Acute exacerbation predicting poor outcomes in idiopathic interstitial pneumonia and advanced lung cancer patients undergoing cytotoxic chemotherapy.

Effective treatment for advanced lung cancer and idiopathic interstitial pneumonia (IIP) remains an unmet medical need. The relationship between chemotherapy's effectiveness in advanced lung cancer and the risk of acute exacerbation of IIP is poorly investigated. There is limited evidence that patients who experience an acute exacerbation of IIPs during cytotoxic chemotherapy have poorer outcomes than those who do not. Among 1004 patients with advanced lung cancer and IIPs enrolled in our published multi-centre retrospective study from 110 Japanese institutions, 708 patients (male: female, 645:63; mean age, 70.4) received first-line chemotherapy. The occurrence of chemotherapy-triggered acute exacerbations of IIPs and overall survival (OS) were analysed. The OS between groups of patients with and without the occurrence of acute exacerbation was compared at four landmark time points (30, 60, 90, and 120 days), starting from the first-line chemotherapy, using the landmark method. The incidence of acute exacerbation in patients who received first-line chemotherapy with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) was more frequent in NSCLC patients than in SCLC (4.2% vs 12.6%; odds ratio [OR]: 3.316; 95% confidence interval [CI] 1.25-8.8). Median survival time was 9.9 months (95% CI 9.2-10.7). Patients who experienced acute exacerbation had significant worse survival outcomes than those who did not at various time points (30 days, hazard ratio [HR]: 5.191, 95% CI 2.889-9.328; 60 days, HR: 2.351, 95% CI 1.104-5.009; 90 days, HR: 2.416, 95% CI 1.232-4.739; and 120 days, HR: 2.521, 95% CI 1.357-4.681). Acute exacerbation during first-line chemotherapy can predict poor survival.Trial Registration number: UMIN000018227.

A Rare Case of Overlapping Durvalumab-induced Myositis, Takotsubo-like Morphological Changes Caused by Myocarditis, and Myasthenia Gravis.

Immune checkpoint inhibitors can cause a range of immune-related adverse events, including myositis, Takotsubo cardiomyopathy, and myasthenia gravis. We herein report a rare case of a 78-year-old man with concurrent durvalumab-induced myositis, Takotsubo-like morphological changes caused by myocarditis, and myasthenia gravis. The patient initially required invasive ventilation and exhibited symptoms of myasthenia gravis after treatment with high-dose steroids. However, he subsequently achieved successful recovery after the administration of intravenous immunoglobulin, plasmapheresis, and high-dose steroids. We advocate vigilant neurological monitoring of patients with immune checkpoint inhibitor-induced myositis, including the assessment of ptosis and other relevant signs, so that prompt treatment can be initiated at the time of emergence or progression of immune checkpoint inhibitor-induced myasthenia gravis.

Successful dabrafenib and trametinib combination therapy in a patient with recurrent BRAFV600E-mutant non-small-cell lung cancer and coexisting radiation pneumonitis.

There have been several reports of drug-induced lung injury caused by molecular-targeted agents. Additionally, medical history of interstitial lung disease and chest irradiation are established risk factors for the development and progression of drug-induced lung injury. Moreover, the presence of fibrosis on chest computed tomography before treatment is a predictive factor for the appearance of pneumonia induced by anticancer drugs. Accordingly, patients with a history of interstitial lung disease or pneumonitis were excluded from clinical trials of dabrafenib and trametinib combination therapy for patients with previously treated BRAF V600E-mutant metastatic non-small-cell lung cancer. This article presents a case of successful dabrafenib and trametinib combination therapy in a patient with BRAF V600E-mutant non-small-cell lung cancer who had a history of radiation pneumonitis and developed recurrence after conventional chemoradiotherapy.

Clinical Results and Hematologic Predictors of Linear Accelerator-Based Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Brain Metastasis in Patients Aged 75 Years or Older: A Retrospective Study.

