Simultaneous Acquisition of T790M Mutation and SCLC Transformation during Targeted Therapy in EGFR-Mutated Lung Adenocarcinoma: A Rare Case Report.

BACKGROUND Various resistance mechanisms of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have been reported, and approximately half of the cases show a T790M point mutation as resistance to EGFR-TKI. In addition, 3-14% of cases of non-small cell lung cancer transform into small cell lung carcinoma (SCLC) during treatment. However, there are few reported cases in which 2 mechanisms of resistance have been observed simultaneously. This report describes a 66-year-old man with initial presentation of stage IIA right-sided lung adenocarcinoma with EGFR gene exon 21 L858R mutation and 3 years of stable disease. During treatment with erlotinib, the patient developed SCLC and adenocarcinoma with EGFR exon 21 L858R and exon 20 T790M mutation. CASE REPORT A 66-year-old man underwent right pneumonectomy plus nodal dissection 2a for right hilar lung cancer and was diagnosed with an EGFR exon21 L858R mutated lung adenocarcinoma. Three years later, pleural dissemination was observed in the right chest wall. Although erlotinib was continued for 52 months, new metastases to the right ribs were detected. Chest wall tumor resection was performed. Based on the World Health Organization classification, the patient was diagnosed with combined SCLC, with EGFR exon21 L858R and exon20 T790M mutation. The patient received 4 cycles of carboplatin plus etoposide, 14 cycles of amrubicin, and 2 cycles of irinotecan. Chemotherapy continued for 25 months. CONCLUSIONS Long-term survival was achieved by chemotherapy after transformation. Since EGFR mutation-positive lung cancer shows a variety of acquired resistances, it is important to consider the treatment strategy of performing re-biopsy.

EGFR-TKI rechallenge in patients with EGFR-mutated non-small-cell lung cancer who progressed after first-line osimertinib treatment: A multicenter retrospective observational study.

BACKGROUND: Rechallenge therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is known to confer some clinical benefit for patients with metastatic EGFR-mutated non-small cell lung cancer (NSCLC). However, little is known about the efficacy of EGFR-TKI rechallenge after resistance to first-line (1L) osimertinib. This study aimed to assess the efficacy and safety of EGFR-TKI rechallenge therapy after resistance to 1L osimertinib in a Japanese clinical setting. METHODS: Between April 2018 and August 2022, 26 patients who progressed after treatment with 1L osimertinib and received EGFR-TKI rechallenge were included in this multicenter retrospective analysis. Patients in whom 1L osimertinib was discontinued owing to toxicity and had subsequent disease progression were also included in the analysis. RESULTS: Overall, the objective response rate for rechallenge therapy was 23.1%. The disease control rate was 53.9%, and the median progression-free survival (PFS) was 3.4 months. Patients who discontinued 1L osimertinib for toxicity had a higher response rate (42.9% vs. 15.8%) and longer PFS than those who discontinued it due to disease progression (median: 11.4 vs. 2.7 months, P = 0.001). Three patients (11.5%) developed rechallenge therapy-associated pneumonitis, two of which were grade ≥3. CONCLUSIONS: Rechallenge with EGFR-TKI after 1L osimertinib resistance showed limited clinical efficacy. However, it could be considered as a subsequent salvage therapeutic option for patients in whom 1L osimertinib was discontinued owing to toxicity.

Predictive Factors Associated with Long-Term Response to Combination Immunotherapy in Patients with Untreated Advanced Non-Small-Cell Lung Cancer: A Multicenter Retrospective Study.

