[The imaging presentations of the fallopian canal cerebrospinal fluid leaking].

Objective: To summarize the imaging presentations of the fallopian canal cerebrospinal fluid leaking (FCCFL). Methods: The high resolution CT (HRCT)and MRI materials of 4 patients (4 ears) with FCCFL confirmed by surgery between August 2016 to November 2023 were retrospectively analyzed. Among these, there were 2 males and 2 females, their ages ranged from 6 to 69 years. Results: All of the FCCFL were unilateral, including 2 on the left and 2 on the right.Clinically, the patients with FCCFL suffered from clear nasal fluid flow, ear tightness, and hearing loss. On CT, all of the affected ears were depicted markedly dilatation of the proximal portion of fallopian canal(FC), the labyrinthine segment and geniculate fossa were involved in 4 cases, and involvement of tympanic segment in 1 case at the same time. The geniculate fossa in the affected side were significantly enlarged, protruding upwards into the tympanic cavity, with one case simultaneously involving the cochlea. On MRI, the hyposignal on T1WI and hypersignal on T2WI or water sequence like cerebrospinal fluid (CSF) were shown in the enlargement FC, without diffusion restriction, and non-enhancing with administration Gadolinium contrast.CSF-like signal effusion was shown in all of the affected tympanum, of which, the CSF-like signal effusion was demonstrated in the area along the superficial petrosal nerve, the right pterygopalatine fossa and the parapharyngeal space. The adjacent intracranial meninges were presented thickening in 3 cases. Conclusion: The imaging appearances of FCCFL present some characteristics:on HRCT, the proximal portions of the affected FC depicts markedly enlargement,especially the geniculate fossa.While they present CSF-like signal, no diffusion restriction, and no enhancement administration, Gadolinium contrast on MRI, accompanying the CSF-like signal effusion in the affected tympanum.

[Evaluation of the predictive effect of PD-L1 expression on survival in early triple-negative breast cancer].

Objectives: To find the prognostic factors related to early triple-negative breast cancer to optimize the therapeutic strategies, and explore the influence of programmed cell death ligand-1(PD-L1)expression in early triple-negative breast cancer on its prognosis, so as to provide support for clinical treatment decisions. Methods: Early triple-negative breast cancer patients treated at the National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences during 1st June, 2009 and 31st Oct, 2015 were enrolled in this study. All the clinicopathological data of patients were collected, and the paraffin sections of the surgical specimens were stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2, secreted protein acidic and rich in cysteine (SPARC), androgen receptor, PD-L1 and other antibodies by the immunohistochemical method. Kaplan-Meier survival and Cox regression curves were used for survival analysis of relevant clinical and pathological results and nomogram survival prediction models were established to explore the influence of relevant factors on the prognosis. Results: A total of 205 patients with triple-negative breast cancer were enrolled. Ninety patients (43.9%) were PD-L1 positive. The median follow-up time was 63 months. Thirty-seven patients were relapsed or recurrent and 16 patients were dead. The 5-year disease-free survival (DFS) rate and overall survival (OS) rate were 86.1% (95% CI: 81.4%-90.8%) and 93.6% (95% CI: 91.0%-97.6%), respectively, in the general population. Univariate Cox regression analysis showed that PD-L1 expression and lymph node metastasis were correlated with DFS and OS (P<0.05). In multivariate analysis, PD-L1 expression was an independent influencing factor of DFS, with PD-L1 positive patients possessing a significant survival benefit in DFS (HR=0.31, 95% CI: 0.13-0.73). Lymph node metastasis was an independent influencing factor of OS, and OS was significantly shortened in patients with positive lymph node metastasis (HR=3.24, 95% CI: 1.15-9.17). PD-L1, lymph node metastasis, menopausal status, Ki-67 index and adjuvant chemotherapy regimen were included to establish the 1- and 3-year DFS and OS nomogram prediction models, resulting in C indices of 0.698 and 0.748, respectively. Conclusions: PD-L1 expression is a predictive biomarker of good prognostic factor in triple-negative breast cancer patients. DFS is significantly prolonged in PD-L1 positive patients and OS also shows a prolongation trend. The nomogram prognosis prediction models have reference values for adjuvant chemotherapy in this patient group.

