Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Extensive-Disease Small-Cell Lung Cancer With Severe Immune-Related Adverse Events Due to Atezolizumab Maintaining a Complete Response for Two Years: A Case Report.

A 75-year-old male with diabetes mellitus was referred to our hospital with an abnormal shadow on chest radiography, based on which he was diagnosed with extensive-disease small-cell lung cancer (ED-SCLC; cT2bN2M1a). The first-line therapy comprised atezolizumab, carboplatin, and etoposide. After four cycles, the patient achieved complete response (CR), and maintenance therapy was initiated with atezolizumab. However, even though CR was maintained, maintenance therapy was discontinued after 16 cycles due to persistent grade 2 anorexia and fatigue. Simultaneously, the HbA1c decreased to 5.5%, and antidiabetic therapy was discontinued. Six months after the last dose of atezolizumab, the patient visited the emergency room because of anorexia, dry mouth, and fatigue. Laboratory findings were as follows: blood glucose was 668 mg/dL, glycated hemoglobin (HbA1c) was 8.8%, urine ketone was 2+, sodium (Na) was 127 mmol/L, potassium (K) was 6.5 mmol/L, creatinine (Cre) was 1.43 mg/dL, and arterial pH was 7.29. Based on these findings, his presentation was consistent with fulminant type 1 diabetes mellitus (T1DM) complicated by diabetic ketoacidosis (DKA). Regular continuous insulin and saline administration was initiated in the intensive care unit, and acidosis and electrolyte abnormalities were corrected. His C-peptide was <0.03 ng/mL. His insulin secretory capacity was considered to be depleted, and he required continuous subcutaneous insulin injections. Glutamic acid decarboxylase and insulin autoantibodies were absent. The complete response persisted without further therapy until two years since the event.

Durvalumab after chemoradiotherapy in non-small cell lung cancer with EGFR mutation: A real-world study (HOT2101).

Durvalumab has been administered to patients with unresectable stage III non-small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty-one patients were EGFR positive and 311 were EGFR negative. In the EGFR-positive group, there were higher proportions of females, never-smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression-free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64-1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment-related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.

Relationship between immune-related adverse events and treatment effectiveness in extensive disease small cell lung cancer.

BACKGROUND: This study aimed to assess the relationship between immune response adverse events (irAEs) and treatment efficacy in patients with extensive disease small cell lung cancer (ED-SCLC). METHODS: We retrospectively evaluated the clinical effects in 40 ED-SCLC patients who had received immune-checkpoint inhibitors (ICIs), platinum agents, and etoposide between September 2019 and September 2021. We identified and compared patients belonging to two groups: irAE and non-irAE. RESULTS: Fifteen patients experienced irAEs, and 25 did not. The median progression-free survival in patients with irAE was longer than that in patients without irAE (12.6 months [95% CI: 6.3-19.3 months] vs. 7.2 months [95% CI: 5.8-7.9 months], p = 0.0108). However, the median overall survival (OS) was similar between irAE and non-irAE groups (27.6 months [95% CI: 15.4-NA] vs. 24.9 months [95% CI: 13.7-NA], p = 0.268). Seven (46.7%) in the irAE group and 20 (80%) in the non-irAE group received sequential therapy. The median OS was prolonged in patients who received first- and second-line therapy than in those who received first-line therapy alone (27.6 months [95% CI: 19.2-NA] vs. 6.6 months [95% CI: 0.3-NA], p = 0.053). Grade ≧ 3 irAEs occurred in five (12.5%) patients. Among them, grade 5 irAEs were observed in two patients, including exacerbation of polymyositis and pulmonary arterial embolism. CONCLUSION: In this study, the development of irAEs did not affect OS in patients with ED-SCLC who received platinum-based agents, etoposide, or ICI therapy. We determined that managing irAEs and administering first- and second-line therapies could contribute to prolonged OS.

Real-world data on the efficacy and safety of immune-checkpoint inhibitors in elderly patients with non-small cell lung cancer.

PURPOSE: Immune-checkpoint inhibitors (ICIs) are effective against advanced non-small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. METHODS: We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. RESULTS: We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75-85) and 66 (range, 34-74) years. The median progression-free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first- or second-line ICI treatment (p = 0.011) and more immune-related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. CONCLUSION: ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Pulmonary varix clearly demonstrated by 3D-CT before pulmonary angiography.

