Phase Ⅰ clinical trials play a crucial role in the research and development of new drugs, serving as the initial studies to assess their safety, tolerability, effectiveness, and pharmacokinetic properties in humans. These trials involve uncertainties regarding safety and efficacy. Comprehensive management of all aspects of phase Ⅰ clinical trials for anti-tumor drugs is crucial to protect the rights and safety of participants. This article provides an in-depth analysis of the key points and precautions necessary for effective quality control throughout the process. The analysis is informed by guidelines such as the “Good Clinical Practice for Drugs” “Key Points and Judgment Principles for Drug Registration Verification” “Key Points and Judgment Principles for Supervision and Inspection of Drug Clinical Trial Institutions” and the standard operating procedures for quality control of the center. Topics discussed include informed consent, inclusion criteria, experimental drugs, biological samples, adverse events, and serious adverse events. The goal is to standardize quality control in phase Ⅰ clinical trials of anti-tumor drugs, ensure the authenticity and reliability of clinical trial data, and protect the rights and safety of participants.

Objective:To explore the clinicopathological and genetic characteristics of sporadic medullary thyroid carcinoma (MTC) and new therapeutic targets for sporadic MTC.Methods:Based on family and personal disease history, we identified 32 sporadic MTC who underwent surgical resection from Jan 2010 to Dec 2022. Clinicopathological and immunohistochemical features were analyzed in all patients, while 6 of them were subject to the whole exome sequencing (WES).Results:Compared with those of low-grade sporadic MTC, patients with high-grade tumors were more likely to have lymph node metastasis at presentation ( χ2=4.428, P=0.040); less likely to be cured by biochemical treatment ( χ2=4.072, P=0.044). Pathological grading scheme, biochemical cure, and TNM stage were independent risk factors of disease free survival. WES was performed on 6 pairs of normal tissues. We screened RET and RAS as driver mutations, and the mutation ratio was 3/6 respectively. Patients with RET or RAS mutations had no recurrence. In addition, we detected PDGFRA somatic mutation, with a mutation ratio of 1/6. Conclusions:For sporadic MTC cases, the pathological grading system has important prognostic value, and RET and RAS somatic mutations are the main driver mutations. PDGFRA are potential therapeutic targets for sporadic MTC.

OBJECTIVE: To analyze the expression of hydroxysteroid dehydrogenase like 2 (HSDL2) in rectal cancer tissues and the effect of changes in HSDL2 expression level on proliferation of rectal cancer cells. METHODS: Clinical data and tissue samples of 90 patients with rectal cancer admitted to our hospital from January 2020 to June 2022 were collected from the prospective clinical database and biological specimen database. The expression level of HSDL2 in rectal cancer and adjacent tissues was detected by immunohistochemistry, and based on the median level of HSDL2 expression, the patients were divided into high expression group (n=45) and low expression group (n=45) for analysis the correlation between HSDL2 expression level and the clinicopathological parameters. GO and KEGG enrichment analyses were performed to explore the role of HSDL2 in rectal cancer progression. The effects of changes in HSDL2 expression levels on rectal cancer cell proliferation, cell cycle and protein expressions were investigated in SW480 cells with lentivirus-mediated HSDL2 silencing or HSDL2 overexpression using CCK-8 assay, flow cytometry and Western blotting. RESULTS: The expressions of HSDL2 and Ki67 were significantly higher in rectal cancer tissues than in the adjacent tissues (P < 0.05). Spearman correlation analysis showed that the expression of HSDL2 protein was positively correlated with Ki67, CEA and CA19-9 expressions (P < 0.01). The rectal cancer patients with high HSDL2 expressions had significantly higher likelihood of having CEA ≥5 μg/L, CA19-9 ≥37 kU/L, T3-4 stage, and N2-3 stage than those with a low HSDL2 expression (P < 0.05). GO and KEGG analysis showed that HSDL2 was mainly enriched in DNA replication and cell cycle. In SW480 cells, HSDL2 overexpression significantly promoted cell proliferation, increased cell percentage in S phase, and enhanced the expression levels of CDK6 and cyclinD1 (P < 0.05), and HSDL2 silencing produced the opposite effects (P < 0.05). CONCLUSION The high expression of HSDL2 in rectal cancer participates in malignant progression of the tumor by promoting the proliferation and cell cycle progress of the cancer cells.
Humans ; CA-19-9 Antigen ; Ki-67 Antigen/metabolism* ; Prospective Studies ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Rectal Neoplasms/genetics* ; Cell Cycle ; Gene Expression Regulation, Neoplastic ; Hydroxysteroid Dehydrogenases/metabolism*

