Genomic evolutional analysis of surgical resected specimen to assess osimertinib as a first-line therapy in two patients with lung cancer harboring EGFR mutation: Case series.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is crucial for patients with lung cancer harboring EGFR mutations. However, almost all patients experience disease progression, regardless of their response to the targeted therapy, necessitating the development of additional treatment options. Two patients with lung cancer harboring EGFR-L858R mutations in exon 21 were treated by surgical resection during successful osimertinib treatment. Because the pathological diagnosis was suspected to be pleural metastasis, osimertinib treatment was continued until disease progression. We analyzed the evolution of genomic alterations and the levels of AXL using tumor specimens obtained by repeated biopsies during the course of treatment: initial diagnosis, operation, and disease progression. Genetic alterations detected at the three time points were dramatically changed and showed reductions in numbers, while EGFR-L858R mutations were detected in all samples tested in both patients. Immunohistochemical expression of AXL remained positive from the beginning of analysis to disease progression. Clonal evolution under oncogenesis is related to gradual accumulation of genomic alterations during tumor growth. However, our case series revealed that volume reduction procedures may cause this phenomenon. Therefore, identification of intrinsic drug-resistant cells in tumors may be as important as detection of acquired genetic alterations.

Development of Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome with Pembrolizumab for Lung Squamous Cell Carcinoma: A Case Report.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs). There are a few case reports of remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) as an irAE. We herein report a 49-year-old Japanese man who developed acute-onset polyarthralgia and edema of the back of both hands and bilateral lower legs after pembrolizumab administration for lung cancer. The patient's lung cancer was in complete remission, leading to the diagnosis of RS3PE induced by pembrolizumab rather than malignancy. When patients show RS3PE during ICI treatment, rheumatologists should consider the possibility of an irAE after excluding malignancy and systemic diseases.

A phase 2 trial of durvalumab treatment following radiation monotherapy in patients with non-small cell lung cancer ineligible for stage III chemoradiotherapy: The SPIRAL-RT study.

BACKGROUND: Although concurrent chemoradiotherapy (CCRT) followed by durvalumab is the standard treatment for patients with stage III non-small cell lung cancer (NSCLC), only half of the patients are allowed to receive CCRT in real-world settings. We evaluated the efficacy and safety of durvalumab after radiation monotherapy for NSCLC patients who are ineligible for chemoradiotherapy. METHODS: A single-arm, prospective, open-label, multicenter phase II trial was conducted in Japan. The patients received radiation (54-66 Gy) followed by durvalumab (10 mg/kg every 2 weeks for up to 12 months). The primary endpoint was the 1-year progression-free survival (PFS) rate. The secondary endpoints were the objective response rate (ORR), PFS, overall survival (OS), and safety. RESULTS: Between September 2019 and April 2021, 33 patients were enroled from eight institutions. The median patient age was 79 years, and the majority of patients were male (78.8%). The 1-year PFS rate was 39.1% (90% confidence interval [CI]: 24.7-54.6%). Three patients (9.1%) had a performance status of 2. The ORR was 42.4% (95% CI: 27.2-59.2%). The median PFS and OS were 8.9 (95% CI: 7.4-19.4) and 20.8 (95% CI: 15.8-not estimable) months, respectively. The most common adverse event was radiation pneumonitis (51.5%). The median treatment duration was 6.4 (range: 0.50-12.0) months for durvalumab. At the endpoint, 30.3% (10/33) of the patients had completed 1 year of durvalumab therapy. CONCLUSIONS: Durvalumab is an effective treatment with tolerable toxicity following radiation monotherapy in stage III NSCLC patients who are ineligible for chemoradiotherapy. TRIAL REGISTRATION: JMA-IIA00434 (jRCT).

Prophylactic treatment of dacomitinib-induced skin toxicities in epidermal growth factor receptor-mutated non-small-cell lung cancer: A multicenter, Phase II trial.

