Objective:To explore the reasonable timing of radiotherapy for epidermal growth factor receptor ( EGFR) mutation-positive non-small cell lung cancer patients with brain metastasis in the era of third-generation targeted drugs. Methods:Clinical data of EGFR mutation-positive non-small cell lung cancer patients with brain metastasis who received first-line treatment with third-generation targeted drugs and stereotactic radiotherapy at Shanghai Armed Police Corps Hospital from September 2019 to May 2022 were retrospectively analyzed. According to the timing of radiotherapy before / after targeted drug resistance, all patients were divided into the early and salvage radiotherapy groups. The proportion of brain metastasis, physical fitness, complete response rate, objective response rate, delaying the progression of brain metastasis and overall survival (OS) were compared between two groups. Kaplan-Meier method was used for survival analysis, log-rank test was used for univariate prognostic analysis, and factors with P <0.1 were included in Cox multivariate analysis. Results:A total of 85 patients were included, including 51 (60%) cases receiving early radiotherapy. Patients who participated in early radiotherapy had a higher proportion of symptomatic brain metastasis (82% vs. 56%, P=0.013) and poorer physical fitness (Kanofsky performance score <70: 61% vs. 26%, P=0.002) compared to patients who underwent salvage radiotherapy. Early radiotherapy significantly improved the complete response rate of intracranial lesions (35% vs. 12%, P=0.015) and objective response rate (88% vs. 71%, P=0.041), delayed the progression of brain metastasis (median intracranial progression free survival: 23.0 months vs. 16.0 months, P=0.005; median intracranial secondary progression free survival: 31.0 months vs. 22.0 months, P=0.021), and improved OS (median OS: 44.0 months vs. 35.0 months, P=0.046). In multivariate analysis, diagnosis-specific graded prognostic assessment score <2.5, mutation of EGFR exon 21, and salvage brain radiotherapy were adverse prognostic factors for OS. Conclusion:In the era of third-generation targeted drugs therapy, early involvement of stereotactic radiotherapy in non-small cell lung cancer patients with brain metastasis can bring greater clinical benefits.

V-ATPases are a class of multi-subunit protein complexes that utilize energy derived from ATP hydrolysis for mediating H + transport across cell membranes, which plays an important role in a range of life activities by acidifying the intracellular and extracellular environment. Variants of V-ATPase genes may lead to complete or partial loss of V-ATPase activity, which in turn may impair the ability of type A intercalated cells in renal tubules to pump H + into the tubular lumen, ultimately resulting in the onset of autosomal recessive distal renal tubular acidosis (dRTA). With the rapid development of molecular techniques, ATP6V0A4 and ATP6V1B1 have now been identified as the pathogenic genes for dRTA. Moreover, animal and cell experiments have substantiated the implication of V-ATPase subunit genes including ATP6V1C2 and ATP6V1G3 in the development of dRTA, though clinical evidence is still limited. This article has reviewed recent progress on the genetic and molecular mechanisms of V-ATPase subunit gene variants which can lead to dRTA, which may shed light on the diagnosis and treatment of this disease.

Objective:To compare the efficacy and side effects of multi-fraction stereotactic radiotherapy (SRT) and single-fraction stereotactic radiosurgery (SRS) in the treatment of brain metastases from colorectal cancer.Methods:A total of 98 patients with brain metastases from colorectal cancer searched from the database of Professional Committee of Brain Metastasis of Shanghai Anticancer Association were recruited in this study. Among them, 46 patients weretreated with SRT and 52 patients with SRS. Clinical characteristics of all patients were analyzed between two groups and the local tumor control rate, median survival time and the incidence of radiation-induced brain injury were compared between two groups.Results:The objective remission rates (ORR) in the SRT and SRS groups were 76.1% and 67.3%, respectively. The 12-month local tumor control rates were 88.3% and 83.9% between two groups, with no statistical difference ( P=0.689). The median overall survival time of all patients was 11.6 months, 10.8 months in the SRT group and 12.7 months in the SRS group. There was no statistical difference between two groups ( P=0.129). Multivariate analysis showed that the main factors leading to poor prognosis included the number of tumors of >3( P=0.026), low GPA score ( P=0.035), and lack of systematic treatment mode and bevacizumab ( P=0.001). There was no statistical difference in the incidence of acute and late radiation-induced brain injury between two groups. Conclusions:Both SRT and SRS are effective therapies for brain metastases from colorectal cancer. The synergistic application of systematic treatment mode may be one of the main reasons affecting the survival time of the patients.

