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A 69-year-old man with refractory lung adenocarcinoma was treated with gemcitabine and vinorelbine. Dyspnea and hypertension developed after the 17th cycle of chemotherapy. Laboratory findings revealed intravascular hemolysis and renal dysfunction. Thrombotic microangiopathy (TMA) was confirmed by renal biopsy. Antihypertensive and steroid therapies were ineffective. After plasmapheresis, intravascular hemolysis and renal dysfunction gradually improved. However, the disease progressed, and he died 6 months after TMA diagnosis. Autopsy revealed similar pathological findings to those of the renal biopsy. It is important to discontinue gemcitabine at the onset of TMA and consider TMA when using gemcitabine for long periods.

After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain–containing phosphatase 2 (SHP2) in the residual cells of ALK/ROS1/EGFR-altered non–small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo. Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC.

We report the case of a 54-year-old man who was treated with nivolumab for recurrent squamous cell lung cancer. After 7 cycles of nivolumab treatment, the patient presented to our hospital with right eye vision loss. Gadolinium-enhanced magnetic resonance imaging of the brain showed enhancement around the optic nerve sheath. This finding and his symptoms led to the diagnosis of optic perineuritis (OPN). Steroid pulse therapy was administered twice although there was no remarkable improvement in his visual field defect. The relationship between OPN and nivolumab is unclear. However, immune-related adverse events caused by immune checkpoint inhibitors should be considered.

Objectives Pembrolizumab is a standard treatment for non-small cell lung cancer (NSCLC) with high-PD-L1 expression; however, its effect is dismal in patients with poor physical condition. Additionally, the effect of immunotherapy is generally limited in NSCLC harboring driver mutations such asEGFR, ALK, or RET gene aberrations. Results We report the beneficial effect of pembrolizumab in a patient with poor performance status and PD-L1+ lung adenocarcinoma with theCCDC6–RET fusion gene and co-occurring NF1/TP53 mutations, complicated by multiple cancer-associated thrombi and respiratory failure. Conclusions Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.

Objectives Immune checkpoint inhibitors offer longer survival than chemotherapy in several clinical trials for advanced non-small cell lung cancer. In subset analyses of clinical trials, immune checkpoint inhibitors extended survival in patients aged ≥65 years, but the effects in patients aged ≥75 years are controversial. We performed multicenter, collaborative and retrospective analyses of immune checkpoint inhibitor efficacy and safety in non-small cell lung cancer patients aged ≥75 years. Methods We retrospectively studied 434 advanced non-small cell lung cancer patients who received immune checkpoint inhibitors from December 2015 to December 2017, and retrospectively applied the Geriatric (G) 8 screening tool with medical records. Results Of the 434 patients who received immune checkpoint inhibitors, 100 were aged ≥75 years. Five patients with performance status 3 were omitted from the final analysis. Immune checkpoint inhibitors were given as a first-line treatment to 20 patients. The objective response rates, median progression-free survival rates and median survival times were 35.0%, 6.1 months and 10.7 months for first-line treatment, and 20.0%, 2.9 months and 14.7 months for second- or later-line treatments, respectively. The median modified G8 score was 11.0. The median survival time was longer in the high modified G8 (≥12.0) group than in the low modified G8 (≤11.0) group (18.7 vs. 8.7 months; P = 0.02). Likewise, the median survival time was 15.5 months (performance status 0–1) vs. 3.2 months (performance status 2) (P Conclusions In this study, immune checkpoint inhibitors were effective and tolerable for patients aged ≥75 years. The modified G8 screening tool and performance status were associated with the outcome of older non-small cell lung cancer patients treated with immune checkpoint inhibitors.

