Publications by authors named "Xiaohua Shi"

70 Publications

Betulinic Acid Ameliorates Cerebral Injury in Middle Cerebral Artery Occlusion Rats through Regulating Autophagy.

ACS Chem Neurosci 2021 Aug 23;12(15):2829-2837. Epub 2021 Jul 23.

Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China.

Cerebral ischemic stroke (CIS) is an acute cerebrovascular disease that is caused by the sudden rupture of blood vessels inside the brain and the intervention of reperfusion to the brain, resulting in severe cerebral injury. Autophagy has been reported to be involved in the occurrence and progression of CIS. Betulinic acid (BA) is a pentacyclic triterpene acid mainly extracted from birch bark. Studies have shown the neuroprotective effects of BA. Here, the effect and mechanism of BA on ischemia-reperfusion induced cerebral injury was explored using a CIS model in vivo via 1 h middle cerebral artery occlusion (MCAO) and 24 h reperfusion in rats and in vitro via oxygen-glucose deprivation/reperfusion (OGD/R) of PC12 cells, respectively. We found that BA not only reduced cerebral injury by reducing oxidative stress but also activated the SIRT1/FoxO1 pathway to suppress autophagy and improve cerebral injury in MCAO rats. These results provide a basis for the potential clinical application of BA.
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http://dx.doi.org/10.1021/acschemneuro.1c00198DOI Listing
August 2021

Association of emergence of new mutations in circulating tumuor DNA during chemotherapy with clinical outcome in metastatic colorectal cancer.

BMC Cancer 2021 Jul 22;21(1):845. Epub 2021 Jul 22.

Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.

Background: The understanding of molecular changes in mCRC during treatment could be used to personalise therapeutic strategies. The aim of our study was to explore the association of circulating tumour DNA (ctDNA) with clinical outcome in metastatic colorectal cancer (mCRC).

Methods: Sequential patients with mCRC receiving standard first-line chemotherapy were included prospectively. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Computed tomography (CT) scans were carried out at baseline and post-C4 (8-10 weeks) and were assessed using Response Evaluation Criteria In Solid Tumours version 1.1 (RECIST v1.1). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA.

Results: A total of 20 patients were prospectively included and treated with either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) (15/20) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) (5/20). Median follow-up was 6.9 months (range 1.6-26.6). Somatic mutations for baseline ctDNA analysis were identified in 85% (17/20) of the patients. Mutation variations of ctDNA after chemotherapy were tested in 16/20 (80.0%) of the patients. In multivariate analyses, a high baseline molecular tumour burden index (mTBI) in ctDNA was associated with a higher risk of disease progression, as well as emergence of new mutations in ctDNA during chemotherapy. Patients with newly detected mutations had shorter progression-free survival (PFS) compared to those without (median 3.0 versus 7.3 months; hazard ratio (HR), 5.97; 95% confidence interval (CI), 0.70-50.69; P = 0.0003). Fold changes in mTBI from baseline to post-C4 were obtained in 80.0% (16/20) of the patients, which were also related to PFS. Patients with fold reduction in mTBI above 0.8-fold had longer PFS compared to those below (median 9.3 versus 4.1 months; HR, 4.51; 95% CI, 1.29-15.70; P = 0.0008).

Conclusions: Newly detected mutations in ctDNA during treatment might potentially be associated with clinical outcome in mCRC and may provide important clinical information.
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http://dx.doi.org/10.1186/s12885-021-08309-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296534PMC
July 2021

Perineural invasion as a prognostic factor in laryngeal squamous cell cancer: a matched-pair survival analysis.

Cancer Invest 2021 Jul 7:1-16. Epub 2021 Jul 7.

Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Background: The purpose of this study was to compare survival outcomes in patients with perineural invasion (PNI)-positive laryngeal squamous cell carcinoma (LSCC) and patients with PNI-negative LSCC.

Methods: A total of 1,272 patients with LSCC, diagnosed between 2008 and 2017, were included in this study. LSCC Patients with and without PNI were matched based on possible confounding factors. Survival analysis was performed using Kaplan-Meier estimates and the Cox proportional hazards model.

Results: OF the 1,272 LSCC patients, 118 (9.28%) were positive for PNI. Compared to PNI-negative patients, PNI-positive LSCC patients had significantly worse overall survival (OS) ( = 0.017), disease-specific survival (DSS) ( = 0.034) and recurrence-free survival (RFS) ( = 0.002). After pair matching, cohorts consisted of 118 patients in the PNI-positive group and 118 in the PNI-negative group. Significantly increased risk of OS (HR, 2.17; 95% confidence interval [CI], 1.29-3.61,  = 0.003), DSS (HR, 2.07; 95% CI, 1.32-3.24,  = 0.004) and RFS (HR, 2.65; 95% CI, 1.59-4.40,  < 0.001) was observed after adjustment for prognostic variables.

Conclusions: Patients with PNI-positive LSCC have significantly worse survival outcomes compared to patients with PNI-negative LSCC.
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http://dx.doi.org/10.1080/07357907.2021.1947311DOI Listing
July 2021

CT-Negative Subarachnoid Hemorrhage Caused by Telangiectasia: A Case Report.

Curr Med Imaging 2021 Jun 8. Epub 2021 Jun 8.

Department of Neurology, China-Japan Union Hospital of Jilin University, China.

Introduction: At present, the mechanism of telangiectasia is unknown, but some evidence suggests that it may be related to genetic abnormalities. Telangiectasia may lead to bleeding of multiple sites. CT-negative subarachnoid hemorrhage is rare, which is mostly related to hemorrhage with a little amount of bleeding. CT-negative subarachnoid hemorrhage due to telangiectasia has not been reported.

Case Report: In this case report, the patient experienced severe headache with nausea, vomiting, and blurred vision for 12 days, and had a history of hypertension. Physical examination revealed a clear state of mind, normal speech, normal limb muscle strength, 2 transverse fingers of neck stiffness, and negative bilateral Babinski signs. Brain CT, MRI, MRA, and MRV showed no obvious abnormalities. SWI suggested the possibility of capillary dilation. The cerebrospinal fluid was pale yellow in appearance after lumbar puncture.

Diagnosis: The patient was diagnosed with subarachnoid hemorrhage(SAH) and capillary dilatation.

Interventions: Therapeutic management of blood pressure and brain edema was started.

Conclusion: Lumbar puncture should be performed when subarachnoid hemorrhage is clinically suspected and CT is negative. While searching for the cause of subarachnoid hemorrhage, the presence of telangiectasia should be ascertained.
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http://dx.doi.org/10.2174/1573405617666210608163746DOI Listing
June 2021

The effect of adjuvant treatment in chronic pelvic inflammation by Fukejing capsules and its influence on hemorheology and inflammatory factors.

