Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel.

INTRODUCTION: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients. METHODS: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients. RESULTS: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0-70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3-9.4) and 16.5 (95% CI: 13.9-22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS. CONCLUSION: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.

Using the neutrophil-to-lymphocyte ratio to predict the outcome of individuals with nonsquamous non-small cell lung cancer receiving pembrolizumab plus platinum and pemetrexed.

BACKGROUND: Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb-Plt-PEM) in nonsquamous non-small cell lung cancer (non-sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non-sq NSCLC. METHODS: We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non-sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan-Meier method were used to compare progression-free survival (PFS) and overall survival (OS). RESULTS: The response rate was 51.2% (95% CI: 44.9-57.5%). The median PFS and OS after beginning Pemb-Plt-PEM were 8.8 (95% CI: 7.0-11.9) months and 23.6 (95% CI: 18.7-28.6) months, respectively. The NLR independently predicted the efficacy of Pemb-Plt-PEM-the PFS and OS were more prolonged in individuals with NLR <5 than in those with NLR ≥5 (PFS: 12.8 vs. 5.3 months, p = 0.0002; OS: 29.4 vs. 12.0 months, p < 0.0001). BMI predicted the treatment response-individuals with BMI ≥22.0 kg/m2 had longer OS than did those with BMI < 22.0 kg/m2 (OS: 28.4 vs. 18.4 months, p = 0.0086). CONCLUSIONS: The NLR significantly predicted PFS and OS, whereas BMI predicted OS, in individuals who initially received Pemb-Plt-PEM for non-sq NSCLC. These factors might be prognosis predictors in non-sq NSCLC.

Probably the Mycobacterium avium Complex around the Staple Line Exacerbated after Radiation Therapy.

The space around the staple line after lung surgery is at high risk of nontuberculosis Mycobacterium pulmonary disease (NTM-PD). Solitary nodules of NTM-PD around the staple line are difficult to distinguish from lung cancer. There is no clear identification from laboratory data and radiologic findings without histological examination. In the present case, we misdiagnosed the pulmonary granulomas with Mycobacterium avium complex pulmonary disease (MAC-PD) as a recurrence of lung cancer. We conducted radiation therapy. The pulmonary granulomas with MAC-PD were exacerbated by irradiation. The effects of radiation therapy for MAC-PD are unknown. When radiation therapy is performed for the patient coexistence with MAC-PD, we should pay attention to exacerbation of MAC-PD.

Pseudocirrhosis caused by lung adenocarcinoma with diffuse liver metastasis: An autopsy case report.

We describe a rare case of a 64-year-old man with lung adenocarcinoma with lymph node and bone metastases who developed pseudocirrhosis. Initial examination revealed a hepatic disorder of unknown cause with narrowing of the portal vein and a low-density area surrounding the portal veins in computed tomography (CT) imaging. Diffuse liver metastasis was diagnosed after percutaneous liver biopsy. During chemotherapy, liver atrophy and irregular liver surface appearance were confirmed with CT. Eventually, the disease progressed to death, and an autopsy was performed. The autopsy demonstrated exacerbation of diffuse liver metastases and cirrhosis-like findings.

Phase II Study of Weekly Nanoparticle Albumin-Bound Paclitaxel as Second- or Third-Line Therapy in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) are poor due to limited treatment options. OBJECTIVE: We conducted a multicenter, single-arm phase II study to prospectively assess the efficacy and safety of weekly nab-PTX in patients with advanced NSCLC with failed cytotoxic chemotherapy. METHODS: Patients with advanced NSCLC having adequate organ functions with a performance status of 0-1 were enrolled. A 100 mg/m2 dose of nab-paclitaxel was administered on days 1, 8, and 15 of a 28-day cycle. Primary endpoint was the objective response rate (ORR). Secondary endpoints were disease control rate (DCR), toxicity profile, progression-free survival (PFS), and overall survival (OS). RESULTS: Between September 2013 and May 2016, 35 patients were enrolled. The ORR was 31.4%, and the DCR was 74.3%. The median PFS was 3.6 months, and the median OS was 11.4 months. The most common grade 3 or 4 toxicities included neutropenia (54.3%), leukopenia (42.9%), and anemia (11.4%). Two patients discontinued chemotherapy due to pneumonitis. CONCLUSIONS: Nab-PTX may be a later-line chemotherapeutic option for previously treated advanced NSCLC.

Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC. METHODS: Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated. RESULTS: Ninety-eight men and 33 women (median age 77 [range 75-87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR. CONCLUSIONS: Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.

Prognostic Significance of Glucose Metabolism as GLUT1 in Patients with Pulmonary Pleomorphic Carcinoma.

