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Key Clinical Message Cytomegalovirus superinfection is associated with a poor prognosis in non‐HIV Pneumocystis pneumonia (PCP) and can cause deterioration of PCP not only simultaneously but also after initiating PCP treatment. Cytomegalovirus pneumonia should be considered in cases with deterioration after initiating PCP treatment; multiple nodular lesions are useful findings for the diagnosis.

Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant

Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non-small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy.A total of 142 patients with advanced non-small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel-Haenszel test.The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely associated with the treatment response (P .05), and the difference in PFS for the mutation-positive versus mutation-negative patients was statistically significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P = .029). Previous radiotherapy also had a positive association with the treatment response (P = .012).The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status and previous radiotherapy might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer.

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged ≥70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence interval: 12.1-40.5%) and the disease control rate was 47.4%. The median PFS was 3.7 months and the median OS was 17.3 months. The grade 3 adverse events observed included rash (13%), diarrhea (5%), interstitial pneumonitis (5%), anorexia (3%) and gastrointestinal bleeding (3%). Grade 4 or 5 adverse events were not observed. The median OS did not differ significantly between patients aged

The diversity of fossorial moles in East and Southeast Asia is contained in the 2 species-rich genera Mogera (8 species) and Euroscaptor (8 or more species), and the 3 monospecific genera Scapanulus, Scaptochirus, and Parascaptor. To better understand the evolution and biogeography of these fossorial moles, we conducted molecular phylogenetic analyses using mitochondrial cytochrome-b (Cytb; 1,140 base pairs [bp]) and 12S rRNA (approximately 830 bp) and nuclear recombination activating gene 1 (Rag1; 1,010 bp) gene sequences from 5 species of Euroscaptor ,6o fMogera, and the single species of Scaptochirus. Phylogenetic estimates revealed 5 distinct lineages of East and Southeast Asian fossorial moles: Mogera, Scaptochirus, Euroscaptor mizura, E. parvidens, and E. malayana–E. klossi–E. longirostris. Our results support the monophyly of Mogera but not Euroscaptor, indicating a need for taxonomic revision of the latter genus. We hypothesize that Mogera originated in the central portion of its range and then dispersed to peripheral islands, such as Taiwan and the Japanese Islands. The fragmented distribution of Southeast Asian Euroscaptor presumably arose from habitat competition (invasion) from Mogera species, long-range dispersal, vicariance events, or a combination of these, explaining the high species richness of fossorial moles in this region.

Rationale: Histoplasmosis occurs most commonly in Northern and Central America and Southeast Asia. Increased international travel in Japan has led to a few annual reports of imported histoplasmosis. Healed sites of histoplasmosis lung infection may remain as nodules and are often accompanied by calcification. Previous studies in endemic areas supported the hypothesis that new infection/reinfection, rather than reactivation, is the main etiology of symptomatic histoplasmosis. No previous reports have presented clinical evidence of reactivation. Patient concerns: An 83-year-old Japanese man was hospitalized with general fatigue and high fever. He had been treated with prednisolone at 13 mg/d for 7 years because of an eczematous skin disease. He had a history of travel to Los Angeles, Egypt, and Malaysia 10 to 15 years prior to admission. Five years earlier, computed tomography (CT) identified a solitary calcified nodule in the left lingual lung segment. The nodule size remained unchanged throughout a 5-year observation period. Upon admission, his respiratory condition remained stable while breathing room air. CT revealed small, randomly distributed nodular shadows in the bilateral lungs, in addition to the solitary nodule. Diagnosis: Disseminated histoplasmosis, based on fungal staining and cultures of autopsy specimens. Interventions: The patient's fever continued despite several days of treatment with meropenem, minocycline, and micafungin. Although he refused bone marrow aspiration, isoniazid, rifampicin, ethambutol, and prednisolone were administered for a tentative diagnosis of miliary tuberculosis. Outcomes: His fever persisted, and a laboratory examination indicated severe thrombocytopenia with disseminated intravascular coagulation. He died on day 43 postadmission. During autopsy, the fungal burden was noted to be higher in the calcified nodule than in the disseminated nodules of the lung, suggesting a pathogenesis involving endogenous reactivation of the nodule and subsequent hematogenous and lymphatic spread. Lessons: Physicians should consider histoplasmosis in patients with calcified nodules because the infection may reactivate during long-term corticosteroid therapy.