OBJECTIVE: This study aimed to evaluate prognostic factors including pre-radiosurgical blood count in elderly patients (EPs) with brain metastasis (BM) who were treated using linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator. METHODS: Between January 2011 and November 2021, 101 consecutive EPs with BM were treated by LINAC-based SRS or fSRT using LINAC with a micro-multileaf collimator. EPs were defined as patients aged ≥75 years. RESULTS: The tumors originated from the lungs (n = 90; 89.1%), colon (n = 2; 2.0%), and others (n = 9; 8.8%) in these EPs. The median pretreatment Karnofsky Performance Status was 80 (range, 40-100). The median follow-up time was 10 months (range, 0-76), as was the median survival. The 6-month, 1-year, and 2-year survival in the EP group was 58.3%, 43.2%, and 28.5%, respectively. Freedom from local failure at 6 months and 1 and 2 years was 97%, 95%, and 91.5%, respectively. Freedom from distant failure at 6 months and 1 and 2 years in EPs was 70.6%, 59.4%, and 54.2%, respectively. A high neutrophil/lymphocyte ratio >5.33 was an unfavorable predictor of prognosis for EPs with BMs treated with SRS and fSRT (P < 0.001). In the EPs, the prognostic factors associated with prolonged survival in the Cox proportional hazards model were being female and a good pretreatment Karnofsky Performance Status. CONCLUSIONS: The findings of our study highlight the efficacy of LINAC-based SRS and fSRT with a micro-multileaf collimator in the treatment of EPs with BMs. Neutrophil/lymphocyte ratio can be an important factor in treatment decisions for EPs with BMs.

A Novel Filtration Membrane for Clustered Circulating Tumor Cell Extraction: A Prospective Feasibility Study.

BACKGROUND/AIM: Circulating tumor cells (CTCs) have garnered attention as biomarkers for therapeutic response and prognosis in malignant neoplasms. Nonetheless, existing literature predominantly relies on surrogate markers of tumor cells or focuses on single-cell CTC, failing to adequately address the challenge of detecting cluster-forming CTCs, which bear considerable prognostic implications. This prospective study aims to validate the efficacy of a novel filtration membrane, namely Soft Micro Pore Filter (S-MPF®), for rare cell recovery in detecting CTCs through the analysis of clinical samples. PATIENTS AND METHODS: Patients with confirmed lung cancer or highly suspected lung cancer based on specific criteria (solid tumor size >2.0 cm, serum carcinoembryonic level >7.5 ng/ml, maximum standard uptake value derived from fluorodeoxyglucose-position emission tomography >2.9) were included in the study. CTCs were extracted from preoperative peripheral arterial blood samples using S-MPF®, and the validity of the filtration system was positively verified. RESULTS: Out of the 25 enrolled patients, 23 had lung cancer. CTC positivity was observed in 17 cases (73.9%), whereas cluster CTC positivity was observed in 16 cases (69.6%), with a median count of two clusters. Single CTC positivity was observed in 11 cases (52.1%), with a median count of one cell. CONCLUSION: The utilization of the newly developed S-MPF® filtration membrane exhibited a high rate of CTC identification, demonstrating its suitability for clinical applications.

Angiopoietin-like 4 Is a Critical Regulator of Fibroblasts during Pulmonary Fibrosis Development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial pneumonia caused by the excessive production and deposition of extracellular matrix components, including type I collagen. Activated fibroblasts, called α-SMA (α-smooth muscle actin)-expressing myofibroblasts, are the major source of type I collagen in pulmonary fibrosis (PF), but the mechanisms underlying disease progression have not been fully elucidated. Here, we obtained lung fibroblasts from patients with IPF from both nonfibrotic and fibrotic areas as determined by a lung computed tomography scan and compared gene expression between these areas by DNA microarray. We found that ANGPTL4 (angiopoietin-like 4) was highly expressed only in fibroblasts from the fibrotic area. ANGPTL4 was selectively expressed in the fibroblastic area of IPF lungs, where the myofibroblast marker α-SMA was also expressed. ANGPTL4 also regulates the gene expression of fibrosis-related markers, cell migration, and proliferation. In addition, ANGPTL4 expression in a murine model of PF induced by treatment with bleomycin was significantly induced in the lungs from the acute to the chronic phase. Single-cell transcriptome analysis during the course of bleomycin-induced PF revealed that Angptl4 was predominantly expressed in the activated fibroblasts and myofibroblasts. Moreover, the administration of recombinant ANGPTL4 to the bleomycin-induced fibrosis model significantly increased collagen deposition and exacerbated the PF. In contrast, the pathogenesis of PF in Angptl4-deficient mice was improved. These results indicate that ANGPTL4 is critical for the progression of PF and might be an early diagnostic marker and therapeutic target for IPF.

