Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data.

BACKGROUND: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. AIMS: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. MATERIALS AND METHODS: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. RESULTS: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). CONCLUSION: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. METHODS: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. RESULTS: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. CONCLUSIONS: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma.

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors. Phenotypic screening of niche factor dependency revealed that EGFR mutations in lung adenocarcinoma are associated with the independence from Wnt ligands. Gene engineering of alveolar organoids reveals that constitutive activation of EGFR-RAS signaling provides Wnt independence. Loss of the alveolar identity gene NKX2-1 confers Wnt dependency, regardless of EGFR signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by the expression status of NKX2-1. Our results highlight the potential of phenotype-driven organoid screening and engineering for the fabrication of therapeutic strategies to combat cancer.

Non-small cell lung cancer with multiple brain metastases remains relapse-free for more than 13 years: A case report.

Brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) is usually associated with a poor prognosis. A 55-year-old Japanese man visited Tokyo Dental College Ichikawa General Hospital with complaints of motor aphasia and fatigue. Enhanced magnetic resonance imaging of the brain revealed multiple tumors. The patient's medical history included lung cancer surgery performed at another hospital 3 months prior to his visit to our hospital. Total resection of the left frontal tumor revealed BM from lung adenocarcinoma. Stereotactic radiosurgery (SRS) was performed for the remaining three BMs. At 9 months after SRS, another new BM was discovered, and SRS was again performed. More than 13 years have elapsed since the last SRS was performed, and the patient has remained relapse-free. To the best of our knowledge, this is the first case report describing a patient with NSCLC with multiple BMs who has remained relapse-free for >13 years with no neurological dysfunction, including cognitive deficit.

Clinical Characteristics and Therapeutic Outcomes of Metastatic Peritoneal Carcinomatosis in Non-Small-Cell Lung Cancer.

BACKGROUND: Metastatic peritoneal carcinomatosis (MPC) is not common in patients with non-small cell lung cancer (NSCLC), and the clinical characteristics and treatment outcomes are still unclear. PATIENTS AND METHODS: We recruited 46 NSCLC patients with MPC at Keio University and affiliated hospitals (Keio Lung Oncology Group) between January 2011 and December 2017, then retrospectively investigated their clinical characteristics and the impact of treatment interventions on their survival. RESULTS: The profile of histological subtype was predominantly adenocarcinoma and 15 patients harbored driver oncogenes. Univariate and multivariate analysis demonstrated that performance status and the presence of a driver oncogene were significantly associated with the prolonged overall survival (OS). Regarding treatment, the median OS in the treatment group (9.3 months) was significantly longer than in the best supportive care group (1.3 months) (P < 0.0001). CONCLUSION: The prognosis of MPC in NSCLC patients who receive only the best supportive care is poor, but therapeutic intervention may improve prognosis.

Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

A case of pulmonary adenocarcinoma showing rapid progression of peritoneal dissemination after immune checkpoint inhibitor therapy.

BACKGROUND: Immune checkpoint inhibitors are standard treatments for non-small cell lung cancer. Unique cases with paradoxical acceleration of the disease after immunotherapy have been reported. These have been described as cases of hyperprogressive disease. CASE PRESENTATION: A 76-year-old man was diagnosed with pulmonary adenocarcinoma with pleural dissemination and liver and adrenal metastases. Genomic analysis revealed neither EGFR mutations nor ALK translocations. Immunohistochemical analysis revealed a programmed death-ligand 1 tumor proportion score of 23%. Chemotherapy with carboplatin, paclitaxel, and bevacizumab resulted in Grade 3 skin eruption and disease progression. Pembrolizumab was initiated as a second-line treatment. However, peritoneal dissemination and ascites developed. The patient died 2 weeks later. The autopsy revealed widespread peritoneal dissemination and an extensive hemorrhagic infarction. CONCLUSION: This was a rare case of hyperprogressive disease with rapid progression of peritoneal dissemination after pembrolizumab treatment.