Cytoskeletal and focal adhesion abnormalities are observed in several types of cancer, including lung cancer. We have previously reported that paxillin (PXN) was mutated, amplified, and overexpressed in a significant number of lung cancer patient samples, that PXN protein was upregulated in more advanced stages of lung cancer compared with lower stages, and that the PXN gene was also amplified in some pre-neoplastic lung lesions. Among the mutations investigated, we previously found that PXN variant A127T in lung cancer cells enhanced cell proliferation and focal adhesion formation and colocalized with the anti-apoptotic protein B Cell Lymphoma 2 (BCL-2), which is known to localize to the mitochondria, among other sites. To further explore the effects of activating mutations of PXN on mitochondrial function, we cloned and expressed wild-type PXN and variants containing the most commonly occurring PXN mutations (P46S, P52L, G105D, A127T, P233L, T255I, D399N, E423K, P487L, and K506R) in a GFP-tagged vector using HEK-293 human embryonic kidney cells. Utilizing live-cell imaging to systematically study the effects of wild-type PXN vs. mutants, we created a model that recapitulates the salient features of the measured dynamics and conclude that compared with wild-type, some mutant clones confer enhanced focal adhesion and lamellipodia formation (A127T, P233L, and P487L) and some confer increased association with BCL-2, Dynamin-related Protein-1 (DRP-1), and Mitofusion-2 (MFN-2) proteins (P233L and D399N). Further, PXN mutants, through their interactions with BCL-2 and DRP-1, could regulate cisplatin drug resistance in human lung cancer cells. The data reported herein suggest that mutant PXN variants play a prominent role in mitochondrial dynamics with direct implications on lung cancer progression and hence, deserve further exploration as therapeutic targets.

Skull morphological characters are used for species and subspecies identification in the manatees, but no comparative study has investigated skull growth. We examined progressive ossification in the cranial sutures of 251 skulls of West Indian manatees, 19 skulls of African manatees and 17 skulls of Amazonian manatees. Degrees of cranial suture fusion were evaluated based on gross observations of skull specimens. Our results suggest that ossification patterns in occipital region sutures follow a fixed sequence in living manatees. In all manatees, the suture between the sphenoid and occipital bones fused first, while the supraoccipital-exoccipital synchondrosis fused last. The ossification sequence observed in manatees was not found in descriptions of other mammals, including the dugong. We concluded that this ossification sequence is a unique, common character of living manatees. We also found two differences in the sequence of occipital region development in two subspecies of the West Indian ma...

A new species of talpine mole from northern Vietnam is described and compared with other species of the genus Euroscaptor. This small mole was assigned to the genus Euroscaptor on the basis of its dental formula, but it also shows unique morphological and karyological characteristics. The new species is externally similar to E. parvidens from southern Vietnam, possessing warty protuberances on the muzzle not seen in other members of this genus. The tail of the new species is much shorter than in E. parvidens and E. malayana, both known to have short tails. The tail is not visible under the fur in the dorsal view, giving it an almost tailless appearance. The skull of the new species is similar to that of E. longirostris, but the palate is characteristically wider. The molars of the upper jaw are of a simple triangular shape, and there is no hypoconulid in the lower molars. The diploid number of the new species was determined to be 2n 5 38, which is a new karyotype for this genus. This mole inhabits the lower elevational areas of northern Vietnam and is partially peripatric with E. longirostris in the type locality. Because of the distribution of another taxon in northern Vietnam, Mogera latouchei, the ecological relationships among 4 species of Vietnamese moles also is discussed.

Summary The musculoskeletal system of the aardvark (Orycteropus afer) tail was morphologically examined in two adult specimens. The tail musculature comprised three muscular groups, viz. a dorsal sacrocaudal system that consisted of the irregularly oriented Musculus sacrocaudalis dorsalis medialis and M. sacrocaudalis dorsalis lateralis, a lateral inter-vertebral connecting system, and a ventral sacrocaudal system characterized by the thick M. sacrocaudalis ventralis lateralis and M. sacrocaudalis ventralis medialis. Both the dorsal and ventral systems possessed large tendon groups that strengthened the tail structure. Computed tomography (CT) examination showed the presence of large but homogeneous cartilaginous inter-vertebral discs, whereas V-shaped bones were situated at the ventral aspect of the caudal vertebrae at the level of the inter-vertebral discs. CT visualization of the tendons and V-shaped bones in various tail positions suggested that these structures contribute to the tunnel digging action by bearing the trunk weight and lending force when the aardvark are displacing the soil by means of the forelimbs.