Objective:To investigate the clinicopathologic features and molecular genetics characteristics of sinonasal tract mucosal malignant melanomas(STMMMs)in elderly patients.Methods:The clinicopathological features, immunohistochemical features and BRAF, C-KIT, NRAS mutations of STMMM in ten elderly patients were retrospectively analyzed.Results:Among the 10 patients, 5 were female and 5 were male.The patients were aged 65-81 years, with an average age of(72.5 ± 8.5)years.The lesions in 7 cases were located in the nasal cavity and paranasal sinuses, and in the other 3 cases were located in the nasopharynx.The morphologies of tumor cells under microscope was complex and diverse, showing plasma cell-like, rhabdomyoblast-like, small cell-like, epithelial-like, and spindle cell-like morphologies.Immunohistochemically, HMB-45 and S-100 were generally positive in 10 cases, and the positive rate of Melan A was 70.0%.The genes detection data showed no mutations in BRAF or NRAS genes in all the 10 cases, while C-KIT exon 11 c. 1666_1667insA mutation was found in one case, and the remaining 9 cases were wild-type for C-KIT.All the 10 cases were followed up for 4~50 months.Three cases survived so far.Conclusions:STMMM in elderly patients are rare and easy to be misdiagnosed.Immunohistochemistry and genetic testing provide guidance for accurate diagnosis and targeted therapy.

The clinical data of 2 children with refractory Mycoplasma pneumoniae pneumonia complicated with intracardiac thrombosis and pulmonary embolism, treated in Tianjin Children′s Hospital from July 2019 to January 2020, were analyzed retrospectively.One patient was an 8-year-old girl, who was admitted to the hospital mainly because of " fever for 5 days and cough for 2 days" . The other patient was a 7-year-old boy, who was admitted due to " intermittent fever with cough for 24 days and chest pain for 1 day" . Both children were complicated with elevated D-dimer levels and positive antiphospholipid antibody.During the treatment, right cardiac thrombosis and pulmonary embolism occurred in both cases, and the manifestations of thrombosis related symptoms were not typical.After the patients received anticoagulation treatment and thrombolytic therapy with urokinase, the cardiac thrombus dissipated and the pulmonary embolism improved.For refractory Mycoplasma pneumoniae pneumonia complicated with intracardiac thrombosis and pulmonary embolism, thrombolytic therapy can be applied to some children in addition to anticoagulant therapy.

Objective:To investigate the correlation between three-dimensional histogram analysis of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)and Gleason score(GS)in prostate cancer(Pca)from two hospital, and its diagnostic efficacy for discriminating low-grade from high-grade Pca.Methods:A total of 102 pathologically confirmed Pca patients in the First Affiliated Hospital of Zhejiang Chinese Medical University and Hangzhou Traditional Chinese Medical Hospital(TCM Hospital)Affiliated to Zhejiang Chinese Medical University from January 2017 to October 2020 were retrospectively analyzed.The quantitative parameters of Pca, including transport constant(K trans), rate constant(K ep), percent volume of the extravascular extracellular space(V e)and fraction of the Intraplasmic contrast volume(V p), were obtained by manually layer by layer delineating of interested regions of all lesions on the original DCE-MRI imaging.Then the three-dimensional histogram analysis of the above parameters were performed to obtain the minimum, maximum, median, mean, area, 10 thpercentile, 25 thpercentile, 75 thpercentile and 90 thpercentile.The correlations between quantitative parameters and GS, and diagnostic efficiencies were analyzed. Results:102 Pca patients were divided into low-grade prostate cancer group(GS≤3+ 4)(n=44)and high-grade Pca group(GS≥4+ 3)(n=58). There were no statistically significant differences in age and location of lesions between the two groups( P>0.05), but there were statistically significant differences in Gleason score, PSA level and lesion diameter between the two groups( U=0.000, 730.000, 711.000, all P<0.05). The median, mean, 10 thpercentile, 25 thpercentile, 75 thpercentile, 90 thpercentile derived from K trans, and K ep(median, mean, 10%, 25%, 75%, 90%)together with maximum of K transand mean for V e were positively correlated with GS( r=0.405 to 0.583, P<0.05), in which mean of K transhad the highest positive correlation( r=0.583, P=0.000). The histogram parameters derived from V pwere negatively correlated with GS( r=-0.301 to 0.341, P<0.05). The area under ROC of 75th percentile derived from K transwas the highest(0.832). When the cut-off value of 75 thpercentile derived from K transwas ≥0.680/min, its Youden index, sensitivity, and specificity were 0.594, 0.776, 0.818, respectively. Conclusions:The three-dimensional histogram of DCE-MRI quantitative parameters has correlation with GS in Pca patients, can be used to discriminate low-grade from high-grade Pca.

