Publications by authors named "Koji Inoue"

176 Publications

Impact of health-related quality of life on repeat protocol biopsy compliance on active surveillance for favorable prostate cancer: results from a prospective cohort in the PRIAS-JAPAN study.

Urol Oncol 2021 Jun 8. Epub 2021 Jun 8.

Department of Urology, Faculty of Medicine, Kagawa University, Kagawa, Japan.

Objectives: This study aimed to evaluate how health-related quality of life (HRQOL) is related to repeat protocol biopsy compliance.

Materials And Methods: We conducted a retrospective analysis using data from a prospective cohort in the Prostate Cancer Research International: Active Surveillance (PRIAS)-JAPAN study between January 2010 and August 2019. We used the Short Form 8 Health Survey (SF-8), as patient-reported outcomes, to assess HRQOL at AS enrollment and the first year of the protocol. The physical component summary (PCS) and mental component summary (MCS) were calculated from SF-8 questionnaires. The primary outcome was the evaluation of the association of HRQOL at enrollment on the first repeat biopsy compliance. The secondary outcome was the comparison of SF-8 scores during AS, stratified by repeat protocol biopsy compliance.

Results: Of 805 patients who proceeded to the first year of the protocol, the non-compliance rate was 15% (121 patients). In the adjusted model, lower MCS at enrollment was significantly associated with the first repeat protocol biopsy non-compliance (odds ratio [OR], 2.134; 95% confidence interval [CI], 1.031-4.42; P = 0.041) but not in lower PCS (OR, 0.667; 95% CI, 0.294-1.514; P = 0.333). All subscales of SF-8 were lower in the non-compliance group than in the compliance group at any point. MCS in the non-compliance group improved over time from the time of AS enrollment (2.34 increased, P = 0.152).

Conclusion: Our data suggest that lower MCS at AS enrollment using patient-reported outcomes was negatively associated with the first repeat protocol biopsy compliance. Our study may support the availability of a simple questionnaire to extract non-compliance.
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http://dx.doi.org/10.1016/j.urolonc.2021.05.003DOI Listing
June 2021

The role of comprehensive analysis with circulating tumor DNA in advanced non-small cell lung cancer patients considered for osimertinib treatment.

Cancer Med 2021 May 12. Epub 2021 May 12.

Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, Japan.

Background: EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified.

Methods: Patients with NSCLC who progressed after treatment with EGFR-TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas ), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next-generation sequencing (NGS) of ctDNA was performed with Guardant360 . Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed.

Results: Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation.

Conclusions: NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M.
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http://dx.doi.org/10.1002/cam4.3929DOI Listing
May 2021

[Risk Factors for Recurrence in Patients with Pathological Lymph Node-Positive Prostate Cancer after Extended Lymph Node Dissection in Laparoscopic and Robotic-Assisted Radical Prostatectomy].

Hinyokika Kiyo 2021 Mar;67(3):83-90

The Department of Urology, Kobe City Medical Center General Hospital.

From April 2007 to April 2018, we performed lymph node dissection in 305 cases of laparoscopic radical prostatectomy and 202 cases of robot-assisted radical prostatectomy at our hospital, and there were 68 cases with positive lymph node metastasis (pN1). Of these 68 cases, we examined retrospectively 62 cases in which extended lymph node dissection (ELND) was performed. The median number of removed lymph nodes was 25 (interquartile range [IQR] ; 18-34) and the median number of metastatic lymph nodes was 1 (IQR ; 1-3). Postoperative prostate-specific antigen (PSA) recurrence was observed in 40 of the 62 patients. The median time to PSA recurrence was 24 months. After univariate analysis, PSA at initial diagnosis (iPSA) of 10 ng/ml or more, pathological Gleason score (pGS) of 8 or more, total number of lymph node metastases of 2 or more, and positive surgical margin (RM+) were found to be riskfactors of PSA recurrence. In multivariate analysis, iPSA of 10 ng/ml or more, pGS of 8 or more and RM+ were independent riskfactors of PSA recurrence (p<0.05). In the cases without riskfactors such as iPSA≥10, pGS≥8, and RM+, immediate postoperative adjuvant therapy may be avoided even with pN1.
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http://dx.doi.org/10.14989/ActaUrolJap_67_3_83DOI Listing
March 2021

Divalent metal transporter-related protein restricts animals to marine habitats.

Commun Biol 2021 Apr 12;4(1):463. Epub 2021 Apr 12.

Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-shi, Chiba, Japan.

Utilization and regulation of metals from seawater by marine organisms are important physiological processes. To better understand metal regulation, we searched the crown-of-thorns starfish genome for the divalent metal transporter (DMT) gene, a membrane protein responsible for uptake of divalent cations. We found two DMT-like sequences. One is an ortholog of vertebrate DMT, but the other is an unknown protein, which we named DMT-related protein (DMTRP). Functional analysis using a yeast expression system demonstrated that DMT transports various metals, like known DMTs, but DMTRP does not. In contrast, DMTRP reduced the intracellular concentration of some metals, especially zinc, suggesting its involvement in negative regulation of metal uptake. Phylogenetic distribution of the DMTRP gene in various metazoans, including sponges, protostomes, and deuterostomes, indicates that it originated early in metazoan evolution. However, the DMTRP gene is only retained in marine species, and its loss seems to have occurred independently in ecdysozoan and vertebrate lineages from which major freshwater and land animals appeared. DMTRP may be an evolutionary and ecological limitation, restricting organisms that possess it to marine habitats, whereas its loss may have allowed other organisms to invade freshwater and terrestrial habitats.
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http://dx.doi.org/10.1038/s42003-021-01984-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041893PMC
April 2021

The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression.

Eur J Cancer 2021 May 7;149:73-81. Epub 2021 Apr 7.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Japan.

Background: Immune checkpoint inhibitors (ICIs) are essential for treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Recently, several studies have shown that the gut microbiome plays an important role in ICI treatment of solid cancers, and antibiotic (ATB) use had a negative impact on the outcomes of ICI treatment via dysbiosis in the gut. However, whether this is applicable to NSCLC remains unclear. The impact of ATBs based on PD-L1 expression also remains unclear.