Chemotherapy versus best supportive care in advanced lung cancer and idiopathic interstitial pneumonias: A retrospective multi-centre cohort study.

BACKGROUND: The clinical questions of whether chemotherapy as initial treatment, compared with best supportive care (BSC), improves overall survival (OS) and whether it increases the occurrence risk of acute exacerbation of idiopathic interstitial pneumonia (IIP) in patients with advanced-stage lung cancer and IIP remain inconclusive. This study addresses these issues, given that chemotherapy-related acute exacerbation of IIP may be a direct cause of mortality in these patients. METHODS: We enrolled 1003 patients from 110 Japanese institutions and collected clinical profiles from 707 and 296 patients in the chemotherapy (men: women, 645:62; mean age, 70.4 ± 6.9 years) and BSC (men: women, 261:35; mean age, 75.2 ± 7.8) groups, respectively. We used propensity score matching to create 222 matched pairs from both groups using patient demographic data (age, sex, smoking status, performance status, history of acute exacerbation of IIP, desaturation on exertion, clinical diagnosis of IIP, high-resolution computed tomography findings, serum fibrotic markers, pulmonary function status, and lung cancer histopathology). Logistic or Cox regression analyses were performed using matched data to assess the effects of chemotherapy on the risk of acute exacerbation of IIP or OS, respectively. RESULTS: In the well-matched cohort, chemotherapy improved OS (hazard ratio: 0.629, 95% confidence interval [CI]: 0.506-0.783, p < 0.0001); however, it involved significant acute exacerbation of IIP (odds ratio: 1.787, 95% CI: 1.026-3.113) compared to BSC. CONCLUSIONS: Compared with BSC, chemotherapy can improve OS in patients with advanced-stage lung cancer and IIP; however, it increases the risk of acute exacerbation of IIP.

A case of perforated immune-related colitis complicated by cytomegalovirus infection during treatment of immune-related adverse effect in lung cancer immunotherapy.

Although immune checkpoint inhibitors (ICIs) can be used for lung cancer treatment, the activated immune response may cause immune-related adverse effects (irAEs). We present here a case of cytomegalovirus (CMV) enterocolitis during steroid therapy for an irAE. A 70-year-old man diagnosed with small-cell lung carcinoma (limited disease) received radiotherapy plus two chemotherapy cycles of cisplatin and etoposide. The tumor exhibited complete response but recurred after 3 years. After treatment with two cycles of carboplatin, etoposide, and atezolizumab, an inhibitors of programmed cell death receptor-1, he was switched to atezolizumab every 3 weeks for maintenance therapy. Diarrhea occurred after nine atezolizumab doses. With a strong suspicion of ICI-induced colitis, we administered methylprednisolone 500 mg for 3 days, followed by oral prednisolone 40 mg/day. Total colonoscopy during the treatment revealed mucosal inflammation of the total colon, suggesting immune-related colitis. Biopsies from the ulceration revealed crypt abscess with highly infiltrative plasma cells and lymphocytes. Furthermore, immunohistochemical staining showed positivity for CMV. With no improvement in watery diarrhea, the prednisolone dose was increased to 80 mg/day on the 11th day, and ganciclovir was additionally administered twice daily on the 26th day. On the 28th day, the patient had abdominal pain, and abdominal computed tomography revealed free air, resulting in the diagnosis of colon perforation. He underwent subtotal colectomy followed by ileostomy as emergency surgery. A colon specimen revealed colitis with CMV infection. We describe colon perforation in a patient with CMV enterocolitis complicated by refractory immune-related colitis.

