Inhibitor of apoptosis proteins (IAP) inhibitor APG-1387 monotherapy or in combination with programmed cell death 1 (PD-1) inhibitor toripalimab in patients with advanced solid tumors: results from two phase I trials.

BACKGROUND: APG-1387 is a novel second mitochondrial-derived activator of caspases mimetic, small-molecule inhibitor targeting inhibitor of apoptosis proteins. We report results from two phase I trials evaluating the tolerability, safety, and antitumor activity of APG-1387 monotherapy and APG-1387 plus toripalimab [a programmed cell death 1 (PD-1) inhibitor] for advanced solid tumors. PATIENTS AND METHODS: Participants aged ≥18 years who had histologically confirmed advanced solid tumors with no appropriate standard of care (or refractory to standard care) were eligible. Patients received escalating intravenous doses of APG-1387 alone or combined with fixed-dose toripalimab (240 mg every 3 weeks) in a '3 + 3' design. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in the monotherapy trial, and recommended phase II dose (RP2D) in the combination therapy trial. Secondary endpoints included the pharmacokinetic and pharmacodynamic profiles and preliminary efficacy in both trials. RESULTS: In the monotherapy trial, 28 subjects were enrolled and received ≥1 treatment cycle. No DLT was reported among the 28 subjects, and the MTD was not reached. One participant (3.6%) had a grade ≥3 treatment-related adverse event (TRAE) of alanine aminotransferase elevation. In efficacy analysis of 23 participants, none achieved an objective response, and the disease control rate was 21.7%. In the combination trial, 22 subjects were enrolled and included in all analyses. There was one DLT of grade 3 lipase elevation. The MTD was not reached. Four grade ≥3 TRAEs occurred in three participants (13.6%), with the most common being lipase elevation (n = 2). The RP2D was 45 mg weekly. The objective response rate was 13.6%, with complete response achieved in one subject, and the disease control rate was 54.5%. CONCLUSIONS: APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors.

[Experience of mesenteric sector fixation in mesenteric torsion treatment].

Objective: The preliminary results was reported regarding the treatment of mesenteric torsion by mesenteric fixation in the last decade, especially preventing recurrence of mesenteric torsion by mesenteric fan-shaped fixation. Methods: We selected 12 patients who received emergency operation in Chongqing Hospital of the First Affiliated Hospital of Guangzhou University of Chinese Medicine from December 2010 to March 2022. All of them were made a definite diagnose of mesenteric torsion by the preoperative CT scan or exploratory laparotomy. The recurrence of mesenteric torsion will be prevented by taking the operation of mesenteric fan-shaped fixation. This technique is suitable for the patient who is suffering total mesenteric torsion, but enteric necrosis is excluded affirmatively. The operation is consists of the following progress: (1) Exploratory laparotomy to check for necrosis of the bowel and for lesions other than torsion. (2) Mesenteric torsion derotation.(3) Mesenteric linear fixation; the right posterior lower border of the small mesentery (terminal ileal mesentery) is intermittently sutured to the posterior peritoneum of the right lower quadrant to increase the width of the base of the small mesentery. (4) Mesenteric fan-shaped fixation, which is fan-shaped to the lower left and fixed in the posterior peritoneum, shortening the length of the mesentery and further increasing the width of the mesentery and posterior peritoneal fixation. Results: A total of 12 patients with mesenteric torsion were treated by operation for 15 times in all. Among them, 3 cases received resection of most small bowel were performed without recurrence; 3 patients received only derotation for a total of 4 times, 2 cases recurred, 1 of them recurred twice; 4 cases underwent derotation and mesenteric linear fixation,and 1 case recurred. Four patients with derotation and mesenteric fan-shaped fixation recovered well without recurrence. Conclusion: Mesenteric fan-shaped fixation may be an effective operative type to reduce or avoid postoperative recurrence of mesenteric torsion.

Association of healthy sleep patterns with risk of mortality and life expectancy at age of 30 years: a population-based cohort study.