Methods: We retrospectively reviewed the medical records of patients with NSCLC who received ICI monotherapy (anti-PD-1 or anti-PD-L1 antibody) at nine institutions from December 2015 to May 2018. Outcomes with use of ATBs during the 2 months before or a month after initiation of ICI treatment, including progression-free survival (PFS) and overall survival (OS), were investigated using the Kaplan-Meier method. Multivariate analysis was also conducted using a Cox proportional hazards model.

Results: A total of 531 patients were included in this study, among whom 98 (18.5%) received ATBs before or after ICI treatment. ATB use was significantly associated with a shorter median OS (11.7 months in the ATB group vs. 16.1 months in the non-ATB group; p = 0.028), whereas the difference in PFS was not significant (3.5 months in both the groups; p = 0.287). We next investigated the association based on PD-L1 expression in the 265 patients for whom PD-L1 expression was determined. There was no significant difference in the median OS or PFS between patients with NSCLC and PD-L1 expression <50% receiving ATBs and those not receiving ATBs (PFS: 3.3 vs. 2.8 months, p = 0.88; OS: 9.5 vs. 17.1 months, p = 0.24). Conversely, patients with NSCLC and PD-L1 expression ≥50% receiving ATBs showed significantly shorter median PFS and OS (PFS: 4.2 vs. 9.4 months, p = 0.012; OS: 11.9 vs. 28.4 months, p = 0.011). The impact of ATBs in patients with NSCLC and PD-L1 expression ≥50% was more significant than that in the entire cohort.

Conclusions: Our results indicate that the impact of ATB use on the efficacy of ICIs differed based on PD-L1 expression in patients with advanced NSCLC. A negative impact of ATB use was found in patients with NSCLC and PD-L1 expression ≥50% but not in those with PD-L1 expression <50%.
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http://dx.doi.org/10.1016/j.ejca.2021.02.040DOI Listing
May 2021

Significance of PD-L1 expression in the cytological samples of non-small cell lung cancer patients treated with immune checkpoint inhibitors.

J Cancer Res Clin Oncol 2021 Mar 29. Epub 2021 Mar 29.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, 700-8558, Japan.

Objectives: The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) in tumor tissue samples is an established clinical biomarker for non-small cell lung cancer (NSCLC). However, the significance of PD-L1 expression in other types of samples has not been fully investigated.

Patients And Methods: We conducted a multicenter retrospective cohort study of advanced NSCLC patients who received ICI treatment during the clinical course and investigated the effects of ICIs according to PD-L1 expression in cytology samples, including cell block and endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) samples.

Results: A total of 264 patients were included in this study: PD-L1 expression was determined in cell block or TBNA specimens in 55 patients, and in tissue samples in 209 patients. Among the former patients, the median progression-free survival (PFS) of those with a TPS for PD-L1 ≥ 50% was significantly longer compared to that of those with a TPS < 50% (6.5 vs. 1.9 months, respectively, p = 0.008). When the cutoff value was set at 1%, the median PFS was 4.2 months in patients with a TPS ≥ 1% and 1.5 months in patients with a TPS < 1% (p < 0.001).

Conclusion: PD-L1 expression determined using cytology specimens predicts the efficacy of ICIs.
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http://dx.doi.org/10.1007/s00432-021-03615-5DOI Listing
March 2021

Possible Roles of Hypotaurine and Thiotaurine in the Vesicomyid Clam .

Biol Bull 2021 02 9;240(1):34-40. Epub 2021 Feb 9.

AbstractVesicomyid clams, which inhabit deep-sea hydrothermal vents and hydrocarbon seeps, are nutritionally dependent on symbiotic, chemoautotrophic bacteria that produce organic matter by using hydrogen sulfide. Vesicomyid clams absorb hydrogen sulfide from the foot and transport it in their hemolymph to symbionts in the gill. However, mechanisms to cope with hydrogen sulfide toxicity are not fully understood. Previous studies on vent-specific invertebrates, including bathymodiolin mussels, suggest that hypotaurine, a precursor of taurine, mitigates hydrogen sulfide toxicity by binding it to bisulfide ion, so as to synthesize thiotaurine. In this study, we cloned cDNAs from the vesicomyid clam for the taurine transporter that transports hypotaurine into cells and for cysteine dioxygenase and cysteine-sulfinate decarboxylase, major enzymes involved in hypotaurine synthesis. Results of reverse-transcription polymerase chain reaction indicate that mRNAs of these three genes are most abundant in the foot, followed by the gill. However, hypotaurine and thiotaurine levels, measured by reverse-phase high-performance liquid chromatography, were low in the foot and high in the gill. In addition, thiotaurine was detected in hemolymph cells. Hypotaurine synthesized in the foot may be transported to the gill after binding to bisulfide ion, possibly by hemolymph cells.
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http://dx.doi.org/10.1086/712396DOI Listing
February 2021

Genomics and Transcriptomics of the green mussel explain the durability of its byssus.

Sci Rep 2021 Mar 16;11(1):5992. Epub 2021 Mar 16.

Department of Biological Information, Tokyo Institute of Technology, Meguro, Tokyo, 152-8550, Japan.

Mussels, which occupy important positions in marine ecosystems, attach tightly to underwater substrates using a proteinaceous holdfast known as the byssus, which is tough, durable, and resistant to enzymatic degradation. Although various byssal proteins have been identified, the mechanisms by which it achieves such durability are unknown. Here we report comprehensive identification of genes involved in byssus formation through whole-genome and foot-specific transcriptomic analyses of the green mussel, Perna viridis. Interestingly, proteins encoded by highly expressed genes include proteinase inhibitors and defense proteins, including lysozyme and lectins, in addition to structural proteins and protein modification enzymes that probably catalyze polymerization and insolubilization. This assemblage of structural and protective molecules constitutes a multi-pronged strategy to render the byssus highly resistant to environmental insults.
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http://dx.doi.org/10.1038/s41598-021-84948-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971044PMC
March 2021

Clinical impact of probiotics on the efficacy of anti-PD-1 monotherapy in patients with nonsmall cell lung cancer: A multicenter retrospective survival analysis study with inverse probability of treatment weighting.

