Efficacy of osimertinib in patients with EGFR-mutation positive non-small cell lung cancer with malignant pleural effusion.

BACKGROUND: As an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), osimertinib has emerged as a standard EGFR-mutation positive treatment for non-small cell lung cancer (NSCLC). However, the efficacy of osimertinib for malignant pleural effusion (MPE) remains understudied. This study aimed to evaluate the impact of osimertinib on time to treatment failure (TTF) and overall survival (OS) in patients with EGFR-mutation positive NSCLC, comparing those with and without MPE. METHODS: This retrospective analysis included patients with advanced or recurrent NSCLC treated with osimertinib at our hospital between April 2016 and June 2021. TTF was defined as the duration from osimertinib initiation to discontinuation, and OS as the duration until death, irrespective of the reason. RESULTS: Among 229 patients receiving osimertinib, 84 had MPE before administration, 39 acquired EGFR exon20 T790M mutation following previous EGFR-TKI therapy, and 45 were EGFR-TKI-naive. Among EGFR-TKI-naive patients, median TTF was 14.8 and 19.8 months for those with and without MPE, respectively (hazard ratio [HR] 1.40; 95% confidence interval [CI]: 0.90-2.18; p = 0.12). Median OS was 32.0 and 42.0 months for patients with and without MPE, respectively (HR 1.43; 95% CI: 0.86-2.38; p = 0.16). Among patients with T790M mutation, median TTF was 12.3 and 13.1 months for patients with and without MPE, respectively (HR 1.03; 95% CI: 0.69-1.55; p = 0.88). Median OS for patients with and without MPE was 23.2 and 24.7 months, respectively (HR 1.09; 95% CI: 0.72-1.67; p = 0.68). CONCLUSION: Among patients with EGFR-mutation positive NSCLC, the evidence of MPE has little effect on survival with osimertinib.

Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer.

BACKGROUND: Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. METHODS: This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. RESULTS: Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. CONCLUSION: Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

Usefulness of blood biomarkers for predicting venous thromboembolism in Japanese patients with cancer.

Prospective studies on risk factors for the occurrence of venous thromboembolism (VTE) in Asian patients with cancer are limited. Therefore, the present study assessed risk factors for VTE, including multiple blood biomarkers and risk scores consisting of several risk factors, in Japanese patients receiving anticancer drug therapy. In this single-center, prospective, observational study, 200 patients with six types of cancer were enrolled and followed for 1 year to observe the occurrence of symptomatic or asymptomatic VTE. The present study evaluated risk factors, Khorana and Vienna cancer and thrombosis study (CATS) scores at enrollment, and longitudinal data on various blood biomarkers. A Vienna CATS score of ≥3 was significantly associated with VTE occurrence (HR, 2.8; 95% CI, 0.9-8.7; P=0.045). In multivariable analysis, there was a significant association between VTE and the presence of pancreatic cancer (HR, 3.2; 95% CI, 1.1-8.8; P=0.028) and high soluble fibrin (HR, 3.7; 95% CI, 1.1-7.8; P=0.036). Covariate analysis using the propensity score also showed a significant association with hemoglobin dichotomized at <100 g/l (HR, 3.9; 95% CI, 1.1-14.0; P=0.034). Longitudinal data indicated that VTE was associated with soluble fibrin baseline values and an increase in D-dimer levels over time. The present results suggested that blood biomarkers are beneficial for predicting the risk of VTE in Japanese patients with cancer. The present study also provided novel evidence for the importance of measuring soluble fibrin in patients with cancer.

Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients.

