[Comparison of follow-up treatment regimens for colorectal cancer liver metastases without objective response to neoadjuvant chemotherapy: direct surgery or surgery after second-line chemotherapy].

Objective: To compare the effect of direct surgery or surgery after second-line chemotherapy for colorectal cancer patients with liver metastases who did not achieve objective remission after neoadjuvant chemotherapy. Methods: A retrospective case cohort study was used. The clinical and pathological data of 107 patients with colorectal cancer liver metastases who did not achieve objective response to neoadjuvant chemotherapy at Department of Hepatobiliary Surgery,Cancer Hospital,Chinese Academy of Medical Sciences from December 2008 to December 2016 were retrospectively collected. There were 71 males and 36 females, median age was 57 years (range: 28 to 79 years). According to the different treatment regimens after neoadjuvant chemotherapy,107 cases were divided into a direct surgery group (direct group,n=65) and an operation after receiving second-line chemotherapy group (second-line group,n=42). The propensity score matching(PSM) of the Logistic regression model was used to match the bilobar distribution of liver metastases and the number of first-line chemotherapy cycles in the two groups of patients. The caliper value was set to 0.10 and the matching ratio was 1∶2. T test, Mann-Whitney U test, χ2 test or Fisher's exat test was used to analyzed the data between the tuo groups, respectively. Survival analysis design was used to investigate the difference in prognosis between the two groups of patients. Results: The follow-up time(M(IQR)) was 56.3(34.3) months (range: 2.1 to 95.0 months),and all patients were followed up. After PSM,there were 28 cases in the direct group and 42 cases in the second-line group, there were no significant differences in whether R0 resection was feasible,blood loss,blood transfusion,postoperative complications and postoperative hospital stay between the two groups (all P>0.05). The 1,3,and 5-year progression-free survival(PFS) rates of the direct group were 40.0%,16.5%,and 11.0%,and the 1,3,and 5-year overall survival(OS) rates were 98.5%,61.2%,and 41.4%,respectively, the second-line group 1,3,5 years PFS rates were 35.7%,14.3%,14.3%,1,3,5-year OS rate were 95.2%,55.1%,44.4%,respectively. The median PFS time of the direct group and the second-line group was 8.5 months and 7.5 months,respectively,and the difference was not statistically significant (P=0.826). The median OS time of the direct group and the second-line group were 33.8 months and 46.9 months,respectively. The difference was not statistically significant(P=0.646).The median PFS time of the direct group and second-line chemotherapy complete remission and partial remission group(CR/PR group) was 10.2 months and 9.1 months,respectively,and the difference was not statistically significant(P=0.669). The median OS time of the direct group and the second-line CR/PR group was 51.0 months and 46.9 months,respectively,and the difference was not statistically significant(P=0.427). The results of survival analysis suggested that major liver resection was an independent prognosis factor for PFS (HR=1.809,95%CI: 1.067 to 3.067,P=0.028) and OS(HR=2.751,95%CI: 1.317 to 5.747,P=0.007). Second-line chemotherapy was not an independent prognostic factor for PFS (HR=0.945, 95%CI:0.570 to 1.567,P=0.828) and OS (HR=0.866,95%CI: 0.468 to 1.602,P=0.646). Conclusions: There is no significant difference in the short-term outcome and long-term prognosis between direct surgery patients and second-line chemotherapy followed by surgery. Second-line chemotherapy is not an independent prognostic factor for colorectal cancer liver metastases patients who fail to achieve objective response after neoadjuvant chemotherapy.

[Effect of macrophage-derived exosomes on promoting hepatic stellate cell activation and platelet-derived growth factor expression].