Purpose Bronchoscopic microsampling (BMS) is a novel and direct method with which to obtain epithelial lining fluid (ELF) from the lungs. Analysis of DNA hypermethylation of tumor suppressor genes (TSGs) is expected to be a sensitive tool for the early detection of lung cancer. It has been reported that the existence of EGFR mutations and EML4-ALK gene rearrangements are related to the sensitivity of corresponding kinase inhibitors. We aimed to evaluate the suitability of ELF as a sample for analyzing molecular changes specific for lung cancer. Patients and methods We collected ELF from 61 lung cancer patients by BMS from the airway close to the peripheral lung nodule and purified the nucleic acids. We performed methylation specific PCR in each ELF as well as matched serum and tumor tissue for TSGs for DNA methylation analysis. We also examined EGFR mutations and EML4-ALK rearrangement. Results The sensitivity for detecting DNA hypermethylation in ELF vs serum was 74.1% vs 18.5%. We found 60.1% of patients had at least one hypermethylation in ELF, while only 27.9% had it in serum. Of note, DNA hypermethylation was detected even in stage I patients (60.0%) and the detection rate was almost the same level in each stage. We also found the sensitivity for detecting EGFR mutation in ELF vs serum was 58.3% vs 8.3%. We detected an EML4-ALK fusion gene using ELF in one patient. Conclusions BMS is an alternative method to detect cancer specific genetic and epigenetic alterations and will be a useful complementary diagnostic tool for lung cancer. Summary Investigation of genetic and epigenetic changes associated with lung cancer has clinical importance for its diagnosis and management. The clinical usefulness of bronchoscopic microsampling (BMS) in lung cancer has not yet been evaluated. This study demonstrates that BMS could be useful for detecting lung cancer specific molecular changes and valuable for early diagnosis and determination of treatment options for lung cancer.

The brachial plexus of the okapi showed the evolutionarily intermediate status between the underived ruminants and the giraffe with elongated neck. Whereas the C6 was the thinnest among the roots of the brachial plexus, the C7, C8 and T1 were much thicker in the okapi. From the data we concluded that the okapi was equipped with the intermediate characteristics of the disappearing C6. Although the nerve of the C6 should be elongated in accordance with the long neck in the Giraffidae, the extraordinary elongation of the C6 may have no advantages in the function of the innervations. In the okapi, therefore, we suggest that the function of the C6 has been mainly replaced with that of C7.

The presacral vertebra of anteaters was examined by three-dimensional CT image analysis of the xenarthrous processes peculiar to the Order Xenarthra. The anteater is equipped with two following articulations in addition to the normal zygapophysial articulation. The dorsal xenarthrous process of the former vertebra articulates to the ventral area of the base of the mammillary process in the later vertebra. The pocket-like structure in the ventral area of the mammillary process receives the dorsal and ventral xenarthrous processes of the former vertebra. The complicated articulations do not obstruct the ability of the giant anteater to flex dorsally and laterally, however aids flexibility and strengthens the caudal thoracic and lumber regions of the animal. The xenarthrous processes and articulations may function as a supporter of the body weight during the bipedal standing posture when the anteater destroys the nests of ants and termites and protects itself from the enemies.

Introduction Epidermal growth factor receptor (EGFR) mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small cell lung cancers (NSCLCs). Currently available methods of EGFR mutation detection rely on direct sequencing. Here, we describe the use of an alternative way to screen EGFR mutations. Methods A total of 109 frozen tumor specimens from NSCLC patients were obtained. For mutational analysis of EGFR exons 18, 19, and 21, reverse transcription-polymerase chain reaction was performed on the cDNA using original primers designed for restriction fragment length polymorphism (RFLP). Results EGFR mutations were detected in 37 patients (34%) by both RFLP and direct sequencing except one case in which it was detected only by RFLP. EGFR mutations were more frequently observed to be significant by multivariate analysis in patients with adenocarcinoma (OR = 5.56), no-smoking history (OR = 4.34), and 65-year-old or younger (OR = 2.64), but not in women (OR = 1.14). Among 37 patients, 18 were treated with gefitinib and 9 responded to the treatment. One patient without any mutation responded. Conclusion RFLP is a useful method for screening EGFR mutations and can also be applied to predicting the sensitivity of NSCLC patients to EGFR-tyrosine kinase inhibitors.