Soluble interleukin-2 receptor (sIL-2R) suppresses effector T-cells. Few studies have assessed serum sIL-2R in patients receiving immunotherapy. We evaluated the association between serum sIL-2R levels and the efficacy of anti-programmed cell death 1/ programmed death-ligand 1 (anti-PD-1/PD-L1) antibody combined with chemotherapy in non-small cell lung cancer (NSCLC) patients. We prospectively enrolled NSCLC patients who received anti-PD-1/PD-L1 antibody combined with platinum-based chemotherapy between 8/2019 and 8/2020 and measured their serum sIL-2R. The patients were divided into high and low sIL-2R groups based on the median of sIL-2R levels at pretreatment. Progression-free survival (PFS) and overall survival (OS) of patients in the high and low sIL-2R groups were compared. The Kaplan-Meier curves of PFS and OS were evaluated using the log-rank test. The multivariate analysis of PFS and OS was performed using the Cox proportional hazard models. Among 54 patients (median age 65, range 34-84), 39 were male and 43 had non-squamous cell carcinoma. The sIL-2R cut-off value was 533 U/mL. Median PFS was 5.1 months (95% CI, 1.8-7.5 months) and 10.1 months (95% CI, 8.3-not reached [NR] months) in the high and low sIL-2R groups (P = 0.007), respectively. Median OS was 10.3 months (95% CI, 4.0-NR months) and NR (95% CI, 10.3-NR months) in the high and low sIL-2R groups (P = 0.005), respectively. Multivariate Cox regression analysis showed that high sIL-2R was significantly associated with shorter PFS and OS. SIL-2R may be a biomarker for the poor efficacy of anti-PD-1/PD-L1 antibody combined with chemotherapy.

Factors related to the diagnosis of lung cancer by transbronchial biopsy with endobronchial ultrasonography and a guide sheath.

BACKGROUND: Transbronchial biopsy (TBB) with endobronchial ultrasonography and a guide sheath (EBUS-GS) is an effective examination tool for the diagnosis of lung cancer. Factors related to making the diagnosis are still not fully understood. METHODS: A total of 367 patients who underwent EBUS-GS and were diagnosed with lung cancer in Saga University Hospital were investigated retrospectively. Clinical characteristics were compared between 244 patients who were diagnosed with lung cancer and 123 patients who were not diagnosed by TBB with EBUS-GS but were diagnosed by other examinations. RESULTS: Size of target lesion, rate of patients with target lesion size ≥20 mm, presence of the bronchus sign, and detection by EBUS imaging were significantly associated with making the diagnosis (all p < 0.01). In patients whose lesion was detected by EBUS imaging, patients with positive findings within the lesion were significantly more often diagnosed by TBB with EBUS-GS than those with positive findings adjacent to the lesion (p < 0.01). The odds ratio (OR) of patients whose lesion was detected by EBUS imaging (OR [95% confidence interval] 14.5 [8.0-26.4]) tended to be higher compared to the ORs of size of lesion ≥20 mm (3.9 [2.2-6.8]) and the bronchus sign (7.5 [4.6-12.2]). CONCLUSION: Targeted lesion diameter ≥20 mm, bronchus sign, and detection by EBUS imaging, especially within the lesion, are important factors for the diagnosis of lung cancer by TBB with EBUS-GS.

EGFR-TKI re-administration after osimertinib failure in T790M mutation loss cases with re-biopsy.

Data on the re-administration of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) after osimertinib failure in patients with T790M-positive non-small cell lung cancer (NSCLC) is limited. EGFR-TKI re-administration efficacy may vary between patients with T790M loss and those with T790M persistent with re-biopsy after osimertinib treatment. Patients who received EGFR-TKI re-administration (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) after osimertinib failure were identified from our database. T790M mutation status before EGFR-TKI re-administration was analyzed via repeat biopsy. We retrospectively evaluated the efficacy of EGFR-TKI re-administration, especially differences according to the T790M mutation status, via repeat biopsy. Until June 2020, 28 patients received EGFR-TKI re-administration and 17 underwent repeat biopsy after osimertinib failure. Patients were divided into three groups, including the T790M loss group, where active mutation persisted and T790M was lost (13/17); T790M remaining group, where both the active mutation and T790M persisted (3/17); and active mutation loss group where both the active mutation and T790M were lost (1/17). The overall response rate (ORR) of EGFR-TKI re-administration in the T790M loss group was 31% and the disease control rate (DCR) was 54%, which were higher than the ORR of 21% and DCR of 43% in the entire patient population. ORR and DCR of the not re-biopsy group were low (9% and 27%, respectively). The therapeutic effect of EGFR-TKI re-administration in patients with T790M-positive NSCLC after osimertinib failure is limited. EGFR-TKI re-administration may be considered in cases of T790M loss after repeat biopsy.

