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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.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.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.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.

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.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.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.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.

Nobuhiro Fujioka,1 Masahiro Kitabatake,2 Noriko Ouji-Sageshima,2 Takahiro Ibaraki,1 Makiko Kumamoto,1 Yukio Fujita,1 Shigeto Hontsu,1 Motoo Yamauchi,1 Masanori Yoshikawa,1 Shigeo Muro,1 Toshihiro Ito2 1Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan; 2Department of Immunology, Nara Medical University, Kashihara, Nara, JapanCorrespondence: Toshihiro ItoDepartment of Immunology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, JapanTel +81-744-22-3051Fax +81-744-29-7503Email toshi-ito@naramed-u.ac.jpPurpose: 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, β-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.Keywords: chronic obstructive pulmonary disease, mesenchymal–epithelial transition, adipose derived mesenchymal stem cell, pulmonary function test

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.

Background: 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 extraction 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. Methods: The new filter (hereafter, soft micropore filter [SMPF]) 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 extraction, 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 extraction 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 extraction 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. Conclusions: 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 sample can be used in clinical settings.

Background The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. Methods We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the ‘TTF of CRZ’ plus the ‘TTF of ALEC’ if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. Results Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P Conclusion The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

The aim of this study was to assess clinical outcomes using linac-based, fractionated, stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for large brain metastasis (LBM) unsuitable for surgical resection. Between January 2009 and October 2018 we treated 21 patients with LBM using linac-based fSRT. LBM was defined as a tumor with ≥30 mm maximal diameter in gadolinium-enhanced magnetic resonance images. LBMs originated from the lung (n = 17, 81%), ovary (n = 2, 9.5%), rectum (n = 1, 4.8%) and esophagus (n = 1, 4.8%). The median pretreatment Karnofsky performance status was 50 (range: 50–80). Recursive partition analysis (RPA) was as follows: Classes 2 and 3 were 7 and 14 patients, respectively. The median follow-up was 5 months (range: 1–86 months). The range of tumor volume was 8.7–26.5 cm3 (median: 17.1 cm3). All patients were basically treated with 35Gy in 5 fractions, except in three cases. The progression-free survival was 3.0 months. The median survival time was 7.0 months. There was no permanent radiation injury in any of the patients. Radiation-caused central nervous system necrosis, according to the Common Terminology Criteria for Adverse Events version 4.0, occurred in one patient (grade 3). One patients received bevacizumab for radiation necrosis. Two patients underwent additional surgical resection due to local progression and cyst formation. For patients with LBM unsuitable for surgical resection, linac-based fSRT is a promising therapeutic alternative.

Purpose: 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. 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%). Results: 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.

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. 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 specific cell subsets that significantly contribute to specific gene expression than widely-used methods.

Background To assess the neuroimaging and clinical outcomes in patients with brainstem metastasis (BSM) treated with linac-based fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator. Methods Between May 2007 and January 2017, 24 patients (15 male and 9 female) with BSM (25 lesions: midbrain, 10; pons, 13; and medulla oblongata, 2) were consecutively treated with linac-based fSRT. BSM originated from the lung (n = 18, 75.0%), colon (n = 3, 12.5%), and breast (n = 3, 12.5%). The median patient age was 67.0 (range: 42–80) years. Recursive partition analysis classified 2 patients as class I, 17 as class II, and 5 as class III. Overall survival was calculated using the Kaplan–Meier method. Results Tumor volume ranged from 0.01 to 7.49 cm3 (median: 0.233 cm3), and patients were treated with a dose of 24–40 Gy in 7–13 fractions. The median OS was 9 months after fSRT (95% confidence interval 4.104–13.896). Large tumor volume, presence of brainstem-related symptoms, poor pretreatment Karnofsky performance status, and recursive partition analysis class III were significantly associated with low overall survival. Tumor volume decreased in 18 metastatic lesions, remained stable in 6, and increased in 1. No patient exhibited permanent radiation injury. Grade 2 nausea and vomiting according to the Common Terminology Criteria for Adverse Events 4.0 occurred in 1 patient who received corticosteroids. Conclusions Linac-based fSRT with a micro-multileaf collimator delivered in the doses of 24–40 Gy in 7–13 fractions is a safe and effective local therapy for patients with BSM.

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.

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. 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.

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

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.

