The incidence and prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of the lung related to methotrexate: A retrospective study.

BACKGROUND AND OBJECTIVE: Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are rare but well-known diseases that manifest during or after methotrexate (MTX) administration. Limited information is available on the clinical characteristics of OIIA-LPD of the lung because only a few cases have been reported. Thus, we aimed to assess the incidence and prognosis of patients with OIIA-LPD of the lung. METHODS: Patients with OIIA-LPD of the lung treated at our institution between January 2008 and July 2020 were retrospectively analysed. RESULTS: Among the 51 patients with OIIA-LPD, 16 (31.3%, 7 men, 9 women) had OIIA-LPD of the lung (median age, 69 [range, 63-82] years). Peripheral lesions were observed in 10 (62.5%), central lesions in two (12.5%), and both lesions in four (25.0%) patients. Nine of the 16 patients underwent bronchoscopic biopsy, seven were diagnosed (diagnostic yield, 77.8%) and, re-biopsy was performed in 2 patients. Eight (50.0%) patients had LPD and six (37.5%) had diffuse large B-cell lymphoma. In the 14 patients with confirmed treatment efficacy, the overall response rate to MTX withdrawal was 71.4%. However, chemotherapy was required in case of larger lesions (three patients). Death related to OIIA-LPD occurred in only one patient, and 11 of the 14 patients were alive during the study period (median follow-up time, 53.7 [range, 4.3-84.2] months). CONCLUSION: The incidence of OIIA-LPD of the lung is 31.3% and higher than that reported previously. The treatment effect of MTX withdrawal seems to be sufficient; however, in some cases, chemotherapy may be required from the beginning.

Mucous Gland Adenoma of the Lung: A Neoplastic Counterpart of Mucinous Bronchial Glands.

Mucous gland adenoma (MGA) is a rare benign tumor that usually arises in the proximal airway and consists of mucus-secreting cells resembling bronchial glands. Here, we report 2 cases of MGAs and describe their morphologic, immunohistochemical, and molecular profiles in comparison with 19 pulmonary tumors of 5 other histologic types with mucinous cells (invasive mucinous adenocarcinoma, mucoepidermoid carcinoma, mixed squamous cell and glandular papilloma, bronchiolar adenoma/ciliated muconodular papillary tumor, and sialadenoma papilliferum). Two MGAs were found in 1 male patient and 1 female patient, located in the bronchus and trachea, respectively. One MGA was examined by RNA sequencing, and no putative driver mutations (including BRAF, KRAS, and AKT1 mutations) or gene fusions were identified. In another case of MGA, V600E mutations of BRAF and E17K mutations of AKT1 were not detected by allele-specific real-time PCR or digital PCR, respectively. However, a gene expression analysis revealed that the MGA presented a specific RNA expression profile with multiple genes enriched in the salivary gland. The gene expression of NKX3.1 was significantly higher in the MGA case in comparison to normal control lungs (P < .001). We then examined NKX3.1 immunohistochemistry for 2 MGAs and 19 tumors of 5 other histologic types. NKX3.1 was positive in MGA (2/2, 100%), whereas all constituent cells, including mucinous cells, were negative for NKX3.1 in other histologic types (0%, 0/19). In normal lung tissue, NKX3.1 was positive for mucinous acinar cells of the bronchial glands. In conclusion, the gene expression profile, taken together with the histologic similarity between MGA and bronchial glands, and the preferred location of the tumors (proximal airways with submucosal glands) suggest that MGA is a neoplastic counterpart of mucinous bronchial glands. NKX3.1 immunohistochemistry can be a sensitive and specific ancillary marker that distinguishes MGA from other histologic mimics.

Continuation of osimertinib in EGFR-mutant non-small-cell lung cancer patients bearing CNS metastasis (EPONA study).