Objective:To summarize the clinical characteristics and genetic features of tyrosine hydroxylase deficiency(THD) caused by TH gene variants for the improvement of the understanding of the disease. Methods:The clinical and genetic data of 33 children with THD caused by TH gene variants were diagnosed in the Department of Neurology of Beijing Children′s Hospital, Capital Medical University from May 2011 to January 2020 and their data were retrospectively collected and analyzed. Results:There were 19 females and 14 males.The age at onset was ranged from 0 to 6.3 years.13 patients developed diseases, accompanied with fever after infection, and 1 patient suffered from hypoxia, 19 patients suffered from no predisposing factors.There were 7 mild TH-deficient dopa-responsive dystonia cases, 16 severe TH-deficient infantile parkinsonism with motor delay cases and 10 very severe TH-deficient progressive infantile encephalopathy cases.Clinical symptoms were fluctuating, including 26 cases of diurnal fluctuation, 22 cases of infection aggravation, and 30 cases of fatigue aggravation.The initial symptoms included tiptoeing and numbness in the limbs(7 cases), motor development retardation or degression (26 cases), fremitus (8 cases), ptosis (2 cases), and status dystonicus (3 cases). Other clinical features had hypermyotonia (23 cases), hypomyotonia (27 cases), decreased movement (27 cases), decreased facial expression (24 cases), fremitus (18 cases), tiptoeing (20 cases), talipes equinovarus (7 cases), ptosis (8 cases), oculogyric crisis (10 cases), salivation (21 cases), dysphagia (12 cases), dysarthria (16 cases), dyspnea (3 cases), increased sleep (10 cases), decreased sleep (5 cases), irritable mood (15 cases), apathetic mood (2 cases), profuse sweating (8 cases), and status dystonicus (6 cases). A total of 6 patients′ right limbs were more severe, and 14 patients′ lower limbs were more severe.Eight patients had family history, and Levodopa treatment was effective for all patients.Ten patients suffered side effects, including dyskinesia and irritability.Four patients were lost follow-up, and 29 patients were followed up between 0.8 and 13.2 years old until Ja-nuary 2020.Totally, 22 patients almost had no such symptoms.Twenty-five TH gene pathogenic variants were discovered in 33 patients.There were 13 novel variants (c.1160T>C, c.1303T>C, c.887G>A, c.1084G>A, c.1097A>T, c.734G>T, c.907C>G, c.588G>T, c.992T>G, c.755G>A, c.184-6C>T, c.1510C>T, c.910G>A) and 2 patients had c. 910G>A variant.Meanwhile, there were 5 hot variants [c.698G>A(13 cases), c.457C>T(9 cases), c.739G>A(6 cases), c.1481C>T(4 cases), c.694C>T(3 cases)]. c.910G>A(2 cases) may be the foun-der variant of Chinese population. Conclusions:THD caused by TH gene variant mostly onsets from infant, with complex clinical features.Most of these patients were severe, and only a few were very severe and mild.Very severe and mild symptoms were easily misdiagnosed.Levodopa treatment was obviously effective.A possible founder variant of Chinese population (c.910G>A) was found.c.698G>A and c. 457C>T mutations mainly appeared in patients with severe and extremely severe THD, while c. 739G>A mainly appeared in patients with mild THD.

To analyze the clinical presentation and the treatment process of one case of colchicine poisoning complicated with extra pontine myelinolysis and discuss its pathogenesis. Increasing the attention of hyponatremia caused by colchicine poisoning is of great significance for improving the prognosis and quality of life of patients.

To analyze the clinical presentation and the treatment process of one case of colchicine poisoning complicated with extra pontine myelinolysis and discuss its pathogenesis. Increasing the attention of hyponatremia caused by colchicine poisoning is of great significance for improving the prognosis and quality of life of patients.

Objective: To analyze the spatial distribution of brain metastases in EGFR-mutant lung cancer and the risk of hippocampal metastasis. Methods: Patients with lung cancer brain metastases diagnosed and treated in the Shanghai Cancer Center Fudan University from 2006 to 2016 were enrolled. The brain metastasis with positive mutation of EGFR gene was screened. The magnetic resonance images of the patients were reviewed and the distribution characteristics of brain metastasis were analyzed. Results: A total of 920 lung cancer patients with brain metastases were screened, 266 of whom had EGFR gene mutation detection, and 131(49%) were identified as EGFR gene mutations. Excluding 17 patients who did not have a head magnetic resonance examination in our hospital, a total of 114 patients and 738 lesions were enrolled in this study. The proportion of brain metastases distributed in each brain region was 22.8%, 19.5%, 22.0%, 13.4%, 3.3%, 16.7%, and 2.2% for frontal, temporal, parietal, occipital lobe, insula, cerebellum, and brainstem, respectively. The number of metastases and cases located in the hippocampus, <5 mm from the hippocampus, <10 mm from the hippocampus, and<15 mm from the hippocampus were 6(0.8%), 10(1.3%), 11(1.4%), and 14(1.8%), 5 cases (4.4%), 8 cases (7.0%), 9 cases (7.9%), and 11 cases (9.6%), respectively. Conclusion EGFR-mutant lung cancer brain metastasis is low risk in the hippocampus and its surrounding 15 mm.

Regulatory T cells ( Treg) play important role in immune homeostasis in physics and hamper the anti-tumor immunity. Depletion of intra-tumor Treg is a critical step to boost the anti-tumor effect in immune therapy. Radiotherapy can induce secretion of TGF-βand IL33 from tumor cells and then increase Treg proliferation and recruitment into tumor through Langerhans cell. Depletion of Treg could increase the local control and abscopal effect of radiotherapy.

