Durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis following concurrent chemoradiotherapy: a multicenter prospective cohort study.

Introduction/Background Durvalumab demonstrated a good efficacy and safety in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in the PACIFIC trial. Although a history of radiation pneumonitis (RP) has been reported to increase the risk of pneumonitis associated with programmed death-1 inhibitors, the safety and efficacy of durvalumab in patients with baseline Grade 1 RP have not been assessed. Therefore, we carried out a multicenter prospective cohort study to evaluate the efficacy and safety of durvalumab in these patients. Patients and Methods This was a multicenter prospective cohort study of 35 patients with Grade 1 RP after CCRT and before durvalumab initiation. This study was a first prespecified analysis for the first 20 patients with the primary objective of assessing the short-term safety; it was assessed 3 months after durvalumab initiation. Results Twenty patients were enrolled in this study between March 1, 2019, and September 3, 2019. Three patients (15%) experienced drug-related Grade ≥3 adverse events, while three patients (15%) had Grade ≥2 pneumonitis/RP within 3 months after durvalumab initiation. Three months after durvalumab initiation, all the patients were alive and four patients (20%) experienced disease progression. Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.).

Risk factors for skeletal-related events in non-small cell lung cancer patients treated with bone-modifying agents.

PURPOSE: The risk factors for skeletal-related events (SREs) among non-small cell lung cancer (NSCLC) patients during treatment with bone-modifying agents (BMAs) are not yet well-understood. METHODS: The medical records of 238 consecutive NSCLC patients treated with BMAs, including zoledronic acid and denosumab, at the Chiba University Hospital from 2012 to 2016 were reviewed in the present study. SREs were defined as either pathologic fractures, spinal cord compression, the need for bone irradiation or surgery, or hypercalcemia. The risk factors for earlier occurrence of the first SRE from the time of the first bone metastasis diagnosis after the initiation of BMA treatment were identified. RESULTS: Of the 238 included patients, 92% (n = 220) had a performance status (PS) of 0-2 at diagnosis of bone metastasis. Forty-eight (20%) patients developed at least one SRE. The most common first SRE was the need for bone irradiation surgery (n = 27, 56%). Significant risk factors included poor PS (hazard ratio [HR]: 4.36; p = .024), male sex (HR: 2.17; p = .022), and the use of zoledronic acid (HR: 1.91; p = .032). The overall survival (OS) from the first bone metastasis diagnosis was 394 days (95% confidence interval [CI]: 331-465). The OS of patients with PS 3 and 4 at the diagnosis of bone metastasis (median: 36 days; 95% CI: 13-50) was significantly (p < 0.0001) shorter than that of patients with PS 0-2 (median: 411 days; 95% CI: 354-558) (HR: 4.53; 95% CI: 2.62-7.35). CONCLUSIONS: Careful observation is needed for patients with the identified risk factors, which include poor PS and male sex, despite the BMA treatment.

Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma.

BACKGROUND: Mucosal melanoma is a rare and aggressive malignancy with poorer response compared with cutaneous melanoma. Prospective trials of immune checkpoint inhibitors in unresectable or metastatic mucosal melanoma have not been reported. PURPOSE: This phase II trial assessed the efficacy and safety of nivolumab monotherapy for unresectable or metastatic mucosal melanoma. PATIENTS AND METHODS: Eligibility criteria were as follows: histological diagnosis of unresectable or metastatic mucosal melanoma; age ≥ 20 years; ECOG performance status 0 or 1; and with measurable lesions. Patients received nivolumab 2 mg/kg every 3 weeks. The primary endpoint was the response rate (RR) according to Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were overall survival, progression-free survival, disease control rate, and toxicity. RESULTS: Twenty patients were enrolled between December 2014 and July 2017. Two patients without measurable lesions and one patient with uveal melanoma were excluded from analysis of efficacy. The best overall RR was 23.5%. One patient achieved a complete response, three partial response, and five stable disease as their best response. The median progression-free survival was 1.4 months (95% CI 1.2-2.8). The median overall survival was 12.0 months (95% CI 3.5 to not reached). The 1-year overall survival was 50.0% (95% CI 25.9-70.0%). Treatment-related adverse events of grades 3 or 4 occurred in 15% (3/20) of the patients. Grade 3 adverse events were resolved by corticosteroid treatment. CONCLUSION: Although this trial met the primary endpoint, the RR was still unsatisfactory. Therefore, further treatment development is required.

Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis. METHODS: In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB-IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0-15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2-21·0) compared with 13·3 months (11·1-15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417-0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3-4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred. INTERPRETATION: The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting. FUNDING: Chugai Pharmaceutical.

Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study.

BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

Amrubicin Monotherapy for Patients with Platinum-Pretreated Non-Gastrointestinal Non-Pancreatic Extrapulmonary Neuroendocrine Carcinoma.

OBJECTIVE: The aim of this study was to investigate the clinical usefulness of amrubicin therapy for patients with non-gastrointestinal (GI) non-pancreatic extrapulmonary neuroendocrine carcinoma (EP-NEC). METHODS: The medical records of patients from the 2 participating institutions were retrospectively reviewed. The eligibility criteria were: patients with non-GI non-pancreatic EP-NEC who received amrubicin monotherapy after platinum-based chemotherapy. Patients in whom the platinum-free interval (interval between the last day of platinum administration and the first subsequent documentation of disease progression) was 90 days or longer were classified into the platinum-sensitive group. RESULTS: The study was conducted in a total of 13 patients identified as eligible. The response rate was 45.4% (5/11). The median progression-free survival and overall survival were 6.0 and 10.6 months, respectively. A platinum-free interval of ≥90 days was identified as a significant predictor of a longer progression-free survival time. Grade 3 or 4 neutropenia was observed in 61.5% (8/13) of the patients. One patient died of treatment-related febrile neutropenia. CONCLUSIONS: Amrubicin monotherapy as second-line chemotherapy after failure of first-line platinum-based chemotherapy showed good efficacy in patients with non-GI non-pancreatic EP-NEC. Neutropenia was encountered as the most serious adverse event.

Feasibility study of first-line chemotherapy using Pemetrexed and Bevacizumab for advanced or recurrent nonsquamous non-small cell lung cancer in elderly patients: TORG1015.

BACKGROUND: The addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous non-small cell lung cancer (NSCLC). To date, there is no evidence to suggest that treatment with a cytotoxic agent plus bevacizumab is more effective than a cytotoxic agent alone for nonsquamous NSCLC in elderly patients. We conducted a feasibility study of pemetrexed plus bevacizumab as a first-line treatment for advanced or recurrent nonsquamous NSCLC in elderly patients. METHODS: Major eligibility and exclusion criteria included: chemotherapy-naive status; non-fitness for bolus combination chemotherapy; stage III/IV or relapsed nonsquamous NSCLC; age ≥70; performance status 0-1; absence of brain metastasis; and no history of hemoptysis and thoracic irradiation. Pemetrexed (500 mg/m(2)) and bevacizumab (15 mg/kg) were administered intravenously on day 1, and repeated every 3 weeks thereafter. The primary endpoint was safety, and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of patients who completed ≥3 cycles. RESULTS: From October 2010 to April 2012, a total of 12 patients were enrolled. No dose-limiting toxicity or treatment-related deaths were observed. Three patients achieved PR, and the ORR was 25 %. The median PFS and OS were 5.4 months (95 % CI 1.1-8.8 months) and 13.6 months (95 % CI 5.3-15.6 months), respectively. Seven of 12 patients (58 %) received ≥3 cycles. CONCLUSIONS: Pemetrexed plus bevacizumab in the treatment of elderly patients with nonsquamous NSCLC was well tolerated and shows promise as first-line treatment. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004263 . Registered on 25 September, 2010.

Safety of a short hydration method for cisplatin administration in comparison with a conventional method-a retrospective study.

OBJECTIVE: Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. METHODS: Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. RESULTS: An elevated serum creatinine level ≥grade 1 was significantly less frequent in the group receiving the short hydration protocol than in the group receiving conventional hydration. Other toxicities were similar between the two groups. Consequently, the completion rate for the planned treatment in the short hydration group (73.0%, 54/74) was significantly higher than that in the conventional hydration group (53.6%, 37/69). CONCLUSIONS: Short hydration is safe, making cisplatin-containing chemotherapy easier to perform.

Phase II study of carboplatin, docetaxel and bevacizumab for chemotherapy-naïve patients with advanced non-squamous non-small cell lung cancer.