[Clinical and laboratory features of SF3B1-mutated myeloproliferative neoplasms].

Objective: To explore the clinical and laboratory characteristics of SF3B1 gene mutations in myeloproliferative neoplasms (MPN) patients. Methods: The clinical data of 273 MPN patients who were diagnosed MPN and treated in the Second Hospital of Tianjin Medical University from November 2017 to March 2023 were retrospectively analyzed. There were 133 males and 140 females, with a median age M(Q1,Q3)of 56(46, 67) years. The molecular biology and cytogenetic characteristics were detected by second-generation sequencing (NGS) and R+G banding techniques, and the clinical and laboratory characteristics of patients with SF3B1 gene mutation were analyzed. Results: SF3B1 gene mutations were found in 13 patients (4.8%, 13/273).The types of SF3B1 mutations included missense (92.3%, 12/13) and nonsense mutations (7.7%, 1/13).Compared to the non-mutant cohort, patients in SF3B1 mutant cohort had older ages [68(51, 76) vs 56(45, 66)years,P=0.025], higher proportion of splenomegaly [46.2%(6/13) vs 15.8%(41/259),P=0.014]and secondary tumor [23.1%(3/13)vs 3.8%(10/260), P=0.018]with higher proportion of bone marrow blast [0.5%(0, 1.5%) vs 0(0, 0.5%),P=0.002] and lower hemoglobin[(104±36) vs (137±40) g/L,P=0.004] and hematocrit [31%(22%, 40%) vs 41%(35%, 52%),P=0.003]. All of the 10 patients in the SF3B1 mutant cohort whose ring sideroblast (RS) could be evaluated showed no RS formation. The overall survival, thrombosis-free survival and leukemia free survival of MPN patients in SF3B1 mutant cohort were 4.0 (2.0, 6.0), 2.0 (0.5, 4.5) and 4.0 (2.0, 6.0) years, respectively, while patients in the non-mutant cohort were 6.0 (3.0, 10.0), 5.0 (1.0, 8.0), 6.0 (3.0, 10.0) years, respectively, there were no statistical significance between two groups (Z=3.69, 1.66, 2.05, all P>0.05).The secondary tumor free survival of SF3B1 mutant cohort patients was 4.0 (2.0, 6.0) years, which was lower than that of non-mutant cohort patients [5.5 (3.0, 10.0) years, Z=18.18, P<0.001). Conclusions: MPN patients with SF3B1 gene mutations are older, more prone to splenomegaly and secondary tumors. They also have a higher proportion of bone marrow blast, lower hemoglobin and hematocrit, and show no RS formation.

[Efficacy and safety of pegylated interferon alpha-2b for patients with myeloproliferative neoplasm].