Am J Transl Res 2021 15;13(4):3480-3486. Epub 2021 Apr 15.

Department of Obstetrics and Gynecology, Yueqing Maternal and Child Care Service Hospital Yueqing 325600, Zhejiang, China.

Objectives: This study investigated and analyzed the therapeutic effect of Fukejing capsules combined with ceftriaxone sodium and metronidazole in treating chronic pelvic inflammation and its influence on hemorheology and inflammatory factors.

Methods: 137 patients with chronic pelvic inflammation admitted to our hospital from March 2018 to April 2020 were selected as the research subjects, and randomly classified into observation group (n=70) and control group (n=67) based on the random number table. The control-group were treated with ceftriaxone sodium and metronidazole, while the observation-group received Fukejing capsules based on the medication taken by the control group. The clinical efficacy, changes of hemorheology indexes and inflammatory factors of the two groups were compared.

Results: The overall response rate of the observation group was critically higher than that of the control group (). The hemorheology indicators of plasma viscosity, the blood viscosity at low and high shear rate of the two groups of patients in post-treatment were notably lower than those in pre-treatment (), and the indexes of the observation group in post-treatment were remarkably lower than that of the control group (). The two groups' degree of serum TNF-α, IL-6 and CRP in post-treatment were critically lower than in pre-treatment (), and the indicators of the observation group in post-treatment were dramatically lower than that of the control group ().

Conclusion: The treatment of Fukejing capsules combined with ceftriaxone sodium and metronidazole is effective in the chronic pelvic inflammation. It can efficiently reduce the blood viscosity of patients and cut down the inflammatory response of the body, which is worthy of clinical promotion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129380PMC
April 2021

Design and Analysis of an Intelligent Toilet Wheelchair Based on Planar 2DOF Parallel Mechanism with Coupling Branch Chains.

Sensors (Basel) 2021 Apr 10;21(8). Epub 2021 Apr 10.

School of Mechanical Engineering, Yanshan University, Qinhuangdao 066004, China.

Due to the fixed size of the structure or the possibility of only simple manual adjustment, the traditional toilet wheelchair cannot easily be adapted to the size of the user or the toilet. In this paper, a planar two-degree-of-freedom parallel mechanism with coupling branch chains is proposed to enable both seat height adjustment and body posture adjustment of a toilet chair, solving the problems of posture adaptability between the user and the machine, and height matching in the process of using the wheelchair-assisted toilet. The model of the parallel mechanism was designed after analyzing the general rules of posture transformation in the human body before and after the toilet process, and the dimensions of each linkage were then determined according to the constraint conditions. By analyzing the degree of freedom, kinematics, workspace, singularity and position of the center of gravity, the rationality of the design was ensured. The weighted average function was used to find the optimal fixed point of the horizontal moving slider, and the actual trajectory at the end of the single driving mode was close to the ideal trajectory. The experimental results show that the adjustable seat height range is 290~550 mm and the adjustable angle range is 0~90°, which can enable disabled people to use the toilet independently.
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http://dx.doi.org/10.3390/s21082677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069320PMC
April 2021

The prognostic significance of tumor deposits in patients with head and neck squamous cell carcinomas.

Ann Transl Med 2021 Mar;9(5):377

Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

Background: A tumor deposit (TD) is a phenomenon that has not been well studied in head and neck squamous cell carcinoma (HNSCC) but might have prognostic significance. The present study was conducted to explore the presence and the prognostic significance of TDs in patients with HNSCCs.

Methods: Six hundred forty-two pathologically confirmed HNSCC patients with neck dissection samples were enrolled in this retrospective study. Patients were followed up and evaluated every 3 months in the first 3 years after surgery, and every 6 months thereafter by physical examination and computed tomography (CT)/magnetic resonance imaging (MRI) scans. The five-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared in the TD and non-TD groups using multivariable analyses and propensity score matching (PSM) methodology (1:1).

Results: The 5-year OS, DSS, and RFS rate of all patients was 77.3%, 80.6%, and 71.9%, respectively. In the multivariable analyses, poorer rates of OS (HR =2.345, P<0.001), DSS (HR =2.818, P<0.001), and RFS (HR =2.536, P<0.001) were observed in the TD versus the non-TD group. In the PSM cohort, eighty-one patients who had TDs were paired with 70 patients without TDs. Significantly diminished rates of DSS (P=0.040) and RFS (P=0.004) were found in the TD versus the non-TD group.

Conclusions: In response to sparse reports regarding TDs in HNSCCs, the present study proposes the TD as an independent poor prognostic factor meriting further research because of its association with diminished OS, DSS, and RFS rates.
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http://dx.doi.org/10.21037/atm-20-4369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033359PMC
March 2021

Alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC): a retrospective study of 27 cases.

Arch Gynecol Obstet 2021 Mar 9. Epub 2021 Mar 9.

Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.

Objective: The aim of the study was to investigate the relative risk factors associated with the prognosis and effective treatments of alpha-fetoprotein (AFP)-producing epithelial ovarian carcinoma (EOC).

Method: We presented three cases of AFP-producing EOC and performed a brief review to summarize the clinicopathological features and prognostic factors of 24 cases that have been previously reported. We evaluated the correlations among prognostic and clinical parameters, such as stage, pathology and chemotherapy regimens. In addition, a retrospective review of these 27 cases was conducted, and survival curves were estimated using the Kaplan-Meier method.

Results: The patients were aged between 23 and 77 years. The median overall survival was 10 months, and ten (37.04%) patients died within 18 months. We compared the overall mean survival times of all patients in different stages, and the results suggest that the postoperative pathological staging is hardly correlated with prognosis (P = 0.76). There was a correlation between pathology and prognosis (P = 0.0018). The mean survival time was longer for patients who had undergone chemotherapy than for those without chemotherapy (14.88 vs 0.65 months) (P < 0.0001). Moreover, although patients had a good response to the regimens for PEB and TC (P = 0.004), there was no significant difference between PEB and TC (P = 0.386).

Conclusions: AFP-producing EOC is uncommon and regarded as an extremely malignant type of tumor. Patients with chemotherapy may have a longer survival time; additionally, PEB and TC may be an optimal selection for this kind of tumor. Further large-scale studies are needed to confirm our findings.
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http://dx.doi.org/10.1007/s00404-021-06017-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942666PMC
March 2021

Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3.

