Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells.

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion, used as first-line agents in treating peptic ulcers. However, we have previously reported that PPIs may diminish the therapeutic effect of anti-vascular endothelial growth factor (VEGF) drugs in patients with cancer. In this study, we explored the effects of vonoprazan, a novel gastric acid secretion inhibitor used for the treatment of peptic ulcers, on the secretion of VEGF in cancer cells and attempted to propose it as an alternative PPI for cancer chemotherapy. The effects of PPI and vonoprazan on VEGF expression in cancer cells were compared by real-time reverse transcription-polymerase chain reaction and ELISA. The interaction of vonoprazan and PPIs with transcriptional regulators by docking simulation analysis. In various cancer cell lines, including the human colorectal cancer cell line (LS174T), PPI increased VEGF messenger RNA expression and VEGF protein secretion, while this effect was not observed with vonoprazan. Molecular docking simulation analysis showed that vonoprazan had a lower binding affinity for estrogen receptor alpha (ER-α), one of the transcriptional regulators of VEGF, compared to PPI. Although the PPI-induced increase in VEGF expression was counteracted by pharmacological ER-α inhibition, the effect of vonoprazan on VEGF expression was unchanged. Vonoprazan does not affect VEGF expression in cancer cells, which suggests that vonoprazan might be an alternative to PPIs, with no interference with the therapeutic effects of anti-VEGF cancer chemotherapy.

Trends in Investigator-Initiated Clinical Studies at a University Hospital after Enforcement of the 2018 Clinical Trials Act in Japan.

In April 2018, the Clinical Trials Act pertaining to investigator-initiated clinical trials was passed in Japan. The purpose of this study was to investigate activity in investigator-initiated clinical studies before and after enforcement of the new Clinical Trials Act. This was done by analysing the records of the Ethics Committee of Tokushima University Hospital, which reviews studies based on the Japanese government's Ethical Guidelines for Medical and Health Research Involving Human Subjects prior to the Clinical Trials Act, and records of the Certified Review Board established at Tokushima University under the Clinical Trials Act in 2018. The number of new applications to these two review boards during fiscal years 2015-2017 (pre-Act) and fiscal years 2018 and 2019 (post-Act) were used as an indicator of activity in investigator-initiated clinical studies. The number of new applications to the Ethics Committee was 303, 261, 316, 303, and 249 in 2015, 2016, 2017, 2018, and 2019, respectively. The data show that the total number of new interventional studies decreased from 50.3 in average in 2015-2017 (pre-Act) to 42 in 2018 and 40 in 2019 (post-Act), respectively. These results suggest that fewer interventional studies were started following enforcement of the new Clinical Trials Act. To confirm this trend and identify contributing factors, further studies are required. In addition, possible way, such as broader contribution of clinical research coordinators, to promote clinical studies in the new Clinical Trials Act era should be examined.

A web-based survey of educational opportunities of medical professionals based on changes in conference design during the COVID-19 pandemic.

Owing to the coronavirus disease 2019 (COVID-19) pandemic, understanding how to hold future online academic conferences effectively is imperative. We assessed the impact of COVID-19 on academic conferences, including facilities and settings for attendance, participation status, cost burden, and preferences for future styles of holding conferences, through a web-based questionnaire survey of 2,739 Japanese medical professionals, from December 2020 to February 2021. Of the participants, 28% preferred web conferences, 60% preferred a mix of web and on-site conferences, and 12% preferred on-site conferences. Additionally, 27% of the presenters stopped presenting new findings at web conferences. The proportion of participants who audio-recorded or filmed the sessions, despite prohibition, was six times higher at web than face-to-face conferences. Since the COVID-19 outbreak, the percentage of participants attending general presentations decreased from 91 to 51%. While web conferencing offers advantages, these are offset by a decrease in presentations pertaining to novel findings and data. Supplementary Information: The online version contains supplementary material available at 10.1007/s10639-022-11032-5.

Reversal of Enantioselectivity in the Conjugate Addition Reaction of Cyclic Enones with the CuOTf/Azolium Catalytic System.

