Publications by authors named "Zhi Peng"

137 Publications

Co-Expression with Membrane CMTM6/4 on Tumor Epithelium Enhances the Prediction Value of PD-L1 on Anti-PD-1/L1 Therapeutic Efficacy in Gastric Adenocarcinoma.

Cancers (Basel) 2021 Oct 15;13(20). Epub 2021 Oct 15.

NHC Key Laboratory of Medical Immunology, Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.

Anti-PD-1/L1 immunotherapy has been intensively used in heavily treated population with advanced gastric adenocarcinoma. However, the immunotherapeutic efficacy is low even in PD-L1 positive patients. We aimed to establish a new strategy based on the co-expression of CMTM6/4 and PD-L1 for patient stratification before immunotherapy. By analyzing the data obtained from TCGA and single-cell RNA sequencing at the mRNA level, and 6-color multiplex immunofluorescence staining of tumor tissues in tissue array and 48-case pre-immunotherapy patients at the protein level, we found that CMTM6/4 and PD-L1 co-expressed in both epithelial and mesenchymal regions of gastric adenocarcinoma. The tumor tissues had higher levels of CMTM6/4 expression than their adjacent ones. A positive correlation was found between the expression of CMTM6/4 and the expression of PD-L1 in tumor epithelium. Epithelial co-expression of CMTM6/4 and PD-L1 in gastric tumor region was associated with shorter overall survival but better short-term response to anti-PD-1/L1 immunotherapy. Thus, we developed a predictive model and three pathological patterns based on the membrane co-expression of CMTM6/4 and PD-L1 in tumor epithelial cells for pre-immunotherapy patient screening in gastric adenocarcinoma.
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http://dx.doi.org/10.3390/cancers13205175DOI Listing
October 2021

Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study.

Cancer Commun (Lond) 2021 Oct 19. Epub 2021 Oct 19.

Department of Gastrointestinal Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, P. R. China.

Background: Current treatment options for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization-negative patients. Here, we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer.

Methods: Patients with HER2-overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety.

Results: Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%-33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48-related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48-related.

Conclusions: RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.
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http://dx.doi.org/10.1002/cac2.12214DOI Listing
October 2021

Clinicopathological Characteristics and Response to Chemotherapy in Treatment-Naive Epstein-Barr Virus Associated Gastric Cancer: A Retrospective Study.

Front Oncol 2021 23;11:611676. Epub 2021 Sep 23.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Epstein-Barr virus associated gastric cancer (EBVaGC) is a special subtype of gastric cancer. However, the perioperative treatment plan and the response to chemotherapy are still uncertain.

Methods: We retrospectively enrolled patients diagnosed with EBVaGC from March 2013 to July 2020 in Beijing Cancer Hospital. Clinicopathological characteristics were recorded. Disease-free survival (DFS) were then calculated, and variants affecting DFS were tested in a Cox proportional regression model.

Results: One hundred sixty consecutive patients were finally included in our study. Of the patients, 96.9% had adenocarcinoma, while five had squamous cell carcinoma component. Most (70.9%) of them were poorly differentiated. Prevalent programmed death-ligand 1 (PD-L1) (69%) and minor HER-2 (3.8%) expression were noticed; all of the patients were MMR proficient (pMMR) or microsatellite stable (MSS). Among 33 patients who experienced neoadjuvant therapy, the number of tumor regression grade (TRG) 1, TRG 2, and TRG 3 was 5, 16, and 12, respectively. Patients with advanced tumor stage and T stage showed poorer response. Thirty-one patients experienced first-line chemotherapy; ORR was 33.3%, and DCR was 61.9%. One hundred forty-seven patients underwent surgery, and 27 of them showed disease recurrence; the 3-year DFS rate was 71.0%. Tumor stage, neoadjuvant chemotherapy, vascular invasion, and negative PD-L1 expression were associated with poorer DFS. Vascular invasion was the independent risk factor of DFS. Only seven patients reached OS with median follow-up time of 14 months.

Conclusion: EBVaGC exhibits unique clinicopathological characteristics. Neoadjuvant chemotherapy may not be suitable for EBVaGC, and EBVaGC exhibited relatively poor response to chemotherapy.
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http://dx.doi.org/10.3389/fonc.2021.611676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495155PMC
September 2021

Alterations in DNA damage response and repair genes as potential biomarkers for immune checkpoint blockade in gastrointestinal cancer.

Cancer Biol Med 2021 Sep 28. Epub 2021 Sep 28.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China.

Objective: Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer.

Methods: We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, = 227), the Janjigian cohort ( = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment.

Results: In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration.

Conclusions: The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0708DOI Listing
September 2021

Current Status and Future Perspective of Immunotherapy in Gastrointestinal Cancers.

Innovation (N Y) 2020 Aug 10;1(2):100041. Epub 2020 Aug 10.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, No. 52 FuCheng Road, Hai-Dian District, Beijing, 100142, China.

Gastrointestinal (GI) cancers represent a major public health problem worldwide. Due to the late detection and high heterogeneity of GI cancers, traditional treatments, including surgery, radiotherapy, chemotherapy, and targeted therapy, have shown limited effects, and the overall prognosis of these patients remains poor. Recently, immunotherapy, involving programmed cell death-1 (PD-1) and its ligand (PD-L1), has shown promising efficacy in several solid cancers and seems to have become a potential treatment option for GI cancers This review focuses on data on the development of immunotherapy-based clinical trials in esophageal cancer, gastric cancer, and colorectal cancer. The predictive biomarkers and combination strategies in clinical trials and translational medicine are also discussed. Finally, prospects for immunotherapy in the treatment of GI cancers are described. Although only a small proportion of patients with GI cancers respond to PD-1/PD-L1 blockade, we strongly believe that precision immunotherapy might improve the overall survival of many more GI cancer patients in the future.
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http://dx.doi.org/10.1016/j.xinn.2020.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454608PMC
August 2020

The Significance of MET Expression and Strategies of Targeting MET Treatment in Advanced Gastric Cancer.

