Comparison of the efficacy of first­/second­generation EGFR­tyrosine kinase inhibitors and osimertinib for EGFR­mutant lung cancer with negative or low PD­L1 expression.

In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with negative or low programmed death ligand-1 (PD-L1) expression, the acquisition rate of the T790M mutation is higher after treatment with first-/second-generation EGFR-tyrosine kinase inhibitors (TKIs) and the progression-free survival (PFS) is longer in patients treated with osimertinib. The present study compared the clinical course after the initiation of each EGFR-TKI monotherapy in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. Data of patients with EGFR-mutant NSCLC with negative or low PD-L1 expression who were treated with EGFR-TKI monotherapy were retrieved and retrospectively analyzed. Between June 2013 and November 2023, 26 and 29 patients were treated with first-/second-generation EGFR-TKIs and osimertinib, respectively. The PFS time was longer in patients treated with osimertinib (median, 22.5 months) than in those treated with first-/second-generation EGFR-TKIs (median, 12.9 months). However, the EGFR-TKI treatment duration, defined as the PFS for osimertinib, or the sum of the PFS for first-/second-generation EGFR-TKIs and sequential osimertinib therapy after the acquisition of the T790M mutation, was similar between patients treated with first-/second-generation EGFR-TKIs (median, 23.0 months) and osimertinib (median, 22.5 months). The Cox proportional hazard model suggested that there was no significant difference in the EGFR-TKI treatment duration between patients treated with first-/second-generation EGFR-TKIs and patients treated with osimertinib (hazard ratio, 1.31, 95% CI, 0.55-3.13). In conclusion, first-/second-generation EGFR-TKIs and osimertinib were associated with a similar EGFR-TKI treatment duration in patients with EGFR-mutant NSCLC with negative or low PD-L1 expression. The findings suggested that both treatments are promising for this population.

Pure Red Cell Aplasia and Chromosomal Abnormality in a Patient With Lung Adenocarcinoma Receiving Immune Checkpoint Inhibitors: A Case Report.

BACKGROUND/AIM: Immune checkpoint inhibitors can induce immune-related adverse events in various organs, thus careful observation is required. CASE REPORT: A 69-year-old man was diagnosed with advanced lung adenocarcinoma and treated with combined therapy of carboplatin plus pemetrexed plus pembrolizumab. After two cycles of treatment, anemia was noted. Myelosuppression due to cytotoxic anticancer agents was suspected and the cytotoxic agents were discontinued, followed by three courses of pembrolizumab monotherapy. However, the anemia persisted, requiring red blood cell transfusions. A bone marrow biopsy revealed erythroblast hypoplasia and chromosomal abnormalities, resulting in a diagnosis of pure red cell aplasia. These adverse events were considered immune-related because of the treatment history with an immune checkpoint inhibitor, and 60 mg/day (1 mg/kg/day) of prednisolone was initiated. Anemia improved, and it did not recur during the tapering of prednisolone. CONCLUSION: Immune-related pure red cell aplasia should be considered for patients presenting anemia during treatment with immune checkpoint inhibitors.

Immune Checkpoint Inhibitor Therapy for Patients With Non-small Cell Lung Cancer Ineligible for Platinum Doublet Chemotherapy.

BACKGROUND/AIM: Combined therapy with immune checkpoint inhibitors plus platinum doublet chemotherapy has a survival advantage over platinum doublet chemotherapy in patients with non-small cell lung cancer. However, a variety of factors make it difficult to administer treatment with platinum doublet chemotherapy in many patients in clinical practice and there are few reports on the efficacy and safety of first-line treatments with immune checkpoint inhibitors for patients who are ineligible for platinum doublet chemotherapy. This observational study aimed to evaluate the efficacy and safety of first-line immune checkpoint inhibitor therapy for this population. PATIENTS AND METHODS: We retrospectively assessed the survival and adverse events from the initiation of first-line immune checkpoint inhibitor therapy, including pembrolizumab or nivolumab plus ipilimumab in patients with non-small cell lung cancer who were ineligible for platinum doublet chemotherapy. RESULTS: Data from 48 patients were analyzed. Seventeen patients showed a performance status (PS) of ≥2 while 16 and 15 patients were considered ineligible for platinum doublet chemotherapy because of age and comorbidities, respectively. The median (95% confidential interval, CI) progression-free survival (PFS) and overall survival (OS) of the 48 patients were 7.1 (1.7-13.7) and 31.7 (8.8-not estimated) months, respectively. The two-year PFS and OS rates (95% CI) were 30.8% (18.2%-47.2%) and 50.7% (33.7%-67.7%), respectively. In patients with a PS of ≥2, the median (95% CI) PFS and OS were 1.6 (1.2-not estimated) and 5.5 (2.3-not estimated) months, respectively. The two-year PFS and OS rates (95% CI) were 34.3% (15.8%-59.2%) and 45.3% (22.2%-70.7%), respectively. CONCLUSION: Patients with non-small cell lung cancer and a PS of 0-1 who were ineligible for platinum doublet chemotherapy had favorable outcome after the initiation of ICI therapy, and even in patients with a PS of ≥2, they achieved high two-year PFS and OS rates.