Objective: To explore the effect of macrophage-derived exosomes on the activation of hepatic stellate cells and its possible mechanism. Methods: Differential ultracentrifugation was used to extract macrophage exosomes. The exosomes were co-cultured with the mouse hepatic stellate cell line JS1, and a control group was established with phosphate buffered saline (PBS). Cell immunofluorescence was used to observe the expressional conditions of F-actin. Cell counting kit-8 (CCK8) was used to detect the survival rate of JS1 cells in the two groups. The activation indices of JS1 cells [collagen type Ⅰ (Col Ⅰ) and α-smooth muscle actin (α-SMA)] and its key signal pathway activation index expression level [transforming growth factor (TGF)-ß1/Smads, platelet-derived growth factor (PDGF)] in the two groups were determined using Western blot and RT-PCR. Data comparison between two groups was performed using an independent sample t-test. Results: The membrane structure of exosomes was clearly observed by transmission electron microscopy. The expression of exosome marker proteins CD63 and CD81 was positive, suggesting that exosomes were successfully extracted. Exosomes were co-cultured with JS1 cells. Compared with the PBS control group, there was no statistically significant difference in the proliferation rate of JS1 cells in the exosomes group (P＞0.05). The expression of F-actin was significantly increased in the exosome group. The mRNA and protein expression levels of α-SMA and ColⅠwere significantly increased in exosome group JS1 cells (all P＜0.05). The mRNA relative expression levels of α-SMA in PBS and exosome group were 0.25±0.07 and 1.43±0.19, respectively, while that of ColⅠ was 1.03±0.04 and 1.57±0.06, respectively. The mRNA and protein expressions of PDGF were significantly increased in exosome group JS1 cells (P＜0.05). The mRNA relative expression levels of PDGF in the PBS group and exosome group were 0.27±0.04 and 1.65±0.12, respectively. There were no statistically significant differences in the mRNA and protein expressions of TGF-ß1, Smad2 and Smad3 between the two groups (P＞0.05). Conclusion: Macrophage-derived exosomes significantly promote the activation of hepatic stellate cells. JS1 cells may be the underlying mechanism for the up-regulation of PDGF expression.

[Clinical characteristics of "classical" and "non-classical" paraneoplastic neurological syndrome].

Objective: To explore the clinical features of classical and non-classical paraneoplastic neurological syndrome (PNS). Methods: From 2015 to 2020, 48 cases of definite PNS admitted to the First Affiliated Hospital of University of Science and Technology of China were retrospectively collected, and classification, clinical characteristics, onconeural antibodies and primary tumors were analyzed. The included cases were divided into classical and non-classical groups according to Graus criteria, and the differences of clinical characteristics, onconeural antibodies, combined tumors, time of diagnosis and mortality were compared between the two groups. Results: Among the 48 confirmed patients, 21 (43.8%) were positive for well-characterized onconeural antibodies. There were 28 cases (58.3%) and 20 cases (41.7%) in classic and non-classical PNS groups, respectively. No significant differences of age, sex, clinical involvement site, characteristic positive antibody type, tumor diagnosis rate and follow-up mortality were found between the two groups (all P>0.05). The time of diagnosis in the non-classical PNS group was 3.0 (2.0, 6.5) months, which was significantly longer than that in the classical PNS group 1.0(0.6, 3.0) months (P<0.05). Meanwhile, the combination rate of non-characteristic antibodies in the classical PNS group (10 cases, 35.7%) was significantly higher than that in the non-classical PNS group (1 case, 5.0%) (P=0.016). During the follow-up, 39 patients (81.3%) with tumor were confirmed, and 29 patients (60.4%) were diagnosed with PNS before the tumor was found. Conclusions: The"non-classical"PNSs are common in clinical settings. Diagnosis may be delayed due to the nonclassical symptoms of the patients. When patients have clinical symptoms related to PNS, onconeural antibodies should be detected and the relevant tumors should also be screened. Patients have positive antibodies but with no tumors should be closely followed up for more than 5 years.

[Predictive factors of poor prognosis in children with acute kidney injury treated with renal replacement therapy].