Newborn screening of inborn errors of metabolism using tandem mass spectrometry has become a public health strategy in many developed countries. Retrospective analyses using stored dried blood specimens have been limited, mainly due to a lack of biochemical information on the long-term stability of acylcarnitines and amino acids in stored specimens. We studied the characteristic profiles of the stability of amino acid, free carnitine, and acyl carnitines in dried blood specimens stored in a refrigerator after newborn screening.Dried blood specimens from 198 healthy newborns, which had been stored in a refrigerator at 5 °C after newborn screening, were prospectively subjected to tandem mass spectrometry analyses after 1, 3, 6 months, 1 and 2 years of storage. We also retrospectively re-analyzed the stored samples from 90 newborns, which had been analyzed and stored at 5 °C for 4 years.We found that proline (Pro) and tyrosine (Tyr) were stable for 2 years, and that alanine (Ala), arginine (Arg), and phenylalanine (Phe) decayed with linear regression. The C0 increased during the time-course of 2 years, whereas most acylcarnitines gradually decayed and some showed a linear correlation. The retrospective analysis of samples stored for 4 years revealed that Ala, Phe, Pro and Tyr were almost stable, leucine (Leu), valine (Val) decayed with linear regression, C0 increased, and C10, C12, C14, C14:1, C16, C18, C18:1 decreased, while maintaining a linear correlation.These data suggested that some metabolic parameters from refrigerator-stored dried blood specimens were applicable for the detection of inborn errors of metabolism.

Variations in offspring production according to feeding strategies or food supply have been recognized in many animals from various ecosystems. Despite an unusual trophic structure based on non-photosynthetic primary production, these relationships remain largely under-studied in chemosynthetic ecosystems. Here, we useRimicarisshrimps from deep-sea hydrothermal vents as a study case to explore relations between reproduction, diets and food supply in these environments. For that, we compared reproductive outputs of three congeneric shrimps differing by their diets. They inhabit vents located under oligotrophic waters of tropical gyres with opposed latitudes, allowing us to also examine the prevalence of phylogenetic vs environmental drivers in their reproductive rhythms. For this we used both our original data and a compilation of published observations on the presence of ovigerous females covering various seasons over the past 35 years. We report distinct egg production trends betweenRimicarisspecies relying solely on chemosymbiosis –R. exoculataandR. kairei– and those relying on mixotrophy –R. chacei– whereR. chaceiproduces broods with higher numbers of smaller eggs. Besides, our data and historical records suggest a reproductive period with substantial proportions of brooding females mostly between January and early April for all examined species whatever the region. Intriguingly, this periodicity does not correspond to seasonal variations in surface production with presence of brooding females during either boreal winter or austral summer. These observations contrast with the long-standing paradigm in deep-sea species for which periodic reproductive patterns have always been attributed to seasonal variations of photosynthetic production sinking from surface. Our results suggest the presence of intrinsic basis for biological rhythms in the deep sea, and bring to light the importance of having year-round observations in order to understand life history of vent animals.

Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm3 and large model, 500 mm3). The results demonstrated that osimertinib significantly inhibited tumor growth in both the conventional and large models; however, maximum tumor regression was attenuated in the large model in which hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-α (TGF-α) expression levels increased. Although the combination of osimertinib and bevacizumab exerted a greater inhibitory effect on tumor growth compared with osimertinib in the conventional model, the effect of this combination therapy was attenuated in the large model. TGF-α attenuated sensitivity to osimertinib in vitro; however, this negative effect was counteracted by the combination of osimertinib and cetuximab, but not osimertinib and bevacizumab. In the large xenograft tumor model, the triple therapy induced the greatest inhibitory effect on tumor growth compared with osimertinib alone and its combination with bevacizumab. Clinical trials of the triple therapy are required for patients with lung cancer with EGFR mutations and HIF-1α/TGF-α.

Increasing research has been conducted about patients’ preferences for their role in treatment decision making. Nowadays, a patient-centred approach, so-called ‘shared decision making,’ emphasises ...

Introduction The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. Methods Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. Results ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs invivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth invitro and invivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. Conclusions High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Anti-programmed cell death 1 (PD-1) antibodies have poor efficacy in epidermal growth factor receptor (EGFR)-mutated lung cancer. We herein report a 72-year-old man with programmed cell death-ligand 1 (PD-L1)-negative lung adenocarcinoma harboring an EGFR mutation that responded to nivolumab for more than 2 years. A pathological examination revealed infiltration of CD8-positive lymphocytes and macrophages expressing CD68, CD206, and PD-L1 into the PD-L1-negative tumor; CD206 expression is a marker of immunosuppressive tumor-associated macrophages (TAMs). The presence of PD-L1-positive TAMs in the tumor environment might be a predictor of a positive response to anti-PD-1 antibodies.

