Elevated Serum Research Articles

7945 Modelling the Factors Associated With Sexual and Mood Symptoms Within the First Year of Anabolic-Androgenic Steroid Cessation in Men

Abstract Disclosure: B. Grant: None. J. Kean: None. N.L. de Silva: None. O. Quinton: None. P. Bassett: None. J. McVeigh: None. A. Lingford-Hughes: None. S. Minhas: None. S. Bhasin: None. W.S. Dhillo: None. C.N. Jayasena: None. Context: Anabolic-androgenic steroids (AAS) are misused by millions of men worldwide to boost muscle size and physical performance. Recent studies have quantified the recovery of cardiovascular markers and testicular function following AAS cessation. Qualitative studies demonstrate that low mood, anxiety, suicidal ideation, and sexual dysfunction are also common following AAS cessation. However, no previous study has focused on quantifying symptoms within the first year of AAS cessation, nor investigated independently associated factors for these symptoms. Methods: Cross-sectional, observational study of 165 men in 3 groups; non-AAS (n=43); current-AAS (n=76); past-AAS ≤1 year (n=46). All participants completed questions on substance misuse, Beck Depression Inventory-II (BDI-II), International Index Erectile Function-15 (IIEF-15), General Anxiety Disorder (GAD-7), Quality-of-life (SF-36), and underwent fasting, morning blood sampling with urine toxicology. Results: As expected, current-AAS had lower gonadotropins and elevated serum total testosterone compared with past-AAS and non-AAS. Sexual function measured using IIEF-15 was impaired in men stopping AAS <1year (past-AAS) compared with current AAS users: (1) total: 69.0 [95% CI 64.0, 71.0], current-AAS; 61.0 [95% CI 56.0, 66.0], past-AAS; p=0.077; (2) erectile function: 30.0 [95% CI 29.0, 30.0], current-AAS; 28 [95% CI 21.0, 29.0], past-AAS; p=0.015; (3) sexual desire: 9.0 [95% CI 8.0, 10.0], current-AAS; 6.0 [95% CI 5.0, 8.0], past-AAS; p<0.0001; (4) overall satisfaction: 10.0 [95% CI 8.0, 10.0], current-AAS; 7.0 [95% CI 7.0, 8.0], past-AAS; p=0.002. Multivariable analysis suggested that psychiatric comorbidity (coefficient -6.5 [95% CI -13.0, -1.3] p=0.03) and AAS cessation (coefficient -10.8 [95% CI -5.6, -17.2]; p<0.001) were associated with lower total IIEF-15 scores.Depression scoring was worse in the past-AAS group compared with non-AAS: BDI-II 4.0 [95% CI 2.0, 7.0], non-AAS; 7.0 [95% CI 4.0, 16.0], past-AAS; p=0.0448. Multivariable analysis suggested that psychiatric comorbidity (OR 2.39 [95% CI 1.60, 3.57]; p<0.001) and lower serum total testosterone (OR 0.85 [95% CI 0.88, 0.94]; p=0.002) were associated with higher BDI-II scores. Energy and fatigue measured using SF-36 was lower in the past-AAS group compared with non-AAS: 70 [95% CI 65, 75], non-AAS; 60 [95% CI 50, 65], past-AAS; p=0.0498. No significant differences in anxiety scoring were detected. Discussion: We report the first, detailed quantification and modelling of symptoms in men currently misusing and stopped AAS within the previous year. These data reveal potentially treatable factors to improve symptoms of AAS cessation if proven within interventional studies. Presentation: 6/2/2024

