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We synthesized N-trans-cinnamyl-N-cyclohexylaniline type aminophosphine 2 and a series of N-2-adamantyl-N-trans-cinnamylaniline type aminophosphines 3. Although aminophosphine 2 failed to find the existence of axial chirality, aminophosphines 3, which exist in the axial chirality in a C(aryl)-N(amine) bond by chiral HPLC analysis as 1-adamantyl type chiral ligands 1. Enantiomeric isomers of 3b, 3c, and 3d were obtained in an enantiomerically pure form. We also identified the palladium-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate with indoles using aminophosphines 3b-d as effective chiral ligands in high enantioselectivities (up to 96% ee).

We synthesized a series of phosphine–olefin-type chiral aminophosphines, and we confirmed that these each exists as two rotamers at the C(aryl)–N(amine) bond. We also investigated the ability of these aminophosphines to act as chiral ligands for Pd-catalyzed asymmetric allylic substitution reactions, such as the alkylation of allylic acetates with malonates or indoles, and we found they gave high enantio­selectivities (up to 98% ee).

A63 -year-old man complaining of anal pain visited our hospital. Three years 6 months previously, the patient underwent endoscopic submucosal dissection(ESD)for early-stage rectal cancer. Based on the pathological findings, adenocarcinoma with invasion to the submucosal layer(2,000 mm)and lymphovascular invasion were diagnosed. Abdominal computed tomography( CT)revealed a solid tumor 50mm in diameter and hematoma measuring approximately 90mm in length adjoining the tumor in the mesorectum. We performed exploratory laparoscopy. Ahematoma was confirmed in the mesentery from the sigmoid colon and rectum. After the surgery, endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)revealed well-differentiated adenocarcinoma. We diagnosed a hematoma associated with mesenteric recurrence following ESD for rectal cancer. The patient received chemotherapy first because of the large size of the recurrent cancer. Four courses of mFOLFOX6(5-FU: bolus 400mg/m / / / 2,2,400mg/m2,oxaliplatin 85 mg/m2) and panitumumab(6 mg/kg)were administered. Based on the CT findings following chemotherapy, the hematoma had disappeared, and the size of the recurrent cancer in the mesorectum reduced to 28 mm. The patient underwent laparoscopic lower anterior resection with D3 lymph node dissection and ileostomy. The postoperative course was uneventful. Currently, the patient has no recurrence.

A 55-year-old man was admitted to our hospital for jaundice. Magnetic resonance cholangiopancreatography showed a mass in the pancreatic head as well as biliary obstruction. We strongly suspected invasive ductal carcinoma of the pancreas. We performed pancreaticoduodenectomy with partial resection of the portal vein. The histopathological diagnosis was small cell carcinoma of the pancreas. We detected metastasis of the right hilar lymph node in PET-CT scan performed 2 months after the surgery and started chemotherapy with cisplatin(CDDP)plus irinotecan(CPT-11). However, we observed recurrent metastasis of the right hilar lymph node 12 months after the surgery. We started second-line chemotherapy with amrubicin( AMR)and radiotherapy. Unfortunately, the patient died from multiple metastases of the left adrenal gland and brain 26 months after the surgery. The prognosis of small cell carcinoma of the pancreas is extremely poor. Multimodal treatment such as chemotherapy, radiotherapy, and curative operation are required for long-term survival.

Two boron complexes of 1-(o-hydroxyphenyl)imidazo[1,5-a]pyridine, which were named as BOHPIP, have been synthesized. These complexes exhibited blue emission in solution with high quantum yields (ΦFL = up to 0.71). In addition, 1-(o-hydroxyphenyl)imidazo[1,5-a]pyridine-BPh2 complex showed the strong blue emission even in the solid state (ΦFL = 0.58).

Asymmetric Diels-Alder reaction was achieved under achiral conditions. Reaction of prochiral 2-methylfuran and N-phenylmaleimide in heptane or hexane solution at 80 °C efficiently gave a conglomerate crystal of exo-type Diels-Alder adduct selectively, and continuous suspension of the reaction mixture with glass beads promoted attrition-enhanced deracemization, leading to an optically active exo-adduct in 90% ee.