Int J Cancer 2021 Jul 26;149(2):473-482. Epub 2021 Mar 26.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan.

The gastrointestinal microbiota was reported as an important factor for the response to cancer immunotherapy. Probiotics associated with gastrointestinal dysbiosis and bacterial richness may affect the efficacy of cancer immunotherapy drugs. However, the clinical impact of probiotics on the efficacy of cancer immunotherapy in patients with nonsmall cell lung cancer (NSCLC) is poorly understood. The outcomes of 294 patients with advanced or recurrent NSCLC who received antiprogrammed cell death-1 (PD-1) therapy (nivolumab or pembrolizumab monotherapy) at three medical centers in Japan were analyzed in our study. We used inverse probability of treatment weighting (IPTW) to minimize the bias arising from the patients' backgrounds. The IPTW-adjusted Kaplan-Meier curves showed that progression-free survival (nonuse vs use: hazard ratio [HR] [95% confidence interval {CI}] = 1.73 [1.42-2.11], log-rank test P = .0229), but not overall survival (nonuse vs use: HR [95%CI] = 1.40 [1.13-1.74], log-rank test P = .1835), was significantly longer in patients who received probiotics. Moreover, the IPTW-adjusted univariate analyses showed that nonuse or use of probiotics was significantly associated with disease control (nonuse vs use: odds ratio [OR] [95%CI] = 0.51 [0.35-0.74], P = .0004) and overall response (nonuse vs use: OR [95%CI] = 0.43 [0.29-0.63], P < .0001). In this multicenter and retrospective study, probiotics use was associated with favorable clinical outcomes in patients with advanced or recurrent NSCLC who received anti-PD-1 monotherapy. The findings should be validated in a future prospective study.
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http://dx.doi.org/10.1002/ijc.33557DOI Listing
July 2021

Correlative atom probe tomography and scanning transmission electron microscopy reveal growth sequence of LPSO phase in Mg alloy containing Al and Gd.

Sci Rep 2021 Feb 4;11(1):3073. Epub 2021 Feb 4.

Department of Materials Science and Engineering, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan.

Atom probe tomography (APT) and transmission electron microscopy (TEM)/scanning transmission electron microscopy (STEM) have been used correlatively to explore atomic-scale local structure and chemistry of the exactly same area in the vicinity of growth front of a long-period stacking ordered (LPSO) phase in a ternary Mg-Al-Gd alloy. It is proved for the first time that enrichment of Gd atoms in four consecutive (0001) atomic layers precedes enrichment of Al atoms so that the formation of AlGd clusters occurs only after sufficient Al atoms to form AlGd clusters diffuse into the relevant portions. Lateral growth of the LPSO phase is found to occur by 'ledge' mechanism with the growth habit plane either {1[Formula: see text]00} or {11[Formula: see text]0} planes. The motion of ledges that give rise to lateral growth of the LPSO phase is considered to be controlled by diffusion of Al atoms.
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http://dx.doi.org/10.1038/s41598-021-82705-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862433PMC
February 2021

Protocol for a multi-site, cluster-randomized, phase III, comparative clinical trial of geriatric assessment of older patients with non-small-cell lung cancer: the ENSURE-GA study.

BMC Geriatr 2021 01 22;21(1):74. Epub 2021 Jan 22.

Department of Internal Medicine, Division of Medical Oncology & Respiratory Medicine, Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501, Izumo, Shimane, Japan.

Background: In Japan, approximately half of all lung cancer patients are aged > 75 years, and the proportion of older patients is increasing. In older patients, it is necessary to consider comorbidities and concomitant drug use to ensure optimal cancer treatment; however, geriatric assessment (GA) is not widely performed. We plan to conduct a study (ENSURE-GA) of GA in older lung cancer patients to determine whether GA with intervention improves patient satisfaction with their treatment.

Methods: The study will be a phase III comparative clinical trial with a cluster-randomized design, and it will be conducted at 81 sites distributed throughout Japan. Approximately 1000 lung cancer patients aged ≥ 75 years will be enrolled in the study. All participants will undergo a standardized GA before starting treatment (using an iPad). At the intervention sites, the GA results and intervention method recommended on the basis of the GA results will be returned as an instant report to guide the physician's choice of intervention. At the control sites, the physician will decide on interventions based on standard practice. All participants will complete a patient satisfaction survey before treatment initiation (after the GA) and 3 months later.

Discussion: The purpose of the ENSURE-GA study is to evaluate whether GA with interventions improves patient satisfaction with treatment outcomes. The study may lead to the increased use of GA and improved treatment of cancer in older adults. The results will also be used to prepare guidelines for treating older cancer patients and will provide a foundation for the development of a standardized geriatric oncology system.

Trial Registration: The study has been registered in the University Hospital Medical Information Network database (no. UMIN000037590). The registration date is August 4, 2019, and the protocol version is 2.0. ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000042853 .).
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http://dx.doi.org/10.1186/s12877-021-02028-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821507PMC
January 2021

[Simple Methods to Prevent Postoperative Inguinal Hernia after Extraperitoneal and Transperitoneal Robot-Assisted Radical Prostatectomy].

Hinyokika Kiyo 2020 Oct;66(10):331-335

The Department of Urology, Kobe City Medical Center General Hospital.

