, is typically incidentally identified in resected specimens of other salivary diseases such as tumors and chronic sialadenitis. A 70-year-old male was referred to our hospital with a 9-month history of continuous swelling in the left parotid region. A physical examination revealed a soft mass in the left parotid gland, which was identified as a cystic mass by computed tomography. A parotid tumor with cystic components was suspected, and partial parotidectomy was performed under general anesthesia. The histopathological findings were consistent with the diagnosis of ADP/H of the salivary gland. This case report emphasizes the necessity for a proper diagnosis of ADP/H of the salivary gland. Further large case series are required for a modification of the definition of ADP/H for its correct diagnosis.
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http://dx.doi.org/10.1159/000478997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582527PMC
July 2017

Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.

Neurology 2017 Sep 18;89(11):1127-1134. Epub 2017 Aug 18.

From the Department of Neurology (S.S., N. Suzuki), Keio University School of Medicine, Tokyo; Department of Respiratory Medicine (N.I.), Hiroshima Prefectural Hospital, Hiroshima; Department of Neurology (F.K.), Saiseikai Central Hospital, Tokyo; Division of Medical Oncology (N. Seki), Teikyo University School of Medicine, Tokyo; Department of Dermatology and Plastic Surgery (S.F.), Faculty of Life Sciences, Kumamoto University, Kumamoto; Department of Plastic and Reconstructive Surgery (K.T.), Hakodate Central General Hospital, Hokkaido; Department of Dermatology (H.U.), Sapporo Medical University School of Medicine, Hokkaido; Department of Medical Oncology (Y.H.), Izumi Municipal Hospital, Osaka; Department of Respiratory Medicine (S.I.), Sapporo Kosei Hospital, Hokkaido; Department of Oncology (Y.O.), Toyonaka Municipal Hospital, Osaka; Department of Dermatology (K.Y.), Nagoya University Graduate School of Medicine, Aichi; Department of Respiratory Medicine and Oncology (T.H.), Nippon Medical School Tama Nagayama Hospital, Tokyo; Department of Dermatology (R.T.), Kawasaki Medical School, Okayama; and Department of Neurology (M.M.), Kanazawa Medical College, Ishikawa, Japan.

Objective: To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan.

Methods: We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used.

Results: There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti-acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity.

Conclusions: The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.
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http://dx.doi.org/10.1212/WNL.0000000000004359DOI Listing
September 2017