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Abstract Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p

Background: A prospective evaluation of non-alcoholic fatty liver disease (NAFLD) during induction therapy for acute lymphoblastic leukemia (ALL) has not been performed. Herein, we prospectively investigated the frequency, risk factors, and outcomes of NAFLD during induction therapy in children and adolescents with B-cell precursor ALL (BCP-ALL). Methods: This study enrolled 74 newly diagnosed BCP-ALL cases aged 1 year and older who were admitted to our department between January 2011 and December 2020. Median age was 6.6 years (1.3–17.5 years). Plain computed tomography (CT) of the upper abdomen was performed before induction therapy, and on days 15 and 29 after initiation of induction therapy. Patients with a liver/spleen CT ratio

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.

Introduction: Immune checkpoint inhibitor (ICI)–based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29–0.72], OW-adjusted HR = 0.52 [95% CI: 0.35–0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70–1.48], OW-adjusted HR = 0.93 [95% CI: 0.65–1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.

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.

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7–7.7) and 18.5 months (95% CI: 3.5–33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8–64.5) and 36.4% (95% CI: 19.0–53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS (p = 0.04) as well as OS (p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.

Nephroblastomatosis (NBM) is a precursor of Wilms tumor. We herein report a case in which Wilms tumor was initially suspected and the affected kidney was removed. The tumor was subsequently diagnosed as intralobar NBM and a favorable outcome was achieved with postoperative chemotherapy. A 2-year-old boy who presented with gross hematuria was found to have an enlarged left kidney with hydronephrosis. Needle biopsy of the left kidney suggested Wilms tumor and left nephrectomy was performed. The tumor was histopathologically diagnosed as intralobar NBM. Although NBM is regarded as a precancerous lesion, a definite treatment plan has not yet been established. In the present case, we used a similar chemotherapy regimen to that for Wilms tumor. Eight years after the completion of chemotherapy, Wilms tumor has not developed or recurred. Appropriate management plans need to be developed by accumulating similar cases.

Abstract Aim Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting. Methods Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N = 93) or surgical resections (N = 14) before first-line pembrolizumab. Results A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%. Conclusion Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS.

Despite the occurrence of various hemorrhagic events during advanced lung cancer treatment, few researchers have reported on their risk factors. Moreover, the development of cancer-related thromboembolism indicates anticoagulant use. However, adverse events such as bleeding should be monitored. In this study, we aimed to identify factors that influence the onset of hemorrhagic events in patients with lung cancer. The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study. A total of 1008 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Multivariate analysis using a Cox proportional hazard model was performed to compare the outcomes of the time to the onset of hemorrhagic events for 2 years after registration. Hemorrhagic events occurred in 115 patients (11.4%), with 35 (30.4%) experiencing major bleeding. Significant risk factors included venous thromboembolism (VTE) (hazard ratio [HR]: 4.003, p < 0.001) and an Eastern Cooperative Oncology Group Performance Status score of 1 (HR: 2.476, p < 0.001). Factors that significantly reduced hemorrhagic event risk were female sex (HR: 0.454, p = 0.002) and M1a status (HR: 0.542, p = 0.038). VTE is a risk factor for hemorrhagic events in patients with advanced lung cancer, and risks associated with anticoagulant therapy should be considered.

Abstract Background Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. Methods The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. Results This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation,

