OBJECTIVE To analyze and identify the metabolites of pirtobrutinib （PTN） in rats， and clarify the possible metabolic pathways of PTN in rats. METHODS Six rats were intragastrically administered with 10 mg/kg PTN suspension. Blood samples were collected from the rats 30 minutes before administration and at 0.25， 0.5， 1， 2， 4， 6， 8， 12， 24 hours after administration. Urine and feces samples were collected 12 hours before administration and 24 hours after administration. UHPLC- Orbitrap Exploris 240 system combined with Compound Discoverer 3.0 and Xcalibur 2.0 software were adopted for structural identification and metabolic pathway analysis of PTN metabolites in rat plasma， urine， and feces. RESULTS A total of 29 PTN metabolites were identified， including 17， 19 and 22 metabolites in plasma， urine and feces， respectively. The metabolic pathways of PTN mainly included oxidation， sulfation， glucuronidation， etc.， and its metabolites were mostly combination products of two or more different metabolic forms. In detail， a total of 26 metabolites were associated with phase Ⅰ metabolic reactions （14 oxidation metabolites， 9 reduction/dehydrogenation metabolites， 8 demethylation metabolites， and 5 hydrolysis metabolites）. Meanwhile， a total of 20 products were involved in phase Ⅱ metabolites （14 sulfation metabolites and 8 glucuronic acid binding metabolites）. CONCLUSIONS PTN exhibits a diverse range of metabolites in rat fecal samples， with the primary metabolic pathways being oxidation， sulfation， glucuronidation， and others.

Objective:To explore the effects of body mass index (BMI) on the incidence of nocturnal hypertension in patients with hypertension.Methods:Totally 341 hospitalized hypertensive patients treated at the Affiliated Hospital of Jining Medical University from February to May 2023 were selected by convenience sampling. Patients' general information, clinical data, and 24-hour ambulatory blood pressure results were collected. A binomial Logistic regression analysis was conducted to investigate the factors affecting the occurrence of nocturnal hypertension in these patients. The relationship between BMI and the incidence of nocturnal hypertension was examined using threshold effect tests and smooth curve fitting.Results:The binomial Logistic regression analysis indicated that blood phosphate level was a factor influencing the occurrence of nocturnal hypertension in hypertensive patients ( P<0.05). Smooth curve fitting and threshold effect test results showed that the relationship between BMI and the incidence of nocturnal hypertension was curve-correlated, with a turning point at 24.61 kg/m 2. To the left of the turning point, there was no correlation ( P=0.130) ; to the right, there was a correlation ( P=0.016) . Conclusions:When the BMI of hypertensive patients exceeds 24.61 kg/m 2, the likelihood of nocturnal hypertension increases with rising BMI, providing a precise intervention target for weight management-based patient care in hypertension.