Pulmonary varix is a rare and usually asymptomatic localized dilation of a pulmonary vein. This disease should be distinguished from other pulmonary and mediastinal diseases, particularly pulmonary arteriovenous malformations. Herein, we encountered a case of pulmonary varix clearly demonstrated by 3-dimensional reconstructed computed tomography (3D-CT) which proved useful in its diagnosis. The 3D-CT enabled easy understanding of the vascular connections and confirmation of the absence of an inflow pulmonary artery. We also performed angiography which showed findings consistent with those obtained by the 3D-CT, thus confirming the diagnosis of pulmonary varix. After the diagnosis, the patient was followed up for several years without any treatment and she remained asymptomatic. On follow-up CT, the lesion remained unchanged.

Current status of first-line treatment with pembrolizumab for non-small-cell lung cancer with high PD-L1 expression.

It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) should be selected for patients with advanced non-small-cell lung cancer (NSCLC) exhibiting high PD-L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0-1) in the COMB group (p < 0.01). With a median follow-up time of 10.6 (range: 0.1-20.6) months, the median progression-free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first-line treatment for NSCLC with high PD-L1 expression and good performance status.

Histologic transformation of epidermal growth factor receptor-mutated lung cancer.

PURPOSE: This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). PATIENTS AND METHODS: We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. RESULTS: In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. CONCLUSION: HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002).

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

High false-negative rate of the anterior spinal artery by intercostobronchial trunk arteriography alone compared to CT during arteriography.

OBJECTIVES: This study aimed to assess the frequencies of the anterior spinal arteries identified by CT during arteriography (CTA) and arteriography alone. METHODS: This retrospective study included 137 vessels in 83 patients who performed both bronchial arteriography and CTA and categorized them into three groups based on the catheter tip locations: intercostobronchial trunk (ICBT), bronchial artery (BA), and intercostal artery (ICA). The frequencies of anterior spinal artery identified by CTA and arteriography alone were compared for each group. RESULTS: ICBT, BA, and ICA groups were evaluated by CTA in 46, 79, and 12 vessels, respectively. By CTA evaluation, anterior spinal artery was identified in seven vessels (15.2%) in ICBT group, 0 in BA group and two (16.7%) in ICA group. The frequencies of anterior spinal artery were significantly higher (p < 0.05) in ICBT and ICA groups than in BA group. By arteriography evaluation alone, a faint anterior spinal artery was identified in two vessels (4.3%) in ICBT group, 0 in BA group, and 1 (8.3%) in ICA group. CONCLUSIONS: Anterior spinal artery branched only from the ICBT or ICA and not from the BA in both arteriography and CTA assessments. There was high false-negative rate (71%) of the anterior spinal artery by ICBT arteriography alone assessment compared to CTA assessment. This result explains one of the reasons that spinal ischemia occurs in arteriography-negative spinal artery cases. ADVANCES IN KNOWLEDGE: False-negative rate of anterior spinal artery was 71% (5/7) by intercostobronchial trunk arteriography alone assessment.

Prognostic factors in patients with advanced non-small cell lung cancer after long-term Anti-PD-1 therapy (HOT1902).

OBJECTIVES: Limited information is available on the appropriate treatment duration of immune checkpoint inhibitors (ICIs). We aimed to identify candidates who would benefit from ICI discontinuation after one year of treatment for metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective multi-institutional observational study examined medical records of all consecutive patients with advanced or recurrent NSCLC, who started ICI monotherapy at 15 institutions in Japan between December 2015 and December 2017. Patients who received initial ICI therapy for >1 year without progressive disease were defined as the long-term treatment (LT) group; others were defined as the non-long-term treatment (NLT) group. Primary outcomes included the prognostic factors in the LT group, whereas secondary outcomes included efficacy of ICI rechallenge, safety, and survival outcomes in the overall population. RESULTS: In total, 676 patients were enrolled, and 114 (16.9 %) were assigned to the LT group. The median time interval from the start of initial ICI administration to data cutoff was 34.3 months (range, 24.1-47.8); thus, all surviving patients were followed-up for at least 2 years from the start of initial ICI. Median progression-free survival (PFS) was longer in the LT than in the NLT group (33.6 months vs. 2.7 months; p < 0.001). On multivariate analysis, significantly better PFS was associated with smoking (hazard ratio [HR]=0.36, p = 0.04), and complete response (CR; HR=uncomputable, p < 0.001) in the LT group. Thirty-seven patients (5.5 %) received ICI rechallenge, including 10 in the LT group. Among patients receiving rechallenge treatment, the median PFS was 2.2 months, with no difference between the LT and NLT groups. CONCLUSIONS: In the LT group, smoking and achieving CR were significantly associated with better PFS. Since rechallenge treatment was not effective, careful consideration is required for discontinuing ICI. However, these prognostic factors are helpful in considering candidates for ICI discontinuation. TRIAL REGISTRATION: UMIN ID, UMIN000041403.