Abstract Background Small-cell lung cancer (SCLC) accounts for 12–15% of lung cancers and has a limited prognosis, with approximately one-third of SCLC patients having a poor performance status (PS). Patients with extensive-stage (ES) SCLC and a poor PS have a poor prognosis. For this population, overall survival from carboplatin and etoposide treatment is 7–8 months, and treatment development is an unmet medical need. Recently, the combination of an anti-PD-L1 (a ligand for programmed cell death 1) antibody and platinum-based chemotherapy has become the standard of care for ES-SCLC patients with a good PS (PS 0–1). We hypothesized that the combination of the anti-PD-L1 antibody durvalumab with carboplatin and etoposide would be feasible and effective for such patients. Methods We initiated a multicenter phase II study of durvalumab combined with carboplatin and etoposide in previously untreated ES-SCLC patients with a poor PS (PS 2–3). Eligible patients will receive durvalumab plus carboplatin and etoposide every 3 to 4 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. The dosages of carboplatin and etoposide for the second and subsequent cycles will be adaptively determined based on the adverse events of the first cycle. A total of 56 patients (43 patients with a PS of 2 and 13 patients with a PS of 3) will be enrolled in this study, with a 24-month enrollment period and a 12-month follow-up. The primary endpoint is the tolerability of carboplatin and etoposide plus durvalumab in previously untreated ES-SCLC patients with a poor PS. The secondary endpoints are the 1-year survival rate, objective response rate, progression-free survival, overall survival, ratio of PS improvement, and safety. Discussion The results of this study are intended to establish the safety and efficacy of carboplatin and etoposide plus durvalumab in patients with ES-SCLC and a poor PS. Trial registration Japan Registry of Clinical Trials (jRCT), jRCTs031200319. Registered 21 January 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs031200319

Proponents of agroecology and food sovereignty are trying to form seed commons as a framework against the formal seed systems established by governments. However, we argue that the formation of seed commons should not be considered as a dichotomy that distinguishes between the government and stakeholders, including farmers, but rather as a dichotomy that divides the scope of activities into those regulated by law and those that can be determined by farmers at their own discretion. Japan, like many other countries, is a signatory to the International Treaty on Plant Genetic Resources for Food and Agriculture and the International Union for the Protection of New Varieties of Plants, both of which contain important elements for the conservation of agricultural biodiversity and agroecology at the national and local level. Based on the proposed dichotomy, this study aims to explore the possibility of creating seed commons for seed sharing in Japan. We clarify the policies and actual conditions surrounding the access and use of seeds and explore the possibility of creating seed commons.

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 Management of cancer-associated venous thromboembolism (VTE) is essential in treatment selection and cancer prognosis. However, to date, there is no method to assess the risk of VTE specifically associated with advanced lung cancer. Our aim was to create a new risk assessment scoring system that can predict the concomitant or incidence of VTE in advanced lung cancer. We used the dataset of 1008 patients with lung cancer in the Rising-VTE/NEJ037 study, of which 100 (9.9%) developed VTE. The items extracted in the multivariate analysis included female sex, adenocarcinoma, performance status, N factor, lymphocyte count, platelet count, prothrombin fragment 1 + 2, and diastolic blood pressure. This model had a maximum score of 8 points, with ≥ 5 points indicating a high risk of VTE. This simple risk-assessment model for VTE complications with advanced lung cancer could help identify cases that required monitoring for VTE.

Background: Antibiotics have been widely and efficaciously used for febrile neutropenia in pediatric patients. However, reports are scant regarding the risk factors for recurrent fever after discontinuation of antibiotics in a neutropenic state. Here, we investigated these factors using data from our previously reported randomized study regarding meropenem and piperacillin/tazobactam for pediatric patients with febrile neutropenia. Procedure: We analyzed a total of 170 febrile episodes where first line antibiotic treatment was effective and discontinued before neutrophil recovery. Results: Recurrent fever was observed in 31 episodes (18%). The median interval from antibiotics discontinuation to recurrent fever was 5 days (0–27 days). Risk factors for recurrent fever were: incomplete remission of original disease; and high white blood cell count, neutrophil count, and C reactive protein levels at start of antibiotics. Moreover, lower neutrophil count at discontinuation of antibiotics, duration of neutropenia, and onset day of febrile neutropenia from start of neutropenia were also risk factors of recurrent fever. In multivariate analysis, neutrophil count at discontinuation of antibiotics