Front Oncol 2021 7;11:719217. Epub 2021 Sep 7.

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.

Background: Accurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC).

Methods: MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. gene amplification was assessed by chromogenic hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells and , and the underlying molecular mechanisms were analyzed by western blot.

Results: MET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth and in MKN45 cells with MET and phosphorylated MET (pMET) high expressions suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity.

Conclusions: MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.
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http://dx.doi.org/10.3389/fonc.2021.719217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453156PMC
September 2021

Osteoblast Response to Copper-Doped Microporous Coatings on Titanium for Improved Bone Integration.

Nanoscale Res Lett 2021 Sep 20;16(1):146. Epub 2021 Sep 20.

Department of Orthopaedics, Guizhou Provincial People's Hospital, Guiyang, 550002, Guizhou, China.

Due to their excellent mechanical properties and good biocompatibility, titanium alloys have become a popular research topic in the field of medical metal implants. However, the surface of the titanium alloy does not exhibit biological activity, which may cause poor integration between the interface of the titanium implant and the interface of the bone tissue and subsequently may cause the implant to fall off. Therefore, surface biological inertness is one of the problems that titanium alloys must overcome to become an ideal orthopedic implant material. Surface modification can improve the biological properties of titanium, thereby enhancing its osseointegration effect. Copper is an essential trace element for the human body, can promote bone formation and plays an important role in maintaining the physiological structure and function of bone and bone growth and development. In this study, a microporous copper-titanium dioxide coating was prepared on the surface of titanium by microarc oxidation. Based on the evaluation of its surface characteristics, the adhesion, proliferation and differentiation of MC3T3-E1 cells were observed. A titanium rod was implanted into the rabbit femoral condyle, and the integration of the coating and bone tissue was evaluated. Our research results show that the microporous copper-titanium dioxide coating has a nearly three-dimensional porous structure, and copper is incorporated into the coating without changing the structure of the coating. In vitro experiments found that the coating can promote the adhesion, proliferation and differentiation of MC3T3-E1 cells. In vivo experiments further confirmed that the titanium copper-titanium dioxide microporous coating can promote the osseointegration of titanium implants. In conclusion, copper-titanium dioxide microporous coatings can be prepared by microarc oxidation, which can improve the biological activity and biocompatibility of titanium, promote new bone formation and demonstrate good osteoinductive properties. Therefore, the use of this coating in orthopedics has potential clinical application.
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http://dx.doi.org/10.1186/s11671-021-03602-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452820PMC
September 2021

Appropriate PD-L1 Cutoff Value for Gastric Cancer Immunotherapy: A Systematic Review and Meta-Analysis.

Front Oncol 2021 1;11:646355. Epub 2021 Sep 1.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Immunotherapy dramatically changed the treatment landscape of gastric cancer in recent years. PD-L1 expression was proposed as a biomarker; however, the treatment strategy according to PD-L1 is still uncertain. Here, we aimed to find the appropriate cutoff value of PD-L1 expression for gastric cancer immunotherapy.

Methods: We did a systematic electronic research of prospective clinical trials of gastric cancer immunotherapy across databases. Studies that provided subgroup analysis results stratified by PD-L1 expression were included. Objective response rate (ORR), disease control rate (DCR), hazard ratio (HR), and 95% confidential interval (CI) of progression-free survival (PFS) and overall survival (OS) at different PD-L1 cutoff values were extracted.

Results: Twelve studies and 6,488 patients in total were finally included for pooled analysis. ORR in allover, PD-L1-negative, combined positive score (CPS) ≥1, CPS ≥5, and CPS ≥10 population was 10%, 3%, 13%, 20%, and 23%, respectively. Immune checkpoint inhibitor (ICI) monotherapy failed to show survival advantage in allover and PD-L1-negative patients. Single-agent ICI therapy prolonged OS (HR = 0.84, 95% CI: 0.74-0.96) but not PFS (HR = 1.38, 95% CI: 0.91-2.09) in PD-L1 CPS ≥1 patients. For combined immunotherapy, ORR in allover, PD-L1-negative, CPS ≥1, CPS ≥5, and CPS ≥10 population was 64%, 57%, 48%, 60%, and 58%, respectively. Allover population could gain survival benefit from combined immunotherapy based on the results from Checkmate-649. OS (HR = 0.81, 95% CI: 0.71-0.92) and PFS (HR = 0.77, 95% CI: 0.69-0.86) were significantly prolonged in PD-L1 CPS ≥1 patients receiving combined immunotherapy.

Conclusion: Efficacy and survival advantages improved with PD-L1 CPS. CPS ≥1 was the cutoff value for ICI monotherapy to gain survival benefit. Combined immunotherapy prolonged PFS and OS in allover population but needs further study to confirm it.
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http://dx.doi.org/10.3389/fonc.2021.646355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440909PMC
September 2021

Comprehensive analysis of pathological changes in hip joint capsule of patients with developmental dysplasia of the hip.

Bone Joint Res 2021 Sep;10(9):558-570

Orthopaedic Department, 920th Hospital of Joint Logistics Support Force, Kunming, China.

Aims: Developmental dysplasia of the hip (DDH) is a complex musculoskeletal disease that occurs mostly in children. This study aimed to investigate the molecular changes in the hip joint capsule of patients with DDH.