We have synthesized a cyan fluorescent benzothiazole-pyridinium salt composite based on D-π-A architecture. This salt was found to work as not only a two- and three-photon excitable fluorophore but also a degradation agent against amyloid fibrils under LED irradiation conditions.

The catalytic asymmetric umpolung reaction of ketimines is of great importance, because it can easily provide chiral amines bearing a tetrasubstituted carbon atom on its asymmetric center. Because amino acids with a tetrasubstituted carbon center are useful due to their wide applicability as pharmaceuticals and chiral building blocks, their enantioselective synthesis has great significance in organic synthesis. Herein, we demonstrate a metal-free novel phase-transfer-catalyzed highly regio- and enantioselective umpolung Michael reaction of α-imino esters, which provides amino acid derivatives in high yields with up to 98 % ee. The products are successfully converted into chiral amino acid derivative and δ-lactone with high enantiopurity.

We found that a Suzuki-Miyaura-type reaction of dibromoalkenes with arylboronic acids using a hydrazone-Cu catalyst system proceeded smoothly under mild conditions to afford the corresponding internal alkyne derivatives in good yields. Furthermore, we succeeded in synthesis of o-allyloxyethynylbenzene derivatives, which are known as effective precursors of various heterocyclic compounds, via this reaction.

We have found that Suzuki–Miyaura-type reactions of o-allyloxy(bromoethynyl)benzenes with arylboronic acids using a hydrazone/Cu catalyst system proceeded smoothly in iPrOH under mild conditions to afford the corresponding o-allyloxy(arylethynyl)benzene derivatives in good yields without decomposition of the allyloxy group. We have further demonstrated that annulation and enyne metathesis of the o-allyloxy(arylethynyl)benzene derivatives using transition-metal catalysts led to various heterocyclic compounds.

The mechanisms underlying anaplastic lymphoma kinase (ALK) resistance have not been well investigated in clinical practice. We herein report the case of a lung cancer patient with carcinomatous meningitis who had an ALK I1171T resistance mutation revealed by direct DNA sequencing of the cerebrospinal fluid after treatment with cytotoxic chemotherapy, crizotinib, and alectinib. I1171T is considered to be sensitive to ceritinib. Although ceritinib was not effective initially, we chose ceritinib again after whole-brain radiotherapy and ventriculoperitoneal shunting. Although the response duration was short, spinal magnetic resonance imaging revealed a marked response. The identification of an acquired ALK resistance mutation will aid in choosing the optimum sequence therapy.

The present status of staging classifications of colorectal liver metastases (CRLM) is summarized. Among prognostic factors published for CRLM undergoing liver resection, the most important variables were maximum size and number of CRLM, primary regional lymph node metastasis, and preoperative carcinoembryonic antigen level. In 2017, the eighth TNM cancer staging system of the Union for International Cancer Control and the American Joint Committee on Cancer introduced a new subdivision of M1 classification of colorectal carcinomas: liver-only CRLM, metastasis to multiple sites or organs including CRLM without peritoneal metastasis, and CRLM with peritoneal metastasis were classified into M1a, M1b, and M1c, respectively. Several classification systems and validation studies were introduced after the beginning of modern chemotherapy. Tumor Burden Score (TBS) utilized a continuum of tumor size and number, indicating continuous prognostic stratification. Overall survival was well separated by zones 1–3. The Memorial Sloan-Kettering Cancer Center-Clinical Risk Score (MSKCC-CRS) provided a statistically significant stratification of patients with regard to overall and recurrence-free survival; however, modified MSKCC-CRS, including predictive markers of disease-free interval, number of CRLM, and CEA level with RAS mutation status outperformed the traditional one. The Iwatsuki score and the Nagashima score also had partial predictive value and was particularly evident for patients in high-risk groups. (K)-RAS and BRAF mutations were also prognostic biomarkers of CRLM. The Beppu nomogram for CRLM undergoing upfront hepatectomy and the Imai nomogram for CRLM after conversion therapy was introduced. Surprisingly, node-positive primary, large number of CRLM at hepatectomy, high CA 19−9 level at hepatectomy, and extrahepatic metastasis were common prognostic factors. With progress in systemic chemotherapy and surgical techniques for liver resection, the appropriate staging classification for CRLM has been changing. A staging classification system is required limited to CRLM patients fit for the era of multidisciplinary treatment.