Pulmonary sarcoidosis with a cavitary lesion in the lung caused by a TNF-α inhibitor: A case report.

A 28-year-old man with ankylosing spondylitis (AS) who was treated with a tumour necrosis factor-alpha (TNF-α) inhibitor, adalimumab, presented with newly detected multiple bilateral pulmonary nodules on chest computed tomography (CT). We suspected bacterial infection, including those caused by acid-fast bacilli, or adalimumab-related condition, such as sarcoidosis. After adalimumab cessation, no resolution of the pulmonary shadows was observed. Moreover, pulmonary cavitation appeared on chest CT at 7 weeks, prompting surgical lung biopsy. Acid-fast bacteria culture of the lung tissue showed negative results. Pathological examination suggested that confluent granulomas associated with sarcoidosis might have obstructed the blood vessels, causing necrosis and lung cavitation. Consequently, prednisolone was initiated, and these shadows were reduced. After administering anti-interleukin (IL)-17A antibody for treatment of AS and prednisolone withdrawal, these shadows were not exacerbated. TNF-α inhibitor-induced sarcoidosis could cause cavitary lesions due to vascular invasion of granulomas.

Long-Term Survival after Linac-Based Stereotactic Radiosurgery and Radiotherapy with a Micro-Multileaf Collimator for Brain Metastasis.

BACKGROUND: this study aimed to evaluate the prognostic factors associated with long-term survival after linear accelerator (linac)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis (BM). METHODS: This single-center retrospective study included 226 consecutive patients with BM who were treated with linac-based SRS or fSRT with a micro-multileaf collimator between January 2011 and December 2018. Long-term survival (LTS) was defined as survival for more than 2 years after SRS/fSRT. RESULTS: The tumors originated from the lung (n = 189, 83.6%), breast (n = 11, 4.9%), colon (n = 9, 4.0%), stomach (n = 4, 1.8%), kidney (n = 3, 1.3%), esophagus (n = 3, 1.3%), and other regions (n = 7, 3.1%). The median pretreatment Karnofsky performance scale (KPS) score was 90 (range: 40-100). The median follow-up time was 13 (range: 0-120) months. Out of the 226 patients, 72 (31.8%) were categorized in the LTS group. The median survival time was 43 months and 13 months in the LTS group and in the entire cohort, respectively. The 3-year, 4-year, and 5-year survival rate in the LTS group was 59.1%, 49.6%, and 40.7%, respectively. Multivariate regression logistic analysis showed that female sex, a pre-treatment KPS score ≥ 80, and the absence of extracranial metastasis were associated with long-term survival. CONCLUSIONS: female sex, a favorable pre-treatment KPS score, and the absence of extracranial metastasis were associated with long-term survival in the current cohort of patients with BM.

Verification of A New Filter for Isolation of Circulating Tumor Cells by Only Blood Filtration.

BACKGROUND/AIM: Since circulating tumor cells (CTCs) are precursors of metastatic lesions, extracting CTCs from whole blood is useful in obtaining information for cancer treatment. One of the CTC isolation methods is the size selection method; however, since the conventional methods are expensive and cumbersome, we developed an affordable and simple filter, whose usefulness is verified in this study. MATERIALS AND METHODS: The new filter [hereafter, soft micropore filter (S-MPF)] is made up of a polyethylene film with a thickness of 15 µm and conical pores having a diameter of 8-10 µm, which are opened uniformly (opening rate, 20%). This filter can filter whole blood by free-falling under gravity. The possibilities of the filter's usage for model CTC isolation, immunostaining, short-term cell culture, and gene mutation detection in extracted model CTCs were verified. RESULTS: S-MPF was able to extract model CTCs with an isolation rate of up to 15%. These model CTCs were detected by cytology, immunostaining, and culture by short-term incubation of filtered cells. Furthermore, genetic mutations were identified in the cultured cells. In addition, CTC isolation from the peripheral blood of patients with lung cancer was demonstrated by setting the volume of collected blood to 15 ml to prevent a low recovery rate. CONCLUSION: The S-MPF can be used to extract model CTCs quickly and easily. Moreover, cytological diagnosis, immunostaining, short-term culture, and gene mutation search are possible with this filter. Given its proven applicability in clinical samples, this filter can be used in clinical settings.