Methods: High-throughput sequencing was used to identify genes that were differentially expressed in hip joint capsules between healthy controls and DDH patients. Biological assays including cell cycle, viability, apoptosis, immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were performed to determine the roles of the differentially expressed genes in DDH pathology.

Results: More than 1,000 genes were differentially expressed in hip joint capsules between healthy controls and DDH. Both gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that extracellular matrix (ECM) modifications, muscle system processes, and cell proliferation were markedly influenced by the differentially expressed genes. Expression of Collagen Type I Alpha 1 Chain (COL1A1), COL3A1, matrix metalloproteinase-1 (MMP1), MMP3, MMP9, and MMP13 was downregulated in DDH, with the loss of collagen fibres in the joint capsule. Expression of transforming growth factor beta 1 (TGF-β1) was downregulated, while that of TGF-β2, Mothers against decapentaplegic homolog 3 (SMAD3), and WNT11 were upregulated in DDH, and alpha smooth muscle actin (αSMA), a key myofibroblast marker, showed marginal increase. In vitro studies showed that fibroblast proliferation was suppressed in DDH, which was associated with cell cycle arrest in G0/G1 and G2/M phases. Cell cycle regulators including Cyclin B1 (CCNB1), Cyclin E2 (CCNE2), Cyclin A2 (CCNA2), Cyclin-dependent kinase 1 (CDK1), E2F1, cell division cycle 6 (CDC6), and CDC7 were downregulated in DDH.

Conclusion: DDH is associated with the loss of collagen fibres and fibroblasts, which may cause loose joint capsule formation. However, the degree of differentiation of fibroblasts to myofibroblasts needs further study. Cite this article:  2021;10(9):558-570.
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http://dx.doi.org/10.1302/2046-3758.109.BJR-2020-0421.R2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479563PMC
September 2021

Cu-Co Co-Doped Microporous Coating on Titanium with Osteogenic and Antibacterial Properties.

J Biomed Nanotechnol 2021 Jul;17(7):1435-1447

Department of Stomatology, The 7th Medical Center, Chinese PLA General Hospital, Beijing 100700, China.

Titanium (Ti) and its alloys are widely used in bone surgery by virtue of their excellent mechanical properties and good biocompatibility; however, complications such as loosening and sinking have been reported post-implantation. Herein we deposited a copper-cobalt (Cu-Co) co-doped titanium dioxide (TUO) coating on the surface of Ti implants by microarc oxidation. The osteogenic and antimicrobial properties of the coating were evaluated by experiments, and we also assessed -catenin expression levels on different sample surfaces. Our results revealed that the coating promoted the adhesion, proliferation, and differentiation of MG63 osteoblasts, and TUO coating promoted -catenin expression; moreover, the proliferation of was inhibited. To summarize, we report that Cu-Co co-doping can enhance the osteogenic and antibacterial activities of orthopedic Ti implants, leading to potentially improved clinical performance.
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http://dx.doi.org/10.1166/jbn.2021.3120DOI Listing
July 2021

Body Composition Measurement Improved Performance of GLIM Criteria in Diagnosing Malnutrition Compared to PG-SGA in Ambulatory Cancer Patients: A Prospective Cross-Sectional Study.

Nutrients 2021 Aug 10;13(8). Epub 2021 Aug 10.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Day Oncology Unit, Peking University Cancer Hospital & Institute, Beijing 100142, China.

Background And Aims: Muscle mass reduction (MMR) is one of the three etiologic criteria in the Global Leadership Initiative on Malnutrition (GLIM) framework. This study aimed to evaluate the value of MMR in GLIM criteria among ambulatory cancer patients.

Methods: A single-center prospective cross-sectional study was conducted. All participants underwent calf circumference (CC) measurement and body composition measurement by bioelectrical impedance analysis (BIA). MMR was identified by CC, fat-free mass index (FFMI), appendicular skeletal muscle index (ASMI), or combinations of the above three indicators. Patients-generated Subjective Global Assessment (PG-SGA) was used as the comparator.

Results: A total of 562 cancer patients receiving intravenous treatment were evaluated. Of the participants, 62.8% (355/562) were male. The median age of the patients was 59.0 years (range, 21-82 y). The median BMI was 22.8 kg/m (range, 14.6-34.5 kg/m). A total of 41.8% of patients were evaluated as malnutrition (PG-SGA ≥ 4), and 11.9% were diagnosed with severe malnutrition (PG-SGA ≥ 9). For the GLIM criteria, the prevalence of malnutrition was 26.9%, and severe malnutrition was 12.3%. For all criteria combinations of GLIM together versus PG-SGA, sensitivity was 60.4% (53.8-66.7), specificity was 97.9% (95.4-99.1), while the accordance between GLIM and PG-SGA was moderate (κ = 0.614). The performance of the GLIM worsened when MMR was excluded (κ = 0.515), with reduced sensitivity (50.2% (43.7-56.8)) and the same specificity (97.9% (95.4-99.1)). Including FFMI and ASMI by BIA can further improve the performance of GLIM than using CC alone (κ = 0.614 vs. κ = 0.565).

Conclusions: It is important to include MMR in the GLIM framework. Using body composition measurement further improves the performance of the GLIM criteria than using anthropometric measurement alone.
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http://dx.doi.org/10.3390/nu13082744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400685PMC
August 2021

The Inconsistent and Inadequate Reporting Of Immune-Related Adverse Events in PD-1/PD-L1 Inhibitors: A Systematic Review of Randomized Controlled Clinical Trials.

Oncologist 2021 Aug 16. Epub 2021 Aug 16.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People's Republic of China.

Background: Immune-related adverse events (irAEs) are of great interest and importance in clinical practice, and many deficiencies and controversies have been noted in the reporting of irAEs. Herein, we aimed to evaluate the current status of irAE reporting in randomized controlled clinical trials (RCTs) of PD-1/PD-L1 inhibitors and to attempt to explain and solve the current pitfalls associated with this reporting.