Herein we present simple methods to prevent postoperative inguinal hernia (IH) after extraperitoneal and transperitoneal robot-assisted radical prostatectomy (RARP). Among 275 patients who underwent RARP between January 2014 and December 2016 at our institution, we evaluated 143 and 115 patients who underwent extraperitoneal-RARP (e-RARP) and transperitoneal-RARP (t-RARP), respectively, after excluding those with intraoperative detection of IH (17 patients). In the e-RARP group, all 143 patients (286 groins) underwent an IH prevention procedure. In the t-RARP group, the first 22 patients (44 groins) did not undergo an IH prevention procedure, whereas 29 patients (37 groins) with patent processus vaginalis (PPV) among the last 93 patients underwent the procedure. The IH prevention procedure during e-RARP included release of the vas deferens from the peritoneum and spermatic cord, and peritoneal dissection of the spermatic cord at the internal inguinal ring. The IH prevention procedure during t-RARP included release of the vas deferens from the peritoneum and spermatic cord, complete circumferential dissection of the peritoneum around the PPV at the level of the internal inguinal ring, and ligation of the PPV with a Hem-o- Loc○R clip. In the e-RARP group, postoperative IH occurred in 3 of the 143 patients (1.9%) during the follow-up period of 22.0±9.2 months. In the first subgroup of t-RARP, postoperative IH developed in 4 of the 22 patients (18%) during the follow-up period of 33.1±12.1 months, whereas in the last t-RARP group, postoperative IH developed in 3 of the 93 patients (3.3%) during the follow-up period of 20.1±8.6 months. Different IH prevention procedures performed in patients undergoing e-RARP and t-RARP were simple and effective in preventing postoperative IH.
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http://dx.doi.org/10.14989/ActaUrolJap_66_10_331DOI Listing
October 2020

Effect of Continued Perioperative Anticoagulant Therapy on Bleeding Outcomes Following Robot-assisted Radical Prostatectomy.

Urology 2021 Feb 25;148:151-158. Epub 2020 Nov 25.

Department of Urology, Kobe City Medical Centre General Hospital, Kobe, Japan.

Objective: To assess the impact of continued perioperative anticoagulant drug administration on bleeding and complications in patients undergoing robot-assisted radical prostatectomy.

Methods: Between January 2014 and January 2020, 620 patients with prostate cancer underwent robot-assisted radical prostatectomies and were retrospectively reviewed. Fourteen patients who discontinued antithrombotic therapy were excluded. Among the 606 included patients, 31 continued anticoagulant therapy during the perioperative phase (anticoagulant group). The anticoagulant group outcomes were compared with those of patients who continued clopidogrel and prasugrel (thienopyridine group = 13), aspirin monotherapy (aspirin group = 61), and no chronic antithrombotic agent (control group = 501). The primary outcome was the incidence of bleeding complications requiring transfusion, additional intervention, or readmission. Secondary outcomes were the incidence of thrombotic complications, estimated blood loss, and overall complication rates.

Results: Among the 31 patients in the anticoagulant group, 20 (65%) used directed oral anticoagulants, 11 (35%) used warfarin, and 5 used combined aspirin. Only 1 (3%) patient in the anticoagulant group required postoperative transfusion, and none required additional interventions or readmission. No significant differences were detected between the anticoagulant and other groups (anticoagulant vs thienopyridine, aspirin, and control groups) regarding bleeding complications (3% vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively), thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively), estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or other high-grade complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively).

Conclusion: Perioperative continuation of anticoagulant use is feasible for patients undergoing robot-assisted radical prostatectomy.
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http://dx.doi.org/10.1016/j.urology.2020.08.095DOI Listing
February 2021

Remarkable response to dacomitinib in a patient with leptomeningeal carcinomatosis due to EGFR-mutant non-small cell lung cancer.

Thorac Cancer 2021 01 28;12(1):114-116. Epub 2020 Oct 28.

Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Fukuoka, Japan.

Dacomitinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, is a standard therapeutic option for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, its efficacy in patients with central nervous system lesions is unclear. Here, we describe a case of EGFR-mutant NSCLC whose neurological symptoms were due to leptomeningeal carcinomatosis that was successfully treated with dacomitinib. After initiation of dacomitinib, the neurological symptoms of the patient were remarkably improved and leptomeningeal dissemination and brain metastases were shown to have regressed on magnetic resonance imaging (MRI) scan. To our knowledge, this is the first report showing the efficacy of dacomitinib in a patient with leptomeningeal carcinomatosis due to EGFR-mutant NSCLC. The current case suggests that dacomitinib is a novel treatment option for patients with EGFR-mutant NSCLC accompanied by central nervous system lesions, even those with symptomatic leptomeningeal carcinomatosis. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: This is the first report showing the efficacy of dacomitinib in a patient with leptomeningeal carcinomatosis due to EGFR-mutant NSCLC. WHAT THIS STUDY ADDS: The current case suggests that dacomitinib is a novel treatment option for patients with EGFR-mutant NSCLC accompanied by CNS lesions, even in those with symptomatic leptomeningeal carcinomatosis.
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http://dx.doi.org/10.1111/1759-7714.13712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779185PMC
January 2021

Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis.

Lung Cancer 2020 12 1;150:83-89. Epub 2020 Oct 1.

Department of Respiratory Medicine, Okayama University Hospital, Japan.

Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC); however, a biomarker to predict their efficacy has not been established. Although human epidermal growth factor receptor-2 (HER2) aberrations constitute a potential mechanism for acquired resistance to EGFR-TKIs, the impact of HER2 on EGFR-TKI treatment outcomes has not been systematically evaluated. In this post-hoc subgroup study, we examined the impact of HER2 on the effect of EGFR-TKIs in patients with NSCLC harboring EGFR mutations.

Materials And Methods: Of 1126 patients with NSCLC enrolled into a prospective cohort study (HER2-CS study), we analyzed data of 356 (32 %) patients with EGFR-mutant tumors. HER2 protein expression levels were determined by immunohistochemistry (IHC) with the gastric cancer criteria. Patients were divided either to an HER2-P group (HER2-IHC2+/3+) or an HER2-N group (HER2-IHC0/1+). We primarily assessed differences in the time-to-treatment failure (TTF) of EGFR-TKI between the groups.