Objective:To explore the relationship between the type of mutation and clinical features, prognosis, and clinical characteristics of chronic granulomatous disease (CGD) caused by compound heterozygous mutations in the NCF2 gene in children. Methods:The clinical data of 1 case of neonatal CGD caused by compound heterozygous mutations of NCF2 gene at Tianjin Children′s Hospital in August 2019 was analyzed, and domestic and international literatures were searched to summarize the clinical characteristics, gene mutation type and prognosis of CGD caused by NCF2 mutation. Results:The diagnosis of CGD was confirmed by the presence of compound heterozygous mutations c. 196_197insA (p.Arg66Glnfs23X) and c. 1180T>G (p.Tyr394Asp) in the NCF2 gene, accompanied with the clinical manifestations of fever, cough, multiple clumps and nodules in the chest CT at 25 days after birth, and the neutrophil respiratory burst test stimulation index(SI) 23.This new mutation was not reported in the Human Genetic Mutation Database.The child had a residual portion of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and was followed up until the age of 9 months with an antifungal drug without recurrent infection.A total of 101 cases of CGD patients with NCF2 gene mutation were reported in domestic and international databases.Totally, 33 cases had SI results, with 22 cases below 3, 11 cases above 3, and 8 cases of missense mutations. Conclusions:c. 196_197insA and c. 1180T>G are new mutations in NCF2 gene that can lead to CGD.CGD patients containing missense mutations in the NCF2 gene may have more residual NADPH oxidase activity.

Objective:To study the efficacy of dental floss traction-assisted endoscopic submucosal dissection (ESD) for gastric angle mucosal lesions.Methods:Data of 127 patients with gastric angle mucosal lesions admitted to the endoscopic center of the First Affiliated Hospital of Xiamen University from January 2015 to December 2018 were retrospectively analyzed. According to the surgical methods, patients were divided into the dental floss traction-assisted ESD group (the traction group, n=51) and the traditional ESD group (the traditional group, n=76). The 41 fibrosis cases were further divided into the traction group (n=23) and the traditional group (n=18). The operation time, en block resection rate, curative resection rate and the incidence of adverse events such as bleeding, muscle layer injury and perforation were compared between the two groups.Results:There was no significant difference in age, sex, lesion size or morphology between the traction group and the traditional group ( P > 0.05). The operation time of the traction group was significantly shorter than that of the traditional group (65.4±36.5 min VS 103.5±43.2 min, P=0.012). The en block resection rate was higher in the traction group [100.00% (51/51) VS 90.79% (69/76), P=0.026], and the curative resection rate was higher too [94.12% (48/51) VS 81.58% (62/76), P=0.042]. The incidences of muscular layer damage [5.88% (3/51) VS 25.00% (19/76), P=0.010] and intraoperative bleeding [47.06% (24/51)VS 82.89% (63/76), P=0.010] were lower in the traction group. Perforation occurred in two patients (2.63%) of fibrosis in the traditional group; no perforation occurred in the traction group. There was no significant difference in the perforation incidence ( P=0.243). In the cases of fibrosis, the operation time of the traction group was significantly shorter compared with that of the traditional group (81.4±29.3 min VS 119.3±37.6 min, P=0.010). The en block resection rate and curative resection rate were also higher in the traction group [100.00% (23/23) VS 72.22% (13/18), P=0.007; 95.65% (22/23) VS 72.22% (13/18), P=0.035]. The incidences of muscular layer damage [8.70% (2/23) VS 72.22% (13/18), P=0.001] and intraoperative bleeding [78.26% (18/23) VS 100.00% (18/18), P=0.035] were lower in the traction group. Conclusion:The dental floss traction-assisted ESD is safe and effective for gastric angle mucosal lesions and fibrotic lesions, with shorter operation time, higher curative resection rate and lower incidence of adverse events.