Materials And Methods: We conducted a systematic review across multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library. The RCTs that compared PD-1/PD-L1 inhibitors with standard treatments were included. The Harms extension of the Consolidated Standards of Reporting Trials (CONSORT) was used to evaluate the completeness of irAE reporting.

Results: A total of 44 articles and 23,759 patients were included in the analysis. The terminology of the irAEs changed over time (p = .01) and was different among immune checkpoint inhibitors (ICIs) (p = .005). Twenty-two of the studies provided a definition of irAE, but only four of them concretely addressed this definition. The incidence of any grade of irAEs ranged from 16.9% to 96%, whereas grade 3-4 irAE ranged from 2% to 23%. The RCTs with combined therapy exhibited a higher incidence of grade 3-4 irAEs (p = .012). Thirty-two studies reported irAEs in the control arms, whereas seven studies reported irAEs only in the experimental arms. Respiratory, endocrine, and gastrointestinal disorders were the most commonly reported irAEs. IrAEs were generally neglected in the introduction or conclusion sections in all of the study reviews and were never subjected to subgroup analyses. Moreover, withdrawals due to severe irAEs, as well as clarifications of the irAE collection methods, were also poorly reported. RCTs using combination therapies in the experimental arms were associated with a higher reporting quality (p = .032). However, the completeness of the reporting did not improve over the last 5 years (p = .076).

Conclusion: The reporting of irAEs was inadequate, and there are still inconsistencies and controversies in the reporting of irAEs. In the future, authors should be encouraged to adhere to the Harms extension of the CONSORT statement.

Implications For Practice: PD-1/PD-L1 inhibitors profoundly changed the landscape of cancer treatment, and thousands of randomized controlled clinical trials (RCTs) were active or completed over the past decade. However, different from chemotherapy or targeted therapy, the profile of immune-related adverse effects (irAE) was unique. An understanding of irAEs is developed mainly from clinical trials; however, inconsistencies and controversies between trials were noted. This study primarily reviewed the evolution of irAE terminology and definitions and evaluated the reporting quality of each RCT. It was found that RCTs using combined immunotherapy were associated with higher quality of irAE reporting. This article identifies the controversies and deficiencies in current irAE reporting and provides possible explanations and suggestions for these inadequacies.
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http://dx.doi.org/10.1002/onco.13940DOI Listing
August 2021

Response to the rechallenge of combination immunotherapy in a patient with late-stage gastric cancer: case report.

Ann Palliat Med 2021 Jun 11. Epub 2021 Jun 11.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China.

Until present, late-stage gastric cancer (GC) remains a refractory disease featured with poor prognosis. However, the upcoming era of immunotherapy turns situations around. Programmed death-1 receptor (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade, an option of immune checkpoints inhibiting, has gained approval for the third-line treatment of patients with locally advanced and/or metastatic GC. Despite its efficacy in a few tumor subtypes, most patients are insensitive to anti-PD-1 monotherapy. Therefore, growing interests arise in combination immunotherapy. To explore the maximal potentials of ICI, oncologists also focus on ICI rechallenge. Here we present a patient with unresected stage IV, Epstein-Barr virus (EBV) unrelated, microsatellite stable and HER2 heterogeneously expressed gastric adenocarcinoma who experienced the failures of previous immunotherapy. He was then rechallenged with identical ICI regime combined with tyrosine kinase inhibiting and anti-HER2 therapy. The patient responded and tolerated well to this regimen and survived with fair living quality after 28 months of treatment. This case suggests that patients who fail frontline immunotherapy still possibly benefit from rechallenge of the same anti-PD-1 regimen. Besides, combination of ICI and other target agents might intrigue a synergistic effect, resulting in enhanced anti-tumor effect, which provides a meaningful therapeutic strategy. Relevant studies are underway of investigation and might be a hotspot for future research.
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http://dx.doi.org/10.21037/apm-21-83DOI Listing
June 2021

Association of Lymphocyte-to-Monocyte Ratio With Survival in Advanced Gastric Cancer Patients Treated With Immune Checkpoint Inhibitor.

Front Oncol 2021 1;11:589022. Epub 2021 Jun 1.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Optimal prognostic biomarkers for patients with gastric cancer who received immune checkpoint inhibitor (ICI) are lacking. Inflammatory markers including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) are easily available. However, its correlation with ICI is unknown in gastric cancer. Here, we evaluated the potential association between LMR, PLR, and SII with clinical outcomes in gastric cancer patients undergoing ICI therapy.

Methods: We examined LMR, PLR, SII at baseline, and 6 (± 2) weeks later in 139 patients received ICI therapy between August 2015 and April 2019 at Peking University Cancer Hospital (Beijing, China). Landmark analysis at 6 weeks was conducted to explore the prognostic value of LMR, PLR, and SII on progress-free survival (PFS), and overall survival (OS). A Cox proportional hazards model was used to compute mortality hazard ratios (HRs) for LMR, adjusting for potential confounders including age, sex, ECOG, tumor location, tumor differentiation, tumor stage, line of therapy, and type of anti-PD-1/PD-L1 therapy.

Results: Among 139 patients, 103 (74.1%) were male, median age was 60 years. Median duration of therapy was 6 cycles. We observed that both LMR at baseline and week 6 were independent prognostic factors. Patients with a higher LMR (≥ 3.5) at baseline or week 6 had superior PFS [baseline: HR 0.58, 95% confidence interval (CI): 0.38-0.91; week 6: HR 0.48, 95% CI: 0.29-0.78] and OS (baseline: HR 0.38, 95% CI: 0.24-0.62; week 6: HR 0.52, 95% CI: 0.31-0.88) compared with patients with a lower LMR (< 3.5). Furthermore, for patients with both LMR ≥ 3.5 at baseline and LMR ≥ 3.5 at week 6 were estimated to have much better PFS (HR 0.41, 95% CI: 0.23-0.72) and OS (HR 0.34, 95% CI: 0.18-0.64) than patients with both LMR < 3.5 at baseline and LMR < 3.5 at week 6.