Objective:To analyze the correlation of glycosylated hemoglobin (HbA 1c) level in the late pregnancy gestational diabetes mellitus (GDM) patients and fetal weights, neonatal Apgar scores, maternal and infant adverse outcomes. Methods:One hundred and eighty-seven pregnant women who were diagnosed with GDM from January 2015 to July 2019 and delivered in Yixing People′s Hospital after standard diagnosis and treatment were divided into four groups (A group: HbA 1c<6.0%, 65 cases; B group: HbA 1c: 6.0% - 6.5%, 49 cases; C group: HbA 1c 6.6%-7.0%, 39 cases; D group: HbA 1c>7.0%, 34 cases) according to the HbA 1c examination results at 28 to 32 weeks of gestation. General data, fetal weights, neonatal Apgar scores and maternal and infant adverse outcomes were compared among the four groups. The correlation between GDM HbA 1c and fetal weights, neonatal Apgar scores and maternal and infant adverse outcomes were analyzed by unconditional Logistic regression. Results:In general data of GDM pregnant women with different HbA 1c levels, only oral glucose tolerance test (OGTT) fasting blood glucose: (4.68 ± 0.60), (4.89 ± 0.69), (5.23 ± 0.90), (6.48 ± 2.17) mmol/L; postprandial 1 h blood glucose: (9.84 ± 1.56), (10.09 ± 1.84), (10.6 ± 2.01), (12.74 ± 4.12) mmol/L; postprandial 2 h blood glucose: (8.65 ± 1.49), (8.86 ± 1.76), (9.28 ± 2.15), (11.56 ± 4.93) mmol/L, showed statistically significant differences ( P<0.05). Among the newborns of GDM pregnant women with different HbA 1c levels, there were statistically significant differences in the macrosomic infant rates: 1.54%(1/65), 10.20%(5/49), 12.82%(5/39), 17.65%(6/34); rates of neonatal Apgar scores<7 points:13.85%(9/65), 16.33%(8/49), 25.64%(10/39), 44.12%(15/34); the proportion of maternal and infant adverse outcomes: 24.62%(16/65), 24.49%(12/49), 28.21%(11/39), 50.00%(17/34), showed statistically significant differences ( P<0.05). After adjusting OGTT by unconditional Logistic regression analysis, HbA 1c (6.6%-7.0% and>7.0%) was independent risk factor for macrosomic infants: OR = 1.430, 95% CI = 1.035-1.977, P = 0.030; OR = 2.042, 95% CI = 1.311-3.180, P = 0.001; maternal and infant adverse outcomes: OR = 1.774, 95% CI = 1.130-2.874, P = 0.010; OR = 3.387, 95% CI = 1.608-7.133, P = 0.001. HbA 1c>7.0% was independent risk factors for neonatal Apgar scores<7 points: OR = 1.848 95% CI = 1.086-3.143, P = 0.023. Conclusions:There was a significant correlation between HbA 1c in GDM pregnant women in the late pregnancy and macrosomic infants, neonatal Apgar scores, and maternal and infant adverse outcomes. In particular, GDM pregnant women with HbA 1c>7.0% should be alert to the risk of macrosomic infants, neonatal Apgar score<7 points, and maternal and infant adverse outcomes.

BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement is a common driver gene of non-small cell lung cancer (NSCLC). Ceritinib is a second-generation ALK inhibitor, which can bring survival benefits to ALK-positive metastatic NSCLC. However, few studies focus on the safety and efficacy of ceritinib in China. Therefore, this study intends to investigate the safety and preliminary efficacy of ceritinib 450 mg with meals in Chinese patients with ALK-positive NSCLC through a real world study. METHODS: From October 2018 to December 2019, patients with ALK-positive NSCLC from 8 medical centers in Sichuan province were recruited in this study. All of these participants received ceritinib 450 mg/d with food. The basic characteristics, adverse effects (AEs) and responses were collected and analyzed in order to evaluate the safety and efficacy of ceritinib. RESULTS: A total of 109 patients were included in this study. Data cutoff was January 23, 2020. The median duration of treatment exposure was 5.87 mon (range: 0.4 mon-15.7 mon). Total AEs were reported in 98 (89.9%) of 109 patients and grade 3 or 4 AEs were reported in 22.9% of patients. Most common AEs (mainly grade 1 or 2) were diarrhea (60.6%), elevated alanine aminotransferase (ALT)(38.5%) and aspartate aminotransferase (AST)(37.6%). As of data cutoff, 45 patients discontinued ceritinib. The overall response rate (ORR) was 37.6% (95%CI: 28.5%-47.4%) and disease control rate (DCR) was 86.2% (95%CI: 78.3%-92.1%). CONCLUSIONS The treatment of ceritinib 450 mg with food for Chinese ALK-positive NSCLC patients had a good safety profile and favorable DCR in real-world setting. However, this conclusion needs to be further verified by large sample, prospective trials.