We surveyed the central mountains and southeastern region of Taiwan and collected 11 specimens of a new species of mole, genus Mogera. The specimens were characterized by a small body size, dark fur, a protruding snout, and a long tail; these characteristics are distinct from those of the Taiwanese lowland mole, M. insularis (Swinhoe, 1862). A phylogenetic study of morphological, karyological and molecular characters revealed that Taiwanese moles should be classified as two distinctive species: M. insularis from the northern and western lowlands and the new species from the central mountains and the east and south of Taiwan. The skull of the new species was slender and delicate compared to that of M. insularis. Although the karyotypes of two species were identical, the genetic distance between them was sufficient to justify considering each as a separate species. Here, we present a detailed specific description of the new species and discuss the relationship between this species and M. insularis based on ecological characteristics and geographic distributions.

// Toshiyuki Hirano 1, * , Hiroyuki Yasuda 1 , Tetsuo Tani 1, * , Junko Hamamoto 1 , Ayano Oashi 1 , Kota Ishioka 1 , Daisuke Arai 1 , Shigenari Nukaga 1 , Masayoshi Miyawaki 1 , Ichiro Kawada 1 , Katsuhiko Naoki 2 , Daniel B. Costa 3 , Susumu S. Kobayashi 3 , Tomoko Betsuyaku 1 , Kenzo Soejima 1 1 Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 2 Keio Cancer Center, Keio University, School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 3 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Hiroyuki Yasuda, e-mail: hiroyukiyasuda@a8.keio.jp Kenzo Soejima, e-mail: ksoejima@cpnet.med.keio.ac.jp Keywords: EGFR mutation, EGFR tyrosine kinase inhibitors, EGFR exon 20 insertion mutations, in vitro modeling, lung cancer Received: August 18, 2015 Accepted: October 03, 2015 Published: October 15, 2015 ABSTRACT EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the “therapeutic window” of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1 st (erlotinib), 2 nd (afatinib) and 3 rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR . An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1 st and 2 nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.

Introduction Mycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense 18F-fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN. Case presentation A 36-year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense 18F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium. Conclusion This is the first report of MAC-SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation.

We present the first karyological study on Kloss's mole Euroscaptor klossi from Chiang Rai Province of Thailand. We used differential chromosome staining methods and determined the diploid and fundamental autosomal numbers to be 36 and 54, respectively. Compared with the G- and C-banded karyotypes of the Japanese mountain mole E. mizura, the karyotype of E. klossi involved a reciprocal translocation followed by a pericentric inversion of chromosomes 1 and 16 of the ancestral karyotype of E. mizura. Some minor C-band duplications supplemented the karyological differences between the two species. The karyotype of E. klossi is distinct from that of the Malaysian mole E. micrura malayana examined previously and these species have distinct scenarios in diverging from the ancestral karyotype of the genus Euroscaptor.

The taxonomy of the East Asian moles of genera Euroscaptor, Parascaptor and Scaptochirus, distributing in the Himalayas to China were controversial both in the generic and specific levels. These genera were named as more than ten species since the beginning of the description by Brian Houghton Hodgson in 1841. Several explorers had the expedition to this area and brought the specimens of these moles to European and American Museums and named them. One of the purpose of this paper is to review the historical note on the discoveries of Asian mole species as the compass to situate the taxonomic problem of these moles. As a matter of taxonomic evaluation, the problem of the usage of dental formula as the generic diagnosis is discussed in the reference of the examples of recent taxonomic works. Distribution of these East Asian talpids are scattered in the mountain regions like plot according from the collecting records by museums. Current museum collections are not enough to examine their local and in...

We report the first karyological description of a southeast Asian mole, the Malaysian mole (Euroscaptor micrura malayana). The karyotype of the Malaysian mole includes 36 chromosomes, which consist of 18 biarmed and 16 acrocentric autosomes and the sex pair. The sex chromosomes are a small meta-submetacentric X chromosome and a minute dot-like Y chromosome, although the latter is somewhat larger than that of some talpid allies. Autosomal complements include one pair of NOR-bearing chromosomes. A comparative G-banding analysis with the Japanese congener E. mizura showed that these two species share high G-banding homology, and their differences on two pairs of chromosomes are explained by a single reciprocal translocation. The karyological similarity of these distant geographic species is discussed in a systematic and evolutionary context, based on comparisons to other species distributed between them.

