Search

Abstract Background Molecular abnormalities in the Wnt/β‐catenin pathway confer malignant phenotypes in lung cancer. Previously, we identified the association of leucine‐rich repeat‐containing G protein‐coupled receptor 6 (LGR6) with oncogenic Wnt signaling, and its downregulation upon β‐catenin knockdown in non‐small cell lung cancer (NSCLC) cells carrying CTNNB1 mutations. The aim of this study was to explore the mechanisms underlying this association and the accompanying phenotypes. Methods LGR6 expression in lung cancer cell lines and surgical specimens was analyzed using quantitative RT‐PCR and immunohistochemistry. Cell growth was assessed using colony formation assay. Additionally, mRNA sequencing was performed to compare the expression profiles of cells subjected to different treatments. Results LGR6 was overexpressed in small cell lung cancer (SCLC) and NSCLC cell lines, including the CTNNB1‐mutated NSCLC cell lines HCC15 and A427. In both cell lines, LGR6 knockdown inhibited cell growth. LGR6 expression was upregulated in spheroids compared to adherent cultures of A427 cells, suggesting that LGR6 participates in the acquisition of cancer stem cell properties. Immunohistochemical analysis of lung cancer specimens revealed that the LGR6 protein was predominantly overexpressed in SCLCs, large cell neuroendocrine carcinomas, and lung adenocarcinomas, wherein LGR6 overexpression was associated with vascular invasion, the wild‐type EGFR genotype, and an unfavorable prognosis. Integrated mRNA sequencing analysis of HCC15 and A427 cells with or without LGR6 knockdown revealed LGR6‐related pathways and genes associated with cancer development and stemness properties. Conclusions Our findings highlight the oncogenic roles of LGR6 overexpression induced by aberrant Wnt/β‐catenin signaling in lung cancer.

Abstract Background The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first‐line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non‐small cell lung cancer (NSCLC). Methods Our study comprised 288 patients with advanced NSCLC who received RD as the second‐line treatment after first‐line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum‐based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. Results Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression‐free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD‐L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. Conclusion Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second‐line RD treatment in patients with advanced NSCLC.

Abstract Background Vascular endothelial growth factor (VEGF) has been identified as one of the resistant mechanisms to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs). However, the relationship between the efficacy of osimertinib and protein expression of VEGF family members in patients with advanced non‐small cell lung cancer (NSCLC) harboring EGFR mutations remains unclear. Methods A total of 76 patients with advanced NSCLC with EGFR major mutations (del19 or L858R) receiving first‐line osimertinib were eligible as the osimertinib (Osi) group, whereas 43 patients receiving first‐ or second‐generation EGFR‐TKIs were compared with the control group. The expression of vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor C (VEGF‐C) in the tumor specimens was analyzed using immunohistochemistry. Results VEGFR2 and VEGF‐C were highly expressed in 65.8% and 51.3% of patients, respectively, in the Osi group, and 69.7% and 76.7%, respectively, in the control group. High VEGFR2 and VEGF‐C levels were significantly associated with poor performance status (PS) and female sex, respectively. In the Osi group, patients with co‐high expression of VEGFR2 and VEGF‐C showed significantly worse progression‐free survival (PFS) and overall survival (OS) than those without co‐high expression. In del19, VEGFR2 was a significant predictor of PFS and OS and independent predictor of OS in multivariate analysis. In L858R, co‐high expression of VEGFR2 and VEGF‐C was identified as a significant predictor of PFS and OS and independent predictor of PFS. Conclusion VEGFR2 and VEGF‐C are highly expressed in EGFR‐mutant NSCLC cells. Increased expression of VEGFR2 was identified as a significant prognostic factor in patients with EGFR del19 mutation who received osimertinib, whereas co‐high expression of VEGFR2 and VEGF‐C was a significant predictor for those with EGFR L858R mutation.

Abstract Background Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb‐Plt‐PEM) in nonsquamous non‐small cell lung cancer (non‐sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil‐to‐lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non‐sq NSCLC. Methods We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non‐sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan–Meier method were used to compare progression‐free survival (PFS) and overall survival (OS). Results The response rate was 51.2% (95% CI: 44.9–57.5%). The median PFS and OS after beginning Pemb‐Plt‐PEM were 8.8 (95% CI: 7.0–11.9) months and 23.6 (95% CI: 18.7–28.6) months, respectively. The NLR independently predicted the efficacy of Pemb‐Plt‐PEM—the PFS and OS were more prolonged in individuals with NLR

Key Clinical Message Although partial hepatic necrosis often occurs following endovascular treatment for bleeding associated with hepatic trauma, it is relatively rare that additional treatment is required. However, invasive procedures such as hepatic resection should sometimes be considered when infection occurs over massive hepatic necrosis. Abstract Although partial hepatic necrosis following endovascular treatment for bleeding associated with hepatic trauma is occasionally experienced, it is relatively rare for the necrotic area of the liver to require additional treatment. However, invasive procedures such as hepatic resection should sometimes be considered when infection occurs over massive hepatic necrosis.

Abstract Purpose The aim of this study was to assess the effectiveness and tolerability of atezolizumab plus carboplatin and etoposide combination chemotherapy in elderly patients with extensive‐disease (ED) small‐cell lung cancer (SCLC). Methods This retrospective study evaluated 65 SCLC patients who received atezolizumab, carboplatin, and etoposide for ED‐SCLC in nine study institutions between August 2019 and September 2020. Clinical efficacy, assessed according to response rate and survival, and toxicity were compared between the elderly (n = 36 patients; median age: 74 years [range: 70–89 years]) and the non‐elderly group (n = 29 patients; median age: 67 years [range: 43–69 years]). Results The response rate was 73.8% (80.5% in the elderly group and 65.5% in the non‐elderly group). There was no significant difference in both the median progression‐free survival (5.5 months vs. 4.9 months, p = 0.18) and the median overall survival (15.4 months vs. 15.9 months, p = 0.24) between the elderly group and the non‐elderly group. The frequencies of grade ≥3 hematological adverse events in the elderly patients were as follows: decreased white blood cells, 36.1%; decreased neutrophil count, 61.1%; decreased platelet count, 8.3%; and febrile neutropenia, 8.3%. One treatment‐related death due to lung infection occurred in the elderly group. Conclusion Despite hematologic toxicities, especially decreased neutrophil count, atezolizumab, carboplatin, and etoposide combination chemotherapy demonstrates favorable effectiveness and acceptable toxicity in elderly patients. Thus, atezolizumab plus carboplatin and etoposide could be the preferred standard treatment modality for elderly patients with ED‐SCLC.

