[Effect of SHP-1 knockout in airway epithelial cells on emphysema phenotype in chronic obstructive pulmonary disease in mice].

Objective: To construct and characterize conditional Src homology region 2 protein tyrosine phosphatase 1 (SHP-1) knockout mice in airway epithelial cells and to observe the effect of defective SHP-1 expression in airway epithelial cells on the emphysema phenotype in chronic obstructive pulmonary disease (COPD). Methods: To detect the expression of SHP-1 in the airway epithelium of COPD patients. CRISPR/Cas9 technology was used to construct SHP-1flox/flox transgenic mice, which were mated with airway epithelial Clara protein 10-cyclase recombinase and estrogen receptor fusion transgenic mice (CC10-CreER+/+), and after intraperitoneal injection of tamoxifen, airway epithelial SHP-1 knockout mice were obtained (SHP-1flox/floxCC10-CreER+/-, SHP-1Δ/Δ). Mouse tail and lung tissue DNA was extracted and PCR amplified to discriminate the genotype of the mice; the knockout effect of SHP-1 gene in airway epithelial cells was verified by qRT-PCR, Western blotting, and immunofluorescence. In addition, an emphysema mouse model was constructed using elastase to assess the severity of emphysema in each group of mice. Results: Airway epithelial SHP-1 was significantly downregulated in COPD patients. Genotyping confirmed that SHP-1Δ/Δ mice expressed CC10-CreER and SHP-1-flox. After tamoxifen induction, we demonstrated the absence of SHP-1 protein expression in airway epithelial cells of SHP-1Δ/Δ mice at the DNA, RNA, and protein levels, indicating that airway epithelial cell-specific SHP-1 knockout mice had been successfully constructed. In the emphysema animal model, SHP-1Δ/Δ mice had a more severe emphysema phenotype compared with the control group, which was manifested by disorganization of alveolar structure in lung tissue and rupture and fusion of alveolar walls to form pulmonary alveoli. Conclusions: The present study successfully established and characterized the SHP-1 knockout mouse model of airway epithelial cells, which provides a new experimental tool for the in-depth elucidation of the role of SHP-1 in the emphysema process of COPD and its mechanism.

[Effect of axillary lymph node status on prognosis of different types of invasive breast cancer].

Objective: To investigate the effect of axillary lymph node status on the prognosis of different types of invasive breast cancer. Methods: Patients with invasive breast cancer of different molecular subtypes diagnosed in the breast cancer prevention and treatment center of Beijing Cancer Hospital from January 2000 to July 2011 were collected as a historical cohort, and the influence of lymph node status on the prognosis of different types of breast cancer was analyzed. Results: A total of 4 269 female breast cancer patients with molecular subtypes [aged (50.8±11.2) years] information and 3 824 female breast cancer patients with complete axillary lymph node status information [aged (50.5±10.9) years] were included in the study, including 3 135 cases with both molecular subtypes and lymph node status information. The 10-year event free survival (EFS) rates of hormone receptor (HR)+/human epidermal growth factor receptor-2(HER2)-, HR-/HER2-and HER2+were 82.2%, 79.0% and 76.8%, respectively; the 10-year overall survival (OS) rates were 88.1%, 83.1% and 84.4%, respectively, and the differences of 3 molecular subtypes in EFS and OS were statistically significant (both P<0.001). The 10-year EFS rate of lymph node positive and negative patients was 68.8% and 88.2%, respectively; the 10-year OS rate was 76.7% and 92.5%, respectively, and the differences of lymph node status in EFS and OS were statistically significant (both P<0.001). In lymph node negative subgroup, 3 subtypes showed similar EFS and OS rate (both P>0.05); In lymph node positive subgroup, 3 subtypes showed significantly different EFS and OS (both P<0.05). No modification effect was detected of lymph node status on the correlation of molecular subtypes and EFS, DDFS and OS(all Pinteractive>0.1). Conclusions: Different molecular subtypes of breast cancer have different prognosis. Compared with molecular subtype, lymph node status may be a more important prognostic factor.

[Long-term recurrence rate and survival in different aged patients with breast cancer undergoing breast conserving therapy].