Chiral functionalized aminals are important core structures of natural products and pharmaceuticals. Their chemo- and regioselective catalytic, asymmetric synthesis has been realized through the umpolung reaction of α-imino amides using a catalyst we originally developed. Functionalized aminals were prepared with high chemoselectivity by treating a hemiaminal intermediate with pyridine in butanol. Evaluation of substrate scope revealed that this transformation could be achieved with a wide range of α-imino amides to produce the desired products in high yields with up to 97 % ee. A mechanistic study suggested that aminal formation proceeded through the ring opening/ring closing equilibrium of the hemiaminal skeleton.

Dynamic enantioselective crystallization enabled the chiral symmetry breaking of two spiropyrans and one spirooxazine. The three spiro compounds afforded racemic conglomerate crystals, and easily racemized in alcoholic solution without irradiation. Optically pure enantiomorphic crystals were obtained by vapor-diffusion crystallization or attrition-enhanced deracemization (Viedma ripening). Their absolute configurations were determined by single-crystal X-ray analysis and each enantiomorphic crystal was correlated with its solid-state circular dichroism (CD) spectrum.

Great effort has been paid to decrease blood loss during hepatectomy. Excessive blood loss and/or allogeneic blood transfusion can cause an increased risk of perioperative morbidity and mortality and may lead to a greater risk of early tumor recurrence (1-4). Hepatic steatosis or steatohepatitis is present in 30–50% of patients in the Western countries and can increase blood loss and morbidity in patients undergoing hepatectomy for colorectal liver metastases (5-7). Steatotic livers are hypertrophic and delicate and are therefore more difficult to mobilize or transect compared to nonsteatotic livers.

Gastric cancer with portal vein tumor thrombosis (GC-PVTT) is a rare condition with a very poor prognosis. A 64-year-old man with GC-PVTT was admitted to our hospital. His carcinoembryonic antigen level was slightly elevated (17.4 ng/ml). Upper gastrointestinal endoscopy showed a type-2 gastric lesion (45 mm × 40 mm) in the gastric antrum. The PVTT originated from the main gastric tumor and continued to the superior mesenteric vein. Fluorodeoxyglucose-positron emission tomography showed high uptake both by the main tumor and PVTT. A distal gastrectomy with D2 lymphadenectomy was performed with simultaneous removal of the PVTT. Pathological examination showed a poorly differentiated adenocarcinoma with neuroendocrine differentiation. Adjuvant chemotherapy with S-1 was administered for 1 year. The patient survived for >5 years with no recurrence. Surgical gastrectomy and complete removal of the PVTT followed by S-1 chemotherapy could be a treatment option that offers improved long-term survival for patients with GC-PVTT.

It is not uncommon for patients with lung cancer to receive supportive care alone. However, the clinical characteristics of these patients have not been fully studied. We conducted a retrospective study to identify the clinical characteristics of definitive lung cancer patients treated with supportive care alone. We retrospectively analyzed the percentage of and reasons for definitive lung cancer patients treated with supportive care alone at a regional cancer center. We also investigated the histological diagnostic approaches, palliative therapy types, primary treatment locations after hospital consultation, and places of death. A total of 1,223 patients were histologically diagnosed as having lung cancer between 2011 and 2014. Of these, 160 (13%) patients were treated with supportive care alone. The primary reason for treatment with supportive care alone was a poor performance status (PS) in almost half of the patients. Overall, 40% of the patients received supportive care at home, and 17% were admitted to a palliative care unit (PCU). Death occurred at home for 17% of the patients and in the PCU for 42% of the patients. This study revealed that 13% of histologically proven lung cancer patients were treated with supportive care alone, mostly because of a poor PS. Only 40% of these patients received home care, suggesting the need for a more accessible home care system for patients and their families.

Irradiation of prochiral (E)-aroylacrylamide with sunlight gave single-handed pyrrolinone quantitatively and with an enantiomeric excess (ee) of over 99 % under absolutely achiral conditions. The phenomenon was explained by photoisomerization and reversible cyclization followed by dynamic crystallization involving deracemization.