Abstract Background In this study, we developed a simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non‐small cell lung cancer (NSCLC) treated with intensity modulated radiotherapy (IMRT). Methods Data of 28 patients with stage IIB to IIIC NSCLC were retrospectively analyzed. All patients were treated with IMRT and a simulated three‐dimensional conformal radiotherapy (3D‐CRT) plan created for them. Dose‐volume parameters of lung were analyzed for their correlation with radiation pneumonitis (RP). Results Over a median follow‐up of 14 months, grade 1 pneumonitis was diagnosed in 14 patients (50%), grade 2 pneumonitis in 11 (39%), and grade 3 pneumonitis in one (4%). Two patients did not develop pneumonitis. None of the patients developed grade 4 or 5 pneumonitis. Regarding dose‐volume parameter ratios between IMRT and simulated 3D‐CRT, receiver operating characteristic analysis showed that mean lung dose (MLD)IMRT/MLD3D‐CRT had the largest area under curve (0.750). Cumulative 6‐month incidences of grade 2 or greater RP were 78.4% versus 19.5% (MLDIMRT/MLD3D‐CRT, ≥1.0 or less); this difference was significant (p

Abstract Background The effect of first‐line chemotherapy on overall survival (OS) may be significantly influenced by subsequent therapy for patients with extensive disease small cell lung cancer (ED‐SCLC). Therefore, we evaluated the relationship between progression‐free survival (PFS), post‐progression survival (PPS), and OS of ED‐SCLC patients treated with atezolizumab plus carboplatin and etoposide as first‐line therapy. Methods We analyzed the data of 57 patients with relapsed ED‐SCLC treated with atezolizumab plus carboplatin and etoposide (AteCE) as first‐line chemotherapy between August 2019 and September 2020. The respective correlations between PFS‐OS and PPS‐OS following first‐line AteCE treatment were examined at the individual patient level. Results Spearman's rank correlation analysis and linear regression analysis showed that PPS strongly correlated with OS (r = 0.93, p

Abstract Background We conducted a multicenter, retrospective study on the efficacy and safety of naldemedine in thoracic cancer patients using opioids in clinical practice. Methods We retrospectively evaluated thoracic cancer patients treated with naldemedine at 10 institutions in Japan. Clinical data of patients administered naldemedine between June 2017 and August 2019 were extracted from electronic medical records. Inclusion criteria were as follows: (i) patients hospitalized for at least seven days before and after naldemedine administration, and (ii) those whose frequency of defecation was entered in the medical records. Results Forty patients were analyzed, and defecation frequency was observed for at least seven days before and after naldemedine administration. The response rate was 65.0% (95% CI: 50.2%–79.7%). The number of defecations increased significantly after naldemedine administration in the overall population, as well as among only those who defecated

Abstract Background Biomarker assessments for nivolumab monotherapy efficacy in previously treated patients with non‐small cell lung cancer (NSCLC) remain unclear. We evaluated whether body mass index (BMI) and Glasgow prognostic score (GPS) are useful for assessing the efficacy of nivolumab alone as a second‐line treatment in patients with pretreated NSCLC. Methods Data of 99 patients treated with second‐line nivolumab monotherapy for NSCLC between January 2016 and December 2019 were evaluated for prognostic values of BMI and GPS to assess their usefulness in predicting progression‐free survival (PFS) and overall survival (OS). Results The Eastern Cooperative Oncology Group‐performance status (PS) independently predicted the second‐line nivolumab monotherapeutic effect; good PS (0–1) correlated with significantly longer PFS (4.3 vs. 1.9 months, log‐rank; p = 0.0004) and OS (17.7 vs. 4.6 months, log‐rank; p

Abstract Objectives Various drug‐sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug‐sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC. Methods We retrospectively analyzed the correlation between clinicopathological features and the expression of drug‐sensitivity‐related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo‐I), and Topo‐II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status. Results Overall, high expression of TS, TUBB3, VEGFR2, Topo‐I, and Topo‐II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo‐II expression were independent unfavorable prognosticators for recurrence‐free survival, and advanced pathological T and N factors, Topo‐II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD‐L1 expression. Conclusions These findings suggest that elevated Topo‐II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC.

Abstract Background For early‐stage non‐small cell lung cancer (NSCLC), surgical resection is considered the most effective treatment strategy and curative treatment. Unfortunately, even after complete resection, almost half of all patients with stage I–IIIA NSCLC relapse and die. Although the possibility of a cure for postoperative recurrence of NSCLC is significantly low, the course of subsequent treatment can possibly affect overall survival (OS). Here, we examined the association of relapse‐free survival (RFS) and post‐progression survival (PPS) with OS in patients with postoperative recurrence of NSCLC. Methods We evaluated 128 patients with NSCLC who underwent complete resection between January 2007 and December 2018. The association between RFS and PPS on OS was examined at the patient level. Results Spearman's rank correlation and linear regression analyses revealed that PPS was strongly correlated with OS (r = 0.83, p

Abstract Background There are no established biomarkers for predicting the efficacy of first‐line pembrolizumab monotherapy in patients with high programmed death‐ligand 1 (PD‐L1) expression. In this study, we investigated whether the Glasgow prognostic score (GPS), neutrophil‐to‐lymphocyte ratio (NLR), and body mass index (BMI) can be used to evaluate the effect of first‐line pembrolizumab monotherapy in patients with advanced non‐small cell lung cancer (NSCLC) who express high levels of PD‐L1. Methods We reviewed data from 142 patients with high PD‐L1 expression who underwent first‐line pembrolizumab monotherapy for NSCLC at six Japanese institutions between February 2017 and June 2019 and assessed the prognostic value of the GPS, NLR, and BMI. The Kaplan–Meier method and Cox proportional hazard models were used to examine differences in progression‐free survival (PFS) and overall survival (OS). The GPS, NLR, and BMI were calculated using C‐reactive protein and albumin concentrations, neutrophil and lymphocyte counts, and body weight and height, respectively. Results The GPS independently predicted the first‐line pembrolizumab monotherapy efficacy, as a good GPS (GPS 0–1) was associated with a significantly better PFS and OS compared to a poor GPS (GPS 2) (PFS: 11.8 vs. 2.9 months, p

Abstract Background 2‐deoxy‐2‐[fluorine‐18] fluoro‐d‐glucose (18F‐FDG) positron emission tomography (18F‐FDG‐PET) is a convenient modality to assess the metabolic activity within tumor cells. However, there is no consensus regarding the relationship between 18F‐FDG uptake and the immune environment in thymic epithelial tumors (TETs). We conducted a clinicopathological study to elucidate the relationship between 18F‐FDG uptake and programmed death ligands 1 and 2 (PD‐L1/PD‐L2) expression in patients with TETs. Methods: A total of 108 patients with histologically confirmed TETs classified as thymomas or thymic carcinomas who underwent surgical resection or biopsy or needle biopsy and 18F‐FDG PET before any treatment between August 2007 and March 2020 were enrolled in this study. Tumor specimens underwent immunohistochemical staining for PD‐L1, PD‐L2, GLUT1, HIF‐1α, VEGFR2, VEGF‐C, and β2 adrenergic receptor. Results: High uptakes of SUVmax, SUVmean, MTV, and TLG were identified in 28 (25.9%), 61 (56.5%), 55 (50.9%), and 55 (50.9%) of 108 patients, respectively. High uptake of SUVmax significantly correlated with PS (performance status) of 1–2, thymic carcinoma, and advanced stage, and SUVmax on 18F‐FDG uptake displayed a close association with PD‐L1 and PD‐L2 expressions, but not with MTV and TLG. Our analysis revealed that SUVmax was identified as being significant relationship for positive PD‐L1/PD‐L2 expression. GLUT1, HIF‐1α, and VEGFR2 were significantly associated with the expression of PD‐L1/PD‐L2 from the biological viewpoint. Conclusion 18F‐FDG accumulation was closely associated with the expression of PD‐L1/PD‐L2, which, in turn, was correlated with glucose metabolism and hypoxia. PD‐L1/PD‐L2 could affect the glucose metabolism and hypoxia in thymic tumor cells.