Results: The HER2 scoring was as follows: IHC0 (n = 76, 21 %), IHC1+ (n = 199, 56 %), IHC2+ (n = 72, 20 %), and IHC3+ (n = 9, 3 %). The patients' demographics were similar in the HER2-P and HER2-N groups. The HER2-P group showed a significantly shorter EGFR-TKI TTF than the HER2-N group (hazard ratio [HR]: 1.657, 95 % confidence interval [CI]: 1.076-2.552; median: 13.3 vs. 19.1 months). The magnitude of the negative impact of TTF was especially dependent on performance status (PS). HER2 expression significantly deteriorated the TTF in the subgroup with PS 2 (HR: 5.497, 95 % CI: 1.510-20.02), but not in that with better PS (HR: 1.437, 95 % CI: 0.899-2.298) (p = 0.015).

Conclusion: In the current cohort, HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs, the effect of which was PS dependent.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.024DOI Listing
December 2020

Impact of previous thoracsic radiation therapy on the efficacy of immune checkpoint inhibitors in advanced non-smasll-cell lung cancer.

Jpn J Clin Oncol 2021 Feb;51(2):279-286

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Objectives: Studies investigating the association between radiation therapy and the efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer have provided inconsistent results, likely due to relatively small cohort sizes. This study investigated the effect of previous thoracic radiation therapy on the efficacy of immune checkpoint inhibitor therapy in a large non-small-cell lung cancer cohort.

Patients And Methods: We conducted a retrospective cohort study using data from 531 non-small-cell lung cancer patients who received monotherapy with programmed cell death protein 1/programmed death-ligand 1 inhibitors at nine institutions. The effects of thoracic radiation therapy on the efficacy of immune checkpoint inhibitors were investigated.

Results: A total of 531 non-small-cell lung cancer patients treated with immune checkpoint inhibitors were included in this study. The progression-free survival period was significantly longer in patients that had received thoracic radiation therapy before immune checkpoint inhibitor therapy compared to those without previous thoracic radiation therapy (median progression-free survival 5.0 vs. 3.0 months, P = 0.0013). A multivariate analysis showed that thoracic radiation therapy was an independent predictive factor of improved progression-free survival (hazard ratio of progression-free survival: 0.79, P = 0.049). In contrast, extra-thoracic radiation therapy was associated with inferior outcomes (median progression-free survival 3.0 vs. 4.2 months, P = 0.0008).

Conclusion: Previous thoracic radiation therapy, but not prior extra-thoracic radiation therapy, enhanced the efficacy of anti-programmed cell death protein 1/programmed death-ligand 1 therapy in non-small-cell lung cancer patients.
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http://dx.doi.org/10.1093/jjco/hyaa180DOI Listing
February 2021

[Necessity of Pelvic Drain Placement after Robot-Assisted Radical Prostatectomy].

Hinyokika Kiyo 2020 Sep;66(9):283-287

The Department of Urology, Kobe City Medical Center General Hospital.

Sixty eight patients had robot-assisted radical prostatectomy (RARP) from January 2016 to April 2017 with estimated blood loss of less than 500 ml. We compared the postoperative complication rates and the length of hospital stay between 34 of these patients who had pelvic drain placement (PD group), and the remaining 34 patients who had no drain placement (ND group). The approach was intraperitoneal in 25 patients in each group. The PD and ND groups were comparable for age (69.5 vs 70 yrs, P=0.459), clinical Gleason Score (6/7/≧8) 2/17/15 vs 3/8/23 (P=0.077), clinical stage (1c/2/3) 3/25/6 vs 1/25/8 (p=0. 539), operative time (311 vs 309 min, P=0.868), and estimated blood loss (p=0.166). The PD group had significantly higher median PSA level than the ND group (8.01 vs 6.25 ng/ml, P=0.023). Incidence of 30- day overall complications in the PD group (35 events) was lower than that in the ND group (38 events). All complications were classified as Clavien Dindo grade I. The postoperative hospital stay was 8 days in the PD group and 7 days in the ND group, showing no prolongation in the ND group. Pelvic drainage may be omitted after RARP without increasing postoperative complications or prolonging the hospital stay.
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http://dx.doi.org/10.14989/ActaUrolJap_66_9_283DOI Listing
September 2020

Utility of immune checkpoint inhibitors in non-small-cell lung cancer patients with poor performance status.

Cancer Sci 2020 Oct 26;111(10):3739-3746. Epub 2020 Aug 26.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Most clinical trials of non-small-cell lung cancer (NSCLC) exclude patients with poor ECOG performance status (PS). Thus, the efficacy of immune checkpoint inhibitors (ICIs) in patients with poor PS remains unclear. Herein, we used data from a retrospective cohort to assess the potential clinical benefits of ICIs in NSCLC patients with poor PS. Data from NSCLC patients who received ICI monotherapy at 9 institutions between December 2015 and May 2018 were retrospectively analyzed. After excluding 4 patients who lacked PS data, a total of 527 ICI-treated patients, including 79 patients with PS 2 or higher, were used for our analyses. The progression-free survival (PFS) and overall survival (OS) of patients with PS 2 or higher were significantly shorter compared with those of PS 0-1 patients (median PFS, 4.1 vs 2.0 months; P < .001 and median OS, 17.4 vs 4.0 months; P < .001). Among NSCLC patients with programmed cell death protein-ligand 1 (PD-L1) expression of 50% or higher who were treated with pembrolizumab as first-line therapy, the median PFS times of patients with PS 2 and 0-1 were 7.3 and 8.1 months, respectively. There was no significant difference in PFS between patients with PS 2 and 0-1 (P = .321). Although poor PS was significantly associated with worse outcomes in NSCLC patients treated with ICIs, pembrolizumab as a first-line treatment in NSCLC patients expressing high levels of PD-L1 could provide a clinical benefit, even in patients with PS 2.
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http://dx.doi.org/10.1111/cas.14590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540975PMC
October 2020

Coronavirus Disease-19 Pneumonia with Facial Nerve Palsy and Olfactory Disturbance.