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., We found that VEGFR2 blockade augmented the anti‐tumor effects of molecular targeted agents in oncogene‐driven NSCLC, particularly in EGFR/ALK/ROS1‐driven NSCLC. We also identified 2 mechanisms underlying the synergistic effects of anti‐VEGFR2 therapy with molecular targeted agents. VEGFR2 blockade not only inhibited tumor angiogenesis but also exerted direct antiproliferative effects on cancer cells.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11–18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11–18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11–18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

Women with estrogen deficiency are at the risk of suffering from neurological symptoms such as memory impairment. In the present study, we investigated the effect of garlic, Allium sativum L. (Asparagales: Amaryllidaceae), treated with subcritical water on memory impairment in ovariectomized (OVX) rats. OVX rats were administered garlic powder for 84 d. Hippocampus-dependent spatial memory was assessed using the Morris water maze test. Escape latency of the OVX rats increased compared with that of sham-operated rats. The prolonged escape latency of the OVX rats decreased to the level of that of sham-operated rats upon the administration of garlic powder (0.5% in feed). The weights of the body, uterus, and brain were not affected by the garlic powder administration. These results suggest that garlic powder treated with subcritical water mitigates memory impairment in OVX rats.

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

Aim Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. Methods Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. Results The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. Conclusion The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.

Background Pirfenidone suppresses the decline of forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF). However, IPF progresses in some patients despite treatment. We analyzed patients with meaningful FVC declines during pirfenidone treatment and explored the factors predictive of disease progression after FVC decline. Methods This study was a retrospective, multicenter, observational study conducted by the Okayama Respiratory Disease Study Group. We defined initial decline in %FVC as 5% or greater per 6-month period during pirfenidone treatment. IPF patients who were treated with pirfenidone and experienced an initial decline from December 2008 to September 2017 were enrolled. Results We analyzed 21 patients with IPF. After the initial decline, 4 (19.0%) patients showed improvement in disease, 11 (52.4%) showed stable disease, and 6 (28.6%) showed progressive disease. There was no significant correlation between %FVC reduction on initial decline and subsequent %FVC change (p = 0.475). Deterioration of high-resolution computed tomography (HRCT) findings on initial decline was observed significantly more often in the progressive versus improved/stable disease groups (100% vs 20.0%, p = 0.009). Conclusions We revealed that deterioration of HRCT findings may predict disease progression after the initial decline in %FVC in IPF patients treated with pirfenidone.

We herein report a case of congestive heart failure which developed during osimertinib treatment. A 78-year-old woman presented with mild exertional dyspnea three weeks after starting osimertinib for the treatment of epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer. She was diagnosed with congestive heart failure caused by the osimertinib. In contrast to trastuzumab, a human epidermal growth factor receptor 2 (HER2) monoclonal antibody that often causes cardiac dysfunction, the causal relationship between osimertinib and cardiotoxicity has so far received little attention and thus remains unclear. However, it inhibits HER2 in addition to mutant EGFR, thereby potentially causing cardiotoxicity.

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non‑small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC‑ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54‑81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post‑operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC‑ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC‑ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC‑ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

Pulmonary pleomorphic carcinoma (PPC) is a rare very aggressive subtype of non-small cell lung cancer. We herein report a case of PPC that showed a rapid response to nivolumab. The patient, whose multiple tumors had progressed very aggressively, was treated with nivolumab, an anti-programmed cell death-1 (PD-1) antibody. The tumors dramatically shrank after one cycle of nivolumab. The tumors were positive for programmed cell death ligand 1 (PD-L1). An immunohistochemical analysis revealed numerous PD-1+, CD68+ and CD206+ macrophages. This PD-1 antibody may be a good treatment option, especially in tumors that express PD-L1 and which show PD-1+ macrophage infiltration.