Rapid genomic profiling of circulating tumor DNA in non-small cell lung cancer using Oncomine Precision Assay with Genexus™ integrated sequencer.

Background: Genomic profiling of tumors from cancer patients facilitates molecular-guided therapy. The turnaround time is one of important issues to deliver results timely for clinical decisions. The Ion Torrent™ Genexus™ Integrated Sequencer automates all next generation sequencing (NGS) workflows and delivers results within a day. Methods: In this study, we conducted a feasibility study to evaluate the detection rate of genomic alterations from cell-free total nucleic acid (cfTNA, containing cfDNA and cfRNA) of 119 non-small cell lung cancer using Oncomine Precision Assay on Genexus™ Integrated Sequencer. Oncomine Precision Assay (OPA) covers actionable mutations, copy number variations and fusion genes and that are applicable for the selection of targeted therapy. cfTNA isolated from plasma (derived from 14 ml of blood) were subjected to the Genexus system for library construction, templating, sequencing, and data analyses. Results: The sequencing resulted in median overall depth of 35,773× and median molecular coverage of 2,192× with cfTNA input ranged from 11 to 36 ng. Among the 119 samples evaluated, we detected at least one genomic alteration in plasma cfTNA of 79 cases (66%). When comparing to standard-of-care testing, the sensitivity and specificity of mutation detection in non-small cell lung cancer related genes using liquid biopsy with Genexus-OPA ranged between 49-67% and 93-100%, respectively. 59% of actionable mutations, which were present in tumor tissues, were detected by the Genexus- Oncomine Precision Assay using plasma cfTNA. Among the 5 mutations detected from liquid biopsy only, three mutations are of level 1 evidence according to OncoKB database, highlighting the clinical utilities of liquid biopsy in addressing tumor heterogeneity. Extrathoracic metastasis and levels of lactate dehydrogenase (LDH), C-reactive protein (CRP) and Carcinoembryonic Antigen (CEA) are found to be associated with increased circulating tumor DNA detection. Conclusions: The Genexus™ Integrated Sequencer system is an automated, accurate NGS system with short turnaround time (TAT) that could assist clinicians to make more timely decision.

Characteristics of central nervous system progression in non-small cell lung cancer treated with crizotinib or alectinib.

BACKGROUND: Most patients treated with anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors for ALK-positive non-small cell lung cancer (NSCLC) develop resistance, leading to metastasis, with progression to the central nervous system (CNS) being a primary concern. Although alectinib has better CNS penetration than crizotinib, patients treated with alectinib also develop CNS progression. CNS metastases more likely occurs during crizotinib treatment due to less blood-brain barrier (BBB) penetration capability than alectinib. CNS progression pattern may be different during crizotinib and alecitinib treatment. Understanding the characteristics of CNS progression is important for developing treatment strategies. AIMS: We compared the clinical-radiographic characteristics of CNS metastases among patients undergoing crizotinib and alectinib treatment for ALK-positive NSCLCs. METHODS AND RESULTS: We retrospectively analyzed the radiographic and clinical characteristics of CNS progression in ALK-positive NSCLC patients treated with crizotinib or alectinib at our hospital between July 2011 and May 2020. CNS and systemic tumor progression were evaluated using computed tomography or magnetic resonance imaging. Fifty-three and 65 patients were treated with crizotinib and alectinib, respectively. Baseline CNS metastasis was observed in 18 and 27 patients in the crizotinib and alectinib groups, respectively. Among the patients in the crizotinib and alectinib groups who developed disease progression, 15/49 (30.6%) and 9/44 (20.5%) had CNS progression, respectively (P = .344). Intra-CNS progression-free survival was significantly longer in the alectinib group than in the crizotinib group (median: 14.0 vs 5.6 months, P = .042). The number of CNS metastases sized ≥3 cm, rate of peritumoral brain edema, and the second progression pattern after treatment continuation was not significantly different between the groups. CONCLUSION: We observed no significant difference in the clinical-radiographic characteristics of CNS progression between patients undergoing crizotinib and alectinib treatments. Local therapy, including stereotactic radiosurgery, for CNS progression may be suitable and important following alectinib and crizotinib treatment.