Intern Med 2020 15;59(14):1773-1775. Epub 2020 Jul 15.

Department of Respiratory Medicine, Ehime Prefectural Central Hospital, Japan.

The novel coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, has spread worldwide from China. There are no case reports from Asia of COVID-19 with facial paralysis and olfactory disturbance. We herein report a case of COVID-19 pneumonia in a Japanese woman who showed facial nerve palsy and olfactory disturbance.
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http://dx.doi.org/10.2169/internalmedicine.5014-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434541PMC
July 2020

Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Jan 10;70(1):101-106. Epub 2020 Jul 10.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama, 700-8558, Japan.

Objectives: Immune checkpoint inhibitors (ICIs) are less effective in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, a small percentage of patients with EGFR-mutant NSCLC do respond, and the characteristics of these patients are not known. Here, we identify the characteristics of patients who may respond to ICI therapy for EGFR-mutant NSCLC.

Patients And Methods: The medical records of NSCLC patients with EGFR mutations who received PD-1/PD-L1 antibody monotherapy at nine institutions were reviewed.

Results: In total, 58 patients with EGFR-mutant NSCLC were analyzed. Various clinical factors such as smoking history and EGFR mutation type were not associated with progression-free survival (PFS) of ICIs, while the PFS of prior EGFR tyrosine kinase inhibitors (TKIs) was inversely associated with that of ICIs. Patients who responded to prior EGFR TKIs for > 10 months exhibited a significantly shorter response to ICIs compared to those who had responded for ≤ 10 months (PFS of ICI: 1.6 vs. 1.9 months; hazard ratio: 2.54; 95% confidence interval 1.26-5.12; p = 0.009). However, patients who responded to ICIs for > 6 months responded to prior EGFR TKIs for significantly shorter periods compared to those who responded to ICIs for ≤ 6 months (PFS of prior EGFR TKI: 5.3 vs. 12.1 months; log-rank test: p = 0.0025).

Conclusion: The duration of response to prior EGFR TKIs could be a predictive marker of ICI therapy in EGFR-mutant NSCLC patients.
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http://dx.doi.org/10.1007/s00262-020-02662-0DOI Listing
January 2021

Randomized Phase II Study of First-Line Biweekly Gemcitabine and Carboplatin Versus Biweekly Gemcitabine and Carboplatin plus Maintenance Gemcitabine in Elderly Patients with Untreated Non-Small Cell Lung Cancer: LOGIK0801.

Oncologist 2020 08 18;25(8):e1146-e1157. Epub 2020 May 18.

Department of Thoracic and Breast Surgery, Oita University, Faculty of Medicine, Oita, Japan.

Lessons Learned: The usefulness of maintenance gemcitabine (GEM) after biweekly carboplatin + GEM in elderly patients with non-small cell lung cancer could not be proved. Superior overall survival was obtained in the group that did not receive maintenance therapy.

Background: The primary objective of this randomized phase II study was to assess progression-free survival (PFS) in elderly patients with advanced non-small cell lung cancer (NSCLC) treated with gemcitabine (GEM) maintenance therapy versus best supportive care following first-line GEM plus carboplatin (CBDCA).

Methods: Elderly chemotherapy-naive patients with stage IIIB or IV NSCLC were randomly assigned 1:1 to the control arm or the study arm. All patients received biweekly combination therapy with GEM and CBDCA (1,000 mg/m GEM and CBDCA at an area under the curve [AUC] of 3 on days 1 and 15, every 4 weeks). In the study arm, patients with objective response or stable disease following three or four cycles of initial chemotherapy received maintenance GEM.

Results: Eighty-four patients were enrolled. The objective response rates (ORRs) were 17.5% in the control arm and 14.0% in the study arm. The most common toxicity was neutropenia (control arm: 47.5% and study arm: 69.8%). The median progression-free survivals were 4.99 months (control arm) and 4.44 months (study arm), and the median overall survivals (OSs) were 21.7 months (control arm) and 8.2 months (study arm).

Conclusion: Our data do not support maintenance GEM after biweekly CBDCA+GEM in elderly patients with NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2020-0322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418367PMC
August 2020

Atypical oncologic failure after laparoscopic and robot-assisted radical cystectomy at a single institution.

Int J Clin Oncol 2020 Jul 18;25(7):1385-1392. Epub 2020 Apr 18.

Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Background: The incidence of atypical oncologic failure in patients with bladder cancer, including peritoneal carcinomatosis, and recurrences at the port site and soft tissue after laparoscopic and robot-assisted radical cystectomy are not well characterized.

Methods: We retrospectively reviewed the records of 52, 51, and 12 patients who underwent open, laparoscopic, and robot-assisted radical cystectomy, respectively, for bladder cancer from 2007 to 2018 at our institution. We identified techniques associated with atypical oncologic failure.

Results: The median follow-up period was 29 months. Among the 115 patients, 29 (25%) experienced oncological recurrences, and 7 (6%), 12 (10%), and 23 (20%) had atypical, local, and distant recurrences, respectively. The laparoscopic and robot-assisted radical cystectomy groups had significantly higher incidences of total atypical oncologic failure than the open radical cystectomy group (p = 0.013), including six, one, and two patients with peritoneal carcinomatosis, port site carcinomatosis, and soft tissue involvement, respectively. All 7 patients with atypical oncologic failure died of cancer; the median time from surgery to death was 9.3 months. All these patients were cT ≧ 3 and had grade 3 disease. In three patients (43%), the pathological tissue contained variants other than urothelial carcinoma. Five (71%) were among the initial twenty patients. Four patients (57%) had histories of intraoperative urine spillage or bladder perforation during transurethral resection.

Conclusions: Patients with cT ≧ 3 stage, with pathological variants other than urothelial carcinoma, and those undergoing procedures that lead to extravesical dissemination should avoid laparoscopic radical cystectomy when the procedures are first introduced.
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http://dx.doi.org/10.1007/s10147-020-01677-yDOI Listing
July 2020

Laparoscopic Repair of Ureteral Diverticulum Caused by Ureterosciatic Hernia.