Abstract Background Mucosa associated lymphoid tissue (MALT) lymphoma of the orbit is rare, often indolent, but can recur, and spread to extra‐nodal sites. Pleural and retroperitoneum recurrences of MALT lymphoma are rare. Case A 65‐year‐old man was referred to our hospital due to right pleural effusion and difficulty in breathing. He had a medical history of having undergone surgery for MALT lymphoma of the left orbit. A chest computed tomography (CT) scan showed right pleural thickness, pleural effusion, and a retroperitoneal mass, spreading from the muscular layer to the subcutaneous layer. The thickened pleural lesion was surgically biopsied and diagnosed as a recurrence of MALT lymphoma. Conclusion Pleural effusion should be carefully examined and monitored for the possibility of recurrence in MALT lymphoma patients.

Abstract Background The effect of second‐line treatment on overall survival (OS) may be affected by subsequent treatment in patients with non‐small cell lung cancer (NSCLC); however, in such patients, the correlation between post‐progression survival (PPS) and OS is unclear. Our study assessed the correlation of progression‐free survival (PFS) and PPS with OS, using individual patient data, in advanced NSCLC patients who were treated with second‐line nivolumab monotherapy, Methods Between January 2016 and March 2019, we evaluated 92 NSCLC patients who received second‐line nivolumab treatment after first‐line platinum‐based combination chemotherapy. Using individual patient data, the correlations of PFS and PPS with OS were examined. Results Linear regression and Spearman rank correlation analysis demonstrated that PPS was strongly correlated with OS (r = 0.85, p

Abstract Background There is currently insufficient information available on effective therapies that can be administered to patients with non‐small cell cancer (NSCLC) who develop resistance to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs). However, sequential treatment via programmed death‐1 (PD‐1) blockade followed by EGFR‐TKI rechallenge is suggested to improve the therapeutic efficacy in such patients. Methods A total of 75 patients with advanced NSCLC harboring sensitive EGFR mutations treated with afatinib, erlotinib, or gefitinib after EGFR‐TKI treatment failure were retrospectively analyzed. Among them, 13 patients were treated with EGFR‐TKI rechallenge immediately after the failure of PD‐1 blockade therapy (experimental group) and the remaining 62 patients did not receive PD‐1 inhibitor therapy before EGFR‐TKI rechallenge (control group). Blood samples were collected at two time points; before the initiation of anti‐PD‐1 therapy and at EGFR‐TKI rechallenge. Results The objective response rates of EGFR‐TKI rechallenge in the experimental and control groups were 46.1% and 16.1%, respectively, with a significant difference (p = 0.026). In the experimental group, the median progression‐free survival (PFS) and overall survival (OS) after EGFR‐TKI rechallenge were 5.0 and 25.0 months, respectively, and no statistically significant difference in the percentage of lymphocytes before immune checkpoint inhibitor (ICI) therapy and EGFR‐TKIs was observed in patients with partial response (PR) and without PR after EGFR‐TKI rechallenge. In particular, the sequential treatment of PD‐1 blockade therapy followed by EGFR‐TKI rechallenge was consecutively repeated three times in two out of 13 patients in the experimental group, and EGFR‐TKI rechallenge consecutively for the third time yielded a PR without increased toxicities. Conclusions EGFR‐TKI rechallenge immediately after PD‐1 blockade treatment was identified as an effective therapy for NSCLC patients with resistance to EGFR‐TKIs.

Abstract Background The safety of pembrolizumab monotherapy in treatment‐naïve non‐small cell lung cancer (NSCLC) patients with high programed death‐ligand 1 (PD‐L1) expression and pre‐existing interstitial lung disease (ILD) has not yet been determined. Here, we aimed to evaluate the prognosis, efficacy and safety associated with pembrolizumab in such settings. Methods In this single‐institution retrospective study conducted from May 2017 to October 2019, pembrolizumab was administered to 72 Japanese patients with treatment‐naïve advanced NSCLC with PD‐L1 tumor proportion score (TPS) ≥50%. Patients with ILD were assigned to the ILD group, and those without to the non‐ILD group. Between‐group comparisons were then performed. Results Of the 72 patients, 61 (84.7%) were male. The median age was 70 years. A total of 64 patients (88.9%) had a smoking history, median PD‐L1 TPS status was 77.5%, and 10 of the 72 patients (13.9%) had ILD on pretreatment computed tomography. The objective response rate (ORR) was 45.8% and disease control rate (DCR) was 75.0%. The ORR was 70.0% and DCR was 90.0% in the ILD group, while the ORR was 41.9% and DCR was 72.6% in the non‐ILD group. The median overall survival was 568 days; the value in the non‐ILD group was 521 days, while in the ILD group was not reached. There was no significant difference between the two groups (log‐lank, P = 0.73). Conclusions Pembrolizumab was administered to patients with pre‐existing ILD with no difference in prognosis compared to patients without ILD. In patients with ILD, physicians should consider the expected long‐term prognosis and risk of adverse events.

Background S‐1 monotherapy is effective and feasible for previously treated patients with advanced non‐small cell lung cancer (NSCLC). However, it is not clear whether its effectiveness and tolerability in elderly patients are equivalent to those in younger patients. Hence, this study aimed to evaluate the efficacy and feasibility of S‐1 monotherapy in elderly patients with NSCLC who had previously received other treatments. Methods We included 96 elderly patients (aged ≥75 years) with advanced NSCLC treated with S‐1 alone as a subsequent‐line treatment at 12 medical facilities between January 2005 and March 2018 in this study. The baseline characteristics of the patients, response to S‐1 monotherapy, and adverse events (AEs) were investigated, retrospectively. Results A total of 68 male and 28 female patients (median age, 78 [range: 75–86] years) were analyzed. In elderly patients who were treated with S‐1 monotherapy as a subsequent‐line treatment, the objective response rate, disease control rate, median progression‐free survival (PFS), and overall survival (OS) were 8.3%, 43.8%, 3.4 months, and 9.6 months, respectively. Observed AEs included anorexia, anemia, nausea, fatigue, reduced platelet count, and skin hyperpigmentation. Treatment‐related death was observed in one patient because of pneumonitis. In patients who experienced no progressive disease, subsequent‐line S‐1 alone was associated with longer PFS and OS. Conclusions S‐1 monotherapy is effective and feasible as a subsequent‐line treatment in elderly patients who were previously treated for NSCLC, and it produces results. S‐1 monotherapy could be one of the treatment choices for elderly patients with previously treated NSCLC.