Amino acid-derived novel chiral hypervalent iodine(V) reagents were synthesized from the corresponding chiral iodoarenes through DMDO oxidations. Their oxidation states were determined by the 13 C NMR chemical shifts of the ipso -carbon of the iodine atom, HRMS analysis, and elemental analyses. They were applied to the enantioselective hydroxylative dearomatization/[4+2]-dimerization cascade reactions of phenol derivatives to afford the desired products with up to 58% ee.

Single-handed alpha-amino acid derivatives were generated from achiral precursors without an external chiral source. Conjugate addition of phenethylamine to an achiral aroylacrylamide under homogeneous conditions gave the alpha-amino amides in quantitative yields, which crystallized as a conglomerate of a P21 crystal system. Dynamic preferential crystallization or attrition-enhanced deracemization resulted in the formation of enantiomorphic crystals of 99% ee.

Hydroxychloroquine (HCQ) is an effective treatment for patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) and has been used for these patients in more than 70 nations. However, in Japan, HCQ has not been approved for CLE or SLE. To establish an appropriate therapeutic regimen and to clarify the pharmacokinetics (PK) of HCQ in Japanese patients with CLE with or without SLE (CLE/SLE), a population pharmacokinetic (PopPK) analysis was performed.In a clinical study of Japanese patients with a diagnosis of CLE irrespective of the presence of SLE, blood and plasma drug concentration-time data receiving multiple oral doses of HCQ sulfate (200-400 mg daily) were analyzed using nonlinear mixed-effects model software. The blood and plasma concentrations of HCQ were analyzed using a high-performance liquid chromatography tandem mass spectrometry method. Model evaluation and validation were performed using goodness-of-fit (GOF) plots, visual predictive check, and a bootstrap.The PopPKs of HCQ in the blood and plasma of 90 Japanese patients with CLE/SLE were well described by a 1-compartment model with first-order absorption and absorption lag time. Body weight was a significant (P0.001) covariate of oral clearance of HCQ. The final model was assessed using GOF plots, a bootstrap, and visual predictive check, and this model was appropriate. Simulations based on the final model suggested that the recommended daily doses of HCQ sulfate (200-400 mg) based on the ideal body weight in Japanese patients with CLE/SLE were in the similar concentration ranges.The PopPK models derived from both blood and plasma HCQ concentrations of Japanese patients with CLE/SLE were developed and validated. Based on this study, the dosage regimens of HCQ sulfate for Japanese patients with CLE/SLE should be calculated using the individual ideal body weight.

C2-Symmetric cyclic polyethers were conveniently provided by the photochemical dimerization of covalently-linked 2-chromonecarboxylic esters. Irradiation of polyethers possessing 2-chromonecarboxylate groups at both ends efficiently promoted intramolecular [2+2] cyclobutane formation leading to 14- to 23-membered cyclic polyethers in good chemical yields and quantum efficiencies. X-ray crystallographic analysis revealed that the stereochemistry of the cyclobutane was the C2-symmetric structure.

We have demonstrated the Mizoroki–Heck reaction of aryl iodides with aryl allyl ethers using 1.5 mol% of imidazo[1, 5-a]pyridine–Pd catalytic system. Aryl cinnamyl ethers were obtained in moderate-to-high yield under mild reaction conditions.

A series of novel polychlorinated compounds were synthesized with using o-chloranil (1) as a source substrate and the detailed structures of the products were elucidated by X-ray analysis. Chemoselective formations of several polychlorinated compounds were achieved by choosing reaction condition, particularly, a kind of mixed solvent. In a mixed solvent of 1,4-dioxane and H2O, three component coupling reaction of 1 gave nonachloro compound, 2-Cl9, through two kinds of oxidative reactions. In the case of a mixed solvent of MeOH and H2O, another coupling reaction of 1 along with addition of the solvent, MeOH, proceeded to afford hexachloro compound, 3-Cl6. The MeO group of 3-Cl6 could be eliminated by heating at 80 °C in a solution of H2O/1,4-dioxane to eventually give a hexachloro dibenzodioxindiol, 4-Cl6OH2.