BACKGROUND: The importance of sleep on cardiovascular health has been increasingly acknowledged. However, the effect of combined sleep behaviors on life expectancy remains understudied. AIM: To investigate the association between sleep patterns with total and cause-specific mortality and life expectancy, using a nationally representative sample of US adults. DESIGN: Population-based cohort study. METHODS: This cohort study included 172 321 adults aged 18 years or older in the National Health Interview Survey (2013-18) with linkage to the National Death Index records up to 31 December 2019. The life expectancy at the age of 30 years by the number of low-risk sleep scores was estimated using a flexible parametric survival model. RESULTS: During a median follow-up of 4.3 years, of the 172 321 adults (50.9% women; mean [SE] age, 46.98 [0.10] years), 8681 individuals died. The adjusted hazard ratios (95% confidence intervals [CI]) of participants with five vs. 0-1 low-risk sleep factors for all-cause, cardiovascular, and cancer mortality were 0.70 (0.63-0.77), 0.79 (0.67-0.93) and 0.81 (0.66-0.98), respectively. Nearly 8% (population attributable fraction 7.9%, 95% CI: 5.5-10.4) of mortality in this cohort could be attributed to suboptimal sleep patterns. When compared to those with 0-1 low-risk sleep factors, life expectancy at the age of 30 years for individuals with all five low-risk sleep factors was 4.7 (95% CI: 2.7-6.7) years greater for men and 2.4 (95% CI: 0.4-4.4) years greater for women. CONCLUSIONS: Our findings suggest that greater adherence to a low-risk sleep pattern may lead to significant gains in life expectancy among US adults.

[Long non-coding RNA ABHD11-AS1 promotes glycolysis in gastric cancer cells to accelerate tumor progression].

OBJECTIVE: To explore the role of long non-coding RNA ABHD11-AS1 in regulation of glycolysis in gastric cancer cells and its molecular mechanism. METHODS: The null plasmid pcDNA-Vector and the overexpression plasmid pcDNA-ABHD11-AS1 were transfected into human gastric cancer cell lines MKN45 and MGC803 with low ABHD11-AS1 expression, and the changes in cell proliferation, colony formation, migration and invasion were examined using CCK-8 assay, colony formation assay and Transwell assay. Glucose uptake and lactate production of the cells were detected to assess the changes in glycolytic activity. The LncMAP database was used to identify potential transcription factors regulated by ABHD11-AS1, and the candidate transcription factor was determined by literature review, and the result was verified using Western blotting. RESULTS: Transfection with pcDNA-ABHD11-AS1 significantly increased ABHD11-AS1 expression in MGC803 and MKN45 cells, which exhibited obviously accelerated cell proliferation (P<0.05), increased colony formation rate and enhanced cell migration and invasion abilities (P<0.01). ABHD11-AS1 overexpression obviously promoted glycolysis in MGC803 and MKN45 cells (P<0.05). Analysis of the database suggested that ABHD11-AS1 may regulate the classical glycolysis-related gene c-Myc in gastric cancer cells. Western blotting demonstrated that the expression of c-Myc increased significantly after upregulating ABHD11-AS1 in gastric cancer cells. CONCLUSION: ABHD11-AS1 promotes glycolysis in gastric cancer cells by upregulating c-Myc to accelerate gastric cancer progression.

[Association between different obesity measurement indexes and serum C-reactive protein in adult women].

Objective: To explore the association of different obesity measurement indexes on serum C-reactive protein (CRP) in Chinese adult women. Methods: The data were obtained from baseline and follow-up surveys of the urban Breast Cancer Screening Program in Shuangliu District, Chengdu. A total of 441 adult women were included in the study. A questionnaire survey, physical examination, and laboratory testing were conducted on the subjects. Multivariate logistic regression model, two-level mixed effects logistic regression model, and restricted cubic spline method were used to investigate the linear and nonlinear correlation between different obesity measurement indexes and serum CRP in adult women. Results: For every 1 unit increase in BMI, waist circumference (WC), and adiposity, the risk of elevated serum CRP or exacerbation of chronic low-grade inflammation in adult women increased by 16.5%, 5.0%, and 11.1% (P<0.05), respectively. Both BMI and adiposity were nonlinear correlated with serum CRP. Using BMI=24.0 kg/m2 as the reference point, serum CRP level increased with the increase of BMI when BMI >24.0 kg/m2. Using adiposity=30% as the reference point, serum CRP level increased with the increase of adiposity when adiposity >30%. Conclusions: Overall, obesity reflected by BMI had the strongest association with serum CRP in adult women, followed by body fat content reflected by adiposity, and central obesity reflected by WC had the weakest association with CRP. Adult women with BMI >24.0 kg/m2 or adiposity >30% are at high risk for obesity-related inflammatory manifestations.