Growing evidence suggests that a broad range of behavioral anomalies in people with autism spectrum disorder (ASD) can be linked with morphological and functional alterations in the brain. However, the neuroanatomical underpinnings of ASD have been investigated using either structural magnetic resonance imaging (MRI) or diffusion tensor imaging (DTI), and the relationships between abnormalities revealed by these two modalities remain unclear. This study applied a multimodal data-fusion method, known as linked independent component analysis (ICA), to a set of structural MRI and DTI data acquired from 46 adult males with ASD and 46 matched controls in order to elucidate associations between different aspects of atypical neuroanatomy of ASD. Linked ICA identified two composite components that showed significant between-group differences, one of which was significantly correlated with age. In the other component, participants with ASD showed decreased gray matter (GM) volumes in multiple regions, including the bilateral fusiform gyri, bilateral orbitofrontal cortices, and bilateral pre- and post-central gyri. These GM changes were linked with a pattern of decreased fractional anisotropy (FA) in several white matter tracts, such as the bilateral inferior longitudinal fasciculi, bilateral inferior fronto-occipital fasciculi, and bilateral corticospinal tracts. Furthermore, unimodal analysis for DTI data revealed significant reductions of FA along with increased mean diffusivity in those tracts for ASD, providing further evidence of disrupted anatomical connectivity. Taken together, our findings suggest that, in ASD, alterations in different aspects of brain morphology may co-occur in specific brain networks, providing a comprehensive view for understanding the neuroanatomy of this disorder., Highlights • Structural alterations of gray (GM) and white matter (WM) in ASD were investigated. • Linked independent component analysis was used for multimodal data analysis. • Alterations of GM and WM in ASD co-occurred in cognitive and affective networks. • Results reveal an integrative view of multiple aspects of structural changes in ASD.

X-linked hypophosphatemic rickets (XLH) is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. Inactivating mutations in the gene encoding phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) have been found to be associated with XLH. Here, we report a 16-year-old female patient affected by hypophosphatemic rickets. We evaluated her serum fibroblast growth factor 23 (FGF23) levels and conducted sequence analysis of the disease-associated genes of FGF23-related hypophosphatemic rickets:PHEX,FGF23, dentin matrix protein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1. She was diagnosed with XLH based on her clinical features and family history. Additionally, we observed elevated FGF23 levels and a novelPHEXexon 9 mutation (c.947G>T; p.Gly316Val) inherited from her father. Although bioinformatics showed that the mutation was neutral, Gly316 is perfectly conserved among humans, mice, and rats, and there were no mutations in other FGF23-related rickets genes, suggesting thatin silicoanalysis is limited in determining mutation pathogenicity. In summary, we present a female patient and her father with XLH harboring a novelPHEXmutation that appears to be causative of disease. Measurement of FGF23 for hypophosphatemic patients is therefore useful for the diagnosis of FGF23-dependent hypophosphatemia.

Individuals with autism spectrum disorders (ASD) often have sensory processing abnormalities. However, limited measures that assess these problems in adults with ASD have been developed till date, particularly in Japan. Robertson and Simmons (2012) developed a self-rating scale to investigate sensory sensitivity: the Glasgow Sensory Questionnaire (GSQ). In the present study, we developed a Japanese version of GSQ and investigated sensory abnormalities in adults with ASD. We compared results of the Japanese version of GSQ in adults between an ASD group ( n = 64) and a control group ( n = 70). In addition, we also administered these individuals with the autism spectrum quotient (AQ), which is a questionnaire for assessing autistic traits. The Japanese version of GSQ scores was significantly higher in the ASD group than that in the control group. The total GSQ score and each sensory subscale showed a positive correlation with AQ in the total study sample. These results indicate that individuals with pronounced autistic traits have more frequent and extreme sensory processing problems compared with that in individuals with less pronounced autistic traits. We also assessed validity of the new test. Cronbach's α of the questionnaire was calculated, and its high value indicates that the Japanese version of GSQ has high reliability.

We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma.