Objective To investigate the clinical features and gene diagnostic bases of childhood L-2 -hydroxyglutaric aciduria (L-2-HGA). Methods The clinical data involving manifestations,laboratory examinations of 4 children with L-2-HGA admitted to Beijing Children′s Hospital Affiliated to Capital Medical University from April 2015 to March 2018 were retrospectively analyzed. Each patient had a follow-up visit ranging from 3 months to 3 years and 2 months after initial examination. Results The 4 patients,of whom 2 were siblings,consisted of 1 male and 3 females,whose age of onset ranged from 8 months old to 3 years old. All of them presented with seizures as their initial symptom. The developmental milestones were all normal before onset,while 3 cases gradually became mentally stagnant. Other symptoms included unsteady gait in 3 cases,slight hand trembling when holding items in 2 cases,and pyramidal impairment in 2 cases. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus were detected by cranial magnetic resonance imaging (MRI)in all patients,and cerebral and cerebellar atrophy was ob-served in 1 case. Organic acid analysis by gas chromatography/ mass spectrometry (GC/ MS)demonstrated notable ele-vation of urinary 2-hydroxyglutaric acid in 3 cases. Pathogenic mutations on L2HGDH gene were detected by target -capture high-throughput sequencing in all 4 patients. The compound heterozygous mutations of c. 845G > A (p. Arg282Gln)and c. 800_801delCA (p. Ser267Ter)were identified in case 1,the homozygous missense mutation of c. 584A > G (p. Tyr195Cys ) in case 2 and case 3,and the homozygous frameshift mutation of c. 407delA (p. Lys136SerfsTer3)in case 4. The variants of c. 800_801delCA and c. 407delA were novel mutations firstly reported in this study. Sanger sequencing verified that parents of the 4 cases were all heterozygous carriers. The follow-up study in 2 cases who were put on high dosage of vitamin B2 and L-carnitine had shown a relatively favorable outcome of mild remission in ataxia and absence of mental degradation and further seizures,while the other 2 cases without specific therapy remained relatively stable. Conclusions The main clinical manifestations of L-2-HGA are mental retarda-tion,seizures and ataxia. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus are specific neuroimaging findings. Significant elevation of urinary 2-hydroxyglutaric acid is the basic feature of the disease,while gene assessment should be the gold standard in the diagnosis of L-2-HGA. Treatment with high dosage of vitamin B2 and L-carnitine might be effective to partial patients.

Objective To investigate whether capsular polysaccharides of Streptococcus pneumoniae serotypes 6A and 6B contained in 13-valent pneumococcal conjugate vaccine ( PCV13 ) could induce cross- protective antibodies against newly discovered serotypes 6C and 6D and the differences between them. Methods New Zealand rabbits were radomly divided into three groups and respectively muscularly administrated with three doses of PCV13, PCV6A and PCV6B on days 0, 14 and 28. PCV6A and PCV6B were conjugates of capsular polysaccharides of serotypes 6A and 6B chemically coupled with diphtheria toxin mutant CRM197. Serum samples were collected on days 0 and 35. Enzyme-linked immunosorbent assay (ELISA) recommended by World Health Organization (WHO) was used to quantitatively measure serotype-specific antibodies to capsular polysaccharides of serotypes 6A, 6B, 6C and 6D. Opsonophagocytosis assay ( OPA) of WHO pneumococcal serology reference laboratory was used to determine antibody functional activities targeting serotypes 6A, 6B, 6C and 6D. Results Immunization rabbits with PCV13 induced the secretion of antibodies to capsular polysaccharides of serotypes 6A and 6B. These antibodies were able to not only cross-react with capsular polysaccharides of serotypes 6C and 6D but also recognize and bind to target Streptococcus pneumoniae serotypes 6A, 6B, 6C and 6D, resulting in the activation of complements and further phagocytosis of target bacteria by differentiated HL60 cells. Bactericid-al titers were largely even among these serotypes except for serotype 6D which was slightly lower. PCV6A could induce antibody against capsular polysaccharide of serotype 6A, which was able to cross-react with capsular pol-ysaccharides of serotypes 6B, 6C and 6D and showed higher bactericidal titers to serotypes 6A, 6B and 6C over serotype 6D. PCV6B could induce antibody against capsular polysaccharide of serotype 6B, which was able to cross-react with capsular polysaccharides of serotypes 6A, 6C and 6D and showed higher bactericidal titers to se-rotypes 6A, 6B and 6C over serotype 6D. Antibody concentrations and bactericidal titers specific to serotypes 6A, 6B, 6C and 6D were significantly increased following immunization with PCV13, PCV6A or PCV6B (P<0. 01). Conclusion PCV13 containing pneumococcal serotypes 6A and 6B induced antibodies against capsular polysaccharides of serotypes 6A and 6B in New Zealand rabbits, which were able to cross-react with capsular polysaccharides of serotypes 6C and 6D and provide cross-protection to bacteria of serotypes 6C and 6D. Both serotypes of 6A and 6B contained in PCV13 contributed to the induction of cross-protective antibodies, especially to serotype 6C.