Background Lung cancer is the leading cause of cancer‐related deaths. Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are effective for advanced non‐small cell lung cancer (NSCLC) harboring EGFR mutations, some patients experience little or no response. The Glasgow prognostic score (GPS) is an inflammation‐related score based on C‐reactive protein (CRP) and albumin concentrations, and has prognostic value in various cancer settings. This study aimed to evaluate whether GPS could predict response of NSCLC to EGFR‐TKIs. Methods This retrospective multicenter study evaluated patients with NSCLC harboring EGFR mutations who received EGFR‐TKI monotherapy from October 2006 to December 2016. GPS values were determined using CRP and albumin concentrations from before initiation of EGFR‐TKIs. The Kaplan‐Meier method and Cox proportional hazard models were used to evaluate progression‐free survival (PFS) and overall survival (OS). Results In 214 patients, 141, 43, and two patients had GPS values of 0, 1, and 2, respectively. The GPS independently predicted the efficacy of EGFR‐TKIs; good GPS (0–1) conferred significantly better PFS (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.38–0.96, P = 0.03) and OS (HR: 0.56, 95% CI: 0.33–0.96, P = 0.03). Multivariate analysis confirmed that a good GPS (0–1) independently predicted good PFS and OS among patients who had PS of 0–1. Good GPS (0–1) independently predicted good OS among patients receiving treatment in first‐line settings. Conclusions The GPS independently predicted the efficacy of EGFR‐TKIs for EGFR‐mutated NSCLC; however, further studies are needed to validate our findings. Key points Significant findings of the study Glasgow prognostic score (GPS) independently predicted the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) treatment for EGFR‐mutated NSCLC. What this study adds The findings presented in this paper will help to identify patients who will be expected to experience limited or no response to EGFR‐TKI treatment by using GPS.

Background Chemoradiotherapy followed by durvalumab is the standard treatment for the patients with local advanced non‐small cell lung cancer (NSCLC). There is a real‐world data about the management of adverse events, such as pneumonitis, according to the different institutions. Here, we present the experience regarding the management of adverse events after the initiation of durvalumab as daily practice. Methods From July 2018 to August 2019, 41 patients with locally advanced NSCLC, who underwent chemoradiotherapy followed by durvalumab, were retrospectively analyzed in the study using our medical records. Results The median age of patients was 72 years (range: 51–80 years). A total of 33 patients were male and eight were female, and 40 patients (98%) received a total radiation dose of 60 Gy as concomitant chemoradiotherapy. The median V20 for the entire cohort was 18.9% (range: 3.5–29.9). Any adverse events during chemoradiotherapy and durvalumab were observed in 32 patients (78.0%), while three patients (7.3%) experienced grade 3 toxicities. In total, 25 (61.0%) patients experienced pneumonitis, four (9.8%) thyroid dysfunction, three (7.3%) myopathy, two (4.9%) rash or eruption, one (2.4%) bowel disease and one (2.4%) malaise. Grade 3 pneumonitis, thyroid dysfunction and myopathy were observed in one (2.4%), one (2.4%) and one (2.4%), respectively. A total of 22 (53.7%) patients were unable to continue durvalumab due to pneumonitis. However, durvalumab was finally readministered to six patients. Conclusions The adherence to lung dose constraints such as V20 as well as close treatment monitoring are a prerequisite for the management of pneumonitis during maintenance therapy with durvalumab.

Background Osimertinib is the most promising treatment option for patients with epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) with acquired T790M resistance. However, recent studies have suggested that osimertinib could increase the frequency of serious adverse events (AEs) if administered immediately after immune checkpoint inhibitor (ICI) treatment. Methods In this single‐institution retrospective study conducted from May 2016 to January 2019, osimertinib was administered to 47 patients with pretreated advanced NSCLC harboring the EGFR mutation. Results Of the 47 patients, 20 (42.6%) were men and 27 (57.4%) were women. The median age was 71 years (range 37–83 years). A total of 19 patients (40.4%) had a smoking history. Furthermore, seven patients (14.9%) received osimertinib immediately after nivolumab therapy, while 40 patients (85.1%) were treated with osimertinib after treatment with drugs other than nivolumab. The frequency of grade 3 or 4 hepatotoxicity was significantly higher in patients with nivolumab prior to osimertinib (4/7; 57.1%) than in those treated with drugs other than nivolumab prior to osimertinib (2/40; 5.0%) (P = 0.0026). Liver biopsies were performed in two patients who received osimertinib immediately after nivolumab. In both patients, CD‐8‐positive T cell infiltration was predominantly observed in the liver tissues. Conclusions The use of osimertinib immediately after nivolumab significantly increased the frequency of grade 3 or higher hepatotoxicity in patients with advanced NSCLC harboring EGFR mutation acquired T790M resistance.

Abstract Background Amrubicin chemotherapy is a treatment option for patients with non‐small cell lung cancer (NSCLC) after third‐line treatment in Japan. Although topoisomerase‐II (Topo‐II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown. Methods Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo‐II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection. Results The majority of enrolled patients were men (68%) with a median age of 67 (range, 43–78) years. The most common histological type was adenocarcinoma (70%). High Topo‐II expression was observed in 13 (30%) of the 44 patients. The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression. Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. Conclusion Low expression of Topo‐II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo‐II inhibitor. Key points Significant findings of the study The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression. Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. What this study adds This study is the first to assess the effects of topoisomerase‐II (Topo‐II), a target of amrubicin, as a prognostic or predictive marker for chemosensitivity and clinical outcomes in the Japanese population.

Abstract Background In patients with epidermal growth factor receptor (EGFR)‐mutated advanced non‐small‐cell lung cancer (NSCLC), epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) treatment has shown a good response. Subsequent treatments jeopardize the ability to determine the effect of first‐line chemotherapy on overall survival (OS). Therefore, using patient‐level data, we aimed to study the associations of progression‐free survival (PFS) and post‐progression survival (PPS) with OS after first‐line EGFR‐TKI treatment in patients with EGFR‐mutated NSCLC. Methods Between November 2006 and December 2016, we analyzed 92 patients with EGFR‐mutated NSCLC treated with first‐line EGFR‐TKI. The correlations of PFS and PPS with OS were analyzed for each patient. Results Spearman's rank correlation and linear regression analyzes showed that PPS correlated highly with OS (r = 0.85, P

Background The aim of our study was to retrospectively assess the incidence of interstitial lung disease (ILD) related to EGFR‐tyrosine kinase inhibitor (TKI) treatment immediately before and/or after the administration of a PD‐1 antibody. Methods We analyzed the data of 26 patients who underwent treatment with EGFR‐TKIs immediately before and/or after the administration of an anti‐PD‐1 antibody. Results Four out of the 26 patients developed ILD during EGFR‐TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti‐PD‐1 antibody. Three of 12 patients who underwent EGFR‐TKI therapy immediately after anti‐PD‐1 antibody treatment experienced osimertinib‐induced ILD. ILD was not observed in the five patients administered an anti‐PD‐1 antibody followed by first or second‐generation EGFR‐TKIs. Conclusion ILD was observed in the treatment sequence of an anti‐PD‐1 antibody followed by osimertinib, but not with first or second‐generation EGFR‐TKIs.