Background: Non-small cell lung cancers (NSCLCs) harboring driver oncogene such as epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement are sensitive to the corresponding molecular targeted tyrosine kinase inhibitors (TKIs). However, acquired resistance inevitably develops, and more effective treatment strategies are needed. Anti-vascular endothelial growth factor (VEGF) antibody bevacizumab significantly prolongs progression free survival when added to first-generation EGFR TKIs in EGFR mutant NSCLC. However, it remains unknown whether anti-VEGF receptor (VEGFR) antibody enhances the efficacy of molecular targeted agents as well. In this study, we investigated combinations with an anti-VEGFR antibody and EGFR or ALK TKIs in preclinical models Materials and Methods: We treated mice bearing subcutaneous tumor cell lines harboring EGFR mutation (PC-9, H3255) or ALK rearrangement (ABC-11, H3122) using combinations of anti-mouse VEGFR antibody DC101 and erlotinib (EGFR TKI) /alectinib (ALK TKI). Neovascularization of the tumors were determined by CD31 immunostaining. To determine the effects of VEGFR antibody on cancer cell itself, we also examined the efficacy of the combinations in vitro. Results: Combination therapy demonstrated significantly better tumor inhibition compared to erlotinib or alectinib alone in all the examined xenograft tumors. CD31 positive blood vessel staining was significantly reduced in the tumors treated with combination therapy. Mutant EGFR transfection in HEK293T cells increased VEGF expression in the cell culture supernatant. Furthermore, MTT assay showed significantly enhanced cell growth inhibition when anti-human VEGFR antibody ramucirumab combined with erlotinib (against PC-9 or H3255 cells) or alectinib (against ABC-11 or H3122 cells) suggesting that anti-VEGFR antibody affects not only on tumor vasculature but cancer cell itself. Consistent with this finding, combination with siVEGFR and erlotinib also inhibited the cell proliferation significantly better than erlotinib alone in PC-9 cells. Conclusion: A significant combination benefit was observed with anti-VEGFR2 antibody and EGFR or ALK TKI both in vivo and in vitro, suggesting anti-VEGFR antibody inhibits not only the blood vessels but may also exert direct anticancer effects. Combination therapy of erlotinib or alectinib and anti-VEGFR2 antibody could be a promising treatment strategy for oncogene addicted NSCLC. Citation Format: Hiromi Watanabe, Eiki Ichihara, Hiroe Kayatani, Hisao Higo, Go Makimoto, Hirohisa Kano, Kazuya Nishii, Naofumi Hara, Kiichiro Ninomiya, Toshio Kubo, Kadoaki Ohashi, Kammei Rai, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura. Significant combination benefit of anti-VEGFR antibody and oncogene-targeted agents in EGFR or ALK mutant NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2131.

Functions of the orbitofrontal cortex include diverse social, cognitive and affective processes, many of which are abnormal in autism spectrum disorders (ASDs). Recently, altered orbitofrontal sulcogyral patterns have been revealed in several psychiatric conditions, such as schizophrenia, indicating a possibility that altered orbitofrontal sulcogyral morphology reflects abnormal neurodevelopment. However, the presence of sulcal alterations in ASD remains unexplored. Using structural magnetic resonance imaging, subtypes of the ‘H-shaped’ sulcus (Type I, II and III, in order of frequency), posterior orbital sulcus (POS) and intermediate orbital sulcus were identified in each hemisphere of adult males with ASD (n = 51) and matched normal controls (n = 55) based on the study by Chiavaras and Petrides. ASD showed a significantly altered distribution of H-shaped sulcal subtypes in both hemispheres, with a significant increase of Type III. A significant alteration in the distribution of sulcal subtypes was also identified in the right hemisphere POS of ASD. Categorical regression analysis revealed that Type I and II expressions predicted a reduced total Autism-Spectrum Quotient score. Furthermore, Type I expression was associated with a reduced ‘attention to detail’ subscale score. The results demonstrate that altered sulcogyral morphology can be a marker for abnormal neurodevelopment leading to the increased risk of developing autism.