Front Immunol 2021 24;12:561793. Epub 2021 Feb 24.

Department of Pathology, Peking Union Medical College Hospital, Molecular Pathology Research Center, Chinese Academy of Medical Sciences, Beijing, China.

Background And Aim: Poor response to immune checkpoint inhibitors (ICIs) has been observed in most triple-negative breast cancer (TNBC) cases (around 80%). Our aim was to investigate the status of mismatch repair (MMR), microsatellite instability (MSI), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) in TNBC.

Methods: A total of 74 TNBC samples were retrospectively analyzed. MMR and MSI were evaluated by immunohistochemistry (IHC) and polymerase chain reaction (PCR) using Promega 1.2 and NCI panels, respectively. PD-L1, LAG-3, and CD8 expression was assessed by IHC.

Results: None of the cases demonstrated deficient MMR (dMMR) or MSI. In total, 43/74 cases (58.1%) were PD-L1+, including 1 tumor PD-L1+, 25 tumor-infiltrating lymphocytes (TILs) PD-L1+, and 17 cases involving concurrence of tumor and TIL PD-L1+. The rate of TIL PD-L1+ was remarkably higher than that of tumor PD-L1+ (P<0.001). We identified 20 LAG-3+ cases (27.0%, 20/74), all of which were PD-L1+. Co-expression of PD-L1 and LAG-3 was noted in 46.5% (20/43) of the PD-L1+ population. In the LAG-3+ subtype (co-expression of PD-L1 and LAG-3), high correlation between TILs PD-L1+ and LAG-3+ was observed (P<0.01). A high frequency of CD8+ (98.6%, 73/74) was observed.

Conclusion: dMMR/MSI characteristics may not be a practical predictive marker for ICIs in TNBC. PD-L1+ is more common in TILs than in tumors. In the PD-L1+ population, approximately half of the cases showed LAG-3 co-expression. For patients with a poor response to PD-1(L1) mono ICI, dual blockade of PD-1(L1) and LAG-3 may be a viable option for the management of TNBC.
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http://dx.doi.org/10.3389/fimmu.2021.561793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943629PMC
June 2021

Predictor of postoperative dyspnea for Pierre Robin Sequence infants.

Open Med (Wars) 2020 30;15(1):915-920. Epub 2020 Sep 30.

Department of Anesthesiology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, Jiangsu, 210008, China.

The aim of this retrospective study is to determine the predictive factors of postoperative dyspnea in infants with Pierre Robin sequence (PRS). Forty children with PRS, who underwent general anesthesia, were retrospectively analyzed. The patient's physiological status and anesthesiology data were collected accordingly, demographic characteristics including age, gender, height and weight at surgery, weight gain, preoperative airway status, tracheal intubation route, American Society of Anesthesiologists grading and airway Cormack-Lehane classification. Weight gain, dyspnea before the operation, Cormack-Lehane grade distribution showed a significant difference between patients with and without postoperative dyspnea ( = 0.0175, = 0.0026, and = 0.0038, respectively). Incompetent weight gain was identified as a predictor ( = 0.0371) of PRS postoperative dyspnea through the binary logistic regression model. In conclusion, this study established an early alerting model by monitoring the weight gain, dyspnea before the operation, Cormack-Lehane grade as potential combinations to predict the risk of postoperative dyspnea for PRS.
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http://dx.doi.org/10.1515/med-2020-0231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712453PMC
September 2020

Comparative efficacy and safety of traditional Chinese medicine for lipodermatosclerosis: A protocol for systematic review and network meta-analysis.

Medicine (Baltimore) 2020 Nov;99(47):e23386

Department of Peripheral Blood Vessel, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong.

Background: Lipodermatosclerosis (LDS) is a severe skin change accompanied by the development of chronic venous disease of the lower extremities. Its main clinical manifestations are erythema, induration, hyperpigmentation, and rough and thickened skin. It may also eventually lead to refractory ulcers, skin necrosis and even cancer. Conventional treatment methods mainly include the intake of oral anabolic hormones or androgen and pressure therapy. However, patients often refuse due to their drug resistance and intolerance. As a clinical irreplaceable treatment method for LDS, traditional Chinese medicine (TCM) has not been compared of the safety and effectiveness so far. Therefore, we cannot wait to use a method to compare the efficacy of TCM for LDS systematically, such as network meta-analysis (NMA).

Methods: We will retrieve the relevant Chinese and English databases comprehensively. All the randomized controlled trials of TCM for LDS from January 2015 to September 2020 will be included. Under the guidance of inclusion criteria, 2 researchers will screen the literature, then assess the risk of bias and extract data. We will use Bayesian NMA to evaluate all available evidence in STATA 14.0 and WinBUGS software.

Results: This study will use Bayesian NMA to evaluate the efficacy and safety of TCM for LDS.

Conclusion: This study provide a reliable theoretical basis for the clinical application of TCM in the treatment of LDS, and contribute to the formulation of treatment guidelines for LDS.
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http://dx.doi.org/10.1097/MD.0000000000023386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676565PMC
November 2020

Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes.

Environ Toxicol 2021 Apr 9;36(4):520-529. Epub 2020 Nov 9.

Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.

Colorectal cancer stem cell (CSC) has been regarded to be the root of colorectal cancer progression. However, there is still no effective therapeutic method targeting colorectal CSC in clinical application. Here, we investigated the effects of dichloroacetate (DCA) on colorectal cancer cell stemness. We showed that DCA could reduce colorectal cancer cell stemness in a dose-dependent manner, which is evident by the decreased expression of stemness markers, tumor cell sphere-formation and cell migration ability. In addition, it was found that DCA trigerred the ferroptosis of colorectal CSC, which is characterized as the upregulation of iron concentration, lipid peroxides, and glutathione level, and decreased cell viability. Mechanistic studies demonstrated that DCA could sequester iron in lysosome and thus trigger ferroptosis, which is necessary for DCA-mediated attenuation on colorectal cancer cell stemness. Taken together, this work suggests that DCA might be a colorectal CSC-killer.
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http://dx.doi.org/10.1002/tox.23057DOI Listing
April 2021

Correlation between microRNA-107 expression level and prognosis in patients with colorectal cancer.

Int J Clin Exp Pathol 2020 1;13(9):2342-2347. Epub 2020 Sep 1.

Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University Suzhou 215153, Jiangsu, China.

