[Efficacy and prognosis of infant kidney transplantation].

Objective: To analyze the effect and prognosis of infant kidney transplantation. Methods: Clinical data of 37 cases of infant kidney transplantation under 3 years old in Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from June 1, 2017 to July 31, 2022 were retrospectively collected. These 37 cases included 31 primary kidney transplantation and 6 secondary kidney transplantation. Kaplan-Meier method was used to draw the survival curve of the transplanted kidney and the recipient, and the prognosis and complications were analyzed. Median follow-up was 18 months (range: 6-66 months). Results: The recipients were 20 males and 17 females, with a median age of 16 months (range: 2 months, 26 days to 36 months) and a median weight of 8 kg (range: 3.2 to 14.0 kg). The youngest child was only 2 months, 26 days old, and weighed only 3.2 kg. The most common primary disease of recipients was congenital nephrotic syndrome (13 cases, 41.9%). Intra-abdominal transplantation occurred in 19 cases (51.3%) and intra-iliac fossa transplantation occurred in the remaining 18 cases (48.6%). Postoperative renal function recovery was delayed in 7 cases (18.9%), and thrombosis caused renal function loss in 5 cases (13.5%), of which 4 cases received second renal transplantation and were successful. During the follow-up period, there were 11 cases of acute rejection (29.7%) and 6 cases of CMV pneumonia (16.2%). The estimated glomerular filtration rate 1 year after transplantation was higher than that 1 month after surgery [(101.9±22.1) vs (71.1±25.6) ml/(min·1.73m2), P<0.001], and remained constant 2 years after transplantation. Both the 1-year and 2-year survival rates of the transplanted kidney were 85.3%, and both the 1-year and 2-year survival rates of the recipients were 96.8%. Conclusion: Although the implementation of infant kidney transplantation is difficult, it can still achieve relatively satisfactory efficacy and prognosis.

[Relationship between obesity and death by multi-morbidity status in older adults in China].

Objective: To explore the relationship between obesity status and death stratified by different multi-morbidity status in older adults in China. Methods: Data for older Chinese adults aged ≥65 years were from Chinese Longitudinal Healthy Longevity Survey (CLHLS). Multi-morbidity patterns based on 13 chronic conditions were explored using exploratory factor analysis. Cox models were used to examine relationships between obesity status and death stratified by disease count and multi-morbidity patterns at baseline, respectively. Besides, obesity status was defined by baseline body mass index and waist circumference. Results: A total of 6 272 participants were included in the analyses. Multi-morbidity including cardio-metabolic, sensory perception and other patterns were identified. For those without any chronic condition, compared with those without central obesity, central obesity was associated with a higher risk for death (HR=1.66, 95%CI:1.04-2.66). For those only with one chronic condition, compared with normal weight, underweight was associated with a higher risk for death (HR=1.41, 95%CI: 1.10-1.80). For those with multi-morbidity, compared with normal weight, underweight increased the risk for death (HR=1.19, 95%CI:1.05-1.34). Compared with those without central obesity, central obesity decreased the risk for death (HR=0.88, 95%CI:0.78-0.99). Conclusions: Relationships between obesity status and death varied by multi-morbidity status in older adults in China. Underweight and non-central obesity were associated with increased risks for death in older adults with only one chronic disease or multi-morbidity. Therefore, it is necessary to pay attention to multi-morbidity status in the management of obesity in older adults and provide effective targeted body weight management plan.

[Mutational spectrum and its prognostic significance in childhood acute lymphoblastic leukemia based on next-generation sequencing technology].