Objective: To examine the difference of long-term recurrence rate and survivals between the young patients and the old patients undergoing breast conserving therapy (BCT). Methods: Women with primary invasive breast cancer receiving BCT between December 1999 and December 2014 were selected retrospectively from the database of Breast Cancer Center, Peking University Cancer Hospital & Institute. The median age of all patients was 47 years (range: 21 to 91 years). The cases were categorized according to age at diagnosis into two subgroups: the ≤40 years group and the>40 years group. A total of 2 778 patients were included: 677 patients in the ≤40 years group and 2 101 patients in the >40 years group. Clinicopathological characteristics between two groups were compared. The recurrence rate and survival were calculated using the Kaplan-Meier method. The differences of outcomes were compared in different aged groups using the Log-rank test. Factors affecting local recurrence, distant disease-free survival (DDFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) were assessed by multivariable Cox proportional hazard models. Results: Proportions of T1 (301/677 vs. 1 160/2 101, χ²=37.660, P<0.01), involved lymph node (314/677 vs. 713/2 101, χ²=34.966, P<0.01) hormone receptor-negative (490/677 vs. 1 581/2 101, χ²=6.981, P=0.030) and neoadjuvant chemotherapy (413/677 vs. 1 010/2 101, χ²=34.272,P<0.01)in the ≤40 years group were higher than that in the>40 years group. Median follow-up duration was 102 months. No significant difference in 10-year local recurrence was found between the two groups (2.5% vs. 1.6%, P=0.147). Ten-year DDFS rate in the ≤40 years group and in the>40 years group was 90.6% and 95.3%, respectively (P<0.01). Ten-year DFS rate in the ≤40 years group and in the>40 years group was 86.5% and 91.1%, respectively (P=0.001). Ten-year BCSS rate in the ≤40 years group and in the >40 years group was 91.0% and 93.7%, respectively (P=0.105). Age was not the prognosis factor of local recurrence. Lymph node status (positive vs. negative: HR=2.73, 95%CI: 1.94 to 3.84, P<0.01), age (≤40 years vs.>40 years: HR=1.73, 95%CI: 1.24 to 2.42, P=0.001) and T stage (>2 cm vs. ≤2 cm: HR=1.61, 95%CI: 1.14 to 2.28, P=0.001) were the prognosis factors of DDFS, and also for DFS. Hormone receptor status (positive vs. negative: HR=0.54, 95%CI: 0.39 to 0.74, P<0.01), lymph node status (positive vs. negative: HR=2.94, 95%CI: 2.12 to 4.07, P<0.01) and T stage (>2 cm vs. ≤2 cm: HR=1.45, 95%CI: 1.05 to 2.01, P=0.025) were the prognosis factors of BCSS. Conclusions: The risk of local recurrence was similar between ≤40 years patient and >40 years patients receiving breast conserving therapy. Worse survivals in the ≤40 years group were found comparing to those in the >40 years group.

[Safety and short-term efficacy analysis of breast-conserving surgery combined with intraoperative radiotherapy for early-stage breast cancer].

Objective: To analyze the safety and short-term efficacy of breast-conserving surgery combined with intraoperative radiotherapy for early-stage breast cancer. Methods: A total of 101 consecutive patients who received breast-conserving surgery plus intraoperative radiotherapy were recruited to summarize the recent follow-up results and clinicopathological data. Univariate analysis and Logistic regression model were used to evaluate the factors affecting the postoperative adverse reactions and cosmetic effects. Results: Among 101 patients, 4 patients had recurrence or metastasis. The 3-years disease free survival rate was 94.9%, and the 3-years cumulative recurrence rate was 5.1%. Univariate analysis showed that the menstrual status and postoperative whole breast radiotherapy were associated with the postoperative adverse reactions (P<0.05). The T stage and applicator diameter were associated with the cosmetic effect (P<0.05). Multivariate analysis indicated that the diameter of the applicator (OR=3.701, P=0.026) and postoperative whole breast radiotherapy (OR=5.962, P=0.005) were independent factors for the postoperative adverse reactions, and the diameter of the applicator (OR=2.522, P=0.037) was an independent factor for the cosmetic effect. Conclusion: Breast-conserving surgery combined with intraoperative radiotherapy shows safety and good short-term efficacy in low-risk early-stage breast cancer.

[Study on the relationship between passive smoking and disease burden of stroke in people aged 60 years and over in Jiangsu province, 2013].