Background It is unclear whether the chemotherapy response improves after exposure to immunotherapy. Antiangiogenic agents have been shown to stimulate the immune system and cause synergistic effects that stimulate tumor shrinkage. We conducted a retrospective study to evaluate improvement of the efficacy of ramucirumab plus docetaxel after the failure of nivolumab as a PD‐1 inhibitor. Methods From February 2016 to December 2017, 152 patients with non‐small cell lung cancer (NSCLC) administered nivolumab in our institution were identified. We reviewed the records of 20 NSCLC patients administered ramucirumab plus docetaxel after nivolumab failure. The overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were investigated. Pegylated granulocyte colony‐stimulating factor was prophylactically administered to 18 patients (90%) after the administration of ramucirumab plus docetaxel. Results The median age of the patients was 70 (range: 55–77) years. Twelve patients were male and eight were female. The histology was adenocarcinoma in 16 patients, squamous cell carcinoma in three, and other in one. The ORR of ramucirumab plus docetaxel was 60%, and the PFS and OS were 169 and 343 days, respectively. Among the 20 patients, 12 achieved a partial response, giving an ORR of 60.0%. Six patients had stable disease and two had progressive disease. The disease control rate was 90%. Gastrointestinal adverse events were frequently observed in 19 patients. Conclusions Ramucirumab plus docetaxel achieved a higher response rate when administered immediately after nivolumab failure compared to regimens without prior nivolumab administration.

Background It remains unclear why radiation clinically provides a synergistic effect when combined with immune checkpoint inhibitors such as nivolumab. The purpose of our study was to retrospectively evaluate whether the therapeutic efficacy of nivolumab is improved as a result of a history of radiotherapy (RT) in patients with previously treated advanced non‐small cell lung cancer (NSCLC). Methods From February 2016 to December 2017, 124 consecutive patients were administered nivolumab for pretreated advanced NSCLC. The patients were divided into RT and non‐RT groups. Results Sixty‐six (53%) of the 124 patients had been administered RT before the initiation of nivolumab, 52 (42%) received extracranial RT, and 40 (32%) were treated with thoracic RT. The median number of nivolumab cycles was 4 (range: 1–43). The overall response rate (ORR) and disease control rate (DCR) of nivolumab in all patients were 28.0% and 58.4%, respectively. The ORR (36.4%) was significantly higher in patients who had received previous RT than in patients who had not received any RT (19%). The therapeutic efficacy of nivolumab was particularly noteworthy in patients with non‐adenocarcinoma and squamous cell carcinoma histology administered extracranial RT, with ORRs of 48.3% and 52.6%, and DCRs of 87.1% and 84.2%, respectively. Conclusion Previous RT was an independent prognostic marker of favorable prognosis after nivolumab administration and improved the response rate to nivolumab treatment. Previous RT was clinically identified to have a synergistic effect with nivolumab treatment, increasing the response rate and improving the outcome of patients with advanced NSCLC.

Whether primary prophylactic pegylated‐granulocyte‐colony stimulating factor (PEG‐G‐CSF) should be administered immediately after the initiation of ramucirumab plus docetaxel (DR) to prevent the occurrence of febrile neutropenia (FN) is unclear. Our retrospective study aimed to elucidate whether PEG‐G‐CSF could control the occurrence of FN as a result of DR in patients with previously treated non‐small‐cell lung cancer. Thirty‐three patients with previously treated non‐small‐cell lung cancer who had received DR were eligible for our analysis. Of the 33 patients, 29 received prophylactic PEG‐G‐CSF immediately after DR, but none developed FN. However, FN was observed in 2 (50%) of the 4 patients that were not administered PEG‐CSF. The overall response and disease control rates in the 29 patients with prophylactic PEG‐GSF were 31% and 62%, respectively. The median progression‐free and overall survival rates of the patients with and without prophylactic PEG‐GSF were 177 and 163 days (P = 0.20), and 628 and 274 days (P = 0.13), respectively. Primary prophylactic PEG‐G‐CSF suppressed the occurrence of FN secondary to the administration of DR.

Abstract Immune checkpoint inhibitors (ICIs) are known to induce gastrointestinal adverse events. Colitis occurs most frequently, and gastritis is less common. A few case reports of gastritis induced by ICIs have indicated that colitis induced by cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) resembles inflammatory bowel disease (IBD) and that programmed death‐1/programmed death ligand‐1 (PD‐1/PD‐L1) inhibitor can also induce the same type of colitis. We herein encountered a case of gastritis arising after 25 cycles of pembrolizumab administration in which the pathological and endoscopic findings resembled those of IBD. ICIs may induce gastritis in a manner similar to the pathogenesis of IBD.

Background. The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small-cell lung cancer (SCLC). Therefore, by using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) or postprogression survival (PPS) and OS after first-line chemotherapies in patients with extensive disease-SCLC (ED-SCLC) treated with carboplatin plus etoposide. Methods. Between July 1998 and December 2014, we analyzed 63 cases of patients with ED-SCLC who were treated with carboplatin and etoposide as first-line chemotherapy. The relationships of PFS and PPS with OS were analyzed at the individual level. Results. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r=0.90, p

The present study investigated whether Helicobacter pylori water extract induces the upregulation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin on human umbilical vein endothelial cells, using an ELISA. The nature of the substances mediating this upregulation was also analyzed. H pylori water extract derived from type strain (NCTC 11637) significantly upregulated intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin to the same extent as interleukin-1. Treatments with extracts from clinical strains showed no significant increases in expression of these adhesion molecules. In a fractionation study, approximately 7 kDa fraction showed peak activity. This activity was tolerant to heating and trypsin digestion. These results indicate that H pylori water extract contains water-soluble, low-molecular, nonprotein substances which induce upregulation of adhesion molecules on human umbilical vein endothelial cells, suggesting that products of H pylori may elicit gastric mucosal inflammation by promoting expression of endothelial adhesion molecules.

Objective: Coatomer subunit alpha (COPA) syndrome, also known as autoinflammatory interstitial lung, joint, and kidney disease, is caused by heterozygous mutations in COPA. We identified a novel COPA variant in 4 patients in one family. We undertook this study to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these 4 patients and by analyzing results from a gene-targeted mouse model., Methods: We performed whole-exome sequencing in 7 family members and measured the type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and in Copa mutant mice that were generated., Results: We identified a heterozygous variant of COPA (c.725T>G, p.Val242Gly) in the 4 affected members of the family. The IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G, as well as the previously reported disease-causing variants, augmented stimulator of interferon genes (STING)-induced type I IFN promoter activities. Copa V242G/+ mice manifested interstitial lung disease and STING-dependent elevation of IFN-stimulated gene expression. In Copa V242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production., Conclusion: V242G, a novel COPA variant, was found in 4 patients from one family. In gene-targeted mice with the V242G variant, interstitial lung disease was recapitulated and augmented responses of the STING pathway, leading to an increase in type I IFN production, were demonstrated., (© 2021, American College of Rheumatology.)