Objective: To investigate the predictive factors of poor prognosis in children with acute kidney injury (AKI) treated with renal replacement therapy (RRT). Methods: In this retrospective case-control study, the clinical data were collected from 134 pediatric patients (82 male, 52 female) with AKI treated with RRT in six tertiary hospitals from May 2015 to June 2018. According to the serum creatinine level at discharge, the patients were divided into the favorable outcome group and unfavorable outcome group. The data of sex, age, primary diseases, AKI stage, time from diagnosis of AKI to start of RRT (h) and whether to start RRT within 24 hours, urine volume and complications between the two groups were compared. Continuous variables were compared by t test and Mann-Whitney U test, and percentage or proportions were compared by Chi square test. The predictive factors of adverse prognosis were analyzed by using univariate and unconditional binary logistic regression analysis. Results: The average age of the 134 AKI patients was (6±4) years. There were 114 patients (85.0%) in the favorable outcome group and 20 patients (15.0%) in the unfavorable outcome group. No statistically significant differences were found between the two groups in terms of sex (χ(2)=2.596, P=0.107), age (t=0.718, P=0.474), primary disease (χ(2)=2.076, P=0.722), AKI stage (χ(2)=0.004, P=0.998), time from diagnosis of AKI to start RRT (h) (P=0.745), whether to start RRT within 24 hours (χ(2)=0.016, P=0.899), urine volume (χ(2)=3.118, P=0.374), fluid overload (χ(2)=0.014, P=0.905), multiple organ dysfunction syndrome (MODS) (χ(2)=2.972, P=0.085), acidosis (χ(2)=3.204, P=0.073), hyperkalemia (χ(2)=2.829, P=0.093), the level of blood urea nitrogen (t=1.351, P=0.179) and serum creatinine (P=0.901) at the beginning of RRT. In the unfavorable outcome group, the proportion of patients with mechanical ventilation (45.0% (9/20) vs. 12.3% (14/114), χ(2)=12.811, P<0.01) and the incidence of extra organ injury (≥3) (30.0% (6/20) vs. 10.5% (12/114), χ(2)=6.365, P=0.041) were higher than those in the favorable outcome group. Logistic regression analysis showed that mechanical ventilation (OR=12.540, 95%CI: 3.376-46.577, P<0.01) and hyperkalemia (OR=4.611, 95%CI: 1.265-16.805, P=0.021) were the predictive factors of poor prognosis in patients with AKI treated with RRT. Conclusion: Mechanical ventilation and hyperkalemia may predict a poor prognosis in AKI patients treated with RRT.

[Prevalence of chronic diseases and associate factors on daily activities in male oldest-olds].

Objective: To investigate the prevalence of chronic diseases in aged ≥80 oldest-olds and related factors influencing their daily activities. Methods: This survey was conducted in the retired cadres in Beijing from 2012 to 2014. A unified questionnaire was used to investigate the general characteristics of the oldest-olds and the activities of daily living (ADL). Information on chronic diseases was extracted from related medical records. Results: A total of 4 472 male oldest- olds, with an average age as (87.1±3.9) years (80-102 years), were included. Nearly half of the elderly people were suffering from 5 or more kinds of chronic diseases, with 43.9% of them having disability on basic daily activities (BADL) with 13.4% of those classified as moderate or severe cases. 38.8% of them had instrumental activities of daily living (IADL) disability, with 28.7% of them were moderate or severe cases. The ADL disability showed an increasing trend along with the increase number of chronic diseases. The proportion of BADL disability increased from 40.5% to 50.6%. Compared with the ones having fewer chronic diseases (≤2 kinds), those with more (≥7 kinds) had an increase of 50.5% risk on BADL disability and 199.4% on IADL disability. Conclusion: We noticed that the male oldest-olds suffered from multiple chronic diseases. The impairment of ADL was higher than the younger elderly. Comorbidity showed heavier impact on ADL, especially on the instrumental activities of daily living.

[Relationship between the weight of hospitalized patients with pulmonary tuberculosis and the oral dose of isoniazid].

Objective: To study the relationship between the weight change trend of initial treatment patients with pulmonary tuberculosis and the dose change trend of isoniazid, and therefore to analyze the appropriate dose of isoniazid. Methods: Data of initial treatment inpatients with pulmonary tuberculosis from May 1955 to December 2012 were retrospectively analyzed. Elderly patients with pulmonary tuberculosis, patients with drug-resistant tuberculosis, extrapulmonary tuberculosis and those with complications were excluded from the study. The time period was separated as 20th century 1950s to 1960s, 1970s, 1980s, 1990s, 21th century 2000s and 2010s. Samples were selected in each year and month between 1950s to 1960s and 1970s. After 1980s, samples of 1 year were taken from each 5 years. The sex, age and weight for every patient were collected, as well as the dose of isoniazid of every inpatient on a day in therapeutic regimen. Meanwhile, the weight change trend of the patients in different ages and the dose change trend of isoniazid were compared. The total number of cases was 1 398, with 924 males and 474 females, averaging (36.7±14.4) years old. Results: The weight of the patients increased when it was compared between that in 1950s to 1960s, 1970s or 1980s and that in 2000s, with a increasing weight of 3 kg, 3.5 kg and 3 kg respectively. The difference showed statistical significance (P<0.003). The difference was also significant when the weight in 70s was compared with that in 2010s (P=0.002). The therapeutic dose of isoniazid remained invariable regardless of the weight change. At 1990s, 2000s and 2010s, the dose of isoniazid per kilogram of body weight would reduce to 0.005 4 g, 0.005 2 g and 0.0054 g relative to patients' weight increase, and the difference was statistically significant (P<0.001). Conclusions: The weight of pulmonary tuberculosis inpatients increased in recent 60 years. The weight has a close relation with the dose of isoniazid. A fixed dose of isoniazid (0.3 g/d) regardless of the weight change could result in low blood drug concentration . To avoid tolerance of isoniazid and increase the cure rates of pulmonary tuberculosis, the dosage of isoniazid should be increased based on the weight increase of patients.