1 Laboratory of Animal Management and Resources, Graduate School of Bio-Agricultural Sciences, Nagoya University, Nagoya, Aichi 464-8601, Japan 2 Experimental Animal Center, Miyazaki Medical College, Miyazaki 889-1692, Japan 3 Wildlife Ecology Laboratory, Forestry and Forest Products Research Institute, Tsukuba, Ibaraki 305-8687, Japan 4 Department of Wildlife and National Parks 43200 Kuala Lumpur, Malaysia

The upper dental formula of the Russian desman Desmana moschata (Linnaeus, 1758) (Insectivora, Talpidae) is considered based on the position of the premaxillary suture (sutura incisiva). From the lateral aspect, this suture extends to the second tooth in the tooth row. From the ventral aspect, the suture connects the common alveolus fossa of the second and third teeth in front of the second tooth on the labial edge and behind it on the lingual edge; consequently, the third tooth in the upper row appears to be derived from the maxilla. Therefore, the upper tooth formula of D. moschata may differ from the traditional fundamental dental formula of eutherian mammals (I3, C1, P4, M3), and consist of two incisors, one canine, five premolars, and three molars (I2, C1, P5, M3). This hypothetical view, however, assumes two changes, a tooth deletion in the incisor row and an addition in the premolar row. The significance of the premaxillary suture and possible pitfalls in using it to define dental formulae are discussed.

Purpose: Third-generation EGFR-tyrosine kinase inhibitors (TKIs) are mutation-specific inhibitors that generally have minimal effects on wild type protein. The mechanisms underlying acquired resistance to third-generation EGFR-TKIs remain relatively uncharacterized. The purpose of this study is to clarify the mechanisms of acquired resistance to third-generation EGFR-TKIs in order to improve the prognosis of lung cancer patients harboring EGFR mutations. Experimental design: We established third-generation EGFR-TKIs resistant cells using a dose-escalation method. The PC9 (EGFR E746-A750del) and H1975 (EGFR L858R+T790M) human NSCLC cell lines were cultured with rociletinib (CO-1686) or osimertinib (AZD9291) for several months. Their resistance to a third-generation EGFR-TKIs was confirmed by the MTS cell proliferation assay. To clarify the heterogeneity of potential resistance mechanisms, those resistant cell lines were subcloned to isolate resistant clones. DNA isolated from the parental and resistant cell clones was then subjected to whole exome sequencing. Copy number alterations and several genetic alterations potentially relevant to EGFR-TKIs sensitivity were detected. Results: We identified Src-AKT pathway contribute to acquired resistance. In addition, we identified that EGFR wild type allele, but not mutation allele, amplification induced acquired resistance. It mirrors the decreased inhibitory pressure for wild type EGFR by mutation-specific EGFR-TKIs. Conclusion: We provide evidence of wild type allele-mediated resistance, a novel concept of acquired resistance, occurring in response to mutation-specific inhibitor therapy in cancer treatment. 1833 /2600characters Citation Format: Keigo Kobayashi, Shigenari Nukaga, Hiroyuki Yasuda, Keita Masuzawa, Jyunko Hamamoto, Ichiro Kawada, Katsuhiko Naoki, Sachiyo Mimaki, Shingo Matsumoto, Koichi Goto, Katsuya Tsuchihara, Tomoko Betsuyaku, Kenzo Soejima. EGFR wild type allele amplification induces acquired resistance to mutation-specific EGFR tyrosine kinase inhibitors in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4111. doi:10.1158/1538-7445.AM2017-4111