Objective: To analyze the disease burden of stroke and its health loss attributable to passive smoking in people aged 60 years and over in Jiangsu province. Methods: Data were retrieved from the Chronic and Non-communicable Diseases and Risk Factors Surveillance in Jiangsu in 2013 and the death registry system in Jiangsu. Combined with the method in Global Burden of Disease Study 2016 (GBD2016), the indicators, such as population attributable fraction (PAF) and disability-adjusted life years (DALY) for stroke due to passive smoking were calculated. Results: In 2013, the mortality rate, age-standardized mortality rate, DALY and DALY rate of stroke in people aged 60 years and over in Jiangsu were 718.15/100 000, 439.28/100 000, 1 179 602 person years and 9 234.99/100 000, respectively. Year of life lost (YLL) accounted for 87.00% of the total DALY. The DALY and corresponding rate of stroke increased rapidly with age, and were higher in women (612 084 person years and 9 319.71/100 000, respectively) than those in men (567 518 person years and 9 145.33/100 000, respectively). The prevalence of passive smoking was 34.04% in people aged 60 years and over in Jiangsu. The PAF, attributable DALY, attributable DALY rate and its age- standardized rate of stroke due to passive smoking in people aged 60 years and over in Jiangsu were 3.88%, 45 769 person years, 358.12/100 000 and 920.64/100 000, respectively; and were also higher for men (4.35%, 24 687 person years, 397.82/100 000 and 515.30/100 000, respectively) than those for women (3.44%, 21 056 person years, 320.60/100 000, 405.34/100 000, respectively). Conclusions: The disease burden of stroke was heavy in the elderly in Jiangsu, and passive smoking might have great influence on the disease burden of stroke. Prevention and control of stroke and passive smoking exposure should be taken actively to improve health for the elderly.

[Analysis on the burden of cardio-cerebral vascular disease deaths attributed to smoking in inhabitants aged 30 years and above in Jiangsu Province].

Objective: To analyze the attributable burden of smoking on the deaths of cardio-cerebral vascular diseases (CCVD) in inhabitants aged 30 years and above in Jiangsu Province. Methods: Comparative risk assessment approach in Global Burden of Disease (GBD) was used with the data from Jiangsu Non-communicable Disease and Behavioral Risk Factor Surveillance System and Death Monitoring Surveillance System in 2013, and population attributable fraction (PAF), years of life lost (YLL), work of potential years of life lost, index of life lost and life loss attributed to smoking were calculated. Results: In 2013, there were 162 158 CCVD deaths aged 30 years and above in the surveillance areas of Jiangsu Province, of which 25 102 deaths were attributed to smoking (PAF: 15.48%, attributed mortality rate: 55.13/100 000). The YLL, work of potential years of life lost and index of life lost were 532 494 person years, 78 024 person years and 9.15 years respectively. The decline of life expectancy was 0.58 years. The PAF of CCVD attributed to smoking in male and female were 27.97% and 3.18%, respectively, and the mortality rate of cardio-cerebral diseases attributed to smoking in male and female were 100.13/100 000 and 11.27/100 000, respectively. The burden of ischemic heart disease and hemorrhagic stroke were most severe, with standardized YLL rate were 3.65‰ and 3.20‰, respectively. Conclusion: Smoking caused a great burden of cardio-cerebral disease deaths in inhabitants in Jiangsu province.

[Evaluation of 10-year risk for ischemic cardiovascular disease in type 2 diabetes aged 35 years old and above in two cities of Jiangsu Province].

Objective: To evaluate the risk of 10-year risk of ischemic cardiovascular disease (ICVD) in patients with type 2 diabetes aged 35 years old and above in two cities of Jiangsu province. Methods: From December 2013 to January 2014, a total of 15 624 patients with type 2 diabetes aged 35 years old and above, who received national basic public health service in Changshu county of Suzhou city, Huai'an and Qinghe districts of Huai'an city, Jiangsu province, were recruited by cluster sampling method. Face-to-face questionnaire survey, anthropometric and laboratory measurements were conducted to collect exposures to ICVD risk factors. Improved Ten Year Risk Assessment Table of ICVD in Chinese was used to assess the risk score and the absolute risk of developing ICVD. Results: The participants were (62.2±9.7) years old, of which 6 137 were men (39.3%). Among the participants, the highest rate of exposure to ICVD risk factors was high systolic blood pressure (74.8%, n=11 685), followed by high total cholesterol (70.7%, n= 11 051).The score of 10-year risk for ICVD was (10.4±3.3) and the median (P(25)-P(75)) value of absolute risk was 15.6% (6.8%-32.7%). 16.7% (n=2 602) participants were under extremely high risk of 10-year risk for ICVD, 23.8% (n=3 714) under high-risk and 24.0% (n=3 746) under middle-risk. Among the total risk score of ICVD, age (49.1%), hypertension (17.7%) and diabetes (15.5%) accounted for relatively high proportion, however, smoking (11.0%) was the most important risk factor except for age (47.4%) and systolic blood pressure (20.5%) in male participants. Conclusion: Patients with type 2 diabetes aged 35 years old and above in two cities of Jiangsu Province have a high risk of developing ICVD for 10 years, especially in elderly, female, hypertension patients and male smokers.

