Abstract Background: Aging is a progressive decline of cellular functions that ultimately affects whole-body homeostasis. Alterations in the gut microbiota associated with aging have been reported, however, these studies were mainly based on the simple comparison of young and old subjects. In this study, we longitudinally analyzed fecal microbial community composition, together with fecal and plasma metabolomes, in C57BL/6J mice over a period of 72 weeks. Result: By using longitudinal microbiome and metabolome analyses, we found aging-related alterations in fecal microbiota and metabolome profiles. There was a significant reduction in gut microbial diversity with ageand, in addition, the fecal metabolome showed a significant decrease in monosaccharides and an increase in the metabolites of energy metabolism. In the age-related change of plasma metabolites, amino acids were significantly increased. The features of age-related changes in the fecal bacteria and metabolites were consistent with those observed in obesity and diabetes studies. Consistently, fecal microbiota transplantation from agedspecific pathogen-free (SPF) mice into young germ-free (GF) mice resulted in increased weight gain and impaired glucose tolerance. Conclusion: Our findings provide new insights into the relationships between host aging and gut environmental changes and may contribute to the development of a solution to aging-related diseases such as obesity.

Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung cancer, estimated to account for 2-5% of all non-small cell lung cancer. Typically, IMA worsens gradually, developing along the alveolar septal wall and causing respiratory failure. KRAS is a major driver mutation in IMA. However, clinical characteristics of patients with IMA vary, with IMA more commonly detected in males with a history of heavy smoking and nonsmoking females. Given the possibility of diverse oncogenic drivers, the objective of the present study was to identify these regulators.

There is an increasing need for comprehensive genetic panel testing at diagnosis for non-small cell lung cancer. However, genetic panel tests require sufficient tissue samples and therefore, cannot always be performed. Conversely, cytological specimens can be collected more easily and safely than tissue biopsy. A new next generation sequencing (NGS) panel test, the lung cancer compact panel™ (LCCP, DNA Chip Research Inc., Tokyo), which received pharmaceutical approval and released in Japan February 2023, allows for the use of cytological specimens.

Immune checkpoint inhibitors (ICI) is the key drug in the treatment of non-small cell lung cancer (NSCLC). PD-L1 status in tumor tissue is known to be a predictive biomarker of ICI. However, the clinical roles of soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma are unclear.

Three years have passed since lorlatinib was approved in Japan in September 2018 for the treatment of ALK+ NSCLC. As not much is known about lorlatinib efficacy when given after first-line (1L) alectinib, we have conducted a real-world observational study. Here, we present the characteristics of patients treated with lorlatinib and determine its clinical efficacy in patients with ALK+ NSCLC.

Background: The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC. Materials and methods: Patients with unresectable, stage III NSCLC and no disease progression after >= 2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models. Results: Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.330.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status. Conclusions: Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable.

Hepatocyte growth factor receptor gene (MET) is one of the important therapeutic target genes in non-small cell lung cancer (NSCLC). Above all MET exon 14 skipping mutation (METex14skipping), which is caused by whole exon 14 deletion, base substitutions, insertions/deletions at the splice donor and acceptor sites, and Y1003 mutation, it is important in determining the decision for administration of selective MET inhibitor. One of the selective oral MET inhibitors, tepotinib, is only used in Japan when METex14skipping is detected by ArcherMET, a next generation sequencer.

Background Bifidobacterium longum supplementation can be used to regulate bowel movement; however, individuals vary in the response to B. longum treatment. One putative factor is the gut microbiota; recent studies have reported that the gut microbiota mediates diet or drug effects. Here, we investigated intestinal features related to B. longum effectiveness in increasing bowel movement frequency. Results A randomized, double-blind controlled crossover trial was conducted with twenty Japanese subjects selected from 50 participants. The subjects received a two-week dietary intervention consisting of B. longum in acid-resistant seamless capsules or similarly encapsulated starch powder. Bowel movement frequency was recorded daily, and time-series fecal collection was conducted for metabologenomic analyses. There were differences among subjects in B. longum intake-induced bowel movement frequency. The responders were predictable by machine learning based on the metabologenomic features of the fecal samples collected before B. longum intake. Between responders and non-responders, the abundances of nine bacterial genera and of three compounds were significantly different. Conclusions Thus, the gut microbiome and metabolome composition have a strong impact on B. longum supplementation effectiveness in increasing bowel movement frequency, and gut metabologenomics enables B. longum supplementation effect prediction before intake. These findings have implications for th e development of personalized probiotic treatments. Trial registration UMIN-CTR, UMIN000018924. Registered 07 September 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021894