Urology 2020 Jun 21;140:e1-e3. Epub 2020 Mar 21.

Department of Urology, Kobe City Medical Centre General Hospital, Chuo-ku, Kobe 650-0047, Japan.

Ureterosciatic hernia and ureteral diverticulum are rare conditions. Only a few cases with surgical management for these conditions have been reported. We report a case of ureteral diverticulum due to ureterosciatic hernia in an 85-year-old woman admitted for septic shock. Computed tomography and retrograde ureterography revealed obstructive ureterosciatic hernia. During intraoperative laparoscopic mesh repair for the hernia after urosepsis treatment, we noted ureteral diverticulum that was also detected endoscopically at the herniated ureter wall. Suture plication was performed to prevent stricture and hernia mesh infection. To our knowledge, this is the first report on ureteral diverticulum due to ureterosciatic hernia.
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http://dx.doi.org/10.1016/j.urology.2020.03.017DOI Listing
June 2020

Surgical outcomes and learning curve of totally intracorporeal ileal conduit urinary diversion following laparoscopic radical cystectomy at a single institution.

Asian J Endosc Surg 2020 Oct 28;13(4):532-538. Epub 2020 Feb 28.

Department of Urology, Kobe City Medical Centre General Hospital, Kobe, Japan.

Introduction: Constant evaluation of the outcomes of laparoscopic intracorporeal urinary diversion is not yet established. This study aimed to describe surgical outcomes and learning curve of intracorporeal ileal conduit (ICIC) following laparoscopic radical cystectomy (LRC) at a single institution.

Methods: From June 2012 to February 2018, 38 patients with bladder cancer underwent LRC with ileal conduit at our institution. Surgical outcomes were compared between ICIC (n = 30) and extracorporeal ileal conduit (ECIC) (n = 8). The learning curve during ICIC with regard to the operative time and complication rate was compared.

Results: No significant differences in patient characteristics between the ICIC and ECIC groups were found. Comparison of outcomes between the ICIC and ECIC groups were as follows: median total operative time, 688 vs 713 minutes; urinary diversion time, 213 vs 192 minutes; and estimated blood loss, 450 vs 420 mL, respectively. The median time to walking and oral intake were similar in both groups. Rates of high-grade complications associated with urinary diversion (Clavien-Dindo grade ≥ III) were 3% in ICIC and 25% in ECIC. Although 25% of ECIC patients developed wound dehiscence (Clavien-Dindo grade IIIb), no patient in the ICIC group had postoperative wound infection. For the learning curve of ICIC (n = 30), urinary diversion time decreased significantly (27 minutes decrease per 10 cases, P = .02). Clavien-Dindo grade ≥ II complication did not occur after 20 cases.

Conclusions: LRC with ICIC could be performed safely with low incidence of severe wound infection compared with ECIC. The incidence and severity of complications also decreased with time.
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http://dx.doi.org/10.1111/ases.12793DOI Listing
October 2020

Genome Sequence of the Euryhaline Javafish Medaka, : A Small Aquarium Fish Model for Studies on Adaptation to Salinity.

G3 (Bethesda) 2020 03 5;10(3):907-915. Epub 2020 Mar 5.

INRAE, UR 1037 Fish Physiology and Genomics, F-35000 Rennes, France, and

The genus consists of 35 medaka-fish species each exhibiting various ecological, morphological and physiological peculiarities and adaptations. Beyond of being a comprehensive phylogenetic group for studying intra-genus evolution of several traits like sex determination, behavior, morphology or adaptation through comparative genomic approaches, all medaka species share many advantages of experimental model organisms including small size and short generation time, transparent embryos and genome editing tools for reverse and forward genetic studies. The Java medaka, , is one of the two species of medaka perfectly adapted for living in brackish/sea-waters. Being an important component of the mangrove ecosystem, is also used as a valuable marine test-fish for ecotoxicology studies. Here, we sequenced and assembled the whole genome of , and anticipate this resource will be catalytic for a wide range of comparative genomic, phylogenetic and functional studies. Complementary sequencing approaches including long-read technology and data integration with a genetic map allowed the final assembly of 908 Mbp of the genome. Further analyses estimate that the genome contains 33% of repeat sequences and has a heterozygosity of 0.96%. The achieved draft assembly contains 525 scaffolds with a total length of 809.7 Mbp, a N50 of 6,3 Mbp and a L50 of 37 scaffolds. We identified 21454 predicted transcripts for a total transcriptome size of 57, 146, 583 bps. We provide here a high-quality chromosome scale draft genome assembly of the euryhaline Javafish medaka (321 scaffolds anchored on 24 chromosomes (representing 97.7% of the total bases)), and give emphasis on the evolutionary adaptation to salinity.
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http://dx.doi.org/10.1534/g3.119.400725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056978PMC
March 2020

Absence of asymptomatic unruptured renal artery pseudoaneurysm on contrast-enhanced computed tomography after robot-assisted partial nephrectomy without parenchymal renorrhaphy.

Asian J Urol 2020 Jan 8;7(1):24-28. Epub 2019 Oct 8.

Department of Urology, Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminami-cho, Chuo-ku, Kobe City, Japan.

Objective: To assess the incidence of asymptomatic unruptured renal artery pseudoaneurysm (RAP) on contrast-enhanced computed tomography (CE-CT) after robot-assisted partial nephrectomy (RAPN) without parenchymal renorrhaphy.

Methods: From May 2016 to December 2017, 78 patients underwent RAPN for renal tumors. Inner suture was performed in the opened collecting system or renal sinus, whereas parenchymal renorrhaphy was not. For hemostasis, the soft coagulation system was used, and absorbable hemostats were placed on the resection bed. CE-CT was carried out within 7 days after surgery. Data on these patients were prospectively collected. A single radiologist determined the diagnosis of RAP.