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

Background : : Febrile neutropenia (FN) remains an important complication in pediatric cancer patients. The present study compared the efficacy of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) with or without intravenous immunoglobulin (IVIG) as second-line therapy for FN in pediatric patients. Methods : : As first-line treatment for FN, 394 episodes in 99 patients were randomly assigned to receive PIPC/TAZ (360 mg/kg/day, maximum 18 g/day) or MEPM (120 mg/kg/day, maximum 3 g/day). Eighty-four episodes in 42 patients were judged as failures, and, thus, were enrolled for second-line treatment. In second-line treatment, antibiotics were switched to MEPM or PIPC/TAZ, and episodes were further randomized for treatment with or without concomitant IVIG at 100 mg/kg/day (maximum 5 g/day) for 3 consecutive days. Results : : The total success rate of second-line treatment was 50.0% (52.0% in PIPC/TAZ and 47.2% in MEPM with or without IVIG, P=0.826). The success rates of patients treated with (IVIG+ group) and without IVIG (IVIG− group) were 53.8 and 46.7%, respectively (P=0.662). In the IVIG+ group, the success rate of patients younger than 8 years old was 78.6%, which was significantly higher than that of those aged 8 years and older (40.0%, P=0.043). Conclusion : : PIPC/TAZ and MEPM were equally effective as second-line treatment. Concomitant IVIG was also effective, particularly in patients younger than 8 years.

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 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.

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors. Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation. Results: Data were available for 1008 patients. The median age was 70 years (range: 30–94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group. Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate. Trial registration: jRCTs061180025.

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 Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Methods This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. Results In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. Conclusion Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. Trial registration The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

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.

Abstract 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 .)

Abstract Background Durvalumab is a standard drug used during maintenance therapy after chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the clinical benefits of durvalumab after chemoradiotherapy in patients with LA-NSCLC with a performance status (PS) of 2 and/or aged > 75 years. As daily carboplatin plus concurrent thoracic radiotherapy is recommended for elderly patients according to guideline, the current phase II study aims to investigate the effect of daily carboplatin plus radiotherapy followed by durvalumab for patients with stage III NSCLC who have a PS of 2 and/or are older. Methods Daily carboplatin plus radiotherapy followed by durvalumab is performed for the patients with stage III NSCLC who have a PS of 2 and/or are older. This is a trial in progress manuscript. Study treatment Daily, intravenous, low-dose carboplatin (30 mg/m2 in a 30-min infusion) is administered to patients 1 h before radiotherapy for the first 20 fractions. Radiotherapy for all patients consisted of 60 Gy administered as 30 fractions over 6 weeks. Durvalumab at a dose of 10 mg/kg/body is intravenously administered every 2 weeks for up to 12 months after chemoradiotherapy. Exploratory assessment In the future, an exploratory investigation will be performed to determine whether the combined assessment of T-cell markers, PD-L1 expression, and tumor mutation burden could predict the outcomes of the regimen. Discussion The results of our study will exhibit the efficacy and tolerability of durvalumab as maintenance therapy after daily carboplatin plus radiotherapy. Trial registration During the first registration (before induction chemoradiotherapy), 70 patients will be included; then, we include 58 patients during the second registration (before durvalumab treatment after chemoradiotherapy). https://jcrb.niph.go.jp/ . Primary endpoint The primary endpoint of the current study is the 12-month progression-free survival (PFS) rate after the initiation of durvalumab. Secondary endpoints The secondary endpoints are the feasibility, objective response, PFS, overall survival, and adverse events.