The patients harboring EGFR-mutated non-small-cell lung cancer, treated with EGFR tyrosine kinase inhibitor will lead to longer survival than those having non-small-cell lung cancer (NSCLC) patient who do not harbor EGFR mutations. This ongoing clinical trial is to investigate the secondary chemoprevention effect of osimertinib from CNS with platinum doublets chemotherapy in patients who had progressive disease outside of CNS lesions. The aim of this randomized, phase II trial is to evaluate platinum and pemetrexed chemotherapy followed by pemetrexed maintenance with or without continuation of osimertinib for secondary CNS prevention in patients with brain metastatic NSCLC with EGFR mutation, with other than CNS lesions, but no progressive disease in the CNS lesion after osimertinib. The primary end point is to assess progression-free survival by investigator assessment. The key secondary end points are overall survival, response rate, time to CNS controlling, time to whole-brain irradiation and safety. Clinical trial registration: Japan Registry of Clinical Trials (jRCT), Japan (jRCTs071200029).

The authors are conducting a clinical trial aimed at improving treatment for individuals diagnosed with non-small-cell lung cancer, a specific type of lung cancer. In some cases, this cancer can spread to the brain. This study focuses on patients whose cancer is stable in the brain but progressing in other parts of the body. The study is comparing two different treatment approaches. One involves a combination of two drugs, platinum and pemetrexed, while the other combines these drugs with a third one called osimertinib. The main objective is to determine if continuing osimertinib treatment benefits these patients. The authors are evaluating the time it takes for the cancer to start growing again, known as progression-free survival, to identify the most effective treatment. Progression-free survival represents the duration that patients live without their disease worsening. This study, the EPONA study, will provide valuable insights into optimizing the treatment of this type of cancer.

Ultrathin bronchoscopic cryobiopsy of peripheral pulmonary lesions.

BACKGROUND AND OBJECTIVE: Ultrathin bronchoscopy aids in the diagnosis of peripheral pulmonary lesions. However, both the working channel and the specimens are small. A 1.1-mm ultrathin cryoprobe that can enter the working channel of the ultrathin bronchoscope is now available, which may overcome the limitations of small specimen size. The aim of this study was to evaluate the feasibility, efficacy and safety of ultrathin bronchoscopic cryobiopsy using an ultrathin cryoprobe for diagnosing peripheral pulmonary lesions. METHODS: Patients with peripheral pulmonary lesions ≤30 mm in diameter were prospectively enrolled in the study. All patients underwent forceps biopsy followed by cryobiopsy using a 3.0-mm ultrathin bronchoscope under radial probe endobronchial ultrasound guidance, virtual bronchoscopic navigation and fluoroscopic guidance. The primary endpoint was the feasibility of cryobiopsy. RESULTS: In total, 50 patients with peripheral pulmonary lesions were enrolled in the study; the median longest diameter on computed tomography was 17.9 mm. Cryobiopsy was performed successfully in 49 patients (98%). Forceps biopsy, cryobiopsy and the combination of these two methods provided a specific diagnosis in 54% (27/50), 62% (31/50) and 74% (37/50) of patients, respectively. The median size of specimens obtained via cryobiopsy was significantly larger than the median size obtained via forceps biopsy (7.0 vs. 1.3 mm2 , respectively, p < 0.001). Mild bleeding during cryobiopsy occurred in 47 patients (94%). No moderate/severe bleeding or pneumothorax occurred. CONCLUSION: Ultrathin bronchoscopic cryobiopsy is feasible, effective and sufficiently safe for the diagnosis of peripheral pulmonary lesions.

Rationale and protocol design of a phase II study of first-line osimertinib treatment for patients with poor performance status and EGFR mutation-positive non-small cell lung cancer (OPEN/TORG2040).

BACKGROUND: Cancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status; however, no evidence exists of the drug's effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status. METHODS: The OPEN/TORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed. DISCUSSION: Our study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs041200100 (registration date: February 12, 2021).

Changes in Pulmonary Function Test Results and Respiratory Symptoms before and after Airway Stent Removal.

