Background and purpose:The third generation of aromatase inhibitors (AI) in postmenopausal hormone receptor-positive patients is the routine treatments in endocrine therapy. The 500 mg fulvestrant showed clini-cal beneifts in patients with previous AI treatment. This study aimed to access the effcacy and safety of 500 mg fulves-trant in estrogen receptor (ER) positive postmenopausal patients who had previous AI treatments with locally advanced and metastatic breast cancer.Methods:This study retrospectively analyzed the clinical data from 188 post-AI ER positive and (or) progesterone receptor (PR)-positive locally advanced and metastatic breast cancer patients treated with 500 mg fulvestrant in Fudan University Shanghai Cancer Center from Jul. 2011 to Dec. 2015. Primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR), clinical beneift rate (CBR) and safety proifle.Results:After the median follow-up of 11.3 months, median PFS was 5.9 months (95%CI: 4.2-7.5), CBR was 40.0% and ORR was 3.4%. COX proportional hazards regression analysis indicated that PFS was correlated with the number of metastatic sites (HR=1.92, 95% CI: 1.2-2.9,P =0.002) and previous lines of chemotherapy (HR=1.52, 95%CI:1.0-2.1,P=0.022). Six patients stopped the treatment for intolerable adverse events.Conclusion:The treatment of 500 mg fulvestrant has a favorable effcacy and safety in treatment of post-AI ER positive postmenopausal patientswith metastatic breast cancer.

Purpose: Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. This study reported the first real-world data of pyrotinib-based therapy in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on efficacy in lapatinib-treated patients and in brain metastasis. Materials and Methods: One hundred thirteen patients with metastatic HER2-positive BC treated with pyrotinib-based therapy in Fudan University Shanghai Cancer Center under non-clinical trial settings from September 1, 2018 to March 1, 2019 were included. Results: Over half patients have received more than two lines of systematic therapy and exposed to two or more kinds of anti-HER2 agents. Most patients received a combined therapy, commonly of pyrotinib plus capecitabine, or vinorelbine or trastuzumab. Median progression-free survival (PFS) was 6.3 months (range, 5.54 to 7.06 months) and objective response rate (ORR) was 29.5%, with two patients (1.9%) achieving complete response. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (9.0 months vs. 5.4 months, p=0.001). ORR for lapatinib-treated patients was 23.2%. Thirty-one of 113 patients have brain metastasis. Median PFS was 6.7 months and intracranial ORR was 28%. For patients without concurrent radiotherapy and/or brain surgery, the ORR was very low (6.3%). But for patients receiving concurrent radiotherapy and/or brain surgery, the ORR was 66.7%, and three patients achieved complete response. Most common adverse event was diarrhea. Conclusion Pyrotinib-based therapy demonstrated promising effects in metastatic HER2-positive BC and showed activity in lapatinib-treated patients. For patients with brain metastasis, pyrotinib-based regimen without radiotherapy showed limited efficacy, but when combined with radiotherapy it showed promising intracranial control.

Objective: To study the factors associated with efficacy of nucleos(t)ide analogues with sequential interferon in HBeAg positive chronic hepatitis B (CHB) patients. Method: HBeAg positive CHB patients treated with nucleoside analogue (NA) treatment received PEG-IFN α-2a 180 μg subcutaneously once weekly.NA was continually used with PEG-IFNα-2a during the first 12 weeks. HBsAg/HBeAg level and HBV DNA load were observed in the sequential pre-treatment (baseline) period, 12 th, 24 th, 36 th, 48 th and 72 nd weeks of sequential therapy in all patients. Result: Of the 56 HBeAg-positive CHB patients, 5 (23.1%) achieved HBsAg loss/seroconversion, the baseline HBsAg level in HBsAg loss/seroconversion group was lower than that of the patients in the group that did not achieve HBsAg loss/seroconversion (2.750 lg IU/ml vs. 3.699 lg IU/ml, t=0.955, P=0.000); the difference was statistically significant in HBsAg decreased at the 12 th, 24 th, 36 th, 48 th week in the course of sequential therapy (0.913 vs 0.149, 2.847 vs 0.189, 4.378 vs 0.248, 4.587 vs 0.274 lg IU/ml) (t=-2.950, P=0.040; t=-8.732, P=0.009; t=-8.483, P=0.001; t=-8.214, P=0.003); 11(19.6%) achieved HBeAg loss/ seroconversion, the HBeAg baseline level in HBeAg loss/seroconversion group was lower than the patients in the group that not achieved HBeAg loss/seroconversion (1.217 lgS/CO vs 1.884 lgS/CO, t=2.061, P=0.044); the difference was statistically significant in HBsAg, HBeAg decreased at 24 th, 36 th, 48 th week in the course of sequential therapy between the two groups (1.330 vs 0.205, 2.084 vs 0.258, 1.972 vs 0.284, lg IU/ml; 1.168 vs 0.455, 1.363 vs 0.461, 1.177 vs 0.447, lg S/CO) (t=2.238, P=0.049; t=2.619, P=0.025; t=2.278, P=0.048); (t=2.273, P=0.043; t=3.415, P=0.001; t=2.271, P=0.049). Conclusions To HBeAg-positive CHB, lower baseline HBsAg, HBeAg level and HBsAg, HBeAg decreased earlier were could predict easier achievement of HBs(e)Ag loss/seroconversion.