Colorectal cancer is one of the most common cancers in the world. This study aimed to investigate the correlation between microRNA-107 (miR-107) expression level and the prognosis in colorectal cancer patients with its clinical significance. 80 cases of cancer tissues and 15 cases of adjacent cancer tissues were collected from colorectal cancer patients treated with surgery from February 2006 to January 2010. The expression of miR-107 was detected by real-time PCR. The correlation between miR-107 expression and clinic pathological factors and survival time of patients was statistically analyzed. The expression level of miR-107 in cancer tissues (0.0213 ± 0.0096) was significantly higher than that in adjacent tissues (0.0355 ± 0.0487). The expressions of miR-107 in patients with different TNM stages, Dukes stages, and lymph node metastasis rates were significantly different (P < 0.05). Cox proportional hazards regression model showed that miR-107 may be an independent factor affecting the prognosis of colorectal cancer patients (P < 0.05). The hazard ratio (HR) was 5.165. MiR-107 is highly expressed in colorectal cancer tissues and is closely related to the pathogenesis, progression, and metastasis of colorectal cancer. MiR-107 is expected to become a new molecular marker to assist the diagnosis, treatment effect and prognosis evaluation of colorectal cancer, and may also become a new target for colorectal cancer biotherapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539887PMC
September 2020

Breast Cancer With a HER2 IHC2+ and FISH HER2/CEP17 Ratio ≥2.0 and an Average HER2 Gene Copy Number <4.0 per Tumor Cell: HER2 mRNA Overexpression Is a Rare Event.

Front Oncol 2020 19;10:985. Epub 2020 Jun 19.

Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

For breast cancer, accurately illustrating HER2 characteristics is a critical precondition for evaluating the prognosis and predicting the efficacy of anti-HER2 therapy. Our purpose was to expose HER2 mRNA expression through an hybridization assay (RNAscope), to aid the identification of HER2 status in breast cancers with a previously controversial classification for patients suffering from a HER2 IHC2+ and HER2/CEP17 ≥2.0 and a <4.0 mean HER2 gene copy number/cell (entitled FISH group 2 by update 2018 HER2 testing guideline). A total of 8,983 cases of breast cancer with a known HER2 status detected by initial IHC, and a necessary reflex FISH assay for those with IHC2+, were retrospectively analyzed. Then, 41 cases of HER2 IHC2+ in the FISH group 2 were collected and a RNAscope was performed. The incidence of breast cancers with IHC2+ and in the FISH group 2 was 0.46% (41/8,983) in our single-institutional study cohort. In most of the cases (27/41, 65.9%), low levels of HER2 mRNA expression (score 1 and 2 by RNAscope) were demonstrated. Only one case (1/41, 2.4%) of high-level HER2 mRNA expression (score 4 by RNAscope), harboring a FISH HER2/CEP17 ratio of 2.06 and an average HER2 copy number of 3.70, was revealed. One case with the highest FISH HER2/CEP17 ratio of 3.90, showed the lowest level of HER2 mRNA expression (score 1 by RNAscope). Two cases with the same highest average HER2 signals/cell (3.95) by FISH possessed score 3 and score 2 with RNAscope, respectively. No cases with a score of 0 by RNAscope occurred in our sample. In the majority of cases (35/41, 85.4%), hypodisomy of chromosome 17 (average CEP17 signals/cell ≤1.75) was observed. There was no significant relationship between the mRNA expression and FISH results (average HER2 signals/cell, average CEP17 copy number, or HER2/CEP17 ratio) and clinicopathological features (ER and PR statuses, Ki 67 index, tumor size, and lymph node metastasis) in our population. HER2 mRNA overexpression was not a feature in our group of patients. Based on our data, breast cancers with HER2 IHC2+ and in FISH group 2 support a categorization of HER2 negative.
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http://dx.doi.org/10.3389/fonc.2020.00985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318106PMC
June 2020

Hsa_circ_0001806 Acts as a ceRNA to Facilitate the Stemness of Colorectal Cancer Cells by Increasing COL1A1.

Onco Targets Ther 2020 30;13:6315-6327. Epub 2020 Jun 30.

Department of Gastroenterology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu 215153, People's Republic of China.

Background: The aberrant expression of circular RNAs (circRNAs) has been identified as a novel trait of cancers. However, the role of circRNAs in colorectal cancer (CRC) remains to be elucidated.

Methods: Informatic analysis was performed to identify circRNAs in CRC tissues and adjacent tissues. Gain- and loss-of-function experiments were constructed to analyze hsa_circ_001806 roles in CRC cell stemness by sphere-formation, ALDH activity, stemness marker expression and tumor-initiating ability assays. CCK8 cell viability was carried out to evaluate hsa_circ_0001806 roles in CRC cell viability. Luciferase reporter and pull-down assays were used to reveal the underlying mechanisms.

Results: Hsa_circ_0001806 was significantly upregulated in CRC tissues and correlated with TNM stage, depth of invasion, lymphatic metastasis and distant metastasis. Hsa_circ_0001806 promoted the stemness of CRC cells, as evident by increasing sphere-formation ability, ALDH1 activity and stemness marker expression while had no effect on cell viability. Mechanistically, the same miR-193-5p-binding sites are shared between hsa_circ_0001806 and COL1A1. Hsa_circ_0001806 upregulates COL1A1 expression in a miR-193-5p-dependent manner, which is essential for hsa_circ_0001806-mediated regulation on CRC cell stemness.

Conclusion: CircRNA hsa_circ_0001806 may act as a promising therapeutic target by facilitating the stemness of CRC cells via activating the hsa_circ_0001806/miR-193a-5p/COL1A1 axis.
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http://dx.doi.org/10.2147/OTT.S255485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335295PMC
June 2020

Postoperative Concurrent Chemoradiotherapy versus Postoperative Radiotherapy Alone for Larynx Squamous Cell Carcinoma Patients with Lymphovascular Invasion: A Propensity Score Matching Study.

Cancer Manag Res 2020 29;12:4063-4071. Epub 2020 May 29.

Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

Purpose: To date, no guidelines have been proposed for the ideal treatment of postoperative larynx squamous cell carcinoma (LSCC) patients with lymphovascular invasion due to a lack of similar studies. The present study was conducted to compare the survival and toxicity in LSCC patients with lymphovascular invasion receiving either postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT). The results can be applied for more appropriate treatment of these patients.

Patients And Methods: Three hundred eighty-eight eligible LSCC patients with lymphovascular invasion were enrolled in this retrospective study. Survival and treatment-related toxicities were compared in the POCRT and PORT group using propensity score matching (PSM) methodology (1:1).