Clinical outcomes of intra-arterial chemotherapy combined with iodine-125 seed brachytherapy in the treatment of malignant superior vena cava syndrome caused by small cell lung cancer.

PURPOSE: Currently there is a lack of effective treatment strategies for malignant superior vena cava syndrome (SVCS). We aim to investigate the therapeutic effect of intra-arterial chemotherapy (IAC) combined with the Single Needle Cone Puncture method for the 125I brachytherapy (SNCP-125I) in treating SVCS caused by stage III/IV Small Cell Lung Cancer (SCLC). MATERIALS AND METHODS: Sixty-two patients with SCLC who developed SVCS from January 2014 to October 2020 were investigated in this study. Out of these 62 patients, 32 underwent IAC combined with SNCP-125I (Group A) and 30 patients received IAC treatment only (Group B). Clinical symptom remission, response rate, disease control rate, and overall survival of these two groups of patients were analyzed and compared. RESULTS: The remission rate of symptoms including dyspnea, edema, dysphagia, pectoralgia, and cough of malignant SVCS in Group A was significantly higher than that in Group B (70.5 and 50.53%, P=0.0004, respectively). The disease control rates (DCR, PR+CR+SD) of Group A and B were 87.5 and 66.7%, respectively (P=0.049). Response rates (RR, PR+CR) of Group A and Group B were 71.9 and 40% (P=0.011). The median overall survival (OS) of Group A was significantly longer than that in Group B which was 18 months compared to 11.75 months (P=0.0360). CONCLUSIONS: IAC treatment effectively treated malignant SVCS in advanced SCLC patients. IAC combined with SNCP-125I in the treatment of malignant SVCS caused by SCLC showed improved clinical outcomes including symptom remission and local tumor control rates than IAC treatment only in treating SCLC-induced malignant SVCS.

[Analysis of clinical and imaging features of 6 cases of linear scleroderma en coup de sabre with central nervous system involvement in children].

Objective: To summarize the clinical and imaging features of linear scleroderma en coup de saber (LSCS) with central nervous system involvement in children. Methods: The clinical data(clinical manifestations and imaging features) of 6 children diagnosed with LSCS with central nervous system involvement who were admitted to Beijing Children's Hospital Affiliated to Capital Medical University from May 2019 to November 2021 were retrospectively analyzed. Results: The 6 patients were all female, aged 6.8 (3.3, 11.0) years at the time of diagnosis, and aged 3.0 (1.7, 4.1) years at the time of discovery of facial skin lesions. Facial skin lesions appeared before neurological symptoms in 5 cases, and neurological symptoms appeared 2 months before skin lesions in 1 case. All the patients had "sword wound" skin lesions on the forehead with alopecia. Neurological manifestations included epileptic seizures in 6 cases, focal neurological defects in 5 cases, and headaches in 2 cases. The intracranial lesions were all ipsilateral to the skin lesions. The magnetic resonance imaging (MRI) of 6 cases showed abnormal signals mainly involving white matter in 1 hemisphere, and 3 cases showed local encephalomalacia. The scattered low signal was observed in 5 cases on susceptibility weighted imaging. Localized brain parenchyma or leptomeninges enhancement was seen on Gadolinium-enhanced sequences in 5 cases. Scattered foci of calcification on the affected side were seen on cranial CT in 4 cases. Skin biopsy was performed in 2 cases. Part of the lesion of the brain was removed in 1 case, and the pathological findings suggested small vasculitis, which was consistent with skin pathological changes. All patients received symptomatic treatment with antiepileptic drugs. Oral prednisone combined with methotrexate was given in 4 cases, and 1 case was given oral prednisone only. One case was presumed to be in the resting stage of the disease due to significant cerebral atrophy in half of the brain, and only antiepileptic drugs were added. The patients were followed up for 6-36 months. The skin lesions of scleroderma and alopecia did not progress in 5 cases, and hemifacial atrophy was developed in 1 case, which was considered to be combined with Parry-Romberg syndrome. The seizures were controlled in 4 cases. One case had reduced seizure frequency but left hemiplegia. One patient still had intractable epilepsy and paroxysmal headache. Conclusions: LSCS with central nervous system involvement is more common in girls, with seizures and neurological defects as the main manifestations. Intracranial lesions are mostly ipsilateral to the skin lesions. Cerebral microbleeds, calcification, and encephalomalacia foci are common, and the pathological changes in skin and intracranial lesions are consistent with small-vessel vasculitis. Prednisone combined with methotrexate treatment has shown some efficacy, but some children remain with refractory epilepsy and neurological deficit symptoms.