BACKGROUND: Dacomitinib significantly improves progression-free survival and overall survival (OS) compared with gefitinib in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations. However, dacomitinib often causes skin toxicities, resulting in treatment discontinuation. We aimed to evaluate a prophylactic strategy for skin toxicity induced by dacomitinib. METHODS: We performed a single-arm, prospective, open-label, multi-institutional phase II trial for comprehensive skin toxicity prophylaxis. Patients with NSCLC harboring EGFR-activating mutations were enrolled and received dacomitinib with comprehensive prophylaxis. The primary endpoint was the incidence of skin toxicity (Grade ≥2) in the initial 8 weeks. RESULTS: In total, 41 Japanese patients participated between May 2019 and April 2021 from 14 institutions (median age 70 years; range: 32-83 years), 20 were male, and 36 had a performance status of 0-1. Nineteen patients had exon 19 deletions and L858R mutation. More than 90% of patients were perfectly compliant with prophylactic minocycline administration. Skin toxicities (Grade ≥2) occurred in 43.9% of patients (90% confidence interval [CI], 31.2%-56.7%). The most frequent skin toxicity was acneiform rash in 11 patients (26.8%), followed by paronychia in five patients (12.2%). Due to skin toxicities, eight patients (19.5%) received reduced doses of dacomitinib. The median progression-free survival was 6.8 months (95% CI, 4.0-8.6 months) and median OS was 21.6 months (95% CI, 17.0 months-not reached). CONCLUSION: Although the prophylactic strategy was ineffective, the adherence to prophylactic medication was quite good. Patient education regarding prophylaxis is important and can lead to improved treatment continuity.

Ramucirumab Plus Docetaxel for Patients with Non-small cell Lung Cancer with Brain Metastases: A Multicenter, Open-Label Single-Arm Phase II Trial.

BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).

Utility of beta-human chorionic gonadotropin in pleural effusions: Report of an autopsy case of a male patient with primary pulmonary choriocarcinoma.

A 69-year-old male patient presented with bloody pleural fluid effusion and elevated beta-human chorionic gonadotropin (ß-hCG) levels obtained by thoracentesis. The patient's condition rapidly deteriorated, and he died. The autopsy revealed primary pulmonary choriocarcinoma. Early diagnosis of choriocarcinoma based on ß-hCG levels in the pleural fluid may be possible.

Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study.

Background: Topoisomerase is an essential enzyme for deoxyribonucleic acid replication, and its inhibitors suppress tumor progression. Amrubicin, a topoisomerase II inhibitor, is mainly used in the second-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). However, the impact of different types of topoisomerase inhibitors for first-line chemotherapy on the efficacy of amrubicin remains unclear. In the present study, we aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors. Methods: This study retrospectively analyzed patients with ES-SCLC who experienced recurrence and were treated with amrubicin at 22 institutions in Japan between April 2015 and November 2020. The progression-free survival of amrubicin monotherapy was investigated using the Kaplan-Meier method. Results: A total of 320 patients were enrolled in this study, with 59 (18%) receiving platinum plus topoisomerase I inhibitor irinotecan and 261 (82%) receiving platinum plus topoisomerase II inhibitor etoposide as first-line treatment. The progression-free survival of amrubicin was significantly longer in the irinotecan group than in the etoposide group (3.2 vs. 2.5 months; P=0.034). Conclusions: These results showed that different types of topoisomerase inhibitors could affect the efficacy of amrubicin monotherapy in the second-line treatment of patients with relapsed ES-SCLC.

A Real-World Analysis of Immune Checkpoint Inhibitor-Based Therapy After Osimertinib Treatment in Patients With EGFR-Mutant NSCLC.

Introduction: The use of immune checkpoint inhibitors (ICIs) with chemotherapy has increased the survival of patients with advanced NSCLC. Nevertheless, the efficacy of ICI treatment for NSCLC with EGFR mutations is limited. Previous studies have not evaluated the efficacy of ICI treatment after osimertinib treatment in real-world settings. Methods: This study performed a retrospective analysis of the association between clinical characteristics and ICI efficacy in patients with EGFR-mutant NSCLC treated with ICIs after osimertinib treatment at 12 institutions in Japan from March 2016 to March 2021. Results: Among 80 patients with EGFR-mutant lung cancer, 42 received ICI monotherapy and 38 received chemoimmunotherapy. In the chemoimmunotherapy group, the progression-free survival (PFS) was significantly longer in the group that exhibited PFS more than 10 months with osimertinib than in the group that exhibited PFS less than or equal to 10 months with osimertinib (8.4 mo versus 3.8 mo, p = 0.026). Nevertheless, there was no significant difference in PFS in the ICI monotherapy group (1.7 mo versus 1.5 mo, p = 0.45). Regardless of the EGFR mutation subtype, PFS of osimertinib treatment was a predictor of the PFS of chemoimmunotherapy (exon 19 deletion mutation: p = 0.03 and exon 21 L858R mutation: p = 0.001). Conclusions: The PFS of osimertinib might be a predictor of PFS of chemoimmunotherapy in patients with EGFR-mutant NSCLC. Further clinical investigations on the predictors of efficacy of administering ICIs after osimertinib treatment are required.