Impact of Renin-angiotensin System Inhibitors on the Efficacy of Anti-PD-1/PD-L1 Antibodies in NSCLC Patients.

BACKGROUND/AIM: The Renin-Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. PATIENTS AND METHODS: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. RESULTS: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). CONCLUSION: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.

Clinical influence of switching companion diagnostic tests for EGFR-TKs from Therascreen to Cobas v2.

BACKGROUND: Several companion diagnostic (CDx) tests for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been approved. In our institute, the CDx test for EGFR-TKIs was changed from the Therascreen test (Therascreen) to the Cobas EGFR v2 test (Cobas) because only Cobas was approved for the use of osimertinib in patients with EGFR-mutated non-small cell lung cancer (NSCLC) with T790M mutations. The clinical influence of switching the CDx test has not yet been examined comprehensively. METHODS: All serial patients with lung cancer tested for EGFR mutations with CDx tests between February 2014 and February 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) were enrolled in this analysis. RESULTS: Therascreen was used as a CDx test for EGFR-TKI therapy in 607 patients between February 2014 and January 2015, and Cobas was used in 621 patients between February 2015 and February 2016. EGFR mutations were detected in 218 patients (35.9%) and 244 patients (39.3%) tested with Therascreen and Cobas, respectively. At the initial diagnosis, 400 and 459 patients were tested with Therascreen and Cobas, respectively. EGFR mutation subtypes, including del19, L858R, and others, were detected in 13.0%, 17.0%, and 2.5% of patients using Therascreen and 17.4%, 14.4%, and 1.5% of patients using Cobas, respectively. CONCLUSIONS: No significant impact of switching from Therascreen to Cobas as the CDx test for EGFR mutations in clinical practice was observed. However, the detection pattern of the EGFR mutation subtypes between the two CDx tests was slightly different. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We examined the influence of changing the EGFR test in 1228 patients in total. The detection rate of EGFR mutations was similar. However, the detection pattern for EGFR subtype mutations was slightly different between the two tests. WHAT THIS STUDY ADDS: Switching CDx tests from target polymerase chain reaction (PCR)- to next-generation sequencing (NGS)-based methods may lead to obvious changes in clinical practice. When the CDx test is required to change, the investigation of this influence is warranted in future studies.

Feasibility of next-generation sequencing test for patients with advanced NSCLC in clinical practice.

BACKGROUND: The usefulness of the Oncomine Dx Target test (Oncomine Dx), a next-generation sequencing (NGS) test, has already been proven in clinical trials. However, NGS requires high-quality tumor samples and takes a long time to generate results. The feasibility of NGS for use in advanced non-small cell lung cancer (NSCLC) patients in clinical practice has not yet been determined. METHODS: Patients serially diagnosed with advanced NSCLC were evaluated in our hospital. The Oncomine Dx, Cobas EGFR mutation test (Cobas EGFR), and ALK-IHC were performed. The patients were divided into four sets: the full analysis set (FAS) that referred to patients diagnosed with NSCLC, the intent to perform companion diagnostics (CDx) set (IPS) that referred to patients in which CDx had been ordered regardless of sample quality, the per-performed CDx set (PPS) that referred to patients who could undergo CDx regardless of the results, and the per-completed CDx set (CCS) that referred to patients in which informative results were received from the CDx. RESULTS: The total number of patients analyzed in the study was 167. The IPS/FAS of Oncomine Dx (80.2%) was lower than that of the ALK-IHC (85.0%) and Cobas EGFR (92.8%). The CCS/FAS of Oncomine Dx (65.9%) was lower than that of the ALK-IHC (82.0%) and Cobas EGFR (92.2%). PPS/IPS and CCS/PPS of the Oncomine Dx with nonsurgical biopsy ranged between 78.6% and 90.9%, which was lower than those patients who underwent surgical resection (95.0% and 100%). CONCLUSIONS: The feasibility of Oncomine Dx in clinical practice was lower than the other CDx. The feasibility of Oncomine Dx will increase by improving the biopsy procedure. KEY POINTS: SIGNIFICANT STUDY FINDINGS: The usefulness of a next-generation sequencing (NGS) test has been proven in clinical trials. The feasibility of NGS is lower than other diagnostics in clinical practice especially with regard to nonsurgical biopsy. WHAT THIS STUDY ADDS: It is necessary to improve the feasibility of NGS in clinical practice. To improve NGS feasibility, turnaround time must be shortened, and larger samples must be obtained during surgical procedures.