Hydroxyamide-functionalized azolium salt (NHC•HI 4) was evaluated for dual enantioselective control in a Cu-catalyzed asymmetric conjugate addition (ACA) reaction. This investigation was based on our previously reported ACA reaction catalyzed using CuOTf combined with NHC•AgI complex 1. It was revealed that the stereocontrol of the catalytic ACA reaction depended on the order of the addition of the substrates. Additionally, the chiral NHC ligand precursors, substrates, the relationship between the catalyst ee (eecat) and product ee (eepro), and halogen counter anion were completely evaluated. These results suggested that the catalytic performance of the CuOTf/4 system was comparable with that of the CuOTf/1 system. Furthermore, to gain knowledge of the Cu species generated using CuOTf and NHC ligand precursor, the reaction of CuOTf with 1 was investigated. Although obtaining the corresponding NHC•CuX species failed, the corresponding NHC•AuCl complex 11 could be synthesized by allowing 1 to react with AuCl•SMe2.

Status of Institutional Review Board Meetings Conducted Through Web Conference Systems in Japanese National University Hospitals During the COVID-19 Pandemic: Questionnaire Study.

BACKGROUND: With the global proliferation of the novel COVID-19 disease, conventionally conducting institutional review board (IRB) meetings has become a difficult task. Amid concerns about the suspension of drug development due to delays within IRBs, it has been suggested that IRB meetings should be temporarily conducted via the internet. OBJECTIVE: This study aimed to elucidate the current status of IRB meetings conducted through web conference systems. METHODS: A survey on conducting IRB meetings through web conference systems was administered to Japanese national university hospitals. Respondents were in charge of operating IRB offices at different universities. This study was not a randomized controlled trial. RESULTS: The survey was performed at 42 facilities between the end of May and early June, 2020, immediately after the state of emergency was lifted in Japan. The survey yielded a response rate of 74% (31/42). Additionally, while 68% (21/31) of facilities introduced web conference systems for IRB meetings, 13% (4/31) of the surveyed facilities postponed IRB meetings. Therefore, we conducted a further survey of 21 facilities that implemented web conference systems for IRB meetings. According to 71% (15/21) of the respondents, there was no financial burden for implementing these systems, as they were free of charge. In 90% (19/21) of the facilities, IRB meetings through web conference systems were already being conducted with personal electronic devices. Furthermore, in 48% (10/21) of facilities, a web conference system was used in conjunction with face-to-face meetings. CONCLUSIONS: Due to the COVID-19 pandemic, the number of reviews in clinical trial core hospitals has decreased. This suggests that the development of pharmaceuticals has stagnated because of COVID-19. According to 71% (15/21) of the respondents who conducted IRB meetings through web conference systems, the cost of introducing such meetings was US $0, showing a negligible financial burden. Moreover, it was shown that online deliberations could be carried out in the same manner as face-to-face meetings, as 86% (18/21) of facilities stated that the number of comments made by board members did not change. To improve the quality of IRB meetings conducted through web conference systems, it is necessary to further examine camera use and the content displayed on members' screens during meetings. Further examination of all members who use web conference systems is required. Our measures for addressing the requests and problems identified in our study could potentially be considered protocols for future IRB meetings, when the COVID-19 pandemic has passed and face-to-face meetings are possible again. This study also highlights the importance of developing web conference systems for IRB meetings to respond to future unforeseen pandemics.

Effects of vonoprazan and proton pump inhibitors on the efficacy of bevacizumab: a multicentre retrospective study.

Gastric acid secretion inhibitors such as proton pump inhibitors (PPIs) and vonoprazan may change the duration of treatment with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for cancer. However, there are no data on this prolongation effect. Here, we aimed to determine whether the use of PPIs or vonoprazan in patients with cancer receiving bevacizumab affected the duration of bevacizumab treatment. This observational study was conducted at two national university hospitals in Japan and involved 222 patients using oral PPIs (N = 190) or vonoprazan (N = 32) at the start of bevacizumab treatment between January 2015 and December 2018. Patients who received only one course of bevacizumab were excluded. The primary endpoint was the duration of bevacizumab treatment. The duration of bevacizumab treatment varied significantly between the PPI and vonoprazan groups. For cancer types other than colorectal cancer (breast, lung, brain, and ovarian cancers), the median duration of treatment was 217 days (p < 0.05) and was longer in the vonoprazan group than in the PPI group. However, for colorectal cancer, the median duration of bevacizumab treatment was 147 days longer in the PPI group than in the vonoprazan group. Selection of appropriate gastric acid secretion inhibitors may improve the therapeutic efficacy of anti-VEGF drugs, including bevacizumab. Oestrogen is a key regulator of this effect and may be responsible for the varying association between PPI or vonoprazan administration and the difference in bevacizumab treatment duration between colon cancer and other cancer types.

