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Chun-Hua Wang,1,2,* Li-Li Liu,1,2,* Ding-Zhun Liao,3,* Mei-Fang Zhang,1,2 Jia Fu,1,2 Shi-Xun Lu,1,2 Shi-Lu Chen,1,2 Hong Wang,1,2 Shao-Hang Cai,1,2 Chris Zhiyi Zhang,1,2 Hui-Zhong Zhang,2 Jing-Ping Yun1,2 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; 2Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; 3Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China *These authors contributed equally to this work Introduction: Prenylated Rab acceptor 1 domain family member 2 (PRAF2), a novel oncogene, has been shown to be essential for the development of several human cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. Materials and methods: PRAF2 mRNA and protein expressions were examined in fresh tissues by quantitative reverse transcription-polymerase chain reaction and Western blot, respectively, and in 518 paraffin-embedded HCC samples by immunohistochemistry. The correlation of PRAF2 expression and clinical outcomes was determined by the Student’s t-test, Kaplan–Meier test, and multivariate Cox regression analysis. The role of PRAF2 in HCC was investigated by cell viability, colony formation, and migration assays in vitro and with a nude mouse model in vivo. Results: In our study, the PRAF2 expression was noticeably increased in HCC tissues at both the mRNA and protein levels compared with that of the nontumorous tissues. Kaplan–Meier analysis indicated that high PRAF2 expression was correlated with worse overall survival in a cohort of 518 patients with HCC. The prognostic implication of PRAF2 was verified by stratified survival analysis. The multivariate Cox regression model revealed PRAF2 as an independent poor prognostic factor for overall survival (hazard ratio = 1.244, 95% CI: 1.039–1.498, P

Background: Few prospective studies explored the incidence and determinant of carotid atherosclerosis (CA) progression (CAP). This community-based prospective study focused on the effects of diabetes mellitus (DM) treatments and glucose levels on CAP risks., Methods: We followed up a group of 657 CA-positive middle-aged adults and elders for CAP. CAP was defined as an increase in the total number of carotid plaque and/or an increase in diameter stenosis by at least 10%., Results: After 4.05 years of followed-up, CAP was detected in 364 (55.4%) subjects. The multivariable-adjusted hazard ratios (HRs) were 1.805 (95% confidence interval [CI]: 1.374-2.358) and 0.694 (95% CI: 0.510-0.944) for elevated fasting plasma glucose (eFPG; FPG≥100 mg/dL) and glucose-lowering medications (GLM), respectively. As compared to GLM-negative+eFPG-positive subjects, the multivariable-adjusted HRs were 0.497 (95% CI: 0.373-0.662), 0.537(95% CI: 0.306-0.942), and 0.586 (95% CI: 0.412-0.833) for GLM-negative+eFPG-negative, GLM-positive+eFPG-negative, and GLM-positive+ eFPG-positive subjects, respectively. The multivariable-adjusted risks of CAP were similar between GLM-negative+eFPG-negative and GLM-positive+ eFPG-positive subjects (p=0.77). Stratified analyses showed that the multivariable-adjusted HRs per 5.0 mg/dL increase in FPG were significantly increased among GLM-negative subjects (HR=1.131; 95% CI: 1.094-1.171) and non-significantly decreased among GLM-positive subjects (HR=0.985; 95% CI: 0.957-1.013)., Conclusion: We found that more than 50% of CA-positive subjects had CAP in 4 years and higher FPG significantly increased and GLM significantly decreased the risks of CAP. Additionally, GLM and FPG demonstrated an interactive effect on CAP risks. It seems possible that GLM may induce effects beyond lowering glucose levels and subsequently lowers CAP risks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chou, Lu, Cheng, Wu and Wang.)

Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens., (© 2024. Springer Nature Limited.)

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The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic tumor microenvironment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks the activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibits pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy., (© 2024 Wiley‐VCH GmbH.)

A cost-effective chemical prelithiation solution, which consists of Li + , polyaromatic hydrocarbon (PAH), and solvent, is developed for a model hard carbon (HC) electrode. Naphthalene and methyl-substituted naphthalene PAHs, namely 2-methylnaphthalene and 1-methylnaphthalene, are first compared. Grafting an electron-donating methyl group onto the benzene ring can decrease electron affinity and thus reduce the redox potential, which is validated by density functional theory calculations. Ethylene glycol dimethyl ether (G1), diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether solvents are then compared. The G1 solution has the highest conductivity and least steric hindrance, and thus the 1-methylnaphthalene/G1 solution shows superior prelithiation capability. In addition, the effects of the interaction time between Li + and 1-methylnaphthalene in G1 solvent on the electrochemical properties of a prelithiated HC electrode are investigated. Nuclear magnetic resonance data confirm that 10-h aging is needed to achieve a stable solution coordination state and thus optimal prelithiation efficacy. It is also found that appropriate prelithiation creates a more Li + -conducing and robust solid-electrolyte interphase, improving the rate capability and cycling stability of the HC electrode., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial., Methods: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis., Results: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029)., Conclusions: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy., (© 2024. The Author(s).)

SNARE proteins (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) play a key role in mediating a variety of plant biological processes. Currently, the function of the SNARE gene family in phytohormonal and abiotic stress treatments in grapevine is currently unknown, making it worthwhile to characterize and analyze the function and expression of this family in grapevine. In the present study, 52 VvSNARE genes were identified and predominantly distributed on 18 chromosomes. Secondary structures showed that the VvSNARE genes family irregular random coils and α-helices. The promoter regions of the VvSNARE genes were enriched for light-, abiotic-stress-, and hormone-responsive elements. Intraspecific collinearity analysis identified 10 pairs collinear genes within the VvSNARE family and unveiled a greater number of collinear genes between grapevine and apple, as well as Arabidopsis thaliana , but less associations with Oryza sativa . Quantitative real-time PCR (qRT-PCR) analyses showed that the VvSNARE genes have response to treatments with ABA, NaCl, PEG, and 4 °C. Notably, VvSNARE2 , VvSNARE14 , VvSNARE15 , and VvSNARE17 showed up-regulation in response to ABA treatment. VvSNARE2 , VvSNARE15 , VvSNARE18 , VvSNARE19 , VvSNARE20 , VvSNARE24 , VvSNARE25, and VvSNARE29 exhibited significant up-regulation when exposed to NaCl treatment. The PEG treatment led to significant down-regulation of VvSNARE1 , VvSNARE8 , VvSNARE23 , VvSNARE25 , VvSNARE26 , VvSNARE31, and VvSNARE49 gene expression. The expression levels of VvSNARE37 , VvSNARE44, and VvSNARE46 were significantly enhanced after exposure to 4 °C treatment. Furthermore, subcellular localization assays certified that VvSNARE37 , VvSNARE44 , and VvSNARE46 were specifically localized at the cell membrane. Overall, this study showed the critical role of the VvSNARE genes family in the abiotic stress response of grapevines, thereby providing novel candidate genes such as VvSNARE37 , VvSNARE44 , and VvSNARE46 for further exploration in grapevine stress tolerance research.