Results: Five-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) of all patients were 48.7%, 58.2%, and 56.0%, respectively. Significantly, higher RFS rates (P=0.040) were found in the POCRT group than the PORT group in the PSM cohort. In the multivariate analysis, higher OS, DSS, and RFS rates were observed in the POCRT group than the PORT group (P=0.049, 0.024, and 0.011 respectively). Patients in the POCRT group presented more acute toxicities than those in the PORT group such as hematological toxicities (25.0% vs 0.9%, P<0.001) and mucositis (35.0% vs 19.1%, P=0.002).

Conclusion: In the context of no ideal treatment for LSCC patients with lymphovascular invasion, the present study proposes POCRT as a preferable modality compared with PORT, as POCRT was associated with higher RFS rates. Higher RFS, DFS, and OS rates were also observed in the POCRT group in the multivariate analysis.
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http://dx.doi.org/10.2147/CMAR.S250621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269631PMC
May 2020

Clinical evaluation of the effectiveness of fusion-induced asymmetric transcription assay-based reverse transcription droplet digital PCR for ALK detection in formalin-fixed paraffin-embedded samples from lung cancer.

Thorac Cancer 2020 08 16;11(8):2252-2261. Epub 2020 Jun 16.

Department of Pathology, Peking Union Medical College Hospital, Molecular Pathology Research Center, Chinese Academy of Medical Sciences, Beijing, China.

Background: Accurate detection of anaplastic lymphoma kinase (ALK) rearrangement is the prerequisite for anti-ALK therapy for the patient with non-small cell lung cancer (NSCLC). Fusion-induced asymmetric transcription assay (FIATA)-based reverse transcription droplet digital PCR (RT-ddPCR) was developed and performed for ALK status survey in NSCLC samples.

Methods: A total of 269 cases of formalin-fixed paraffin-embedded (FFPE) specimens from NSCLC, in which ALK status was confirmed by both fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), were analyzed by FIATA-based RT-ddPCR.

Results: In the ALK-positive group, the 3' ALK transcript copies range was 336.6-107 955.4, and the R3 [(the ratio of the 3' ALK transcript copy numbers to the internal reference gene transcript copy numbers) × 100] was 17.23-672.77. In the ALK-negative group, the 3' ALK transcript copies range was 3.7-1370.6, and the R3 range was 0.10-15.57. The lowest R3 level in the ALK-positive group was significantly higher than the highest R3 level in the ALK-negative group. A positive correlation between the proportion of cancer cells in the tissue section and ALK RNA expression level (R3) was found (P < 0.05). There was no relationship between the percentage of FISH positive cells or FISH positive signal patterns and R3 level of the ALK gene. Compared with FISH and IHC, the clinical sensitivity and specificity of FIATA-based RT-ddPCR for ALK detection were 100%, respectively.

Conclusions: An absolute quantitative FIATA-based RT-ddPCR was developed and validated for ALK fusion detection in NSCLC. This method can rapidly, accurately, and objectively classify ALK types and help with individual therapy.
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http://dx.doi.org/10.1111/1759-7714.13535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396369PMC
August 2020

Co-effects of C/Ag dual ion implantation on enhancing antibacterial ability and biocompatibility of silicone rubber.

Biomed Mater 2020 09 26;15(6):065003. Epub 2020 Sep 26.

Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China. These authors contributed equally to this work.

Although silicone implants are the most popular choice around the world for breast augmentation, reconstruction, and revision, due to the poor antibacterial properties and limited biocompatibility of silicone rubber (SR), one of the major complications, capsule contracture, is a lingering problem. To overcome the two main shortcomings, a dual ion implantation technique was applied to modify the surface of SR with the basic skeleton element of organic matter, carbon (C) and the broad-spectrum bactericide, silver (Ag). We present surface characterization, toxicological effects, and evaluation of the mechanical, antibacterial and biocompatible properties of C and Ag co-implanted SR (C/Ag-SRs). After ion implantation, surface roughness and tensile strength of these new materials increased. Biotoxicity was fully assessed by in vitro experiments on human fibroblasts and in vivo experiments on rats, showing that the low-Ag groups met safety standards. Both the anti-bacterial adhesion and bactericidal abilities of C/Ag-SRs were superior to those of SR, which had few antibacterial activities, especially against Staphylococcus epidermidis. With respect to biocompatibility, the adhesion of fibroblasts was promoted, while their proliferation was moderately inhibited on ion-implanted surfaces. After subcutaneous implantation in rats for 7, 30, 90 and 180 d, the capsular thickness around C/Ag-SRs was significantly lower than that around the SR. Additionally, there was no difference in the inflammatory reaction after 7 d of retention in vivo between C/Ag-SRs and SR. The results demonstrate that C/Ag-SRs are desirable shell materials for breast implants.
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http://dx.doi.org/10.1088/1748-605X/ab99d3DOI Listing
September 2020

Pattern of immune infiltration in lung cancer and its clinical implication.

Clin Chim Acta 2020 Sep 1;508:47-53. Epub 2020 May 1.

Departments of Health Check-up Center, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, PR China. Electronic address:

Background: Tumor-infiltrating immune cells play an essential role in prognosis and survival after therapy. However, previous works have not made clear about the diversity of distinct cell types that participate in the immune response. We determined the composition of tumor-infiltrating immune cells and their correlation with prognosis in lung cancer based on a metagene approach (known as CIBERSORT) and online databases.

Methods: A total of 22 tumor-infiltrating immune cells were estimated to confirm the associations between the immune infiltration pattern and survival. As a result, the proportions of activated NK cell, monocytes, M0 macrophages and M1 macrophages in 56 cancer samples were significantly higher than those in 56 paracancerous samples.

Results: Univariate Cox regression analysis displayed that the proportions of NK cell and monocytes were significantly associated with prognosis. Hierarchical clustering analysis predicted five clusters by the method of within sum of squares errors (wss), which exhibited different infiltrating immune cell composition and prognosis.

Conclusions: The proportions of tumor-infiltrating immune cells as well as cluster patterns were associated with the prognosis, which provided potential therapeutic targets for lung cancer.
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http://dx.doi.org/10.1016/j.cca.2020.04.036DOI Listing
September 2020

Distinct gene expression profiles associated with clinical outcomes in patients with ovarian clear cell carcinoma and high-grade serous ovarian carcinoma.

J Ovarian Res 2020 Apr 15;13(1):38. Epub 2020 Apr 15.

Department of Gynaecologic Oncology, Peking Union Medical College Hospital, 1 Shuaifuyuan, Dongcheng-qu, Beijing, People's Republic of China.