Background Pleurodesis is the standard of care for non‐small cell lung cancer (NSCLC) patients with symptomatic malignant pleural effusion (MPE). However, there is no standard management for MPE uncontrolled by pleurodesis. Most patients with unsuccessful MPE control are unable to receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of MPE. This multicenter, phase II study investigated the effects of bevacizumab plus chemotherapy in nonsquamous NSCLC patients with unsuccessful management of MPE. Methods Nonsquamous NSCLC patients with MPE following unsuccessful tube drainage or pleurodesis received bevacizumab (15 mg/kg) plus chemotherapy every three weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE at eight weeks. Secondary endpoints included pleural progression‐free survival (PPFS), safety, and quality of life (QoL). Results A total of 20 patients (median age: 69 years; 14 males; 20 adenocarcinomas; six epidermal growth factor receptor mutations) were enrolled in nine centers. The PECR was 80% and the primary end point was met. The PPFS and the overall survival (OS) were 16.6 months and 19.6 months, respectively. Patients with high levels of VEGF in the MPE had shorter PPFS (P = 0.010) and OS (P = 0.002). Toxicities of grade ≥ 3 included neutropenia (50%), thrombocytopenia (10%), proteinuria (10%), and hypertension (2%). The cognitive QoL score improved after treatment. Conclusions Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE, and should be considered as a standard therapy in this setting. Key points Significant findings of the study Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE. What this study adds Bevacizumab plus chemotherapy should be considered as a standard treatment option for patients with uncontrolled MPE. Clinical trial registration UMIN000006868 was a phase II study of efficacy of bevacizumab plus chemotherapy for the management of malignant pleural effusion (MPE) in nonsquamous non‐small cell lung cancer patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ‐013B) (http://umin.sc.jp/ctr/).

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.

Thin-film sensors were used to measure the oil film pressure distribution at the piston pin-bore interface in order to ascertain the stress distribution on the piston pin of a gasoline engine during actual operation. Thin-film sensors have been manufactured by a sputtering method to a total film thickness of about 3–6 μm. The features of thin-film sensors have been utilized to successfully measure the oil film pressure on engine main bearings, connecting rod bearings and piston skirts of both diesel and gasoline automotive engines. However, as engine lubrication conditions have become more severe year by year, it has become necessary to develop thin-film pressure sensors with higher durability. The use of diamond-like carbon (DLC) coating for the protective film of the thin-film sensor has enabled accurate measurement of oil film pressure under engine operating conditions. The AVL EXCITETM Power Unit was used in simulations with the application of elastic fluid lubrication theory. The calculated values were compared with measured data, and a comparison was made of the effect of the model constraint condition.

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.

BackgroundImmune checkpoint inhibitor (ICI) therapy has been described to markedly improve patient survival. However, reports describing the antitumor therapeutic efficacy and safety of ICIs in patients with autoantibodies are scarce.MethodsThis study examined the efficacy and feasibility of ICIs in antinuclear antibody (ANA)-positive patients with non-small cell lung cancer (NSCLC). An ANA titer greater than 1:40 and 1:80 was defined as positive and high, respectively. Patients who were treated with ICIs at Saitama Medical University, International Medical Center between January 2016 and December 2018 were retrospectively reviewed.ResultsOne hundred and nineteen of the 266 patients (44.7%) who received nivolumab, pembrolizumab, and atezolizumab had positive ANA titers. Their median age was 69 (range, 39–84) years. The overall response rate of the ANA-positive patients was 35.9% (37/103), which was not less than that of the ANA-negative group. The median progression-free survival in the ANA-positive group was 6.3 months versus 4.3 months in the ANA-negative group (p = 0.08). Twenty-seven ANA-positive patients (10.2%) had high ANA titers. However, ICI efficacy was not decreased in these patients. Regardless of the cutoff of ANA titers (1:40 or 1:80), the rate of patients who experienced adverse events were not significantly different between the two groups.ConclusionThe administration of ICIs to ANA-positive patients has clinical benefits. The prevalence of adverse events in the ANA-positive group was not higher than that in the ANA-negative group.