Hemodynamic parameters have been correlated with stroke, hypertension, and arterial stenosis. While only a few small studies have examined the link between hemodynamics and diabetes mellitus (DM). This case-control study enrolled 417 DM patients and 3475 non-DM controls from a community-based cohort. Peak systolic velocity (PSV), end-diastolic velocity (EDV), blood flow velocity (MFV), pulsatility index (PI), and the resistance index (RI) of the common carotid arteries were measured by color Doppler ultrasonography. Generalized linear regression analyses showed that as compared to the non-DM controls, the age-sex-adjusted means of PSV, EDV, and MFV were - 3.28 cm/sec, - 1.94 cm/sec, and - 2.38 cm/sec, respectively, lower and the age-sex-adjusted means of RI and PI were 0.013 and 0.0061, respectively, higher for the DM cases (all p-values < 0.0005). As compared to the lowest quartiles, the multivariable-adjusted ORs of DM for the highest quartiles of PSV, EDV, MFV, RI, and PI were 0.59 (95% confidence interval [CI] 0.41-0.83), 0.45 (95% CI 0.31-0.66), 0.53 (95% CI 0.37-0.77), 1.61 (95% CI 1.15-2.25), and 1.58 (95% CI 1.12-2.23), respectively. More importantly, the additions of EDV significantly improved the predictabilities of the regression models on DM. As compared to the model contained conventional CVD risk factors alone, the area under the receiver operating curve (AUROC) increased by 1.00% (95% CI 0.29-1.73%; p = 0.0059) and 0.80% (95% CI 0.15-1.46%; p = 0.017) for models that added EDV in continuous and quartile scales, respectively. Additionally, the additions of PSV and MFV also significantly improved the predictabilities of the regression models (all 0.01 < p-value < 0.05). This study reveals a significant correlation between DM and altered hemodynamic parameters. Understanding this relationship could help identify individuals at higher risk of DM and facilitate targeted preventive strategies to reduce cardiovascular complications in DM patients., (© 2024. The Author(s).)

Background: The assessment of future risk of cardiovascular diseases (CVD) is strongly recommended for all asymptomatic adults without CVD history. Carotid atherosclerosis (CA) is a preclinical phenotype of CVDs. However, data on estimated future CVD risks with respect to preclinical atherosclerosis are limited. This community-based study aimed to assess the relationships between predicted CVD risks and CA. Methods: We enrolled 3908 subjects aged 40-74 years without CVD history and calculated their 10-year CVD risks using the Framingham Risk Score (FRS) and the Pooled Cohort Equations (PCE). Carotid plaque (CP) at the extracranial carotid arteries was determined by high-resolution B-mode ultrasonography and further classified into mild or advanced CA. Results: The means of FRS for CP-negative and mild and advanced CA were 9.0%, 14.4%, and 22.1%, respectively ( p -value < 0.0001). The corresponding values for PCE score were 4.8%, 8.8%, and 15.0%, respectively ( p -value < 0.0001). The odds ratios (ORs) of having CP per 5.0% increase in FRS and PCE score were 1.23 (95% CI, 1.19-1.28) and 1.36 (95% CI, 1.28-1.44), respectively. The corresponding values of having advanced CA were 1.24 (95% CI, 1.19-1.29) and 1.38 (95% CI, 1.30-1.48), respectively. Among the models of FRS or PCE plus other conventional CVD risk factors, the FRS + age model had the highest discrimination for the presence of CP (AUROC, 0.7533; 95% CI, 0.7375-0.7691) as well as for the presence of advanced CA (AUROC, 0.8034; 95% CI, 0.7835-0.8232). The calibration of the FRS + age models for the presences of CP and advanced CA was excellent (χ 2 = 8.45 [ p = 0.49] and 10.49 [ p = 0.31], respectively). Conclusions: Estimated future CVD risks were significantly correlated with risks of having CA. Both FRS and PCE had good discrimination for the presences of CP and advanced CA.

Background: Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis., Methods: HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method., Result: There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white, of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73 months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30 months vs.16.13 months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics., (© 2023. The Author(s).)

Growth arrest-specific gene 7 (Gas7) was involved in various cellular functions, although its specific roles and molecular mechanisms in hepatocellular carcinoma (HCC) remained unclear. So the current study was to investigate the role of Gas7 in HCC. Our findings revealed that Gas7 was downregulated in various HCC cell lines and low Gas7 expression was associated with decreased overall survival in patients with HCC. Additionally, our functional assays showed that Gas7 inhibited cell proliferation and migration, induced cell cycle arrest, apoptosis, and autophagy, and enhanced oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway. We also observed that transcription factorSp1 was responsible for inhibiting Gas7. These findings provide insights into the role and elucidated a potential mechanism of Gas7 in HCC progression and metastasis. It was also observed that the Sp1/Gas7/PI3K/Akt axis was critical for malignant phenotype and oxaliplatin sensitivity in HCC. Therefore, Gas7 can be considered as a prognostic predictor and therapeutic target for HCC., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest in this work., (Copyright © 2023. Published by Elsevier Inc.)

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host&apos;s antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.

Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers., (© 2023 by The American Society of Hematology.)