A case of allergic bronchopulmonary aspergillosis successfully treated with mepolizumab.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an allergic pulmonary disease comprising a complex hypersensitivity reaction to Aspergillus fumigatus. Clinical features of ABPA are wheezing, mucoid impaction, and pulmonary infiltrates. Oral corticosteroids and anti-fungal agents are standard therapy for ABPA, but long-term use of systemic corticosteroids often causes serious side effects. CASE PRESENTATION: A 64-year-old woman was diagnosed with ABPA based on a history of bronchial asthma (from 40 years of age), elevated total IgE, the presence of serum precipitating antibodies and elevated specific IgE antibody to A. fumigatus, and pulmonary infiltration. Bronchoscopy showed eosinophilic mucoid impaction. Systemic corticosteroid therapy was initiated, and her symptoms disappeared. Peripheral eosinophilia and pulmonary infiltration recurred five months after cessation of corticosteroid treatment. Systemic corticosteroids were re-initiated and itraconazole was added as an anti-fungal agent. The patient was free of corticosteroids, aside from treatment with a short course of systemic corticosteroids for asthma exacerbation, and clinically stable with itraconazole and asthma treatments for 3 years. In 2017, she experienced significant deterioration. Laboratory examination revealed marked eosinophilia (3017/µL) and a chest computed tomography (CT) scan demonstrated pulmonary infiltration in the left upper lobe and mucoid impaction in both lower lobes. The patient was treated with high-dose inhaled corticosteroid/long-acting beta-agonist, a long-acting muscarinic antagonist, a leukotriene receptor antagonist, and theophylline; spirometry revealed a forced expiratory volume in 1 s (FEV1) of 1.01 L. An uncontrolled asthma state was indicated by an Asthma Control Test (ACT) score of 18. Mepolizumab, 100 mg every 4 weeks, was initiated for the treatment of severe bronchial asthma with ABPA exacerbation. Bronchial asthma symptoms dramatically improved, and ACT score increased to 24, by 4 weeks after mepolizumab treatment. Peripheral eosinophil count decreased to 174/µL. Spirometry revealed improvement of lung function (FEV1: 1.28 L). A chest CT scan demonstrated the disappearance of pulmonary infiltration and mucoid impaction. CONCLUSIONS: To our knowledge, this is the first case of ABPA to be treated with mepolizumab. Dramatic improvements were observed in symptoms, lung function, peripheral eosinophil counts, and chest images. Mepolizumab could serve as an alternative treatment with the potential to provide a systemic corticosteroid-sparing effect.

A Case of Influenza B and Mycoplasma pneumoniae Coinfection in an Adult.

A 19-year-old woman was referred to our hospital because of a persistent fever and cough that lasted for over a week. Influenza B virus infection was diagnosed using the rapid test kit. Initially, the patient was diagnosed with influenza B infection associated with lobar pneumonia and treated with an anti-influenza virus drug and sulbactam/ampicillin. The patient's fever persisted, and her respiratory condition worsened. On day 5, a computed tomography (CT) scan revealed an extension of the consolidation areas in the left lung and new opacities in the right lung. The antibiotic treatment was changed to meropenem and levofloxacin, and the patient's physical condition gradually improved. A sputum sample revealed the presence of Mycoplasma pneumoniae-specific DNA. Both influenza B virus and M. pneumoniae infections were confirmed serologically. This was a case of coinfection with influenza B virus and M. pneumoniae in a healthy young woman. The M. pneumoniae pneumonia diagnosis was delayed because the predominant feature observed in the CT scan was dense consolidation. M. pneumoniae should be considered as one of the causative pathogens in influenza coinfection cases with CT scan images presenting dense consolidation.

Imatinib dramatically alleviates pulmonary tumour thrombotic microangiopathy induced by gastric cancer.

Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare complication of cancer, which can be lethal due to progressive pulmonary hypertension (PH). Several case reports have demonstrated that imatinib, a platelet-derived growth factor receptor-tyrosine kinase inhibitor, can improve severe PH in patients with PTTM.We describe the case of a 56-year-old woman. Her mean pulmonary arterial pressure (mPAP) was 47 mm Hg, and her dyspnoea worsened rapidly over several days. Although pulmonary embolism was not observed on CT, enlargement of the para-aortic lymph nodes was detected. Gastro-oesophageal endoscopy revealed signet-ring cell carcinoma. We diagnosed her as having PTTM based on her clinical course, and started treatment with imatinib. Five days after its administration, her mPAP decreased dramatically. She was discharged and lived without symptoms of PH until her death due to systemic metastasis of carcinoma. In some cases of PTTM, imatinib may be an effective therapeutic option for PH.