INTRODUCTION: Combination immunotherapy is widely used in clinical practice as the first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, predictive factors associated with long-term response to combination immunotherapy have not been well investigated. Herein, we compared the clinical findings, including systemic inflammatory nutritional biomarkers, between responders and nonresponders to combination immunotherapy. In addition, we investigated the predictive factors associated with long-term response to combination immunotherapy. METHODS: This study included a total of 112 previously untreated advanced NSCLC patients who received combination immunotherapy at eight institutions in Nagano prefecture between December 2018 and April 2021. The responders were defined as those who achieved progression-free survival for 9 months or longer with combined immunotherapy. We evaluated predictive factors associated with long-term response, and the favorable prognostic predictors associated with overall survival (OS) using statistical analyses. RESULTS: The responder and nonresponder groups included 54 and 58 patients, respectively. Compared with the nonresponder group, the responder group had significantly younger age (p = 0.046), higher prognostic nutritional index (44.8 vs. 40.7, p = 0.010), lower C-reactive protein/albumin ratio (CAR) (0.17 vs. 0.67, p = 0.001), and a higher rate of complete plus partial response (83.3% vs. 34.5%, p < 0.001). The area under the curve and optimal cut-off value for CAR were 0.691 and 0.215, respectively. The CAR and best objective response were identified as independent favorable prognostic predictors associated with OS in the multivariate analyses. CONCLUSION: The CAR and best objective response were suggested to be useful predictors of long-term response in NSCLC patients who received combination immunotherapy.

Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study).

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for EGFR-mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon EGFR mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against EGFR-dependent resistance after osimertinib treatment, although these have not been prospectively investigated. Methods: The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive EGFR mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023. Discussion: The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established. Registration: UMIN Clinical Trial Registry: UMIN000049225.

C-PLAN index as a prognostic factor for patients with previously untreated advanced non-small cell lung cancer who received combination immunotherapy: A multicenter retrospective study.

BACKGROUND: Combination immunotherapy (immune checkpoint inhibitors and cytotoxic anticancer agents) is widely used as first-line treatment for advanced non-small cell lung cancer (NSCLC). However, the therapeutic effect of combination immunotherapy has not been fully investigated. C-reactive protein, performance status, lactate dehydrogenase, albumin, and derived neutrophil-to-lymphocyte ratio (C-PLAN) are useful biomarkers for predicting the prognosis of NSCLC; however, there are no reports examining the C-PLAN index, which combines these five factors in a single prognostic factor. METHODS: We retrospectively collected data from 178 patients with previously untreated advanced NSCLC who received combination immunotherapy at multicenter institutions in Nagano Prefecture between December 2018 and April 2022. We investigated the utility of the C-PLAN index as a prognostic factor using Cox regression analysis and correlated it with survival. RESULTS: The good and poor C-PLAN index groups included 85 and 93 patients, respectively. The good C-PLAN index group had a longer median progression-free survival (PFS) (10.7 vs. 6.0 months; p = 0.022) and overall survival (OS) (25.3 vs. 16.5 months; p = 0.003) than the poor C-PLAN index group. The C-PLAN index was an independent favorable prognostic factor that correlated with PFS and OS in multivariate analysis. The good C-PLAN index group had a higher proportion of never-smokers (16.5 vs. 4.3%; p = 0.007) and stage III disease/postoperative recurrence (32.9 vs. 15.1%; p = 0.005) than the poor C-PLAN index group. CONCLUSION: The C-PLAN index is a useful prognostic factor for patients with previously untreated advanced NSCLC undergoing combination immunotherapy.

Predictive value of post-treatment C-reactive protein-to-albumin ratio in locally advanced non-small cell lung cancer patients receiving durvalumab after chemoradiotherapy.

BACKGROUNDS: The PACIFIC trial established durvalumab consolidation therapy after concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the predictive factors of durvalumab efficacy in this population. This study aimed to validate the predictive use of inflammation-related parameters in patients with LA-NSCLC treated with CCRT plus durvalumab. METHODS: We recruited 76 LA-NSCLC patients who received CCRT followed by durvalumab from 10 Japanese institutions. The neutrophil-to-lymphocyte ratio (NLR), C-reactive protein-to-albumin ratio (CAR), and prognostic nutrition index (PNI) were measured before (pre-treatment) and 2 months after (post-treatment) durvalumab induction. Cox proportional hazards analysis was used to examine prognostic factors associated with progression-free survival (PFS) after durvalumab therapy. RESULTS: The median follow-up time was 17 (range, 3.3-35.8) months. The median PFS and overall survival (OS) times were 26.1 and 33.7 months, respectively. Durvalumab was discontinued in 47 (61.8%) patients, with non-infectious pneumonitis being the most common reason. Post-treatment CAR (cutoff, 0.2) was a significant stratifying factor in survival comparison (<0.2 vs. ≥ 0.2, median PFS, not-reached vs. 9.6 months. Log-rank, p = 0.002). Multivariate analysis with a Cox proportional hazards model showed that post-treatment CAR was an independent prognostic factor for PFS (hazard ratio, 3.16, p = 0.003). CONCLUSIONS: This study suggests that post-treatment CAR has predictive value for LA-NSCLC patients treated with CCRT plus durvalumab consolidation therapy.