Background: Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD). Recently, genome-wide association studies (GWAS) identified several single nucleotide polymorphism (SNP) significantly correlated with DM. The study aimed to explore the relationships of the top significant DM SNPs with carotid atherosclerosis (CA)., Methods: We used a case-control design and randomly selected 309 cases and 439 controls with and without, respectively, carotid plaque (CP) from a community-based cohort. Eight recent GWAS on DM in East Asians reported hundreds of SNPs with genome-wide significance. The study used the top significant DM SNPs, with a p-value < 10 -16 , as the candidate genetic markers of CA. The independent effects of these DM SNPs on CA were assessed by multivariable logistic regression analyses to control the effects of conventional cardio-metabolic risk factors., Results: Multivariable analyses showed that, 9 SNPs, including rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, and rs9937354, showed promising associations with the presence of carotid plaque (CP). Among them, rs9937354, rs10842993, rs7180016, and rs4383154 showed significantly independent effects. The means (SD) of the 9-locus genetic risk score (9-GRS) of CP-positive and -negative subjects were 9.19 (1.53) and 8.62 (1.63), respectively (p < 0.001). The corresponding values of 4-locus GRS (4-GRS) were 4.02 (0.81) and. 3.78 (0.92), respectively (p < 0.001). The multivariable-adjusted odds ratio of having CP for per 1.0 increase in 9-GRS and 4-GRS were 1.30 (95% CI 1.18-1.44; p = 4.7 × 10 -7 ) and 1.47 (95% CI 1.74-9.40; p = 6.1 × 10 -5 ), respectively. The means of multi-locus GRSs of DM patients were similar to those of CP-positive subjects and higher than those of CP-negative or DM-negative subjects., Conclusions: We identified 9 DM SNPs showing promising associations with CP. The multi-locus GRSs may be used as biomarkers for the identification and prediction of high-risks subjects for atherosclerosis and atherosclerotic diseases. Future studies on these specific SNPs and their associated genes may provide valuable information for the preventions of DM and atherosclerosis., (© 2023. The Author(s).)

Background: Hypertension, hyperlipidemia, and diabetes mellitus (DM) are common cardiovascular disease (CVD) comorbidities and well-known major determinants of atherosclerosis. However, their combined effects and relative contributions have not been well explored. This study aimed to characterize the characteristics of carotid atherosclerosis and dissect the relative effects of these common CVD comorbidities on the presence and severity of carotid atherosclerosis in community-dwelling elderly individuals., Methods: We enrolled 817 elders from communities in northern Taiwan. We evaluated their cardiovascular risk profiles and scanned their extracranial carotid arteries using high-resolution ultrasonography systems., Results: The prevalence rates for hypertension, hyperlipidemia, and DM were 45.4%, 37.1%, and 16.8%, respectively. Sixty-two (7.6%) and 188 (23.0%) elderly had all three and two of these common CVD comorbidities, respectively. The prevalent rates of carotid plaque and moderate-to-severe atherosclerosis were 62.9% and 35.5%, respectively. The percentages of one or more common CVD comorbidities in elders with carotid plaque and moderate-to-severe atherosclerosis were 78.2% and 83.1%, respectively. Multivariate analyses showed that the number of common CVD comorbidities was the most predictive determinant. Multivariable-adjusted odds ratios (ORs) per comorbidity for the presence of carotid plaque and advanced carotid atherosclerosis were 1.52 (95% CI, 1.28-1.81) and 1.57 (95% CI, 1.28-1.93), respectively. Models containing hypertension and DM were the second most predictive. Combinatory analyses showed distinct relationship patterns between carotid atherosclerosis and hypertension, hyperlipidemia, and DM. Hypertension was significantly correlated with higher ORs for the presence of carotid plaque and advanced carotid atherosclerosis but not for hyperlipidemia., Conclusion: Carotid plaques are highly prevalent in community-dwelling elders. The number of common CVD comorbidities was the most predictive determinant of carotid plaques and advanced carotid atherosclerosis. Our results indicate that to reduce the impact of atherosclerotic diseases, blood pressure controls precede the control of blood lipids and glucose in the community-dwelling elders., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Purpose: Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes., Experimental Design: We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography-mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant., Results: At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02)., Conclusions: This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention., (©2022 American Association for Cancer Research.)

Background: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values., Methods: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method., Result: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001)., Conclusion: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy., (© 2022. The Author(s).)

Reactive oxygen species impair the blood vessels, leading to the initiation of atherosclerosis, and migration and proliferation of vascular smooth muscle cells and neovascularization by endothelial cells of vasa vasorum are essential for atherosclerosis development. Obg-like ATPase 1 (OLA1), a negative regulator in cellular responses to oxidative stress, binds to breast cancer susceptibility gene 1 (BRCA1), which protects vascular endothelial and smooth muscle cells against reactive oxygen species. However, it is not known whether OLA1 is genetically correlated with atherosclerosis. Here, we conducted two independent population-based case-control studies to explore the effects of variants in OLA1 genes on preclinical atherosclerosis. A total of 564 and 746 subjects who had thicker and normal carotid intima-media thickness (cIMT), respectively, were enrolled. Among 55 screened SNPs, rs35145102, rs201641962, rs12466587, rs4131583, and rs16862482 in OLA1 showed significant associations with cIMT. SNP rs35145102 is a 3'-utr variant and correlates with the differential expression of OLA1 in immune cells. These five genetic markers form a single closely linked block and H1-ATTGT and H2-GCCTC were the top two most prevalent 5-locus haplotypes. The H1 + H1 genotype negatively and H1 + H2 genotype positively correlated with thicker cIMT. The five identified SNPs in the OLA1 gene showed significant correlations with cIMT. Furthermore, we found that OLA1 was required for migration and proliferation of human aortic endothelial and smooth muscle cells and regulated vascular tube formation by human aortic endothelial cells. Therefore, these genetic variants in the OLA1 gene may serve as markers for risk prediction of atherosclerotic diseases.

Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1β derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1β blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy., Significance: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: High technical complexity limits the wide use of transradial approach (TRA) chemoembolization in the management of liver cancer. We sought to construct a thoracoabdominal aorta CTA-based nomogram model to identify ideal candidates for TRA chemoembolization in patients with liver cancer. Methods: Patients who had received thoracoabdominal aorta CTA before TRA chemoembolization from 2018 to 2020 were retrospectively enrolled and randomly divided into a training set and a validation set. The clinical characteristics and CTA features were collected to build a clinical model. Univariate and multivariate analyses were used to identify significant clinical-radiological variables. A CTA-based nomogram model was constructed by using multivariate logistic regression analysis. The predictive performance, as well as discrimination efficacy of the model, was evaluated by ROC analysis and calibration plot. Results: Vascular variation ( P =0.028), Myla classification ( P =0.030), length from left subclavian artery to the left subclavian artery ( P =0.017), and angle between common hepatic artery and abdominal aorta ( P =0.017) were identified as important factors associated with the technical complexity of TRA chemoembolization, indicated by fluoroscopy time of the total procedure. The CTA-based nomogram model was established by these abovementioned variables, which demonstrated good predictive ability in both the training cohort (AUC=0.929) and validation cohort (AUC= 0.769), with a high C-index of 0.928 and 0.827 respectively. Moreover, satisfactory calibrations were confirmed by the Hosmer-Lemeshow test with P values of 0.618 and 0.299 in the training cohort and validation cohort. Conclusion: Our study constructs a novel CTA-based nomogram, which can serve as a useful tool to identify ideal candidates for TRA chemoembolization in patients with liver cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background/purpose: Atherosclerosis and diabetes mellitus (DM) are both severe chronic diseases that cause huge burdens on patients' families and societies. Connections between the two diseases have brought high attention recently, however, population-based study with large sample size was few. The study aimed to explore the relationship between carotid atherosclerosis and DM., Methods: We enrolled 3908 adults aged 40-74 years from communities and measured their cardio-metabolic profiles and scanned their carotid arteries bilaterally., Results: The overall prevalence rates of carotid plaque and DM were 34.4 and 10.7%, respectively. The age-specific prevalence rates of DM and carotid plaque were nearly linearly correlated in both sexes (both Pearson's correlation coefficient r > 0.97). The prevalence rates of carotid plaque, total plaque number ≥3, maximum diameter stenosis ≥30%, and plaque score ≥3 were 53.6, 24.8, 19.1, and 28.6%, respectively, in DM patients and were 32.1, 9.4, 9.8, and 11.2%, respectively, in non-DM controls. After adjustment for other conventional risk factors, the multivariable-adjusted OR of having carotid plaque was 1.60 (95% CI 1.27-2.01) and were 2.06 (95% CI 1.55-2.75), 1.33 (95% CI 0.99-1.78), and 2.03 (95% CI 1.55-2.65) for total plaque number ≥3, maximum diameter stenosis ≥30%, and plaque score ≥3, respectively., Conclusion: We demonstrated that prevalences of DM were linearly correlated with prevalences of carotid plaque and DM patients had higher prevalence rates of carotid plaque and more advanced carotid atherosclerosis than non-DM controls. Our results indicated the need to address the role of DM in atherosclerosis development., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Pancreatic acinar cell carcinoma (PACC) is rare, and its appropriate treatment remains unknown. We aim to explore the characteristics and optimal treatment of it., Methods: The data on clinicopathologic characteristics, molecular alteration, treatment, and survival of patients diagnosed with PACC at the Sun Yat-sen University Cancer Center from 2005 to 2020 were collected. The optimal treatment was explored by co-analyzing our results and published literatures., Results: Twenty-two PACC patients were enrolled. Eight of 17 non-metastatic patients received adjuvant chemotherapy. The patients receiving fluoropyrimidine-based regimen (n = 3) had a better median disease-free survival (mDFS) than those with gemcitabine-based regimen (n = 5) (unreached vs 27 months). Eight metastatic patients received first-line chemotherapy. Four patients received second-line chemotherapy. The objective response rate (ORR) of the fluoropyrimidine-based regimen was 85.7% (6/7), much better than that of the gemcitabine-based regimen (0/5). One patient who had responded to the first-line FOLFIRINOX (5-fluorouracil + oxaliplatin + leucovorin + irinotecan) regimen received olaparib as maintenance treatment for 5 months with good tolerance. Thirty-one published literatures, with a total of 86 cases, were included in the co-analysis. The ORR of the first-line fluoropyrimidine-based regimen (n = 47) was higher than that of gemcitabine-based regimen (n = 39) (59.6% vs 15.3%, P  < .001). Eight of 11 patients treated with the FOLFIRINOX regimen achieved partial response (PR)., Conclusions: For patients with metastasis, a fluorouracil-based regimen such as FOLFIRINOX may be preferred, and maintenance treatment of poly ADP-ribose polymerase (PARP) inhibitors after effective platinum-containing treatment for breast cancer susceptibility gene (BRCA) mutation patients must be assessed., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The manuscript has received preprint service on Research Square—https://www.researchsquare.com/article/rs-177880/v1., (© The Author(s) 2022.)

Background: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood., Methods: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors., Results: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors., Conclusions: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.)., (Copyright © 2022 Massachusetts Medical Society.)

Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating β-catenin translocation. In addition, we found that Nup93 interacted with β-catenin directly, independent of importin. Furthermore, LEF1 and β-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-β-catenin pathway for HCC therapeutics., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Gastric cancer (GC) patients with Epstein-Barr virus (EBV) positivity have demonstrated promising response with immunotherapy. We assessed the efficacy and safety of camrelizumab as salvage treatment in EBV-positive mGC. In this single-arm, phase 2 prospective clinical trial (NCT03755440), stage IV EBV-positive GC patients who failed/could not tolerate previous lines of chemotherapy were given intravenous camrelizumab 200 mg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response, and toxicity. Exploratory analysis included the associations between treatment response and tumor mutation burden (TMB), programmed cell death ligand-1 (PD-L1) expression. Six eligible patients were enrolled in the first stage of the study. No patient achieved an objective response; thus, the study did not proceed to the second stage. The DCR was 67% (4/6). The median PFS rate was 2.2 months (95% CI: 1.5-not reached [NR]) and median OS was 6.8 months (95% CI: 1.7-NR). All treatment-related adverse events were grade 1-2, with reactive cutaneous capillary endothelial proliferation (n=4 [67%]) being the most commonly observed event. The only patient with PD-L1 combined positive score >1 had disease progression. Two stable disease and one disease progression were observed in three patients with TMB >10 Mut/Mb. EBV positivity may not be a good predictor for response to camrelizumab in mGC. Newer biomarkers are needed to identify EBV-positive mGC respondents who might benefit from immunotherapy., Competing Interests: None., (AJCR Copyright © 2021.)