Supported bimetallic catalysts have been studied because of their enhanced catalytic properties due to metal-metal interactions compared with monometallic catalysts. We focused on galvanic deposition (GD) as a bimetallization method, which achieves well-defined metal-metal interfaces by exchanging heterogeneous metals with different ionisation tendencies. We have developed Ni@Ag/SiO 2 catalysts for CO oxidation, Co@Ru/Al 2 O 3 catalysts for automotive three-way reactions and Pd-Co/Al 2 O 3 catalysts for methane combustion by using the GD method. In all cases, the catalysts prepared by the GD method showed higher catalytic activity than the corresponding monometallic and bimetallic catalysts prepared by the conventional co-impregnation method. The GD method provides contact between noble and base metals to improve the electronic state, surface structure and reducibility of noble metals., (© 2018 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Procaterol hydrochloride hydrate (procaterol) is a β 2 -adrenergic receptor agonist that induces a strong bronchodilatory effect. The procaterol dry powder inhaler (DPI) has been frequently used in patients with bronchial asthma or chronic obstructive pulmonary disease. We evaluated the bioequivalence and safety between the new procaterol DPI (new DPI) and the approved procaterol DPI (approved DPI). This study was a randomized, double-blind, double-dummy, crossover comparison to evaluate the pharmacodynamic equivalence of the new DPI and the approved DPI in patients with bronchial asthma. Primary efficacy variables were area under the concentration-time curve (AUC) forced expiratory volume in the first second (FEV 1 )/h and maximum FEV 1 during the 480-minute measurement period. Patients were divided into 2 groups, New-DPI-First (n = 8) and Approved-DPI-First (n = 8), according to the investigational medical product that was administered first. Patients inhaled 20 μg of procaterol in each period. FEV 1 was measured by a spirometer at predose and at 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after each investigational medical product administration. Equivalence was evaluated by confirming that the 2-sided 90%CIs for the difference between the new and the approved DPI in means of AUC (FEV 1 )/h and maximum FEV 1 were within the acceptance criteria of -0.15 to 0.15 L. The difference in means of AUC (FEV 1 )/h and maximum FEV 1 was 0.041 L and 0.033 L, respectively, and the 90%CI was 0.004 to 0.078 L and -0.008 to 0.074 L, respectively. These CIs were both within the acceptance criteria. The new DPI was assessed as being bioequivalent to the approved DPI., (© 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Guillain-Barré syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (ΔIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and ΔIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (≥5 points) were associated with an increased risk for mechanical ventilation. Patients with ΔIgG <1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and ΔIgG in GBS are clinically relevant in Japan., (© 2017 Peripheral Nerve Society.)

Background: The periprocedural protocol for atrial fibrillation (AF) ablation commonly includes anticoagulation therapy. Apixaban, a direct oral anticoagulant, is currently approved for clinical use; however, little is known about the effects of residual apixaban concentration on bleeding complications during/after AF ablation. Therefore, we measured residual apixaban concentration by using mass spectrometry and examined the anticoagulant's residual effects on bleeding complications., Methods: Fifty-eight patients (Mean age of 64.7±12.5 years; 31 males, 27 females) were enrolled and administered apixaban twice daily. We analyzed trough apixaban concentration, activated clotting time (ACT), heparin dose, and bleeding complications during/after AF ablation. Apixaban concentrations were directly measured using mass spectrometry., Results: Bleeding complications were observed in 19 patients (delayed hemostasis at the puncture site, 16; hematuria, 3; hemosputum, 1). No patient required blood transfusion. The mean trough apixaban concentration was significantly lower in patients with bleeding complications than without (152.4±73.1 vs. 206.8±98.8 ng/mL respectively, P =0.037), while the heparin dose to achieve ACT>300 s was significantly higher in patients with bleeding complications (9368.4±2929.0 vs. 7987.2±2135.2 U/body respectively, P =0.046). Interestingly, a negative correlation was found between the trough apixaban concentration and the heparin dose to achieve ACT>300 s ( P =0.033, R=-0.281)., Conclusions: Low residual plasma apixaban is associated with a higher incidence of bleeding complications during/after AF ablation, potentially because of a greater heparin requirement during AF ablation.

Background: Amiodarone is associated with a number of significant adverse effects, including elevated transaminase levels, pulmonary fibrosis, arrhythmia, and thyroid dysfunction. Although thyroid dysfunction is considered to be a common and potentially serious adverse effect of amiodarone therapy, the exact pathogenesis remains unknown because of its complex manifestations. Therefore, the prevalence of, and risk factors for, amiodarone-induced thyroid dysfunction in Japanese patients were investigated in the present study., Methods: A retrospective analysis of patients treated with amiodarone between January 2012 and December 2013 was performed. A total of 317 patients with euthyroidism, or subclinical hyperthyroidism or hypothyroidism, were enrolled in this study., Results: After being treated with amiodarone, 30 (9.5%) and 60 patients (18.9%) developed amiodarone-induced hyperthyroidism and amiodarone-induced hypothyroidism, respectively. Ten (33.3%) patients with amiodarone-induced hyperthyroidism and 40 (66.6%) with amiodarone-induced hypothyroidism were diagnosed within two years of the initiation of amiodarone therapy. Dilated cardiomyopathy (DCM) [Adjusted odds ratio (OR) 3.30 (95% confidence interval (CI): 1.26-8.90)], and cardiac sarcoidosis [Adjusted OR 6.47 (95% CI: 1.60-25.77)] were identified as predictors of amiodarone-induced hyperthyroidism. The baseline free thyroxine (T4) level [Adjusted OR 0.13 (95% CI: 0.03-0.68)], and thyroid-stimulating hormone (TSH) level [Adjusted OR1.47 (95% CI: 1.26-1.74)] were identified as predictors of amiodarone-induced hypothyroidism., Conclusion: DCM and cardiac sarcoidosis were identified as risk factors for amiodarone-induced hyperthyroidism. Risk factors for amiodarone-induced hypothyroidism included higher baseline TSH level and lower baseline free T4 level, suggesting that subclinical hypothyroidism may be a potential risk factor for the development of amiodarone-induced hypothyroidism.