The optimal tumor marker for predicting the prognosis of advanced thymic carcinoma (ATC) remains unclear. We conducted a multi-institutional retrospective study of patients with ATC. A total of 286 patients were treated with chemotherapy. Clinicopathological information, including serum tumor markers, was evaluated to determine the overall survival (OS) and progression-free survival (PFS). The carcinoembryonic antigen, cytokeratin-19 fragment, squamous cell carcinoma (SCC) antigen, progastrin-releasing peptide, neuron-specific enolase (NSE), and alpha-fetoprotein levels were evaluated. In the Kaplan–Meier analysis, the OS was significantly shorter in the patients with elevated NSE levels than in those with normal NSE levels (median, 20.3 vs. 36.8 months; log-rank test p = 0.029; hazard ratio (HR), 1.55; 95% confidence interval (CI), 1.05–2.31 (Cox proportional hazard model)); a similar tendency regarding the PFS was observed (median, 6.4 vs. 11.0 months; log-rank test p = 0.001; HR, 2.04; 95% CI, 1.31–3.18). No significant differences in the OS and PFS were observed among the other tumor markers. In both univariate and multivariate analyses of the patients with SCC only, the NSE level was associated with the OS and PFS. Thus, the NSE level may be a prognostic tumor marker for thymic carcinoma, regardless of histology.

Integration of scientific knowledge into negotiations of the Multilateral Environment Agreements (MEAs) is crucial to effective implementation of those MEAs by ensuring uniformity in their terminology. Recent innovations in the field of biotechnology provoked a discussion over “Digital Sequence Information” (DSI) in fora of several MEAs. In the context of this discussion, the term DSI remains ambiguous and encompasses a wide range of concepts, including, at least, DNA/RNA base sequence data. We focused on how the term “DSI” was regarded in negotiations of the Convention on Biological Diversity and the International Treaty on Plant Genetic Resources for Food and Agriculture, analyzed the changes of terminology for DSI in the opinions or views of the Parties in the supreme decision-making bodies of these agreements from the perspective of the MEAs implementation. Based on these efforts we suggest the ways and means to support challenges regarding integration of scientific knowledge into MEAs.

Background: Although survival of children with hematological diseases and cancer has increased dramatically, life-threatening complications due to bacterial infections occur in 5–10% of febrile episodes in pediatric cancer patients. A prospective randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) with or without intravenous immunoglobulin (IVIG) as second-line therapy for pediatric patients with febrile neutropenia (FN). Procedure: As first-line therapy for FN, 105 patients with 434 episodes were randomly assigned to receive MEPM or PIPC/TAZ. A total of 71 pediatric patients and 144 episodes were judged as failures and enrolled for second-line treatment. In second-line treatment, patients were randomized to a group of MEPM and PIPC/TAZ with or without IVIG. MEPM was given to patients who received PIPC/TAZ as first-line treatment, and PIPC/TAZ was given to patients who received MEPM as first-line treatment. Results: The total success rate of second-line therapy was 49.3%. MEPM with or without IVIG was effective in 44.3% of cases, and PIPC/TAZ with or without IVIG was effective in 55.3%; this difference was not significant. The success rate in patients with serum IgG under 1000 mg/dl was 41.3% in the MEPM or PIPC/TAZ group and 64.3% in the MEPM + IVIG or PIPC/TAZ + IVIG group (p = 0.028). Conclusions: The present results suggest that PIPC/TAZ is as effective as MEPM and safe for second-line treatment of FN in pediatric patients. Furthermore, IVIG appears very effective for patients with low serum IgG levels. Keywords: Meropenem, Piperacillin/tazobactam, Immunoglobulin, Febrile neutropenia