[Analysis of clinical features and poor prognostic factors of acute hematogenous osteomyelitis in children].

Objective: To analyze the clinical characteristics, pathogenic bacteria, complications and risk factors of prognosis of acute hematogenous osteomyelitis in children. Methods: The clinical manifestations, laboratorg tests, etiological charateristics and clinical data of 107 patients with acute hematogenous osteomyelitis admitted to Beijing Children's Hospital from January 2017 to December 2020 were retrospectively analyzed. According to the drug sensitivity results of Staphylococcus aureus, the group was divided into methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) group; according to the presence or absence of complications, the group was divided into the group with and without complications; according to the prognosis of the follow-up children, the group was divided into good prognosis and poor prognosis. The χ2 test or Mann-Whitney U test used for comparison between groups, and Logistic regression was used to analyze the risk factors for complications and prognosis. Results: Of the 107 patients, 62 were males and 45 were females. The age of presentation was 5.6 (1.7, 10.0) years, including 5 patients (4.7%) age from >28 days to 3 months, 46 patients (43.0%) age from >3 months to 5 years, 43 patients (40.2%)>5-12 years of age, and 13 patients (12.1%)>12-18 years of age. The first symptoms were acute fever in 35 patients (32.7%), limb pain in 24 patients (22.4%), and fever with limb pain in 23 patients (21.5%). Pathogen culture was positive in 75 patients (70.1%), Streptococcus pyogenes, Salmonella enterica and Escherichia coli in 1 case (1.4%) each, and Staphylococcus aureus in 72 cases (96.0%), among them, 47 cases were MSSA, 22 cases were MRSA, and 3 cases had positive reports of Staphylococcus aureus from other hospitals without drug-sensitive tests. The proportion of infected children living in rural areas and receiving surgical treatment was higher in the MRSA group than in the MSSA group (14 cases (63.6%) vs. 18 cases (38.3%) and 21 cases (95.5%) vs. 33 cases (70.2%), χ2=3.87, 4.23, both P<0.05). Sixty-five children had no complications while 42 children (39.3%) suffered from complications. Common complications consisted of 19 cases (17.8%) of sepsis, 17 cases (15.9%) of septic arthritis, and 12 cases (11.2%) of venous thrombosis. The group with complications showed higher mental changes, decreased appetite and (or) weakness, positive pathogenic cultures, and time from admission to surgery than the group without complications (18 cases (42.9%) vs. 9 cases (13.8%), 20 cases (47.6%) vs. 12 cases (18.5%), 34 cases (81.0%) vs. 41 cases (63.1%), 3.5 (2.0, 6.0) vs. 2.0 (1.0, 4.0) d,χ2=11.38, 10.35, 3.89, Z=2.21, all P<0.05). The poor prognosis group had more comorbidities, combined local complications, and positive aureus than the good prognosis group (10/15 vs. 34.9% (30/86), 7/15 vs. 17.4% (15/86), 14/15 vs. 61.6% (53/86), χ2=5.39, 6.40, 4.42, all P<0.05). Multifactorial Logistic regression analysis showed that acute phase C-reactive protein (CRP) was both an independent risk factor for complications (OR=1.01, 95%CI 1.01-1.02) and an independent risk factor for poor prognosis (OR=1.01, 95%CI 1.00-1.02). Conclusions: The first symptoms of acute hematogenous osteomyelitis are acute fever, limb pain, and fever with limb pain are most common. Staphylococcus aureus is the most common pathogenic organism. Those with loss of appetite and (or) weakness, mental changes, positive pathogenic cultures, and longer time between admission and surgery are prone to complications. Those with complications, combined local complications, and positive for Staphylococcus aureus had a poor prognosis. Elevated CRP is an independent risk factor not only for complications but for poor prognosis as well.

