[CIC-rearranged sarcoma: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features and differential diagnosis of CIC-rearranged sarcoma (CRS). Methods: Five CRSs of 4 patients (2 biopsies of pelvic cavity and lung metastasis from case 4) diagnosed in the First Affiliated Hospital of Nanjing Medical University were enrolled from 2019 to 2021. All cases were evaluated by clinical presentation, H&E, immunohistochemical staining and molecular analysis and the related literature was reviewed. Results: There were one male and three females, the age at diagnosis ranged from 18 to 58 (mean 42.5) years. Three cases were from the deep soft tissues of the trunk and one case from the skin of foot. Grossly, the tumor size ranged from 1 to 16 cm. Microscopically, the tumor was arranged in nodules or solid sheets. The tumor cells were typically round or ovoid, with occasional spindled or epithelioid morphology. The nuclei were round to ovoid with vesicular chromatin and prominent nucleoli. Mitotic figures were brisk (>10/10 HPF). Rhabdoid cells were seen in four of five cases. Myxoid change and hemorrhage were observed in all samples and two cases showed geographic necrosis. Immunohistochemically, CD99 was variably positive in all samples, while WT1 and TLE-1 were positive in four of five samples. Molecular analysis showed CIC-rearrangements in all cases. Two patients succumbed within 3 months. One had mediastinal metastasis 9 months after surgery. One underwent adjuvant chemotherapy and remained tumor-free 10 months after diagnosis. Conclusions: CIC-rearranged sarcoma is uncommon and shows aggressive clinical course with dismal prognosis. The morphological and immunohistochemical characteristics can largely overlap with a variety of sarcomas; hence, knowledge of this entity is vital to avoid potential diagnostic pitfalls. Definitive diagnosis requires molecular confirmation of CIC-gene rearrangement.

[Clinical characteristics of digestive system cancers metastatic to the heart].

Objective: To investigate the clinical features of patients with cardiac metastases from digestive system tumors. Methods: This retrospective study collected and analyzed the medical records of patients with cardiac metastases from digestive system tumors who received treatments in the Cancer Hospital, Chinese Academy of Medical Sciences between January 1999 and January 2021. Kaplan-Meier method was used for survival analysis. Results: A total of 19 patients were identified. The primary tumors were esophageal squamous cell carcinoma (n=7), gastric or gastroesophageal junction adenocarcinoma (n=6), hepatobiliary cancers (n=3) and colorectal cancers (n=3). 16 patients had pericardial metastases, 2 patients had right atrium metastases, and 1 patient had left ventricle metastasis. The most common symptom was dyspnea, which was present in 8 cases. 7 patients received locoregional treatment, while 11 patients underwent systemic therapies. The median overall survival from diagnosis of primary cancer was 31.4 months, and the median overall survival time from diagnosis of cardiac metastasis was 4.7 months. Conclusion: Cardiac metastasis from digestive system tumors is associated with low incidence and a poor prognosis. Systemic treatment remains the cornerstone of management, while novel anti-tumor drugs may improve therapeutic efficacy.

[Advanced progress of ex vivo biosensor assay in toxicological evaluation].

The ex vivo biosensor assay is developed to assess the health effects and toxicological mechanism of environmental pollutants with internal environment homeostasis changes by integrating the in vivo exposure evaluation, in vitro outcomes analysis, and systematic environment component screening. This toxicology testing model combines the real-world exposure of people in the field and the study of molecular mechanism exploration in lab experiments to overcome the shortcomings of a single toxicology method. It provides a new technique and perspective for toxicity testing and risk assessment in mesoscale between macroscopic population study and microscopic mechanism exploration.

[Analysis of the trend and spatial clustering of gastric cancer deaths in Shandong Province from 1970 to 2013].