[The effectiveness of individualized treatment regimen on smear-positive retreatment pulmonary tuberculosis with mono- and poly-drug resistance].

Objective: To analyze and evaluate the effectiveness of individualized treatment regimen in the therapy of smear-positive retreatment pulmonary tuberculosis with mono-and poly-drug resistance, and therefor to provide information on how to develop rational individualized regimen for retreatment tuberculosis cases with drug resistance. Methods: This was a multi-centered, prospective cohort study. Totally 254 cases of sputum positive tuberculosis with previous treatment history during the period from July 1, 2009 to August 30, 2016 were included in the analysis. All the cases were randomly divided into 3 groups and received therapy after randomization into treatment groups. After 3 months, cases with multidrug resistant tuberculosis, extensively drug-resistant tuberculosis, non-tuberculosis mycobacterial infection and those with smear-positive but culture-negative tuberculosis were excluded according to result of sputum culture and drug susceptibility test (DST). In treatment group A (individualized treatment group), 86 cases with an average age of (42.1±13.7) years for men and (38.5±12.8) years for women, were treated with individualized regimen, which allowed drug replacement on the basis of standard regimen (2SHRZE/6HRE) according to DST result. Treatment duration was recalculated after drug replacement and the total length should be 12 months or more. If the DST result did not show drug resistance, the patients would continue the 8 months' standard treatment. In treatment group B (intensified retreatment regimen group), 86 cases with an average age of (43.2±14.2) years for man and (37.9±14.1) years for women, received intensified retreatment regimen (2HL(2)EZS/2HL(2)EZS(3)/4HL(2)E). The dose for H was 0.3 g/d for patients with body weight <50 kg, and 0.4~0.5 g/d for higher body weight (≥50 kg); The doses for L(2,)E and Z were 0.6 g, 2/w; 0.75, 1/d and 0.5g, 3/d. In treatment group C (standard treatment group), 82 cases with an average of (42.5±11.9) years for man and (38.6±12.8) years for women, were treated with standardized regimen recommended by national tuberculosis program (2HREZS/6HRE). In both group B and C, the total treatment duration was 8 months and the drugs were not replaced for mono-and poly-drug resistance. Treatment outcomes of the 3 groups were analyzed, the status of drug replacement in group A was analyzed, and the adjustment of dose of H and R according to patients' body weight was observed. SPSS 19.0 was used for data analysis. Results: The treatment cure rates for group A, B and C were 73.3%(63/86), 76.7%(66/86) and 50%(41/82), and the treatment success rates were 80.2%(69/86), 84.9%(73/86) and 62.2%(51/82) respectively. Treatment failure was 8.1%(7/86), 4.7%(4/86) and 19.5%(16/82) in 3 groups. There were significant differences in the above indicators for group A and B in comparison with group C(χ(2)=13.127, P=0.001). However, there was no difference observed between group A and B(χ(2)=0.646, P=0.422). In group A, tuberculosis specialized hospitals using regular doses for R was only 38.7%(12/31). After 3 years' follow-up, no-relapse-success for group A was 66.7% (10/15). Conclusions: Inappropriate individualized treatment would increase treatment failure for retreatment tuberculosis. Higher doses of H and R and prolonged extensive therapy phase could contribute to increased treatment success.