Objective: To evaluate the efficacy and safety of pegylated interferon alpha-2b (PEG-IFN-α2b) in the treatment of myeloproliferative neoplasm (MPN). Methods: Thirty-four MPN patients receiving PEG-IFN-α2b treatment in the Second Hospital of Tianjin Medical University from August 2019 to October 2022 were prospectively included. Among the patients, 9 were male and 25 were female, and the median age [M (Q1, Q3)] was 57 (19, 78) years. Patients' clinical characteristics were collected and the follow-up was performed. As of January 30, 2023, the follow-up period [M(Q1, Q3)] was 24 (16, 33) months. The efficacy, safety and changes in immune cell and cytokine levels after 12 and 24 months of treatment were analyzed. Results: During the follow-up period, 4 patients dropped out, and the efficacy was evaluable in 30 patients. Following 12 and 24 months of treatment, the complete hematologic response (CHR) rates were 57.1% (16/28) and 75.0% (18/24), respectively. The complete molecular response (CMR)+partial molecular response (PMR) rates were 27.3% (6/22) and 55.0% (11/20), respectively. The bone marrow histopathological overall response rates (ORR) were 34.6% (9/26) and 47.6% (10/21), respectively. At 12 and 24 months of treatment, the proportions of CD8+HLA-DR+T cells, effector T cell subpopulations, CD56bright natural killer (NK) cells, and plasmacytoid dendritic cells (pDC) were higher than the pre-treatment levels, while the proportion of CD56dim NK cells was lower than the pre-treatment level (all P<0.05). The levels of motif chemokine ligand 10 (CXCL10), tumor necrosis factor (TNF)-α and TNF-ß in bone marrow all increased from those prior to treatment, while the levels of vascular endothelial growth factor (VEGF) and interleukin (IL-4) decreased from those prior to treatment (all P<0.05). Among hematological adverse reactions, white blood cells decrease [47% (16/34)] was observed with high incidence. Among non-hematological adverse reactions, asthenia [44.1% (15/34)] and transaminases increase [32.3% (11/34)] were observed with high incidences. Conclusions: PEG-IFN-α2b has high hematologic, molecular, and bone marrow histopathological response rates in the treatment of MPN. It can reduce malignant clone loads and regulate the immune microenvironment and is safe and well tolerated overall.

[Analysis of risk factors for thromboembolism in patients with JAK2V617F gene mutation positive myeloproliferative neoplasms].

Objective: To analyze the risk factors of thrombosis in patients with JAK2V617F mutation positive myeloproliferative neoplasms (MPN). Methods: A total of 223 MPN patients with JAK2V617F mutation in the Second Hospital of Tianjin Medical University from September 2017 to May 2023 were retrospectively enrolled, including 111 males and 112 females, aged [M(Q1,Q3)] 57(21,66) years. According to the presence or absence of thromboembolism during follow-up, the patients were divided into thrombosis group (n=102) and non-thrombosis group (n=121). The clinical characteristics, laboratory characteristics, cytogenetics and other disease progression and survival of the two groups of patients were analyzed. As of March 31, 2023, the follow-up period [M (Q1, Q3)] was 6 (3, 10) years. The influencing factors of thrombosis in JAK2V617F positive MPN patients were analyzed by using the Cox risk model. Results: Among 223 JAK2V617F positive MPN patients, 144 were polycythemia vera (PV), 51 were essential thrombocythemia (ET) and 28 were primary myelofibrosis (PMF). The mutation rates of ASXL1 and BCORL1 genes in the thrombosis group were 19.6% (20/102) and 6.9% (7/102), respectively, which were higher than those in the non-thrombosis group [9.1% (11/121) and 0.8% (1/121)] (both P<0.05). The proportion of monocytes, C-reactive protein (CRP), interleukin-1ß (IL)-1ß, IL-8 and tumor necrosis factor-ß (TNF-ß) increased in the thrombosis group were higher than those in the non-thrombosis group (all P<0.05). Multivariate analysis showed that age≥60 years (HR=2.132, 95%CI: 1.376-3.303, P=0.001), history of thrombosis (HR=3.636, 95%CI: 2.121-6.202, P<0.001), ASXL1 mutation positive (HR=2.245, 95%CI: 1.093-3.231, P=0.022) and elevated TNF-ß (HR=2.009, 95%CI: 1.113-3.624, P=0.021) were risk factors for thrombosis in JAK2V617F positive MPN patients. Conclusions: In addition to age, history of thrombosis and positive ASXL1 mutation, elevated TNF-ß is also an influencing factor of thrombosis in JAK2V617F positive MPN patients. Intervention of inflammation may have a certain effect on the prevention and treatment of thrombosis.

Efficacy of spesolimab for the treatment of generalized pustular psoriasis flares across pre-specified patient subgroups in the Effisayil 1 study.