Background: The precise pathogenesis of ankylosing spondylitis (AS) is still largely unknown at present. Our previous study found that toll-like receptor 4 (TLR4) downregulated and performed immunoregulatory dysfunction in mesenchymal stem cells from AS patients (AS-MSCs). The aim of this study was to explore the expression profiles of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in TLR4-primed AS-MSCs, and to clarify the potential mechanisms., Methods: The immunoregulatory effects of MSCs were determined after TLR4 activation. Next, the differentially-expressed (DE) lncRNAs and mRNAs between AS-MSCs and TLR4-primed AS-MSCs [stimulated by lipopolysaccharide (LPS)] were identified via high-throughput sequencing followed by quantitative real-time PCR (qRT-PCR) confirmation. Finally, bioinformatics analyses were performed to identify the critical biological functions, signaling pathways, and associated functional networks involved in the TLR4-primed immunoregulatory function of AS-MSCs., Results: A total of 147 DE lncRNAs and 698 DE mRNAs were identified between TLR4-primed AS-MSCs and unstimulated AS-MSCs. Of these, 107 lncRNAs were upregulated and 40 were downregulated (fold change ≥2, P<0.05), while 504 mRNAs were upregulated and 194 were downregulated (fold change ≥2, P<0.05). Five lncRNAs and five mRNAs with the largest fold changes were respectively verified by qRT-PCR. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated that the DE mRNAs and lncRNAs were highly associated with the inflammatory response, such as NOD-like receptor (NLR) signaling pathway, the TNF signaling pathway and the NF-κB signaling pathway. Cis-regulation prediction revealed eight novel lncRNAs, while trans-regulation prediction revealed 15 lncRNAs, respectively. Eight core pairs of lncRNA and target mRNA in the lncRNA-transcription factor (TF)-mRNA network were as follows: PACERR-PTGS2, LOC105378085-SOD2, LOC107986655-HIVEP2, MICB-DT-MICB, LOC105373925-SP140L, LOC107984251-IFIT5, LOC112268267-GBP2, and LOC101926887-IFIT3, respectively., Conclusions: TLR4 activation in AS can enhance the immunoregulatory ability of MSCs. Eight core pairs of lncRNA and target mRNA were observed in TLR4-primed AS-MSCs, which could contribute to understanding the potential mechanism of AS-MSC immunoregulatory dysfunction., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-5020). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic., Competing Interests: Declaration of interests O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine, Merck, Prelude Therapeutics, and Janssen, and is on the scientific advisory board of Envisagenics, Pfizer Boulder, and AIChemy. O.A.-W. has received prior research funding from Loxo Oncology and H3 Biomedicine unrelated to this work. S.X.L. has served as a consultant (uncompensated) for PTC Therapeutics. B.R. has served as a consultant for Bayer and Roche. D.Z. reports clinical research support to his institution from Astra Zeneca, Plexxikon, and Genentech and personal/consultancy fees from Merck, Synlogic Therapeutics, Tesaro, Bristol Myers Squibb (BMS), Genentech, Xencor, Memgen, Calidi Biotherapeutics, and Agenus. L.A.D. is a member of the board of directors of Personal Genome Diagnostics (PGDx) and Jounce Therapeutics. L.A.D. is a compensated consultant to PGDx, 4Paws (PetDx), Innovatus CP, Se’er, Delfi, Kinnate, and Neophore. L.A.D. is an uncompensated consultant for, but has received clinical trial support from, Merck. L.A.D. holds equity in PGDx, Jounce, Se’er, Delfi, Kinnate, and Neophore and divested equity in Thrive Earlier Detection in 2021. His spouse holds equity in Amgen. J.D.W. is a consultant for Amgen, Apricity, Arsenal IO, Ascentage Pharma, AstraZeneca, Astellas, Boehringer Ingelheim, BMS, Chugai, Dragonfly, F Star, Eli Lilly, Georgiamune, IMVAQ, Merck, Polynoma, Psioxus, Recepta, Trieza, Truvax, Sellas, and Werewolf Therapeutics. J.D.W. has grant/research support from BMS and Sephora. J.D.W. reports equity in Tizona Pharmaceuticals, Imvaq, Beigene, Linneaus, Apricity, Arsenal IO, and Georgiamune. T.M. is an inventor on patents involving the use of anti-PD-1 antibodies. T.M. is a consultant for Immunos Therapeutics and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ. T.M. receives research funding from BMS, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea Therapeutics. S.X.L., O.A.-W., and R.K.B. are inventors on a patent application submitted by FHCRC related to this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pathologic diagnosis of hepatocellular carcinoma (HCC) can be challenging in differentiating from benign and non-hepatocytic malignancy lesions. The aim of this study was to investigate the potential utility of α-fetoprotein (AFP) mRNA RNAscope, a sensitive and specific method, in the diagnosis of HCC., Methods: Three independent retrospective cohorts containing 2216 patients with HCC, benign liver lesions, and non-hepatocytic tumours were examined. AFP was detected using ELISA, IHC (Immunohistochemistry), and RNAscope. Glypican3 (GPC3), hepatocyte paraffin-1 (HepPar-1), and arginase-1 (Arg-1) proteins were detected using IHC., Results: AFP RNAscope improved the HCC detection sensitivity by 24.7-32.7% compared with IHC. In two surgical cohorts, a panel of AFP RNAscope and GPC3 provided the best diagnostic value in differentiating HCC from benign hepatocytic lesions (AUC = 0.905 and 0.811), and a panel including AFP RNAscope, GPC3, HepPar-1, and Arg-1 yielded the best AUC (0.971 and 0.977) when distinguishing HCC from non-hepatocytic malignancies. The results from the liver biopsy cohort were similar, and additional application of AFP RNAscope improved the sensitivity by 18% when distinguishing HCC from benign hepatocytic lesions., Conclusions: AFP mRNA detected by RNAscope is highly specific for hepatocytic malignancy and may serve as a novel diagnostic biomarker for HCC.

Importance: Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone., Objective: To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant., Design, Setting, and Participants: Clinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months)., Interventions: Eight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8])., Main Outcomes and Measures: The primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates., Results: Forty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10-5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths., Conclusions and Relevance: In this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS.

Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma., Methods: In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10 -5 ) up to a maximum of 5 years. Patients who completed at least four cycles of treatment were included in the analysis of the primary endpoint, and patients who had completed at least one dose of treatment on protocol were assessable for secondary endpoints. The study was registered at ClinicalTrials.gov, NCT02538198, and is now closed to accrual., Findings: Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p<0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug., Interpretation: Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease., Funding: Memorial Sloan Kettering and Celgene., Competing Interests: Declaration of interests MA reports personal fees from Invivoscribe, Biocartis, and AstraZeneca, outside the submitted work. BD reports personal fees from Medscape, outside the submitted work. ADo reports grants from Roche; grants and personal fees from Takeda; and personal fees from PeerView, Physician's Education Resource (PER), Seattle Genetics, and EUSA Pharma, outside the submitted work. SG reports personal fees and advisory role (scientific advisory board) from Actinnum, Celgene, Bristol Myers Squibb, Sanofi, Amgen, Pfizer, GlaxoSmithKline, JAZZ, Janssen, Omeros, Takeda, and Kite, outside the submitted work. HH reports grants from Celgene, during the conduct of the study; and grants from Celgene, Takeda, and Janssen, outside the submitted work. CH reports Honorarium from Invivoscribe, outside the submitted work. MH reports research funding from the Swedish Blood Cancer Foundation, the Karolinska Institute Foundations, and clinical trial collaborations with GlaxoSmithKline, Amgen, and Daiichi Sankyo. NK reports research funding through Amgen and participates in advisory board with Medimmune. OLah reports serving on Advisory Board for MorphoSys. OLan reports grants from Amgen, Janssen, and Takeda; Data Monitoring Committee from Janssen, Merck, and Takeda; and personal fees from Amgen, Janssen, GlaxoSmithKline, AstraZeneca, and The Binding Site, outside the submitted work. AML reports grants from Novartis, during the conduct of the study; grants from Bristol Myers Squibb; personal fees from Trillium Therapuetics; grants, personal fees and non-financial support from Pfizer; and grants and personal fees from Janssen, outside the submitted work. AML also has a patent US20150037346A1 with royalties paid. SM reports research funding from Allogene Therapeutics, Juno/Bristol Myers Squibb, Takeda Oncology, and Janssen Oncology; personal fees from Plexus communication, and Physician Education Resource, outside the submitted work. MS reports personal fees and other from Angiocrine Bioscience and Omeros Corporation; personal fees from McKinsey & Company, Kite, and i3Health, outside the submitted work. GLS reports research funding from Janssen and Amgen outside the submitted work. US reports personal fees from Physicians Educations Resources; grants and other from Celgene/Bristol Myers Squibb; other from Janssen; and grants from Parker Institute for Cancer Immunotherapy and Myeloma Crowd, outside the submitted work. ELS reports personal fees from Bristol Myers Squibb, Fate Therapuetics, Precision Biosciences, and Chimera Therapuetics, outside the submitted work. ELS has several patents for varying CAR T cells and antibody products for multiple myeloma with royalties paid to Bristol Myers Squibb. CT reports other from Janssen Research and Development outside the submitted work. KT reports non-financial support from The Binding Site; and grants and personal fees from Sebia, outside the submitted work. DJC, ADe, SD, HJL, SXL, KM, FM, KM, TP, LR, MR, and EHR declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

A liquid chromatography-tandem mass spectrometry assay was developed and qualified for the multiplexed quantitation of a small molecule stimulator of soluble guanylate cyclase (sGC) and its target engagement biomarker, 3',5'-cyclic guanosine monophosphate (cGMP), in ocular tissues and plasma from a single surrogate matrix calibration curve. A surrogate matrix approach was used in this assay due to the limited quantities of blank ocular matrices in a discovery research setting. After optimization, the assay showed high accuracy, precision, and recovery as well as parallelism between the surrogate matrix and the biological matrices (rabbit plasma, vitreous, and retina-choroid). This assay provided pharmacokinetic and target engagement data after intravitreal administration of the sGC stimulator. The nitric oxide-sGC-cGMP pathway is a potential target to address glaucoma. Increasing sGC-mediated production of cGMP could improve aqueous humor outflow and ocular blood flow. The sGC stimulator showed dose-dependent exposure in rabbit vitreous, retina-choroid, and plasma. The cGMP exhibited a delayed yet sustained increase in vitreous humor but not retina-choroid. Multiplexed measurement of both pharmacokinetic and target engagement analytes reduced animal usage and provided improved context for interpreting PK and PD relationships.

Objective: Albumin-to-alkaline phosphatase ratio (AAPR), a newly developed blood biomarker, has been reported to have prognostic value in several types of cancer. This study aimed to investigate the predictive value of AAPR in patients with early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) as initial therapy., Methods: This retrospective study analyzed 445 patients with newly diagnosed HCC undergoing RFA as initial therapy. A series of survival analyses were performed to evaluate the prognostic value of AAPR. Univariate and multivariate analyses were performed to identify independent prognostic factors. An AAPR-based nomogram was constructed, and its predictive performance was validated., Results: Patients with a low AAPR had a significantly reduced recurrence-free survival (RFS) and overall survival (OS) compared with those with a high AAPR. AAPR was found to be an independent prognostic indicator and showed superior discrimination efficacy than other liver function indices. The AAPR-based nomogram had a concordance index value of 0.72 (95% confidence interval [CI]: 0.65-0.79) in the training cohort and 0.72 (95% CI: 0.63-0.81) in the validation cohort, which significantly outperformed other existing staging systems., Conclusions: AAPR serves as a promising indicator of prognosis in patients with early-stage HCC undergoing RFA. The AAPR-based nomogram might contribute to individualized prognosis prediction and clinical decision making.

Background: Inflammation-based prognostic scores have been increasingly used for prognosis prediction in malignant tumors. However, no existing study has comprehensively evaluated these scores in combined hepatocellular-cholangiocarcinoma (cHCC-CCA)., Objective: This study aimed to identify a robust inflammation-based prognostic predictor for cHCC-CCA., Methods: We retrospectively analyzed 220 patients pathologically confirmed as Allen type C cHCC-CCA. The univariate and multivariate analyses were used to explore the associations between clinical variables and prognosis of cHCC-CCA. The propensity score-matching (PSM) was performed to reduce the effects of potential cofounders and selection bias. Finally, the predictive values of different inflammation-based indices were compared by using time-dependent receiver operating characteristic (ROC) curves., Results: The systemic immune-inflammation index (SII) and aspartate aminotransferase to platelet ratio index (APRI) were identified as independent prognostic predictors in multivariate analysis. After PSM, the survival differences were still significant between SII-high group and SII-low group (P= 0.016 for RFS and P= 0.001 for OS). Further ROC analysis showed that the SII harbored the largest 1-, 3- and 5-year area under the curves (AUC) values as compared with other scores., Conclusions: The SII may serve as a preferable predictor of both recurrence-free survival (RFS) and overall survival (OS) in patients with cHCC-CCA.