Long-Term Survival of Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor Monotherapy in Real-World Settings.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. PATIENTS AND METHODS: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. RESULTS: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. CONCLUSIONS: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.

Two cases of chronic obstructive pulmonary disease evaluated by dynamic-ventilatory digital radiography for pulmonary function and assessment of treatment efficacy.

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Suitability of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration versus Paired Transbronchial Biopsy Specimens for Evaluating Programmed Death Ligand-1 Expression in Stage III and IV Lung Cancer: A Comparative Retrospective Study.

Objectives: Cancer cells usually escape tumor-reactive T-cell responses using immune checkpoint proteins, such as programmed death protein-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1). These proteins can be blocked by immune checkpoint inhibitors (ICIs); the decision on ICI-based first-line treatment for advanced lung cancers depends on the PD-L1 levels in tumor specimens. Determining the PD-L1 expression conventionally requires histological specimens from resected tumors and core biopsy specimens. Non-small cell lung cancer (NSCLC) is usually diagnosed at stage III or IV; therefore, only small biopsy specimens, such as those obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are available. However, the suitability of EBUS-TBNA specimens determining the PD-L1 expression levels in advanced lung cancers remains unclear. Materials and Methods: Here, we investigated the concordance rate of PD-L1 expression between EBUS-TBNA and matched transbronchial biopsy (TBB) specimens. Using the 22C3 anti-PD-L1 antibody (immunohistochemistry), we determined the PD-L1 expression levels in paired specimens obtained from 69 patients (50 with advanced NSCLC and 19 with small cell lung cancer [SCLC]), as well as the efficacy of ICIs in these patients. Results: The concordance rate of PD-L1 expression between the EBUS-TBNA and TBB specimens was 78.3%. The κ values referent to the PD-L1-positive expression rate between EBUS-TBNA and TBB specimens were 0.707 and 0.676 at cutoff limits of ≥1% and ≥50%, respectively. Among the 19 SCLC patients, 16 (84.2%) exhibited no PD-L1 expression in both EBUS-TBNA and TBB specimens. Notably, the progression-free survival of patients with ≥50% PD-L1 expression in the paired specimens who received ICI treatment was 8.3 months. Conclusion: Collectively, our results validate the use of EBUS-TBNA specimens for the determination of the PD-L1 expression levels in the context of NSCLC and SCLC.

Molecular features of tumor-derived genetic alterations in circulating cell-free DNA in virtue of autopsy analysis.

In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis.

Late-onset programmed cell death protein-1 inhibitor-induced pneumonitis after cessation of nivolumab or pembrolizumab in patients with advanced non-small cell lung cancer: a case series.