Crystallization-induced diastereomer transformation of valuable thiohydantoin derivatives was developed for the first time. Three thiohydantoins synthesized from three (R)-N-phenethylthioureas and benzoylformyl chloride were obtained as diasteromeric mixtures. These thiohydantoins have aminal carbons at the chiral center which could be epimerized via ring-opening and –closing reactions under suitable conditions. The suspension of the diastereomixture of thiohydantoins in a small amount of solvent selectively converged to crystals composed of a single diastereomer in a quantitative fashion. Stereoselective switching of diastereoselectivity by CIDT of one thiohydantoin was achieved with a suitable solvent.

The management of grade 1 checkpoint inhibitor pneumonitis (CIP) is to withhold immune checkpoint inhibitors; however, the natural history of this condition is unknown. We herein report the case of a woman with squamous cell lung cancer who was a long-term survivor after CIP. After 4 rounds of treatment with nivolumab, a chest CT revealed a reticular pattern and ground-glass attenuation with shrinkage of the primary nodule. Nivolumab treatment was withheld without the administration of steroids. Although she remained asymptomatic, subsequent images revealed an increasing interstitial shadow until 2 months after the stop of nivolumab treatment. Thereafter, the interstitial shadow began to improve spontaneously without steroid treatment. Moreover, although the patient has not received additional therapy, disease control of lung cancer has been obtained within a follow-up period of more than 3 years. Although the exacerbation of CIP may appear on images for several months, asymptomatic cases can be followed without the administration of steroids. If the tumor had already responded prior to the onset of CIP, a favorable long-term prognosis can be expected.

We have designed and synthesized an iridium(III) complex of pincer type imidazo[1,5-a]pyridine ligand. The complex has a broad absorption band and shows the yellow emission in solution. When the complex was used as a photocatalyst in the visible-light-induced oxidative coupling reaction of benzylic amines, the corresponding imines were obtained in quantitative yields.

BACKGROUND: Despite the favorable response, most brain metastases (MBs) acquire resistance to TKIs. T790M is the most common mechanism and accounts for approximately half of acquired resistance to TKIs. The aim of this study is to clarify the role of T790M in the acquired resistance of BMs, and optimal treatment for BMs progressed after TKI. METHOD: Upfront TKI was performed for BMs from EGFR-mutated NSCLC, and TKI was changed at progression. Gefitinib, erlotinib, afatinib and osimertinib were used and the selection of these TKIs were owing to the physicians’ decision. During the disease course, re-biopsies of progressed diseases were performed to verify mutations of EGFR, and the incidences of T790M were compared among the organs biopsied. The time to CNS-progression (TCP) were evaluated for each TKI. RESULTS: 141 cases were enrolled. Gefitinib was used only as the first line TKI (n=91). Erlotinib was selected for both the gefitinib-naïve patients (n=27) and after gefitinib (n=51). Afatinib (n=21) and osimertinib (n=17) were selected for only recurrent cases. TCPs after gefitnib, erlotinib, afatinib, and osimertinib were 13.4, 20.1, 19.9, and 13.8months, respectively. The history of treatment with gefitinib did not affect the TCP after erlotinib (HR:1.37, 95%CI:0.61–3.25, P=0.451). Re-evaluations of EGFR was performed using 107 samples (lung:51, serum:25, CNS:22, others:9) from 88 cases. The incidence of T790M from CNS samples was 9.1% (Tumor:1/6, CSF:1/16), and was significantly lower than that from the other organs (lung:50.1%, surum:28.0%, others:44.4%) (Odds ratio:0.130, P=0.001). The extremely low incidence of T790M and satisfied effects of TKIs even after TKI-failure suggested the different mechanism of acquired resistance of BMs to TKIs in compared with the extracranial lesions. CONCLUSIONS: T790M played only a limited role in acquired resistance of BMs to TKIs, and alterations of the types of TKIs were still recommended for the progressed BMs after TKI.

A novel regioselective cyclization reaction of N-cinnamoylthioureas leading to six- or five-membered heterocyclic compounds was developed. N-Cinnamoylthioureas in the presence of trifluoroacetic acid (TFA) underwent the well-established intramolecular cycloaddition reaction to give 2-imino-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-ones in good yields. On the other hand, the reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proceeded in an unprecedented "umpolung" cyclization fashion to afford five-membered 2-imino-1,3-thiazolidin-4-ones and/or 2-thioxoimidazolidine-4-ones. The reaction was considered to occur via a cycloadduct of DBU with the cinnamoyl moiety followed by intramolecular attack of the thiourea group.