Background: It is unclear whether catheter ablation (CA) for atrial fibrillation (AF) affects the long-term prognosis in the elderly. This study aims to evaluate the relationship between CA and long-term outcomes in elderly patients with AF., Methods: Patients more than 75 years old with non-valvular AF were prospectively enrolled between August 2011 and December 2017 in the Chinese Atrial Fibrillation Registry Study. Participants who underwent CA at baseline were propensity score matched (1:1) with those who did not receive CA. The outcome events included all-cause mortality, cardiovascular mortality, stroke/transient ischemic attack (TIA), and cardiovascular hospitalization., Results: Overall, this cohort included 571 ablated patients and 571 non-ablated patients with similar characteristics on 18 dimensions. During a mean follow-up of 39.75 ± 19.98 months (minimum six months), 24 patients died in the ablation group, compared with 60 deaths in the non-ablation group [hazard ratio (HR) = 0.49, 95% confidence interval (CI): 0.30-0.79, P = 0.0024]. Besides, 6 ablated and 29 non-ablated subjects died of cardiovascular disease (HR = 0.25, 95% CI: 0.11-0.61, P = 0.0022). A total of 27 ablated and 40 non-ablated patients suffered stroke/TIA (HR = 0.79, 95% CI: 0.48-1.28, P = 0.3431). In addition, 140 ablated and 194 non-ablated participants suffered cardiovascular hospitalization (HR = 0.84, 95% CI: 0.67-1.04, P = 0.1084). Subgroup analyses according to gender, type of AF, time since onset of AF, and anticoagulants exposure in initiation did not show significant heterogeneity., Conclusions: In elderly patients with AF, CA may be associated with a lower incidence of all-cause and cardiovascular mortality., (Copyright and License information: Journal of Geriatric Cardiology 2020.)

[This corrects the article DOI: 10.1158/2643-3230.BCD-20-0102.]., (©2020 American Association for Cancer Research.)

Objective: This study explored the thromboembolism risk of low-risk atrial fibrillation (AF) patients (CHA 2 DS 2 -VASc score of 0 or 1 for male and 1 or 2 for female) with different clinical characteristics to provide the basis for anticoagulation decision-making in these patients. Methods: We prospectively enrolled consecutive 2 862 nonvalvular low-risk AF patients between August 2011 to December 2018 in China-AF (China Atrial Fibrillation Registry) Study, their CHA 2 DS 2 -VASc score was 0 or 1 for male and 1 or 2 for female. According to their age, sex, presence or absence of hypertension, diabetes mellitus, congestive heart failure, and vascular disease at the time of enrolling, patients were divided into CHA 2 DS 2 -VASc score 0 score group, 1 score group, and 2 score group. Patients were followed up every 6 months by outpatient clinic visit or telephone interview. The outcome was a thromboembolic event, including ischemic stroke and systemic embolism. Univariate Cox regression analysis was used to compare the thromboembolism risk between the patients with different risk factors and CHA 2 DS 2 -VASc score 0 group. Results: A total of 2 862 low-risk atrial fibrillation patients were enrolled in this study. 915 patients (32.0%) were female, and age was (55.0±10.7) years old. There were 933 patients (32.6%) in CHA 2 DS 2 -VASc score 0 group, 1 401 patients (49.0%) in score 1 group and 528 patients (18.5%) in score 2 group. During follow-up (median 1.5 years, 5 811.82 person-years), 33 cases of thromboembolic events were recorded, the annual rate of thromboembolism was 0.57% (95% CI 0.40%~0.80%). The number of thromboembolic events in patients with CHA 2 DS 2 -VASc score 0, 1 and 2 were 8, 11 and 14, respectively, and the annual thromboembolism event rates were 0.40% (95% CI 0.20%-0.81%), 0.39% (95% CI 0.22%-0.71%) and 1.34% (95% CI 0.80%-2.27%), respectively. The risk of thromboembolism of CHA 2 DS 2 -VASc score 2 group ( HR =3.53, 95% CI 1.48-8.44; P =0.005), especially female patients aged 65-74 years in CHA 2 DS 2 -VASc score 2 group ( HR =2.67, 95% CI 1.63-4.38; P <0.000) was significantly higher than that in patients of CHA 2 DS 2 -VASc score 0 group. Conclusion: Low-Risk Atrial Fibrillation patients with CHA 2 DS 2 -VASc score 2, especially female patients aged 65-74 years old with CHA 2 DS 2 -VASc score 2 are at higher risk of thromboembolism in low-risk AF patients. For such patients, intensified oral anticoagulant therapy might be helpful to reduce the risk of thrombolism.

To study the seasonal pollution characteristics and sources of water-soluble inorganic ions in atmospheric PM 2.5 in Suqian City, 171 samples were collected at three monitoring points, which were in the water vapor channel, from May 2017 to January 2018. The mass concentrations of PM 2.5 and nine water-soluble inorganic ions were analyzed. The results showed that the annual average concentration of water-soluble inorganic ions in PM 2.5 in Suqian City was (44.08±34.61) μg ·m -3 , accounting for 41.8% of PM 2.5 . The concentrations of these species were in the order of ρ (NO 3 - ) > ρ (SO 4 2- ) > ρ (NH 4 + ) > ρ (ρl - ) > ρ (Na + ) > ρ (Ca 2+ ) > ρ (K + ) > ρ (F - ) > ρ (Mg 2+ ); NO 3 - , SO 4 2- , and NH 4 + accounted for 75.6% of the total water-soluble ions. The annual average ratio of ρ (NO 3 - ) to ρ (SO 4 2- ) was 1.53±0.88, indicating that mobile sources contributed more to PM 2.5 pollution. Based on the correlation analysis of NH 4 + and SO 4 2- , NO 3 - may exist in the form of (NH 4 ) 2 SO 4 , NH 4 HSO 4 , or NH 4 NO 3 . According to the principal component analysis, secondary transformation, industrial pollution, biomass burning, and dust were the major sources of water-soluble inorganic ions. PM 2.5 concentrations were positively related to relative humidity in winter. Water vapor transmission is more likely to promote PM 2.5 accumulation in winter.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O -linked N -acetylglucosamine ( O -GlcNAc) modification, and O -GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O -GlcNAcase (OGA), the enzyme that removes O -GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O -GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O -GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O -GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O -GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O -linked N- acetylglucosamine ( O -GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O -GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies., (Copyright © 2020 by The Author(s).)

Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos ( n = 21), OR = 4.7 (95% confidence interval, 1.3-16.7), and African American Blacks ( n = 33), OR = 3.5 (1.1-11.5), as compared with White patients ( n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated ( P > 0.05) with adverse outcome: hypertension ( n = 56), OR = 2.2 (0.9-5.4); diabetes ( n = 18), OR = 0.9 (0.3-2.9); age >65 years ( n = 63), OR = 1.8 (0.7-4.6); high-dose melphalan with autologous stem cell transplant <12 months ( n = 7), OR = 0.9 (0.2-5.4); and immunoglobulin G <650 mg/dL ( n = 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome., Significance: Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome. See related commentary by Munshi and Anderson, p. 218 . This article is highlighted in the In This Issue feature, p. 215 ., Competing Interests: M. Hultcrantz reports personal fees from Curio Science (consulting) and Intellisphere, LLC (consulting), and grants from the Swedish Blood Cancer Foundation and Karolinska Institute Foundations outside the submitted work. J. Richter reports personal fees from Celgene, Bristol-Myers Squibb, Janssen, Oncopeptides, X4 Pharmaceuticals, Sanofi, Secura Bio, Adaptive Biotechnologies, Antengene, Karyopharm, and AstraZeneca outside the submitted work. C.A. Rosenbaum reports other from Amgen (research funding), Akcea (honoraria), and Celgene (honoraria) outside the submitted work. E.L. Smith reports personal fees from Bristol-Myers Squibb (consultant), Fate Therapeutics (consultant), and Precision Biosciences (consultant) outside the submitted work, as well as patents for CAR T cells for the treatment of multiple myeloma pending, issued, licensed, and with royalties paid from Bristol-Myers Squibb. N. Korde reports personal fees from AstraZeneca (advisory board) and other from Amgen (research funding) outside the submitted work. S. Mailankody reports other from Allogene Therapeutics (research support to institution), Juno/Bristol-Myers Squibb (research support to institution), Janssen (research support to institution), Takeda Oncology (research support to institution), Physician Education Resource [honoraria for continuing medical education (CME) activity], and Plexus Education (honoraria for CME activity) during the conduct of the study. U.A. Shah reports grants from Parker Institute for Cancer Immunotherapy and Celgene, and personal fees from Physicians's Education Resource outside the submitted work. C. Tan reports personal fees from Janssen outside the submitted work. A. Rossi reports other from Bristol-Myers Squibb (advisory board), Janssen (advisory board), and Amgen (advisory board) outside the submitted work. D. Madduri reports other from Foundation Medicine (consultant), Janssen (consultant), Legend (consultant), GlaxoSmithKline (consultant), Sanofi (consultant), Kinevant (consultant), Bristol-Myers Squibb (consultant), and Celgene (consultant) outside the submitted work. A. Chari reports grants and personal fees from Janssen (research funding, advisory board, consultant), Celgene (research funding, advisory board, consultant), Novartis Pharmaceuticals (research funding, advisory board, consultant), Amgen (research funding, advisory board, consultant), Seattle Genetics (research funding, advisory board), and Millenium/Takeda (research funding, consultant); grants from Pharmacyclics (research funding); and personal fees from Bristol-Myers Squibb (consulting), Karyopharm (advisory board, consultant), Sanofi Genzyme (advisory board), Oncopeptides (advisory board), Antengene (consultant), GlaxoSmithKline (advisory board), and Secura Bio (consultant/advisory board) outside the submitted work. M.J. Braunstein reports grants and personal fees from Janssen (research funding, advisory board) and personal fees from Celgene (advisory board), Takeda (advisory board), Karyopharm (advisory board), Amgen (advisory board), and AstraZeneca (advisory board) outside the submitted work. R. Reshef reports personal fees from Gilead, Atara, Magenta, Novartis, Bristol-Myers Squibb, and Pfizer outside the submitted work. F.E. Davies reports personal fees from Adaptive Biotech Roche, Takeda, Sanofi, and Amgen, and grants and personal fees from Bristol-Myers Squibb/Celgene and Janssen outside the submitted work. S. Jagannath reports other from Bristol-Myers Squibb (consulting), Janssen Pharmaceuticals (consulting), Karyopharm Therapeutics (consulting), Legend Biotech (consulting), Sanofi (consulting), and Takeda (consulting) outside the submitted work. S. Lentzsch reports personal fees from Caelum Biosciences (shareholder, patent holder, and scientific advisor), Sorrento, Janssen, and Celularity, and grants from Karyopharm and Sanofi outside the submitted work. O. Landgren reports grants from Amgen, Janssen, and Takeda; personal fees from Amgen (scientific talks), Janssen (scientific talks), and Bristol-Myers Squibb (scientific talks); and other from Janssen (independent data monitoring committee, IDMC), Takeda (IDMC), and Merck (IDMC) outside the submitted work. No potential conflicts of interest were disclosed by the other authors., (©2020 American Association for Cancer Research.)

Background: Epstein-Barr virus-associated gastric cancer (EBVaGC) has unique clinicopathologic features and our present understanding of its treatment outcome is limited. Here, we investigated the clinical outcomes of resectable and metastatic EBVaGC cases with regards to their respective treatment., Methods: We retrieved the data of EBVaGC patients treated at our center from October 2014 to June 2019. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) for stage I-III patients, progression-free survival (PFS) and objective response rate (ORR) for stage IV patients., Results: Patients classified as stage I-III accounted for 83.7% of the total 197 cases analyzed. Two patients had mismatched repair-deficiency. The 5-year OS rate of the entire cohort was 63.51% [95% (confidence interval (CI): 52.31-72.76%]. Tumor-node-metastasis (TNM) stage and gastric stump cancer were identified as independent prognostic factors for OS. The 3- and 5-year DFS rate for stage I-III patients were 83.72% (95% CI: 75.86-89.19%) and 73.83% (95% CI: 60.39-83.32%), respectively. TNM stage III, neural invasion, lymphovascular invasion, and baseline plasma EBV-DNA positive were correlated with shorter DFS. The ORR and disease control rate (DCR) for metastatic EBVaGC patients to first-line therapy were 29.0% and 90.3% (median PFS: 9.8 months), respectively, and to second-line therapy were 25.0% and 75.0%, respectively. Seven patients received anti-PD1 therapy and had an ORR of 28.5% and a median PFS of 2.8 months., Conclusions: EBVaGC patients have few metastases, long DFS, and high DCR. TNM stage and gastric stump cancer were independent prognostic factors for OS., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)