Gefitinib Treatment Was Unsuccessful for Central Diabetes Insipidus Due to Pituitary Metastasis of Lung Adenocarcinoma.

We herein report a rare case of advanced lung adenocarcinoma with central diabetes insipidus due to pituitary metastasis. Although treatment with gefitinib was dramatically effective, the symptoms of diabetes insipidus did not improve. Radiotherapy for pituitary metastasis was effective to control diabetes insipidus; however, we could not cease the administration of 1-deamino-8-D-arginine vasopressin (DDAVP). It is important for physicians to positively consider radiotherapy for pituitary metastases even if favorable tumor control is achieved with chemotherapy when diabetes insipidus becomes clinically overt. Furthermore, continuous DDAVP administration may be needed to treat central diabetes insipidus.

Outbreaks of influenza B infection and pneumococcal pneumonia at a mental health facility in Japan.

BACKGROUND: Japan has an aging population and an increasing number of patients who reside in long-term care and mental health facilities. Both pneumococcal pneumonia and influenza B infection outbreaks have been observed in these populations, although no reports have described concurrent outbreaks of pneumococcal pneumonia and influenza B infection in these facilities. CASE PRESENTATION: Six patients and two staffs were initially diagnosed with influenza B infection at a mental health facility on March 14, 2015. By March 21, influenza B infection was diagnosed in 26 patients and 10 staff; all individuals received anti-influenza drugs. On March 19, two patients were diagnosed with pneumococcal pneumonia, and seven patients had developed pneumococcal pneumonia by March 24. Six of these seven patients also had influenza B infection. All individuals who developed pneumococcal pneumonia were hospitalized and treated using ampicillin/sulbactam at our hospital, and their symptoms subsequently subsided. Among the seven pneumococcal strains that were frozen and stored, two strains were type 3 and five strains were type 11A/E. Pulsed-field gel electrophoresis testing revealed that each of the serum types were from the same clone. CONCLUSION: It appears that an outbreak of influenza B infection was followed by the spread of multi-clone pneumococcal pneumonia among elderly patients at a mental health facility. Therefore, it may be prudent to use vaccinations to prevent the spread of pneumococcal pneumonia among elderly patients and this diagnosis should be actively considered during outbreaks of influenza infection at elder care facilities.

Self-assessment of Allergic Rhinitis and Asthma (SACRA) Questionnaire-based Allergic Rhinitis Treatment Improves Asthma Control in Asthmatic Patients with Allergic Rhinitis.

Objective This study was conducted to investigate whether the add-on treatment of allergic rhinitis (AR) based on the Self-assessment of Allergic Rhinitis and Asthma (SACRA) questionnaire for assessing AR control improves both AR and asthma control in asthmatic patients with AR. Methods This multi-center prospective study was performed in Nagano prefecture, Japan. Two hundred five asthmatic patients and 23 respiratory physicians participated in the study. We administered add-on AR treatments based on the results of the SACRA questionnaire. After the first SACRA questionnaire, 67 asthmatic patients agreed to receive an add-on AR treatment. Three months after the AR treatment, a secondary SACRA questionnaire, asthma control test (ACT), and pulmonary function tests were performed. Results After the add-on AR treatment, the visual analogue scales (VASs) for AR and asthma, as assessed by the SACRA questionnaire and ACT score, were significantly improved in the patients of the AR+ group. With regard to the pulmonary function tests, the percent predicted vital capacity, and percent predicted forced expiratory volume in one second were also significantly improved. Regardless of whether the patients had previously undergone leukotriene receptor antagonists (LTRA) treatment, the VASs for AR and asthma and the ACT score were significantly improved in the AR+ group. However, the vital capacity (VC), forced vital capacity (FVC) and forced expiratory volume (FEV1) were only significantly improved in the AR+ group that had previously undergone LTRA treatment. Conclusion SACRA questionnaire-based add-on AR treatment would be convenient for the detection of AR by respiratory physicians and would offer improved asthma control. This questionnaire can also be used to assess the therapeutic effects.