e20577 Background: Nivolumab, an immune checkpoint inhibitor, is now approved as standard treatment for pre-treated advanced non-small cell lung cancer (NSCLC) based on the results from mega clinical trials with carefully selected patients. We sought to clarify the real-world efficacy and safety of nivolumab and to identify the clinical factors influencing the efficacy. Methods: This study enrolled 142 patients with pre-treated advanced NSCLC who had been administered nivolumab (3mg/kg, Q2W) from January to July 2016 at Keio University and affiliated hospitals in Japan. We retrospectively evaluated objective responses, adverse events (AEs), and analysed clinical factors associated with the response. Results: The overall response rate and disease control rate were 17% and 62%, respectively. The rate of any grade AEs was 45%, while the rate of grade 3-4 AEs was 13%. Among patient’s clinical factors such as age, gender, ECOG performance status, types of carcinoma, epidermal growth factor receptor ( EGFR)/ anaplastic lymphoma receptor tyrosine kinase (ALK) mutation status, smoking status, number of previous treatment lines, presence of central nervous system (CNS) metastasis and presence of prior radiotherapy, “ EGFR/ALK mutation negative” and “administration of prior radiotherapy” were independently associated with the good response to nivolumab treatment by multivariate logistic regression analysis (OR NA/ p < 0.01, OR 5.4/ p < 0.01, respectively). None of the 19 EGFR/ALK mutation positive patients showed response. Although a significant difference was not recognized between “current, former smokers” and “never smokers” (chi-square test, p = 0.1), a subsequent analysis showed smoking pack years (PY) was significantly higher in responders than in non-responders ( t-test, p = 0.035). Conclusions: The objective responses and the profiles of AEs confirmed in our study were similar to those observed in Checkmate 057/017 trials. We can use nivolumab safely regardless of age or number of treatment lines. EGFR/ALK mutation and presence of prior radiotherapy were key clinical factors statistically associated with the nivolumab efficacy.

A 76-year-old woman, diagnosed 5 years previously with an asymptomatic mediastinal bronchogenic cyst, was referred to our department as the mass had grown slightly larger. Contrast-enhanced computed tomography and magnetic resonance imaging scans revealed an azygous vein aneurysm with a pulmonary arterial thromboembolism. The patient was treated with heparin for 5 days, and anticoagulation therapy with edoxaban was continued for 12 months. The thrombus resolved, and the aneurysm remained unchanged. An azygous vein aneurysm is a very rare condition that causes pulmonary arterial thromboembolism. Although surgical resection is indicated for patients with azygous vein aneurysms with a risk of rupture and pulmonary embolism, we chose anticoagulation therapy because of the patient's advanced age. This case suggests that the azygous vein aneurysm is one of the differential diagnoses for a mediastinal mass and that anticoagulation therapy can be the treatment of choice for pulmonary arterial thromboembolism with an azygous vein aneurysm.

A detailed analysis was done on the karyotypes of four species of mole in the genera Euroscaptor and Mogera using a G-banding technique. All four species examined had a chromosome number of 2n = 36, as reported previously. Euroscaptor mizura and M. wogura from Aichi Prefecture had almost the same chromosome constitution and G-banding patterns. These common karyotypes were considered to be equivalent to the hypothetical ancestral karyotype of Mogera, since two distinct genera derived from an ancestor share G-banding homologies. According to this hypothesis, the karyotype of M. imaizumii might have been derived from the ancestral karyotype through pericentric inversion in one pair of acrocentrics, chromosome 11. Two geographically isolated populations of M. tokudae had different karyotypes: the Echigo population had the same karyotype as M. imaizumii, whereas the Sado population had a derivative karyotype that was able to be explained by pericentric inversions in three pairs of acrocentrics, remain...

Lung cancer is a heterogeneous disease encompassing a wide array of genetic abnormalities. The MET receptor tyrosine kinase is altered in many lung cancers, especially non–small cell lung cancer (NSCLC), and clinical trials of MET inhibitors that are under way are documenting cases of acquired resistance. On the basis of the evidence that the RON tyrosine kinase receptor can also be overexpressed in NSCLC, we evaluated the potent MET/RON dual kinase inhibitor LY2801653 in this setting. LY2801653 was more efficacious than the MET/ALK/RON/ROS inhibitor crizotinib with a distinct pattern of downstream signaling effects. Using the PamGene platform, we found that inhibition of MET and RON was associated with decreased phosphorylation of CBL, PI3K, and STAT3. In classic and orthotopic mouse xenograft models of lung cancer, LY2801653 decreased tumor growth, dramatically inhibiting mitotic events and angiogenesis. Taken together, our results argued that specific targeting of the MET/RON kinases could provide robust inhibition of cell proliferation and tumor outgrowth in multiple in vitro and in vivo models of NSCLC. These findings offer a robust preclinical proof of concept for MET/RON targeting by LY2801653 as a promising small-molecule modality to treat NSCLC. Cancer Res; 74(3); 884–95. ©2013 AACR.