[Application of decision curve on evaluation of MRI predictive model for early assessing pathological complete response to neoadjuvant therapy in breast cancer].

Objective: To construct a dynamic enhanced MR based predictive model for early assessing pathological complete response (pCR) to neoadjuvant therapy in breast cancer, and to evaluate the clinical benefit of the model by using decision curve. Methods: From December 2005 to December 2007, 170 patients with breast cancer treated with neoadjuvant therapy were identified and their MR images before neoadjuvant therapy and at the end of the first cycle of neoadjuvant therapy were collected. Logistic regression model was used to detect independent factors for predicting pCR and construct the predictive model accordingly, then receiver operating characteristic (ROC) curve and decision curve were used to evaluate the predictive model. Results: ΔArea(max) and Δslope(max) were independent predictive factors for pCR, OR=0.942 (95%CI: 0.918-0.967) and 0.961 (95%CI: 0.940-0.987), respectively. The area under ROC curve (AUC) for the constructed model was 0.886 (95%CI: 0.820-0.951). Decision curve showed that in the range of the threshold probability above 0.4, the predictive model presented increased net benefit as the threshold probability increased. Conclusions: The constructed predictive model for pCR is of potential clinical value, with an AUC>0.85. Meanwhile, decision curve analysis indicates the constructed predictive model has net benefit from 3 to 8 percent in the likely range of probability threshold from 80% to 90%.

[Impact of adjuvant chemotherapy on the prognosis of hormone receptor negative breast cancer with residual lymph node disease after neoadjuvant chemotherapy].

Objective: To explore the influence of adjuvant chemotherapy on the prognosis of hormone receptor negative breast cancer with residual lymph node disease(RLND)after neoadjuvant chemotherapy. Methods: A total of 110 hormone receptor negative breast cancer patients treated with 4-8 cycles of neoadjuvant chemotherapy were respectively analysed between 2002 and 2012. Residual lymph node disease was comfirmed by subsequent radical mastectomy. Then all these patients were classified into two groups: patients treated with adjuvant chemotherapy(group A) and patients untreated with adjuvant chemotherapy(group B). Results: All patients were female, the median age was 54.5 years old(IQR: 47-59 years). The median follow-up time was 61 months(IQR: 51-88 months). There were 82 patients (74.5%) in group A, and 28 patients (25.5%) in group B. The five-year disease-free survival (DFS) rate was 76.2% in group A and 57.6% in group B. The distant disease-free survival (DDFS) rate was 78.9% in group A and 60.4% in group B. Overall survival (OS) rate was 81.0% in group A and 60.0% in group B. Multivariate analysis showed that there were significant differences for DDFS rate (group A vs group B, P=0.033; hazard ratio [HR], 5.256; 95% confidence interval [95%CI], 1.14-24.17) and OS rates (group A vs group B, P=0.011; HR, 7.478; 95%CI, 1.58-35.30) between two groups. Conclusion: The patients who have hormone receptor negative breast cancer with RLND after neoadjuvant chemotherapy, may benefit from postoperative adjuvant chemotherapy.

[Breast-conserving surgery with immediate partial breast reconstruction using pedicled thoracodorsal artery perforator flap: a clinical analysis of 33 patients].

Objective: To explore the application value of pedicled thoracodorsal artery perforator flap in immediate partial breast reconstruction for breast cancer. Methods: This study is a prospective case series studies. Totally 128 cases of primary breast cancer patients who prepared to receive the breast-conserving surgery combine with immediate partial breast reconstruction of pedicled thoracodorsalartery perforator flap were enrolled in Breast Cancer Prevention and Treatment Center of Peking University Cancer Hospital from June 2013 to March 2016. Finally, the operations had been completed successfully in 33 eligible cases. All patients were female with a median age of 40 years (ranging from 22 to 52 years). The perforator vessel location, the donor area design, the post-operative complications, the influence of radiation and chemotherapy had been evaluated. Results: The average diameter of thoracic dorsal artery perforators measured by Doppler ultrasound before the operation was (1.5±0.4) mm (ranging from 0.6 to 2.7 mm). The average size of flaps was 15 cm×6 cm. The average time of operations was (271±72) minutes (ranging from 120 to 245 minutes). Drainage tube removed on (4.7±2.1) days after operation (ranging from 3 to 12 days). All patients received follow-up, and there was no local recurrence and distant metastasis during a median follow-up of 17(12) months (M(Q(R))) (ranging from 5 to 38 months). All TDAP flaps were survival, the wound complication rates was 6% (2/33). Conclusions: The breast reconstruction of pedicled thoracodorsal artery perforator flap is a good choice of repairing local breast defect of breast conserving surgery.Its advantages are no-influence of latissimus dorsi function and little complications in donor area.

