Synchronous Double Primary Lung Adenocarcinomas With EGFR L858R Point Mutation and MET Exon 14 Skipping Mutation.

Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) L858R and mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S1 and another nodule in the left S1+2. Bronchoscopic biopsy diagnosed the right S1 nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S1 adenocarcinoma detected EGFR L858R mutation. The 18F-fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S1 and the left S1+2 nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT1bN2M0) of adenocarcinoma in the right S1 and suspected another primary lung cancer in the left S1+2. Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S1 cancer achieved partial response (PR), while the left S1+2 nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S1+2 nodule (cT1bN3M0, c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S1+2 cancer achieved and maintained PR by capmatinib, the right S1 cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered.

Concordance between cryobiopsy and forceps biopsy specimens in assessment of immunohistochemistry staining for non-small cell lung carcinoma.

Background: Cryobiopsy is recently being promoted for biopsy of tumors in the lung periphery in precision medicine for lung cancer; the obtained tissue samples have been reported to be more useful compared to those obtained using forceps, because of the larger volume and higher quality. However, the influence of freezing and thawing of tissues when performing cryobiopsy on the results of immunohistochemistry (IHC) has not been completely understood. Methods: In this study, consecutive patients who underwent diagnostic bronchoscopy with cryobiopsy for peripheral pulmonary lesions (PPLs) at our institution between June 2017 and November 2021 were reviewed retrospectively. Specimens of diagnosed cases of unresectable or recurrent non-small cell lung carcinoma (NSCLC) were selected. We compared the results of IHC assessment for programmed death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), and human epidermal growth factor receptor 3 (HER3) in cryobiopsy specimens versus conventional forceps biopsy specimens from the same site in the same procedure. Results: Twenty-four of 40 patients were male (60%). The most frequent histologic type of cancer was adenocarcinoma (n=31, 77.5%), followed by NSCLC (n=4, 10%), squamous cell carcinoma (n=3, 7.5%), and others (n=2, 5%). The concordance rates of the tumor proportion scores (TPSs) for PD-L1, IHC score for HER2 and, IHC scores for HER3 were 85%, 72.5%, and 75%, respectively; the weighted kappa were 0.835, 0.637, and 0.697, respectively. Conclusions: Freezing and thawing associated with cryobiopsy had virtually no effect on the results of IHC. We suggest that cryobiopsy specimens would therefore be ideal for precision medicine and translational research.

Diagnostic efficacy of cryobiopsy for peripheral pulmonary lesions: A propensity score analysis.

OBJECTIVES: Recently introduced cryobiopsy can provide quantitatively and qualitatively excellent specimens. However, few studies have directly compared the diagnostic yield of cryobiopsy for peripheral pulmonary lesions (PPLs) with that of conventional sampling methods. MATERIAL AND METHODS: We retrospectively reviewed data from consecutive patients who underwent diagnostic bronchoscopy using radial endobronchial ultrasound and virtual bronchoscopic navigation for PPLs (October 2015 to September 2020). Patients who underwent cryobiopsy were assigned to the cryo group, whereas those who did not undergo cryobiopsy were assigned to the conventional group. The diagnostic outcomes of both groups were compared using propensity score analyses. RESULTS: A total of 2,724 cases were identified, including 492 and 2,232 cases in the cryo and conventional groups, respectively. Propensity scoring was performed to match baseline characteristics, and 481 pairs of cases were selected for each matched group (m-group). The diagnostic yield was significantly higher in the m-cryo group than in the m-conventional group (89.2% vs. 77.6%, odds ratio [OR] = 2.36 [95% confidence interval [CI] = 1.65-3.38], P < 0.001). Propensity score stratification (OR = 2.35 [95% CI = 1.71-3.23]) and regression adjustment (OR = 2.54 [95% CI = 1.83-3.52]) also demonstrated the diagnostic advantages of cryobiopsy. The subgroup analysis revealed that cryobiopsy was notably effective for lesions in the middle lobe/lingula, right/left lower lobe, lesions with ground-glass opacity, and lesions invisible on chest radiography. Although there were more cases of grade 2 and 3 bleeding in the m-cryo group than in the m-conventional group (38.0% vs. 10.2% and 1.5% vs. 0.8%, respectively; P < 0.001), no grade 4 bleeding was observed. CONCLUSION: The propensity score analyses revealed that cryobiopsy was associated with a higher diagnostic yield for PPLs than conventional sampling methods. However, increased bleeding risk should be noted as a potential complication.