Objective: To investigate the distribution characteristics and trends of mortality and spatial aggregation of gastric cancer in Shandong Province from 1970 to 2013. Methods: The mortality data of gastric cancer from 1970 to 1974, 1990 to 1992 and 2004 to 2005 were collected from the first, second and third retrospective sampling survey of causes of death in Shandong Province, respectively. The mortality data of gastric cancer from 2011 to 2013 were collected from the all-cause surveillance data of Shandong Province. The crude mortality rate and age-standardized mortality rate were used to describe the death level of gastric cancer. The age-standardized mortality rate of Shandong Province was calculated based on Segi's world standard population, and the age-standardized mortality rate of counties (cities and districts) was calculated based on the Chinese population in 1964.The factors influencing the difference of gastric cancer mortality in different periods were decomposed by using the method of differential decomposition of mortality, and the contributions of population and non-population factors in different periods were estimated.Using ArcGIS 10.2 software, the death level of gastric cancer in different counties (cities and districts) in Shandong province from 1970 to 1974 and 2011 to 2013 were visualized. DeoDa 1.12 software was used for global and local spatial autocorrelation analysis. Results: The crude death rate and age-standardized death rate of gastric cancer in Shandong province increased firstly and then decreased during 1970-2013, and the crude death rate of gastric cancer increased from 18.33/100 000 in 1970-1974 to 28.51/100 000 in 2011-2013. Segi's age-standardized mortality rate for gastric cancer decreased from 20.94 per 100 000 in 1970-1974 to 18.17 per 100 000 in 2011-2013.From 1990 to 1992, from 2004 to 2005 and from 2011 to 2013, the contribution value of non-population factors to the increase of crude gc mortality was 95.59%, 48.45% and -20.57%, respectively, showing a continuous downward trend. The Moran's I index of crude mortality of gastric cancer in Shandong province from 1970 to 1974 and from 2011 to 2013 were 0.77 and 0.57, respectively, and the Moran's I index of age-normalized mortality was 0.75 and 0.44, respectively. Local autocorrelation analysis showed that there were 31 and 19 high aged-mortality areas of gastric cancer in 1970-1974 and 2011-2013 respectively, and 7 overlapping counties (cities and districts), 6 of which were located in Jiaodong area. Conclusion: The crude mortality and age-standardized mortality of gastric cancer in Shandong province increased first and then decreased from 1970 to 2013, and the distribution of gastric cancer mortality had obvious spatial aggregation and changed with time.

[The Breast Cancer Cohort Study in Chinese Women: the methodology of population-based cohort and baseline characteristics].

Objective: Breast cancer has been the first cancer among women with the incidence increasing gradually. In September 2016, the Breast Cancer Cohort Study in Chinese Women (BCCS-CW) was initiated, aiming to establish a standardized and sharable breast cancer-specific cohort by integrating the existing cohort resource and improving the quality of follow-up. The BCCS-CW may provide a research basis and platform for the precision prevention and treatment of breast cancer in etiology identification, prevention, early diagnosis, treatment, and prognosis prediction. Methods: We conducted a population-based perspective cohort by questionnaire interview, anthropometry, biological specimens, breast ultrasound and mammography. The cohort was followed by using regional health surveillance and ad hoc survey. Results: Finally, BCCS-CW included 112 118 women, in which 55 419 women completed the standardized investigation and blood specimens were collected from 54 304 women. The mean age of participants was 51.7 years old, 62.7% were overweight or obese, and 48.9% were menopausal. Conclusion: The BCCS-CW will provide population-based cohort resource and research platform for the precise prevention and treatment of breast cancer in Chinese women.

[Clinical research: why we must mater the essentials].

Learning clinical research methods, we must master the essentials. Essentials are the theories, principles and methods that make a discipline a unique discipline, without which the discipline will no more exist. Essentials are those things that are long-lasting and reliable, those that address the most important issues, those that are most frequently used in practice, and those that normally should not be compromised. The core underlying theories of epidemiological research are causation and errors control. The essentials often have profound theoretical underpinnings and difficult to grasp. We will truly believe the theories and observe the principles only when we have truly grasped them.

[Using Markov Chain Monte Carlo methods to estimate the age-specific case fatality rate of COVID-19].

Objectives: The COVID-19 epidemic has swept all over the world. Estimates of its case fatality rate were influenced by the existing confirmed cases and the time distribution of onset to death, and the conclusions were still unclear. This study was aimed to estimate the age-specific case fatality rate of COVID-19. Methods: Data on COVID-19 epidemic were collected from the National Health Commission and China CDC. The Gamma distribution was used to fit the time from onset to death. The Markov Chain Monte Carlo simulation was used to estimate age-specific case fatality rate. Results: The median time from onset to death of COVID-19 was M=13.77 (P(25)-P(75): 9.03-21.02) d. The overall case fatality rate of COVID-19 was 4.1% (95%CI: 3.7%-4.4%) and the age-specific case fatality rate were 0.1%, 0.4%, 0.4%, 0.4%,0.8%, 2.3%, 6.4%, 14.0 and 25.8% for 0-, 10-, 20-, 30-, 40-, 50-, 60-, 70- and ≥80 years group, respectively. Conclusions: The Markov Chain Monte Carlo simulation method adjusting censored is suitable for case fatality rate estimation during the epidemic of a new infectious disease. Early identification of the COVID-19 case fatality rate is helpful to the prevention and control of the epidemic.