Background: Pediatric patients under treatment for acute myeloid leukemia (AML) are at high risk for invasive fungal infection (IFI). We evaluated the efficacy of prophylactic administration of voriconazole (VRCZ) with two different doses. Methods: Between October 2005 and June 2011, 17 children and adolescents (aged 0–20 years) undergoing chemotherapy for AML were prophylactically administered with 5 mg/kg/d of oral VRCZ. Furthermore, 22 AML patients (aged 0–19 years) were administered 10 mg/kg/d of oral VRCZ between July 2011 and December 2014. The incidences of IFI with two different doses of VRCZ were compared. Results: Irrespective of the dosage of VRCZ, eight patients developed IFI. Of these eight patients, four belonged to the 5 mg/kg/d group and four to the 10 mg/kg/d group. Cumulative incidences of IFI at 180 days after the initiation of chemotherapy were not different between the 5 mg/kg/d and 10 mg/kg/d groups. The trough plasma VRCZ concentration in the 10 mg/kg/d group ranged from < 0.09 μg/mL to 2.17 μg/mL, with a median level of 0.27 μg/mL, and patients with the targeted trough concentration (1–4 μg/mL) comprised only 18.8% of the evaluable patients in this group, whereas the trough plasma VRCZ concentration of the evaluable patients in the 5 mg/kg/d group were all below the limit of sensitivity (< 0.09 μg/mL). Conclusion: More dose escalation is required based on this study. As VRCZ concentration is considerably influenced by genetic polymorphisms and drug–drug interactions, VRCZ should be used under therapeutic drug monitoring to keep effective drug concentrations. Keywords: acute myeloid leukemia, concentration, invasive fungal infection, prophylaxis, voriconazole

Objectives: Programmed death-1(PD-1)/programmed death ligand-1 (PD-L1) antibodies have clinical benefits for cancer patients facing immune-related adverse events (irAEs). However, the effect of steroid use on the prognosis of patients with non-small cell lung cancer (NSCLC) receiving PD-1 blockade remains unclear. Methods: NSCLC patients with complete response (CR)/partial response (PR) or stable disease (SD)/not evaluable (NE) status plus progression-free survival (PFS) of 180 days after PD-1 blockade from December 2015 to December 2018 were retrospectively registered in our study and were divided into two groups: those with and without systemic steroid use for irAEs. Results: In total, 126 patients who had benefitted from PD-1 blockade were enrolled in our study; among them, 44 received systemic steroids for irAEs, and 82 had no adverse events or, if they did, did not receive systemic steroids. Among the 44 patients requiring steroids, interstitial lung disease (ILD), adrenal insufficiency, diarrhea, and liver dysfunction were observed in 19, 9, 4, and 4 patients, respectively. More side effects were observed in the group treated by steroids. The median PFS and overall survival (OS) in patients with and without systemic steroid use were 11.7 and 16.0 months (p < 0.037) and 35.0 and 41.0 months (p < 0.28), respectively. In univariate and multivariate analyses of survival, systemic steroid treatment for irAEs was significantly associated with PFS. The occurrence of ILD, adrenal insufficiency, and fever was significant in patients who used systemic steroids for irAEs. Conclusions: Patients administered systemic steroids for irAEs due to PD-1 blockade treatment exhibited shorter PFS than those who were not. Systemic steroids might affect survival after PD-1 blockade even for patients who once acquired its clinical benefit.

The aim of this study was to elucidate risk factors for mortality after developing sepsis in pediatric patients with hematologic and malignant disorders. Methods: A total of 90 patients (43 boys, 47 girls) with various hematologic and malignant diseases who experienced sepsis between June 2006 and March 2014 were enrolled. Clinical and laboratory features of 134 episodes of sepsis observed in the 90 patients were compared between those with and without sepsis-related death which was defined as death within 14 days after sepsis. Results: Age at hospitalization, sex, and type of underlying disease did not differ between patients with and without sepsis-related death. Sepsis episode-based univariate analysis identified patients with a history of relapse or in a refractory state of underlying disease (p