Japanese cedar () and Japanese cypress () plantations account for approximately 30% of the total forested area in Japan. Both are arbuscular mycorrhizal trees that leach more NO in response to nitrogen (N) deposition than do forests of ectomycorrhizal trees. However, little information is available about the size of N exports from these plantations. The aim of this study was to evaluate nonpoint source N exports from a N-saturated plantation. We collected stream water samples in base-flow (25 samples) and storm-flow conditions (20 events) in a watershed (2.98 ha) where Japanese cypress and Japanese cedar were planted in 1969 (41 yr old). The annual NO export was calculated from load-discharge relationships. Atmospheric N deposition was also determined. The stream water contained high NO concentrations (160 and 165 μmol L during base flow and storm flow, respectively), indicating N saturation in the watershed. High bulk atmospheric N deposition (16.5 kg N ha yr) could explain the N saturation. There were only small variations in NO concentrations in stream water in response to discharge volume, because of the N saturation of the forest ecosystem. Consequently, there were only small errors in estimating annual NO exports from the studied watershed. The annual NO export was high (36.1 kg N ha yr), comparable to values reported for agricultural and urbanized areas. These results suggest that N-saturated forest plantations can become important nonpoint N sources. Our results also suggest that N exports from forest plantations across Japan should be quantified to evaluate nonpoint source N accurately., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Background: N(1),N(12)-diacetylspermine (DiAcSpm) is a recently identified tumor marker. Its concentration increases in the urine of cancer patients at early clinical stages. To utilize this characteristic feature and thus contribute to the early detection of cancer, we developed an immunochromatographic determination system for DiAcSpm., Methods: We examined the factors that affect the performance and stability of our determination system, including antibody selection and the conditions for the formation of stably dispersed antibody-coated gold nanoparticles. We then tested the performance of the system by determining the DiAcSpm concentration in human urine samples., Results: We constructed an immunochromatographic strip using anti-DiAcSpm antibody-coated gold nanoparticles in the conjugate pad and an acetylspermine-protein conjugate (a DiAcSpm mimic) immobilized on the analyzing membrane. The use of the immunochromatographic strip and an immunochromato-reader allowed for the quantitative determination of DiAcSpm in the range of 20 to 700 nM. The analytical values obtained by this method were well correlated with those determined by a colloidal gold aggregation procedure using an automatic biochemical analyzer. The immunochromatographic strip was stable for at least 8 weeks at 50°C., Conclusions: A competitive immunochromatographic device for DiAcSpm determination was developed in this study. This simple device will contribute to increasing the opportunities for early cancer detection and timely care., (© 2014 Wiley Periodicals, Inc.)

Background: KRAS and epidermal growth factor receptor (EGFR) mutations are thought to play an important role in the carcinogenesis of lung adenocarcinoma. However, clinicopathological findings of KRAS mutated adenocarcinoma cases have not yet been fully clarified. The authors analyzed the relationship between the KRAS mutation and corresponding clinicopathological findings, focusing on nonmucinous and mucinous bronchioloalveolar elements., Methods: EGFR and KRAS mutations were detected in DNA samples extracted from 182 surgically resected tissues of lung adenocarcinomas by the Smart Amplification Process. The relations between gene mutation status and clinicopathological features were analyzed. All adenocarcinoma cases were divided into bronchioloalveolar carcinoma (BAC), adenocarcinoma with bronchioloalveolar features, and adenocarcinoma without BAC components (non-BAC). BAC/adenocarcinoma with bronchioloalveolar features tumors were further assessed for the presence of mucinous features., Results: EGFR and KRAS mutations were found in 76 and 30 cases, respectively. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features was found in 22 cases, which included 10 nonmucinous and 12 mucinous tumors. Of 19 cases with mucinous BAC/adenocarcinoma with bronchioloalveolar features, KRAS mutations were detected in 12, but no EGFR mutation was detected. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features had significantly earlier pathological stages and more favorable prognoses than did non-BAC. Mucinous BAC/adenocarcinoma with bronchioloalveolar features showed less smoking history than did nonmucinous BAC/adenocarcinoma with bronchioloalveolar features and non-BAC. Furthermore, transversion type KRAS mutations were more common in non-BAC., Conclusions: KRAS mutated adenocarcinomas can be divided into BAC/adenocarcinoma with bronchioloalveolar features and non-BAC types. Non-BAC adenocarcinoma is related to smoking history and has a poor prognosis. BAC/adenocarcinoma with bronchioloalveolar features adenocarcinoma, however, has a more favorable prognosis, and mucinous BAC/adenocarcinoma with bronchioloalveolar features has little relationship to smoking history., (Copyright © 2011 American Cancer Society.)

The opsin gene family encodes G protein-coupled seven-transmembrane proteins that bind to a retinaldehyde chromophore for photoreception. It has been reported that opsin 5 is expressed in mammalian neural tissue, but its function has been elusive. As a first step to understand the function for opsin 5 in the developing eye, we searched for chicken opsin 5-related genes in the genome by a bioinformatic approach and isolated opsin 5 cDNA fragments from the embryonic retina by RT-PCR. We found that there are three opsin 5-related genes, designated cOpn5m (chicken opsin 5, mammalian type), cOpn5L1 (chicken opsin 5-like 1), and cOpn5L2 (chicken opsin 5-like 2), in the chicken genome. Quantitative PCR analysis has revealed that cOpn5m is the most abundant in the developing and early posthatching neural retina. In situ hybridization analysis has shown that cOpn5m is specifically expressed in subsets of differentiating ganglion cells and amacrine cells. These results suggest that the mammalian type opsin 5 may contribute to the development of these retinal cells in the chicken.

The aim of the present study was to estimate the time course change in cytochrome P450 3A (CYP3A) activity during repeated doses of erythromycin. Twelve healthy male volunteers participated in this randomized, 4 x 4 Latin square design study. The pharmacokinetics of a single oral dose of midazolam, a probe for CYP3A activity, were assessed in 4 conditions: (1) midazolam (5 mg) without erythromycin (EM0), (2) erythromycin 2 days + midazolam (2.5 mg) (EM2), (3) erythromycin 4 days + midazolam (2.5 mg) (EM4), and (4) erythromycin 7 days + midazolam (2.5 mg) (EM7). The dose of erythromycin was 800 mg/d. Erythromycin produced a 2.3-, 3.4-, and 3.4-fold increase in dose-corrected area under the curve of midazolam for EM2, EM4, and EM7, respectively, as compared with EM0 (P <.05/6). A significant prolongation of terminal half-life was observed in EM4 and EM7. The relationship between the duration of erythromycin treatment and total clearance of midazolam indicated that a plateau level of CYP3A inhibition can be achieved by 4 days or more of erythromycin treatment. The repeated treatment with erythromycin yields CYP3A inhibition in a duration-dependent manner. A 4-day course of erythromycin treatment produces 90% or more of the maximal inhibition of CYP3A in humans.

This study was undertaken to clarify the influence of repeated oral administration of Ginkgo biloba extract (GBE) on CYP2C9 and CYP3A4. CYP2C9 probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10 male healthy volunteers before and after GBE intake (360 mg/d) for 28 days, and they received 75 g glucose after the dosing of tolbutamide. Plasma drug concentrations and blood glucose levels were measured. The area under concentration versus time curve (AUC0-infinity) for tolbutamide after GBE intake was slightly but significantly (16%) lower than that before GBE intake. Concomitantly, GBE tended to attenuate AUC0-2 of blood glucose-lowering effect of tolbutamide. AUC0-infinity for midazolam was significantly (25%) increased by GBE intake and oral clearance was significantly (26%) decreased. Thus, it is suggested that the combination of GBE and drugs should be cautious in terms of the potential interactions, especially in elderly patients or patients treated with drugs exerting relatively narrow therapeutic windows.