Background: Ovarian clear cell carcinoma (OCCC) is the second most common ovarian cancer after serous carcinoma in Southeast Asia. OCCC has a more unfavourable clinical outcome due to a poor response to platinum-based chemotherapy compared with serous carcinoma. The identification of biomarkers related to the prognosis of OCCC is critically important for an improved understanding of the biology that drives OCCC progression and leads to poor outcomes. To detect differences in gene expression profiles between OCCC and high-grade serous ovarian carcinoma (HGSOC), twelve patients with OCCC and twelve patients with HGSOC were recruited in whom the pathological diagnosis was confirmed on surgically resected specimens.

Results: Compared with HGSOC, OCCC has 609 differentially expression genes, and 199 are significantly different (P < 0.05). These genes are involved in the cell cycle, apoptosis, DNA damage repair, the PI3K pathway and so on. There were 164 differentially expressed genes in the PI3K pathway. There were 35 overexpressed genes in OCCC, while there were 12 overexpressed genes in HGSOC. Among these differentially expressed genes, we found that the MET gene and the CCNE1 gene were overexpressed in OCCC and associated with a worse prognosis.

Conclusions: In conclusion, there are many differentially expressed genes in OCCC and HGSOC, which indicates that the two kinds of tumours differ greatly in tumourigenesis and provides a theoretical basis for targeted therapy in the future. Further studies need to be performed to clarify the association of the differentially expressed genes with the unfavourable prognosis in OCCC.
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http://dx.doi.org/10.1186/s13048-020-00641-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161165PMC
April 2020

Primary non-Hodgkin lymphoma of the tongue base: the clinicopathology of seven cases and evaluation of HPV and EBV status.

Diagn Pathol 2020 Apr 1;15(1):30. Epub 2020 Apr 1.

Department of Pathology and Otolaryngology, UC Irvine School of Medicine, UC Irvine Medical Center, Irvine, USA.

Objectives: Non-Hodgkin's lymphoma (NHL) primarily derived from the base of the tongue, is rare. Human papillomavirus (HPV) and Epstein-Barr virus (EBV) are important aetiological risk factors for tumours of the head and neck. This study describes the clinicopathological features of NHL in the tongue base and the status of HPV and EBV in these cases.

Methods: Seven cases were identified from the Pathological Registry Database at Peking Union Medical College Hospital (PUMCH). The study utilized immunochemistry, in situ hybridization (ISH), and gene rearrangement to confirm the disease and and performed a clinical follow up for each case.

Results: All 7 lymphomas were localized at the base of the tongue. Six of the cases exhibited tongue base masses with smooth surface membranes. One case presented as multiple deep ulcers. The most common histologic subtype was diffuse large B-cell lymphoma (DLBCL), which occurred in five cases. The other two cases were mantle cell lymphoma (MCL) and peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). One of the DLBCL cases was positive for HPV DNA and diffusely expressed P16 protein. During the follow up period, the MCL patient and an elderly DLBCL patient died. The remaining five patients were alive through the end of follow up.

Conclusions: Most lymphomas of the tongue base manifest as an endogenous mass without membranous change. The most common subtype of NHLs of the tongue base is DLBCL, and the occurrence at this site may have a good prognosis. With proper therapy, even late stage tongue base lymphomas can be suppressed and remain in remission.
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http://dx.doi.org/10.1186/s13000-020-00936-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110811PMC
April 2020

Application of integrated positron emission tomography/magnetic resonance imaging in evaluating the prognostic factors of head and neck squamous cell carcinoma with positron emission tomography, diffusion-weighted imaging, dynamic contrast enhancement and combined model.

Dentomaxillofac Radiol 2020 Jul 3;49(5):20190488. Epub 2020 Apr 3.

Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Objectives: This study was designed to investigate the distribution of the independent parameters of PET and MR in tumour differentiation and staging and to evaluate the diagnostic efficiency of the independent parameters and combined model of PET/MR in the tumour differentiation of head and neck squamous cell carcinoma (HNSCC).

Methods: The patients with the preliminary diagnosis of HNSCC were included and underwent the integrated PET/MR The parameters included the diffusion-weighted imaging, dynamic contrast enhancement and PET. The correlations between different parameters and the distribution in groups of tumour differentiation and staging were analysed. The combined model was established with complementary PET/MR parameters. The diagnostic efficiency of the independent parameters and combined model in the tumour differentiation were analysed by receiver operating characteristic curve.

Results: The correlations between the parameters of dynamic contrast enhancement and PET were most significant. There were significant differences between the well-differentiated group and the moderately/poorly differentiated group in terms of the mean values of apparent diffusion coefficient (ADC) and standardised uptake value (SUV) ( < 0.05). The distributions among different tumour stage groups were not statistically different in all the parameters. The diagnostic efficiency of tumour differentiation increased in the order of Kmean, SUVmean, ADCmean, and the combined model.

Conclusions: Compared with the independent parameter, the combination of multiple parameters with PET/MR can further improve the diagnostic performance of tumour differentiation in HNSCC.
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http://dx.doi.org/10.1259/dmfr.20190488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333468PMC
July 2020

ALK detection in lung cancer: identification of atypical and cryptic ALK rearrangements using an optimal algorithm.

J Cancer Res Clin Oncol 2020 May 3;146(5):1307-1320. Epub 2020 Mar 3.

Department of Pathology, Peking Union Medical College Hospital, Molecular Pathology Research Center, Chinese Academy of Medical Sciences, Beijing, 100730, China.

Purpose: IHC, FISH, and NGS are common methods of ALK evaluation in NSCLC. The purpose of this study was to investigate whether ALK false positives or false negatives occurred more often in daily routines. An approach to identify ALK fusion was then proposed.

Materials And Methods: We analyzed 1815 cases of NSCLC, including 83 (4.6%) ALK IHC positives. Total 182 samples (62 ALK+ and 120 ALK-) were examined via FISH, RT-ddPCR, NGS, RT-qPCR and RNAscope to confirm ALK status.

Results: One ALK FISH false negative was found, which harbored two genomic rearrangements involved in EML4-ALK (exon 13:exon 20) fusion. One ALK IHC false negative was confirmed depending on a rare ALK FISH-positive pattern and ALK RNAscope positive but ALK fusion was not found via NGS. In addition, an atypical ALK FISH-positive pattern was observed in an IHC-positive case with chromosome 2 inversion leading to EML4-ALK (exon 6:exon 20) fusion. EML4-ALK fusion was determined in one case with an atypical FISH patterns by RT-qPCR. Rare complicated genomic rearrangements involved in a novel ALK fusion of EML4-ALK (exon 7:exon 14) were distinguished in an ALK IHC and FISH double-positive case.