Conclusions: Baseline and early changes in LMR were strongly associated with survival in gastric cancer patients who received ICI therapy, and may serve to identify patients most likely to benefit from ICI.
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http://dx.doi.org/10.3389/fonc.2021.589022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203902PMC
June 2021

Dysregulated KRAS gene-signaling axis and abnormal chromatin remodeling drive therapeutic resistance in heterogeneous-sized circulating tumor cells in gastric cancer patients.

Cancer Lett 2021 Oct 11;517:78-87. Epub 2021 Jun 11.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Electronic address:

The mechanism by which heterogeneous-sized circulating tumor cells (CTCs) in gastric cancer (GC) patients are resistant to the targeted therapy and/or chemotherapy remains unclear. This study investigated prognostic value and genomic variations of size-heterogenous CTCs, in an attempt to unravel the molecular mechanisms underlying the therapeutic resistance, which is relevant to poor prognosis in GC. Aneuploid CTCs, detected in 111 advanced GC patients, were categorized into small (≤white blood cell [WBC], 25.54%) and large (>WBC, 74.46%) cells. Pre-treatment patients possessing ≥3 baseline small CTCs with trisomy 8 (CTCs) or ≥6 large multiploid CTCs (CTCs) showed an inferior median progression-free survival. Moreover, the cut-off value of ≥6 CTCs was also an effective prognosticator for poor median overall survival. Single cell-based DNA sequencing of 50 targeted CTCs indicated that CTCs and CTCs harbored distinct gene variations respectively. Mutations in the KRAS and Rap1 pathway were remarkably abundant in CTCs, whereas several unique mutations in the MET/PI3K/AKT pathway and SMARCB1 gene were identified in CTCs. Obtained results suggested that CTCs and CTCs exhibited different mechanisms to therapy resistance and correlated with patients' poor outcome.
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http://dx.doi.org/10.1016/j.canlet.2021.06.002DOI Listing
October 2021

Clinicopathological features and lymph node and distant metastasis patterns in patients with gastroenteropancreatic mixed neuroendocrine-non-neuroendocrine neoplasm.

Cancer Med 2021 07 10;10(14):4855-4863. Epub 2021 Jun 10.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, China.

Objective: Owing to its rarity and heterogeneity, the biological behavior and optimal therapeutic management of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) have not been established. Herein, we aimed to evaluate the clinicopathological characteristics and metastatic patterns of MiNEN.

Methods: Continuous clinicopathological data of MiNEN patients treated at our hospital were retrospectively collected and analyzed.

Results: This study had enrolled 169 patients since January 2010 to January 2020. Pathological components were assessed in 129 patients with MiNEN (76.3%), and a focal (non-)neuroendocrine component was observed in 40 patients (23.7%; <30% of the tumor). Among the enrolled patients, 80 underwent surgical removal of the primary tumor and lymph nodes (LNs), and 34 with distant metastasis underwent biopsy of both primary tumor and metastatic lesions. In patients with LN metastasis, 68.8% (55/80) exhibited a pure component of either neuroendocrine (NE) or adenocarcinoma/squamous carcinoma (AS) in metastatic LNs, while 20% (16/80) showed different components in different LNs, and only 11.2% (9/80) exhibited both NE and AS components in the same LN. In patients with distant metastases, 26.5% (9/34) possessed coexisting NE and AS components in the distant metastases, 70.6% (24/34) were regarded as a pure NE component, and 2.9% (1/34) were comprised of a pure AS component.

Conclusion: Lymph node and distant metastases exhibited distinct metastatic patterns in patients with MiNEN. The major pathological component in regional LNs may have influenced the proportion of the two components within the primary tumor, but distant metastases were dominated by the NE component.
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http://dx.doi.org/10.1002/cam4.4031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290235PMC
July 2021

[Bioinformatics Analysis of the Influence of Coronavirus Infection on Hematopoietic System and Potential Intervention Drugs and Their Significance for COVID-19].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 Jun;29(3):975-982

Medical School of Chinese PLA, Beijing 100853,China,Department of Hematology, The Second Medical Center, Chinese PLA General Hospital, Beijing 100853, China,E-mail:

Objective: To analyze and predict the effect of coronavirus infection on hematopoietic system and potential intervention drugs, and explore their significance for coronavirus disease 2019 (COVID-19).

Methods: The gene expression omnibus (GEO) database was used to screen the whole genome expression data related with coronavirus infection. The R language package was used for differential expression analysis and KEGG/GO enrichment analysis. The core genes were screened by PPI network analysis using STRING online analysis website. Then the self-developed apparent precision therapy prediction platform (EpiMed) was used to analyze diseases, drugs and related target genes.

Results: A database in accordance with the criteria was found, which was derived from SARS coronavirus. A total of 3606 differential genes were screened, including 2148 expression up-regulated genes and 1458 expression down-regulated genes. GO enrichment mainly related with viral infection, hematopoietic regulation, cell chemotaxis, platelet granule content secretion, immune activation, acute inflammation, etc. KEGG enrichment mainly related with hematopoietic function, coagulation cascade reaction, acute inflammation, immune reaction, etc. Ten core genes such as PTPRC, ICAM1, TIMP1, CXCR5, IL-1B, MYC, CR2, FSTL1, SOX1 and COL3A1 were screened by protein interaction network analysis. Ten drugs with potential intervention effects, including glucocorticoid, TNF-α inhibitor, salvia miltiorrhiza, sirolimus, licorice, red peony, famciclovir, cyclosporine A, houttuynia cordata, fluvastatin, etc. were screened by EpiMed plotform.