It remains unclear whether the accumulation of 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) before the initiation of anti-programmed death-1 (PD-1) antibody can predict the outcome after its treatment. The aim of this study is to retrospectively examine the prognostic significance of 18F-FDG uptake as a predictive marker of anti-PD-1 antibody. Eighty-five patients with previously treated non-small cell lung cancer (NSCLC) who underwent 18F-FDG-positron emission tomography (PET) just before administration of nivolumab or pembrolizumab monotherapy were eligible in our study, and metabolic tumor volume (MTV), total lesion glycolysis (TLG) and the maximum of standardized under value (SUVmax) on 18F-FDG uptake were assessed. Objective response rate, median progression-free survival and median overall survival were 36.6%, 161 days and 716 days, respectively. The frequency of any immune-related adverse events was significantly higher in patients with low 18F-FDG uptake on PET than in those with high uptake. By multivariate analysis, the tumor metabolic activity by TLG and MTV was identified as an independent prognostic factor for predicting outcome after anti-PD-1 antibody therapy, but not SUVmax, predominantly in patients with adenocarcinoma. Metabolic tumor indices as TLG and MTV on 18F-FDG uptake could predict the prognosis after anti-PD-1 antibodies in patients with previously treated NSCLC.

Background: Although the concept of induction therapy followed by surgical resection for locally advanced non-small cell lung cancer (LA-NSCLC) has found general acceptance, the appropriate indications and the strategy for this treatment are still controversial. Methods: From 2000 through 2008, 36 patients received concurrent chemoradiotherapy followed by surgery. We retrospectively reviewed these cases, analyzed the outcomes and examined the prognosis. Results: The median radiation dose given was 60 Gy. Chemotherapy included a platinum agent in all cases; cisplatin-based chemotherapy was administered to 9 cases, and a carboplatin-based chemotherapy regimen was administered to 27. A complete resection was performed in 94% of the patients. Seventeen (47.2%) patients exhibited a complete pathological response, and downstaging was induced in 26 (72%) cases. The morbidity and 30-day mortality rates were 11.1 and 0%, respectively. The 5-year overall survival rate in the patients with complete resection (n = 33) was 83.3%. Conclusions: Induction chemoradiotherapy followed by surgery for LA-NSCLC provided a favorable prognosis for selected patients. A complete pathological response was found in about half of cases. This strategy is feasible and was associated with low morbidity and high resectability rates, suggesting that it contributed to improving the treatment results.

Molecular targeting therapy for non-small cell lung cancer (NSCLC) has clarified the importance of mutation testing when selecting treatment regimens. As a result, multiple-gene mutation tests are urgently needed. We developed a next-generation sequencer (NGS)-based, multi-gene test named the MINtS for investigating driver mutations in both cytological specimens and snap-frozen tissue samples. The MINtS was used to investigate the EGFR, KRAS, BRAF genes from DNA, and the ERBB2, and the ALK, ROS1, and RET fusion genes from RNA. We focused on high specificity and sensitivity (≥0.99) and even included samples with a cancer cell content of 1%. The MINtS enables testing of more than 100 samples in a single run, making it possible to process a large number of samples submitted to a central laboratory, and reducing the cost for a single sample. We investigated 96 cytological samples and 190 surgically resected tissues, both of which are isolated in daily clinical practice. With the cytological samples, we compared the results for the EGFR mutation between the MINtS and the PNA-LNA PCR clamp test, and their results were 99% consistent. In the snap-frozen tissue samples, 188/190 (99%) samples were successfully analyzed for all genes investigated using both DNA and RNA. Then, we used 200 cytological samples that were serially isolated in clinical practice to assess RNA quality. Using our procedure, 196 samples (98%) provided high-quality RNA suitable for analysis with the MINtS. We concluded that the MINtS test system is feasible for analyzing "druggable" genes using cytological samples and snap-frozen tissue samples. The MINtS will fill a needs for patients for whom only cytological specimens are available for genetic testing.