Awareness of the immune-related adverse event of programmed cell death protein-1 (PD-1) inhibitor-induced pneumonitis is important. Herein, we report the clinical course of 3 patients suspected to have PD-1 inhibitor-induced pneumonitis after cessation of PD-1 inhibitor treatment. In case 1, a 62-year-old man was diagnosed with stage IVA adenocarcinoma. Nivolumab monotherapy was prescribed as second-line therapy and later discontinued due to financial reasons. Seven months after the final administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis. The patient was immediately prescribed prednisolone (1 mg/kg p.o. daily), and the pneumonitis resolved after 1.5 months. In case 2, a 68-year-old man was diagnosed with stage IVB squamous cell carcinoma. Nivolumab monotherapy was prescribed as fourth-line therapy. After the second administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis; nivolumab was discontinued, and the patient was immediately prescribed prednisolone (1 mg/kg p.o. daily). Eight months after the final administration of nivolumab, the patient again developed nivolumab-induced pneumonitis. The pneumonitis resolved without additional medication. In case 3, a 69-year-old man was diagnosed with stage IVB adenocarcinoma. Pembrolizumab monotherapy was initiated as sixth-line therapy, and it was discontinued after 4 cycles due to disease progression. Four months after the final dose of pembrolizumab, the patient developed what we diagnosed as pembrolizumab-induced pneumonitis. The patient immediately received a high intravenous dose of methylprednisolone (1,000 mg per day for three days). The pneumonitis and respiratory failure progressed, and he died 8 weeks after the onset of the pneumonitis. We report pneumonitis after discontinuation of ICIs in 3 patients. We confirm that, although uncommon, PD-1 inhibitor-induced irAEs can develop after treatment discontinuation. Further accumulation of cases and clarification of the clinical features of patients with irAEs, such as the time of onset, imaging findings, and treatment outcomes are needed.

NOTCH alteration in EGFR-mutated lung adenocarcinoma leads to histological small-cell carcinoma transformation under EGFR-TKI treatment.

BACKGROUND: Molecular targeted therapy has been developed as an innovative treatment for metastatic cancer. Epidermal growth factor receptor (EGFR) mutation is one of the most important and frequent oncogenic drivers in non-small-cell lung cancer, and EGFR-tyrosine kinase inhibitors are indispensable drugs for mutation-positive patients. Currently, the acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a problem, the mechanism of which has not been elucidated. The histological transformation from original adenocarcinoma to small-cell carcinoma is rare; however, it has been detected in many cases after EGFR-TKI treatment. This study aimed to evaluate mutational status in two different histological types and further elucidate the molecular pathogenesis. METHODS: Three patients with EGFR-mutant lung cancer who underwent a histological transformation to small-cell carcinoma after growth factor receptor-TKI treatment were enrolled in this study. Two samples per patient were collected from histologically different lesions, and DNA samples were extracted from formalin-fixed, paraffin-embedded tumor tissues. The paired samples were subjected to next-generation sequencing of 160 cancer-related genes. Based on the sequencing results, the expression levels of related proteins were validated using reverse-transferase polymerase chain reaction and immunohistochemical staining. RESULTS: The following five variants were common among the three cases: MTOR, JAK1, NOTCH2, CSF1R, and MAP2K2. The former four variants were additive to small-cell carcinoma, and the last variant was lost. Both TP53 and Rb1 alterations were detected in adenocarcinoma. Notch2 expression was negative in small-cell carcinoma in both reverse-transcriptase polymerase chain reaction analysis and immunohistochemical staining. ASCL1 expression increased after histological transformation detected using both methods in one case, only these samples were evaluable. CONCLUSIONS: Notch and ASCL1 signaling are the master regulators of neuroendocrine differentiation in small-cell lung carcinoma. Our results suggest that the Notch-ASCL1 axis may also play an essential role in the transformation of small-cell carcinoma under TP53 and RB1 inactivation.

Multiplex gene-panel testing for lung cancer patients.

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.

Dynamic-Ventilatory Digital Radiography in Air Flow Limitation: A Change in Lung Area Reflects Air Trapping.

OBJECTIVE: The aim of this study was to determine the utility of dynamic-ventilatory digital radiography (DR) for pulmonary function assessment in patients with airflow limitation. METHODS: One hundred and eighteen patients with airflow limitation (72 patients with lung cancer before surgery, 35 patients with chronic obstructive pulmonary disease [COPD], 6 patients with asthma, and 5 patients with asthma-COPD overlap syndrome) were assessed with dynamic-ventilatory DR. The patients were instructed to inhale and exhale slowly and maximally. Sequential chest X-ray images were captured in 15 frames per second using a dynamic flat-panel imaging system. The relationship between the lung area and the rate of change in the lung area due to respiratory motion with respect to pulmonary function was analyzed. RESULTS: The rate of change in the lung area from maximum inspiration to maximum expiration (Rs ratio) was associated with the RV/TLC ratio (r = 0.48, p < 0.01) and the percentage of the predicted FEV1 (r = -0.33, p < 0.01) in patients with airflow limitations. The Rs ratio also decreased in an FEV1-dependent manner. CONCLUSION: The rate of change in the lung area due to respiratory motion evaluated with dynamic DR reflects air trapping. Dynamic DR is a potential tool for the comprehensive assessment of pulmonary function in patients with COPD.