Conclusion: SARS coronavirus infection can affect the hematopoietic system by changing the expression of a series of genes. The potential intervention drugs screened on these grounds are of useful reference significance for the basic and clinical research of COVID-19.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2021.03.051DOI Listing
June 2021

PTCH1 mutation promotes antitumor immunity and the response to immune checkpoint inhibitors in colorectal cancer patients.

Cancer Immunol Immunother 2021 May 24. Epub 2021 May 24.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.

Immunotherapy has emerged as an effective therapeutic strategy for various cancers, including colorectal cancer (CRC), but only a subset of MSI-H patients can benefit from such therapy. Patched1 (PTCH1) is a frequently altered gene in CRCs and its mutations contribute to unregulated Hedgehog (Hh) signaling. In the study, we evaluated the association of PTCH1 mutations with CRC immunity based on our single-center cohort and multiple cancer genomic datasets. Among 21 enrolled patients, six (28.6%) harbored a PTCH1 mutation based on WES analyses. In CRC patients, the PTCH1 mutation subgroup experienced a higher durable clinical benefit rate than the PTCH1 wild-type subgroup (100% vs. 40%, P = 0.017). In addition, patients with the PTCH1 mutation experienced greater progression-free survival (PFS, P = 0.037; HR, 0.208) and overall survival (OS, P = 0.045; HR, 0.185). A validation cohort from the MSKCC also confirmed the correlation between PTCH1 mutation and better prognosis (P = 0.022; HR, 0.290). Mechanically, diverse antitumor immune signatures were more highly enriched in PTCH1-mutated tumors than in PTCH1 wild-type tumors. Furthermore, PTCH1-mutated tumors had higher proportions of CD8 + T cells, activated NK cells, and M1 type macrophage infiltration, as well as elevated gene signatures of several steps in the cancer-immunity cycle. Notably, the PTCH1 mutation was correlated with tumor mutational burden (TMB), loss of heterozygosity score, and copy number variation burden. Our results show that the mutation of PTCH1 is a potential biomarker for predicting the response of CRC patients to immunotherapy.
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http://dx.doi.org/10.1007/s00262-021-02966-9DOI Listing
May 2021

A genomic mutation signature predicts the clinical outcomes of immunotherapy and characterizes immunophenotypes in gastrointestinal cancer.

NPJ Precis Oncol 2021 May 4;5(1):36. Epub 2021 May 4.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.

The association between genetic variations and immunotherapy benefit has been widely recognized, while such evidence in gastrointestinal cancer remains limited. We analyzed the genomic profile of 227 immunotherapeutic gastrointestinal cancer patients treated with immunotherapy, from the Memorial Sloan Kettering (MSK) Cancer Center cohort. A gastrointestinal immune prognostic signature (GIPS) was constructed using LASSO Cox regression. Based on this signature, patients were classified into two subgroups with distinctive prognoses (p < 0.001). The prognostic value of the GIPS was consistently validated in the Janjigian and Pender cohort (N = 54) and Peking University Cancer Hospital cohort (N = 92). Multivariate analysis revealed that the GIPS was an independent prognostic biomarker. Notably, the GIPS-high tumor was indicative of a T-cell-inflamed phenotype and immune activation. The findings demonstrated that GIPS was a powerful predictor of immunotherapeutic survival in gastrointestinal cancer and may serve as a potential biomarker guiding immunotherapy treatment decisions.
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http://dx.doi.org/10.1038/s41698-021-00172-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096820PMC
May 2021

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Gastric Cancer 2021 07 4;24(4):913-925. Epub 2021 May 4.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Hai-Dian District, Fu-Cheng Road 52, Beijing, 100142, China.

Purpose: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.

Patients And Methods: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.

Results: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).

Conclusion: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.

Clinical Trial Information: NCT02881190.
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http://dx.doi.org/10.1007/s10120-021-01168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205919PMC
July 2021

The Positive Effect of ZnS in Waste Tire Carbon as Anode for Lithium-Ion Batteries.

Materials (Basel) 2021 Apr 24;14(9). Epub 2021 Apr 24.

Centre for Clean Environment and Energy, Gold Coast Campus, Griffith University, Gold Coast, QLD 4222, Australia.

There is great demand for high-performance, low-cost electrode materials for anodes of lithium-ion batteries (LIBs). Herein, we report the recovery of carbon materials by treating waste tire rubber via a facile one-step carbonization process. Electrochemical studies revealed that the waste tire carbon anode had a higher reversible capacity than that of commercial graphite and shows the positive effect of ZnS in the waste tire carbon. When used as the anode for LIBs, waste tire carbon shows a high specific capacity of 510.6 mAh·g at 100 mA·g with almost 97% capacity retention after 100 cycles. Even at a high rate of 1 A·g, the carbon electrode presents an excellent cyclic capability of 255.1 mAh·g after 3000 cycles. This high-performance carbon material has many potential applications in LIBs and provide an alternative avenue for the recycling of waste tires.
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http://dx.doi.org/10.3390/ma14092178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122980PMC
April 2021

Flexible Carbon Nanotubes Confined Yolk-Shelled Silicon-Based Anode with Superior Conductivity for Lithium Storage.

Nanomaterials (Basel) 2021 Mar 11;11(3). Epub 2021 Mar 11.