Glucose metabolism is necessary for tumor progression, metastasis, and survival in various human cancers. Glucose transporter 1 (GLUT1), in particular, plays an important role in the mechanism of ¹8F-FDG (2-[¹8F]-fluoro-2-deoxy-d-glucose) within tumor cells. However, little is known about the clinicopathological significance of GLUT1 in patients with pulmonary pleomorphic carcinoma (PPC). Adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, poorly differentiated carcinoma, large cell carcinoma, and others were identified as epithelial components, and spindle-cell type, giant-cell type, and both spindle- and giant-cell types were identified as sarcomatous components. This study was performed to determine the prognostic impact of GLUT1 expression in PPC. Patients with surgically resected PPC (n = 104) were evaluated by immunohistochemistry analysis to detect GLUT1 expression and determine the Ki-67 labeling index using specimens of the resected tumors. GLUT1 was highly expressed in 48% (50/104) of all patients, 42% (20/48) of the patients with an adenocarcinoma component, and 53% (30/56) of the patients with a nonadenocarcinoma component. High expression of GLUT1 was significantly associated with advanced stage, vascular invasion, pleural invasion, and tumor cell proliferation as determined by Ki-67 labeling. GLUT1 expression and tumor cell proliferation were significantly correlated according to the Ki-67 labeling in all patients (Spearman's rank; r = 0.25, p < 0.01). In multivariate analysis, GLUT1 was identified as a significant independent marker for predicting a poor prognosis. GLUT1 is an independent prognostic factor for predicting the poor prognosis of patients with surgically resected PPC.

Efficacy and safety of first-line pembrolizumab monotherapy in elderly patients (aged ≥ 75 years) with non-small cell lung cancer.

PURPOSE: Pembrolizumab is an effective front-line treatment for advanced non-small cell lung cancer (NSCLC) in patients expressing high levels of programmed death-ligand 1 (PD-L1). However, it is unclear whether first-line pembrolizumab has similar efficacy among elderly (aged ≥ 75 years) and younger patients. This study aimed to investigate the safety and efficacy of front-line pembrolizumab monotherapy in older adults with NSCLC expressing high PD-L1. METHODS: A total of 128 patients with advanced NSCLC expressing high PD-L1, including 47 older adults, received first-line pembrolizumab monotherapy at ten institutions in Japan, between February 2017 and February 2018. Data related to patient characteristics, efficacy of pembrolizumab therapy, and the type and severity of adverse events were recorded. RESULTS: Overall, 47 patients [40 men and 7 women; median age 79 (range 75-88) years] were included in our analysis. In patients who received first-line pembrolizumab monotherapy, overall response, disease control rates, median progression-free survival (PFS), and median overall survival (OS) were 53.1%, 74.4%, 7.0 months, and not reached, respectively. Common adverse events included anorexia, fatigue, skin rash, and hypothyroidism. Two treatment-related deaths were noted, due to pneumonitis and infection. First-line pembrolizumab monotherapy was associated with improved PFS in patients with non-progressive disease (PD). In patients with non-PD and good performance status (PS), pembrolizumab monotherapy improved OS. CONCLUSIONS: Elderly patients with NSCLC expressing high PD-L1 tolerated front-line pembrolizumab monotherapy well. Their survival outcomes were equivalent to those of younger patients. In patients with non-PD, first-line pembrolizumab monotherapy may improve PFS; in conjunction with good PS, it additionally improves OS.

Predictors of Discontinuance of Oral Feeding in Patients With Advanced Alzheimer Dementia and Aspiration Pneumonia in Japan: A Single-center, Retrospective Observational Study.

BACKGROUND: Difficulty with oral feeding, the most commonly observed complication of Alzheimer disease (AD) in its final stages, occurs in 86% of AD patients and may prevent achievement of oral feeding after aspiration pneumonia. However, no reliable indicators of discontinuance of oral feeding have yet been identified. We therefore aimed to identify predictors of discontinuance of oral feeding in postaspiration pneumonia patients with AD. MATERIALS AND METHODS: Relevant clinical and laboratory data of 60 patients with AD admitted to our hospital in Japan for aspiration pneumonia were retrospectively compared between oral feeding and discontinuance groups. RESULTS: The study groups differed in interval since diagnosis of AD, CURB-65 score, pneumonia severity index score, and proportion of patients who died (higher in the discontinuance group) and body mass index (BMI), Mini Mental State Examination (MMSE) score, and functional independence measure score (lower in the discontinuance group). According to multivariate logistic regression analysis of all identified independent variables, only CURB-65 and MMSE scores and BMI are significant predictors of discontinuance of oral feeding after aspiration pneumonia in patients with advanced AD. CONCLUSIONS: In patients with advanced AD, discontinuance of oral feeding after aspiration pneumonia may be predicted by CURB-65 and MMSE scores and BMI.

Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma.