Objective ToinvestigatetheMSCTand MRIcharacteristicsoffocalnodularhyperplasia(FNH)oftheliverwithout centralscar.Methods Aretrospectiveanalysisofimagingdatawascarriedoutin10patientswithFNH withoutcentralscar,confirmed bypathologyandfollowGupreview.PlainscanandenhancedCT wereperformedin10patients,5ofwhomunderwenttheplainscan andenhancedMRI.Results Lesionswerehomogeneousandslightlylowdensityin10casesonplainMSCT,andhypoGorisoGintensity onT1WIandhyperGorisoGintensityonT2WIin5cases.Nocentralscarwasfoundinalltheselesions.Thecorrelationcoefficientsof thechangeofCTvaluewere0.772onportalvenousphaseand0.827ondelayedphaseinnormalhepaticgroupandlesiongroup(P＜0.05).Theenhancedvolumeof8lesionswasslightlylargerontheportalvenousanddelayedphasethanthatonarterialphase.Conclusion MSCTand MRIcanclearlydisplaytheimagefeaturesofFNH withoutcentralscar.Thereisastrongcorrelationoftheenhancement curvebetweenthelesionsandnormalliverparenchymaonportalvenousanddelayedphase,whichishelpfulformoreaccuratediagnosis.

Objective To investigate the safety and feasibility of totally laparoscopic transabdominalhiatal approach in the treatment of Siewert type Ⅱ adenocarcinoma of esophagogastric junction (AEG).Methods The retrospective and descriptive study was conducted.The clinicopathological data of 11 patients with Siewert type Ⅱ AEG who were admitted to Affiliated Hangzhou First People's Hospital of Zhejiang University School of Medicine from May 2017 to July 2018 were collected.There were 8 males and 3 females,aged 56-72 years,with an average age of 63 years.Patients underwent radical resection of AEG by totally laparoscopic transabdominalhiatal approach.Observation indicators:(1) surgical situations and postoperative recovery;(2) postoperative pathological examination;(3) follow-up and survival situations.Follow-up using outpatient examination and telephone interview was performed to detect postoperative adjuvant chemotherapy,complications,food intake,anastomosis patency,tumor recurrence and metastasis,and survival up to December 2018.Measurement data with normal distribution were presented as Mean±SD,measurement data with skewed distribution were presented as M (range),and count data were represented as absolute number or percentage.Results (1) Surgical situations and postoperative recovery:all the patients underwent totally laparoscopic radical resection of Siewert type Ⅱ AEG by transabdominal-hiatal approach,without conversion to open surgery or perioperative death.Of the 11 patients,8 underwent total gastrectony including 3 combined with splenic hilar lymph node dissection and 3 underwent proximal gastrectomy with double-tract reconstruction.Operation time,time of superior overlap esophagojejunostomy,volume of intraoperative blood loss,time for initial out-of-bed activities,time to first flatus,time to initial liquid diet intake,time of drainage tube removal were respectively (245± 39)minutes,(60± 12) minutes,(75±23) mL,(24± 8) hours,(2.4± 0.5) days,(3.5 ± 0.8) days,(8.2 ± 1.3) days respectively.There was no serious complication including postoperative hemorrhage,anatomotic fistula or death.Three patients had left pleural effusion,and were cured after thoracic drainage.The duration of postoperative hospital stay was (11.0±3.0) days.(2) Postoperative pathological examination:all the 11 patients had negative upper surgical margin.The length of proximal margin,tumor diameter,total number of lymph lodes harvested,and number of lower mediastinal lymph lodes harvested were (2.1 ±0.2) cm,(2.6±0.9) cm,(36.0±4.0)/case and (2.3± 0.8)/case.Pathological examination showed adenocarcinoma in all the 11 patients.pTNM staging:2 cases were in stage Ⅰ B,4 cases in stage Ⅱ A,3 cases in stage Ⅱ B and 2 cases in stage Ⅲ A.(3) Follow-up and survival situations:11 patients were follow-up for 6-19 months,with a median time of 9 months.Chemotherapy regimeus were formulated according to the pathological examination.Nine patients received postoperative adjuvant chemotherapy,and 2 in stage Ⅱ B received no postoperative adjuvant chemotherapy.During the follow-up,11 patients had no obvious reflux symptom or choking feeling,and the anastomosis was patent as evaluated by oral contrast agent and gastroscopy.There was no tumor recurrence and metastasis or death in the 11 patients.Conclusion Totally laparoscopic transabdominal-hiatal approach applied in the radical resection is safe and feasible for the treatment of Siewert type Ⅱ AEG,with good short-term outcomes.