Feasibility of the modified balloon occlusion method using a 6-Fr balloon catheter in transbronchial lung cryobiopsy.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is useful for diagnosing diffuse parenchymal lung diseases (DPLD). To prevent bleeding during TBLC, the balloon occlusion method has been recommended. However, displacement can occur occasionally, especially with a 4-Fr balloon. We aimed to investigate whether the use of a 6-Fr balloon would allow tamponade at a more proximal position and decrease balloon displacement in TBLC under flexible bronchoscopy. METHODS: We retrospectively reviewed 20 patients with DPLD who underwent TBLC using the modified balloon occlusion method between June 2019 and May 2021. RESULTS: The median number of TBLCs was three (range, 2-5). The most common balloon placement site was the right basal bronchus (14 patients). Mild and moderate bleeding was seen in 10 patients each. Successful balloon occlusion was achieved in all patients without dislocation. CONCLUSION: The modified balloon occlusion method in TBLC under flexible bronchoscopy might be a reasonable option for bleeding prevention.

Cerebral Infarction Caused by Trousseau's Syndrome Associated With Lung Cancer.

Background: Lung cancer is one of the common cancers that can cause Trousseau's syndrome. However, there are few reports of cerebral infarction due to Trousseau's syndrome associated with lung cancer. The aim of this study is to investigate the clinical features of lung cancer-related cerebral infarction and effective management practice. Methods: Japanese patients diagnosed with Trousseau's syndrome-related cerebral infarction associated with lung cancer between August 2012 and November 2021 in our hospital were retrospectively enrolled. Clinical data, treatment, and outcomes of the patients were collected. Results: Ten patients were enrolled. The median age was 65 years (range: 43 - 84 years). All patients had advanced lung cancer. The histological types were adenocarcinoma (n = 8), pleomorphic carcinoma (n = 1), and small cell lung cancer (n = 1). Recurrent cerebral infarction occurred in six patients. Among four patients who had continued heparin since the initial infarction, recurrence occurred in one. D-dimer was high in all 10 patients at the initial cerebral infarction. D-dimer level at the time of recurrent cerebral infarctions was higher than that at the first cerebral infarctions. Since performance status declined in nine patients, one patient continued anticancer drugs after cerebral infarction. Four patients died within 100 days of the onset of cerebral infarction. Conclusions: Cerebral infarction of lung cancer-related Trousseau's syndrome has poor prognosis. Heparin may be effective in controlling the condition. In addition, D-dimer may serve as a marker of cancer-related thrombosis.

Osimertinib-Induced Unilateral Diffuse Alveolar Hemorrhage in a Patient With Pulmonary Adenocarcinoma.

A 70-year-old man with lung adenocarcinoma was admitted to our hospital due to progressive dyspnea, 4 months after osimertinib initiation. His chest radiograph and computed tomography revealed ground-glass opacities and consolidations dominantly in the upper left lung. He took neither antiplatelet nor anticoagulation agent. No abnormality in coagulation was detected. Bronchoalveolar lavage fluid (BALF) became serially and increasingly hemorrhagic, and confirmed the diagnosis of alveolar hemorrhage. After steroid pulse therapy and withdrawal of osimertinib, his condition gradually improved, accompanied by regression of ground-glass opacities and consolidations. Osimertinib causes not only interstitial pneumonia but also alveolar hemorrhage. The consolidations may spread not bilaterally, but be localized unilaterally. We have to keep this rare adverse event in mind, and consider immediate withdrawal of osimertinib and treatment with steroid. Increased lymphocytes in the BALF may be a potential indicator of sensitivity to steroid and favorable prognosis in diffuse alveolar hemorrhage.

Transformation From Adenocarcinoma to Pleomorphic Carcinoma as an Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Pulmonary pleomorphic carcinoma is a very rare histological type of primary lung cancer, and usually provides aggressive clinical courses. A 65-year-old Japanese woman was diagnosed by transbronchial biopsy of the primary tumor as c-stage IV (cT4N3M1b) of adenocarcinoma harboring L858R point mutation in the exon 21 of epidermal growth factor receptor (EGFR). She received EGFR tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) and subsequently cytotoxic chemotherapies. Gefitinib achieved partial response, but was switched to erlotinib due to elevated serum aspartate transaminase. After resistance to EGFR-TKIs, the second transbronchial re-biopsy revealed pulmonary pleomorphic carcinoma. Both carcinomatous and sarcomatous components retained the L858R mutation, but did not acquire T790M mutation. This case suggested that the histological transformation to pulmonary pleomorphic carcinoma may be one of mechanisms of drug resistance to EGFR-TKIs.