Computed tomography-guided bronchoscopy in the diagnosis of small peripheral pulmonary lesions: A retrospective study of 240 examinations in a single academic center.

BACKGROUND: Factors that affect the diagnostic yield in computed tomography (CT)-guided bronchoscopy have not yet been fully evaluated. To improve the diagnostic yield of peripheral pulmonary lesions (PPLs) by CT-guided bronchoscopy, we quantitatively analyzed factors affecting the diagnostic yield. METHODS: The data were collected for 240 PPLs in 237 patients examined by using CT-guided bronchoscopy between October 2003 and November 2011 in our respiratory center. The association of diagnostic yield with the CT bronchus sign (CT-BS), lesion size, location, number of tissue specimens, and type of bronchoscope was retrospectively assessed. RESULTS: The diagnostic yield of PPLs with negative CT-BS was significantly lower (2.9%) than that for PPLs with positive CT-BS (52.2%; p<0.01). Among the PPLs with positive CT-BS, the yield was significantly higher in those in the left S(3) than for lesions in other bronchial segments (83.3% vs. 50.3%; p<0.05). Lesion size was not significantly associated with diagnostic yield. The yield was significantly lower in PPLs without lung tissue specimens than in lesions with biopsy specimens (p<0.01). Moreover, a thin bronchoscope produced a higher yield in comparison with other bronchoscope types (66.0% vs. 47.6%; p<0.05). Multivariate analysis revealed that the number of biopsy specimens was an independent factor affecting diagnostic yield. CONCLUSIONS: CT-guided bronchoscopy is valuable in the diagnosis of PPLs with positive CT-BS regardless of lesion size; however, PPLs with negative CT-BS are not good candidates for CT-guided bronchoscopy. Obtaining tissue specimens by biopsy is a critical factor in diagnosing PPLs.

Combination of virtual bronchoscopic navigation with conventional transbronchial needle aspiration in the diagnosis of peribronchial pulmonary lesions located in the middle third of the lungs.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is frequently applied to the diagnosis of central airway lesions, and endobronchial ultrasound with a guide sheath (EBUS-GS) is mainly used for the diagnosis of peripheral pulmonary lesions. However, there remains an unmet need to improve the diagnostic yields for peribronchial pulmonary lesions located along the secondary/tertiary and fourth/fifth bronchi (the "middle third zone" of the lungs), which neither EBUS-TBNA nor EBUS-GS can easily approach. METHODS: A combination of virtual bronchoscopic navigation (VBN) with conventional TBNA was utilized for the cytological diagnosis of 15 patients with small pulmonary lesions (less than 20mm in diameter) in the middle third zone between March 2012 and January 2015 in our respiratory institute. The lesions were traced using the VBN system, and then the VBN was operated and guided by the vision of actual bronchoscopy. The TBNA site was determined by VBN, and the specimens were obtained using conventional TBNA under X-ray fluoroscopy. The diagnosis was made based on the cytological findings of the specimens. RESULTS: Adequate specimens were obtained in 12 (80.0%) of the cases through the novel technique of combining TBNA with VBN in bronchoscopic examinations. Seven out of the ten malignant cases (70.0%) were definitely diagnosed by this procedure. No adverse effects were experienced, except for an acceptable amount of bleeding. CONCLUSIONS: The combination of VBN with conventional TBNA was advantageous and safe for the cytological diagnosis of small peribronchial pulmonary lesions in the middle third zone of the lungs.