Treatment of transient prosopagnosia with a tyrosine kinase inhibitor in a case of brain metastasis from EGFR-mutated lung adenocarcinoma.

Background: Prosopagnosia is a rare form of apraxia, in which a person has normal memory and vision, but has impaired cognition of human faces that are manifested through symptoms such as not being able to recognize the face of a familiar person, one has known or not being able to remember the face of a person. Here, we report the case of a patient with transient prosopagnosia associated with brain metastasis from epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma who was treated with tyrosine kinase inhibitors (TKIs). Case Description: A 52-year-old right-handed man with lung adenocarcinoma was introduced to our department because brain metastasis. On admission, he complained that he could not recognize his wife's face, but he could recall her face based on her voice. MRI revealed a right temporo-occipital enhancing lesion with perifocal edema and dissemination that were indicative of brain metastasis from lung adenocarcinoma. Two weeks after open biopsy, he was started on TKI therapy with osimertinib at a dosage of 80 mg/day. An MRI scan taken 1 month later revealed shrinkage of the metastasis. In addition, he had recovered from transient prosopagnosia and returned to normal life. Conclusion: In this study, the TKI osimertinib was administered to a patient with brain metastasis of EGFR-mutated lung adenocarcinoma who presented with prosopagnosia, and the patient's lesion shrunk and his symptoms were reversed with this treatment.

TAS-Seq is a robust and sensitive amplification method for bead-based scRNA-seq.

Single-cell RNA-sequencing (scRNA-seq) is valuable for analyzing cellular heterogeneity. Cell composition accuracy is critical for analyzing cell-cell interaction networks from scRNA-seq data. However, droplet- and plate-based scRNA-seq techniques have cell sampling bias that could affect the cell composition of scRNA-seq datasets. Here we developed terminator-assisted solid-phase cDNA amplification and sequencing (TAS-Seq) for scRNA-seq based on a terminator, terminal transferase, and nanowell/bead-based scRNA-seq platform. TAS-Seq showed high tolerance to variations in the terminal transferase reaction, which complicate the handling of existing terminal transferase-based scRNA-seq methods. In murine and human lung samples, TAS-Seq yielded scRNA-seq data that were highly correlated with flow-cytometric data, showing higher gene-detection sensitivity and more robust detection of important cell-cell interactions and expression of growth factors/interleukins in cell subsets than 10X Chromium v2 and Smart-seq2. Expanding TAS-Seq application will improve understanding and atlas construction of lung biology at the single-cell level.

Fractal dimension in CT low attenuation areas is predictive of long-term oxygen therapy initiation in COPD patients: Results from two observational cohort studies.

BACKGROUND: Some chronic obstructive pulmonary disease (COPD) patients develop hypoxemia with disease progression, with some even requiring long-term oxygen therapy (LTOT). Lung function, especially diffusing capacity, and the annual decline in PaO2, are reported to be predictive factors of chronic respiratory failure. However, the association between lung morphometry evaluated using computed tomography (CT) images and LTOT initiation is unknown. METHODS: We retrospectively evaluated the relationship between clinical indices, including pulmonary function, body mass index (BMI), and CT parameters, at baseline and LTOT initiation in two prospective COPD cohorts. In the Nara Medical University cohort (n = 76), the low attenuation area (LAA) and its fractal dimension (fractal D) were adapted as the indices for parenchymal destruction in CT images. The association between these CT measurements and LTOT initiation was replicated in the Kyoto University cohort (n = 130). RESULTS: In the Nara Medical University cohort, lower BMI (hazard ratio [HR]:0.70, p = 0.006), lower % diffusing capacity (%DLCO) (HR: 0.92, p = 0.006), lower %DLCO/VA (HR, 0.90, p = 0.008), higher RV/TLC (HR, 1.26, p = 0.012), higher LAA% (HR: 1.18, p = 0.001), and lower fractal D (HR: 3.27 × 10-8, p < 0.001) were associated with LTOT initiation. Multivariate analysis in the Kyoto University cohort confirmed that lower %DLCO and lower fractal D were independently associated with LTOT initiation, whereas LAA% was not. CONCLUSION: Fractal D, which is the index for morphometric complexity of LAA in CT analysis, is predictive of LTOT initiation in COPD patients.