Successful Treatment of Allergic Bronchopulmonary Aspergillosis Using a Combination of Inhaled Fluticasone Furoate/Vilanterol and Oral Voriconazole.

Systemic corticosteroids are considered to be the standard treatment for allergic bronchopulmonary aspergillosis (ABPA). However, there is controversy regarding use of inhaled corticosteroid (ICS) therapy for ABPA. Here we report a case of ABPA that was successfully treated with inhaled fluticasone furoate/vilanterol (FF/VI) and oral voriconazole (VRCZ). The patient was a 62-year-old Japanese man with bronchiectasis and diabetes mellitus who presented with fever, cough, and purulent sputum. Computed tomography scans of the chest showed consolidation in the left upper and lower lobes. Laboratory investigations revealed an abnormal increase in the number of eosinophils (3,340/mm3) and elevated levels of C-reactive protein (3.04 mg/dL) and serum immunoglobulin E (IgE) (763 U/mL). Eight days after admission, he experienced a sudden attack of asthma. Aspergillus-precipitating antibodies were positive and Aspergillus fumigatus was detected in sputum culture. These results were consistent with a diagnosis of ABPA, and he was started on inhaled FF/VI and oral VRCZ. Systemic corticosteroids were not used because of the patient's history of diabetes mellitus and left atrial thrombus. His symptoms and consolidation improved significantly after treatment. He has not experienced an exacerbation for more than 3 years. In mild cases of ABPA in which total IgE is relatively low, inhaled FF/VI in combination with oral VRCZ can be considered as an alternative treatment to systemic corticosteroids in patients with ABPA.

Low Body Mass Index Is an Independent Prognostic Factor in Patients With Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.

BACKGROUND: Sarcopenia and obesity have been suspected as factors associated with efficacy of treatment and prognosis in various malignancies. This study aimed to investigate the association of pretreatment sarcopenia and visceral obesity with efficacy and prognosis of first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for patients with non-small cell lung cancer (NSCLC) and positive EGFR mutation. METHODS: We retrospectively collected 167 NSCLC patients with mutant EGFR who had started EGFR-TKI monotherapy between October 2007 and August 2018 at our hospital. We classified 167 patients into two groups, according to the definition of underweight based on the World Health Organization (WHO) body mass index (BMI) classification and the Japanese sex-specific cut-off values of the following computed tomography (CT) images-assessed markers of pretreatment sarcopenia or visceral obesity, such as psoas muscle index (PMI), intramuscular adipose tissue content (IMAC) and visceral-to-subcutaneous fat ratio (VSR) at lumbar vertebra L3 level. We compared overall survival (OS) and progression-free survival (PFS) of two groups by Kaplan-Meier curves and log-rank tests. Using multivariate Cox proportional hazard analyses adjusted by age, neutrophil-to-lymphocyte ratio, performance status, EGFR mutation types and EGFR-TKI lines, and extra-pulmonary metastases or three or more than 3 metastatic sites, we searched independent prognostic factors of OS and PFS of EGFR-TKI therapy. RESULTS: The OS (median 26.0 vs. 32.3 months, P = 0.02) and PFS (9.1 vs. 14.8 months, P = 0.03) of patients with BMI < 18.5 were significantly shorter than those of patients with BMI ≥ 18.5. However, there was no significant difference in OS and PFS according to PMI, IMAC and VSR. The multivariate analyses detected only BMI < 18.5 as an unfavorable prognostic factor of shorter OS (hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.03 - 2.81, P = 0.04) and PFS (HR 1.72, 95% CI 1.11 - 2.67, P = 0.02). CONCLUSIONS: Pretreatment underweight was a significant prognostic factor of poor PFS and OS of EGFR-TKI therapy. However, neither pretreatment sarcopenia nor visceral obesity was associated with prognosis of EGFR-TKI. Underweight may be a surrogate for advanced disease burden.