[A case of arrhythmia caused by barium carbonate poisoning].

Barium carbonate poisoning is mostly caused by mistaken ingestion in clinical cases, and self-administration of poisoning is rare. In November 2020, Tianjin Occupational Disease Prevention Hospital admitted a patient with severe hypokalemia complicated with arrhythmia after taking poison. It is very important to take timely and effective potassium supplementation, symptomatic and detoxification treatment in the course of treatment. At the same time, closely observing the changes of vital signs and taking quick and accurate rescue measures in the event of malignant arrhythmia are the keys to ensuring the success of rescue. In this paper, the clinical data of the case were retrospectively analyzed, providing reference for the diagnosis and treatment of similar clinical cases.

Single-Step Mechanism for Regioselective Nitration of 9,10-BN-Napthalene with Acetyl Nitrate in the Gas Phase.

The energetics of the regioselective mononitration of 9,10-BN-naphthalene with acetyl nitrate (H3C2NO4) were modeled with ab initio simulations in the gas phase and an acetonitrile solvent. The single-electron-transfer (SET) nitration mechanism leading to a σ-complex and a single-step nitration mechanism were modeled. The energy barrier for the single-step mechanism was lower than that for the SET mechanism in the gas phase. However, the two are much more energetically competitive in the solvent. The σ-complex was found to be unstable in the gas phase owing to the interaction with the counterion. Using the single-step mechanism, the carbon site 1 nearest boron had the lowest activation energy for nitration of 22.6 kcal/mol, while site 3 had the second lowest barrier of 24.6 kcal/mol. Details on the molecular structures at intermediate and transition states as well as charges in different configurations are discussed.

A detailed multi-omics analysis of GNB2 gene in human cancers.

The Guanine-nucleotide binding protein 2 (GNB2) encodes for ß2 subunit (Gß2) of the G-protein complex. Keeping in view the increased demand of reliable biomarkers in cancer, the current study was planned to extensively explored GNB2 expression variation and its roles in different cancers using online available databases and diverse methodology. In view of our results, the GNB2 was notably up-regulated relative to corresponding controls in twenty three cancer types. As well, the elevated expression of GNB2 was found to be associated with the reduced overall survival (OS) of the Liver Hepatocellular Carcinoma (LIHC) and Rectum Adenocarcinoma (READ) only out of all analyzed cancer types. This implies GNB2 plays vital role in the tumorigenesis of LIHC and READ. Several additional analysis also explored six critical pathways and few important correlations related to GNB2 expression and different other parameters such as promoter methylation, tumor purity, CD8+ T immune cells infiltration, and genetic alteration, and chemotherapeutic drugs. In conclusion, GNB2 gene has been identified in this study as a shared potential biomarker (diagnostic and prognostic) of LIHC and READ.

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.