Effisayil 1 was a multicentre, randomized, double-blind, placebo-controlled study of the anti-interleukin (IL)-36 receptor monoclonal antibody, spesolimab, in patients presenting with a generalized pustular psoriasis (GPP) flare. Previously published data from this study revealed that within 1 week, rapid pustular and skin clearance were observed in patients receiving spesolimab versus placebo. In this pre-specified subgroup analysis, the efficacy of spesolimab was evaluated according to patient demographic and clinical characteristics at baseline in patients receiving spesolimab (n = 35) or placebo (n = 18) on Day 1. Efficacy was by assessed by achievement of primary endpoint (Generalized Pustular Psoriasis Physician Global Assessment [GPPGA] pustulation subscore of 0 at Week 1) and key secondary endpoint (GPPGA total score of 0 or 1 at Week 1). Safety was assessed at Week 1. Spesolimab was found to be efficacious and had a consistent and favourable safety profile in patients presenting with a GPP flare, regardless of patient demographics and clinical characteristics at baseline.

A Novel MR Imaging Sequence of 3D-ZOOMit Real Inversion-Recovery Imaging Improves Endolymphatic Hydrops Detection in Patients with Ménière Disease.

BACKGROUND AND PURPOSE: The detection rate of premortem MR imaging endolymphatic hydrops is lower than that of postmortem endolymphatic hydrops in Ménière disease, indicating that current MR imaging techniques may underestimate endolymphatic hydrops. Therefore, we prospectively investigated whether a novel high-resolution MR imaging technique, the 3D zoomed imaging technique with parallel transmission real inversion-recovery (3D-ZOOMit real IR), would improve the detection of endolymphatic hydrops compared with conventional 3D TSE inversion-recovery with real reconstruction. MATERIALS AND METHODS: Fifty patients with definite unilateral Ménière disease were enrolled and underwent 3D-ZOOMit real IR and 3D TSE inversion-recovery with real reconstruction 6 hours after IV gadolinium injection. The endo- and perilymph spaces were scored separately. The contrast-to-noise ratio, SNR, and signal intensity ratio of the 2 sequences were respectively calculated and compared. The presence of endolymphatic hydrops was evaluated. RESULTS: The endolymphatic space in the cochlea and vestibule was better visualized with 3D-ZOOMit real IR than with conventional 3D TSE inversion-recovery with real reconstruction (P < .001). There were differences between the 2 sequences in the evaluation of no cochlear hydrops and cochlear hydrops (both, P < .017). All contrast-to-noise ratio, SNR, and signal intensity ratio values of 3D-ZOOMit real IR images were statistically higher than those of conventional 3D TSE inversion-recovery with real reconstruction (all, P < .001). CONCLUSIONS: The 3D-ZOOMit real IR sequences are superior to conventional 3D TSE inversion-recovery with real reconstruction sequences in visualizing the endolymphatic space, detecting endolymphatic hydrops, and discovering contrast permeability.

The Use of Episodic Memory Tests for Screening in Clinical Trials for Early Alzheimer's Disease: A Comparison of the Free and Cued Selective Reminding Test (FCSRT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

