Predictors of survival among Japanese patients receiving first-line chemoimmunotherapy for advanced non-small cell lung cancer.

BACKGROUND: First-line chemoimmunotherapy (CIT) has improved overall survival (OS) and progression-free survival (PFS) outcomes among patients with non-small cell lung cancer (NSCLC). The immunological and nutritional statuses of patients fluctuate during treatment using immune checkpoint inhibitors, and are closely related to treatment outcomes. However, it is unclear whether these markers are significant in patients who are receiving CIT. METHODS: This retrospective single-center study evaluated 34 consecutive Japanese patients with NSCLC who were treated using first-line CIT. Previously reported markers that reflect immunological and nutritional statuses were evaluated at three time points: at the start of CIT, after three weeks, and at the end of induction therapy. RESULTS: The median PFS was 7.2 months (95% confidence interval: 6.3 months-not reached) and the median OS was not reached (95% confidence interval: 9.6 months-not reached). The PFS duration was significantly associated with the baseline neutrophil-to-lymphocyte ratio and the three-week values for the modified Glasgow prognostic score, C-reactive protein-albumin ratio, prognostic nutrition index, and advanced lung cancer inflammation index. The OS duration was significantly associated with the pre-treatment values for the neutrophil-to-lymphocyte ratio and advanced lung cancer inflammation index, as well as the prognostic nutrition index at the end of induction therapy. CONCLUSIONS: Immunological and nutritional markers could be useful for predicting the outcomes of CIT for Japanese patients with advanced non-small cell lung cancer. The timing of their evaluation may also be important. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Overall survival in patients receiving first-line chemoimmunotherapy for advanced lung cancer were associated with pretreatment values of neutrophil-to-lymphocyte ratio, advanced lung cancer inflammation index, and the prognostic nutrition index at the end of induction therapy. WHAT THIS STUDY ADDS: Repetitive evaluation of immunological and nutritional markers may be useful for guiding prognostication and treatment selection for Japanese patients with advanced lung cancer.

Significance of inflammatory indexes in atezolizumab monotherapy outcomes in previously treated non-small-cell lung cancer patients.

Cancer immunotherapy, including atezolizumab monotherapy, is a promising alternative strategy for patients with advanced non-small-cell lung cancer (NSCLC). Several inflammatory indices have been reported as potential biomarkers regarding the effectiveness of various treatments. This study aimed to analyze the efficacy of atezolizumab monotherapy using baseline inflammatory markers in NSCLC patients. We retrospectively enrolled 81 NSCLC patients who received atezolizumab monotherapy at six different medical institutions in Japan. The Cox proportional hazards model was used to assess the impact of the clinical variables, including inflammatory indexes, on clinical outcomes. Median progression-free survival (PFS) and overall survival (OS) were 60 days and 252 days, respectively. The objective response rate was 7.4%, and the disease control rate was 54.3%. Patients with high neutrophil to lymphocyte ratio (NLR), low lymphocyte to monocyte ratio (LMR), and/or high platelet to lymphocyte ratio (PLR), at baseline, demonstrated substantially shorter PFS and OS compared to those with a low NLR, high LMR, and/or low PLR. The multivariate analysis demonstrated that a high baseline NLR was substantially associated with short PFS and short OS. Our retrospective observations suggest that inflammatory indices may be a potential negative prognostic factor of atezolizumab monotherapy outcomes in NSCLC patients.

Drug-induced interstitial lung disease associated with dasatinib coinciding with active tuberculosis.

A 69-year-old woman was diagnosed with a breakpoint cluster region-Abelson-positive chronic myeloid leukaemia and treated with dasatinib for 14 months. She presented with one month of high-grade fever and persistent dry cough. Chest computed tomography revealed non-segmental subpleural consolidation, ground-glass opacities, and interlobular septal thickening. The bronchoalveolar lavage (BAL) and transbronchial lung biopsy confirmed a diagnosis of drug-induced interstitial lung disease (ILD) associated with dasatinib. Then, systemic corticosteroid treatment was initiated, which was effective and the interstitial shadow disappeared after two weeks. The acid-fast bacilli culture test of BAL fluid after three weeks was positive for Mycobacterium tuberculosis, and combination therapy with four antituberculosis drugs was added. It is known that drug-induced ILD and susceptibility to infection associated with dasatinib occur in a dose-dependent manner. This is the first case of dasatinib-induced ILD which coincided with active tuberculosis.