[Airway parameters and reference value range of high-resolution CT reconstruction in general population].

Objective: To investigate the measurement of small airways by high-resolution CT and image post-processing software. Screen and analyze the reconstructed airway parameters in order to find the best imaging biomarker parameters of small airway changes and calculate the reference value range; meanwhile, explore its influencing factors. Methods: From a water plant and a medical school, 169 cases of the general population aged 20 to 60 were selected as research objects, and questionnaire surveys and CT tests were performed, and CT data were reconstructed with image post-processing software. The reference value range of the general population was evaluated, and a linear mixed effect model was used to adjust the age, gender, height, BMI, and smoking status, and analyze the influencing factors of airway parameters. Results: The ratio of sixth-grade tracheal wall area to total tracheal area in the Left B1+2 to carina was (53.01±13.35) %, Left B9 to carina was (50.44±12.98) %, Right B1 to carina was (52.73±12.22) %, and Right B9 to carina was (52.93±11.85) %. The ratio of nineth-grade tracheal wall area to total tracheal area in the Left B1+2 to carina was (44.08±14.66) %, Left B9 to carina was (42.44±15.89) %, Right B1 to carina was (46.51±14.03) %, and Right B9 to carina is (43.54±15.87) %. BMI affect the area of the tracheal wall, all p value<0.05. Conclusion: High-resolution CT small airway morphology can make a preliminary assessment of the susceptible population of small airway-related diseases based on a range of reference values, and prevent and control it in combination with influencing factors.

[Study on fibrosis changes in the lungs of mice caused by repeated inhalation of polyhexamethyleneguaidine disinfectant].

Objective: To explore the lung damage caused by repeated inhalation of polyhexamethyleneguanidine (PHMG) disinfectant aerosol and the corresponding toxicological characteristics. Methods: Thirty four-week-old mice of C57BL/6N strain were randomly divided into three groups, the control group, low-dose group, and high-dose group. Each group had 5 male mice and 5 female mice. Lab II-level purified water was used in the control group. The PHMG disinfectant aerosol was generated by using the ultrasonic atomization of the aqueous solution containing PHMG. The PHMG concentrations in the low-and high-dose groups were 0.1 mg/ml (0.01%) and 1 mg/ml (0.1%), respectively. The concentration of PHMG in the post-chemical exposure room was 1.03 mg/m(3) and 9.09 mg/m(3) according to the air sampler analysis. The experimental mice were exposed to the PHMG in dynamic respiratory exposure mode for 4 hours every day in 21 days. After 21-day exposure, bronchia alveolus lung fluids (BALFs) were used to evaluate the inflammatory cells in the lungs, and pathological evaluation, special staining and immunohistochemical methods were further performed to evaluate the key indicators of pulmonary fibrosis. Results: Compared to the control group, the body weight of mice in the high-dose group was significantly decreased (P<0.05), while that of mice in the low-dose group did not significantly differ (P>0.05). The number of inflammatory cells in BALFs of low-dose exposed mice was slightly reduced, and the lung tissue pathology began to show lung damage with early fibrosis symptoms (P<0.05). The pathological examination of mice in the high-dose group showed changes in pulmonary fibrosis. Immunohistochemical staining showed that pulmonary fibrosis marker, α-SMA, was significantly increased in low-dose group and high-dose group (P<0.05). Conclusion: The repeated inhalation of PHMG disinfectant could cause lung damage such as pulmonary fibrosis in mice. It could suggest that special warnings should be given to this common disinfectant and respiratory protection measures should be adopted during industrial production and daily use.

[Progress in respiratory toxicity of polyhexamethyleneguaidine disinfectant and mechanism exploration].