Peripheral CD4 memory T cells predict the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer.

Immune checkpoint inhibitors have significantly improved the prognosis in patients with non-small cell lung cancer, compared with cytotoxic agents. However, the prediction of treatment response is often difficult, even after assessing the tumor programmed death-ligand 1 expression. We conducted this observational study to analyze the association between the differentiation of peripheral CD4 + T cells and the efficacy of immune checkpoint inhibitor therapy. We enrolled patients who were diagnosed with non-small cell lung cancer and received immune checkpoint inhibitor therapy between 2020 and 2022. Blood samples were collected at the start of immune checkpoint inhibitor therapy, and the expressions of PD-1, CCR7, and CD45RA in peripheral CD4 + T cells were analyzed by flow cytometry. The association between the findings of flow cytometry and survival after the initiation of the immune checkpoint inhibitor therapy was evaluated. Forty patients with non-small cell lung cancer were enrolled. The Cox proportional hazards model showed that an increased proportion of CD45RA-CD4 + T cells was associated with a reduced risk of progression after adjustment for performance status, tumor programmed death-ligand 1 expression level, mutation status of the epidermal growth factor receptor gene, and combined therapy with cytotoxic agents. The present study showed that the proportion of peripheral CD45RA- CD4 + T cells was associated with progression-free survival after the initiation of immune checkpoint inhibitor therapy, independent of several clinical factors.

Association Between the Severity of Immune-related Adverse Events and the Prognosis in Patients With Non-small Cell Lung Cancer Receiving Treatment With Immune Checkpoint Inhibitors.

BACKGROUND/AIM: Among patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI), survival is reported to be longer in those experiencing immune-related adverse events (irAEs). We evaluated the progression-free survival (PFS) in the absence of further treatment after ICI therapy was discontinued because of the emergence of irAEs in patients with NSCLC. PATIENTS AND METHODS: Data from patients with NSCLC in whom ICI therapy was discontinued because of the development of irAEs were retrospectively analyzed. The primary endpoint was the PFS from the last day of administration of ICIs, in the absence of any further treatment. RESULTS: A total of 162 patients with NSCLC received treatment with ICIs between January 2016 and December 2021. Among them, ICI therapy was discontinued in 33 patients because of the appearance of irAEs. The median (95% confidence interval) PFS in the absence of any treatment after the last administration of ICIs was 7.2 (4.2-12.3) months. According to the Common Terminology Criteria for Adverse Events, the Cox proportional hazards model was used to identify the severity of irAEs, which were determined to be significantly associated with the PFS in the absence of any further treatment after the last administration of ICI therapy. CONCLUSION: Although the present study showed that the PFS in patients with NSCLC was relatively long in the absence of any further treatment after the last administration of ICIs, the PFS was associated with the severity of the irAEs, and some patients showed early disease progression or death.

Associations of immune checkpoint inhibitor therapy efficacy with clinical parameters and tumor­infiltrating CD68­positive cell counts in patients with EGFR­mutant non­small cell lung cancer.