BACKGROUND: Screening procedures for early Alzheimer's disease (AD) trials seek to efficiently identify participants who fulfill clinical and biomarker criteria for AD and enrich for those most likely to experience significant clinical progression during the study. Episodic memory performance is often assessed in screening, but the utility of different memory tests for optimizing screening efficiency and/or rates of clinical progression remains uncertain. OBJECTIVES: Cross-study comparisons of the effects of inclusion criteria based on performance on the Free and Cued Selective Reminding Test (FCSRT) or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) on screen-failure rates for episodic memory and ß-amyloid (Aß) positivity (by CSF or PET) and on subsequent rates of clinical disease progression in randomized participants across three clinical trials in early (prodromal-to-mild) AD. DESIGN: Secondary analyses of cross-sectional and longitudinal clinical trial data. SETTING: Multi-center international clinical trials. PARTICIPANTS: Individuals with prodromal-to-mild AD screened and/or randomized in clinical trials for crenezumab (CREAD, CREAD2) or semorinemab (Tauriel). Cross-sectional analyses of screening data for episodic memory impairment included participants from CREAD2 (n=2897) and Tauriel (n=887) and for Aß positivity included participants from CREAD (n=1138), CREAD2 (n=1119), and Tauriel (n=483). Longitudinal analyses of rates of clinical progression included participants from CREAD (n=779), CREAD2 (n=773), and Tauriel (n=331). MEASUREMENTS: Cross-sectional analyses examined eligibility rates per cutoffs defined for the FCSRT (CREAD, CREAD2) or RBANS (Tauriel) and per Aß positivity using CSF and/or PET biomarkers. Longitudinal analyses examined rates of clinical progression on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), and Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). RESULTS: Lower rates of study eligibility per episodic memory criteria were seen with the FCSRT (CREAD2) relative to the RBANS (Tauriel), but similar rates of eligibility per Aß positivity criteria were seen amongst participants with episodic memory impairment per the cutoffs used on either assessment. Similar rates of clinical decline over 18 months on the CDR-SB, ADAS-Cog13, and ADCS-ADL were observed in study populations enriched using the FCSRT (CREAD, CREAD2) or the RBANS (Tauriel). CONCLUSIONS: Cutoffs for episodic memory impairment on the FCSRT used in the CREAD and CREAD2 studies are more stringent than those on the RBANS used in the Tauriel study, resulting in lower rates of eligibility. However, given that study enrichment with either test yields similar rates of Aß positivity and clinical progression, considerations beyond these factors may drive the decision of which assessment to use for screening in early AD clinical trials.

[The correlation between reflux esophagitis and Helicobacter pylori infection based on natural population].

Objective: Reflux esophagitis (RE) may be negatively correlated with Helicobacter pylori (H. pylori) infection, but the conclusion and relevant mechanism is still controversial. This study proposed to explore the correlation between RE and H. pylori infection based on natural population. Methods: From July 2013 to December 2014, 3 940 residents aged 40-69 years were recruited in Linqu County of Shandong Province and Hua County of Henan Province by the whole sampling method. All the subjects underwent gastroscopy, and gastric mucosa biopsy specimens were collected for pathological diagnosis and Warthin-Starry (WS) staining to identify H. pylori infection. Venous blood samples of some subjects were collected for H. pylori immunoglobulin G (H. pylori-IgG) detection. Also, demographic and sociological data were collected. Chi-square test and logistic regression were used to analyze the correlation between RE and H. pylori infection. Results: A total of 359 cases of RE were detected. Excluding RE and other upper gastrointestinal organic diseases, 3 382 cases were considered as controls. Chi-square test showed that WS staining positive rate in RE group was significantly lower than that in control group (P=0.023), but there was no significant difference in the positive rate of H. pylori-IgG between the two groups (P=0.281). There were significant differences between RE group and control group in gender composition, age, body mass index (BMI), smoking, alcohol consumption, education level and mucosal active inflammation. Multivariate regression analysis showed that RE was negatively correlated with gastric mucosa active inflammation [OR=0.754 (95%CI 0.600-0.949), P=0.016], and positively correlated with male [OR=4.231 (95%CI 3.263-5.486), P<0.001], age ≥60 years, BMI≥24 kg/m2 [OR=1.540 (95%CI 1.220-1.945), P<0.001]. Compared to those aged 40-49 years and 50-59 years, the odds ratio (OR) of RE in these aged ≥60 years were 1.566 (95%CI 1.144-2.143, P=0.005) and 1.405 (95%CI 1.093-1.805, P=0.008). Conclusion: RE is more closely related to H. pylori present infection. Multivariate analysis showed that RE is negatively correlated with active inflammation of gastric mucosa caused by H. pylori infection, and positively correlated with male, overweight and aged ≥60 years.

[The changes of blood-labyrinth barrier in idiopathic sudden sensorineural hearing loss and the relationship with clinical features and prognosis].