BACKGROUND: In the primary analysis of the HER2CLIMB trial, tucatinib added to trastuzumab and capecitabine significantly improved overall survival (OS) and progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report efficacy and safety outcomes, including the final OS and safety outcomes from follow-up in HER2CLIMB. PATIENTS AND METHODS: HER2CLIMB is a randomized, double-blind, placebo-controlled trial in patients with locally advanced or metastatic HER2+ breast cancer, including patients with brain metastases. Patients were randomized 2 : 1 to receive tucatinib or placebo, in combination with trastuzumab and capecitabine. After the primary analysis (median follow-up of 14 months), the protocol was amended to allow for unblinding sites to treatment assignment and cross-over from the placebo combination to the tucatinib combination. Protocol prespecified descriptive analyses of OS, PFS (by investigator assessment), and safety were carried out at ∼2 years from the last patient randomized. RESULTS: Six hundred and twelve patients enrolled in the HER2CLIMB trial. At a median OS follow-up of 29.6 months, median duration of OS was 24.7 months for the tucatinib combination group versus 19.2 months for the placebo combination group [hazard ratio (HR) for death: 0.73, 95% confidence interval (CI): 0.59-0.90, P = 0.004] and OS at 2 years was 51% and 40%, respectively. HRs for OS across prespecified subgroups were consistent with the HR for the overall study population. Median duration of PFS was 7.6 months for the tucatinib combination group versus 4.9 months for the placebo combination group (HR for progression or death: 0.57, 95% CI: 0.47-0.70, P < 0.00001) and PFS at 1 year was 29% and 14%, respectively. The tucatinib combination was well tolerated with a low rate of discontinuation due to adverse events. CONCLUSIONS: With additional follow-up, the tucatinib combination provided a clinically meaningful survival benefit for patients with HER2+ metastatic breast cancer.

[Comparison on short-term safety outcomes between off-pump and on-pump coronary artery bypass grafting by experienced surgeons: a single center study with 31 075 cases].

Objective: To compare the short-term outcomes between off-pump and on-pump coronary artery bypass graft (CABG) by experienced surgeons with similar surgical team in a single large-volume cardiac surgery center. Methods: A total of 31 075 patients with multivessel coronary disease who underwent isolated off-pump or on-pump CABG between January 1, 2009 and December 31, 2019 by experienced surgeons in Fuwai hospital were enrolled in this retrospective study. Patients was divided into on-pump CABG group and on-pump CABG group on an intention-to treat basis. Short term safety endpoints, including 30 days mortality, composite endpoint of major morbidity or mortality, prolonged postoperative length of stay (PLOS), and prolonged ICU length of stay (PICULOS), and distal anastomosis were compared between the two groups. Mortality was evaluated on 30 days post operation, other endpoints were collected before discharge. After 1∶1 propensity-score matching of baseline characteristics for on-pump and off-pump CABG, postoperative endpoints were compared with use of McNemar's test and further adjusted with the use of a logistic regression model. Results: After propensity-score matching, 10 243 matched pairs of patients were included in the final analysis, there were 4 605(22.5%) females and mean age was (60.7±8.6) years. The standardized differences were less than 5% for all baseline variables in matched cohort. Univariate analysis indicated lower risk of 30 days mortality (0.2% vs. 0.7%, P<0.001), major morbidity or mortality (5.7% vs. 8.8%, P<0.001), PLOS (3.2% vs. 4.9%, P<0.001), PICULOS (9.4% vs. 12.2, P<0.001), and lower number of distal anastomosis ((3.3±0.8) vs. (3.6±0.8), P<0.001) in off-pump CABG group than in on-pump CABG group. After adjustment of cofounders, multivariate analysis showed that off-pump CABG was still associated with a lower risk of 30 days mortality (OR=0.29, 95%CI: 0.09-0.87, P=0.027), composite endpoint of major morbidity or mortality (OR=0.60, 95%CI: 0.53-0.68, P<0.001), PLOS (OR=0.64, 95%CI 0.54-0.75, P<0.001), PICULOS (OR=0.76, 95%CI: 0.69-0.84, P<0.001). Conclusions: Off-pump CABG is related with superior short-term safety outcomes than on-pump CABG by experienced surgeons in our center.

[The value of serum dehydroepiandrosterone sulfate in differential diagnosis of Cushing's syndrome].