IgG4-related lung disease progressing to respiratory failure.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic immune-mediated, fibroinflammatory disorder categorized as proliferative or fibrotic depending on the responsiveness of corticosteroid treatment. IgG4-related lung disease (IgG4-RLD) accounts for 13-14% of IgG4-RD cases, but respiratory failure is quite rare. A 71-year-old man diagnosed with interstitial lung disease was referred to our department after a 10-month observational period. He presented with respiratory failure at the first visit, with significant elevations in serum IgG4 levels and histopathological findings meeting the criteria of IgG4-positive plasma cells and IgG4/IgG-positive plasma cell ratio in transbronchial lung biopsy and inguinal lymph node biopsy, resulting in a diagnosis of IgG4-RD. Systemic corticosteroid treatment promptly ameliorated the respiratory failure. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography showed significant FDG accumulation in the lung fields, indicating the proliferative and reversible status of IgG4-RLD, which responded well to corticosteroid treatment. The patient recovered from respiratory failure even after a 10-month observational period.

Osimertinib-Associated Toxic Epidermal Necrolysis in a Lung Cancer Patient Harboring an EGFR Mutation-A Case Report and a Review of the Literature.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening dermatologic adverse events in the same category, caused by a delayed-type drug hypersensitivity reaction. Although skin toxicity is common during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib-associated TEN is quite rare-thus far, only one report has been published from China. We report a case of an 80-year-old Japanese woman with lung adenocarcinoma harboring an EGFR-sensitizing mutation who was treated with osimertinib as the first-line treatment. Forty-six days after osimertinib induction, diffuse erythematous rash rapidly spread over the patient's trunk along with vesicles and purpuric macules; furthermore, she developed targetoid erythema on the face. Despite osimertinib discontinuation and corticosteroid treatment, diffuse erythema with Nikolsky's sign, general epidermal detachment, erosion and loose blisters developed over her entire body including the face. Based on her symptoms, TEN was diagnosed and thus, intravenous immunoglobulin was immediately administered for 4 days. The treatment ameliorated TEN-associated skin toxicity and caused epithelialization. Reports on osimertinib-associated SJS/TEN are scarce and only one report each on SJS and TEN from China is available. This is the first report of osimertinib-associated TEN from Japan. Cases of EGFR-TKI-associated SJS/TEN have been reported predominantly from Asian countries, suggesting ethnicity and genetic linkage play a role in the underlying mechanism.

Atezolizumab in combination with carboplatin and etoposide for heavily treated small cell lung cancer.

Atezolizumab was the first immune checkpoint inhibitor (ICI) to be introduced as a first-line treatment option for extensive-stage small cell lung cancer (ES-SCLC), in combination with carboplatin and etoposide (CE) chemotherapy. However, SCLC treatment options after progression to first-line chemotherapy are limited, warranting the readministration of previously used drugs. In combination with atezolizumab, CE readministration may theoretically be effective, based on two tentative mechanisms: its additive and synergistic effects on cytotoxic chemotherapy. The additive effect is based on the IFCT-1603 trial in which the Kaplan-Meier estimates of both progression-free survival (PFS) and overall survival (OS) in the atezolizumab group exhibited a tail plateau in the selected population. Conversely, an anti-PD-L1 antibody synergistic effect on platinum compounds was assessed in a preclinical study, which was reinforced by clinical data. Thus, atezolizumab in combination with CE may be a treatment option in heavily treated patients. Here, we describe the first case of a heavily treated ES-SCLC patient treated with chemoimmunotherapy, resulting in a partial response and a durable PFS. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY AND WHAT THIS STUDY ADDS: CE readministration with atezolizumab may be effective based on two tentative mechanisms. Additive and synergistic effects of atezolizumab on CE have been previously suggested via a clinical trial and preclinical study, respectively. This is reflected in the current case in clinical settings.

Vogt-Koyanagi-Harada disease during chemoimmunotherapy for non-small cell lung cancer.