An intrahepatic portosystemic venous shunt is a relatively rare abnormality that can cause encephalopathy owing to hyperammonaemia. Two patients with encephalopathy owing to intrahepatic portosystemic venous shunts were treated with transcatheter emboli sation using the AMPLATZER Vascular Plug II. Both patients achieved complete obliteration, which was confirmed on dynamic CT. Their symptoms that had been related to portalsystemic encephalopathy subsequently improved after the intervention. No short-term complications were observed in either patient. We recommend that the AMPLATZER Vascular Plug II be used for embolis ation owing to its superior safety and utility when compared with metallic coils or other liquid embolic materials.

Background The insular cortex comprises multiple functionally differentiated sub-regions, each of which has different patterns of connectivity with other brain regions. Such diverse connectivity patterns are thought to underlie a wide range of insular functions, including cognitive, affective, and sensorimotor processing, many of which are abnormal in autism spectrum disorder (ASD). Although past neuroimaging studies of ASD have shown structural and functional abnormalities in the insula, possible alterations in the sub-regional organization of the insula and the functional characteristics of each sub-region have not been examined in the ASD brain. Methods Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 36 adult males with ASD and 38 matched typically developed (TD) controls. A data-driven clustering analysis was applied to rs-fMRI data of voxels in the left and right insula to automatically group voxels with similar intrinsic connectivity pattern into a cluster. After determining the optimal number of clusters based on information theoretic measures of variation of information and mutual information, functional parcellation patterns in both the left and the right insula were compared between the TD and ASD groups. Furthermore, functional profiles of each sub-region were meta-analytically decoded using Neurosynth and were compared between the groups. Results We observed notable alterations in the anterior sector of the left insula and the middle ventral sub-region of the right insula in the ASD brain. Meta-analytic decoding revealed that whereas the anterior sector of the left insula contained two functionally differentiated sub-regions for cognitive, sensorimotor, and emotional/affective functions in TD brain, only a single functional cluster for cognitive and sensorimotor functions was identified in the anterior sector in the ASD brain. In the right insula, the middle ventral sub-region, which is primarily specialized for sensory- and auditory-related functions, showed a significant volumetric increase in the ASD brain compared with the TD brain. Conclusions The results indicate an altered organization of sub-regions in specific parts of the left and right insula of the ASD brain. The alterations in the left and right insula may constitute neural substrates underlying abnormalities in emotional/affective and sensory functions in ASD. Electronic supplementary material The online version of this article (doi:10.1186/s13229-016-0106-8) contains supplementary material, which is available to authorized users.

In interactive social situations, it is often crucial to be able to take another person's perspective when evaluating one's own or another person's specific trait; individuals with autism spectrum disorder (ASD) critically lack this social skill. To examine how perspective-dependent self- and other-evaluation processes modulate functional connectivity in ASD, we conducted a functional magnetic resonance imaging study in which 26 high-functioning adults with ASD and 24 typically developed (TD) controls were asked to decide whether an adjective describing a personality trait correctly described the participant himself/herself ("self") or the participant's mother ("other") by taking either the first (1P) or third person (3P) perspective. We observed that functional connectivity between the left sensorimotor cortex and the left middle cingulate cortex was enhanced in TD control individuals taking the 3P perspective, this enhancement was significantly reduced in ASD, and the degree of reduction was significantly correlated with the severity of autistic traits. Furthermore, the self-reference effect on functional connectivity between the left inferior frontal cortex and frontopolar cortices was significantly enhanced in TD control individuals taking the 3P perspective, whereas such effect was reversed in ASD. These findings indicate altered effects of perspective on the functional connectivity, which may underlie the deficits in social interaction and communication observed in individuals with ASD.