Polyhexamethylene guanidine (PHMG) is a high molecular guanidine compound with a broad spectrum of antibacterial effects. Since the outbreak of the 'humidifier disinfectant-induced lung injury' event in South Korea, the respiratory toxicity of PHMG had become a public concern. An epidemiological survey in Korea found that PHMG-containing disinfectants were an important risk factor for pulmonary fibrosis. Animal experiments also showed that the exposure to PHMG through the respiratory tract could cause irreversible fibrosis in the lungs. TGF-ß signaling pathway, epithelial-mesenchymal transition and pulmonary inflammation might be the main pathways that could mediate PHMG-induced pulmonary fibrosis. This article provided an overview of the characteristics of population exposure to PHMG and research progress in the field of respiratory toxicology and recommendations for the rational and standard of using PHMG-related products in China.

[Atypical epithelioid hemangioendothelioma: a clinicopathological analysis of eight cases].

Objective: To study the clinicopathological features, diagnosis, and differential diagnosis of atypical epithelioid hemangioendothelioma (EHE). Methods: Eight cases of atypical EHEs were collected from Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) between 2010 and 2018. EnVision method and fluorescence in situ hybridization (FISH) were used to detect immunophenotype, WWTR1-CAMTA1 and TFE3 gene rearrangement, respectively. Results: There were 4 males and 4 females, ranging from 42 to 59 years (median 47.5 years). The tumors located in soft tissue (3 cases), lung (3 cases), liver (1 case) and chest wall (1 case). One soft tissue EHE involved also adjacent fibula and pleural involvement was present in all three lung cases at the diagnosis. Regional lymph node metastases were present in two cases (one involving soft tissue tumor and one involving liver). Morphologically, the tumor cells were epithelioid with abundant eosinophilic cytoplasm, moderate to marked nuclear pleomorphism, irregular nuclear membrane, unevenly chromatin, and prominent nucleoli. The cells arranged in cords, small nests or solid pattern. The mitotic rate was 4.3 mitoses/2 mm(2) on average (ranging 2 to 9). Tumor necrosis was seen in every case. Among all 8 cases, blister cells were found upon careful observation. Myxohyaline stroma was present in 6 cases. Immunohistochemically, tumor cells expressed CD31 (8/8), CD34 (7/8), ERG (8/8), CKpan (2/7), and CAMTA1 (4/6). None of the tested cases stained for TFE3 (0/6). WWTR1-CAMTA1 fusion gene by FISH was found in all tested 6 cases and TFE3 gene rearrangement was not detected in any. Available clinical follow-up was obtained in 7 cases and the intervals range from 6 to 55 months (average 19.6 months). Six patients had metastasis and 3 patients died of disease. One patient was alive with no evidence of disease. Conclusions: Atypical EHE is a more aggressive tumor than classic EHE, with histological features including high nuclear grade, increased mitotic activity, the presence of solid growth pattern and tumor necrosis. The differential diagnoses include epithelioid angiosarcoma, carcinoma and epithelioid sarcoma.

[The clinical reports on adrenal insufficiency of patients with advanced solid tumors accepting anti-PD-1 antibody, SHR-1210 therapy].

Objective: To investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti- programmed cell death protein-1 (PD-1) antibody, SHR-1210 therapy. Methods: The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR-1210 therapy at our institution between April 27, 2016 and June 8, 2017 were collected. The levels of plasma adrenocorticotropic hormone (ACTH) and cortisol were evaluated in 96 patients. The clinical manifestations, laboratory tests and radiologic data were collected to define the immune-related adrenal insufficiency. Results: Until December 14th, 2018, no SHR-1210 related primary adrenal insufficiency occurred, and the incidence of immune-related secondary adrenal insufficiency was 1.0% among the 96 patients, which was identified as grade 2. No patient developed grade 3-4 adrenal insufficiency. The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue, anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR-1210, the hypocortisolism occurred on the 279th day, and the headache emerged on the 291th day. The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR-1210. Conclusions: The incidence of SHR-1210 related adrenal insufficiency of patients with advanced solid tumors is low, and the symptoms can be effectively ameliorated by hormone replacement therapy. The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.

[Evaluation on the effect of salt reduction intervention among fourth-grade primary school students and their parents in Shandong Province].

In order to evaluate the intervention effect of the school-based salt reduction model, 28 primary schools were selected in Shandong Province in September 2014 and randomly divided into intervention group (1 361 students, 1 306 parents) and control group (1 364 students,1 340 parents). A series of "small hands and big hands" salt reduction intervention activities were conducted in intervention group for 8 months. After the intervention, the total awareness rate of salt reduction knowledge, the total holding rate of related beliefs and the total reporting rate of related behaviors were 70.65%, 80.30% and 67.03% among students, and 85.66%, 93.77% and 87.93% among parents, in the intervention group, which were higher than those in the control group (37.12%, 66.52% and 50.07% among students; 55.11%, 87.52% and 57.96% among parents) (all P values <0.05). The school-based salt reduction model is effective and feasible.