Objective To explore the difference in efficacy between multiparametric MRI (Mp-MRI) based on prostate imaging reporting and data system version 2 (PI-RADS v2) and abbreviated biparametric MRI (Bp-MRI) in detecting prostate cancer (PCa) and clinically significant prostate cancer (csPCa), and to evaluate the consistency of image interpretation between different readers. Methods The imaging, pathological and clinical data of patients with prostatic Mp-MRI in our hospital from February 2015 to June 2018 were retrospectively analyzed. At the beginning, 250 patients were randomly selected. Two radiologists visually evaluated the images of those patients using two 5-point scoring schemes based on Mp-MRI and Bp-MRI. The remaining cases were independently proceeded by one of the radiologists using two schemes respectively. Weighted Kappa test was used to assess the consistency of the results interpreted by the two radiologists. The receiver operating characteristic (ROC) curve was used to evaluate the efficiency of the two scoring schemes in detecting PCa and csPCa, and with Z test to investigate whether there was any difference in detection efficiency between the two schemes. Results Nine hundred and seventy eight patients were eventually enrolled in the study. The results of the consistency assessment showed that there was good agreement between the two radiologists, whether using Mp-MRI or Bp-MRI, with the weighted Kappa coefficient of 0.800 and 0.812, respectively. The ROC curve analysis showed that the area under the curve (AUC) of PCa detected by Mp-MRI and Bp-MRI was 0.873 and 0.879, respectively, and the AUC of csPCa detected was 0.922 and 0.932, respectively. In addition, there was no statistically significant difference between the AUC of PCa and csPCa detected by the two schemes (P>0.05). Conclusion The Bp-MRI scoring scheme has good stability in the evaluation of benign and malignant prostate, and its detection efficiency of PCa or csPCa is not lower than that of standard Mp-MRI based on PI-RADS v2.

Objective To evaluate the accuracy of measurements of atherosclerotic middle cerebral artery (MCA) stenosis with 3.0 T high-resolution magnetic resonance imaging (HR-MRI).Methods Forty patients with symptomatic atherosclerotic stenosis of middle cerebral artery (MCA) confirmed by digital subtraction angiography (DSA) in the Affiliated Hospital of Binzhou Medical College from September 2017 to May 2018 were enrolled in the study.Patients were scanned by HR-MRI sequence (including T1WI,T2WI,PDWI).The MCA M1 stenosis rate on HR-MR images was assessed by warfarin-aspirin symptomatic intracranial artery disease (WASID) method and area measurement algorithm,respectively,and based on the stenosis rate the degree of stenosis (semi-quantitative measurement) was determined.The accuracy of the two measurement methods was evaluated with DSA results as the gold standard.Results The HR-MRI images showed the structure of the vessel wall clearly in 30 patients meeting the measurement requirements.The inner edge of the vessel was clearly distinguishable and smooth,showing eccentric stenosis.The stenosis rate of MCA measured by DSA,WASID method and area measurement algorithm were (82± 17)％,(70± 12)％,(81 ± 16)％,respectively (P＞0.05).The result of area measurement algorithm was better correlated with DSA (r=0.893);and the coincidence of the stenosis degree rate of two measurement method was 90％(27/30).Conclusion The area measurement algorithm based on the HS-MRI has high accuracy in measuring the degree of MCA stenosis,which is of high clinical application value.