Linac-based stereotactic radiosurgery and fractionated stereotactic radiotherapy with a micro-multileaf collimator for brain metastasis in the primary motor cortex.

This study aimed to assess the clinical outcomes of linear accelerators (linac)-based, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis in the primary motor cortex (BMPMC). Thirty-five consecutive patients with BMPMC who were treated by linac-based SRS or fSRT between January 2012 and March 2020 were analyzed. BMPMC was defined as a tumor located in the precentral gyrus on gadolinium-enhanced magnetic resonance imaging (MRI) and T2-weghted imaging (T2WI). In total, 35 patients with 37 metastases were analyzed. The median follow-up time was 13 (range: 1-97) months. The tumor volume was 0.05-26.5 (median: 0.62) cm3. All patients were treated with SRS or fSRT using 35 Gy with 7 Gy per fraction daily. The median survival time (MST) was 16.9 months. The pretreatment KPS and RPA class significantly differed in terms of MST on the log-rank tests. Seven symptomatic patients had hemiparesis before SRS or fSRT. All symptomatic patients, except one with facial paresis and one who died within 3 months, experienced improvement at a 3 month follow-up. None of the patients presented with persistent radiation injury at the final follow-up. Two patients presented with grade 3 radiation-related central nervous system necrosis, which was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In BMPMC, SRS and fSRT had good tumor control and did not cause serious complications. Therefore, they are suitable treatment options with an acceptable safety profile.

Duodenal Metastasis of Pulmonary Pleomorphic Carcinoma: A Case Report.

Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung sarcomatoid carcinoma that has a poor prognosis, and no standard therapy has been established. Here, we report the case of a 74-year-old man with PCC who showed rare duodenal metastasis. He was referred to our hospital with a mass shadow in the right lung. The patient was diagnosed with PPC clinical stage II B on the basis of immunohistochemical staining from bronchoscopy, and the tumor proportion score of programmed death-ligand 1 was 80%. He did not want any treatment. A year and a half later, progressive anemia was detected. The primary tumor was stable; however, abdominal computed tomography and esophagogastroduodenoscopy revealed a duodenal tumor with stenosis. He was diagnosed with duodenal metastasis from PPC, and he underwent gastrojejunal bypass surgery to prevent bowel obstruction. After surgery, he received pembrolizumab for chemotherapy. However, owing to the progression of peritoneum dissemination, he died 2 months later due to the onset of melena.

Salvage Surgical Resection after Linac-Based Stereotactic Radiosurgery for Newly Diagnosed Brain Metastasis.

BACKGROUND: This study aimed to assess the clinical outcomes of salvage surgical resection (SSR) after stereotactic radiosurgery and fractionated stereotactic radiotherapy (SRS/fSRT) for newly diagnosed brain metastasis. METHODS: Between November 2009 and May 2020, 318 consecutive patients with 1114 brain metastases were treated with SRS/fSRT for newly diagnosed brain metastasis at our hospital. During this study period, 21 of 318 patients (6.6%) and 21 of 1114 brain metastases (1.9%) went on to receive SSR after SRS/fSRT. Three patients underwent multiple surgical resections. Twenty-one consecutive patients underwent twenty-four SSRs. RESULTS: The median time from initial SRS/fSRT to SSR was 14 months (range: 2-96 months). The median follow-up after SSR was 17 months (range: 2-78 months). The range of tumor volume at initial SRS/fSRT was 0.12-21.46 cm3 (median: 1.02 cm3). Histopathological diagnosis after SSR was recurrence in 15 cases, and radiation necrosis (RN) or cyst formation in 6 cases. The time from SRS/fSRT to SSR was shorter in the recurrence than in the RNs and cyst formation, but these differences did not reach statistical significance (p = 0.067). The median survival time from SSR and from initial SRS/fSRT was 17 and 74 months, respectively. The cases with recurrence had a shorter survival time from initial SRS/fSRT than those without recurrence (p = 0.061). CONCLUSIONS: The patients treated with SRS/fSRT for brain metastasis need long-term follow-up. SSR is a safe and effective treatment for the recurrence, RN, and cyst formation after SRS/fSRT for brain metastasis.