BACKGROUND: Airway stenting is a useful form of palliation for patients with airway stenosis/fistulas; the stent can be removed after addressing the cause of the airway disorder. Patients with airway stents often complain of coughing and difficulty with expectoration, so the use of such stents can negatively affect pulmonary function and worsen symptoms. OBJECTIVES: The aim of this study was to compare pulmonary function and respiratory symptoms before and after stent removal. METHODS: Patients who would later undergo simple airway stent removal were prospectively recruited in two institutions. All stents were removed using both rigid and flexible bronchoscopes with patients under general anesthesia. Pulmonary function tests were performed before stent removal and at 1 and 4 weeks after stent removal. All patients self-reported their respiratory symptoms using a 100-mm visual analog scale (VAS). RESULTS: Of the 31 patients enrolled, 28 (23 with malignant stenoses, 3 with benign stenoses, and 2 with fistulas [21 silicone and 7 metallic stents]) were included in analyses. Pulmonary function measurements before stent removal and at 1 and 4 weeks after stent removal were as follows: vital capacity, 3.00, 3.04, and 3.08 L (p = 0.387); forced expiratory volume in 1 s, 1.96, 1.96, and 2.12 L (p = 0.034); and peak expiratory flow, 3.60, 4.28, and 5.06 L/s, respectively (p < 0.001). Symptoms (cough, sputum production, difficulty with expectoration, and dyspnea) evaluated using the VAS improved significantly after stent removal. No complications were encountered during removal. CONCLUSION: Removal of unnecessary airway stents improves pulmonary function and respiratory symptoms. Any stent that is no longer functioning should be removed.

EUS-B-FNA Enhances the Diagnostic Yield of EBUS Bronchoscope for Intrathoracic Lesions.

INTRODUCTION: Endobronchial ultrasound (EBUS) bronchoscopes have been used mainly through the airway for EBUS-guided transbronchial needle aspiration (EBUS-TBNA); however, they can also be used through the esophagus. The esophageal approach, endoscopic ultrasound with bronchoscope-guided fine needle aspiration (EUS-B-FNA), has gradually become popular, as it can evaluate lesions that cannot be accessed through the airway. PURPOSE: This study aimed to evaluate the value of adding EUS-B-FNA to EBUS-TBNA performed by pulmonologists for intrathoracic lesions in the clinical setting. METHODS: Between March 2009 and March 2020, all patients who underwent EUS-B-FNA and EBUS-TBNA for diagnostic purposes were included and retrospectively analyzed at a single institution. RESULTS: A total of 1794 procedures using an EBUS bronchoscope including, EBUS-TBNA, EUS-B-FNA, and the combination of EBUS-TBNA and EUS-B-FNA for evaluating intrathoracic lesions, were performed. We finally analyzed 276 patients who underwent EUS-B-FNA for diagnostic purposes. EUS-B-FNA provided diagnostic materials from only EBUS-TBNA-inaccessible lesions in 26 patients and in 18 patients whose conditions were inappropriate for bronchoscopy (e.g., respiratory failure, airway stenosis, etc.). EUS-B-FNA provided diagnostic results in four patients with non-diagnostic EBUS-TBNA results. EUS-B-FNA was preferable to EBUS-TBNA in 4.4% (48 of 1091) of patients; therefore, adding EUS-B-FNA to EBUS-TBNA increased the diagnostic yield from 72.6% (1043 of 1437) to 75.9% (1091 of 1437). CONCLUSION: Pulmonologists are able to enhance diagnostic yields by acquiring the EUS-B-FNA technique.

Thin bronchoscopic cryobiopsy using a nasobronchial tube.

BACKGROUND: Transbronchial lung cryobiopsy is useful when diagnosing lung lesions. However, prevention of associated bleeding complications is essential. This study aimed to evaluate the safety and efficacy of our novel bronchoscopic cryobiopsy technique, which uses a long nasobronchial tube to prevent blood flooding the central airway. METHODS: Patients with localized or diffuse lung lesions were prospectively enrolled and underwent cryobiopsy using a 1.9 mm diameter cryoprobe and a 4.0 mm diameter thin bronchoscope under conscious sedation. For cryobiopsy, a long silicone tube (inner diameter, 5.0 mm) was advanced through the nose to the target bronchus, then wedged to drain blood under thin-tube bronchoscopic control. The primary endpoint was the frequency of bleeding complications. RESULTS: Of the 80 patients initially enrolled, 73 that underwent at least one cryobiopsy were ultimately included. Mild bleeding during cryobiopsy occurred in 58 patients (79.5%), but there was no moderate or severe bleeding. Other complications occurred in four patients (two pneumothorax, one pneumomediastinum, and one pneumonia). Tube dislocation was noted in eight patients (11%). Cryobiopsy specimens were significantly larger than forceps biopsy specimens (9.0 mm2 vs. 2.7 mm2, P < .001) and allowed specific diagnoses in 50 patients (68.5%). CONCLUSIONS: Thin bronchoscopic cryobiopsy using a nasobronchial tube in consciously sedated patients is safe and effective. Trial registration Date of registration: 24/06/2019. UMIN-Clinical Trials Registry; Identifier: UMIN000037156 https://www.umin.ac.jp/ctr/index.htm.