Objective: To evaluate the changes and diagnostic value of serum dehydroepiandrosterone sulfate (DHEAS) in Cushing's syndrome (CS) with different etiologies. Methods: The study retrospectively recruited patients diagnosed as CS in Drum Tower Hospital affiliated to Nanjing University Medical School between January 2012 and June 2019, including 36 patients (8 males, 28 females, with an average age of 44 years) with Cushing disease (CD) and 64 patients (6 males, 58 females, with an average age of 39 years) with adrenal CS (ACS). Meanwhile, 97 patients diagnosed as nonfunctional adrenal adenoma (NFA) were also included as controls. Clinical characteristics, laboratory data, adrenocorticotropic hormone (ACTH), serum DHEAS level and sex-and age-adjusted DHEAS ratio of the three groups were collected. The sensitivity and specificity of DHEAS and its ratio in differential etiology diagnosis of CS were compared using receiver operating characteristic (ROC) curve analysis. Results: Compared to NFA group, ACS patients had lower DHEAS levels [0.39 (0.39, 0.63) µmol/L vs 2.96 (1.92, 4.60) µmol/L, P<0.01] and lower DHEAS ratio [0.58 (0.27, 0.98) vs 3.95 (3.08, 6.83), P<0.01]. DHEAS [6.49 (4.32, 11.63) µmol/L] and DHEAS ratio [9.17 (4.49, 15.41)] in CD patients were significantly higher compared to those in NFA and ACS patients (all P<0.01). There were 53 ACS patients (82.8%) with suppressed ACTH level (<2.2 pmol/L) and 11 patients (17.2%) with normal/high ACTH level (≥2.2 pmol/L). The level of 24 hour urine free cortisol in normal/high ACTH level group was lower than the suppressed ACTH group [(1 299±511) nmol/24 h vs (1 972±876) nmol/24 h, P=0.04]. No significant differences were found in the DHEAS and DHEAS ratio between the two groups. ROC analysis showed that the area under the curve of serum DHEAS and DHEAS ratio in diagnosing ACS from CD was 0.997 and 0.990, respectively. The optimal cut-off values for DHEAS and its ratio were 2.06 µmol/L and 2.10, respectively. The diagnostic sensitivity and specificity of DHEAS were 97.5% and 100%, and those of DHEAS ratio were 95.0% and 100%, respectively. Conclusion: There are significant differences in serum DHEAS level and DHEAS ratio between ACS and CD patients, which might be used as indicators for the identification of the two main CS etiologies, especially in the identification of ACS patients without plasma ACTH suppression from CD patients.

[Clinical features and outcomes of surgical versus conservative management in patients with subclinical Cushing's syndrome].

Objective: To examine the clinical characteristics and metabolic features of subclinical Cushing's syndrome (SCS), and determine the effects of surgical or conservative approaches on the hormone levels and metabolic comorbidities in patients with SCS, thereby providing the evidence for decision-making in SCS management. Methods: A total of 56 consecutive SCS patients were selected in Drum Tower Hospital Affiliated to Nanjing University Medical School between 2010 and 2018, with 41 patients undergoing surgical treatment and 15 patients receiving conservative therapy. Meanwhile, 56 and 68 cases of sex-and age-matched patients diagnosed as nonfunctional adrenal adenoma (NFA) and adrenal Cushing's syndrome (CS) were included respectively. Clinical characteristics of patients in different groups were compared. Hormone levels and metabolic comorbidities were also observed during follow-up. Results: There were 56 SCS patients, including 15 males and 41 females, with an age of (52.0±12.6) years. The circadian rhythms of adrenocorticotropic hormone (ACTH) and cortisol disappeared in CS and SCS groups. Compared to NFA group, patients with SCS were characterized by suppressed plasma ACTH level [2.40 (1.11, 4.33) pmol/L vs 4.23 (2.74, 6.26) pmol/L], elevated midnight cortisol level [(240±121) nmol/L vs (59±8) nmol/L] and increased cortisol level after 1 mg overnight dexamethasone suppression test [(241±130) nmol/L vs (34±12) nmol/L] (all P<0.01). The derangement of ACTH-cortisol axis was more obvious in CS patients compared to SCS patients. The prevalence of hypertension, glucose intolerance, dyslipidemia and osteopenia/osteoporosis were higher in SCS patients compared to NFA patients (75.0% vs 41.1%, 33.9% vs 12.5%, 62.5% vs 28.6%, 35.7% vs 8.9%, all P<0.05). The 24-hour urine free cortisol correlated positively with systolic blood pressure, glycated hemoglobin A1c (HbA1c) and fasting blood glucose in SCS patients (r=0.335, 0.562 and 0.463, respectively, all P<0.05). In the surgical group, body weight, body mass index (BMI) and blood pressure decreased significantly after surgery (all P<0.05). Glucose intolerance/diabetes mellitus improved in 6 of 9 patients, BMI of 4 of 11 overweight/obesity patients normalized, and hypertension in 54.5% of patients (12/22) showed improvement after surgery. However, no alterations of hormone levels and metabolic parameters were observed in conservatively-managed patients. Conclusions: Patients with SCS are characterized by mild autonomous cortisol secretion and increased risk of metabolic comorbidities. Compared with conservative management, hormone abnormalities were corrected and metabolic abnormalities were improved in some SCS patients after surgery.