Objective: To study the factors associated with efficacy of nucleos(t)ide analogues with sequential interferon in HBeAg negative chronic hepatitis B (CHB) patients. Methods: HBeAg negative CHB patients with NA treatment received PEG-IFNα 2a 180 μg subcutaneously once weekly. NA was continually used with PEG-IFN 2a during the first 12 weeks. HBsAg level and HBV DNA load were observed in the sequential pre-treatment (baseline), 12th, 24th, 36th, 48th, 72nd and 96th weeks of sequential therapy in all patients. Results: Of the 26 HBeAg negative CHB patients, 6 (23.1%) achieved HBsAg loss/seroconversion. The comparison between HBsAg loss/ seroconversion group and the group not achieved HBsAg loss/ seroconversion showed that the baseline HBsAg level in HBsAg loss/seroconversion group was 2.210 log₁₀IU/ml, was lower than (t=-4.252, P=0.000) HBsAg-positive patients (3.385 log₁₀IU/ml) in the groupp that not achieved HBsAg loss/seroconversion, the difference was statistically significant in HBsAg decreased at 72^nd, 96^th week in the course of sequential therapy (3.511 vs. 0.723log₁₀IU/ml, 4.291 vs. 0.737 log₁₀IU/ml) (t=6.712, P=0.000, t=13.319; P=0.000, 0.00); the difference was not statistically significant in age, gender and NA therapy time between the two groups; 12 (46.2%) of patients achieved sustained virologic response (SVR), the baseline of HBsAg level was 2.575 log₁₀IU/ml, was less than (t=-4.319, P=0.000) the patients who did not achieve SVR (3.576 log₁₀IU/ml), the difference was statistically significant in HBsAg decrease of each time in the course of sequential therapy between the two groups (0.612 vs. 0.088, 1.192 vs. 0.107, 1.566 vs. 0.167, 1.817 vs. 0.176, 2.424 vs. 0.193, 2.188 vs. 0.014, log₁₀IU/ml) (t=3.109, 4.717, 4.500, 4.544, 5.560, 4.265, P=0.008, 0.010, 0.001, 0.001, 0.000, 0.003), the difference was not statistically significant in gender and NA therapy time, the difference was statistically significant in age (30.8 vs. 39.9 years) ( t=-2.219, P=0.038). Of 9 CHB patients whose baseline HBV DNA were positive, 5 patients (55.6%) had HBV DNA loss after sequential treatment, the patients whose HBV DNA loss with HBsAg decreased at 12^th week in the course of sequential therapy, but there was no influence in the HBsAg decrease/loss after 12^th week, the difference was not statistically significant in age, gender, NA therapy time, HBsAg and HBsAg decrease in the course of sequential therapy between HBV DNA-negative and HBV DNA-positive groups. Conclusions To HBeAg-negative CHB, patients with low baseline HBsAg (2 log10 IU/ml level) and significantly lower HBsAg decrease early were more likely to receive SVR. Among them, prolonged interferon therapy is easier to achieve HBsAg loss/seroconversion.