Background: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. Patients and methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo <= 12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). Results: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n 473) or placebo (n 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC >= 25%, <25%, >= 1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC >= 25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), >= 1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42 -0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC >= 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), >= 1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. Conclusions: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

BACKGROUND:Although total tumour volume (TTV) may have prognostic value for hepatic resection in certain solid cancers, its importance in colorectal liver metastases (CRLM) remains unexplored. This study investigated its prognostic value in patients with resectable CRLM.METHOD:This was a retrospective review of patients who underwent hepatic resection for CRLM between 2008 and 2017 in a single institution. TTV was measured from CT images using three-dimensional construction software; cut-off values were determined using receiver operating characteristic (ROC) curve analyses. Potential prognostic factors, overall survival (OS) and recurrence-free survival (RFS) were determined using multivariable and Kaplan-Meier analyses.RESULTS:Some 94 patients were included. TTV cut-off values for OS and RFS were 100 and 10 ml respectively. Right colonic primary tumours, primary lymph node metastasis and bilobar liver metastasis were included in the multivariable analysis of OS; a TTV of 100 ml or above was independently associated with poorer OS (hazard ratio (HR) 6·34, 95 per cent c.i. 2·08 to 17·90; P = 0·002). Right colonic primary tumours and primary lymph node metastasis were included in the RFS analysis; a TTV of 10 ml or more independently predicted poorer RFS (HR 1·90, 1·12 to 3·57; P = 0·017). The 5-year OS rate for a TTV of 100 ml or more was 41 per cent, compared with 67 per cent for a TTV below 100 ml (P = 0·006). Corresponding RFS rates with TTV of 10 ml or more, or less than 10 ml, were 14 and 58 per cent respectively (P = 0·009). A TTV of at least 100 ml conferred a higher rate of unresectable initial recurrences (12 of 15, 80 per cent) after initial hepatic resection.CONCLUSION:TTV was associated with RFS and OS after initial hepatic resection for CRLM; TTV of 100 ml or above was associated with a higher rate of unresectable recurrence.

Abstract Background The incidence and prevalence of Crohn’s disease (CD) are increasing globally. The efficacy of elemental nutrition (EN) for CD has been reported for decades. Recent studies demonstrated that elemental diet (ED), one of the types of EN, which contains individual amino acids, sugars (mono- or polysaccharides), and low fat, improves the anti-TNFa antibody therapy outcome by reducing the loss of response and has the preventive effect against the postoperative recurrence. Given its excellent safety, ED can be a promising concomitant therapeutic option for CD. However, the underlying mechanisms of ED remain unclear. Imbalance of the gut microbiota, dysbiosis, is thought to be involved in CD pathogenesis. Meanwhile, diet influences gut microbiota. We hypothesised that ED exerts clinical efficacy by shifting the gut microbiota to the anti-inflammatory environment. We also believe that investigating human samples is crucial to obtain mechanistic insights into ED therapy, considering species-specific differences in interactions between the host and microbiota. In this study, we examined the impact of ED on the intestinal bacterial compositions as well as metabolites in human subjects. Methods Four healthy individuals participated in the study. The subjects continued their dietary habits for 2 weeks after the registration of the study and then replaced 900 kcal/day of their regular diet with 900 kcal/day of ED (time point 1, T1). ED was continued for 2 weeks (T2). After the withdrawal of ED, subjects resumed their original dietary habits for 2 weeks until the endpoint of this study (T3). Faecal samples were collected from all subjects at all time points, T1-3. Faecal DNA and metabolites were extracted and analysed with 16S rRNA gene amplicon sequencing and metabolomic analysis, respectively. This study was approved by the Institutional Review Board of Kyorin University School of Medicine (IRB No. 720) and performed in accordance with the principles of the Declaration of Helsinki. Results Interindividual differences were observed in the gut bacterial compositions (Figure 1) as well as metabolites (Figure 2) at all time points. Changes over time varied among subjects. On the other hand, some bacteria (e.g. [Ruminococcus] gnavus group and Parabacteroides) and metabolites including short-chain fatty acids and bile acids changed significantly between time points among the 4 subjects. The bacterial and metabolite profiles at T3 were different from those T1 in all subjects. Conclusion The alterations of the gut microbiota induced by ED vary with each individual. Some microbes and metabolites change commonly across the subjects. ED may have a lasting effect on the gut environment even after the withdrawal.