Objective: This study analyzed the correlation between genetic mutation and prognostic significance in childhood acute lymphoblastic leukemia (ALL) . Methods: Targeted exome by next-generation sequencing (NGS) technology was used to carry out molecular profiling of untreated 141 children with ALL in Fujian Medical University Union Hospital from November 2016 to December 2019. Correlation of genetic features and clinical features and outcomes was analyzed. Results: Among the 141 pediatric patients with ALL, 160 somatic mutations were detected in 83 patients (58.9% ) , including 37 grade Ⅰ mutations and 123 grade Ⅱ mutations. Single nucleotide variation was the most common type of mutation. KRAS was the most common mutant gene (12.5% ) , followed by NOTCH1 (11.9% ) , and NRAS (10.6% ) . RAS pathway (KRAS, FLT3, PTPN11) , PAX5 and TP53 mutations were only detected, and NRAS mutations was mainly found in B-ALL while FBXW7 and PTEN mutations were only found, and NOTCH1 mutation was mainly detected in T-ALL. The average number of mutations detected in each child with T-ALL was significantly higher than in children with B-ALL (4.16±1.33 vs 2.04±0.92, P=0.004) . The children were divided into mutation and non-mutation groups according to the presence or absence of genetic variation. There were no statistically significant differences in sex, age, newly diagnosed white blood cell count, minimal or measurable residual disease monitoring results, expected 3-year event-free survival (EFS) and overall survival (OS) between the two groups (P>0.05) . On the other hand, the proportion of T-ALL and fusion gene negative children in the mutant group was significantly higher than the non-mutation group (P=0.021 and 0.000, respectively) . Among the patients without fusion gene, the EFS of children with grade I mutation was significantly lower than children without grade I mutation (85.5% vs 100.0% , P=0.039) . Among children with B-ALL, the EFS of those with TP53 mutation was significantly lower than those without TP53 mutation (37.5% vs 91.2% , P<0.001) . Conclusion: Genetic variation is more common in childhood ALL and has a certain correlation with clinical phenotype and prognosis. Therefore, targeted exome by NGS can be used as an important supplement to the traditional morphology, immunology, cytogenetics, and molecular biology classification.

Selpercatinib for lung and thyroid cancers with RET gene mutations or fusions.

Aberrations in oncogene RET (rearranged during transfection) have been found to be the cause of different kinds of malignancies, especially in lung and thyroid cancers. Targeted therapy of RET-altered cancers using multi-kinase inhibitors (MKIs) has demonstrated limited clinical efficacy due to off-target toxicity. In May 2020, the U.S. Food and Drug Administration (FDA) approved a novel specific RET inhibitor for use in some subtypes of lung and thyroid cancers with RET alterations. In this review, we summarize the mechanism of action, pharmaceutical properties and clinical data of selpercatinib, and share some of our perspectives.

Pralsetinib for the treatment of non-small cell lung cancer.

The identification of oncogenic drivers and the subsequent development of targeted therapies have been established as biomarker-based care for metastatic non-small cell lung cancer (NSCLC) patients. Rearranged during transfection (RET) events have been reported to be oncogenic drivers in NSCLC and were more common in patients who i) were young; ii) had adenocarcinoma histology; and iii) had never smoked. Phase II studies indicated the limited efficacy of multi-targeted tyrosine kinase inhibitors in patients with NSCLC that have a confirmed RET event. Consequently, there has been ongoing research to develop more potent and specific RET tyrosine kinase inhibitors. Recently, a novel and specific RET inhibitor, pralsetinib (BLU-667), has been reported to have excellent efficacy and low off-target toxicity in RET cancer patients. In this review, we summarize the clinical data regarding the use of pralsetinib in NSCLC patients.

Lurbinectedin for the treatment of small cell lung cancer.

Small cell lung cancer (SCLC) is a rapidly progressive, aggressive metastatic and lethal subtype of lung cancer. Unfortunately, there has been little progress regarding the development of novel treatments for SCLC. However, lurbinectedin, a transcriptional inhibitor, has emerged as a potential novel treatment for cancer. It produces antitumor efficacy by inhibiting oncogenic transcription activity, inducing the accumulation of DNA double-strand breaks and modulating the tumor microenvironment (TME). Data from phase I/II trials indicates that lurbinectedin has significant antitumor efficacy and tolerable adverse effects in SCLC patients. Furthermore, lurbinectedin is efficacious in platinum-sensitive and platinum-resistant SCLC patients and in those with SCLC relapse after second-line treatment. In 2020, the U.S. Food and Drug Administration (FDA) approved lurbinectedin for the treatment of adult patients with metastatic SCLC or for patients that have received platinum-based chemotherapy. In this review, we discuss the molecular profile and the preclinical and clinical studies of lurbinectedin in the treatment of SCLC patients.