Vogt-Koyanagi-Harada disease (VKHD) is a rare systemic granulomatous autoimmune disease that affects melanocyte-rich organs such as eye, inner ear, meninges, skin, and hair. VKHD leads to chronic uveal inflammation accompanied by a decline in visual acuity in some patients when appropriate corticosteroid treatment was not initiated in an early phase. Immune checkpoint inhibitors (ICIs) are widely used in the treatment of several kinds of cancers and chemoimmunotherapy has become the standard of care in the first-line treatment of non-small cell lung cancer (NSCLC). While ICIs induce immune-related adverse events, drug-induced VKHD is quite rare with only four reports in the ICI monotherapy; three patients with melanoma and one patient with NSCLC. We describe the first case of VKHD during chemoimmunotherapy including pembrolizumab in a patient with NSCLC, which was successfully treated with corticosteroid without any sequela.

Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation.

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer.

BACKGROUND: Treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR-mutated non-small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. PATIENTS AND METHODS: We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR-TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. RESULTS: We enrolled 27 patients who harbored EGFR-activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P < 0.01, respectively). Patients with uncommon EGFR mutations or without T790M mutations exhibited a significantly longer median progression-free survival than those with common EGFR mutations or with T790M mutations (P = 0.003 and P = 0.03, respectively). CONCLUSION: Patients with uncommon EGFR mutations and without T790M mutations are associated with the best outcomes for treatment with immunotherapy among those with EGFR-mutated NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders with EGFR mutations.

A single-round selection of selective DNA aptamers for mammalian cells by polymer-enhanced capillary transient isotachophoresis.

A single-round DNA aptamer selection for mammalian cells was successfully achieved for the first time using a capillary electrophoresis (CE)-based methodology called polymer-enhanced capillary transient isotachophoresis (PectI). The PectI separation yielded a single peak for the human lung cancer cell line (PC-9) complexed with DNA aptamer candidates, which was effectively separated from a free randomized DNA library peak, ensuring no contamination from free DNA in the PC-9-DNA aptamer complex fraction. The DNA aptamer candidates obtained after a single-round selection employing counter selection with HL-60 were proven to bind selectively and form kinetically stable complexes with PC-9 cells. Interestingly, most aptamer candidates showed high binding ability (Kd = 70-350 nM) with different extents of binding on the cell surface. These facts proved that a single-round selection for mammalian cells by PectI is feasible to obtain various types of aptamer candidates, which have high-affinity even for non-overexpressed but unique targets on the cell surface in addition to overexpressed targets.

Association between habitual coffee consumption and normal or increased estimated glomerular filtration rate in apparently healthy adults.

Habitual coffee consumption is associated with the prevention of type 2 diabetes, which often accompanies diabetic nephropathy. However, the relationship between coffee consumption and kidney function is unclear. Therefore, we investigated the associations between habitual coffee consumption and kidney function and damage assessed by the estimated glomerular filtration rate (eGFR) and proteinuria using dipstick urinalysis, respectively, in a cross-sectional study of 342 apparently healthy adults. Habitual coffee consumption was defined as drinking one or more cups of coffee per d. eGFR in coffee consumers (n 182; 80.1 (sd 15.0) ml/min per 1.73 m(2)) was significantly higher than that in non-coffee consumers (n 160; 76.9 (sd 12.6) ml/min per 1.73 m(2)) (P < 0.05). Multivariate logistic analysis showed that, compared with non-coffee consumption, coffee consumption was significantly associated with normal or increased eGFR (NIGFR) ( >or= 90 ml/min per 1.73 m(2)), but not proteinuria, which was not attenuated, even after adjustment for age, sex, smoking, tea consumption and other cardiovascular risks (OR 2.91; 95 % CI 1.51, 5.61; P = 0.001). When we took into account eGFR measured 1 year before in a subgroup of the subjects (n 262), coffee consumption (n 142) had a significant relationship with eGFR, which was consistently higher with a difference of 4.0 ml/min per 1.73 m(2) compared with non-coffee consumption (P = 0.01; two-way repeated ANOVA). Similar associations were observed in both sexes when data were reanalysed according to sex. In conclusion, our findings suggest that habitual coffee consumption is associated with NIGFR independently of clinical confounders. Further studies are needed to confirm this association and to explore whether the effect of coffee consumption on eGFR is beneficial for the kidney.