Immune checkpoint inhibitor (ICI) therapy has been less effective in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations than in patients with EGFR wild-type NSCLC. This retrospective study was conducted to investigate the associations of clinical parameters with the efficacy of ICI therapy in patients with EGFR-mutant NSCLC. Clinical information was retrieved from the medical charts, and immunohistochemical analysis was performed in some cases to determine the tumor-infiltrating CD68-positive cell count. Data from 46 patients were included in the analysis. The median (95% confidence interval) progression-free survival and overall survival from the initiation of ICI therapy was 1.4 months (1.0-1.7 months) and 6.4 months (3.9-19.0 months), respectively. Analysis using a Cox proportional hazards model revealed that tumor programmed death-ligand 1 expression was associated with the overall survival of patients with EGFR-mutant NSCLC after ICI treatment. The tumor-infiltrating CD68-positive cell count was evaluated in 11 patients. Comparison using the log-rank test revealed that the progression-free survival time after ICI treatment was longer in the patients with lower tumor-infiltrating CD68-positive cell counts than those with higher tumor-infiltrating CD68-positive cell counts. The present analysis demonstrated that PD-L1 expression and the tumor-infiltrating CD68-positive cell count may be associated with the efficacy of ICI therapy in patients with NSCLC harboring EGFR mutations.

Efficacy of immune checkpoint inhibitor therapy in patients with pulmonary sarcomatoid carcinoma in clinical practice.

OBJECTIVE: Studies have suggested the potential efficacy of immune checkpoint inhibitors (ICIs) for pulmonary sarcomatoid carcinoma. This multicenter observational study was conducted to evaluate the efficacy of systemic ICI therapy and chemoradiation followed by durvalumab therapy for pulmonary sarcomatoid carcinoma. METHODS: We analyzed the data of patients with pulmonary sarcomatoid carcinoma who received systemic ICI therapy or chemoradiation followed by durvalumab therapy between 2016 and 2022. RESULTS: In this study, data of a total of 22 patients who received systemic ICI therapy and four patients who received chemoradiation followed by durvalumab therapy were analyzed. In the patients who received systemic ICI therapy, the median progression-free survival after initiation of therapy was 9.6 months, and the overall survival did not reach the median. The 1-year progression-free survival rate and overall survival rate were estimated to be 45.5% and 50.1%, respectively. Although the log-rank test revealed no significant association between the tumor expression level of programmed death ligand-1 (tumor proportion score evaluated using 22C3 antibody: ≥50% vs. <50%) and the survival duration, the majority of patients showing long-term survival showed a tumor proportion score of ≥50%. Of four patients treated with chemoradiation followed by durvalumab therapy, two patients showed an overall survival of ≥30 months, whereas the remaining two patients died within 12 months. CONCLUSION: The progression-free survival of patients who received systemic ICI therapy was 9.6 months, suggesting that ICI therapy might be effective in patients with pulmonary sarcomatoid carcinoma.

Association of Tumor PD-L1 Expression With Time on Treatment Using EGFR-TKIs in Patients With EGFR-Mutant Non-small Cell Lung Cancer.

BACKGROUND/AIM: The association between tumor PD-L1 expression and the rate of acquisition of the T790M mutation during treatment with first-/second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a matter of study. This retrospective study was conducted to evaluate the association of tumor PD-L1 expression with the time on treatment under EGFR-TKIs in patients with EGFR-mutant non-small cell lung cancer (NSCLC), treated with first-/second-generation EGFR-TKIs. PATIENTS AND METHODS: We conducted a retrospective review of the medical charts of patients with EGFR-mutant NSCLC treated with first- /second-generation EGFR-TKIs. Time on treatment with EGFR-TKIs was defined as the sum of progression-free survival period (PFS) from the start of treatment with first- /second-generation EGFR-TKIs and the PFS from the start of osimertinib treatment after acquisition of the T790M mutation. Tumor PD-L1 expression was evaluated using the 22C3 antibody. RESULTS: Data of a total of 49 patients were analyzed, including 20 patients with negative tumor PD-L1 expression (tumor proportion score <1%) and 29 patients with positive tumor PD-L1 expression (tumor proportion score ≥1%). In the negative tumor PD-L1 expression group, the T790M mutation was detected in 12 (75%) of the 16 patients. In the positive tumor PD-L1 expression group, the T790M mutation was detected 6 (31.6%) out of the 19 patients in whom it was tested. The median (95% confidence interval) time on treatment with EGFR-TKIs was 21.7 (12.9-24.8) months and 12.3 (5.6-22.2) months in the negative and positive tumor PD-L1 expression groups, respectively. Analysis using a Cox proportional hazards model identified performance status and presence/absence of tumor PD-L1 expression as significantly associated with the time on treatment with EGFR-TKIs. CONCLUSION: EGFR-mutant NSCLC patients with negative tumor PD-L1 expression showed a higher rate of acquisition of the T790M mutation and implementation rate of osimertinib therapy, leading to a longer time on treatment with EGFR-TKI.