The first case of COVID-19 occurring as community-acquired pneumonia in Hokkaido, Japan and our preventive measures against nosocomial infection.

We report a case of a 59-year-old man with coronavirus disease 2019 (COVID-19). He had visited a hospital for fever and cough and been treated with antibiotics for pneumonia in the right upper lobe. However, he gradually progressed to dyspnea and consulted our hospital. His chest radiographs showed bilateral pneumonia shadows and his CT showed ground glass opacities and consolidation. Although we treated him with broad-spectrum antibiotics, the pneumonia shadow rapidly progressed and mechanical ventilation was administered. We collected sputum from the bronchus using bronchoscopy to detect microorganisms, and RT-PCR tests confirmed COVID-19 pneumonia. He was transferred to a designated hospital. In order to prevent the occurrence of nosocomial infections, close contacts within the hospital and medical staff were suspended from their work for two weeks. No secondary infection with COVID-19 appeared. This was the first case of COVID-19 occurring as community-acquired pneumonia in Hokkaido, Japan.

A new ENG mutation in a Japanese family with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations.

We present a case series of four siblings with hereditary hemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformations (PAVM). The patients' mother has HHT. Case 1: A 22-year-old man developed dyspnea and epistaxis. CT revealed a large PAVM, treated by segmentectomy. Case 2: A 27-year-old woman developed epistaxis and dyspnea. CT revealed three PAVMs, treated by partial resection. Case 3: A 20-year-old woman developed dyspnea. CT revealed multiple PAVMs, treated with endovascular occlusion of the largest one. Case 4: A 12-year-old woman developed epistaxis. CT revealed multiple PAVMs, observed without treatment. Genetic testing identified a new mutation, ENG c.1517T>C (p.Leu506Pro), in all patients and their mother. We suspect that HHT in these patients may be associated with this ENG mutation.

Serum surfactant protein D predicts the outcome of patients with idiopathic pulmonary fibrosis treated with pirfenidone.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal pulmonary disease with poor prognosis. Pirfenidone, the first antifibrotic drug, suppresses the decline in forced vital capacity (FVC) and improves prognosis in some, but not all, patients with IPF; therefore, an indicator for identifying improved outcomes in pirfenidone therapy is desirable. This study aims to clarify whether baseline parameters can be predictors of disease progression and prognosis in patients with IPF treated with pirfenidone. METHODS: We retrospectively investigated patients with IPF who started treatment with pirfenidone between December 2008 and November 2014 at the Sapporo Medical University Hospital. Patients treated with pirfenidone for ≥6 months were enrolled in this study and were observed until November 2015. We investigated the association of clinical characteristics, pulmonary function test results, and blood examination results at the start of pirfenidone with the outcome of patients. RESULTS: Sixty patients were included in this study. In multivariate logistic regression analysis, % predicted FVC and serum surfactant protein (SP)-D levels were predictors of a ≥10% decline in FVC in the initial 12 months. In the Cox proportional hazards model, these two factors predicted progression-free survival. Pack-years, % predicted diffusing capacity for carbon monoxide, and SP-D levels predicted overall survival. CONCLUSIONS: The serum SP-D level was a predictor of disease progression and prognosis in patients with IPF treated with pirfenidone. In addition, this analysis describes the relative usefulness of other clinical parameters at baseline in estimating the prognosis of patients with IPF who are candidates for pirfenidone therapy.

Occult Thyroid Follicular Carcinoma Diagnosed as Metastasis to the Chest Wall.

Chest wall tumors are relatively rare, and hematogenous metastasis to the chest wall is very rare. We herein describe a rare case of occult thyroid carcinoma as metastasis to the chest wall in an 80-year-old woman. The patient received detailed examinations of the chest wall tumor, and the results suggested that she had occult thyroid carcinoma. Surgery was then performed to remove all of her thyroid. As a result, she was diagnosed with follicular carcinoma of the thyroid. We report an extremely rare case of occult thyroid carcinoma diagnosed as hematogenous metastasis to the chest wall.