Objective: To investigate the impact of clinicopathological features, gene rearrangements and protein expression of bcl-6, bcl-2, C-MYC and chemotherapy regime on the prognosis of patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Methods: Thirty-three cases of PCNS-DLBCL diagnosed from January 2006 to December 2016 at Zhejiang Cancer Hospital were collected. The expression of CD10, bcl-6, bcl-2, MUM1 and MYC were detected by immunohistochemical staining (IHC). The presence of EB virus was detected by in situ hybridization(EBER). Copy number variation (ICN) and translocation status of bcl-6, bcl-2 and C-MYC genes were detected by fluorescence in situ hybridization (FISH). The relationship between the above indexes and the prognosis was analyzed by univariate, bivariate survival analysis and multiple Cox hazard regression analysis. Results: The study included 33 patients of PCNS-DLBCL, without evidence of primary or secondary immunodeficient disease. Male to female ratio was 1.36∶1.00, and the average age was 56 years. Twenty cases had single lesion while 13 had multiple lesions. Deep brain involvement was seen in 12 cases. All patients underwent partial or total tumor resection. Five patients received whole brain post-surgery radiotherapy, nine patients received high-dose methotrexate (HD-MTX) based chemotherapy, and 12 patients received whole-brain radiotherapy combined with HD-MTX based chemotherapy. Severn patients received no further treatment and rituximab was used in 8 patients. According to the Hans model, 27 cases were classified as non-GCB subtypes (81.8%). Bcl-2 was positive in 25 cases (75.8%, 25/33) and highly expressed in 8 (24.2%). MYC was positive in 12 cases (36.4%) and double expression of bcl-2 and MYC was seen in 6 cases. EBER positive rate was 10.0%(3/30), all of which had multiple lesions. Two bcl-6 gene translocations and 3 amplifications were found in 28 patients. Two translocations, 3 ICN or with both bcl-2 gene translocation and ICN were found in 30 patients. Four ICNs of C-MYC gene were found in 28 patients. Elevated protein in cerebrospinal fluid (CSF) was found in 13 patients. LDH increased in 10 cases. Follow-up period was 2-90 months with the average survival time of (23.0±3.7) months and two-year survival rate of 39.0%. Univariate survival analysis showed that overexpression of bcl-2 protein (≥70%) and MYC protein (≥40%), bcl-2 gene abnormality (including copy number increase and translocation), C-MYC gene copy number increased were adverse factors for survival. C-MYC/ bcl-2 gene double hit was seen in 2 cases. Bivariate survival analysis found that of bcl-2/MYC protein double expression and bcl-2 and C-MYC genes double aberration were significantly associated with adverse outcomes. Cox multivariate risk regression analysis found that gender, cerebrospinal fluid protein increasing, and ICN of C-MYC gene were independent poor prognostic factors. DH-MTX based comprehensive chemotherapy was associated with better prognosis. Conclusions Double hit at genomic level (copy number variations and gene rearrangements) and double protein expression of bcl-2 and C-MYC in PCNS-DLBCL are significantly associated with an adverse outcome. DH-MTX based comprehensive treatment may prolong the patient survival.

Extranodal nature killer/T cell lymphoma (ENKTCL) is a highly aggressive non-Hodgkin lymphoma (NHL) with a high mortality. ENKTCL is epidemic in Asia and Latin America, especially in China, Japan and South Korea. EBV has been proved to be associated closely with ENKTCL; however, specific molecular mechanism which can explain how the neoplasm develops is still unclear. Chinese population seems to be more susceptible to this lymphoma and Chinese scientists have made great contributions to the pathogenesis and the treatments of ENKTCL. This review mainly introduces the recent progress of molecular pathogenesis of ENKTCL.