Background and Objective: A concomitant dosage regimen of a histamine 2 receptor antagonist with a proton pump inhibitor (PPI) effectively decreases the incidence of nocturnal acid breakthrough, which is one of the problems encountered when acid-related diseases are treated with a PPI alone. We compared the effectiveness of an increased dosage regimen of rabeprazole with that of a concomitant dosage regimen of rabeprazole with famotidine, relative to cytochrome P450 (CYP) 2C19 genotype status, on nocturnal acid inhibition., Methods: Fifteen Helicobacter pylori-negative volunteers, consisting of 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took 20 mg rabeprazole, 40 mg rabeprazole, and 20 mg rabeprazole plus 20 mg famotidine at bedtime (at 10 PM) for 8 days. The subjects then underwent 24-hour intragastric pH monitoring on day 8., Results: For the 20-mg rabeprazole, 40-mg rabeprazole, and concomitant dosage regimens, the median percent times and ranges when nocturnal intragastric pH values were lower than 4.0 were 78.8% (47.5%-98.0%), 45.3% (29.0%-52.2%), and 15.5% (0.0%-40.8%), respectively, for homozygous EMs; 51.0% (7.0%-91.6%), 41.3% (33.0%-59.0%), and 18.5% (8.4%-31.9%), respectively, for heterozygous EMs; and 4.5% (2.0%-31.2%), 9.5% (0.0%-31.1%), and 9.3% (0.0%-14.7%), respectively, for PMs. Although significant differences in acid inhibition between the different CYP2C19 genotypes were observed when rabeprazole alone was given (P = .016 for 20 mg rabeprazole and P = .023 for 40 mg rabeprazole), such differences were not observed when famotidine was concomitantly given (P = .206)., Conclusions: The combination regimen of famotidine plus rabeprazole is more effective for nocturnal acid inhibition in homozygous and heterozygous EMs than the increased dosage regimen of rabeprazole. This concomitant therapy could be a rescue regimen for patients with nocturnal acid breakthrough refractory to a standard PPI therapy who are likely to be CYP2C19 EMs.

Objective: For the treatment of gastroesophageal reflux disease, intragastric pH should be lower than 4.0 for no more than 4 hours a day (<16.7%). We aimed to develop optimal dosage regimens for rabeprazole to control nocturnal acidity in relation to cytochrome P450 (CYP) 2C19 genotypes., Methods: Fifteen Helicobacter pylori -negative volunteers, comprising 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took placebo and rabeprazole, at a dose of 20 or 40 mg once daily (at 10 pm ) for 8 days. Plasma rabeprazole concentrations and 24-hour intragastric pH were determined on days 7 and 8, respectively. Because the nocturnal intragastric pH was lower than 4.0 for more than 16.7% of the time with once-daily regimens in homozygous EMs and heterozygous EMs, they were administered 20 mg rabeprazole twice daily (8 am and 10 pm ) or 10 mg rabeprazole 4 times daily (8 am , 12:30 pm , 6 pm , and 10 pm )., Results: With 40 mg rabeprazole once daily, the median percent time with nocturnal pH lower than 4.0 was less than 16.7% in PMs (9.5% [range, 3.0%-31.1%]) but not in homozygous EMs (45.3% [range, 29.0%-52.2%]) ( P = .043) and heterozygous EMs (41.3% [range, 33.0%-59.0%]) ( P = .043). The mean plasma rabeprazole concentrations differed among the different CYP2C19 genotype groups. With 20 mg rabeprazole twice daily and 10 mg rabeprazole 4 times daily, the median percent times with nocturnal pH lower than 4.0 were 5.0% (range, 0.0%-42.0%) and 1.0% (range, 5.0%-7.1%) in heterozygous EMs and 62.0% (range, 10.8%-68.3%) and 14.7% (range, 0.0%-41.7%) in homozygous EMs, respectively, and plasma concentrations were sustained longer than with the once-daily regimens., Conclusions: We propose that rabeprazole dosage regimens for sufficient acid inhibition are 20 mg once daily for PMs, 20 mg twice daily for heterozygous EMs, and 10 mg 4 times daily for homozygous EMs or heterozygous EMs.

To determine correlations among the levels of urinary MMP-9 and type-IV collagen, hyperglycemia, urinary protein excretion, and renal injuries in patients with type 2 diabetic nephropathy, we measured levels of urinary MMP-9 and protein, blood urea nitrogen (BUN), serum creatinine (s-Cr), fasting plasma glucose (FPG), and glycohemoglobin A1c (HbA1c) in 47 diabetic patients and 14 healthy adults. Urinary type-IV collagen was also measured in 28 diabetic patients and seven healthy adults. Patients with diabetic nephropathy were divided into two groups: 1). patients with normoalbuminuria or microalbuminuria (0-299 mg/g.Cr; n=27), and 2). patients with macroalbuminuria (>300 mg/g.Cr; n=20). The mean level of urinary MMP-9 in group 2 was significantly higher than those in healthy adults (P<0.05), and the levels of urinary MMP-9 in patients with diabetic nephropathy increased in accordance with the clinical stage of the disease. The levels of urinary MMP-9 tended to be correlated with HbA1c in these patients, but the correlation was not statistically significant. The mean level of urinary type-IV collagen in group 2 of patients with diabetic nephropathy was significantly higher than that in group 1 and healthy adults. Levels of urinary type-IV collagen in patients with diabetic nephropathy also increased in accordance with the clinical stage of the disease. The results suggest that measurements of urinary MMP-9, as well as urinary type-IV collagen, may be useful for evaluating the degree of renal injuries in patients with type 2 diabetic nephropathy, especially in the early stage., (Copyright 2004 Wiley-Liss, Inc.)

An 89-year-old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome p450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration-time curve and the mean residence time of candesartan were both increased 2.5-fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.

Background and Objectives: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD., Methods: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients., Results: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups., Conclusions: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.

Background: Sildenafil is a selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, an enzyme that is abundant in both lung and penile tissues. Sildenafil is widely used to dilate penile arteries, suggesting that it may also dilate pulmonary arteries in patients with pulmonary hypertension. However, the long-term hemodynamic effects and safety of the drug in pulmonary hypertension are not known., Methods: One patient with primary pulmonary hypertension and another with secondary pulmonary hypertension caused by collagen disease were given 50 mg oral sildenafil during cardiac catheterization for assessment of the acute hemodynamic effects of the drug. The patients were then given maintenance treatment with 25 mg oral sildenafil twice a day. Long-term hemodynamic effects were evaluated by repeated cardiac catheterization after 3 months, with the last oral dose given 15 hours before the procedure. The acute hemodynamic effects of sildenafil after the long-term treatment were studied during the same cardiac catheterization., Results: Sildenafil did not affect aortic pressure, but it significantly decreased pulmonary artery pressure and increased cardiac index, thereby reducing pulmonary vascular resistance. Long-term maintenance therapy with 25 mg oral sildenafil twice a day remarkably improved the clinical condition of the patients, without causing any adverse effects; New York Heart Association functional classification returned to class II (from class III). The acute efficacy of sildenafil was well preserved after the long-term treatment; there was no tolerance., Conclusions: The data strongly suggest that sildenafil can be used as a valuable pulmonary vasodilator in patients with pulmonary hypertension, with good long-term hemodynamic effects and safety. The results necessitate larger trials to confirm these observations in a larger cohort of patients.