Tepotinib hydrochloride for the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is one of the most devastating cancers with high mortality worldwide. By inhibiting the activity of specific molecular targets in the cancer cells, tyrosine kinase inhibitors (TKIs) have become a standard treatment in combating NSCLC. Tepotinib hydrochloride is an orally bioavailable, mesenchymal-epithelial transition (MET) TKI developed mainly for selected NSCLC patients with METex14 skipping mutations. Tepotinib demonstrated durable clinical response in phase II clinical trials, which led to its approval for use in Japan and breakthrough therapy designation and accelerated approval in the U.S. These progresses highlighted tepotinib as a promising candidate for NSCLC patients. This review summarizes the pharmacological profile of tepotinib, preclinical studies and landmark clinical trials of tepotinib. In addition, we share our perspectives on the future direction of tepotinib as a novel anticancer drug.

[Clinical features and prognosis of ETV6-RUNX1-positive childhood B-precursor acute lymphocyte leukemia].

Objective: To investigate the clinical features and prognosis of ETV6-RUNX1-positive childhood B-precursor acute lymphocyte leukemia (B-ALL) . Methods: The clinical data of 927 newly diagnosed children with B-ALL admitted to the Fujian Medical University Union Hospital from April 2011 to May 2020 were retrospectively analyzed. According to the results of ETV6-RUNX1 gene, the patients were divided into ETV6-RUNX1(+) and ETV6-RUNX1(-) groups. The clinical features and prognosis between the two groups were compared. Among the 182 children with ETV6-RUNX1(+), 144 patients received the Chinese Childhood Leukemia Collaborative Group (CCLG) -ALL 2008 protocol (CCLG-ALL 2008 group) and 38 received the China Childhood Cancer Collaborative Group (CCCG) -ALL2015 protocol (CCCG-ALL 2015 group) . The efficacy, serious adverse effects (SAE) incidence, and treatment-related mortality (TRM) of the two groups were also compared. Results: Of the 927 B-ALL patients, 189 (20.4% ) were ETV6-RUNX1(+). The proportion of patients with risk factors (age ≥10 years or <1 year, white blood cell count ≥50×10(9)/L) in the ETV6-RUNX1(+) group was significantly lower than that in the ETV6-RUNX1(-) group (P=0.000, 0.001, respectively) , while the proportion of patients with good early response (good response to prednisone, d15 or d19 MRD <1% , and d33 or d46 MRD<0.01% in induction chemotherapy) in the ETV6-RUNX1(+) group was significantly higher than that in the ETV6-RUNX1(-) group (P=0.028, 0.004, respectively) . The 5-year EFS and OS of the ETV6-RUNX1(+) group were significantly higher than those of the ETV6-RUNX1(-) group (EFS: 89.8% vs 83.2% , P=0.003; OS: 90.2% vs 86.3% , P=0.030) . The incidence of infection-related SAE and TRM was significantly higher than that of CCCG-ALL 2015 group. A statistical difference was observed between the incidence of infection-related SAE of the two groups (27.1% vs 5.3% , P=0.004) , but no difference in TRM (4.9% vs 0, P=0.348) . Conclusion: ETV6-RUNX1(+)B-ALL children have fewer risk factors at diagnosis, better early response, lower recurrence rate, and good prognosis than that of ETV6-RUNX1(-)B-ALL children. Reducing the intensity of chemotherapy appropriately can lower the infection-related SAE and TRM and improve the long-term survival in this subtype.

[Discussion on early warning, prevention and control of emerging infectious diseases from a macroscopic perspective based on big data and effective distance model: enlightenment of COVID-19 epidemic data in China].