Real-World Efficacy of First-Line Pembrolizumab in Patients With Advanced or Recurrent Non-Small-Cell Lung Cancer and High PD-L1 Tumor Expression.

BACKGROUND: In clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent. PATIENTS AND METHODS: Ninety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics. RESULTS: The objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease. CONCLUSION: The outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.

Successful Treatment of Advanced Thymic Carcinoma with Carboplatin plus nab-Paclitaxel and Maintenance Monotherapy with nab-Paclitaxel: Two Case Reports.

A standard chemotherapy regimen for advanced thymic carcinoma has not yet been established. We treated 2 cases of thymic carcinoma with carboplatin plus nanoparticle albumin-bound (nab)-paclitaxel, and nab-paclitaxel maintenance therapy. The first case was a 68-year-old female, admitted for dyspnea and left shoulder pain. Chest computed tomography (CT) showed a huge mass in the anterior mediastinum, pleural and pericardial effusions, and multiple lung metastases. Specimens obtained from the anterior mediastinal mass by CT-guided needle biopsy revealed squamous cell carcinoma of the thymus, which was in stage IVB. The patient was administered carboplatin plus nab-paclitaxel as first-line treatment. After 3 cycles of chemotherapy, a partial response was observed with marked shrinkage of the tumor. Following 6 cycles of chemotherapy, nab-paclitaxel maintenance therapy was initiated. Disease progression was seen 9.1 months after initiation of treatment. The patient experienced no serious adverse events. The second case was a 70-year-old male who had productive cough, dyspnea, and right-sided chest pain. Chest CT revealed a huge mass in the anterior mediastinum, pericardial effusion, and multiple lymphadenopathies. Specimens obtained from station 11s by endobronchial ultrasound-guided transbronchial needle aspiration revealed undifferentiated thymic carcinoma, which was in stage IVB. Six cycles of carboplatin plus nab-paclitaxel were administered, followed by 5 cycles of nab-paclitaxel for maintenance. A partial response was seen, which was sustained for more than 13 months. The patient experienced no serious adverse events. These cases show that chemotherapy with carboplatin plus nab-paclitaxel and nab-paclitaxel as maintenance therapy can be a useful regimen for advanced thymic carcinoma.

Repeated bronchoconstriction attenuates the cough response to bronchoconstriction in naïve guinea pigs.

BACKGROUND: Cough variant asthma (CVA) is recognized as a precursor of bronchial asthma (BA). However, the cough response to bronchoconstriction differs between these similar diseases. Repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators may impact the cough response. METHODS: We investigated the influence of repeated bronchoconstriction on the cough response to bronchoconstriction using naïve guinea pigs. Bronchoconstriction was induced for 3 consecutive days and changes in the cough response and lipid mediators, such as PGE2, PGI2, and cysteinyl-LTs (Cys-LTs), in BAL fluid (BALF) were assessed. We investigated the effect of endogenous PGI2 on the cough response by employing a PGI2 receptor antagonist. In order to investigate the cough response over a longer period, we re-evaluated the cough response 2 weeks after repeated bronchoconstriction. RESULTS: The number of coughs induced by bronchoconstriction were significantly decreased by repeated bronchoconstriction. The levels of PGE2, PGI2, and Cys-LTs, and the ratio of PGI2/PGE2 were significantly increased, following repeated bronchoconstriction. This decrease in the cough response was suppressed by pretreatment with a PGI2 receptor antagonist. Two weeks after repeated bronchoconstriction, the cough response returned to the same level as before repeated bronchoconstriction along with a concomitant return of lipid mediators, such as PGE2, PGI2, and Cys-LTs and the ratio of PGI2/PGE2. CONCLUSIONS: Our results suggest that repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators contribute to the difference in cough responses to bronchoconstriction in CVA and BA.