Docetaxel Plus Ramucirumab With Primary Prophylactic Pegylated Granulocyte-Colony Stimulating Factor Support for Elderly Patients With Advanced NSCLC: A Multicenter Prospective Single Arm Phase 2 Trial: DRAGON Study (WJOG9416L).

Introduction: Docetaxel plus ramucirumab could be a promising treatment for chemo-naive elderly patients with NSCLC, but high incidence of febrile neutropenia (FN) is a critical concern. We thus adopted a routine primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) to reduce FN and maximize the efficacy of docetaxel plus ramucirumab in elderly patients. Methods: This is a single arm phase 2 trial for chemo-naive elderly patients (aged ≥75 y) with advanced NSCLC. Docetaxel (60 mg/m2, d 1) plus ramucirumab (10 mg/kg, d 1) with PEG-G-CSF (3.6 mg, d 2) was administered every 3 weeks until progression. The primary end point was overall response rate (ORR) (expected ORR: 35%). Results: Between February 2018 and January 2021, 54 patients were enrolled. Median age was 78 (range: 75-86). A total of 21 (38.9%) partial response, 22 (40.7%) stable disease, nine (16.7%) progressive disease, and two (3.7%) not assessable were confirmed, resulting in ORR of 38.9% (90% confidence interval [CI]: 27.7%-51.0%) and disease control rate of 79.6%. Median progression-free survival and overall survival were 5.2 (95% CI: 4.2-6.9) and 12.7 (95% CI: 10.2-18.9) months, respectively. There were one (1.9%) FN, two (3.7%) bleeding grade greater than or equal to 3, and one (1.9%) treatment-related death (pneumonitis). Pneumonitis occurred in five patients (9.3%). Main adverse events grade greater than or equal to 3 were observed: four (7%) thrombocytopenia; three (5.6%) neutropenia; six (11.1%) hyposodium; five (9.3%) infection; five (9.3%) hypertension; four (7.4%) anorexia; and three (5.6%) oral mucositis. Conclusions: Docetaxel plus ramucirumab with PEG-G-CSF revealed efficacy and safety for chemo-naive elderly patients with NSCLC. Primary prophylactic PEG-G-CSF highly prevented FN.

Pre-Existing Interstitial Lung Abnormalities Are Independent Risk Factors for Interstitial Lung Disease during Durvalumab Treatment after Chemoradiotherapy in Patients with Locally Advanced Non-Small-Cell Lung Cancer.

Introduction/Background: Chemoradiotherapy (CRT) followed by durvalumab, an immune checkpoint inhibitor, is the standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a life-threatening toxicity caused by these treatments; however, risk factors for the ILD have not yet been established. Interstitial lung abnormalities (ILAs) are computed tomography (CT) findings which manifest as minor interstitial shadows. We aimed to investigate whether ILAs could be risk factors for grade-two or higher ILD during durvalumab therapy. Patients and Methods: Patients with NSCLC who received durvalumab after CRT from July 2018 to June 2021 were retrospectively enrolled. We obtained patient characteristics, laboratory data, radiotherapeutic parameters, and chest CT findings before durvalumab therapy. Results: A total of 148 patients were enrolled. The prevalence of ILAs before durvalumab treatment was 37.8%. Among 148 patients, 63.5% developed ILD during durvalumab therapy. The proportion of patients with grade-two or higher ILD was 33.8%. The univariate logistic regression analysis revealed that older age, high dose-volume histogram parameters, and the presence of ILAs were significant risk factors for grade-two or higher ILD. The multivariate analysis showed that ILAs were independent risk factors for grade-two or higher ILD (odds ratio, 3.70; 95% confidence interval, 1.69−7.72; p < 0.001). Conclusions: We showed that pre-existing ILAs are risk factors for ILD during durvalumab treatment after CRT. We should pay attention to the development of grade-two or higher ILD during durvalumab treatment in patients with ILAs.

Efficacy of Chemoimmunotherapy in NSCLC Patients With Brain Metastasis With or Without Prior Brain Radiotherapy.

BACKGROUND/AIM: Many patients with advanced lung cancer develop brain metastasis (BM); however, few reports confirming the efficacy of immune checkpoint inhibitors (ICIs) plus chemotherapy in non-small cell lung cancer (NSCLC) patients with symptomatic BM have been published. Therefore, we retrospectively evaluated the effects of chemoimmunotherapy in NSCLC patients who did or did not receive prior brain radiotherapy. PATIENTS AND METHODS: A total of 103 patients with advanced NSCLC who received ICIs plus chemotherapy at our hospital from January 2019 to July 2021 were retrospectively enrolled. RESULTS: Patients with BM tended to have shorter progression-free survival (PFS) and overall survival (OS) compared with patients without BM. The maximum size of BM and the proportion of patients with symptomatic BM were greater among patients who received brain radiotherapy before chemoimmunotherapy. However, patients who received prior brain radiotherapy had better PFS and OS compared with patients who did not receive prior brain radiotherapy. CONCLUSION: Patients who received prior brain radiotherapy experienced a superior therapeutic benefit of ICIs plus chemotherapy, including those with larger and more symptomatic BM.