Results: Median (range) data were as follows: Patient age, 65 (19-82) years; radiographic tumor size, 30 (12-95) mm; operating time, 166 (102-294) min; warm ischemic time, 16 (7-67) min; and blood loss, 15 (0-4450) mL. One patient (1.6%) required a perioperative blood transfusion. No patient required conversion to open surgery or nephrectomy. CE-CT was carried out at median 6 (3-7) days after surgery. CE-CT showed no RAP development in all 61 patients. Urinary leakage was not observed. One patient had acute cholecystitis, a postoperative complication classified as Clavien-Dindo grade higher than 3, which was treated with cholecystectomy. Positive surgical margin was identified in four patients (6.6%).

Conclusion: RAPN using soft coagulation and absorbable hemostats without renorrhaphy appears to be feasible and safe. Our technique could eliminate the risk of RAP.
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http://dx.doi.org/10.1016/j.ajur.2019.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962716PMC
January 2020

The impact of body mass index on the efficacy of anti-PD-1/PD-L1 antibodies in patients with non-small cell lung cancer.

Lung Cancer 2020 01 18;139:140-145. Epub 2019 Nov 18.

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.

Objectives: Body mass index (BMI) is reported to be associated with the efficacy of immune checkpoint inhibitors (ICIs) in solid tumors such as melanomas. However, it remains unclear whether such a relationship exists in non-small cell lung cancer (NSCLC) treated with programmed cell death protein 1 (PD-1)/ programmed death-ligand 1(PD-L1) inhibitors. The purpose of this study was to investigate the relationship between BMI and the efficacy of ICI treatment in patients with advanced NSCLC.

Materials And Methods: The medical records of NSCLC patients who received PD-1/PD-L1 antibody monotherapy at nine institutions between December 2015 and May 2018 were reviewed retrospectively. The effect of BMI was investigated in two cohorts. Cohort 1 included patients with NSCLCs with high PD-L1 expression (≥ 50 %) treated with pembrolizumab as first-line therapy, and cohort 2 included patients with NSCLCs treated with nivolumab/pembrolizumab/atezolizumab as second- or later-line treatment.

Results: A total of 513 from nine institutions were analyzed (84 in cohort 1, 429 in cohort 2). Using a BMI cut-off value of 22 kg/m2, which is an ideal BMI in our country (high BMI:22.0 and low BMI:22.0), there was no significant difference in the PFS or OS between the high and low BMI patients in cohort 1. However, in cohort 2, survival was significantly longer in patients with a high versus low BMI (PFS: 3.7 vs. 2.8 months, p = 0.036; OS: 15.4 vs. 13.5 months, p = 0.021).

Conclusion: BMI was significantly associated with the efficacy of ICIs in patients with NSCLC treated with second- or later-line PD-1/PD-L1 inhibitors in our cohort.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.011DOI Listing
January 2020

Updated Survival Data for a Phase I/II Study of Carboplatin plus Nab-Paclitaxel and Concurrent Radiotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer.

Oncologist 2020 06 24;25(6):475-e891. Epub 2019 Oct 24.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Lessons Learned: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen.

Background: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC).

Methods: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS).

Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period.

Conclusion: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2019-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288639PMC
June 2020

Longitudinal monitoring of somatic genetic alterations in circulating cell-free DNA during treatment with epidermal growth factor receptor-tyrosine kinase inhibitors.

Cancer 2020 01 10;126(1):219-227. Epub 2019 Sep 10.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: The aim of this study was to evaluate the potential of liquid biopsy for prediction of the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment and for assessment of the changes in genetic alterations during such treatment.

Methods: Plasma samples were prospectively collected from non-small cell lung cancer patients with EGFR-activating mutations during EGFR-TKI treatment until disease progression and were analyzed for such mutations with droplet digital polymerase chain reaction and for other somatic alterations with next-generation sequencing.

Results: One hundred patients, including 87 who were EGFR-TKI naïve, were enrolled. Median progression-free survival was significantly shorter for EGFR-TKI-naïve patients with EGFR-activating mutations detected in plasma at baseline than for those without them (7.9 vs 19.0 months; P < .001), with the values being significantly longer for initially positive patients who became negative for these mutations at 12 or 24 weeks than for those who remained positive. An increase in the number of alleles positive for EGFR-activating mutations in plasma during treatment was associated with disease progression, with a hazard ratio of 4.72 (95% CI, 2.07-10.79; P < .001) for EGFR-TKI-naïve patients showing an increase within 36 weeks. For 55 patients with available samples, the total number of somatic alterations (other than activating mutations or T790M of EGFR) in plasma was higher at disease progression than at baseline (33 vs 19; P = 0.04).

Conclusion: Liquid biopsy shows potential for prediction of EGFR-TKI efficacy and elucidation of clonal tumor evolution during targeted therapy.
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http://dx.doi.org/10.1002/cncr.32481DOI Listing
January 2020

[Traumatic Adrenal Injury : A Single-Institution Experience].

Hinyokika Kiyo 2019 Jul;65(7):271-275

The Department of Urology, Kobe City Medical Center General Hospital.

Traumatic adrenal injury is quite rare. From January 2008 to March 2018, out of 287 patients with genitourinary trauma, 23 patients (8%) were diagnosed with traumatic adrenal injury at Kobe City Medical Center General Hospital. We retrospectively reviewed the medical records and assessed the traumatic category, image findings and outcome. All 23 patients were bluntly injured. The causes of traumatic adrenal injury were motor vehicle accident (11 patients : 48%) and falls (9 patients : 39%). The majority of injuries occurred on the right side (18 patients : 78%). Associated injuries occurred in all 23 patients, most frequently in the liver (57%) and ribs (57%). Extravasation of contrast materials was identified on computed tomography (CT) in 4 patients (17%). Although 22 patients (96%) were conservatively managed, only 1 patient was treated by transcatherter arterial embolization because of hypotension. One patient died of intraabdominal bleeding. To our knowledge, the present study is the largest on traumatic adrenal injury in Japan.
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http://dx.doi.org/10.14989/ActaUrolJap_65_7_271DOI Listing
July 2019