[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.

[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.

[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.

[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.

[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.

Effects of ulinastatin on inflammatory response and cognitive function after hip arthroplasty for the elderly patients with femoral neck fracture.

OBJECTIVE: To investigate the effects of ulinastatin on inflammatory response and cognitive function after hip arthroplasty for the elderly patients with femoral neck fracture. PATIENTS AND METHODS: A total of 80 patients with femoral neck fracture receiving hip arthroplasty in our hospital from August 2016 to February 2017 were selected and divided into observation group (n=40) and control group (n=40) using a random number table. The control group was treated with hip arthroplasty and symptomatic and supportive treatment after operation, while the observation group was treated with ulinastatin based on the treatment means of control group. The changes in antioxidant capacities, plasma noradrenaline (NA) and adrenaline (A) levels between the two groups before and after intervention were compared. The changes in neuron-specific enolase (NSE) and plasma S-100B protein levels before intervention and at 48 h after intervention were also compared. Moreover, the changes in mini-mental state examination (MMSE) scores during intervention and the Harris hip scores before intervention and at discharge between the two groups were compared. Finally, the off-bed walking time and postoperative discharge time of the two groups were recorded. RESULTS: After intervention, the levels of malondialdehyde (MDA) and superoxide dismutase (SOD) and the total antioxidant capacity in observation group were significantly superior to those in observation group before intervention and control group after intervention (p<0.05). After intervention, the levels of NA and A in observation group were lower than those in control group (p<0.05), and the levels of interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and high-sensitivity C-reactive protein (hs-CRP) in observation group were also lower than those in control group (p<0.05). At 48 h after intervention, the levels of NSE and plasma S-100B protein in observation group were significantly lower than those in observation group before intervention and control group at 48 h after intervention (p<0.05). At 12 h, 24 h and 48 h after intervention, the MMSE scores of observation group were superior to those of control group in the same period (p<0.05). After intervention, the Harris hip score of observation group was superior to that of control group before and after intervention (p<0.05). The postoperative discharge time of observation group was earlier than that of control group (p<0.05), and the off-bed walking time was also earlier than that of control group (p<0.05). CONCLUSIONS: The combined application of ulinastatin could effectively reduce the oxidative stress and inflammatory response, improve the neurological functions, and promote the postoperative recovery in the elderly patients with femoral neck fracture after hip arthroplasty.

[Some reflections on evidenced-based medicine, precision medicine, and big data-based research].

Evidence-based medicine remains the best paradigm for medical practice. However, evidence alone is not decisions; decisions must also consider resources available and the values of people. Evidence shows that most of those treated with blood pressure-lowering, cholesterol-lowering, glucose-lowering and anti-cancer drugs do not benefit from preventing severe complications such as cardiovascular events and deaths. This implies that diagnosis and treatment in modern medicine in many circumstances is imprecise. It has become a dream to identify and treat only those few who can respond to the treatment. Precision medicine has thus come into being. Precision medicine is however not a new idea and cannot rely solely on gene sequencing as it was initially proposed. Neither is the large cohort and multi-factorial approach a new idea; in fact it has been used widely since 1950s. Since its very beginning, medicine has never stopped in searching for more precise diagnostic and therapeutic methods and already made achievements at various levels of our understanding and knowledge, such as vaccine, blood transfusion, imaging, and cataract surgery. Genetic biotechnology is not the only path to precision but merely a new method. Most genes are found only weakly associated with disease and are thus unlikely to lead to great improvement in diagnostic and therapeutic precision. The traditional multi-factorial approach by embracing big data and incorporating genetic factors is probably the most realistic way ahead for precision medicine. Big data boasts of possession of the total population and large sample size and claims correlation can displace causation. They are serious misleading concepts. Science has never had to observe the totality in order to draw a valid conclusion; a large sample size is required only when the anticipated effect is small and clinically less meaningful; emphasis on correlation over causation is equivalent to rejection of the scientific principles and methods in epidemiology and a call to give up the assurance for validity in scientific research, which will inevitably lead to futile interventions. Furthermore, in proving the effectiveness of intervention, analyses of real-world big data cannot displace the role of randomized controlled trial. We expressed doubts and critiques in this article on precision medicine and big data, merely hoping to stimulate discussing on the true potentials of precision medicine and big data.

Clinico-biological significance of suppressor of cytokine signaling 1 expression in acute myeloid leukemia.

Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.

Evaluation of novel assays for the detection of human papilloma virus in self-collected samples for cervical cancer screening.

The aim of this study was to evaluate the performance of three new high-risk human papillomavirus (HPV) assays for primary cervical cancer screening, by using self-collected samples, and to identify an HPV assay that could overcome the major obstacles faced during large-scale population-based screening. Two hundred and ten women showing abnormal cervical cytology (and referred for a colposcopy) were recruited in this study. Self-collected samples obtained from all women were tested with the Cobas, Seq, and BioPerfectus Multiplex Real Time HPV assays; simultaneously, clinician-collected samples (from the same women) were tested with the gold-standard Cobas HPV assay. The results of all the assays were consistent. The sensitivity, positive predictive value, and negative predictive value for cervical intraepithelial neoplasia 2+ (CIN2+) and CIN3+ were comparable between the self-collected samples tested with the three new assays and the clinician-collected samples tested with the Cobas HPV assay (P > 0.05). The single-genotype HPV load per sample did not differ significantly between the self- and clinician-collected samples (P = 0.195). In conclusion, the results of this study demonstrated the applicability of the three new HPV assays for primary cervical cancer screening based on self-collection.

Genetic alterations and their clinical implications in older patients with acute myeloid leukemia.

A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.

TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.

The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.

Loss of STAG2 causes aneuploidy in normal human bladder cells.

The aim of this study was to determine how the function of human stromal antigen 2 (STAG2) plays an important role in proper chromosome separation. STAG2 mRNA in normal bladder cells and bladder tumor cells was evaluated by RT-PCR. The protein levels of STAG2 in normal bladder cells and bladder tumor cells were determined by western blot. A cell proliferation assay was used to measure the growth of tumor cells and STAG2-inhibited normal cells, and STAG2- inhibited normal cells were subjected to karyotype analysis. Both STAG-2 mRNA and protein expression levels were lower in bladder cancer cells compared to the controls. Knockdown of STAG2 caused aneuploidy in normal bladder cells, leading to a decreased expression of the cohesin complex components SMC1, SMC3 and RAD21, but there was no obvious effect of STAG2 knockdown on cell proliferation. Our study indicated that abnormal expression of STAG2 could cause aneuploidy in normal bladder cells.

Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome.

Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.