An Exploratory Trial of EPI-589 in Amyotrophic Lateral Sclerosis (EPIC-ALS): Protocol for a Multicenter, Open-Labeled, 24-Week, Single-Group Study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent. OBJECTIVE: This protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS). METHODS: EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2'-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. RESULTS: This trial began data collection in September 2021 and is expected to be completed in October 2023. CONCLUSIONS: This study can provide useful data to understand the characteristics of EPI-589. TRIAL REGISTRATION: Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42032.

Hydroxy-amide functionalized azolium salts for Cu-catalyzed asymmetric conjugate addition: stereocontrol based on ligand structure and copper precatalyst.

A series of hydroxy-amide functionalized azolium salts have been designed and synthesized for Cu-catalyzed asymmetric conjugate addition reaction. The (CH(2))(2)-bridged hydroxy-amide functionalized azolium ligand precursors 2, in addition to the previously reported CH(2)-bridged azolium salts 1, have been prepared from readily available enantiopure ß-amino alcohols. The combination of a Cu species with 1 or 2 efficiently promoted the 1,4-addition reaction of cyclic enones with dialkylzincs. For example, the reaction of 2-cyclohepten-1-one (17) with Bu(2)Zn in the presence of catalytic amounts of Cu(OTf)(2) and 1 gave (S)-3-butylcycloheptanone (20) in 99% yield and 96% ee. On the other hand, when the reaction was carried out under the influence of Cu(OTf)(2) combined with 2, (R)-20 in preference to (S)-20 was obtained in 98% yield and 80% ee. In this manner, the enantioselecvity was switched by controlling the structure of chiral ligand. Additionally, the reversal of enantioselectivity was also achieved by changing the Cu precatalyst from Cu(OTf)(2) to Cu(acac)(2) with the same ligand. The combination of Cu(acac)(2) with CH(2)-bridged azolium salt 1 in the reaction of 17 with Bu(2)Zn led to formation of (R)-20 as a major product in 55% yield and 80% ee. This result was in contrast to the Cu(OTf)(2)/1 catalytic system, where the 1,4-adduct with opposite configuration was obtained. Moreover, use of the Cu(acac)(2)/2 catalytic system produced (S)-20, while (R)-20 was formed by the Cu(OTf)(2)/2 catalytic system. Thus, it was found that either varying the linker of the chiral ligands or changing the counterion of Cu species between a OTf and acac ligand initially on the metal led to dual enantioselective control in the 1,4-addition reaction.

SU6668, a multiple tyrosine kinase inhibitor, inhibits progression of human malignant pleural mesothelioma in an orthotopic model.

BACKGROUND AND OBJECTIVE: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the mesothelium with high chemotherapeutic resistance. In this study, the preclinical therapeutic activity of the multiple tyrosine kinase inhibitor, SU6668, against MPM was examined. METHODS: Two human MPM cell lines with different pro-angiogenic cytokine expression, Y-MESO-14 cells that express high levels of vascular endothelial growth factor (VEGF) and MSTO-211H cells that express high levels of basic fibroblast growth factor (bFGF), were orthotopically inoculated into the thoracic cavities of mice with severe combined immunodeficiency. The mice with MPM were treated or not treated with SU6668 (200 mg/kg/day). RESULTS: SU6668 abrogated the proliferation of endothelial cells stimulated by VEGF or bFGF, but did not directly affect the growth of human MPM cells in vitro. In this orthotopic implantation model, treatment with SU6668 effectively reduced tumour weight and pleural effusion volumes, in association with inhibition of the growth of tumour vasculature. More importantly, treatment with SU6668 significantly prolonged survival time in mice with MPM. CONCLUSIONS: These findings suggest that SU6668 has a promising therapeutic effect on the progression of MPM in vivo through its anti-angiogenic effects.

Research Ethics Consultation in Nursing Studies.