Objective Although sedation with fentanyl and midazolam during bronchoscopic examination is widely accepted in the USA and Europe, it is not routine practice in Japan. The objective of the present study was to evaluate sedation with fentanyl and midazolam during bronchoscopy. Methods Thirty-seven patients were enrolled prospectively between November 2014 and July 2015 at Okayama University Hospital. Fentanyl (20 μg) was administered to the patients just before the examination, and fentanyl (10 μg) and midazolam (1 mg) were added as needed during the procedure. A questionnaire was administered 2 hours after the examination. In the questionnaire, patient satisfaction was scored using a visual analog scale as follows: great (1 point), good (2 points), normal (3 points), uncomfortable (4 points) and very uncomfortable (5 points). An additional question ('Do you remember the bronchoscopic examination?') was also used. Predefined matters for investigation (e.g. blood pressure, heart rate, oxygen saturation and complications) were recorded. Results The enrolled patients included 13 males and 24 females; the median age was 67 (range: 31-87) years. The patients received a median dose of fentanyl of 45.4 μg (range: 30-100 μg) and midazolam of 2.56 mg (range: 1-10 mg). Twenty-six patients (70.2%) agreed to undergo a second bronchoscopic examination, and the average levels of discomfort and re-examination were 2.02 points for each. Only 37.8% of the patients remembered the bronchoscopic examination. No severe complications were reported. Conclusions Sedation with fentanyl and midazolam during bronchoscopic examination should be recommended for use in Japan.

People with Asperger's syndrome (AS) experience mental comorbidities, and behavioral symptoms that can deepen social isolation and handicaps. We compared the frequency of mental and behavioral symptoms, motor abnormality, and life history between adults with AS and those with no mental disorders but with disturbance of social functions and communication skills (ND) from our outpatient clinic. Participants with AS (n = 99) as compared with ND subjects (n = 63) showed significant higher rate of depressive mood, anxiety, unstable emotion, mood swings, oversensitivity to normal situation obsessive compulsive symptoms, persecutory idea, loss of energy, insomnia carelessness, restlessness, confusion in new environments, episodic agitation, inflexible adherence, egocentric behavior, self harm, circumscribed interest, poor lifestyle habits, non-athleticism, clumsiness, bulling at school, school non-attendance, social withdrawal, and lack of friendships. In AS, emotional instability and confusion in new environments might lead to social isolation. The findings demonstrated that individuals with AS experience greater social isolation and distress, as well as a wider range of mental and behavioral symptoms and disturbances of motor skills as compared to healthy subjects with disturbances of social functions and communication skills. These factors are interrelated and may be used as supplementary methods for differential diagnosis of AS from other conditions.

Little is known about the cognitive profiles of high-functioning Pervasive Developmental Disorders (PDD) in adults based on the Wechsler Intelligence Scale III (WAIS-III). We examined cognitive profiles of adults with no intellectual disability (IQ > 70), and in adults with Asperger's disorder (AS; n = 47), high-functioning autism (HFA; n = 24), and pervasive developmental disorder not otherwise specified (PDDNOS; n = 51) using the WAIS-III. Verbal Intelligence (VIQ)–Performance Intelligence (PIQ) differences were detected between the three groups. Full Intelligence (FIQ) and VIQ scores were significantly higher in AS than in HFA and PDDNOS. Vocabulary, Information, and Comprehension subtest scores in the Verbal Comprehension index were significantly higher in AS than in the other subgroups, while Digit-Symbol Coding and Symbol Search subtest scores in the Processing Speed index were significantly lower in HFA. The findings demonstrated cognitive profiles characteristic of adults with high-functioning PDD.

Dysfunction of the prefrontal cortex has been previously reported in individuals with Asperger's disorder. In the present study, we used multi-channel near-infrared spectroscopy (NIRS) to detect changes in the oxygenated hemoglobin concentration ([oxy-Hb]) during two verbal fluency tasks. The subjects were 20 individuals with Asperger's disorder and 18 age- and IQ-matched healthy controls. The relative [oxy-Hb] in the prefrontal cortex was measured during the category and letter fluency tasks. The mean total [oxy-Hb] during the category fluency task did not differ significantly between the groups; however, during the letter fluency task, the mean [oxy-Hb] in persons with Asperger's disorder was significantly lower than that in controls. These results suggested task-relevant or task-specific prefrontal dysfunction in persons with Asperger's disorder.

e21147Background: Several kinds of immune checkpoint inhibitors (ICIs) have demonstrated longer survival compared with chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the effe...

e21034Background: Immune checkpoint inhibitors (ICIs) offer longer survival than chemotherapy in advanced non-small cell lung cancer (NSCLC). In subset analyses, ICIs extended survival compared to ...