Recently, for about 20 years, museums and art-museums have contributed greatly to the social education in Japan. Especially, we have obtaind great success, in cultural movements in local districts. In recent years, many researches concerning ancient ruins have had remarkable success, and we have got a high reputation for our success in archaeology. We had exhibit many archaeological materials and goods, but we did not have any ideal glass for exhibition cases. Moreover, many art-museums had to be built in the local cities and towns. So we need huge volume of non colored glass and non reflecting glass for the exhibition cases in the museums and art-museums. We succeeded in developing ideal glass for exhibition cases. This glass is now used widely in Japan and worldwide.

症例は55歳の女性. 平成7年5月頃より喀痰, 咳嗽が出現し, 次第に労作時呼吸困難が増強することから近医を受診した. 胸部単純写真で右上・中肺野に広範な浸潤影を指摘され, TBLBにて肺腺癌と診断された. 化学療法は無効であったが, 経過とともに増加する多量の喀痰に対してインドメタシン吸入 (75rng/日) を開始したところ, 数日のうちに著明な喀痰の減少が認められた. 患者は肺癌の進行により死亡したが, これらの薬剤は患者のQOL改善に非常に有効であった.

Details of the karyological relationship between the lesser Japanese shrew-mole Dymecodon pilirostris (2n = 34) and the greater Japanese shrew-mole Urotrichus talpoides (2n = 34) were examined by five differential-staining techniques, namely, G-, C-, NOR-, Q- and CMA-banding. Staining revealed that thirteen autosomal pairs and the sex chromosomes of the two species exhibited strong homology in terms of banding patterns. The remaining three autosomal pairs, nos.13, 14 and 15, exhibited distinct interspecific differences both in banding patterns and in the morphology of the respective chromosomes. These interspecific differences can be explained by the presence or absence of an unusual (G-, C-, NOR- and Q-band-negative, but CMA-band-positive) region of chromatin, by the pericentric inversion inv (14) (p13q31), and by duplication of C-heterochromatin, respectively. It has been suggested that the unusual chromatin found in U. talpoides might contain highly repetitive GC-rich sequences, even though it...

A 62-year-old man was seen at the hospital because of dysphagia. Upper gastrointestinal series and endoscopic examination showed a type 2 lesion at the cardia and a Borrmann type 5 lesion in the stomach. Biopsy specimens demonstrated squamous cell carcinoma and signet ring cell carcinoma, respectively. A collision tumor was strongly suspected. The resected material showed the type 2 lesion measuring 6.0×5.0cm and the Borrmann type 5 lesion measuring 8.5×5.5cm which located close to each other at the cardia. Histologically, the esophageal squamous cell carcinoma and the gastric signet ring cell carcinoma were separated only by a thin fibrous tissue, and there was no histological transition between two lesions. With respect to metastatic sites, only one component from each tumor was seen.

Electronic Devices has been geting more popular in our social life. On the other hand they have to be produced higher and more strict specification. Especially, the higher durability is required for electric communication equipments for satelit, underground and submarin, which have to endure as long as 20 years. In contrast, consumer-use equipments is less than 10 years. This is because the fomer is to be used under severer circumstances than the latter. We have frequently an obstacle to reliablity of heavy-duty electronic components. It is called "Out-break of Metal Whisker." This reaction takes place on the surface of electro-plated components which have been left in the field for several years. These whiskers causes short-circuit damages. In this paper we show the results of analysis on damages caused by metal whiskere and propose prevention measures aganst such damages.

Amorphous carbon is made from organic high polymer by the choise of suitable baking condition and atmospher gasses in the baking oben. In the 500℃ baking, organic high polymer shrink itself, and then it set up shrinkage about 25% in bolume in the 1000℃ baking. Baked organic high polymer in the 200℃ has phisical properties as high polymer, but in the 500℃ baking it has the property of carbon, and then in the 1000℃ up baking it has the phisical property of pure carbon. These properties clarified by the IR spectroanalysis. In the 1000℃ up baking it is gorwing up [002] plane, and shows 0.245 nm layers in the molecular structure. These properties clarified by the X-Ray diffraction analysis. And then, in the 2000℃ baking it shows many 0.245 nm layers in its moleculer structure and it is clarified that it grows up as the tape layer by the high power and high resolution electronic microscopic examinations.