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.

Nintedanib is a multi‐target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82‐year‐old man with non‐small cell lung carcinoma complicated by IPF who was treated with nintedanib. High‐resolution computed tomography (HRCT) showed a subpleural basal‐predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6‐min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non‐small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF., We present a case of an elderly patient with non‐small cell carcinoma with underlying idiopathic pulmonary fibrosis (IPF) who was treated with nintedanib. After seven months, partial remission of the lung cancer was observed without progression of IPF. This report indicates the possibility that nintedanib monotherapy could suppress lung cancer in patients with IPF.

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., Highlights • Systemic anticoagulation for Trousseau syndrome generally has a poor prognosis. • There is no established treatment for cancer-associated cerebral infarction. • We performed endovascular therapy for cerebral infraction due to Trousseau syndrome. • Endovascular therapy was effective for recanalization of the occluded artery. • An NIHSS score of 0 was achieved with no recurrence.

Background Previous clinical trials demonstrated that alectinib (ALEC) produced fewer adverse events compared to crizotinib (CRZ). Data regarding adverse events (AE) in clinical practice, however, is limited. We reviewed ALK-rearranged NSCLC patients treated with crizotinib or alectinib in institutions of the West Japan Oncology Group, and the safety of CRZ and ALEC were evaluated using the real-world data. Methods We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups, the CRZ, or the ALEC group. To evaluate the safety of each ALK-inhibitor, we compared the AEs between the CRZ and the ALEC groups. Results Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There was no significant difference in the frequencies of ILD, renal dysfunction, and digestive dysfunction between the CRZ and the ALEC groups.(p = 0.905, p = 0.7208, p = 0.1735) Meanwhile, liver dysfunction was significantly more frequent in the CRZ group compared to the ALEC group.(50.7% in CRZ group vs. 29.1% in ALEC group, p = 0.0313) In adverse events of grade 3 or more, liver dysfunction remained significantly different in frequency between the two groups.(13.3% in CRZ vs. 3.9% in ALEC, p Conclusions In clinical practice, the patients treated with CRZ exhibited a trend to discontinue CRZ at a higher rate due to AE compared to the ALEC group. The PFS of patients treated with ALEC, even in the patients who experience AE due to CRZ, was more than 2 years. Clinical trial identification UMIN000028605. Legal entity responsible for the study Nobuyuki Yamamoto. Funding Pfizer. Disclosure K. Ito: Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony: Chugai; Honoraria (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Kyorin; Research grant / Funding (institution): Daiichi-Sankyo. T. Yamanaka: Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): Chugai; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Boehringer Ingelheim; Advisory / Consultancy: Giiead Sciences; Advisory / Consultancy: Bayer. D. Fujimoto: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Taiho Pharmaceutical Co; Honoraria (self): Chugai Pharmaceutical Co; Honoraria (self): MSD KK; Honoraria (self): Boehringer Ingelheim Japan Inc; Honoraria (self): Eli Lilly Japan KK,. M. Mori: Honoraria (institution), Speaker Bureau / Expert testimony: Chugai. H. Tanaka: Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Taiho pharmaceuticals; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (institution): Ono pharmaceuticals; Honoraria (self), Research grant / Funding (institution): Chugai pharmaceuticals; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Takeda pharmaceuticals; Research grant / Funding (institution): Merck Serono. S. Teraoka: Honoraria (self): Chugai Pharmaceutical. O. Hataji: Honoraria (self): Chugai; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Boerhringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Daiichi-Sankyo; Honoraria (self), Research grant / Funding (institution): Kyorin; Honoraria (self): Eli Lilly. A. Bessho: Honoraria (self), Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer Japan Inc. A. Kubo: Honoraria (self), Research grant / Funding (self): Boehringer Ingerheim; Honoraria (self), Research grant / Funding (self): Chugai; Honoraria (self), Research grant / Funding (self): Eli Lilly; Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Ono Pharma. K. Nakagawa: Honoraria (self), Advisory / Consultancy: Astellas Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Pfizer Japan; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Company; Honoraria (self): KYORIN Pharmaceutical; Honoraria (self): MEDICUS SHUPPAN,Publishers; Honoraria (self): Thermo Fisher Scientific K.K; Honoraria (self): Nichi-Iko Pharmaceutical ; Honoraria (self): Hisamitsu Pharmaceutical; Research grant / Funding (institution): Eisai Co; Research grant / Funding (institution): PAREXEL International Corp. N. Yamamoto: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Chugai. All other authors have declared no conflicts of interest.