Coexistence of Emphysema With Non-small-cell Lung Cancer Predicts the Therapeutic Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND/AIM: Chronic obstructive pulmonary disease coexisting with non-small-cell lung cancer (NSCLC) was reported to be associated with a longer progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICIs). In the present study, we investigated the impact of emphysematous change on the treatment response to ICIs in patients with NSCLC. PATIENTS AND METHODS: A total of 153 patients with advanced NSCLC who received ICIs (nivolumab, pembrolizumab, or atezolizumab) at our hospital from January 2016 to May 2019 were retrospectively enrolled. RESULTS: According to the Goddard scoring system, 71 (46.4%) patients were classified as having emphysema and 82 (53.6%) as having no emphysema. Multivariate analysis showed that a good performance status and coexisting emphysema (hazard ratio=0.49; 95% confidence intervaI=0.28-0.84; p=0.010) were independent predictors of a better PFS. CONCLUSION: Recognizing emphysema coexisting with NSCLC may help predict the therapeutic efficacy of ICIs in such patients.

Ambulance use for low-acuity conditions by long-term care facilities for older adults.

PURPOSE: Increased ambulance calls affect the timely transportation of patients. Recently, ambulance uses from long-term care facilities (LTCFs) for older adults has been increasing. The aim of this study was to investigate to what extent LTCFs used ambulances for low-acuity conditions. METHODS: Ambulance records from the fire department of Misato City were used. The participants were patients aged 65 years or older transported from all types of LTCFs (including public nursing homes, geriatric health services facilities, private nursing homes, and group homes) and homes. The proportions of ambulance use for low-acuity conditions and their 95% confidence intervals (CI) were calculated and compared by time (daytime and night-time) and day (weekdays and holidays) of ambulance use for each type of residence. RESULTS: Of 12,494 participants, 1336 (11%) were transported from LTCFs, and 326 (2.6%) for low-acuity conditions. Of 326 patients with low-acuity conditions, 69% were transported from LTCFs. The proportion of low-acuity conditions was 17% among those transported from LTCFs, while it was only 1% among those from homes. The proportion of low-acuity conditions was significantly greater during night-time than daytime among those from public nursing homes, geriatric health services facilities, and group homes, while this proportion was greater on weekdays than holidays among those from geriatric health services facilities. CONCLUSION: This study found a large number of instances of ambulance use for low-acuity conditions by LTCFs. To reduce unnecessary ambulance use for low-acuity conditions efficiently, LTCFs should be assisted in making proper assessments of both patients' conditions and appropriate ambulance use.

Observation of thermoacoustic chaotic oscillations in a looped tube.

This study presents experimental observations of chaotic thermoacoustic oscillations induced in a looped tube with respect to both temporal and spatial dimensions and compares them with those in a resonance tube system. The wave propagation directions observed in thermoacoustic systems showing periodic behaviors are confirmed in the chaotic case, from cold to hot sides in the stack in a looped system, and with reflections at the ends of a resonance tube system. Although both systems are similar in their route to chaos and correlation dimensions of the chaotic attractor, a recurrence visualization method reveals differences in the distribution of temporal patterns resulting from the mode competition between the natural frequencies of the systems.

Clinical utility of fractional exhaled nitric oxide and blood eosinophils counts in the diagnosis of asthma-COPD overlap.

Background: Asthma-COPD overlap (ACO) is difficult to diagnose because it is characterized by persistent airflow limitation, and patients present with several manifestations that are usually associated with both asthma and COPD. In this retrospective study, we aimed to evaluate the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and blood eosinophil counts for the clinical diagnosis of ACO. Patients and methods: A total of 121 patients were divided into two study groups, COPD alone or ACO, which was based on criteria from the joint document by the Global Initiative for Asthma and the Global initiative for chronic Obstructive Lung Disease. From July 2014 to April 2017, FeNO levels and blood eosinophil counts were measured in specimens from patients naïve to inhaled corticosteroids (ICS) and those using ICS. Receiver operating characteristic curve analysis was used to determine the cutoff values of FeNO and blood eosinophil levels that provided the best differential diagnosis between ACO and COPD. Results: Among a total of 121 patients, 65 patients were diagnosed with COPD and 56 patients with ACO. The FeNO level was higher in patients with ACO than in patients with COPD (median 24.5 vs 16.0 ppb, respectively; P<0.01). Among patients naïve to ICS, the area under the receiver operating characteristic curve of FeNO values was 0.726, and the optimal diagnostic cutoff level of FeNO was 25.0 ppb, with 60.6% sensitivity and 87.7% specificity for differentiating ACO from COPD. FeNO (≥25.0 ppb) combined with blood eosinophil counts (≥250/µL) showed 96.1% specificity. Conclusion: These results demonstrate that the FeNO level combined with blood eosinophil count is useful for the differential diagnosis between ACO and COPD.

Bifurcation diagram of coupled thermoacoustic chaotic oscillators.