Despite the importance and acceptance of research ethics consultation as an entity in many medical research areas, little is known about its status in nursing research. Focusing on inquiries from nurse researchers, we retrospectively analyzed records of integrated clinical research consultation, provided by members of the Clinical Research Center independently of the research ethics committee, at a Japanese university hospital during 2018-2019. Among various consultations in nursing studies (n = 101), 43 were related to research ethics. The main issues in research ethics consultation were compatibility with guidelines (n = 28; 65%) and application of ethics review (n = 12; 28%). Future studies should investigate international settings and address the relevance of research ethics consultation to promote proper nursing studies.

Radiation-associated Angiosarcoma Presenting as Massive Pleural Effusion.

A 67-year-old man was admitted to our hospital for massive pleural effusion. He had a history of mandibular gingival carcinoma treated with radiation therapy (RT). Based on the cytology findings of pleural effusion and a thoracoscopic pleural biopsy, we finally diagnosed him with radiation-associated angiosarcoma. Retrospective cell-block immunocytochemistry with pleural effusion also showed potential utility for the diagnosis. This case highlights the importance of considering the possibility of radiation-associated secondary cancer in patients with pleural effusion who have a history of RT.

Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

Academic investigators' interest in promoting specified clinical trials†:†Questionnaire survey before and after implementation of the Clinical Trial Act.

Background : Enforcement of the 2018 Clinical Trials Act (CTA) in Japan resulted in strict and complicated regulations surrounding intervention studies. Few Japan-specific measures have been developed to promote intervention studies in Japan despite concerns about CTA's negative influence on such studies. Therefore, this study examined the changes in academic investigators' interest in conducting clinical studies before and after enforcement of the CTA to determine measures to promote specified clinical trials. Methods : We conducted a questionnaire survey with investigators belonging to the Institute of Biomedical Sciences, Tokushima University Graduate School, before and after enforcement of the CTA. Results : Investigators had lesser interest in intervention studies in the post-questionnaire survey (post) group than in the pre-questionnaire survey (pre) group. Their desire for "project management" was significantly higher in the post-group than in the pre-group. Their desire for "support for preparing documents when conducting specified clinical trials" was significantly higher in the group interested in conducting specified clinical trials than that in the not-interested group. Conclusion : We revealed that investigators were highly interested in "project management" and "support for preparing documents when conducting specified clinical trials" after enforcement of the CTA. Measures for these desires may promote specified clinical trials. J. Med. Invest. 68 : 71-75, February, 2021.

Reversal of stereoselectivity in the Cu-catalyzed conjugate addition reaction of dialkylzinc to cyclic enone in the presence of a chiral azolium compound.

Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et(2)Zn catalyzed by Cu(OTf)(2) in the presence of an azolium salt derived from a chiral beta-amino alcohol gave (S)-3-ethylcyclohexanone (31) in good enantioselectivity. Among a series of chiral azolium compounds examined, the benzimidazolium salt (10) having both a tert-butyl group at the stereogenic center and a benzyl substituent at the azolium ring was found to be the best choice of ligand in the Cu(OTf)(2)-catalyzed reaction. Good enantioselectivity was observed when the reaction was conducted by employing a benzimidazolium derivative rather than an imidazolium derivative. The influence of the substituent at the azolium ring on the stereoselectivity of the reaction was also examined. In addition, from the results of the reaction catalyzed by Cu(OTf)(2) combined with an azolium compound derived from (S)-leucine methyl ester, it was found that the hydroxy side chain in the chiral ligand is probably crucial for the enantiocontrol of the conjugate addition reaction. On the other hand, it was discovered from a screening test of copper species that the reversal of enantioselectivity was realized by allowing 30 to react with Et(2)Zn in the presence of Cu(acac)(2) combined with the same ligand precursor to afford (R)-31 as a major product. The influence of the stereodirecting group at the chiral ligand on the stereoselectivity in the Cu(acac)(2)-catalyzed reaction differed completely from that observed in the Cu(OTf)(2)-catalyzed reaction. Reaction with a cyclic enone consisting of a seven-membered ring such as 2-cyclohepten-1-one (40) resulted in increasing the enantioselectivity of the reaction. Thus, treatment of 40 with Et(2)Zn catalyzed by Cu(OTf)(2) combined with a benzimidazolium salt produced the corresponding (S)-conjugate adduct in a 92:8 enantiomer ratio (er), while the Cu(acac)(2)-catalyzed reaction with the same ligand afforded (R)-product in a 9:91 er.