Background: An asthma-specific questionnaire, the Asthma Health Questionnaire (AHQ) was developed for Japanese asthmatic patients. A self-administered 37-item version (AHQ-37) consisting of 36 disease-specific items and a Face Scale was designed for socially active patients. Methods: Exploratory factor analysis, test-retest reliability, internal consistency, concurrent validity and longitudinal validity were evaluated. A total of 326 asthma patients (202 men; range of age from 18 to 65 years) answered the AHQ-37 twice. Results: Each item of the AHQ-37 was well accepted by the patients with answering rates of 95 to 100%. Six subscales (Asthmatic Symptoms, Emotion, Daily Activity, Factors which Worsened Symptoms, Social Activity and Economics) were extracted by factor analysis. Psychometric testing showed high feasibility, good repeatability and good internal consistency. The Face Scale moderately correlated with all subscales except for Economics, indicating that the Face Scale alone could measure global quality of life (QOL) functioning of asthmatic patients. Concurrent validity with peak-flow values was insufficient (Spearman’s correlation coefficient = 0.05−0.27), showing that the peak flow alone could not estimate QOL. In longitudinal validity, however, changes in peak-flow values had an impact on the Asthmatic Symptoms, Daily Activity and Factors which Worsened Symptoms (P = 0.000−0.419), indicating that changes in peak-flow were important to asthmatic patients’ QOL. Conclusions: The QOL of asthmatic patients must be evaluated by asthma-specific questionnaires, such as the AHQ-37.

Commensal organisms are frequent causes of pneumonia. However, the detection of these organisms in the airway does not mean that they are the causative pathogens; they may exist merely as colonizers. In up to 50% cases of pneumonia, the causative pathogens remain unidentified, thereby hampering targeting therapies. In speculating on the role of a commensal organism in pneumonia, we devised the battlefield hypothesis. In the "pneumonia battlefield," the organism-to-human cell number ratio may be an index for the pathogenic role of the organism. Using real-time PCR reactions for sputum samples, we tested whether the hypothesis predicts the results of bacteriological clinical tests for 4 representative commensal organisms: Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas spp., and Moraxella catarrhalis. The cutoff value for the organism-to-human cell number ratio, above which the pathogenic role of the organism was suspected, was set up for each organism using 224 sputum samples. The validity of the cutoff value was then tested in a prospective study that included 153 samples; the samples were classified into 3 groups, and each group contained 93%, 7%, and 0% of the samples from pneumonia, in which the pathogenic role of Streptococcus pneumoniae was suggested by the clinical tests. The results for Haemophilus influenzae, Pseudomonas spp., and Moraxella catarrhalis were 100%, 0%, and 0%, respectively. The battlefield hypothesis enabled legitimate interpretation of the PCR results and predicted pneumonia in which the pathogenic role of the organism was suggested by the clinical test. The PCR reactions based on the battlefield hypothesis may help to promote targeted therapies for pneumonia. The prospective observatory study described in the current report had been registered to the University Hospital Medical Information Network (UMIN) registry before its initiation, where the UMIN is a registry approved by the International Committee of Medical Journal Editors (ICMJE). The UMIN registry number was UMIN000001118: A prospective study for the investigation of the validity of cutoff values established for the HIRA-TAN system (April 9, 2008).

Efficacy of short-course therapy with cephalosporins for treatment of group A β-hemolytic streptococcus (GABHS) pharyngitis is still controversial. Subjects were 226 children with a history of at least one episode of GABHS pharyngitis. Recurrence within the follow-up period (3 weeks after initiation of therapy) occurred in 7 of the 77 children in the 5-day treatment group and in 1 of the 149 children in the 10-day treatment group; the incidence of recurrence being significantly higher in the 5-day treatment group. Bacteriologic treatment failure (GABHS isolation without overt pharyngitis) at follow-up culture was observed in 7 of the 77 children in the 5-day treatment group and 17 of the 149 children in the 10-day treatment group. There was no statistical difference between the two groups. A 5-day course of oral cephalosporins is not always recommended for treatment of GABHS pharyngitis in children who have repeated episodes of pharyngitis.