A rare case of Trichosporon mycotoxinivorans and Cryptococcus neoformans co-infection in lung.

A 70-year-old woman with liver cirrhosis caused by primary biliary cirrhosis and rheumatoid arthritis was found to have multiple pulmonary nodular shadows in the right middle and lower lung fields on chest radiography. The multiple pulmonary nodules and masses rapidly increased over 2 months. Trichosporon mycotoxinivorans and Cryptococcus neoformans were identified in brushing specimens, bronchial lavage, and transbronchial lung biopsy specimens. The patient was diagnosed as having a co-infection of the lung with T. mycotoxinivorans and C. neoformans, and was treated with fluconazole. Although the pulmonary shadows were under control with treatment, she died 5 months later due to liver failure. We report herein a rare case of co-infection of the lung with T. mycotoxinivorans and C. neoformans.

Paraneoplastic Limbic Encephalitis Complicated with Small Cell Lung Cancer at the Time of Recurrence.

Paraneoplastic limbic encephalitis (PLE) is a rare neurologic disorder that can complicate various malignancies, including lung cancer. PLE is most frequently found the initial presentation of lung cancer. In this study, we reported the case of a 74-year-old Japanese woman who developed PLE after partial remission of small cell lung cancer (SCLC) by first-line systemic chemotherapy. Brain magnetic resonance imaging showed no metastatic tumor or cerebrovascular disease. Anti-glutamic acid decarboxylase (GAD) and anti-amphiphysin antibodies were detected in her serum. She was diagnosed as having PLE related to the recurrence of SCLC and received high-dose glucocorticoid, and sequentially systemic chemotherapy with amrubicin. Unfortunately, these treatments did not improve her disease progression and she died 4 months later. Although PLE rarely occurs at the time of SCLC recurrence, physicians should pay attention to PLE onset even after chemotherapy.

Discontinuation due to immune-related adverse events is a possible predictive factor for immune checkpoint inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) should be anticipated with treatment by immune checkpoint inhibitors (ICIs). Although the relationship between irAEs and efficacy of ICI has been reported, it has not yet been clarified whether the benefit from ICI outweighs the low frequency of proceeding to subsequent therapies after discontinuation due to irAEs. METHODS: The study comprised 61 patients with non-small cell lung cancer who underwent treatment with ICIs (nivolumab or pembrolizumab monotherapy) at the Saga University Medical School Hospital from December 2015 to January 2018. Therapeutic effect and progression-free survival (PFS) were compared between the irAEs discontinuation group (AEg) and the group with discontinuation due to all causes other than irAEs (Non-AEg). RESULTS: A total of 30% patients(18/61) had therapy discontinued due to irAEs: 22.5% (9/40) with nivolumab and 42.9% (9/21) with pembrolizumab. The response rate was 50.0% in the AEg and 8.1% in the on-AEg (P = 0.001). The median PFS was significantly longer in the AEg (9.3 months; 95% CI 2.1-12.1) than in the non-AEg (1.9 months; 95% CI 0.9-3.6): HR 0.45 (95%CI 0.20-0.89; log-rank test P = 0.026). The prevalence of drug-induced interstitial lung disease (ILD) was 6.1% (3/49) in cases without interstitial pneumonia (IP) as the underlying disease, whereas it was 50% (6/12) in cases with IP (P = 0.001). CONCLUSION: Discontinuation of treatment with ICIs due to irAEs predict a good response to ICIs and favorable outcome since their anti-cancer effects continue even after discontinuation. However, the presence of IP as the underlying disease increases the risk of drug-related ILD onset.

Primary Chest Wall MYC/BCL6 Double-hit Lymphoma with t (3;7) (q27;p12) and t (8;14) (q24;q32) Translocations.