Asymmetric intermolecular boron Heck-type reactions via oxidative palladium(II) catalysis with chiral tridentate NHC-amidate-alkoxide ligands.

Chiral dimeric tridentate NHC-amidate-alkoxide palladium(II) complexes, 3a and 3b, effected oxidative boron Heck-type reactions of aryl boronic acids with both acyclic and cyclic alkenes at room temperature to afford the corresponding coupling products with high enantioselectivities. The high degree of enantioselection, far superior to existing methods, stems from differences in the nonbonding interactions in the proposed transition states, due to the influence from bulky substituents of the alkene substrates and the "counter axial groups" of the palladium(II) catalysts.

Air/Water-Stable Tridentate NHC-Pd Complex; Catalytic C-H Activation of Hydrocarbons via H/D Exchange Process in D(2)O.

While developing novel catalysts for carbon-carbon or carbon-heteroatom coupling (N, O, or F), we were able to introduce tridentate NHC-amidate-alkoxide palladium(II) complexes. In aqueous solution, these NHC-Pd(II) complexes showed high ability for C-H activation of various hydrocarbons (cyclohexane, cyclopentane, dimethyl ether, THF, acetone, and toluene) under mild conditions.

The clinical features of older patients with lung cancer in comparison with their younger counterparts.

BACKGROUND: Older patients with lung cancer have increased over the past decades. Several standard treatments for older patients were established, but their clinical features in real world clinics remain unknown. Thus, we performed a retrospective study to clarify the clinical features of them. METHODS: The patients with lung cancer who were admitted to our hospital between April 1, 2012 and March 31, 2015 were retrospectively analyzed. Patients older than 75 years were defined as older patients. Standard treatments were based on the guidelines. RESULTS: In total, 333 patients were analyzed. The older patients had a poor performance status (PS), more comorbidities, and fewer opportunities to receive standard treatments. The prognosis of the older patients who received standard treatments was superior to that of those who did not. The therapeutic efficacy of standard treatments for older patients with stages I and II diseases was similar to their younger counterparts. However, the prognosis of older patients with advanced stage, especially stage III disease, was poor. The tolerability of first-line chemotherapy by older patients was comparable with their younger counterparts, but the older patients had fewer opportunities to receive several chemotherapy regimens, even second line chemotherapy. CONCLUSIONS: We should positively consider standard treatments for older patients. However, not only their shorter life expectancy but also their poor PS and multiple comorbidities that sometimes render patients unable to receive standard treatments and several chemotherapy regimens, make their prognosis poor. The standard treatments for older patients, especially in locally advanced stages, require modification.

A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non-small cell lung cancer patients with interstitial lung disease.

OBJECTIVES: The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD. MATERIALS AND METHODS: A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open-label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%). CONCLUSION: This is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046).

A case of pulmonary pleomorphic carcinoma with malignant phenotypes induced by ZEB1-associated epithelial-mesenchymal transition.

A 60-year-old man was admitted to our hospital with non-small cell lung cancer (NSCLC). Imaging and pathological studies revealed NSCLC, not otherwise specified (NOS), at clinical stage T3N1M0 stage IIIA. We started radiotherapy alone because of obstructive pneumonia and end-stage renal disease, but the tumors progressed rapidly and resulted in death due to air obstruction by pharyngeal metastasis. The cancer was diagnosed as pleomorphic carcinoma in an autopsy. Viable lung tumor cells, which were resistant to radiotherapy, and the pharyngeal metastasis had mesenchymal phenotypes and expressed ZEB1 but not SNAI1. These observations indicated that ZEB1-associated epithelial-mesenchymal transition has malignant features including resistance to radiotherapy and aggressive metastatic potential. ZEB1-associated EMT may be an important mechanism to understand the pathophysiology of pleomorphic carcinoma.

Asymmetric intermolecular heck-type reaction of acyclic alkenes via oxidative palladium(II) catalysis.

Herein, we report an asymmetric intermolecular Heck-type reaction of acyclic alkenes by using a palladium-pyridinyl oxazoline diacetate complex under oxidative palladium(II) catalysis conditions. A premade palladium-ligand complex afforded higher enantioselectivities than a corresponding premixed palladium-ligand system, while offering enhanced asymmetric induction when compared to known intermolecular Heck-type protocols.