Objective: To investigate the clinical features and prognosis in patients with idiopathic sudden sensorineural hearing loss (ISSNHL) with blood-labyrinth barrier breakdown (BLB-B). Methods: Clinical data of patients with unilateral ISSNHL hospitalized from December 2017 to December 2018 were retrospectively analyzed. According to the results of 3D-FLAIR MRI and enhanced MRI scanning, these patients were divided into two groups, i.e., normal and abnormal inner ear groups. The patients in abnormal inner ear group were further divided into two subgroups: BLB-B and BLB-B with exudation. The differences and correlations among the groups in clinical characteristics, in terms of gender, age, deafness side, basic diseases, dizziness/vertigo, vestibular function, hearing loss degree, as well as classification of hearing curve, and prognosis were analyzed by statistical software SPSS 23.0. Results: Data were collected from 150 cases, in which 68 were male and 82 were female, aged (46.2±14.6) years, including 67 cases with normal inner ears and 83 cases with abnormal inner ears (13 cases with BLB-B; 70 cases with BLB-B and exudation). The dizziness/vertigo incidence, side ratio, hearing loss degree, classification of hearing curve, vestibular dysfunction (vestibular double temperature test, HIT and VAT) and therapeutic effect were different between normal and abnormal inner ear groups (P<0.05). The dizziness/vertigo incidence, side ratio, hearing loss degree, classification of hearing curve, vestibular dysfunction (vestibular double temperature test, o/cVEMP, HIT and VAT) and therapeutic effect were different among normal inner ear, BLB-B and BLB-B with exudation groups (P<0.05). Pairwise comparison between groups revealed that vestibular dysfunction (vestibular double temperature test, o/cVEMP, HIT and VAT) and therapeutic effect were different between normal inner ear and BLB-B groups (P<0.05); The dizziness/vertigo incidence, side ratio, hearing loss degree, classification of hearing curve, vestibular dysfunction (vestibular double temperature test, o/cVEMP, HIT and VAT) and therapeutic effect were different between normal inner ear and BLB-B with exudation groups (P<0.05). There was no significant different between BLB-B and BLB-B with exudation groups. Conclusion: BLB-B displayed by 3D-FLAIR MRI manifestation in ISSNHL patients indicates more serious cochlear and vestibular dysfunction, and worse therapeutic effect.

[Correlation analysis of 3D-FLAIR MRI characteristics of the inner ear and vestibular function in the patients with vestibular neuritis].

Objective: The characteristics of 3D-FLAIR MRI images of the inner ear of patients with vestibular neuritis were preliminarily studied to explore the possible pathogenesis of vestibular neuritis, and the correlation analysis was conducted in combination with vestibular function to provide a basis for accurate diagnosis of vestibular neuritis. Methods: A total of 36 patients with vestibular neuritis (VN) from December 2019 to October 2020 were collected from the Vertigo Department of Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University. There were 36 cases (18 females, 18 males) with unilateral acute vestibular neuritis, 17 cases of left ear and 19 cases of right ear. According to the results of 3D-FLAIR MRI in the inner ears, the patients were divided into the enhanced group and the non-enhanced group (the health side served as the normal control group). The results of vestibular function examination in the two groups were compared. SPSS19.0 software was used for statistical processing to analyze the relationship between the vestibular function and the characteristics of 3D-FLAIR imaging in the inner ears. Results: Abnormal enhancement of 3D-FLAIR was found in 31 cases (86.1%) of the 36 cases, including 14 cases of both vestibular nerve and vestibular terminal organ enhancement, eight cases of superior vestibular nerve enhancement alone, seven cases of vestibular terminal organ enhancement alone, and two cases of cochlear enhancement alone. Observation of abnormal reinforcement of vestibular nerve showed: twenty-one cases of superior vestibular nerve reinforcement, one case of superior and inferior vestibular nerve reinforcement. No abnormalities were found in 3D-FLAIR of inner ear in 5 cases. According to the analysis of vestibular function results, there were 19 cases (52.8%) with total vestibular involvement, sixteen cases (44.4%) with superior vestibular involvement alone, and one case (2.8%) with inferior vestibular involvement alone. Comparison of vestibular function between the five cases (non-enhancement group) and the 31 cases (enhanced group) in the 3D-FLAIR group of the inner ears showed that the CP values of caloric tests in the enhanced group were higher (60.81±3.49 vs 34.12±7.37), with statistically significant difference (t=-2.898, P<0.01). Conclusion: In patients with vestibular neuritis, 3D-FLAIR MRI scan of the inner ear provides visual imaging evidence for clinical practice, considering that the lesion site of vestibular neuritis is not only in the vestibular nerve, but also in the vestibular end organ. Patients with 3D-FLAIR enhanced in the inner ear may have more significant vestibular function damage.