We herein report a rare case of acute bilateral renal and splenic infarctions occurring during chemotherapy for lung cancer. A 60-year-old man presented with acute and intensive upper abdominal and back pain during chemotherapy with cisplatin and etoposide for lung cancer. Contrast-enhanced computed tomography (CT) revealed bilateral renal and splenic infarctions. After the administration of unfractionated heparin his pain was relieved with a clearance of the infarctions in the CT findings and a recovery of renal dysfunction. Enhanced coagulation by lung cancer and arterial ischemia by chemotherapy may therefore contribute to the development of these infarctions.

We evaluated sequential dynamic contrast-enhanced CT (DCE-CT) scans to assess the possibility of early prediction of treatment responses by quantifying the tumor size reduction and the change in tumor enhancement during and after a course of radiotherapy (RT). Thirty-nine patients with non-small-cell lung cancer were treated with RT for initial treatment. DCE-CT scan was performed within one week before the beginning of treatment, after 17 or 18 fractions (34 or 36 Gy), and 1 week and 1 month after the end of RT. The correlation between the relative decrease in tumor diameter and that in the attenuation value was evaluated. Nineteen patients were evaluated in this study. The median tumor size was 39.5 mm at the start of treatment, 30.8 mm at 34-36 Gy, and 16.1 mm 1 month after the end of RT. The relative decrease in tumor diameter at 34-36 Gy well correlated with that 1 month after treatment (r = 0.85, r: Pearson's correlation coefficient, p < 0.001). Relative change in the attenuation value at the rim of the tumor at 34-36 Gy did not significantly correlate with the change in tumor diameter 1 month after the completion of RT, but in the center of the tumor, the change of the attenuation value in the delayed phase correlated with the change in tumor diameter. The decrease of tumor diameter during RT may be predictive of treatment response. The relative change of tumor enhancement in the center of the tumor in the delayed phase correlated with tumor shrinkage 1 month after the completion of RT.

Thymus-derived forkhead box p3+ naturally occurring regulatory T cells (nTreg) are thought to circulate throughout the body to maintain peripheral immunological self-tolerance through interactions with dendritic cells (DCs), resulting in regulation of conventional T cells. However, the chemokine receptors, which are putatively involved in the in vivo migration of nTreg, have not been fully established. Here, we demonstrated that lymph node nTreg preferentially migrated to the paracortical area of lymph nodes after adoptive transfer, where they were observed to make contact frequently with CD8α+ DCs and CD8α− CD11b− DCs. This migration of nTreg to the paracortical areas was impaired severely when cells were prepared from CCR7-deficient mice. However, to some extent, CCR7-independent migration of nTreg in such CCR7-deficient mice was also observed, but this occurred mainly in the medullary high endothelial venules. Taken together, these data provide the evidence that CCR7 mediates nTreg migration to the paracortical areas of lymph nodes under steady-state conditions; however, CCR7-independent migration also takes place in the medulla.

The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-gamma and TNF-alpha were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-beta and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.

A 88-year-old woman, who had lived in a nursing home, was admitted to our hospital because of the suspicion of pulmonary tuberculosis. She had a cough, fever and diarrhea on admission. She suffered from sepsis because Listeria monocytogenes was isolated from only the blood culture twice. We immediately administered imipenem/cilastatin to her on admission. She simultaneously had pulmonary non-tuberculous mycobacterial infection because the chest roentgenogram showed a cavity in the right upper lung field and Mycobacterium intracellulare was isolated from the sputum many times. She was treated with isoniazid, rifampicin and clarithromycin for the pulmonary non-tuberculous mycobacterial infection. Her condition improved soon after the administration of IPM/CS but a low grade fever and cough persisted. L. monocytogenes and M. intracellulare are important pathogens in the elderly because cell-mediated immunity mainly works as host defenses against both organisms.