Objective: To elucidate the functions of peripheral blood NK cells in chronic hepatitis B patients treated with interferon. Methods: Venous whole blood samples were obtained from patients in the immune clearance (IC) phase treated with peg-interferon-alpha-2a (Peg-IFNα-2a) at baseline (t=0), 12 weeks (t=12) and 24 weeks (t=24). The frequencyies of peripheral blood CD3^-CD56⁺ NK cells, CD56^brightNK cells and CD56^dimNK cells, the expression level of IFNAR2 and NKp46 on NK cells were detected by flow cytometry. The levels of serum HBV DNA, HBsAg, HBeAg and ALT were detected by Ditan Hospital clinical laboratory. Results: Forty-one patients in the IC phase treated with Peg-IFNα-2a, including 21 poor response (PR) patients and 20 good response (GR) patients, were recruited for this study. Theresult were as follows: The frequency of peripheral blood CD3^-CD56⁺ NK cells was increased at week 24 in GR compared with the baseline(11.74, 5.69%-18.15% vs 13.7, 9.36-20.18%, P>0.05), and it also was increased in PR(8.94, 6.26%-14.15% vs 12.5, 7.64-16.55%, P>0.05). The frequency of peripheral blood CD56^brightNK cells was increased at week 24 in GR compared with the baseline(9.49, 6.2%-12.48% vs 12.98, 7.75%-20.93%, P>0.05), and it also was increased in PR(11.45, 8.27%-19.13% vs 17.52, 12.3%-22.42%, P=0.0239). The expression level of NKp46 on NK cells was significantly increased at week 24 in GR compared with the baseline(90.55, 83.8-94.78 vs 93.8, 92.28-96.4, P=0.0263), but it was not increased in PR(95, 90.6-96.15 vs 94.3, 92.1-95.6, P>0.05). The expression level of NKp46^high on NK cells was significantly increased at week 24 in GR compared with the baseline(12.4, 8.58-19.08 vs 39.3, 23.15-49.3, P=0.0011), at that range of the increase was significantly higher than PR(14.2, 9.78-17.65 vs 27.58, 19.13-36.56, P=0.006). Conclusions The frequencies of peripheral blood CD3^-CD56⁺ NK cells and CD56^brightNK cells were increased from patients in the IC phase treated with Peg-IFNα-2a. The expression level of NKp46 on NK cells was increased in GR patients treated with Peg-IFNα-2a. The expression level of NKp46^high on NK cells was significantly increased, especially in GR patients treated with Peg-IFNα-2a.

Objective Antiviral therapy should be adopted for chronic hepatitis B (CHB) patients with significant liver fibrosis to decrease the risk of liver related complications.Fibrosis assessment during antiviral treatment is a key step in antiviral therapy evaluation.Liver biopsy is the gold standard for assessing the degree of liver fibrosis.However,liver biopsy is difficult to perform more than one time after a long-term effective treatment because of the cost and risk of life-threatening complications.In this study we aimed to evaluate changes of liver fibrosis during 4 years of entecavir(ETV) treatment by non-invasive fibrosis markers in CHB patients who need antiviral therapy.Methods Totally 268 HBeAg negative treatment-naive CHB patients were enrolled and liver biopsy were performed before starting antiviral therapy in this study.Totally173 patients who needed antiviral therapy (liver fibrosis stages≥ F2,Metavir scoring system) were treated with ETV for at least 4 year.A clinical and virological evaluation was performed at baseline and again at 12,24,36 and 48 months during ETV treatment.Fibrosis-4 (FIB-4) index was used to assess dynamic changes of liver fibrosis in HBeAg negative CHB patients after 1,2,3 and 4 years of ETV treatment.Results Liver biopsy was performed for all enrolled patients at baseline.According to Metavir fibrosis stages,numbers of patients with FI,F2,F3 and F4 were 95,108,50 and 15,respectively.The FIB-4 index enabled the effective identification of patients with severe fibrosis (Metavir F3-F4) with an area under the ROC curve of 0.775 (95％CI 0.716-0.834).The FIB-4 values significantly decreased in F2 and F3 patients after 1 and 2 years ETV therapy (P＜0.01),respectively.But for F4 patients,FIB-4 values decreased significantly at year 4 (P＜0.05).Conclusions FIB-4 values decreased significantly during 4-year ETV treatment in HBeAg-negative CHB patients indicating that these noninvasive fibrosis tests might be useful for monitoring improvement of liver fibrosis and assessing treatment efficacy during long-term ETV treatment.