Key Laboratory of Materials Physics, and Anhui Key Laboratory of Nanomaterials and Nanotechnology, Institute of Solid State Physics, Chinese Academy of Sciences, Hefei 230031, China.

The further deployment of silicon-based anode materials is hindered by their poor rate and cycling abilities due to the inferior electrical conductivity and large volumetric changes. Herein, we report a silicon/carbon nanotube (Si/CNT) composite made of an externally grown flexible carbon nanotube (CNT) network to confine inner multiple Silicon (Si) nanoparticles (Si NPs). The in situ generated outer CNTs networks, not only accommodate the large volume changes of inside Si NPs but also to provide fast electronic/ionic diffusion pathways, resulting in a significantly improved cycling stability and rate performance. This Si/CNT composite demonstrated outstanding cycling performance, with 912.8 mAh g maintained after 100 cycles at 100 mA g, and excellent rate ability of 650 mAh g at 1 A g after 1000 cycles. Furthermore, the facial and scalable preparation method created in this work will make this new Si-based anode material promising for practical application in the next generation Li-ion batteries.
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http://dx.doi.org/10.3390/nano11030699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001621PMC
March 2021

Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.

Clin Cancer Res 2021 Jun 25;27(11):3069-3078. Epub 2021 Mar 25.

Department of GI Oncology, Beijing Cancer Hospital, Beijing, P.R. China.

Purpose: Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for unresectable, advanced, or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Camrelizumab shows promising antitumor activity in advanced or metastatic G/GEJ adenocarcinoma in a phase I study. We reported the outcomes of cohort 1 in a multicenter, open-label, phase II trial, which assessed camrelizumab in combination with CAPOX followed by camrelizumab plus apatinib as a first-line combination regimen for advanced or metastatic G/GEJ adenocarcinoma.

Patients And Methods: Systemic treatment-naïve patients with EGFR2-negative advanced or metastatic G/GEJ adenocarcinoma received initial camrelizumab plus CAPOX for 4-6 cycles, and patients without progressive disease were administrated subsequent camrelizumab plus apatinib. Primary endpoint was objective response rate (ORR).

Results: All 48 enrolled patients comprised the efficacy and safety analysis population. The ORR was 58.3% [95% confidence interval (CI), 43.2-72.4] with this combination regimen. Median duration of response was 5.7 months (95% CI, 4.4-8.3). Median overall survival was 14.9 months (95% CI, 13.0-18.6), and median progression-free survival was 6.8 months (95% CI, 5.6-9.5), respectively. The most common grade ≥3 treatment-related adverse events (>10%) were decreased platelet count (20.8%), decreased neutrophil count (18.8%), and hypertension (14.6%). Treatment-related death occurred in 1 patient (2.1%) due to abnormal hepatic function and interstitial lung disease.

Conclusions: Camrelizumab combined with CAPOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first-line therapy for patients with advanced or metastatic G/GEJ adenocarcinoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4691DOI Listing
June 2021

Image-based method for the angular vibration measurement of a linear array camera.

Appl Opt 2021 Feb;60(4):1003-1012

Measurements of angular vibration of aerial cameras in a variety of operating conditions are critical to analyze the performance of the vibration isolation system. Instead of using an additional optical system to measure the angular motion of the camera, an image-based and easy-to-implement method is proposed for the linear array camera to measure the image motions captured by the camera directly. The natural frequencies of the vibration isolation were also measured by laboratory vibration test. For image vibration measuring, the angular vibration is represented in image motion by the relationship between the image motion and angular motion of the camera. Based on the pushbroom imaging principle, the image motion at the edge of the foreground image of the linear object is extracted using image processing technology including image segment and edge detection methods. Then the image motion is analyzed in the time and frequency domains. The proposed method has been successfully demonstrated for the angular vibration measurement by a flight test. The results of the vibration sensors and the position and orientation system of the flight tests are also given to validate the effectiveness and accuracy of the proposed approach.
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http://dx.doi.org/10.1364/AO.413355DOI Listing
February 2021

Magnesium deficiency in liver cirrhosis: a retrospective study.

Scand J Gastroenterol 2021 Apr 1;56(4):463-468. Epub 2021 Mar 1.

Department of Biochemistry and Immunology, Medical Research Center, Institute of Medicine, Jishou University, Jishou, China.

Background: Magnesium, known as "the forgotten electrolyte", is an essential element of life. Magnesium deficiency is implicated in many diseases, including liver cirrhosis. This study aimed to explore the prevalence of magnesium deficiency in liver cirrhosis and investigate the relationship between magnesium levels and complication of liver cirrhosis and clinical outcomes.

Patients And Methods: Cirrhotic patients with serum magnesium levels measured were retrospectively identified from 2016 to 2017. Demographics, laboratory parameters, complications were collected. The Child-Pugh class, MELD score, and ALBI score were calculated.

Results: The mean serum magnesium level of all 152 patients was lower than the normal, including 92 patients diagnosed with magnesium deficiency. Compared to Child-Pugh class A, magnesium levels were significantly lower in the patients with Child-Pugh class B or C ( = 10.26,  < .05). Magnesium levels were also considerably lower in the group with MELD score ≥21, compared to the other two groups with MELD score < 15 or 15-20 ( = 6.59,  < .05). Similarly, magnesium levels were significantly lower in the group with ALBI score > -1.39 (grade 3), compared to the other two groups with ALBI with score ≤ -2.6 (grade 1) or > -2.6, ≤ -1.39 (grade 2) ( = 8.44, <.001). Furthermore, magnesium levels were lower in cirrhotic patients with infection. Magnesium-deficient patients had lower transplant-free survival rates than non-deficient patients.