Abstract Background Peak oxygen consumption (peak VO2) is a major prognostic parameter in heart failure (HF). Previous studies have shown a relationship between peak VO2 and impaired oxygen uptake and utilization in the peripheral muscles. The purpose of this study was to clarify the determinant of increased peak VO2 by cardiac rehabilitation (CR) in patients with HF. Methods We performed echocardiography during upright ramp bicycle cardiopulmonary exercise test in 30 HF patients (61±1 years of age, 80% male) before and 6 months after CR. HR reserve was determined as the change in HR from rest to peak exercise, expressed as a percentage of the predicted maximal HR reserve. Elastance index (EAI) and LV end-systolic elastance index (ELVI) were derived as the ratio of end-systolic pressure to stroke volume index and end-systolic volume index, respectively. End-systolic pressure was estimated from the equation 0.9 × brachial systolic blood pressure. Ventriculo-arterial coupling (VAC) was calculated as the quotient of EAI and ELVI. The ratio of LDEDVI to E/e' mean was used to evaluate LV diastolic compliance. Systemic vascular resistance index was calculated as mean arterial pressure divided by echocardiography calculated cardiac index and multiplied by 80. The arterial venous oxygen content difference (C (A-V) O2 gradient) was calculated by using the Fick equation as: VO2/echocardiography calculated cardiac output. Results Peak VO2 and C (A-V) O2 gradient were increased by CR. However, heart rate reserve, systolic reserve, VAC, diastolic reserve and vasodilation reserve were unchanged by CR (Table 1). Conclusions Increased oxygen uptake and utilization in the peripheral muscles, rather than cardiac function reserve, may be determinants of increased peak VO2 by CR in HF. Table 1 Funding Acknowledgement Type of funding source: None

Objective There are few detailed studies about peripheral branch resection of the posterior nasal nerves in the inferior turbinate; thus, this study aimed to investigate this. Methods Patients who underwent submucosal turbinoplasty with or without resection of the peripheral branches of posterior nasal nerves in the inferior turbinate were included. Results The resection of the posterior nasal nerves with turbinoplasty significantly reduced detection and recognition thresholds on olfactory testing. The rhinorrhoea severity, detection threshold and recognition threshold were significantly lower after resection of the posterior nasal nerves with turbinoplasty than after turbinoplasty alone, although there were no significant differences between the two groups before surgery. Conclusion This is the first study to show that the resection of the peripheral branches of the posterior nasal nerves in the inferior turbinate with turbinoplasty more effectively inhibits allergic symptoms compared with turbinoplasty alone. It also showed that the resection of the peripheral branches of the posterior nasal nerves can inhibit olfactory dysfunction.