Clinical significance of tumor mutation burden and DNA damage repair in advanced stage non-small cell lung cancer patients.

OBJECTIVE: This study aimed to investigate the impact of tumor mutational burden (TMB) and DNA damage repair (DDR) gene alteration on overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A DNA library of cancer cells from 67 NSCLC patients in stages III-IV was constructed for next-generation sequencing (NGS). Geneseeq422 probes were used for hybridization enrichment. The target-enriched library was sequenced on HiSeqNGS platforms, and we analyzed the relevant signaling pathways. Then, we correlated the OS of the patients with TMB and DDR mutations. RESULTS: Many significant alterations were found, including in the EGFR, p53, KRAS, RB1, ERBB2, NF1, DNMT3A, ALK, MYC, PIK3CA, ROS1, BRAF, ARID1A, PTEN, CDKN2A, and FGF19 genes. We also identified many mutations in the genes relevant to the DDR pathway. Interestingly, we found that the TMB of patients with DDR gene mutations was dramatically higher than that in the DDR wild-type (WT). Univariable analysis showed that DNMT3A, RB1, DDR pathway-related gene mutations, and TMB were critical factors for the effects on OS. Multivariable analysis confirmed that DNMT3A and mutations in the DDR pathway-related genes were important for predicting OS. CONCLUSIONS: Multiple mutations in the genes of the DDR pathway caused higher TMB levels, which resulted in longer OS. By contrast, OS was significantly longer in patients with non-DNMT3A mutations than in those with DNMT3A variants. DNMT3A alteration in NSCLC patients led to poor outcomes.

Associations between circulating bone-derived hormones lipocalin 2, osteocalcin, and glucose metabolism in acromegaly.

PURPOSE: The aim was to examine changes in the bone-derived hormone lipocalin 2 (LCN2) levels in patients with active acromegaly and to investigate the potential roles of LCN2 and osteocalcin in glucose metabolism. METHODS: We recruited 50 consecutive acromegalic patients. Of those, 39 patients with complete postoperative follow-up data were included. Thirty sex-, age-, and BMI-matched healthy individuals were recruited as normal controls. The pre- and postoperative serum LCN2 and osteocalcin levels were compared. The homeostasis model assessment insulin resistance (HOMA-IR) index and secretion [ß-cell function (HOMA-ß)] were calculated. RESULTS: Compared with controls, acromegalic subjects had lower LCN2 levels (34.15 ± 9.95 vs 57.50 ± 29.75 ng/mL, P < 0.01) and higher osteocalcin levels (55.45 ± 34.02 vs 19.46 ± 6.69 ng/mL, P < 0.01). Acromegalic patients also had elevated HOMA-IR levels, and the HOMA-ß and the area under the curve for insulin (AUC INS) levels were slightly but nonsignificantly increased. The serum levels of LCN2 significantly increased after surgery (37.03 ± 9.73 vs 45.15 ± 15.33 ng/mL, P < 0.05), and those of osteocalcin significantly decreased [43.51 (26.73-65.66) vs 24.79 (18.39-32.59) ng/mL, P < 0.01]. Total lean mass was the only positive predictor of LCN2, and elevated serum IGF-I was a positive predictor of osteocalcin. Low LCN2 and elevated serum osteocalcin levels were predictors of the AUC INS, and osteocalcin was a positive predictor of HOMA-ß. CONCLUSION: The bone-derived hormones, osteocalcin and LCN2 changed significantly in active acromegaly, were altered after treatment and served as predictors of ß-cell function in acromegaly. This study shows that the bone could be involved in regulating glucose metabolism in acromegaly.