Primary chest wall lymphoma is rare and typically associated with chronic pleural inflammation. Double-hit lymphoma (DHL), which is defined as aggressive mature B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, is a highly aggressive malignancy that tends to have extranodal involvement and is resistant to standard immunochemotherapy. We herein report a 55-year-old man with no history of chronic pleural inflammation, diagnosed with primary chest wall DHL with MYC/BCL6 rearrangement, and harboring a unique BCL6 translocation, t (3;7) (q27;p12). After six courses of intensive chemotherapy, he has achieved complete remission. To our knowledge, this is the first case report of primary chest wall DHL.

Primary Pulmonary Colloid Adenocarcinoma: How Can We Obtain a Precise Diagnosis?

A 76-year-old asymptomatic man was found to have a mass in the right lower lung field. Although the presence of a mucinous component in the majority of the tumor was shown by magnetic resonance imaging, the presence of cancer cells was suspected by contrast enhancement on computed tomography (CT) and based on the partial accumulation in the marginal regions of the tumor on fluorodeoxyglucose-positron emission tomography (FDG-PET). A transbronchial lung biopsy was non-diagnostic, but resection of the mass resulted in a diagnosis of colloid adenocarcinoma. The findings from combined contrast CT and FDG-PET may raise the suspicion of colloid adenocarcinoma and prompt the consideration of surgical resection.

Signet Ring Cell Carcinoma of Unknown Primary Complicated with Pulmonary Tumor Thrombotic Microangiopathy and Krukenberg Tumor.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare disease that shows hypoxia with severe pulmonary hypertension related to malignant tumor. Diagnosis is difficult due to rapid clinical progression and the need to demonstrate pathological findings from lung biopsy. A 64-year-old woman visited our hospital with hypoxia and pulmonary hypertension. Diffuse granular shadows in the centrilobular area and ground-glass shadows in both lungs and left ovarian tumor were found on radiological imaging. PTTM was suspected, but pulmonary artery blood aspiration by right cardiac catheter failed to detect cancer cells. We could not obtain lung or ovary biopsies because of hypoxia or pulmonary hypertension. The patient died due to respiratory failure. Signet ring cell carcinoma of unknown primary, PTTM, and Krukenberg tumor were diagnosed on autopsy. Since early diagnosis facilitates adequate treatment, physicians should not miss the opportunity for biopsy in cases of suspected PTTM.

Current Status and Problems of T790M Detection, a Molecular Biomarker of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors, with Liquid Biopsy and Re-biopsy.

BACKGROUND/AIM: The purpose of this study was to consider appropriate application of liquid and re-biopsy through analysis of current status in practice. PATIENTS AND METHODS: We performed a retrospective analysis of 22 patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who exhibited 1st/2nd generation EGFR-tyrosine kinase inhibitors resistance. The cobas® method was used to detect T790M with re-biopsy and the mutation-biased PCR and quenched probe method was used with liquid biopsy. RESULTS: T790M detection rate was 52% with re-biopsy and 58% with liquid biopsy. The concordance between tissue and plasma was 58%. One patient who was T790M-positive with liquid biopsy showed heterogeneity among metastatic lesions in terms of osimertinib efficacy, as revealed by T790M detection with re-biopsy. CONCLUSION: Liquid biopsy reflects the whole body, whereas re-biopsy is useful for spatial diagnosis. Considering these characteristics, a combination of liquid and re-biopsy contribute to enhanced treatment.

Sjögren Syndrome Complicated with Cystic Lung Disease and Pulmonary Amyloidosis.

A 72-year-old Japanese woman was noted to have multiple cystic lung shadows and infiltrates on chest radiography and computed tomography (CT). She complained of dryness of the mouth and eyes, but she did not have respiratory symptoms, such as cough, sputum production, and dyspnea. Her laboratory findings showed high titers of anti-SSA/Ro and anti-SSB/La antibodies. Surgical lung biopsy was performed and demonstrated pathologic findings of amyloid light-chain deposition and bronchiolitis with lymphocytic infiltration. Taken altogether, she was diagnosed as Sjögren syndrome with bronchiolitis and pulmonary amyloidosis. Since then, she has been carefully followed up without treatment. After 6 years, the cystic lung lesions on CT gradually enlarged and increased in number, but she remained to have no respiratory symptoms and no manifestations of lymphoma. Here, we report a rare case of Sjögren syndrome complicated with cystic lung disease and pulmonary amyloidosis.