Hyperventilation (HV) is widely used to induce EEG abnormalities and epileptic seizures. However, it is still controversial how long it should be done in routine EEG. We analyzed 1,184 routine EEG data recorded in our institution between October, 2016 and September, 2017. Among them, 970 patients tried to perform HV lasting 4 min, and 949 patients completed it age mean, range. During HV, interictal epileptiform discharges (IED) were induced in 82 patients (9%). Generalized IED were seen in 70 patients, focal IED in eight, bi-temporal slow wave in three, and rhythmic theta activity (focal) in one. IED appeared only after 3-min HV in 11 patients (13%) out of 82. Epileptic seizures were induced by HV in 25 patients (3%). Absence seizures occurred in 23 patients, and focal seizures in two. Two patients (12%) had seizures after 3-min HV. No adverse event occurred during 4-min HV, not only during this study period, but also more than 40 years of our practice. We concluded that 4-min HV is effective and safe for epilepsy patients.

application/pdf, The elongation of poly(A) tails in cytoplasm is essential for oogenesis and early embryogenesis in Xenopus laevis. mGLD-2 is a mouse homologue of Xenopus cytoplasmic poly(A) polymerase xGLD-2. We found an association of mGLD-2 with cytoplasmic polyadenylation components, CPEB and CPSF described in Xenopus oocytes. To clarify the role of mGLD-2 in mouse, we produced an mGLD-2 disrupted mouse line by homologous recombination. In spite of the ubiquitous expression of mGLD-2, the disrupted mice were apparently normal and healthy. Moreover, it was demonstrated that mGLD-2 disruption did not affect the poly(A) tail elongation in oocytes using reporter RNAs. Coincide with these observations, the maturation of the oocytes was normal and the mice were fertile. Thus mGLD-2 is dispensable for full-term development and oogenesis. Our results also indicate that there is another source of cytoplasmic poly(A) polymerase in mouse.

Cytoplasmic polyadenylation of mRNAs is involved in post-transcriptional regulation of genes, including translational activation. In addition to yeast Cid1 and Cid13 and mouse TPAP, GLD-2 has been recently identified as a cytoplasmic poly(A) polymerase in Caenorhabditis elegans and Xenopus oocytes. In this study, we have characterized mouse GLD-2, mGLD-2, in adult tissues, meiotically maturing oocytes, and NIH3T3 cultured cells. mGLD-2 was ubiquitously present in all tissues and cells tested. mGLD-2 was localized in the nucleus as well as in the cytoplasm of somatic, testicular, and cultured cells. Transfection of expression plasmids encoding mGLD-2 and the mutant proteins into NIH3T3 cells revealed that a 17-residue sequence in the N-terminal region of mGLD-2 probably acts as a localization signal required for the transport into the nucleus. Analysis of reverse transcriptase-polymerase chain reaction indicated the presence of mGLD-2 mRNA in the oocytes throughout meiotic maturation. However, 54-kDa mGLD-2 was found in the oocytes only at the metaphases I and II after germinal vesicle breakdown, presumably due to translational control. When mGLD-2 synthesis was artificially inhibited and enhanced by injection of double-stranded and polyadenylated RNAs into the germinal vesicle-stage oocytes, respectively, oocyte maturation was significantly arrested at the metaphase-I stage. These results suggest that mGLD-2 may act in the ooplasm on the progression of metaphase I to metaphase II during oocyte maturation.

Mucopolysaccharidosis II (Hunter syndrome), a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), has variable clinical phenotypes. Total by nearly 400 different mutations have been identified in IDS gene from patients with Hunter syndrome. Herein, we reported a patient who has a novel mutation in IDS gene with a severe clinical phenotype. Genetic analysis of the IDS gene revealed a novel 1-bp deletion in position c.1053T in exon 8 and resulting in a frameshift with a premature stop codon. Enzyme replacement therapy (ERT) using idursulfase (Elaprase®) was conducted to the patient and it improved hepatosplenomegaly, white blood cells and platelets number, and decreased the level of urinary glycosaminoglycan. ERT was proved to be effective at least in part in even an adult patient with severe type of Hunter syndrome.