We designed and synthesized a series of N,N-disubstituted allylic amine type aminophosphines 2, 3 and 4, which are derivatives of chiral ligands 1. Aminophosphines 2-4 (except 2a) exist in C(aryl)-N(amine) bond axial chirality by chiral HPLC analysis. Both enantiomeric isomers of 4b were successfully obtained in an enantiomerically pure form. We demonstrated that 1a, 1b, and 4b can be used as effective chiral ligands for the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with malonates in high enantioselectivities (up to 90% ee).

A 70-year-old man with a growing liver tumor had undergone subtotal gastrectomy with pancreaticoduodenectomy for gastric cancer (T4b P0 H0 N1, Stage IIIB) 30 months before admission to our hospital. Enhanced computed tomography revealed two hypervascular nodules in segments 4 and 8. After histological diagnosis of small liver metastases from gastric cancer in segment 8, the patient underwent open microwave coagulation therapy (MCT) for the tumor (diameter: 30 mm) in segment 4. MCT was performed by using 1.5-cm and 3-cm monopolar needle electrodes with 22 times of puncture under the condition of 100 W × 60 sec. Liver abscess developed at the MCT site; however, it was decreased with percutaneous drainage. The patient is alive, without tumor recurrence even after 15 years since the MCT. This successful case proves that appropriate MCT is a promising treatment for patients with gastric liver metastases.

The enantioselective oxidative coupling of 2-naphthols in water was established using dinuclear vanadium(V/IV) catalysis with O2 as the sole co-oxidant. In the vanadium-catalyzed reaction, the corresponding coupling products were obtained in good to excellent yields with up to 94% enantiomeric excess. In water, racemization of the coupling product was suppressed even at high temperature (70 °C).

Unprecedented absolute asymmetric synthesis was carried out using frozen chirality derived from chiral crystals of achiral coumarin-3-carboxamide and carbenoids. An enantioselective cycloaddition reaction with a sulfur ylide gave an optically active cyclopropane up to 97% ee. Furthermore, a cycloaddition reaction with dichlorocarbene gave dihydrofuran in 93% ee. Nucleophilic addition of ylide or carbene occurs from the side of the carbonyl oxygen atom to avoid steric hindrance of substituents on the nitrogen atom.

Photodimerization of 3-arylindenones in solution and in the solid state was examined. Irradiation of 3-arylindenones in benzene exclusively gave C2-symmetric anti-HH cyclobutane dimers in good yields. In contrast, photolysis in the solid state afforded syn-HH cyclobutane dimers efficiently, which was considerably influenced by the molecular arrangement in the crystal lattice.

We found that the hydrazone–Pd-catalyzed direct intermolecular reaction of o-alkynylphenols with allylic acetates afforded the corresponding 2-substituted-3-allylbenzofuran derivatives. This reaction proceeded smoothly at room temperature using a hydrazone–Pd catalyst system.

Background Integrated positron emission tomography (PET) with computed tomography (CT) is a useful modality to investigate lymph node metastases for non-small cell lung cancer, but is less sensitive for normal-sized lymph nodes. We sometimes encounter cases with radiologically normal lymph nodes and unsuspected mediastinal metastases detected by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, few studies have investigated staging in patients with radiologically normal mediastina, and the accuracy of EBUS-TBNA staging for radiologically normal mediastina and hila is unclear. Methods This study was a retrospective, single-institution review of a prospectively maintained database at Chiba Cancer Center between May 1, 2008, and September 1, 2013. We analyzed 113 non-small cell lung cancer patients with both CT-negative and PET/CT-negative lymph nodes (N0) in preoperative nodal staging performed by EBUS-TBNA. After preoperative staging was performed, patients with either N0 or N1 clinical staging underwent surgery. Final N factors were determined by mediastinal lymphadenectomy. Results In our study, the overall rate of N2 disease was 17.6% (20 of 113). For nodal staging by EBUS-TBNA, the sensitivity, specificity, negative predictive value, and diagnostic accuracy were 35.0% (7 of 20), 100% (93 of 93), 87.7% (93 of 106), and 88.4% (100 of 113), respectively. There were no severe complications from EBUS-TBNA staging. Conclusions The overall rate of unsuspected N2 was not low. EBUS-TBNA was accurate and feasible for preoperative mediastinal nodal staging of non-small cell lung cancer with both CT-negative and PET/CT-negative lymph nodes. The sensitivity of EBUS-TBNA for radiologically normal mediastina and hila was low. Further investigations are required.