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

[Comparison of hip offset and rotation center reconstruction between robot-assisted and manual total hip arthroplasty].

Objective: To compare the differences of hip offset and rotation center reconstruction between robot-assisted and manual total hip arthroplasty (THA). Methods: Patients underwent robot-assisted and manual THA from May to September of 2020 in the First Affiliated Hospital of Chongqing Medical University were enrolled in this study. The patients included 27 patients (28 hips) in robot-assisted THA (rTHA) group and 29 patients (31 hips) in manual THA (mTHA) group. In rTHA group, there were 16 males and 11 females, with a mean age of (59±13) years. In mTHA group, there were 18 males and 11 females, with a mean age of (63±14) years. Basic information, including gender, age, body mass index (BMI), diagnosis and functional scoring etc, were recorded. In rTHA group, Mako robot system was used for preoperative planning, intraoperative real-time location and navigation. In mTHA group, traditional preoperative template design and surgical procedure were carried out. Operation time and functional scoring were compared postoperatively. Femoral offset, acetabular offset, global offset, rotation center changes in vertical and horizontal directions were measured on pelvis X-ray and analyzed. The correlation between intraoperative feedback of global offset change in robot system and postoperative measured global offset were analyzed. Results: Operation time in rTHA group was (80±10) min, which was statistically longer than that in mTHA group ((58±18) min, P<0.001). With 6 months' follow-up, the Harris scoring in rTHA group was 94.9±2.8, which was statistically higher than that in mTHA group (93.1±2.8, P=0.017), however there was no statistic difference in WOMAC scoring between rTHA and mTHA group (7.0±3.8 vs 7.1±2.4, P=0.840). Absolute global offset change within 5 mm, 5-10 mm and lager than 10 mm were 71.4%(20/28), 28.6%(8/28) and 0 in rTHA group, which were 45.2%(14/31), 29.0%(9/31) and 25.8%(8/31) in mTHA group (all P<0.05). A positive relation was found between intraoperative feedback of global offset change in robot system and postoperative measured global offset in rTHA group (r=0.77, P<0.001). It was found that rotation center changes concentrated in outer upper quadrant in both groups, and rotation center change in rTHA group concentrated mainly in the area less than 10 mm, however, rotation center change in mTHA group was more dispersive compared with rTHA group. Conclusion: rTHA may accurately reconstruct hip offset and rotation center, intraoperation feedback of global offset change may be an effective reference.

SPINK1 contributes to proliferation and clonal formation of HT29 cells through Beclin1 associated enhanced autophagy.

We aimed to explore the molecular mechanism that were involved in SPINK1-induced proliferation and clonogenic survival of human colorectal carcinoma (CRC) HT29 cells. Initially, we generated HT29 cells either permanently silencing or overexpressing SPINK1 protein. The results showed that SPINK1 overexpression (OE) significantly stimulated the proliferation and clonal formation of HT29 cells at the varied time points. Secondly, we found SPINK1 OE enhanced the ratio of LC3II/LC3I and the level of autophagy-related gene 5 (ATG5), whereas SPINK1 knockdown (Kd) reversed the above outcome under normal culturing and/or fasting condition in the cells, indicating its role in autophagy enhancement. Moreover, LC3-GFP-transfected SPINK1-OE HT29 cells strengthened the fluorescence intensity compared with the untransfected control. Chloroquine (CQ) significantly decreased the level of autophagy in both control and SPINK1-OE HT29 cells. The autophagy inhibitors, CQ and 3-Methyladenine (3-MA), remarkably inhibited the proliferation and colony formation of SPINK1-OE HT29 cells, while ATG5 upregulation resulted in the growth of the cells, suggesting the important function of autophagy in cell's growth. Thirdly, SPINK1-induced autophagy was independently of mTOR signaling as p-RPS6 and p-4EBP1 were activated in SPINK1-OE HT29 cells. Instead, Beclin1 up and down regulation were clearly observed in SPINK1-OE and SPINK1 Kd HT29 cells, respectively. Moreover, Beclin1 silencing apparently reduced autophagy in SPINK1-OE HT29 cells, indicating that SPINK1-induced autophagy was closely associated with Beclin1. Collectively, SPINK1-promoted proliferation and clonal formation of HT29 cells were closely associated with Beclin1 associated enhanced autophagy. The above findings would open a new window for probing the role of SPINK1-related autophagic signaling in the pathogenesis of CRC.