Phase II study of multidisciplinary therapy combined with pembrolizumab for patients with synchronous oligometastatic non-small cell lung cancer TRAP OLIGO study (WJOG11118L).

BACKGROUND: Synchronous oligometastatic non-small cell lung cancer (NSCLC) is generally characterised by the limited number of metastases at the time of diagnosis. Several clinical trials have shown that local ablative therapy (LAT) at all sites of the disease might be beneficial for patients with oligometastatic NSCLC. In recent years, the combination of programmed cell death 1 (PD-1) inhibitors or programmed cell death ligand 1 with cytotoxic chemotherapy has become a new standard treatment for patients with metastatic NSCLC. Furthermore, multisite LAT would inherently reduce the overall tumour burden, and this could promote T cell reinvigoration to enhance the efficacy of PD-1 inhibitors. Few studies have evaluated the efficacy of the combination of PD-1 inhibitors with LAT at all sites of disease. The aim of the present multicentre single-arm phase II study is to evaluate the efficacy of LAT at all sites of disease following standard platinum doublet chemotherapy with pembrolizumab in patients with oligometastatic NSCLC. METHODS: Thirty patients with synchronous oligometastatic NSCLC will be enrolled in the trial. All patients will receive 2-4 cycles of a systemic treatment including pembrolizumab and chemotherapy as induction therapy. Patients who will receive LAT will be determined by a multidisciplinary tumour board, including medical oncologists, radiation oncologists, and thoracic surgeons. LAT will be administered at all sites of disease within 21-56 days of the last dose of induction therapy and will be followed by maintenance therapy within 42 days of the last day of LAT. The primary endpoint is the progression-free survival (PFS) rate of 24 months from the date of initiation of LAT. The secondary endpoints are toxicity, response to induction therapy, PFS, overall survival, and the frequency of LAT. DISCUSSION: This study will provide novel data on the efficacy and safety profile of the combination of LAT and chemotherapy plus immune-checkpoint inhibitors in patients with synchronous oligometastatic NSCLC. If the primary endpoint of this study is met, extensive phase III studies further assessing this strategy will be recommended. TRIAL REGISTRATION: jRCT identifier: jRCTs041200046 (date of initial registration: 28 October 2020).

The Role of Rigid Bronchoscopic Intervention for Bronchial Carcinoid.

Bronchial carcinoid is a rare malignant tumor that is categorized as a typical carcinoid or atypical carcinoid. Many institutions use flexible bronchoscopy for diagnosis. However, due to the hemorrhagic nature of the tumor, the amount of specimen obtained is often small, making it difficult to obtain an accurate diagnosis. The use of rigid bronchoscopy may not only contribute to obtaining a diagnosis but also be beneficial in the treatment plan. The aim of this study was to evaluate the efficacy of rigid bronchoscopic interventions for the diagnosis and treatment of bronchial carcinoids. All patients with bronchial carcinoids who underwent rigid bronchoscopic intervention under general anesthesia at our institution between June 2006 and August 2018 were analyzed retrospectively. Eight patients [3 men and 5 women; median age, 71 years (range 45-82 years)] were eligible for the analysis. None of the cases had accurate subtyping preoperatively before intervention. In contrast, all cases were diagnosed as carcinoid with subtypes (5 patients had typical carcinoid and 3 had atypical carcinoid) following rigid bronchoscopic intervention. All respiratory symptoms improved immediately after the procedure. One instance of bleeding occurred, and was easily controlled by argon plasma coagulation and intraluminal administration of epinephrine under flexible and rigid bronchoscopy. Four patients (3 with typical carcinoid and 1 with atypical carcinoid) underwent radical surgery sequentially, and no recurrences were observed. We conclude that rigid bronchoscopic intervention is safe and effective for accurate diagnosis and improvement of respiratory symptoms in patients with bronchial carcinoids.

Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L).

BACKGROUND: Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy. METHODS: This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2-16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients. RESULTS: In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2-32.1%) and 53.7% (95%CI: 37.4-69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1-4.5) and 11.3 (95%CI: 8.6-16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3-4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection. CONCLUSIONS: Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.

Safety and tolerability of selumetinib as a monotherapy, or in combination with docetaxel as second-line therapy, in Japanese patients with advanced solid malignancies or non-small cell lung cancer.

OBJECTIVE: This Phase I study (NCT01605916) investigated the safety, tolerability and pharmacokinetic profile of selumetinib plus docetaxel as second-line therapy in Japanese patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), or selumetinib monotherapy in Japanese patients with advanced solid malignancies. METHODS: All enrolled patients received single-dose selumetinib 25, 50 or 75 mg, followed by a 3-day washout. Combination therapy cohorts then started a 21-day cycle of docetaxel 60 mg/m2 plus selumetinib 25 or 75 mg twice-daily (BID) on Day 1. Thereafter, selumetinib BID continued for 20 days; patients received ≤6 cycles. Following single-dosing, monotherapy cohorts underwent a 21-day cycle of selumetinib 25, 50 or 75 mg BID. RESULTS: Thirty-three patients were enrolled and 25 assigned to treatment (combination, n = 8; monotherapy, n = 17). Most frequent adverse events (AEs) included: vomiting, decreased appetite, diarrhea, nausea and stomatitis (combination cohorts); gastrointestinal disorders, skin and subcutaneous tissue disorders (monotherapy cohorts). Grade 3 dose-limiting toxicities: febrile neutropenia, causally related to combination therapy (n = 3); pneumonitis, selumetinib 50 mg monotherapy (n = 1). Selumetinib 75 mg monotherapy and selumetinib 25 mg plus docetaxel 60 mg/m2 were tolerated; selumetinib 75 mg plus docetaxel 60 mg/m2 was not tolerated. Selumetinib pharmacokinetic profile was similar when administered as a monotherapy or in combination with docetaxel. CONCLUSIONS: Selumetinib 75 mg monotherapy was tolerated in Japanese patients with NSCLC. Due to the overall selumetinib AE profile, the maximum tolerated dose was not determined for combination therapy or monotherapy. Selumetinib 75 mg BID plus docetaxel 60 mg/m2 was not tolerated in this patient population.

Sterilized talc pleurodesis for malignant pleural effusions: a Phase II study for investigational new drug application in Japan.

BACKGROUND: Malignant pleural effusion is a commonly seen complication of malignancies such as lung and breast cancers. In Western countries, talc is frequently used as a standard therapeutic agent (pleurodesis agent) with the aim of alleviating symptoms including dyspnea and chest pain. Talc is not recognized as a pleurodesis agent in Japan. The aim of this study was to verify the efficacy and safety of sterilized talc (NPC-05) for the introduction of talc in Japan. METHODS: The study was a single-arm, open-label, investigator-initiated trial conducted jointly at six institutions. The subjects were 30 patients with malignant pleural effusions. A solution of 4 g NPC-05 suspended in 50 ml physiological saline was instilled into the pleural space to perform pleurodesis. RESULTS: The efficacy of NPC-05 for pleural adhesion 30 days after pleurodesis was 83.3% (25/30 cases). Amelioration of dyspnea and pain (chest pain) was seen. Commonly seen adverse effects were increased C-reactive protein (CRP) and fever. Nearly all adverse events were phenomena previously reported as adverse effects of talc. No acute respiratory distress syndrome (ARDS) or other serious side effects occurred. CONCLUSION: The efficacy and safety of NPC-05 for malignant pleural effusion in Japanese patients was verified, and the clinical outcomes with talc were confirmed to be the same as previously reported in other countries. There is thought to be a high level of need for this agent in the treatment of malignant pleural effusion in Japan.