[Revisit to observation and experiment: real world study cannot replace randomized controlled trial].

In epidemiology, intervention is normally used to define what experiment is intervention studies are equaled to experimental studies. Experimental studies are also considered scientifically more rigorous than observational ones. Intervention is generally referred to human activities that can interfere or change natural conditions. The intervention by definition may not necessarily be beneficial to the study subjects (although exposing harmful interventions to humans are unethical) and activities by the researcher, by the subject himself, or by any third party and either now or in the past can all form "effective" interventions. For example, interventions that can damage the optic nerve by any of the three parties can all help the researcher establish the relation between the optic nerve and vision. In the same sense, an activity that a study subject initiated in the past, such as smoking, would also constitute a valid intervention. As a result, a cohort study on smoking and lung cancer would also be an experiment. From the above arguments, we can see that intervention alone does not suffice to distinguish between experiment and observation. As we equal experiment to higher scientific rigorousness than observation, only can study designing features of intervention studies be used to define experiment. In intervention trials, randomization is the defining feature that makes randomized controlled trials differ from, and scientifically more rigorous than, controlled observational studies and has been commonly used to define experiment. If we have to divide clinical research into experiment and observation, randomized controlled trials would be experimental and non-randomized studies of intervention are trials but not experiment. Big data, real-world studies are not experiment and cannot replace randomized trials in confirmation of efficacy if comparison groups are not formed by randomization. Real world studies cannot replace randomized controlled trials. This is the most important message this paper wishes to convey.

[Characteristics of invisible cervical intraepithelial neoplasia â ¢ under colposcopy].

Objective: To explore the human papilomavirus (HPV) genotypes and epithelial thickness of invisible cervical intraepithelial neoplasia Ⅲ (CIN Ⅲ) under colposcopy. Methods: One hundred and sixty-nine biopsies from 93 patients with a final diagnosis of CIN Ⅲ were extracted from the Shenzhen cervical cancer screening trial Ⅱ (SHENCCAST Ⅱ) . The SHENCCAST Ⅱ was conducted from 2009 to 2010. All the cervical blocks from these patients were re-cut and placed on 6 slides, i.e. sandwich model, with the top and bottom sections being stained with HE, the top second be processed for other studies, 3 sections for HPV genotypes by matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) assay. The thickness of squamous epithelium of CIN Ⅲ was measured by a microscope (×10) after re-cut. Colposcope directed CIN Ⅲ biopsies positively was defined as visible CIN Ⅲ, while random CIN Ⅲ biopsies positively was defined as invisible CIN Ⅲ. Results: HPV16 positivity was 37.2% (16/43) and 55.6% (70/126) between invisible and visible CIN Ⅲ biopsies, respectively (χ(2)=4.318, P=0.038) . Forty-nine cases of the 93 CIN Ⅲ patients were HPV16 positive, while 44 of them non-HPV16 positive. The proportion of patients with ≥45 years of age for other non-HPV16 positive 40.9% (18/44) was significantly higher than that HPV16 positive 20.4% (10/49; χ(2)=4.630, P=0.031) . Patients with HPV16 positive were more likely to have lesions ≥1 quadrant (χ(2)=7.786, P=0.005) than other non-HPV16 positive. Compared the average epithelium thickness of invisible CIN Ⅲ tissue (140±12) µm, the average epithelium thickness of visible CIN Ⅲ tissue (161±9) µm was thicker. There was statistical difference between two groups (t=4.383, P=0.038). The mean average epithelial thickness of CIN Ⅲ with HPV16 positive (172±11) µm was thicker than that the mean average epithelial thickness of CIN Ⅲ with non-HPV16 positive (130±10) µm (t=4.784, P=0.031) . Conclusions: Invisible lesions is difficult to identify under colposcopy and is related to non-HPV16 positive, small lesion size and thinner squamous epithelium. For non-HPV16 positive or older women should be performed colposcope directed biopsies and randomly multi-sites biopsies by colopscopy, which may be helpful to improve the detection of CIN Ⅲ and to reduce miss diagnosis.