Comparison of TGSE-BLADE DWI, RESOLVE DWI, and SS-EPI DWI in healthy volunteers and patients after cerebral aneurysm clipping

Diffusion-weighted magnetic resonance imaging is prone to have susceptibility artifacts in an inhomogeneous magnetic field. We compared distortion and artifacts among three diffusion acquisition techniques (single-shot echo-planar imaging [SS-EPI DWI], readout-segmented EPI [RESOLVE DWI], and 2D turbo gradient- and spin-echo diffusion-weighted imaging with non-Cartesian BLADE trajectory [TGSE-BLADE DWI]) in healthy volunteers and in patients with a cerebral aneurysm clip. Seventeen healthy volunteers and 20 patients who had undergone surgical cerebral aneurysm clipping were prospectively enrolled. SS-EPI DWI, RESOLVE DWI, and TGSE-BLADE DWI of the brain were performed using 3 T scanners. Distortion was the least in TGSE-BLADE DWI, and lower in RESOLVE DWI than SS-EPI DWI near air–bone interfaces in healthy volunteers (P < 0.001). Length of clip-induced artifact and distortion near the metal clip were the least in TGSE-BLADE DWI, and lower in RESOLVE DWI than SS-EPI DWI (P < 0.01). Image quality scores for geometric distortion, susceptibility artifacts, and overall image quality in both healthy volunteers and patients were the best in TGSE-BLADE DWI, and better in RESOLVE DWI than SS-EPI DWI (P < 0.001). Among the three DWI sequences, image quality was the best in TGSE-BLADE DWI in terms of distortion and artifacts, in both healthy volunteers and patients with an aneurysm clip

Identification of targetable kinases in idiopathic pulmonary fibrosis

Background Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). Methods Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). Results Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. Conclusions We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF

Success of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer

Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I.

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients

Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease

A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy

Vessel wall MR imaging in neuroradiology

Vessel wall MR imaging (VW-MRI) has been introduced into clinical practice and applied to a variety of diseases, and its usefulness has been reported. High-resolution VW-MRI is essential in the diagnostic workup and provides more information than other routine MR imaging protocols. VW-MRI is useful in assessing lesion location, morphology, and severity. Additional information, such as vessel wall enhancement, which is useful in the differential diagnosis of atherosclerotic disease and vasculitis could be assessed by this special imaging technique. This review describes the VW-MRI technique and its clinical applications in arterial disease, venous disease, vasculitis, and leptomeningeal disease

Rapidly Progressive Multiple Cavity Formation in Necrotizing Pneumonia Caused by Community-acquired Methicillin-resistant Staphylococcus aureus Positive for the Panton-Valentine Leucocidin Gene

A 66-year-old man was transferred to our hospital for pneumonia that was resistant to sulbactam/ampicillin and levofloxacin therapy. Chest computed tomography showed the rapidly progressive formation of multiple cavities. Methicillin-resistant Staphylococcus aureus (MRSA) was isolated, and the patient was diagnosed with necrotizing pneumonia caused by community-acquired MRSA (CA-MRSA). The MRSA strain had type IV staphylococcus cassette chromosome mec and genes encoding Panton-Valentine leucocidin (PVL). CA-MRSA necrotizing pneumonia with the PVL gene is rare; only three cases have been previously reported in Japan. We administered anti-MRSA antibiotics and the patient achieved complete clinical and radiological improvement

Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study

Purpose Immune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC. Methods We analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003). Results A total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p  Conclusion ICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.<br