Irinotecan monotherapy as third- or further-line treatment for patients with small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a very aggressive cancer and recurrence is inevitable. Treatment of recurrent disease is important for improving the prognosis of patients with SCLC. METHODS: We conducted a retrospective observational study to investigate the efficacy and safety of irinotecan monotherapy as third- or further-line treatment in patients with SCLC. RESULTS: Data of 15 patients who had received irinotecan monotherapy as third- or further-line treatment between 2004 and 2019 were analyzed. The median progression-free survival duration (95% confidence interval) from the initiation of treatment with irinotecan was 2.7 (1.4-3.8) months, and the median overall survival duration (95% confidence interval) from the initiation of irinotecan treatment was 10.0 (3.9-12.9) months. Partial response, stable disease or non-complete response/non-progressive disease, and progressive disease were observed in 1, 6, and 8 patients, respectively. Adverse events ⩾ grade 3 in severity were observed in 2/2 (100%) patients who were homozygous for UGT1A1 mutation, 2/3 (66.7%) patients who were heterozygous for UGT1A1 mutation, 4/6 (66.7%) patients who had wild-type UGT1A1, and 2/4 (50.0%) patients in whom the UGT1A1 mutation status was unknown. CONCLUSION: Our results suggest that irinotecan monotherapy can be a useful alternative treatment option in the third-line setting for patients with SCLC.

Case Series of Pleomorphic Carcinoma of the Lung Treated With Immune Checkpoint Inhibitors.

AIM: We report, herein, three cases of pleomorphic carcinoma of the lung treated with immune checkpoint inhibitors. Case 1: A 73-year-old man was diagnosed as having pleomorphic carcinoma of the lung and treated with pembrolizumab alone. However, he showed no response and died 4 months after the initiation of the treatment. Case 2: A 66-year-old man was diagnosed as having pleomorphic carcinoma of the lung. He was started on a combination regimen of pembrolizumab plus carboplatin plus nab-paclitaxel, and a remarkable response was observed. Case 3: A 49-year-old man was diagnosed as having pleomorphic carcinoma of the lung. He was started on pembrolizumab monotherapy as second-line treatment. Eleven months after the treatment initiation, computed tomography revealed the decrease of tumor diameter. CONCLUSION: Immune checkpoint inhibitor therapy is expected to improve the prognosis of patients with pleomorphic carcinoma of the lung.

Immune Checkpoint Inhibitor for Non-small Cell Lung Cancer With Negative or Low Tumor PD-L1 Expression.

Background/Aim: We conducted a retrospective analysis of the survival durations of 25 patients diagnosed as having non-squamous cell non-small cell lung cancer with negative or low tumor programmed death-ligand 1 (PD-L1) expression treated with immune checkpoint inhibitor (ICI) monotherapy. Patients and Methods: The progression-free (PFS) and overall (OS) survival were calculated from the initiation of ICI monotherapy. The association between the patient characteristics and the PFS was analyzed using Cox proportional hazards model. Results: The median PFS was 2.6 months, and the 12-month PFS rate was 9.3%. The median OS was 5.5 months, and the 12-month OS rate was 39.8%. A Cox proportional hazards model identified the neutrophil/lymphocyte ratio and presence of liver metastasis as being significantly associated with PFS. Conclusion: Our findings suggest that a subset of patients with non-squamous cell non-small cell lung cancer who show negative or low tumor PD-L1 expression could benefit from ICI monotherapy.

Association of Tumor PD-L1 Expression with the T790M Mutation and Progression-Free Survival in Patients with EGFR-Mutant Non-Small Cell Lung Cancer Receiving EGFR-TKI Therapy.