Objective: To provide a system for warning, preventing and controlling emerging infectious diseases from a macroscopic perspective, using the COVID-19 epidemic data and effective distance model. Methods: The dates of hospitalization/isolation treatment of the first confirmed cases of COVID-19 and the cumulative numbers of confirmed cases in different provinces in China reported as of 23 February, 2020 were collected. The Location Based Service (LBS) big data platform of "Baidu Migration" was employed to obtain the data of the proportion of the floating population from Wuhan to all parts of the country. Effective distance models and linear regression models were established to analyze the relationship between the effective distance and the arrival time of the epidemic as well as the number of cumulative confirmed cases at provincial and municipal levels. Results: The arrival time of the epidemic and the cumulative number of confirmed cases of COVID-19 had significant linear relationship at both provincial and municipal levels in China, and the regression coefficients of each linear model were significant (P<0.001). At the provincial level, the effective distance could explain about 71% of the variation of the model with arrival time along with around 90% of the variation for the model in the cumulative confirmed case magnitude; at the municipal level, the effective distance could explain about 66% of the variation for the model in arrival time, and about 85% of the variation of the model with the cumulative confirmed case magnitude. Conclusions: The fitting degree of the models are good. The LBS big data and effective distance model can be used to estimate the track, time and extent of epidemic spread to provide useful reference for early warning, prevention and control of emerging infectious diseases.

[Strategy and clinical outcome of deceased donor kidney transplantation for presensitized recipients].

Objective: To explore the management strategy and clinical outcome of renal transplantation in presensitized recipients using deceased donor kidneys. Methods: From January 2011 to June 2018, twenty-one presensitized patients, including 8 with positive donor specific antibodies (DSA) and 13 with positive panel-reactive antibodies (PRA) but no DSA, received renal retransplantation from deceased donors in our center. The incidence of delayed graft function (DGF) and acute rejection (AR), changes of DSA, and the graft and patient survival were retrospectively analyzed. Results: None of the renal allografts had primary non-function (PNF) and DGF after transplantation. Four of the 13 recipients with PRA(+)/DSA-had a total of 5 episodes of acute cell-mediated rejection (CMR), while 5 of 8 recipients with pre-existing DSA(+) developed AR, including 3 cases with CMR alone and 2 cases with mixed AR. All episodes of rejection were successfully reversed after targeted treatment. Interestingly, of the 8 recipients with positive preformed DSA, 4 cases with positive DR-DSA and/or class Ⅰ-DSA had their DSA disappeared after transplantation, whereas DQ-DSA remained positive in 4 of 5 recipients. After a median follow-up of 26 months, all recipients maintained normal renal allograft function, and the survival rates of both graft and recipient were 100%. Conclusions: With the use of deceased donors, kidney transplantation can be successfully performed in presensitized patients by appropriate HLA-matching screening, choosing donor kidneys with good quality, and the combination of optimal perioperative treatment.

TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

BACKGROUND: Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. OBJECTIVE: To evaluate the association of pharmacokinetic parameter TC > 0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. METHODS: A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxel™ kit. The patients' PTX TC > 0.05 (the time during which PTX plasma concentration exceed 0.05µmol/L) were calculated based on pharmacokinetic analysis. RESULTS: The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 µmol/L; (2) the PTX TC > 0.05 ranged from 14 to 38h with a median time of 27h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC > 0.05 between CR+PR and SD+PD; (4) with the increasing value of TC > 0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC > 0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC > 0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC > 0.05 at 26 to 30h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. CONCLUSION: PTX TC > 0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors.

[Risk factors for acute rejection in living-donor kidney transplant recipients in China: a subgroup analysis of a multi-center, registry study].

Objective: To evaluate pre-and early post-transplantation risk factors for acute rejection(AR) in kidney recipients. Methods: This subgroup analysis of a multi-center registry study was conducted on living-donor kidney transplant recipients in China with 10 years of follow-up. This study analyzed 1 255 recipients including 921 males(73.4%) and with a mean age of (33±10)years. Data from patients were first analyzed with univariate analysis and then multivariate analysis was used for finding out the potential risk factors of AR. Results: A total of 106(8.4%) patients were suspected with AR after kidney transplantation, while 1 149 patients were considered as non-AR. Multivariable analysis demonstrated a significant influence of recipient age and cold ischemia time(CIT) on the occurrence of AR(OR: 0.956, 95% CI: 0.923-0.990; OR: 1.006, 95% CI: 1.002-1.011, respectively). The frequency of severe infection was significantly higher in the AR group than non-AR group(38.7% vs 10.8%; P<0.000 1). The occurrence of new-onset diabetes mellitus and tumors was similar in the two groups. Conclusions: Recipient age and CIT are risk factors for AR after living-donor kidney transplantation. Reducing CIT and intensive management of younger recipient could benefit kidney transplant patients.