Amino acid transporters are necessary for tumor growth, metastasis, and survival of various neoplasms; however, the clinicopathological significance of L-type amino acid transporter 1 (LAT1) and 4F2 cell surface antigen (4F2hc) in patients with pulmonary pleomorphic carcinoma (PPC) remainsunknown. The aim of this study is to clarify the prognostic impact of these amino acid transporters in PPC. One hundred five patients with surgically resected PPC were assessed by immunohistochemistry. The expression of LAT1 and 4F2hc, and Ki-67 labeling index were investigated using specimens of the resected tumors. LAT1 and 4F2hc were highly expressed in 35% and 53% of all patients (n = 105, P < .01), 25% and 48% of patients with an adenocarcinoma component (n = 48, P = .02), and 44% and 58% of patients with a nonadenocarcinoma component (n = 57, P = .18), respectively. A high LAT1 expression was significantly related to advanced disease, lymphatic permeation, tumor cell proliferation, and 4F2hc expression. By multivariate analysis, LAT1 and 4F2hc were identified as significant independent markers for predicting a worse prognosis. LAT1 is highly expressed in PPC, and high LAT1 expression can serve as a significant predictor linked to a worse prognosis in patients with PPC.

Isoniazid-induced Pure Red Cell Aplasia in a Patient with Sarcoidosis: A Patient Summary and Review of the Literature.

A 41-year-old woman treated with isoniazid (INH) for latent tuberculosis infection and an oral corticosteroid for sarcoidosis developed severe anemia two months after initiating INH. A bone marrow examination showed erythroblastopenia, and a diagnosis of INH-induced pure red cell aplasia (PRCA) was made. Her reticulocyte count and hemoglobin levels improved two weeks after discontinuation of INH. A literature review of INH-induced PRCA shows that it occurs very rarely in the context of autoimmune disorders. This report describes a case of INH-induced PRCA occurring in a patient with sarcoidosis.

Albumin-binding of diclofenac and the effect of a site II inhibitor in the aqueous humor of cataract patients with the instillation of diclofenac.

Diclofenac instillation has been used widely in cataract surgery to prevent postoperative inflammation. Since diclofenac binds strongly to albumin in the circulation, it does not have a sufficient effect on patients in whom diclofenac binds strongly to albumin in the aqueous humor. A decrease in diclofenac binding and an increase in free diclofenac levels are necessary in these patients. The binding of diclofenac to albumin was investigated in the aqueous humor. In a diclofenac binding assay with albumin in the aqueous humor of individual patients, diclofenac was extracted from aliquots of the aqueous humor, and its total levels were measured using ultra high performance liquid chromatography (UHPLC). Free diclofenac levels were measured using ultrafiltration and UHPLC. The albumin-binding fraction of diclofenac was 0.8 or higher in the aqueous humor of some patients. Ibuprofen significantly inhibited diclofenac binding to site II of albumin in mimic aqueous humor, but not in pooled aqueous humor. This difference may have been due to the weak binding of diclofenac to site II in the pooled aqueous humor. Flurbiprofen was used instead of diclofenac. Flurbiprofen has been shown to bind more strongly than diclofenac to the same site of albumin. Thus, the inhibitory effect of ibuprofen on the binding of flurbiprofen to albumin was investigated in pooled aqueous humor. The results indicated that ibuprofen significantly inhibited the flurbiprofen binding. An effective diclofenac administration method may be established for clinical application by the instillation of an appropriate inhibitor of binding to the albumin site II.

An advanced objective structured clinical examination using patient simulators to evaluate pharmacy students' skills in physical assessment.

OBJECTIVE: To implement an advanced objective structured clinical examination (OSCE) in the curriculum and to evaluate Japanese pharmacy students' skills in physical assessment such as measuring pulse and blood pressure, and assessing heart, lung, and intestinal sounds. DESIGN: An advanced OSCE was implemented in a hospital pharmacy seminar as a compulsory subject. We programmed patient simulators with 21 different patient cases in which normal and abnormal physiological conditions were produced. The virtual patients were then used to evaluate the physical assessment skills of fifth-year pharmacy students. ASSESSMENT: Significant differences were observed between the average of all the detailed evaluations and the mean results for the following skills: pulse measurement, blood pressure measurement, deflating the cuff at a rate of 2-3 mmHg/sec, listening to heart sounds, and listening to lung sounds. CONCLUSION: Administering an advanced OSCE using virtual patients was an effective way of assessing pharmacy students' skills in a realistic setting. Several areas in which pharmacy students require further training were identified.

Novel water-soluble sedative-hypnotic agents: isoindolin-1-one derivatives.

We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(-), 5(-), 27(-), and 47(-) [JM-1232(-)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD50s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD50s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD50/HD50) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(-) [JM-1232(-)] is being considered as the most potential candidate for clinical trials in humans.

Stereocontrolled total synthesis of a polyfunctional carotenoid, peridinin.

Peridinin, which was isolated from the planktonic algae dinoflagellates causing red tides, is a highly oxidized carotenoid containing an allene and a characteristic (Z)-gamma-ylidenebutenolide function in the main conjugated polyene chain in addition to functionalized cyclohexane rings at both ends of the molecule. We achieved a stereocontrolled total synthesis of peridinin by featuring the Sharpless asymmetric epoxidation under precise reaction conditions, Wittig reaction with silylfuranmethylide followed by photosensitized oxygenation, stereocontrolled Pd-catalyzed one-pot (Z)-gamma-ylidenebutenolide synthesis, and modified Julia-Kocienski olefination. This synthesis is the first example of controlling the stereochemistry of polyfunctional allenic carotenoids.