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), we compared the progression-free survival (PFS) and proportion of acquisition of T790M mutation of the epidermal growth receptor gene (EGFR) after first-line treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patient groups with and without tumor expression of programmed death ligand-1 (PD-L1). METHODS: Data of patients with EGFR-mutant NSCLC were retrospectively analyzed. Tumor PD-L1 expression was evaluated by immunohistochemistry using the 22C3 antibody. T790M gene mutation was evaluated by Cobas EGFR assay using tissues or humoral specimens. RESULTS: Data of 47 patients with EGFR-mutant NSCLC were analyzed. The median (95% confidence interval) PFS in the PD-L1-negative and -positive patient groups were 12.9 (9.7-15.4) months and 9.0 (5.1-12.3) months, respectively (p = 0.029). T790M gene mutation was analyzed in 27 patients. The proportion of acquisition of T790M mutation of EGFR after first-line treatment with an EGFR-TKI was higher in the PD-L1-negative patient group than in the PD-L1-positive patient group (8/11 patients (72.7%) vs. 4/16 patients (25.0%); p = 0.022). CONCLUSIONS: Patients with negative tumor PD-L1 expression showed longer PFS and a higher proportion of acquisition of T790M mutation of EGFR after first-line treatment with an EGFR-TKI.

Relationship between Patient Characteristics and the Timing of Provision of Explanation about DNAR to Patients with Advanced Lung Cancer.

Objective The aim of the present study was to analyze the relationship between the patient characteristics and the timing of provision of an explanation about "Do Not Attempt Resuscitation (DNAR)" by attending physicians to advanced lung cancer patients. Methods We conducted a retrospective analysis of patients with advanced or postoperative recurrent lung cancer in whom systemic therapy was initiated between 2015 and 2016. Results The data of a total of 74 patients with lung cancer, including 59 patients with non-small cell lung cancer and 15 with small cell lung cancer were analyzed. The median overall survival of the patients was 10.0 months. Records of the explanation about DNAR by the physicians were available for 57 of the 74 (77.0%) patients. For 48 (64.9%) patients, the explanation was provided after the discontinuation of anticancer treatment, and for 9 (12.2%) patients, it was provided during the course of anticancer treatment. The provision of an explanation about DNAR during the course of treatment was associated with a poor performance status at the start of treatment (p=0.028), the tumor histology (p=0.037), the presence of driver gene mutation in the tumor (p=0.029), and shorter survival after the discontinuation of anticancer treatment (p<0.001). Conclusion The results suggested that the timing of provision of an explanation about DNAR was associated with patient characteristics and the predicted prognosis.

Clinical Parameters for Predicting the Survival in Patients with Squamous and Non-squamous-cell NSCLC Receiving PD-1 Inhibitor Therapy.

We explored the associations between progression-free survival (PFS) after the initiation of PD-1 inhibitor therapy and the clinical parameters in patients with NSCLC. We reviewed the clinical data of patients with NSCLC treated with PD-1 inhibitor. Data of a total of 36 patients, including 16 patients with squamous cell NSCLC and 20 patients with non-squamous cell NSCLC were reviewed. Multivariate analyses identified EGFR status, C-reactive protein (CRP), and PFS following previous therapy as being significantly associated with the PFS after initiation of PD-1 inhibitor therapy in patients with NSCLC. In patients with squamous cell NSCLC, the blood neutrophil/lymphocyte ratio (NLR), serum lactate dehydrogenase (LDH), serum C-reactive protein (CRP), and PFS following previous therapy were identified as being significantly associated with the PFS after initiation of PD-1 inhibitor therapy. However, none of these associations, except for PFS following previous therapy, were found in patients with non-squamous cell NSCLC. NLR, LDH and CRP were associated with the PFS after initiation of PD-1 inhibitor therapy in patients with squamous cell NSCLC, and PFS following previous therapy was the common parameter associated with the PFS after initiation of PD-1 inhibitor therapy in both squamous-cell NSCLC and non-squamous-cell NSCLC patients.

Peripheral PD1-positive CD4 T-Lymphocyte Count Can Predict Progression-free Survival in Patients With Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitor.

BACKGROUND/AIM: Little information is available about the association between peripheral T-lymphocyte expression of programmed cell death protein 1 (PD1) and the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer (NSCLC). We analyzed the PD1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in peripheral blood T-lymphocytes of patients with NSCLC receiving immune checkpoint inhibitor therapy. PATIENTS AND METHODS: Patients with NSCLC who were scheduled to receive treatment with immune checkpoint inhibitors were prospectively enrolled in this study between November 2017 and November 2018. Peripheral blood samples were obtained within 1 week before or after the initiation of treatment with an immune checkpoint inhibitor. RESULTS: Flow cytometry was conducted in 19 patients. Patients were treated with nivolumab, pembrolizumab, or atezolizumab. The group with a high percentage of PD1+CD4+ T-lymphocytes relative to the total CD4+ T-lymphocyte count had a longer progression-free survival [median=6.0 (95% confidence intervaI=0.5-not estimated) months] than the group with a low percentage of PD1+CD4+ T-lymphocytes [median=1.1 (95% confidence intervaI=0.4-5.0) months; p=0.034, log-rank test]. However, no significant associations were detected with the percentages of CTLA4+CD4+, PD1+CD8+ or CTLA4+CD8+ T-lymphocytes in the peripheral blood. CONCLUSION: A high percentage of peripheral CD4+PD1+ T-lymphocytes was associated with a longer progression-free survival in patients receiving treatment with an immune checkpoint inhibitor. The systemic immune system may have an influence on the efficacy of immune checkpoint inhibitor therapy in patients with NSCLC.