Conclusion: False negative of ALK IHC, FISH and NGS results were found in our cohort, but none was false ALK positive. False ALK negatives should be more concerned than false positives. ALK rearrangements with cryptic ALK fusion patterns could be identified using our algorithm. Non-squamous non-small cell lung cancer was recommended for priority detection.
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http://dx.doi.org/10.1007/s00432-020-03166-1DOI Listing
May 2020

Mesenchymal stem cell-derived exosomes protect beta cells against hypoxia-induced apoptosis via miR-21 by alleviating ER stress and inhibiting p38 MAPK phosphorylation.

Stem Cell Res Ther 2020 03 4;11(1):97. Epub 2020 Mar 4.

Fujian Provincial Key Laboratory of Transplant Biology, 900th Hospital, Xiamen University, 156th XiErHuan Road, Fuzhou, 350025, China.

Background: Hypoxia is a major cause of beta cell death and dysfunction after transplantation. The aim of this study was to investigate the effect of exosomes derived from mesenchymal stem cells (MSCs) on beta cells under hypoxic conditions and the potential underlying mechanisms.

Methods: Exosomes were isolated from the conditioned medium of human umbilical cord MSCs and identified by WB, NTA, and transmission electron microscopy. Beta cells (βTC-6) were cultured in serum-free medium in the presence or absence of exosomes under 2% oxygen conditions. Cell viability and apoptosis were analysed with a CCK-8 assay and a flow cytometry-based annexin V-FITC/PI apoptosis detection kit, respectively. Endoplasmic reticulum stress (ER stress) proteins and apoptosis-related proteins were detected by the WB method. MiRNAs contained in MSC exosomes were determined by Illumina HiSeq, and treatment with specific miRNA mimics or inhibitors of the most abundant miRNAs was used to reveal the underlying mechanism of exosomes.

Results: Exosomes derived from MSC-conditioned culture medium were 40-100 nm in diameter and expressed the exosome markers CD9, CD63, CD81, HSP70, and Flotillin 1, as well as the MSC markers CD73, CD90, and CD105. Hypoxia significantly induced beta cell apoptosis, while MSC exosomes remarkably improved beta cell survival. The WB results showed that ER stress-related proteins, including GRP78, GRP94, p-eIF2α and CHOP, and the apoptosis-related proteins cleaved caspase 3 and PARP, were upregulated under hypoxic conditions but were inhibited by MSC exosomes. Moreover, the p38 MAPK signalling pathway was activated by hypoxia and was inhibited by MSC exosomes. The Illumina HiSeq results show that MSC exosomes were rich in miR-21, let-7 g, miR-1246, miR-381, and miR-100. After transfection with miRNA mimics, the viability of beta cells under hypoxia was increased significantly by miR-21 mimic, and the p38 MAPK and ER stress-related proteins in beta cells were downregulated. These changes were reversed after exosomes were pretreated with miR-21 inhibitor.

Conclusions: Exosomes derived from MSCs could protect beta cells against apoptosis induced by hypoxia, largely by carrying miR-21, alleviating ER stress and inhibiting p38 MAPK signalling. This result indicated that MSC exosomes might improve encapsulated islet survival and benefit diabetes patients.
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http://dx.doi.org/10.1186/s13287-020-01610-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055095PMC
March 2020

DNA Mismatch Repair Deficiency Detection in Colorectal Cancer by a New Microsatellite Instability Analysis System.

Interdiscip Sci 2020 Jun 25;12(2):145-154. Epub 2020 Jan 25.

Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS), Beijing, 100730, China.

Background: Although microsatellite instability (MSI) is most commonly detected in colorectal cancer (CRC), improvement in MSI analysis method can always help us better assessing MSI phenotypes and gaining useful information in challenging cases. The purpose of current study is to explore whether the ProDx® MSI analysis System (ProDx® MSI) can improve MSI classification in CRC.

Methods: We compared the MSI profiles of 97 FFPE samples from CRC patients by ProDx® MSI with Promega MSI analysis System 1.2 and NCI panel. The result is then confirmed by IHC test, which evaluate MMR protein expression. Furthermore, next generation sequencing was performed to double confirm the specimens with discordant results.

Results: Among the total 97 CRC cases, 35 were scored as MSI-High by ProDx® MSI, Promega MSI analysis System 1.2, and NCI panel simultaneously. Three extra MSI-High cases were identified by ProDx® MSI. These three cases were classified as MSI-Low by NCI panel, while two of these as MSI-Low, and 1 as MSS by Promega MSI analysis System 1.2. ProDx® MSI had higher concordance with IHC detection compared with Promega MSI Analysis System 1.2 and NCI panel at 99.0%, 96.9%, and 95.9%, respectively. The ProDx® MSI distinguished MSI status with 100% sensitivity and 98.4% specificity. Our data showed that MSI-High phenotype occurred most frequently in tumor development stage I and stage II.

Conclusions: The colorectal cancer can be classified according to MSI status accurately by ProDx® MSI. More cases with MSI-High feature may be revealed by ProDx® MSI than by previous test systems in colorectal cancer.
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http://dx.doi.org/10.1007/s12539-020-00358-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244613PMC
June 2020

Peripheral primitive neuroectodermal tumors: A retrospective analysis of 89 cases and literature review.

Oncol Lett 2019 Dec 18;18(6):6885-6890. Epub 2019 Oct 18.

Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P.R. China.

Peripheral primitive neuroectodermal tumors (pPNETs) are rare, small cell carcinomas with a poor prognosis. The aim of the present study was to describe therapeutic approaches, outcomes and probable prognostic factors. The clinical features, treatments, and outcomes of 89 consecutive patients with pPNET treated at the Peking Union Medical College Hospital from 1999 to 2018 were retrospectively reviewed. A total of 43 males and 46 females were included in the study, with a median age of 25 years (range, 5-73 years). The predominantly affected regions were the abdomen and pelvis, followed by the thoracopulmonary region. The mean primary tumor size was 12.6 cm (range, 1-30 cm). A total of 16 patients (18%) initially presented with metastasis. A total of 46 patients received combined therapy, 35 received mono-therapy, and 8 underwent only biopsy with no further treatment. The period of observation ranged from 1-232 months. The median overall survival (OS) time was 15 months [95% confidence interval (CI), 9-21 months], with 3- and 5-year OS rates of 32 and 25%, respectively. Large tumor size [adjusted hazard ratio (aHR)=3.65; 95% CI, 2.07-6.42; P<0.001), metastasis at initial presentation (aHR=4.34, 95% CI, 2.23-8.42; P<0.001), and combined modality treatment (aHR=0.16, 95% CI, 0.06-0.39; P<0.001) were significantly associated with OS. The prognosis of pPNET is, overall, poor. Large tumor size and metastasis at initial presentation are associated with poorer outcomes. This highly malignant tumor requires an aggressive combination of radical resection, chemotherapy and radiotherapy, when indicated.
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http://dx.doi.org/10.3892/ol.2019.11011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865547PMC
December 2019

EGFR T790M detection in formalin-fixed paraffin-embedded tissues of patients with lung cancer using RNA-based in situ hybridization: A preliminary feasibility study.