Smoking and incidence of insomnia: a systematic review and meta-analysis of cohort studies.

OBJECTIVE: This study investigated the impact of smoking on the incidence of insomnia. STUDY DESIGN: Systematic review and meta-analysis of cohort studies. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, and OVID were searched through March 2020. Cohort studies reporting the effect of smoking on the incidence of insomnia were included. We quantitatively analyzed the basic framework and study characteristics and then pooled estimate effects with 95% confidence intervals (CIs) of outcomes of each included study using fixed-effects meta-analyses. RESULTS: This systematic review included six cohort studies involving 12,445 participants. Quantitatively summarized results suggested that smoking could significantly increase the incidence of insomnia (odds ratio [OR]: 1.07, 95% CI: 1.02, 1.13). Regular smoking was significantly associated with the incidence of insomnia (OR = 1.07, 95% CI: 1.01, 1.13). As for occasional smokers and ex-smokers, the pooled analysis did not indicate a significant association (occasional smoker: OR = 2.09, 95% CI: 0.44, 9.95; ex-smoker; OR = 1.02, 95% CI: 0.67, 1.54). Subgroup analysis by age, gender ratio, and region showed a statistically significant relationship between smoking and the incidence of insomnia in specific groups. CONCLUSIONS: Integrated longitudinal observational evidence identified smoking as a significant risk factor of insomnia. Considering the limited amount of available studies, more high-quality and prospective cohort studies of large sample sizes are needed to explore details of this association.

[Evaluation of the efficacy and safety of combination of gemcitabine and nedaplatin for patients with HER-2 negative metastatic breast cancer].

Objective: To assess the therapeutic efficacy and safety of the gemcitabine combined with nedaplatin (GN) chemotherapy for metastatic human epidermal growth factor receptor-2 (HER-2) negative breast cancer patients. Methods: Forty-five patients with HER-2 negative recurrent metastatic breast cancer who had received prior adjuvant or neoadjuvant therapy with anthracycline and/or taxanes were enrolled. All the patients received GN regime from January 2014 to February 2019. The therapeutic efficacy was evaluated according to response evaluation criteria in solid tumors (RECIST) 1.1. The adverse response was evaluated and monitored according to common terminology criteria for adverse events (CTCAE). The progression-free survival (PFS) and overall survival (OS) and prognostic factors were also analyzed. Results: All of the 45 patients received 4 course GN, 1 of them achieved complete response, 21 achieved partial response. The objective response rate was 48.9 (95% CI: 33.7%-64.1%). Grade 3-4 hematological toxicities include leukopenia occurred in 10 (22.2%) of patients, neutropenia in 13 (28.9%) patients, and thrombocytopenia in 8 (17.6%) patients. The grade 3-4 hematological toxicities mainly manifested as nausea and vomiting, and the incidence was 4.4% (2/45). Among the 45 patients, 34 died, the median PFS was 5.1 (95% CI: 3.9-6.1) months and the median OS was 17.6 (95% CI: 13.1-20.9) months. Conclusion: The combination of gemcitabine and nedaplatin is an effective and tolerable treatment for metastatic breast cancer patients previously treated with anthracyclines and/or taxanes.