[A Retrospective Study Analyzing the Clinical Course of Patients with Non-Small Cell Lung Cancer Receiving Local or Systemic Therapy after Post-Operative Recurrence].

BACKGROUND: While systemic therapy is one of the therapeutic options available for post-operative recurrence of non-small cell lung cancer, efficacy of local therapy for locoregional recurrence or limited metastatic lesions has also been reported. OBJECTIVE: We aimed to evaluate the clinical course of patients with post-operative recurrence(locoregional or limited metastatic lesion)after receiving local or systemic therapy. METHODS: Clinical data were retrospectively analyzed and survival duration was compared using the logrank test. RESULTS: A total of 22 patients were included. Median progression-free survival in patients receiving local therapy, systemic chemotherapy, or a combination of both therapies was 15.1 months, 6.3 months, and 13 months, respectively. Two patients receiving treatment with EGFR-TKI did not show disease progression at 41.3 months and 45.8 months(p=0.265). Median overall survivals in patients receiving local therapy, systemic chemotherapy, or a combination of both therapies were 26.5 months, 20 months, and 37.9 months, respectively(p=0.510). After the treatment, 6 patients showed regrowth of the recurrent lesion, 8 patients showed remote metastases, and 2 patients showed both regrowth of the recurrent lesion and remote metastases. CONCLUSION: Patients who received treatment including local therapy showed longer survival duration, but statistical significance was not detected. Our study suggested that regrowth of the recurrent lesion and remote metastases can be equally observed after treatment.

Outcome and prognostic factors in patients with small cell lung cancer who receive third-line chemotherapy.

AIMS AND BACKGROUND: It is reported that about 20% of patients with small cell lung cancer (SCLC) receive third-line chemotherapy. We conducted a retrospective study to investigate the outcome and prognostic factors of patients with SCLC who receive third-line chemotherapy. METHODS AND STUDY DESIGN: The medical records of patients with SCLC who received third-line chemotherapy at our institution were reviewed. Overall survival (OS) from the initiation of third-line chemotherapy was evaluated, and the association between OS and patient characteristics was assessed by the log-rank test. RESULTS: A total of 73 patients with SCLC were treated with cytotoxic drugs between 2004 and 2012, and 19 patients received third-line chemotherapy. Median OS from initiation of third-line chemotherapy was 8.5 months. Patients with higher body mass index (BMI) (P = 0.0071), lower levels of lactate dehydrogenase (LDH) (P = 0.0036), higher levels of hemoglobin (P = 0.048), longer time to progression (TTP) from the initiation of second-line treatment (P = 0.0036), and better response to second-line treatment (P = 0.029) had longer duration of OS. CONCLUSIONS: It is suggested that TTP and tumor response in second-line chemotherapy, serum levels of LDH and hemoglobin, and BMI at initiation of third-line chemotherapy could be possible prognostic factors.

Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma.