PURPOSE: To evaluate a 3-drug combination of carboplatin, docetaxel and bevacizumab as a front-line chemotherapy for patients with advanced non-squamous non-small cell carcinoma (NSCLC), a single arm phase II study was conducted. METHODS: Patients with stage IIIB/IV or postoperative recurrent non-squamous NSCLC were treated with carboplatin (targeted area under the curve of 6 mg h/L), docetaxel (60 mg/m(2)), and bevacizumab (15 mg/kg) on day 1, repeated every 3 weeks for 4 to 6 cycles, followed by maintenance with bevacizumab every 3 weeks until disease progression or occurrence of predefined toxicity. The planned patient number was 40, and the primary endpoint was progression free survival (PFS) as assessed by independent reviewers. RESULTS: One patient refused the treatment after enrollment; thus, 39 patients were treated and analyzed. The 3-drug therapy was delivered for a median of 4 cycles, and 54 % of the patients proceeded to the maintenance therapy for a median of 4 cycles. The overall response rate was 74.4 % (29/39), with a 95 % confidence interval (CI) of 60.0 to 88.7 %. The median PFS and overall survival (OS) were 6.2 months (95 % CI, 4.8-8.5 months) and 22.4 months (95 % CI, 11.3-26.2 months), respectively. Toxicities of grade 3 or higher included neutropenia in 71.8 %, febrile neutropenia in 23.1 %, and hypertension in 38.5 % of the patients, but they were transient and manageable. CONCLUSION: The primary endpoint was met. The regimen yielded promising results with an excellent overall response rate, PFS, and OS for chemotherapy-naïve patients with advanced non-squamous NSCLC. Further studies are warranted.

Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) eliminates many epigenetic modifications that characterize differentiated cells. In this study, we tested whether functional differences between chronic obstructive pulmonary disease (COPD) and non-COPD fibroblasts could be reduced utilizing this approach. Primary fibroblasts from non-COPD and COPD patients were reprogrammed to iPSCs. Reprogrammed iPSCs were positive for oct3/4, nanog, and sox2, formed embryoid bodies in vitro, and induced teratomas in nonobese diabetic/severe combined immunodeficient mice. Reprogrammed iPSCs were then differentiated into fibroblasts (non-COPD-i and COPD-i) and were assessed either functionally by chemotaxis and gel contraction or for gene expression by microarrays and compared with their corresponding primary fibroblasts. Primary COPD fibroblasts contracted three-dimensional collagen gels and migrated toward fibronectin less robustly than non-COPD fibroblasts. In contrast, redifferentiated fibroblasts from iPSCs derived from the non-COPD and COPD fibroblasts were similar in response in both functional assays. Microarray analysis identified 1,881 genes that were differentially expressed between primary COPD and non-COPD fibroblasts, with 605 genes differing by more than twofold. After redifferentiation, 112 genes were differentially expressed between COPD-i and non-COPD-i with only three genes by more than twofold. Similar findings were observed with microRNA (miRNA) expression: 56 miRNAs were differentially expressed between non-COPD and COPD primary cells; after redifferentiation, only 3 miRNAs were differentially expressed between non-COPD-i and COPD-i fibroblasts. Interestingly, of the 605 genes that were differentially expressed between COPD and non-COPD fibroblasts, 293 genes were changed toward control after redifferentiation. In conclusion, functional and epigenetic alterations of COPD fibroblasts can be reprogrammed through formation of iPSCs.

Current status of medical oncology in Japan--reality gleaned from a questionnaire sent to designated cancer care hospitals.

OBJECTIVE: Medical oncology in Japan has a relatively short history, with specialist certification starting in 2006, resulting in 867 certified medical oncologists as of 2014. Although the national government has appointed 397 Designated Cancer Care Hospitals, little is known about the actual situations of medical oncology services at these institutions. METHODS: Questionnaires regarding the presence of a medical oncology department, the number of physicians in the department, the presence of certified medical oncologists and the degree of the medical oncologists' responsibilities for drug therapies in adults with solid cancers were sent to all 397 institutions between 21 January and 1 May 2013. RESULTS: The response rate was 68.0%. Among the responses, 39.4% of the institutions had medical oncology departments with a median of three physicians. Most of the medical oncology departments were primarily responsible, as evaluated according to patient number, for the treatment of limited disease categories. The medical oncologists were significantly more responsible for molecular-targeted therapy than for chemotherapy in head and neck cancer or for cytokine therapy in renal cell carcinoma. The wide variety of adverse events associated with molecular-targeted therapy might have enhanced the roles of medical oncologists. As the proportion of hospitals with a medical oncology department increased according to the number of certified medical oncologists working at the institution, cultivating medical oncologists seems to be an urgent task for advancing medical oncology in Japan. CONCLUSIONS: The present study provides fundamental data for the future development of medical oncology in Japan. The present study is to uncover the current situation of medical oncology in Japan.