How Many Passes Are Needed for Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Sarcoidosis? A Prospective Multicenter Study.

BACKGROUND: While endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used as an initial diagnostic procedure for pathological confirmation of sarcoidosis, it is unclear how many passes are required to obtain diagnostic materials. OBJECTIVES: The aim of this study was to determine the number of needle passes needed for the diagnosis of stage I/II sarcoidosis using EBUS-TBNA. METHODS: At three institutions, 109 patients with suspected stage I/II sarcoidosis were recruited and underwent 6 passes of EBUS-TBNA for the main target lesion. Additional EBUS-TBNA for other lesions was permitted. The cumulative yields of needle passes for detecting noncaseating epithelioid cell granulomas were analyzed. RESULTS: A total of 109 patients underwent EBUS-TBNA for 184 lesions. EBUS-TBNA identified specimens containing granulomas in 81 of 92 patients (88%) with a final diagnosis of sarcoidosis. The cumulative yields through the first, second, third, fourth, fifth, and sixth passes for the main target lesion were 63, 75, 82, 85, 86 and 88%, respectively. In the 55 patients that underwent EBUS-TBNA for multiple lesions, the cumulative yields of 2 passes per lesion for 2 lesions (total of 4 passes) and of 4 passes for single lesions were 86 and 84%, respectively (p = 1.00). CONCLUSIONS: If rapid on-site cytological evaluation is not available, we recommend at least 4 passes per patient for either single or multiple lesions with EBUS-TBNA for pathological diagnosis of stage I/II sarcoidosis.

[Cost Effectiveness and Health Economics of Immune Checkpoint Inhibitors for Non-Small Cell Lung Cancer].

Immune checkpoint inhibitors (ICIs) are available for the treatment of advanced non-small cell lung cancer (NSCLC). ICIs have improved the overall survival of patients with NSCLC; however, their cost effectiveness needs to be evaluated because of the high cost associate with a longer duration of the treatment. Although the cost effectiveness is similar between standard chemotherapy and ICIs in second-line setting, treatment with ICIs in the first-line is expensive. Survival curves have shown a plateau at the tail after treatment with ICIs. These findings suggest that ICIs treatment could result in longer survival or cure, thereby contributing to a reduction in healthcare cost. Currently, there are no definite biomarkers for evaluating cost effectiveness of ICIs, and more reliable biomarkers in addition to PD-L1 are required.

Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.

Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks.

Ultrathin Bronchoscopy with Multimodal Devices for Peripheral Pulmonary Lesions. A Randomized Trial.

RATIONALE: The combination of an ultrathin bronchoscope, navigational technology, and endobronchial ultrasound (EBUS) seems to combine the best of mutual abilities for evaluating peripheral pulmonary lesions, but ultrathin bronchoscopes that allow the use of EBUS have not been developed so far. OBJECTIVES: To compare the diagnostic yield of transbronchial biopsy under EBUS, fluoroscopy, and virtual bronchoscopic navigation guidance using a novel ultrathin bronchoscope with that using a thin bronchoscope with a guide sheath for peripheral pulmonary lesions. METHODS: In four centers, patients with suspected peripheral pulmonary lesions less than or equal to 30 mm in the longest diameter were included and randomized to undergo transbronchial biopsy with EBUS, fluoroscopy, and virtual bronchoscopic navigation guidance using a 3.0-mm ultrathin bronchoscope (UTB group) or a 4.0-mm thin bronchoscope with a guide sheath (TB-GS group). MEASUREMENTS AND MAIN RESULTS: A total of 310 patients were enrolled and randomized, among whom 305 patients (150, UTB group; 155, TB-GS group) were analyzed. The ultrathin bronchoscope could reach more distal bronchi than the thin bronchoscope (median fifth- vs. fourth-generation bronchi; P < 0.001). Diagnostic histologic specimens were obtained in 74% (42% for benign and 81% for malignant lesions) of the UTB group and 59% (36% for benign and 70% for malignant lesions) of the TB-GS group (P = 0.044, Mantel-Haenszel test). Complications including pneumothorax, bleeding, chest pain, and pneumonia occurred in 3% and 5% in the respective groups. CONCLUSIONS: The diagnostic yield of the UTB method is higher than that of the TB-GS method. Clinical trial registered with www.umin.ac.jp/ctr/ (UMIN 000003177).