Background: World-wide, esophageal cancer is a growing epidemic and patients frequently present with advanced disease that is surgically inoperable. Hence, chemotherapy is the predominate treatment. Cytotoxic platinum compounds are mostly used, but their efficacy is only moderate. Newer alkylating agents have shown promise in other tumor types, but little is known about their utility in esophageal cancer. Methods: We utilized archived human esophageal cancer samples and esophageal cancer cell lines to evaluate O-6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) hypermethylation status and determined sensitivity to the alkylating drug temozolomide (TMZ). Immunoblot analysis was performed to determine MGMT protein expression in cell lines. To assess and confirm the effect of TMZ treatment in a methylated esophageal cancer cell line in vivo , a mouse flank xenograft tumor model was utilized. Results: Nearly 71% (12/17) of adenocarcinoma and 38% (3/8) of squamous cell carcinoma (SCC) patient samples were MGMT hypermethylated. Out of four adenocarcinoma and nine SCC cell lines tested, one of each histology was hypermethylated. Immunoblot analyses confirmed that hypermethylated cell lines did not express the MGMT protein. In vitro cell viability assays showed the methylated Kyse-140 and FLO cells to be sensitive to TMZ at an IC 50 of 52-420 μM, whereas unmethylated cells Kyse-410 and SKGT-4 did not respond. In an in vivo xenograft tumor model with Kyse-140 cells, which are MGMT hypermethylated, TMZ treatment abrogated tumor growth by more than 60%. Conclusion: MGMT methylation may be an important biomarker in subsets of esophageal cancers and targeting by TMZ may be utilized to successfully treat these patients.

Improved thin-fim composite low pressure type reverse osmosis (RO) menbranes has been developed. The menbranes exhibits high salt and Organic materials rejection and high flux at low operating pressures. Low pressure type menbranes are classified into (1) high rejetion type RO menbranes and (2) loose RO (Nanofiltration) menbranes.We will review the performance and aplications of resent low pressure type RO menbranes. The ultra-low pressure type RO membrane “ES10”, recently developed, exhibits up to 99.5% NaCl rejection, 95% isopropanol rejection and 30 m3/d (8-inch element) when tested at 0.75Mpa (107psi) and 25°C on 500 ppm solution.

A 72-year-old man with refractory anemia with an excess of blasts developed overt leukemia with leukothrombocytosis. Hematological and physical findings closely resembled those of an accelerated or blastic phase of chronic myelocytic leukemia. The cytogenetic anomaly of i(17q) was observed during the course. The present case is suggestive of the diversities of myelodysplastic syndromes (MDS), including relationships between MDS and myeloproliferative disorders (MPD) and acute leukemia.

The effects of Ca2+ and Mg2+ on the molecular motion of the polar head group in phosphatidylserine (PS) bilayers were measured by the time-resolved fluorescence depolarization method probed by 1,2-dihexadecanoyl-sn-glycero-3-phospho-[N-(4-nitrobenzo- 2-oxa-1,3-diazole)]ethanolamine [formula: see text] (NBD-PE). By this method, the rate and width of the molecular motion at the fluorescent moieties in the probe molecules could be evaluated as the wobbling diffusion rate (Dw, s-1) and the half cone angle of the wobbling cone (theta c, degree). The values of Dw and theta c measured for NBD-PE embedded in bovine brain phosphatidylserine bilayers were 3.7 x 10(7) s-1 and 46 degrees in the absence of divalent cations at 25 degrees C. When 3 mM of Ca2+ was added, both Dw and theta c distinctly dropped to 1.7 x 10(7) s-1 and 38 degrees, respectively. By the addition of 3 mM of Mg2+, however, only Dw decreased to 2.7 x 10(7) s-1 and theta c remained unchanged. These results show that both Ca2+ and Mg2+ decrease the rate of motion at the head part in PS molecules, but only Ca2+ narrows the distance between the neighboring head groups. Since Mg2+ does not promote vesicle fusion, it appears that the deformation at the head group region in the bilayer structure induced by Ca2+ is an important step in the membrane fusion process.