Incidence, risk factors and treatment outcomes of extravasation of cytotoxic agents in an outpatient chemotherapy clinic.

OBJECTIVE: Extravasation, the accidental leakage of an anticancer agent from a vessel into the surrounding tissues, can lead to irreversible local injuries and severe disability. Despite its considerable clinical importance, evidence-based information on extravasation in chemotherapy is lacking. This study characterized the clinical features of extravasation and identified issues to be resolved in current cancer chemotherapy performed in outpatient settings. METHODS: We retrospectively reviewed the medical charts of patients who received chemotherapy and sustained extravasation in our Outpatient Chemotherapy Clinic from April 2007 to August 2012. Chemotherapy administration and extravasation management procedures were standardized using the in-house chemotherapy guideline. RESULTS: Among 43 557 patients who received chemotherapy, 35 (0.08%) experienced extravasation. The duration between the start of infusion and extravasation was >2 h in 28 (80.0%) patients. The severity of extravasation was Grades 1, 2 and 3 in 28, 2 and 5 patients, respectively-three of whom were associated with port trouble. The contributing factor for extravasation was walking in 11 (31.4%) patients. All extravasations were cured without surgical intervention by management according to our guidelines. CONCLUSIONS: The incidence of extravasation is as low as 0.08%, using our in-house chemotherapy guideline. Extravasation from implanted ports tends to be severe.

A DPC Database Study on the Safety of Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel in Non-small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan. METHODS: This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95% confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were - 64.2 days (95% CI - 93.0 to - 35.4 days) and - 46.0 days (95% CI - 73.5 to - 18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials. CONCLUSIONS: The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041507.

A DPC Database Study on the Safety of Atezolizumab/Carboplatin/Etoposide in Extensive-Disease Small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, carboplatin, and etoposide (ACE) therapy is a standard of care for extensive-disease small cell lung cancer (SCLC); however, its safety data are scarce, limiting generalization to the Japanese population. METHODS: This study aimed to compare the safety of ACE versus carboplatin and etoposide (CE) therapies in Japanese patients using the Diagnosis Procedure Combination (DPC) database by comparing the incidence of adverse events (AEs). Retrospective data on clinical background and AEs were extracted from the DPC database. Incidence rates and restricted mean survival times (RMSTs) up to 6 months were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A total of 330,774 patients were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes, of whom 277 were included in the ACE cohort and 478 in the CE cohort. Among the 19 AEs, the incidence of skin disorder and thyroid dysfunction was significantly higher in the ACE cohort compared with the CE cohort. The adjusted incidence rate ratios were 2.38 (95% confidence interval [CI] 1.04-5.43) for skin disorder and 6.92 (95% CI 2.00-23.89) for thyroid dysfunction. The adjusted RMST differences were - 8.2 days (95% CI - 16.0 to - 0.4 days) for skin disorder and - 8.8 days (95% CI - 15.7 to - 1.9 days) for thyroid dysfunction. CONCLUSIONS: This study provides evidence regarding the safety of ACE combination therapy in Japanese clinical practice using the DPC database, with results comparable to those reported in pivotal clinical trials. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041508.

Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Phosphodiesterase-4 inhibition augments human lung fibroblast vascular endothelial growth factor production induced by prostaglandin E2.