[Association between Efficacy of Pemetrexed and EGFR Mutation Status for EGFR Mutated Lung Carcinoma].

BACKGROUND: Subgroup analysis of Japanese patients in a LUX-Lung 3 trial showed different progression-free survival(PFS) after cisplatin (CDDP) plus pemetrexed (PEM) treatment between patients in the exon 21 L858R (L858R) group (8.3 months) and the exon 19 deletion (19 del) group (3.1 months). PEM may have different efficacies in patients with L858R or 19 del. METHODS: Consecutive patients with advanced/recurrent non-small cell lung cancer (NSCLC)harboring activating EGFR mutations were treated with platinum combined with PEM at our institute. The primary endpoint was to compare PFS of L858R patients to that of 19 del patients, among all patients with EGFR-mutated NSCLC. RESULTS: Thirty-two patients treated between 2009 and 2013 were included. The median age was 67 years (range: 40-78 years). Thirteen patients (41%) had L858R and 19 patients (59%) had 19 del. Patients were treated with CDDP(n=5)or carboplatin (n=27) combined with PEM. Compared with the 19 del group, the L858R group included more female patients(64% versus 47%, p=0.002), fewer patients treated with CDDP (8%versus 21%, p=0.018), and more patients with PEM maintenance therapy (50%versus 29%, p=0.003). The median number of cycles of platinum combined with PEM was 4(range: 1-6), and 13 patients received maintenance therapy. The response rate(RR)was 33.3% among L858R and 22.2% among 19 del (p=0.651). The median PFS was 5.13 months for L858R and 5.40 months for 19 del (p=0.824, HR=1.098, 95% CI: 0.48-2.50). The median overall survival (OS) was 29.17 months for L858R and 32.60 months for 19 del (p=0.232, HR=1.75, 95%CI: 0.69-4.45). CONCLUSIONS: This study did not show that PFS after platinum combined with PEM of L858R was superior to that of 19 del. RR and OS were consistent with PFS. A prospective trial is warranted to confirm the results of this study.

Feasibility and accuracy of molecular testing in specimens obtained with small biopsy forceps: comparison with the results of surgical specimens.

BACKGROUND: During bronchoscopy, small biopsy forceps are increasingly used for the diagnosis of peripheral pulmonary lesions. However, it is unclear whether the formalin-fixed paraffin-embedded specimens sampled with the small biopsy forceps are suitable for the determination of genotypes which become indispensable for the management decision regarding patients with non-small cell lung cancer. OBJECTIVES: The aim of this study was to evaluate the feasibility and accuracy of molecular testing in the specimens obtained with 1.5-mm small biopsy forceps. METHODS: We examined specimens in 91 patients, who were enrolled in our previous 3 studies on the usefulness of thin bronchoscopes and given a diagnosis of non-small cell lung cancer by bronchoscopy with the 1.5-mm biopsy forceps, and then underwent surgical resection. An experienced pathologist examined paraffin-embedded specimens obtained by bronchoscopic biopsy or surgical resection in a blind fashion on epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements and KRAS mutations. RESULTS: Twenty-five (27%), 2 (2%) and 5 (5%) patients had an EGFR mutation, ALK rearrangement and KRAS mutation, respectively, based on the results in surgical specimens. EGFR, ALK and KRAS testing with bronchoscopic specimens was feasible in 82 (90%), 86 (95%) and 83 (91%) patients, respectively. If molecular testing was feasible, the accuracy of EGFR, ALK and KRAS testing with bronchoscopic specimens for the results with surgical specimens was 98, 100 and 98%, respectively. CONCLUSION: The results of molecular testing in the formalin-fixed paraffin-embedded specimens obtained with the small forceps, in which the genotype could be evaluated, correlated well with those in surgically resected specimens.