BACKGROUND AND OBJECTIVE: In asthma, reduced histone deacetylase activity and enhanced histone acetyltransferase activity in the lungs have been reported. However, the precise function of Sirtuin 1 (Sirt1), a class III histone deacetylase, and the effect of the Sirt1 activator SRT1720 on allergic inflammation have not been fully elucidated. METHODS: The effect of SRT1720, a synthetic activator of Sirt1, in an ovalbumin (OVA)-induced asthma mouse model was investigated. The effect of SRT1720 and resveratrol on OVA stimulation in splenocytes from OVA-sensitized and challenged mice was also examined. RESULTS: In OVA-sensitized and challenged mice (OVA mice) compared with saline-sensitized and challenged mice (control mice), Sirt1 messenger RNA expression in the lungs was decreased (P = 0.02), while cellular infiltration, airway eosinophilia and bronchoalveolar lavage (BAL) fluid levels of interleukin (IL)-4, IL-5 and IL-13 were increased (P < 0.01). In OVA mice, SRT1720 treatment decreased total and eosinophil cell counts and IL-5 and IL-13 levels in the BAL fluid compared with the vehicle treatment (P < 0.05). In OVA mice, SRT1720 treatment also decreased inflammatory cell lung infiltrates histologically (P = 0.002). Both SRT1720 and resveratrol suppressed OVA-induced cell proliferation and IL-6 (P < 0.05) and tumour necrosis factor-α (TNF-α) (P < 0.05) production in splenocytes (P < 0.01). CONCLUSIONS: The Sirt1 activator SRT1720 suppressed inflammatory cell infiltration and cytokine production in an OVA-induced mouse model of asthma. SRT1720 and resveratrol suppressed OVA-induced splenocyte proliferation and TNF-α and IL-6 production. Sirt1 activators might have beneficial effects in asthmatics by suppressing inflammation.

Miliary brain metastasis presenting with calcification in a patient with lung cancer: a case report.

INTRODUCTION: Miliary brain metastasis is an extremely rare form of brain metastasis which can present with atypical imaging findings. We report the case of a patient with miliary brain metastasis of lung cancer showing calcification in metastatic lesions. CASE PRESENTATION: A 68-year-old Japanese woman was diagnosed with lung adenocarcinoma. Brain computed tomography revealed multiple small calcified lesions in both cerebral hemispheres. Mutation of the epidermal growth factor receptor gene (exon 21, L858R) in lung cancer cells was detected, and treatment with gefitinib was initiated. A partial response was observed; however, the patient was readmitted to our hospital because of regrowth of the primary lesion and complaints of nausea, headache, and difficulty walking. Brain magnetic resonance imaging revealed scattered tiny nodules enhanced by gadolinium. A diagnosis of leptomeningeal carcinomatosis was made on the basis of cerebrospinal fluid cytology. The patient's general status worsened, and she died 356 days after the day of first medical examination. Upon autopsy, the brain was found to be edematous and swollen. Lung carcinoma cells were diffusely disseminated on the meningeal surface. Metastatic foci of small nodular form, accompanied by calcifications, were also found in the brain parenchyma. We diagnosed miliary metastasis of lung carcinoma. CONCLUSIONS: To the best of our knowledge, this is the third report of calcified miliary brain metastasis confirmed by autopsy. We describe calcified lesions that increased in size during the clinical course of nine months. Brain computed tomography findings that reveal multiple small calcified lesions in patients with malignancy should raise suspicion of miliary brain metastasis.

SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice.

Silent information regulator 2 (SIR2) is a highly conserved protein, the mammalian orthologue of which, SIRT1, exhibits histone deacetylase activity. SIRT1 is involved not in only longevity due to caloric restriction but in a variety of diseases such as diabetes, cardiovascular dysfunction and neurodegeneration. However, accumulating evidence shows that SIRT1 is overexpressed in various types of malignant cells, and its inhibitors suppress the growth of tumor cells. The relationship between SIRT1 and metastasis remains to be clarified. Here, we examined the effect of SRT1720, a SIRT1 activator, on lung metastasis of breast cancer cells. 4T1 breast cancer cells were subcutaneously implanted into syngeneic BALB/c mice and SRT1720 was administered alone or with an antitumor agent, cisplatin. As expected, cisplatin decreased the lung metastasis score, whereas SRT1720 increased metastasis irrespective of cisplatin. In the primary tumors, cisplatin suppressed the mRNA level of angiopoietin-like protein 4 (angptl4), a lung metastasis-promoting gene product of breast cancer, but SRT1720 reduced the effectiveness of cisplatin. The results obtained with animal experiments were in accordance with those in human cancer cells; SRT1720 significantly increased the amount of VEGF secreted from MDA-MB-231 cells. Moreover, a transendothelial cell migration assay showed that SRT1720 promotes the migration of MDA-MB-231 cells across an endothelial cell layer despite the presence of cisplatin. These findings imply that SRT1720 promotes the pulmonary metastasis of breast cancer cells and SIRT1 may be an important target for suppressing metastasis to the lung.