A thermoacoustic chaotic oscillator is a fluid system that presents thermally induced chaotic oscillations of a gas column. This study experimentally reports a bifurcation diagram when two thermoacoustic chaotic oscillators are dissipatively coupled to each other. The two-parameter bifurcation diagram is constructed by varying the frequency mismatch and the coupling strength. Complete chaos synchronization is observed in the region with a frequency mismatch of less than 1% of the uncoupled oscillator. In other regions, synchronization between quasiperiodic oscillations and that between limit-cycle oscillations and amplitude death are observed as well as asynchronous states.

Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma.

Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.

TAFRO Syndrome with Disseminated Intravascular Coagulation Successfully Treated with Tocilizumab and Recombinant Thrombomodulin.

TAFRO syndrome is a systemic inflammatory disorder that is characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. Although thrombocytopenia is one of the major features of TAFRO syndrome, complications of disseminated intravascular coagulation (DIC) are not common. The therapeutic strategy for TAFRO syndrome complicated by DIC has not been established. We herein describe a case of TAFRO syndrome with DIC that was successfully treated with tocilizumab (an anti-IL-6 receptor antibody) and recombinant thrombomodulin (rTM). This case suggests a possible therapeutic benefit of rTM in patients with TAFRO syndrome complicated by DIC.

On-off intermittency in coupled chaotic thermoacoustic oscillations.

This paper documents on-off intermittency observed in coupled thermoacoustic chaotic oscillations. Mode competition between two or three oscillation modes engenders chaotic oscillations through quasiperiodic oscillations introduced by a local cross-sectional change in a gas-filled tube. Complete synchronization is then obtained by connecting two thermoacoustic chaotic oscillators via a rigid plate with an orifice. From the analysis of pressure fluctuations, theoretical statistical scaling laws related to the laminar phases, spectral density, and amplitude probability distribution are found to be satisfied in the coupled thermoacoustic oscillators, when the thermoacoustic complete synchronization breaks down through an on-off intermittency route with the decreased orifice size.

Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285-94. ©2016 AACR.

Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-ß-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts.

Transforming growth factor-ß (TGF-ß) is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1) also has an established role. TGF-ß is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-ß in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-ß-dependent epithelial-mesenchymal transition (EMT) and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-ß induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-ß-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-ß-induced endogenous production of PAI-1 and TGF-ß in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-ß-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin. We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-ß and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-ß. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-ß could be a promising therapeutic strategy for pulmonary fibrosis.

Involvement of leukotriene B4 in dermatophyte-related itch in mice.

BACKGROUND: Proteinase-activated receptor-2 (PAR2) is involved in dermatophyte-induced scratching and leukotriene B4 (LTB4) release from keratinocytes. We investigated whether PAR2-mediated LTB4 production is involved in dermatophyte-induced scratching. METHODS: Dermatophyte extract was injected intradermally and scratching was observed in mice. LTB4 was determined by enzyme immunoassay. RESULTS: Dermatophyte extract-induced scratching was inhibited by zileuton (5-lipoxygenase inhibitor), ONO-4057 (LTB4 antagonist), FSLLRY-NH2 (PAR2 antagonist), and anti-PAR2 antibody. Dermatophyte extract injection increased the cutaneous content of LTB4, which was inhibited by zileuton and FSLLRY-NH2. CONCLUSION: These results suggest the involvement of LTB4 in dermatophyte-associated itch. LTB4 production might be due to PAR2 stimulation in the skin.

Involvement of serine protease and proteinase-activated receptor 2 in dermatophyte-associated itch in mice.

We investigated the involvement of serine protease and proteinase-activated receptor 2 (PAR(2)) in dermatophyte-induced itch in mice. An intradermal injection of an extract of the dermatophyte Arthroderma vanbreuseghemii (ADV) induced hind-paw scratching, an itch-related behavior. ADV extract-induced scratching was inhibited by the opioid receptor antagonists naloxone and naltrexone, the serine protease inhibitor nafamostat mesylate, and the PAR(2) receptor antagonist FSLLRY-NH(2). ADV extract-induced scratching was not inhibited by the H(1) histamine receptor antagonist terfenadine or by mast cell deficiency. Heat pretreatment of the ADV extract markedly reduced the scratch-inducing and serine protease activities. Proteolytic cleavage within the extracellular N terminus of the PAR(2) receptor exposes a sequence that serves as a tethered ligand for the receptor. The ADV extract as well as tryptase and trypsin cleaved a synthetic N-terminal peptide of the PAR(2) receptor. The present results suggest that serine protease secreted by dermatophytes causes itching through activation of the PAR(2) receptors, which may be a causal mechanism of dernatophytosis itch.

[Case of pulmonary dirofilariasis with cavity formation in a young woman].

A 22-year-old woman was referred to our hospital because of an abnormal shadow in her chest X-ray found on a medical examination. Chest CT showed a 16-mm nodule with cavity formation in the left lung. We did not reach a definitive diagnosis by blood test and bronchoscopy. Because we could not exclude the possibility of a malignancy, lung partial resection was performed by video-assisted thoracoscopic surgery for treatment and diagnosis. We recognized the Dirofilaria immitis by pathological diagnosis and we diagnosed this case as pulmonary dirofilariasis. It seemed to be a valuable case that the patient was young, at 22 years old, and there was, cavity formation, which is comparatively rare in pulmonary dirofilariasis.