Endovascular therapy for cerebral infarction due to Trousseau syndrome in a patient with non-small cell lung cancer.

We describe a case of Trousseau's syndrome in a patient with lung carcinoma. A 69-year-old man presented with pleural effusion. Further evaluation revealed EGFR mutation-positive non-small cell carcinoma in the upper lobe with extensive lymph node, bone, and brain metastases. Administration of osimertinib, an EGFR tyrosine kinase inhibitor, resulted in partial tumor response, but caused osimertinib-induced pneumonitis 10 weeks later. Prednisolone restrained lung injury progression and was gradually tapered. However, he presented with impaired consciousness and right hemiplegia. Magnetic resonance imaging revealed a left middle cerebral artery M1 segment occlusion. D-dimer level was elevated to 19.5 µg/mL. In the absence of atherosclerotic or cardiogenic thrombi, these findings led to the diagnosis of Trousseau syndrome. Endovascular therapy, but not tissue plasminogen activator, improved his condition with no recurrences. These treatment strategies are crucial to restore function in patients with potentially disabling cerebral infarction due to Trousseau syndrome.

Human Adipose-Derived Mesenchymal Stem Cells Ameliorate Elastase-Induced Emphysema in Mice by Mesenchymal-Epithelial Transition.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a worldwide problem because of its high prevalence and mortality. However, there is no fundamental treatment to ameliorate their pathological change in COPD lung. Recently, adipose-derived mesenchymal stem cells (ADSCs) have attracted attention in the field of regenerative medicine to repair damaged organs. Moreover, their utility in treating respiratory diseases has been reported in some animal models. However, the detailed mechanism by which ADSCs improve chronic respiratory diseases, including COPD, remains to be elucidated. We examined whether human ADSCs (hADSCs) ameliorated elastase-induced emphysema and whether hADSCs differentiated into alveolar epithelial cells in a murine model of COPD. METHODS: Female SCID-beige mice (6 weeks old) were divided into the following four groups according to whether they received an intratracheal injection of phosphate-buffered saline or porcine pancreatic elastase, and whether they received an intravenous injection of saline or hADSCs 3 days after intratracheal injection; Control group, hADSC group, Elastase group, and Elastase-hADSC group. We evaluated the lung function, assessed histological changes, and compared gene expression between hADSCs isolated from the lung of Elastase-hADSC group and naïve hADSCs 28 days after saline or elastase administration. RESULTS: hADSCs improved the pathogenesis of COPD, including the mean linear intercept and forced expiratory volume, in an elastase-induced emphysema model in mice. Furthermore, hADSCs were observed in the lungs of elastase-treated mice at 25 days after administration. These cells expressed genes related to mesenchymal-epithelial transition and surface markers of alveolar epithelial cells, such as TTF-1, ß-catenin, and E-cadherin. CONCLUSION: hADSCs have the potential to improve the pathogenesis of COPD by differentiating into alveolar epithelial cells by mesenchymal-epithelial transition.

Adrenal insufficiency in immunochemotherapy for small-cell lung cancer with ectopic ACTH syndrome.

SUMMARY: Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted. LEARNING POINTS: The immune checkpoint inhibitor atezolizumab has recently been approved for the treatment of small-cell lung cancer (SCLC). Approximately 1-6% of tumour ectopically produce ACTH and cause ectopic ACTH syndrome (EAS) as an endocrine paraneoplastic syndrome. The use of combined chemotherapy and atezolizumab in the ectopic ACTH syndrome secondary to small-cell lung cancer may cause a precipitous fall in circulating ACTH/cortisol, resulting in symptomatic adrenal insufficiency The advances in cancer therapy and treatment for endocrine paraneoplastic syndrome need to be adapted.