Objective:To study the predictors of postpartum hepatitis in pregnant women with chronic HBV infection.Methods:In this retrospective study, liver function and hepatitis B virology tests of pregnant women with chronic HBV infection at delivery and within 48 weeks were collected from the clinical medical system after the enrollment of eligible patients. Statistical analysis was performed on the obtained data.Results:A total of 533 pregnant women meeting the criteria were enrolled, and the average age of all patients was 29.5±3.7. A total of 408 pregnant women took antiviral drugs during pregnancy for prevention of mother-to-child transmission; 231 patients developed hepatitis within 1 year after delivery. There were significant differences in alanine transaminase (ALT), aspartate transaminase (AST), HBV DNA during delivery, hepatitis B e antigen (HBeAg) during delivery and baseline HBeAg between patients with and without hepatitis. Multivariate binary logistic regression analysis showed that HBeAg ( OR=0.19, 0.074-0.473; P<0.001), ALT ( OR=1.05, 1.021-1.071; P<0.001), albumin ( OR=0.91, 0.833-0.995; P=0.038), platelet ( OR=0.995, 0.992-0.999; P=0.01), neutrophils ( OR=0.98, 0.973-0.995; P=0.004) had significant difference. Conclusions:Baseline HBeAg and ALT are powerful predictors of postpartum hepatitis in pregnant women with chronic HBV infection.

Objective: To explore the association between the efficacy of peg-IFN and the complexity of TP and RT regions of hepatitis B virus (HBV) in chronic hepatitis B. Methods: Patients with HBeAg positive, HBV DNA positive chronic hepatitis B were given peg-interferon 180 μg once a week for subcutaneous injection, and baseline information was collected from baseline and after 12 weeks’ treatment. The baseline HBV DNA TP and RT fragments were amplified, database, high-throughput sequencing, and the average genetic distance calculation. Results: Data of 108 patients were analyzed by logistic regression. RT area fragment Markov distance and TP area fragment Shannon quotient for HBV DNA response were calculated. ALT level is good for HBeAg response. HBsAg level is bad for HBsAg response. Conclusions The complexity of the baseline TP and RT regions may be associated with the efficacy of peg-interferon therapy for CHB.

Objective: To explore the persistent viral response rate (SVR) in patients with refractory chronic hepatitis C after interferon (IFN) (peginterferon 360 μg qw) and ribavirin (PR) therapy failure. The SVR of patients with refractory chronic hepatitis C was improved by PR combined with direct antiviral agents (DAA) and proper extension of the course of therapy was applied. Methods: Seventeen cases of refractory chronic hepatitis C after IFN(peginterferon 360 μg qw) and ribavirin therapy failure were given PR combined with DAA treatment. The side effects were observed and corresponding adjustments were made on drug dosage, and SVR was recorded. Results: The 17 cases completed the whole course of treatment with PR combined with DAA for 24 weeks. All the 17 patients obtained rapid viralogical response (RVR) and SVR. After treatment, the SVR rate was 100% in patients including those with virologic relapse, retreated or previously non-responsive patients with refractory chronic hepatitis C. The adverse reaction of PR combined with DAA 24 weeks was generally mild. Conclusions The use of PR combined with DAA re-treatment in patients with refractory chronic hepatitis C can achieve SVR and shorten the treatment time. PR combined with DAA re-therapy is one of effective treatments to improve the rate of sustained viral response in patients with refractory chronic hepatitis C.

Objective: To observe the changes of peripheral blood picture of CHB with Peg-IFN, and explored the relationship between the changes and decline of HBV DNA, clearance of HBsAg. Methods: Patients with CHB treated with Peg-IFN α-2 a in the Second Division of Liver Disease in Beijing Ditan Hospital were monitored for blood routine examination and Liver function, kidney function, thyroid function of baseline and weeks 2, 4, 8, 12, 24, 36, 48, and weeks 12, 24, and 48 after the end of treatment for chronic hepatitis B, and HBV DNA, HBsAg. Results: The decrease of peripheral blood cells began to occur at week 2 of treatment. For CHB with HBeAg negative patients, white blood cells, lymphocyte, neutrophils, hemoglobin and platelets significantly decreased at 2 weeks, while a minimum value occurred at 48 weeks. The recovery was obvious at the end of treatment (48 weeks), and reached pre-treatment levels at 48 weeks after the end of treatment. For CHB with HBeAg positive patients, white blood cells, neutrophils, hemoglobin and platelets significantly decreased at 2 weeks, while a minimum value was found at 36-48 weeks. The recovery was obvious at the end of treatment (48 weeks), and reached pre-treatment levels at 48weeks after the end of treatment. For patients with CHB, hemoglobin declined by more than13.64% at 36th week, which means that the patient would have a predictive significance for decrease of HBV DNA, and drops of more than 0.33% at 2nd week means that the patient would have a predictive significance for clearance of HBsAg. Conclusions During the treatment with interferon, the variation regularity of blood picture for predicting result have a certain effect, which may help predict and monitor the change of blood picture in clinical work.