The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39–2.49; P

The heterogeneous partition coefficient (λ) for Ra in BaCO3 (witherite) was determined by coprecipitation using the free drift method. Initially, CO2 (100 %) was bubbled through a solution equilibrated with witherite. After a small amount of Ra was added into the solution, coprecipitation was induced by a slow increase in pH, caused by degassing CO2(g) from the solution. Kinetically controlled precipitation was restricted to be slow because of the slow degassing of CO2(g). The observed low precipitation rate allowed for the equilibrium partitioning of elements during coprecipitation of witherite. The value of λ derived for Ra was (1.3 ± 0.7) × 10−1, a value similar to that obtained from the coprecipitation of Ra in CaCO3 (calcite). The obtained results indicated that partitioning of Ra in carbonate-based minerals was not dependent on the similarity of its ionic radius with that of the metal in the host carbonate.

The aqueous solubility of BaSeO4(cr) was studied at 23 ± 2 ℃ as a function of Na2SeO4 concentrations (0.0001 to 4.1 mol kg –1) and equilibration periods (3 to 596 d). The equilibrium, approached from both the under- and over-saturation directions, in this system was reached rather rapidly (≤3 d). The SIT and Pitzer's ion-interaction models were used to interpret these data and the predictions based on both of these models agreed closely with the experimental data. Thermodynamic analyses of the data show that BaSeO4(cr) is the solubility-controlling phase for Na2SeO4 concentrations –1. The log 10 K 0 value for the BaSeO4(cr) solubility product (BaSeO4(cr) ⇌ Ba2++ SeO4 2– ) calculated by the SIT and Pitzer models were very similar (− 7.32 ± 0.07 with Pitzer and − 7.25 ± 0.11 with SIT). Although the BaSeO4(cr) solubility product and Ba concentrations as a function of Na2SeO4 concentrations predicted by both the SIT and Pitzer models are similar, the models required different sets of fitting parameters. For examples, 1) interpretations using the SIT model required the inclusion of Ba(SeO4)2 2– species with log 10 K 0 = 3.44 ± 0.12 for the reaction (Ba2++ 2SeO4 2– ⇌ Ba(SeO4)2 2– ), whereas these species are not needed for Pitzer model, and 2) at Na2SeO4 concentrations >0.59 mol kg –1 it was also possible to calculate the value for log 10 K 0 for the solubility product of a proposed double salt (Na2Ba(SeO4)2(s) ⇌ 2Na++ Ba2++ 2SeO4 2– ) which for the SIT model is − (8.70 ± 0.29) whereas for the Pitzer model it is − (9.19 ± 0.19). The ion-interaction/ion-association parameters hitherto unavailable for both the SIT and Pitzer models required to fit these extensive data extending to as high ionic strengths as 12.3 mol kg –1 were determined. The model developed in this study is consistent with all of the reliable literature data, which was also used to extend the model to barium concentrations as high as 0.22 mol kg –1 and pH ranging from 1.4 to 13.8, in addition to selenium concentrations as high as 4.1 mol kg –1.

Enantioselective oxidative-coupling of polycyclic phenols, such as 2-anthracenol, 9- or 3-phenanthrol, and 5-chrysenol was established by using vanadium(V/IV) catalysis under air or O2 as a co-oxidant. In the vanadium catalyzed reaction, the corresponding coupling products were obtained in good to excellent yields with up to 93% enantiomeric excess.