Objective To evaluate the role of chemokine CXC-ligand 16 (CXCL16) in renal fibrosis following renal ischemia-reperfusion (I/R) injury in mice.Methods Twenty-four healthy male C57BL/6 mice,aged 8-10 weeks,weighing 20-30 g,were divided into 4 groups (n =6 each) using a random number table method:sham operation group (group S),sham operation plus anti-CXCL16 antibody group (group S+A),group I/R,and I/R plus anti-CXCL16 antibody group (group I/R+A).Renal ischemia was induced by occlusion of the left renal artery for 30 min followed by 72-h reperfusion,and the fight kidney was removed on 5th day in anesthetized mice.CXCL16 antibody 5 mg/kg and the equal volume of normal saline were intraperitoneally injected at 72 h after reperfusion twice a week for 2 consecutive weeks in I/R+A and I/R groups,respectively.Sham operation was performed,and the equal volume of CXCL16 antibody 5 mg/kg and normal saline were intraperitoneally injected at 72 h after reperfusion twice a week for 2 consecutive weeks in S+A and S groups,respectively.Orbital venous blood samples were collected at day 14 after reperfusion for determination of serum blood urea nitrogen (BUN) and creatinine (Cr) concentrations.Animals were then sacrificed and the left kidney was removed for measurement of the renal fibrosis size (using Sirius red staining),expression of t-smooth muscle actin (α-SMA),fibronectin (FN) and type Ⅰ collagen (Col-Ⅰ) in renal tissues by Western blot.Results Compared with group S,the serum BUN and Cr concentrations and renal fibrosis size were significantly increased,and the expression of α-SMA,FN and Col-Ⅰ was up-regulated in group I/R (P＜0.05).Compared with group I/R,the serum BUN and Cr concentrations and renal fibrosis size were significantly decreased,and the expression of α-SMA,FN and Col-Ⅰ was down-regulated in group I/R+A (P＜0.05).Conclusion CXCL16 is involved in the process of renal fibrosis following renal I/R injury in mice.

In recent years , there are increasing articles concerning Epstein-Barr virus associated lymphoproliferative disorder (EBV+LPD), and the name of EBV +LPD is used widely.However,the meaning of EBV+LPD used is not the same , which triggered confusion of the understanding and obstacles of the communication.In order to solve this problem.Literature was reviewed with combination of our cases to clarify the concept of EBV +LPD and to expound our understanding about it .In general, it is currently accepted that EBV +LPD refers to a spectrum of lymphoid tissue diseases with EBV infection , including hyperplasia , borderline lesions , and neoplastic diseases .According to this concept , EBV+LPD should not include infectious mononucleosis ( IM ) and severe acute EBV infection ( EBV +hemophagocytic lymphohistiocytosis, fatal IM, fulminant IM, fulminant T-cell LPD), and should not include the explicitly named EBV+lymphomas ( such as extranodal NK/T cell lymphoma , aggressive NK cell leukemia , Burkitt lymphoma, and Hodgkin lymphoma , etc.) either.EBV +LPD should currently include: ( 1 ) EBV +B cell-LPD:lymphomatoid granulomatosis , EBV +immunodeficiency related LPD , chronic active EBV infection-B cell type, senile EBV +LPD, etc.(2) EBV +T/NK cell-LPD:CAEBV-T/NK cell type, hydroa vacciniforme, hypersensitivity of mosquito bite, etc.In addition, EBV+LPD is classified, based on the disease process , pathological and molecular data , as 3 grades:grade1, hyperplasia ( polymorphic lesions with polyclonal cells ); grade 2, borderline ( polymorphic lesions with clonality ); grade 3, neoplasm (monomorphic lesions with clonality).There are overlaps between EBV +LPD and typical hyperplasia, as well as EBV+LPD and typical lymphomas .However , the most important tasks are clinical vigilance , early identification of potential severe complications , and treating the patients in a timely manner to avoid serious complications , as well as the active treatment to save lives when the complications happened .