Background In the Phase III PACIFIC trial of patients with unresectable, Stage III non-small cell lung cancer (NSCLC) without progression after chemoradiotherapy (CRT), durvalumab significantly improved the primary endpoints progression-free survival (PFS) and overall survival (OS) versus placebo and was well-tolerated. Any-grade pneumonitis or radiation pneumonitis (‘pneumonitis') occurred in 161 (33.9%) and 58 (24.8%) patients treated with durvalumab and placebo, respectively, with similar grade 3/4 rates (3.6% and 3.0%). Exploratory analyses were performed to investigate the efficacy of durvalumab in patients who developed pneumonitis. Methods Patients with WHO PS 0/1 (irrespective of tumor PD-L1 status) with ≥2 cycles of platinum-based CRT were randomized (2:1), 1–42 days following CRT, to durvalumab 10mg/kg intravenously every 2 weeks or placebo for up to 12 months, stratified by age, sex, and smoking history. PFS and time to death or distant metastasis (TTDM) were assessed by blinded independent central review using RECIST v1.1. The impact of pneumonitis on efficacy was assessed via Cox proportional hazards models. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. Results As of 22 March 2018, 713 patients were randomized of whom 709 received treatment. Using a step-wise approach, pneumonitis was assessed via univariate analyses and, when adjusted for the occurrence of (time-dependent) pneumonitis in the models, OS, PFS, and TTDM were consistent with results for the ITT population (Table). The pneumonitis time-dependent covariate was not significant (P>0.1) in all models.Table1459PD OS, PFS, and TTDM, adjusted for the time-dependent occurrence of pneumonitis* and for the ITT populationTableNo. of events/no. of patients (%)HR (95% CI) for durvalumab vs. placeboDurvalumabPlaceboAdjusted for the time-dependent occurrence of pneumonitis**ITT population***OS183/476 (38.4)116/237 (48.9)Model 1 (base model)0.70 (0.55–0.88)0.68 (0.53–0.87)Model 20.65 (0.51–0.83)−PFS243/476 (51.1)173/237 (73.0)Model 1 (base model)0.54 (0.45–0.66)0.51 (0.41–0.63)Model 20.52 (0.42–0.64)−TTDM182/476 (38.2)126/237 (53.2)Model 1 (base model)0.57 (0.45–0.71)0.53 (0.41–0.68)Model 20.53 (0.41–0.67)−Data cutoff: 22 March 2018.*Pneumonitis occurred on Tx and within 90 days of last dose or prior to subsequent anticancer therapy (whichever occurred earlier).**A Cox proportional hazards model adjusted for the time-dependent occurrence of pneumonitis using two sets of covariate models was used (with the Breslow method to control for ties): (1) accounting for stratification factors at randomization: age at randomization ( Conclusions Treatment benefit with durvalumab versus placebo was maintained regardless of the occurrence of pneumonitis, which predominantly occurred with low-grade severity as previously reported. These findings suggest that low-grade pneumonitis should not deter use of durvalumab. Clinical trial identification NCT02125461 (release date: 29 April 2014). Editorial acknowledgement Andrew Gannon, MS, MA, of Cirrus Communications (New York, NY), an Ashfield company, in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J.F. Vansteenkiste: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: BMS. J. Naidoo: Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche/Genentech. C. Faivre-Finn: Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Elekta; Travel / Accommodation / Expenses: Pfizer. M. Ozguroglu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Jannsen; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel / Accommodation / Expenses: BMS. A. Villegas: Speaker Bureau / Expert testimony: AstraZeneca. D. Daniel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Janssen Research and Development; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis Pharmaceuticals Corporation; Research grant / Funding (institution): Abb Vie, Inc.; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merus NV; Research grant / Funding (institution): Daiichi Sankyo. S. Murakami: Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical. R. Hui: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. K.H. Lee: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca. B.C. Cho: Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): MOGAM Institute; Research grant / Funding (self): Dong-A ST; Research grant / Funding (self): Champions Oncology; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Yuhan; Advisory / Consultancy, Research grant / Funding (self): Ono; Research grant / Funding (self): Dizal Pharma; Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy: MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc. K. Kubota: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Novaltis; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Kyowa Hakko KIRIN. M. Taboada: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Wadsworth: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P.A. Dennis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.J. Antonia: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self): CBMG; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Memgen; Advisory / Consultancy, Travel / Accommodation / Expenses: FLX Bio; Shareholder / Stockholder / Stock options: Cellular Biomedicine Group.