Background Immune checkpoint inhibitors (ICPi) have dramatically changed the treatment of non-small cell lung cancer (NSCLC), but the effect of these agents on brain metastases (BM) has not been clearly elucidated. We retrospectively evaluated the effect of ICPi on BM. Methods NSCLC patients who harbored BM treated with ICPi in out institution were enrolled. History of radiation therapy (RT) to the brain was not included in the selection criteria. The primary endpoint was overall survival after the initiation of ICPi (OS), and the secondary endpoints were duration of ICPi administration, causes of withdrawal, responses of BM, time to the first response of BM, and the incidence of radiation necrosis (RN). Results 35 NSLC with BM were treated with ICPi: nivolmab in 21, pembrolizumab in 13, and athezolizumab in 1 case. Among these cases, BM were progressive in 25 but stable in 10 cases at the initiation of ICPi. At the time of evaluation, ICPi were already withdrawn in 26 cases and the median administration time was 2.4 (0.5 to 25.9) months. The cause of withdrawal was progression of extracranial lesions in 8, progression of BM in 6, and adverse events or PS deterioration in the others. In competing risk analysis, the times to progression of extra- and intra-cranial lesions were not different. The responses of BM were evaluable in 28 cases: CR in 3, PR in 9, SD in 10 and PD in 6 cases. ICPi had been sequentially administrated after RT in one of the 3 CR and all of the 9 PR cases. The objective response rate was 76.9% after sequential RT/ICPi, but only 13.3% after ICPi alone (P = 0.002). The median time to the first response of BM was 1.0 (0.4 to 3.0) months after RT/ICPi and 1.3 (0.3 to 3.6) months after ICPi alone (n.s.). The median OS was 14.8 (95% CI: 8.8 to 22.7) months after the initiation of ICPi, and majority (90.5%) of the deaths were owing to the progression of extracranial disease. Among the 24 cases with history of RT to the brain, RN was observed in 7 (29.2%) and required necrotomy in 2 cases, even though ICPi could safely be continued after craniotomy in these 2 cases. Conclusions ICPi alone showed only limited efficacy on BM and were recommended to be administrated sequentially with RT. RN was the major neurological adverse event, and necrotomy was one of the choices to manage RN during ICPi. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Enantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro-type monoaryl phosphine catalyst, (R)-SITCP, was found to promote the formal [4+2] cycloaddition of saccharin-derived ketimines and α-methyl allenoate to afford the corresponding six-membered N-heterocycles in high yields and excellent regioselectivities with up to 93% ee.

Background The optimal medical management to delay the progression of aortic aneurysms has not been fully clarified, and the only standard treatment at present is antihypertensive therapy. Previous studies have shown beneficial effects of selective mineralocorticoid receptor (MR) antagonists on cardiovascular remodeling. The aim of the present study was to investigate the effect of a selective MR antagonist on aortic aneurysm progression. Methods Seven-week-old C57BL/6J male mice were administered with angiotensin II and β-aminopropionitrile for 4 weeks. The mice received either vehicle or eplerenone, a selective MR antagonist (100 mg/kg daily) every day by gavage, starting at 7 weeks of age. The production of inflammatory cytokines in cultures of high mobility group box-1–stimulated macrophages with or without a MR antagonist was also analyzed using an enzyme-linked immunosorbent assay. Results Although no differences were found in the peak systolic blood pressure between the experimental groups, the mice in the eplerenone group showed a significant reduction in aneurysm development. On histologic analysis, coarse and stretched elastic fibers were markedly improved in the aortic wall in the eplerenone group. Real-time polymerase chain reaction of both aortic wall and perivascular adipose tissue demonstrated the expression of tumor necrosis factor-α, interleukin-6, and matrix metalloproteinase-2 was significantly decreased in eplerenone group, and that of monocyte chemoattractant protein-1 in the aortic wall was also significantly decreased. Macrophage infiltration in the aortic wall and perivascular adipose tissue in the eplerenone group was also significantly decreased. The production of tumor necrosis factor-α and interleukin-6 in macrophage culture, which was stimulated by high mobility group box-1 and CpG oligodeoxynucleotides, was also significantly decreased in the eplerenone group. Conclusions Eprelenone suppressed aortic aneurysm progression through an anti-inflammatory effect. Thus, selective MR antagonists might be effective in preventing the progression of aortic aneurysms.

The introduction of a 1,3-propanediamine unit at the 3-position of ( S )-BINOL using a methylene spacer led to the formation of a chiral bifunctional organocatalyst for the aza-Morita–Baylis–Hillman (aza-MBH) reaction. The organocatalyst 1k mediated aza-MBH transformations with high chemical yields and with up to 82% ee.

An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 + 2] cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and high enantioselectivities.