Thorac Cancer 2019 10 13;10(10):1936-1944. Epub 2019 Aug 13.

Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Background: Following drug resistance in patients with lung cancer treated by EGFR TKIs, a biopsy is required to obtain sufficient cancer tissue for T790M detection in order to select potential beneficiaries suitable for third-generation EGFR TKIs, such as osimertinib. The purpose of this study was to explore the feasibility of using a new in situ analysis technique based on RNA target sequences to detect EGFR T790M in lung cancer.

Methods: A total of 28 formalin-fixed paraffin-embedded (FFPE) samples from 24 lung adenocarcinoma patients archived in Peking Union Medical College Hospital from 2015 to 2016 were collected. The BaseScope T790M detection technique by in situ hybridization on FFPE slides was used to analyze the mutation of EGFR T790M, and then the results were compared with the data acquired by Scorpions ARMS assay, which is the so-called gold standard for EGFR gene mutation testing. The sensitivity and specificity of the BaseScope T790M detection technique were preliminarily evaluated.

Results: Of the 28 FFPE specimens, the average proportion of T790M-positive cells was 35.78% ± 17.68% in 18 samples with EGFR T790M, confirmed by Scorpions ARMS assay, Compared with real-time PCR assay, the sensitivity and specificity of BaseScope T790M were all 100% in our cohort.

Conclusion: BaseScope T790M assay could be completed on only one FFPE slide and the visualized molecular result overplayed with histomorphological information perfectly, so it may be the alternative method for EGFR T790M evaluation. BaseScope assay has potential clinical utility, and it will be necessary to carry out validation with a large number of cases.
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http://dx.doi.org/10.1111/1759-7714.13169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775006PMC
October 2019

HER2 double-equivocal breast cancer in Chinese patients: a high concordance of HER2 status between different blocks from the same tumor.

Breast Cancer Res Treat 2019 Nov 6;178(2):275-281. Epub 2019 Aug 6.

Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Purpose: Human epidermal growth factor receptor 2 (HER2) status is both an independent prognostic factor and a predictive factor for the efficacy of targeted therapy for breast cancer, so it is critical to accurately detect HER2 protein expression and/or gene amplification. According to the recommendations of the 2013 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines for HER2 breast cancer testing, an additional test should be pursued on a different block from the same tumor as one of the options for patients with immunohistochemistry (IHC) 2+ and a HER2/CEP17 ratio of < 2.0 with an average HER2 signals per tumor cell of ≥ 4.0 and < 6.0 by reflex test using dual-probe fluorescence in situ hybridization (FISH) (double-equivocal HER2). Our aim in this study is to explore the consistency of HER2 status between the two blocks.

Methods: We retrospectively analyzed 5685 primary invasive breast cancers between April 2015 and January 2019 from Peking Union Medical College Hospital. For cases with double-equivocal HER2 revealed in initial blocks, HER2 gene status was evaluated by FISH in a different block from the same tumor. The FISH score was interpreted according to the 2013 ASCO/CAP guidelines for HER2 testing.

Results: In our cohort of 5685 specimens, the overall HER2 IHC3+, 2+, 1+ and 0 cases were 20.5%, 31.8%, 28.3%, and 19.5%, respectively. Then, 13.7%, 66.3%, and 20.0% of HER2 amplification, non-amplification, and equivocation rates were found, respectively, in IHC2+ patients (n = 1777) by reflex FISH assay. For specimens with double-equivocal HER2 (n = 333), HER2 status was assessed in another block from the same tumor by FISH and then the frequency of HER2 positive, negative, and equivocation was estimated at 5.7%, 22.5%, and 71.8%, respectively. Because double-equivocal HER2 cases are classified in the HER2 negative category by the 2018 ASCO/CAP HER2 testing guidelines, only 1.3% (19/1511) of HER2 positive patients were determined through additional HER2 testing in another block from the HER2 negative population.

Conclusions: HER2 status in different blocks from the same tumor in primary invasive breast cancer was highly concordant. Our data supported the recommendation of the 2018 ASCO/CAP HER2 testing guidelines in breast cancer to remove the suggestion for additional HER2 testing using another block contained in the previous version.
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http://dx.doi.org/10.1007/s10549-019-05387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797640PMC
November 2019

Successful treatment with osimertinib and its subsequent resistance mechanism in a patient with non-small-cell lung cancer harboring acquired EGFR T790M mutation after recovery from AC0010-induced interstitial lung disease.

Onco Targets Ther 2019 10;12:5545-5549. Epub 2019 Jul 10.

Department of Respiratory Medicine, Peking Union Medical College Hospital, Beijing 100730, People's Republic of China.

Objective: Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)can occasionally lead to interstitial lung disease (ILD), and the appropriate treatment after recovery from ILD remains controversial. AC0010 is an investigational third-generation TKI used in China to selectively target the T790M mutation. Here, we describe a patient who developed ILD after AC0010 treatment and was then successfully re-challenged with osimertinib.

Methods: The patient was a 67-year-old male with a diagnosis of metastatic pulmonary adenocarcinoma with an L858R mutation on exon 21. Acquired T790M mutation was confirmed by re-biopsy after progression on erlotinib treatment. The patient was treated with AC0010, and developed ILD 54 days after treatment initiation. Following his recovery from ILD, osimertinib (80 mg/day) was administered with no adverse effects. After progression on osimertini\b 11 months later, a histological transformation from adenocarcinoma to large-cell neuroendocrine carcinoma was confirmed by re-biopsy, with a marked increase in serum neuron-specific enolase.

Conclusions: This is the first report of interstitial pneumonitis caused by AC0010. Osimertinib re-challenge after recovery from ILD was a safe and effective treatment option. Our report further highlights that pathological transformation of large-cell neuroendocrine carcinoma represents one of the resistance mechanisms of osimertinib, and may be accompanied by an increase in serum neuron-specific enolase.
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http://dx.doi.org/10.2147/OTT.S204689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628610PMC
July 2019
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