We encountered 8 adult cases of pulmonary toxocariasis. Five were asymptomatic, 1 had transient chest pain, 1 suffered from arthralgia and migrating skin pain, and 1 had chest discomfort due to pneumothorax. Infection was associated with the consumption of raw liver with paratenic hosts in 5 patients. The cause was suspected to be contact with infected young dogs in 1 case and was undetermined in 2 cases. All 8 cases showed some abnormalities in their laboratory examination results including eosinophilia (500/microl) and elevated IgE (100 IU), and all had positive results in serological examinations for the larval excretory-secretory product of Toxocara canis. In 7 patients, excluding the patient with pneumothorax, chest computed tomography demonstrated multiple small pulmonary lesions, most of which were either nodules with halos, or ground-glass opacities. One patient recovered without medication, while the other 7 were treated with albendazole (ABZ) with good responses. Although the optimal duration of ABZ therapy has not been established, 4 weeks or longer seemed necessary to obtain a complete cure in pulmonary toxocariasis.

Positron emission tomography (PET), especially F-18 fluorodeoxyglucose (FDG)-PET, has been recently used to verify the target volume in radiation treatment planning (RTP) for malignancies. The utility of FDG-PET/CT in defining gross tumor volume (GTV) has been shown in many studies, and the target delineation by a fixed threshold of the maximum standardized uptake value (40-50%) is suggested to be useful in RTP for lung cancer, head and neck cancer, etc. But, the spatial resolution, sensitivity, and specificity of PET are not always enough to define the difference between the GTV and the clinical target volume(CTV). Furthermore, FDG-PET is frequently used in the clinical staging before the treatment, and is also applied to the response evaluation after the treatment. This review focuses on the developing applications of PET in radiation oncology.

CD25+CD4+ regulatory T cells (Treg) play pivotal roles in the host response to tumors. However, their exact location in vivo is largely unknown. The forkhead/winged helix transcription factor, Foxp3, is specifically expressed in naturally occurring Treg (nTreg) and programs their development and function. In this study, we produced a rabbit polyclonal antibody (pAb), which can detect mouse Foxp3 protein in situ. Results using this pAb revealed that Foxp3+CD4+ nTreg cells occur in direct contact with CD11c+ dendritic cells (DCs), and Foxp3-CD4+ and CD8+T lymphocytes in the T cell regions of lymphoid tissues from normal and tumor-bearing mice. The numbers of Foxp3+CD4+ nTreg cells are significantly increased in draining, but not nondraining, lymph nodes (LNs) and spleen (SPL) of tumor-bearing mice. Furthermore, a small number of nTreg could be also found at the tumor site. These observations support the notion that the numbers of Foxp3+CD4+ nTreg are increased by tumors and may contribute to the immunosuppression observed in tumor-bearing hosts at secondary lymphoid organs and also possibly at the tumor site.

We previously reported that B lymphocyte chemoattractant (BLC; CXCL13) was highly and ectopically expressed in aged (NZB × NZW)F1 (BWF1) mice developing lupus nephritis, and that B1 cells were preferentially chemoattracted toward BLC. We demonstrate in this study that B1 cells fail to home to the peritoneal cavity in aged BWF1 mice developing lupus nephritis, and that they are preferentially recruited to the target organs including the kidney, lung, and thymus when injected i.v. In contrast, B1 cells homed to the peritoneal cavity in aged BALB/c mice as effectively as in young mice. Accumulation of B1 cells to the omentum milky spots was also impaired in aged BWF1 mice compared with young mice. CD11bhighF4/80high cells with macrophage morphology were confirmed to be a major cell source for BLC in the peritoneal cavity both in young and aged BWF1 mice. However, the number of BLC-producing peritoneal macrophages was markedly decreased in aged BWF1 mice. These results suggest that the decreased number of BLC-producing peritoneal macrophages together with ectopic high expression of BLC in aged BWF1 mice result in abnormal B1 cell trafficking during the development of murine lupus.

Mycobacterium avium (M. avium) has been described traditionally as an opportunistic organism that causes disseminated disease in the human immunodeficiency virus (HIV)-positive population and that acts as a pulmonary pathogen in patients with underlying lung disease such as chronic obstructive pulmonary disease (COPD) or previously diagnosed tuberculosis. Pulmonary involvement of M. avium may range from asymptomatic colonization of the airway to invasive parenchymal or cavitary disease. However, endobronchial lesions involved in M. avium infection are rare in either immunocompetent or immunosuppressed hosts. We report here endobronchial mycobacterial infection in a HIV-negative patient.