[Impact of the response of primary tumor to preoperative chemotherapy and anti-HER2 therapy on survival of HER2-positive breast cancer patients].

OBJECTIVE: To study the impact of anti-HER2 therapy and response of primary tumor on distant disease free survival (DDFS) of the patients with HER2-positive breast cancer. METHODS: The clinical data of the patients with HER2-positive breast cancer treated with neoadjuvant systemic therapy were analyzed retrospectively. RESULTS: Patients treated with preoperative anti-HER2 therapy and chemotherapy had a significant improved pathological complete response (pCR) rate (48.4%) compared with those treated with preoperative chemotherapy (17.2%) (P=0.000). The median follow-up period was 62(6-160) months. The 5-year DDFS in patients with anti-HER2 therapy and patients without anti-HER2 therapy was 93.5% and 83.3% respectively (P=0.006). The 5-year DDFS in patients achieving a pCR and patients not achieving a pCR was 94.7% and 82.6% respectively(P=0.001). Among patients achieving a pCR, anti-HER2 therapy did not improve DDFS significantly (P=0.960). Benefits of anti-HER2 therapy in DDFS among patients without a pCR achieved statistical significance (P=0.028). CONCLUSIONS: Combination of neoadjuvant anti-HER2 therapy and chemotherapy resulted in a higher pCR rate in HER2-overexpressing primary breast cancer. Patients treated with neoadjuvant systemic therapy who achieved a pCR have excellent outcome regardless of whether they received anti-HER2 therapy.

[Relationship of clinicopathological features and chemotherapeutic outcomes in women with BRCA1 and BRCA2 mutation-negative familial breast cancer].

OBJECTIVE: To explore the relationship of clinicopathological features and response to neoadjuvant chemotherapy in women with BRCA1 and BRCA2 mutation-negative familial breast cancer. METHODS: A total of 6 200 women with breast cancer were treated at our hospital from October 2003 to December 2012. All subjects underwent genetic testing for BRCA1 and BRCA2 genes. Patients with BRCA1 and BRCA2 mutations were excluded. This cohort of 5 842 patients with BRCA1 and BRCA2 mutation-negative breast cancer was classified as two groups: familial breast cancer patients (n=480) and sporadic breast cancer patients (n=5 362). The clinicalpathological data and response to neoadjuvant chemotherapy of the 480 patients with BRCA1 and BRCA2 mutation-negative familial breast cancer and the 5 362 patients with BRCA1 and BRCA2 mutation-negative sporadic breast cancer were compared retrospectively. Then the influencing factors of response to neoadjuvant chemotherapy were analyzed. RESULTS: Among the BRCA1 and BRCA2 mutation-negative breast cancer patients, 4.4% of the patients were diagnosed before 30 years of age in the familial breast cancer group, significantly higher than that of 2.6% in the sporadic breast cancer group(P=0.020). 5.0% of the patients in the familial breast cancer group had bilateral breast cancer, significantly higher than that of 2.7% in the sporadic breast cancer group (P=0.004). Compared with BRCA1 and BRCA2 mutation-negative sporadic breast cancer patients, the relative risk of early-onset breast cancer (≤ 30 years) and bilateral breast cancer were 1.73 and 1.91, respectively, significantly higher than that in the BRCA1 and BRCA2 mutation-negative familial breast cancer cases (P=0.020 and P=0.004). 2 964 patients in this cohort of 5 842 case sreceived neoadjuvant chemotherapy.The pathologic complete response (pCR) rate was significantly higher in the BRCA1 and BRCA2 mutation-negative familial breast cancer group than in the BRCA1 and BRCA2 mutation-negative sporadic breast cancer group (21.7% vs. 14.0%, P=0.001). Independent factors associated with pCR in BRCA1 and BRCA2 mutation-negative breast cancer patients were tumor size less than 2 cm (P=0.012), histologic grade Ⅲ (P<0.001), triple-negative breast cancers (P<0.001), and BRCA1 and BRCA2 mutation-negative familial breast cancer(P=0.001). CONCLUSIONS: Compared with BRCA1 and BRCA2 mutation-negative sporadic breast cancer, BRCA1 and BRCA2 mutation-negative familial breast cancer is more likely diagnosed before the age of 30 years and has a higher risk to develop bilateral breast cancer. BRCA1 and BRCA2 mutation-negative familial breast cancers are more likely to respond to neoadjuvant chemotherapy than BRCA1 and BRCA2 mutation-negative sporadic breast cancer.