Lung fibroblasts are believed to be a major source of vascular endothelial growth factor (VEGF), which supports the survival of lung endothelial cells and modulates the maintenance of the pulmonary microvasculature. VEGF has been related to the pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). Prostaglandin E2 (PGE2) stimulates VEGF production from lung fibroblasts via the E-prostanoid (EP)-2 receptor. The EP2 signaling pathway uses cyclic adenosine monophosphate (cAMP) as a second messenger, and cAMP is degraded by phosphodiesterases (PDEs). This study investigates whether phosphodiesterase inhibition modulates the human lung fibroblast VEGF production induced by PGE2. Human fetal lung fibroblasts were cultured with PGE2 and PDE inhibitors. The PDE4 inhibitors roflumilast, roflumilast N-oxide, and rolipram with PGE2 increased VEGF release, as quantified in supernatant media by ELISA. In contrast, PDE3, PDE5, and PDE7 inhibitors did not affect VEGF release. Roflumilast increased VEGF release with either an EP2 or an EP4 agonist. Roflumilast augmented the cytosolic cAMP levels induced by PGE2 and VEGF release with other agents that use the cAMP signaling pathway. Roflumilast-augmented VEGF release was completely inhibited by a protein kinase A (PKA) inhibitor. Roflumilast with PGE2 increased VEGF mRNA levels, and the blockade of mRNA synthesis inhibited the augmented VEGF release. The stimulatory effect of roflumilast on VEGF release was replicated using primary healthy and COPD lung fibroblasts. These findings demonstrate that PDE4 inhibition can modulate human lung fibroblast VEGF release by PGE2 acting through the EP2 and EP4 receptor-cAMP/PKA signaling pathway. Through this action, PDE4 inhibitors such as roflumilast could contribute to the survival of lung endothelial cells.

Venous Stent Placement for Malignant Vena Cava Syndrome in a Patient with Liposarcoma.

BACKGROUND Reports of venous stenting for inferior vena cava (IVC) syndrome (IVCS) due to sarcoma are limited, and the treatment's efficacy and safety are not clear. CASE REPORT A 36-year-old woman with myxoid liposarcoma was admitted to the Department of Respiratory Medicine for treatment of bilateral lower-leg edema and to be evaluated for acute liver dysfunction. She was 13 years old when she was diagnosed with myxoid liposarcoma. Over the next 18 years, she had 4 tumor resections and 1 round of radiation therapy. She had been on chemotherapy for 4 years and then pazopanib at the age of 35. The edema did not improve after admission despite treatment with diuretics. Computed tomography revealed a huge liposarcoma occupying the right thoracic cavity and a compressed IVC, which caused the edema. Although doxorubicin was administered as fifth-line treatment, there was no response. Since there was no additional chemotherapy regimen, her prognosis was considered to be less than 6 months. She could not be discharged to her home since she was unable to walk due to the edema; therefore, IVC stenting was performed to improve her dysmotility. After IVC stenting, the lower-leg edema improved without any adverse events, enabling her to walk and eventually return home. CONCLUSIONS In patients with IVCS caused by rare malignancies such as myxoid liposarcoma, an IVC stent can be safely implanted and can help to alleviate symptoms. IVC stenting can improve symptoms and allow for home care, resulting in improved quality of life.

Effectiveness and Safety of Atezolizumab Monotherapy in Previously Treated Japanese Patients With Unresectable Advanced or Recurrent NSCLC: A Multicenter, Prospective, Observational Study (J-TAIL).

Introduction: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial. Methods: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated. Results: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively. Conclusions: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.

Clinical Characteristics and Risk Factors of Lung Injury Induced by Nab-Paclitaxel.

Background/Aim: Nab-paclitaxel (Nab-PTX) has been widely used to treat several advanced cancers. Nab-PTX can cause drug-induced lung injury (DILI); however, its clinical and radiographic features have not been clarified. We aimed to assess the clinical characteristics of Nab-PTX-induced lung injury and identify its associated risk factors. Patients and Methods: We retrospectively investigated 304 patients who received Nab-PTX at Chiba University Hospital between November 2010 and November 2017. We obtained information regarding the clinical course, laboratory findings, and chest computed tomography findings from their medical records. Results: Forty-one patients (13%) developed DILI. Grade 1 lung injury occurred in 27 patients (8.8%), grade 2, 8 patients (2.6%); grade 3, 3 patients (0.9%); grade 4, 1 (0.3%); and grade 5, 2 (0.6%). Multivariate analysis revealed that age >56 years (odds ratio [OR]: 3.0), pre-existing interstitial lung changes (OR: 3.2), and combined drugs with gemcitabine (OR: 2.7) were independent risk factors for DILI owing to Nab-PTX administration. Conclusion: Nab-PTX-induced lung injury is not rare; however, most cases are asymptomatic (grade 1). Older age, pre-existing interstitial lung changes, and combined drugs with gemcitabine could increase the incidence of Nab-PTX-induced lung injury; such patients should be treated with greater care.