Conclusion: Magnesium deficiency is highly prevalent in cirrhotic patients. Magnesium deficiency is related to worse transplant-free survival, infection and the severity of liver cirrhosis.
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http://dx.doi.org/10.1080/00365521.2021.1888154DOI Listing
April 2021

Partial splenic embolization combined with endoscopic therapies and NSBB decreases the variceal rebleeding rate in cirrhosis patients with hypersplenism: a multicenter randomized controlled trial.

Hepatol Int 2021 Jun 27;15(3):741-752. Epub 2021 Feb 27.

Department of Gastroenterology, Qilu Hospital of Shandong University, Wenhua Xi Road, 107, Jinan City, 250012, Shandong Province, People's Republic of China.

Background: Global research on endoscopic therapies in combination with partial splenic embolization (PSE) for variceal hemorrhage (VH) is limited. Therefore, we aimed to evaluate the efficacy and safety of endoscopy plus PSE (EP) treatment in comparison to endoscopic (E) treatment for the secondary prophylaxis of VH in cirrhosis patients with hypersplenism.

Methods: Cirrhosis patients with hypersplenism (platelet count < 100, 000/µL) and those who had recovered from an episode of VH were enrolled in a multicenter randomized controlled trial. The participants were randomly assigned into EP and E groups in a 1:1 ratio. The primary endpoint was variceal rebleeding, and the secondary endpoints were severe variceal recurrence and mortality during the 2-year follow-up. Hematological indices, serum biochemical parameters, and the Child-Pugh score were measured at each time point.

Results: From June 2016 to December 2019, 108 patients were enrolled in the study, among which 102 patients completed the protocol (51 in EP and 51 in E group). The rebleeding rate of the varices was significantly reduced in the EP group compared to that in the E group during the 2 years (16% vs. 31%, p < 0.001). The EP group showed a significantly lower variceal recurrence rate than the E group (22% vs. 67%, p < 0.001). The COX proportional hazard models revealed that grouping was an independent predictor for variceal rebleeding (H = 0.122, 95% CI 0.055-0.270, p < 0.001) and variceal recurrence (hazard ratio, H = 0.160, 95% CI 0.077-0.332, p < 0.001). The peripheral blood cell count, Child-Pugh class/score, albumin concentration, and coagulation function in the EP group improved significantly compared to the values observed in the E group at any time point (p < 0.05).

Conclusions: The EP treatment was more effective in preventing variceal rebleeding and variceal recurrence than the conventional E treatment during the secondary prophylaxis of VH in cirrhosis patients with hypersplenism. Furthermore, the EP treatment could significantly increase the peripheral blood cell count and albumin concentration and also improved the coagulation function and the Child-Pugh score.

Clinical Trials Registration: Trial registration number ClincialTrials.gov: NCT02778425. The URL of the clinical trial: https://clinicaltrials.gov/.
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http://dx.doi.org/10.1007/s12072-021-10155-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286949PMC
June 2021

Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review.

Hered Cancer Clin Pract 2021 Jan 9;19(1). Epub 2021 Jan 9.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China.

Background: Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs).

Case Presentation: We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib.

Conclusion: Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.
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http://dx.doi.org/10.1186/s13053-021-00165-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797131PMC
January 2021

Efficacy and Safety of Nab-Paclitaxel Plus S-1 versus Nab-Paclitaxel Plus Gemcitabine for First-Line Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma.

Cancer Manag Res 2020 9;12:12657-12666. Epub 2020 Dec 9.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing 100142, People's Republic of China.

Objective: Nab-paclitaxel plus gemcitabine (nab-P/G) has been established as a standard first-line treatment in metastatic pancreatic ductal adenocarcinoma (PDAC). S-1, as an oral fluoropyrimidine derivative, demonstrated effective for PDAC. This study aimed to evaluate the efficacy and safety of first-line chemotherapy with nab-paclitaxel plus S-1 (nab-P/S) versus nab-P/G in patients with advanced PDAC.

Methods: Patients with advanced PDAC receiving nab-P/S (n = 65) or nab-P/G (n = 45) as first-line chemotherapy between November 2013 and June 2019 were reviewed.

Results: The objective response rate (ORR) and disease control rate were numerically higher with nab-P/S than with nab-P/G (38.5% vs 28.9%, = 0.30, 73.8% vs 66.7%, = 0.42, respectively). ORRs of the primary lesion were similar for both groups (30.8% and 22.2%, = 0.32). The median progression-free survival and overall survival were comparable between the two groups (5.5 vs 5.7 months, = 0.34, 10.2 vs 11.3 months, = 0.74, respectively). Nab-P/S was associated with a numerically lower risk of adverse events, especially hematologic adverse events.

Conclusion: Nab-P/S could be a convenient alternative with similar efficacy and a favorable safety profile compared with nab-P/G as first-line chemotherapy for advanced PDAC, as well as an option for neoadjuvant therapy.
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http://dx.doi.org/10.2147/CMAR.S263773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733895PMC
December 2020

The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration.

Biomaterials 2021 01 23;268:120555. Epub 2020 Nov 23.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, And Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, And Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China. Electronic address:

Osteoarthritis (OA) is a major cause of disability and socioeconomic loss worldwide. However, the current pharmacological approaches used to treat OA are largely palliative. Being the hallmark of OA, the cartilage extracellular matrix (ECM) destruction and abnormal homeostasis is gaining more attention as a therapeutic target in cartilage regeneration. Moreover, during the progression of OA, the cartilage ECM shows significant pathological alternations, which can be promising biomarkers in identifying the pathological stages of OA. In this review, we summarize the role of abnormal ECM homeostasis in the joint cartilage during OA. Furthermore, we provide an update on the cartilage ECM derived biomarkers and regenerative medicine therapies targeting cartilage ECM which includes preclinical animal models study and clinical trials.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120555DOI Listing
January 2021
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