Pediatric pulmonary tuberculoma with a solid pulmonary nodule detected on chest computed tomography.

A 14-year-old girl underwent a medical checkup for Mycobacterium tuberculosis infection because her grandmother had been diagnosed with pulmonary tuberculosis three months earlier. The interferon-gamma release assay (IGRA) showed a positive result. The patient's chest X-ray findings were normal. Chest computed tomography (CT) showed a single mass lesion in the right lower lobe of the lung. A sputum smear of acid-fast bacilli was positive; however, the polymerase chain reaction results for tuberculosis were negative. We diagnosed the patient with pulmonary tuberculosis based on the fact that she had come in contact with a tuberculosis patient. Six weeks later, a liquid culture examination for acid-fast bacilli was found to be positive and the acid-fast bacillus was identified as M. tuberculosis. The use of chest CT is not routinely recommended in all children suspected of having M. tuberculosis infection. However, IGRA-positive children who report frequent contact with infected individuals should undergo CT tomography if chest X-rays do not show any abnormal shadows.

Viral infections in patients with an acute exacerbation of idiopathic interstitial pneumonia.

BACKGROUND: Patients with slowly progressive idiopathic interstitial pneumonia, including idiopathic pulmonary fibrosis, often deteriorate, thus suggesting that the clinical course may be unpredictable. Such episodes are termed acute exacerbation of idiopathic interstitial pneumonia. The etiology of an acute exacerbation of idiopathic interstitial pneumonia is unknown. In this study, we tested the hypothesis that an acute exacerbation of idiopathic interstitial pneumonia is induced by respiratory viral infections. METHODS: Bronchoalveolar lavage fluid obtained from patients with an acute exacerbation of idiopathic interstitial pneumonia was tested for viral nucleic acid using polymerase chain reaction. RESULTS: Only 1 of the 14 patients with an acute exacerbation of idiopathic interstitial pneumonia exhibited evidence of respiratory syncytial virus B, and 2 patients exhibited evidence of cytomegalovirus. Seven patients fulfilled the diagnostic criteria of idiopathic pulmonary fibrosis. CONCLUSIONS: Most cases with an acute exacerbation of idiopathic interstitial pneumonia are not caused by a viral infection.

[A case of pulmonary pleomorphic carcinoma treated with S-1 following radiotherapy].

Pleomorphic carcinoma is a rare malignancy of the lung. Here we present a 68-year-old man who was admitted to our hospital for examination of an abnormal radiogram of the chest. The radiogram revealed a large mass in the right lung field. A chest computed tomographic (CT) scan demonstrated a nonsegmentalmass like consolidation. Percutaneous CT-guided fine-needle needle biopsy from the lung was performed, and the specimen demonstrated pulmonary pleomorphic carcinoma. The patient was initially treated with two courses of cisplatin (CDDP) and docetaxel (DOC), and still showed progressive disease (PD). Therefore, we administered S-1 following radiotherapy. The chest CT revealed partial response after 4 months. We experienced a pulmonary pleomorphic carcinoma which showed a response to salvage chemotherapy with S-1.

[A case of lung cancer showing marked reduction of pleural effusion by bevacizumab in combination with carboplatin and paclitaxel].

A 63-year-old man was admitted to our hospital because of dyspnea. Chest computed tomographic(CT)scans showed right pleural effusion. He was diagnosed with adenocarcinoma of the lung(cTXN2M1a, stage IV). Although combination chemotherapy with 80 mg/m / 2 cisplatin(CDDP)and 60 mg/m2 docetaxel hydrate(DOC)was performed for 3 courses, the pleural effusion increased. As he had a progressive disease, his chemotherapy was changed to a new combination of AUC5 carboplatin(CBDCA), 200mg/m / 2 paclitaxel(PTX)and 15 mg/kg bevacizumab. After 2 courses, the pleural effusion dramatically decreased. During 6-month follow-up after the initial consultation, there has been no exacerbation.