6545 Weekly Somapacitan Reduces Serum C-reactive Protein Levels in Adult Patients with Growth Hormone Deficiency

Abstract Disclosure: Y. Seki: None. S. Morimoto: None. M. Ikemoto: None. N. Takano: None. K. Yamashita: None. K. Bokuda: None. D. Watanabe: None. A. Ichihara: None. Background: Adult growth hormone deficiency (GHD) is known to be associated with increased inflammation. Our previous research revealed a significant association between GHD and elevated serum C-reactive protein (CRP) levels. Limited studies have demonstrated a significant association between GH replacement therapies and CRP levels; only two reports showed a significant reduction in serum CRP levels with daily somatropin. This study aimed to investigate the effects of weekly somapacitan on serum CRP levels in adult patients with GHD. Methods: We prospectively observed serum CRP levels as the primary outcome before and 6 months after somapacitan treatment in adult patients with GHD with no history of GH supplementation therapy within the past 6 months. Secondary outcomes included anthropometric data, IGF-1 levels, and kidney and liver functions. The somapacitan dose was titrated based on IGF-1 levels during the 6-month treatment period. Results: Eight adult patients (mean age 50±17, male 4 [50%]) with GHD received weekly somapacitan treatment. Of the patients, 2 (25%) had ACTH deficiency, 2 (25%) had TSH deficiency, and 2 (25%) had gonadotropin deficiency. Two patients (25%) were on glucocorticoid replacement. The somapacitan dose at 6 months was 1.9 (1.5-2.6) mg/week. Weekly somapacitan significantly increased serum IGF-1 level (48 [29-122] to 125 [63-205] ng/mL, P = 0.001) and IGF-1 SD score (-3.3 [-5.3-0.9] to -0.7 [-3.0-0.8], P = 0.008) and significantly decreased serum CRP level (0.243 [0.056-0.464] to 0.093 [0.036-0.290] ng/mL, P = 0.008). However, it did not affect body weight (80.6±11.6 to 79.8±10.5 kg, P = 0.67) or serum creatinine (0.74±0.13 to 0.68±0.21 mg/dL, P = 0.35) and alanine aminotransferase (60 [20-99] to 48 [21-85] U/L, P = 0.23) levels. Changes in CRP levels were significantly correlated with changes in IGF-1 levels (rs = -0.83, P = 0.010) and IGF-1 SD scores (rs = -0.79, P = 0.021). Conclusion: GH supplementation therapy with weekly somapacitan reduced serum CRP levels in adult patients with GHD without affecting body composition or kidney and liver functions. Presentation: 6/3/2024

6774 Recurrent Hypoglycemia In Malignant Insulinoma With Multiple Liver Metastases Successfully Managed With Octreotide

Abstract Disclosure: K. Kim: None. S. Mascarell: None. Introduction: Insulinoma is a rare functional pancreatic neuroendocrine tumor (pNET) with the incidence of 1-4/million person-years. Malignant insulinomas with locoregional invasion or metastases consist 10% among insulinomas. While the treatment of a single insulinoma is surgical resection, treatment of malignant insulinoma requires a comprehensive approach. Due to the low prevalence of the disease, data on therapeutic modalities of malignant insulinomas are limited. We hereby present a case of malignant insulinoma in which recurrent hypoglycemia was successfully managed with octreotide. Case: A 36 year old female diagnosed with grade III well differentiated pNET with multiple metastases to the liver and abdominal lymph nodes 1 year ago was admitted for recurrent hypoglycemic episodes. She reported progressively worsening hypoglycemia for the past 1 month. She was eating every 2 hours including her sleeping hours to prevent hypoglycemia. Due to recurrent hypoglycemia she required hospitalization with IV dextrose. After 13 hours of fasting in the ICU, hypoglycemia due to insulin hypersecretion was confirmed with blood glucose 51 mg/dL and elevated serum insulin 51.11 uIU/mL (1.9-23uIU/mL). She underwent the short octreotide test which showed suppressed insulin (5.25 uIU/mL) 6 hours after receiving 100 mcg of octreotide. She was started on octreotide 50 mcg every 12 hours and monitored for further hypoglycemic episodes. She tolerated octreotide without any side effects including hypoglycemia. She was discharged home with a continuous glucose monitor (CGM) and transitioned to intramuscular lanreotide 20mg injections every 4 weeks as an outpatient. No further hypoglycemic episodes occurred. Discussion: Few cases report treatment of hypoglycemia in malignant insulinoma with octreotide. Octreotide has the dual effect of suppressing insulin secretion and tumor growth on insulinomas that express SSTR2 receptors. However, because somatostatin agonists also inhibit the secretion of glucagon, in insulinomas without SSTR2 expression, octreotide can aggravate hypoglycemia. This was especially a concern for our patient with a large tumor burden. Thus the short octreotide test was conducted. We suggest that the octreotide test of 100 mcg SQ octreotide injection followed by hourly measurements of glucose and insulin levels is a useful and convenient test to predict efficacy while monitoring for octreotide induced hypoglycemia. Finally the use of CGM in the outpatient setting enabled successful transition to octreotide LAR which improved the patient’s quality of life greatly by enabling once a month injections. Presentation: 6/3/2024

7426 Tamoxifen-Induced Ovarian Hyperstimulation in a Pre-Menopausal Patient with Breast Cancer History: Spontaneous Resolution with Conservative Management

Abstract Disclosure: S. Gondi: None. M. Contento: None. A. Leiter: None. Background: Tamoxifen is a selective estrogen receptor modulator (SERM) that competitively binds to estrogen receptors (ER) on tumors and inhibits the effect of estrogen, which is used in the treatment and prevention of ER-positive breast cancer. Tamoxifen therapy has been reported to increase serum estrogens and cause ovarian hyperstimulation in premenopausal women, but knowledge on how to manage these conditions is limited. Clinical Case: A 36-year-old pre-menopausal female with history of malignant neoplasm of the right breast (ER positive) who completed neoadjuvant chemotherapy, lumpectomy, and radiation, on tamoxifen for seven years presented with new-onset oligomenorrhea. Laboratory testing done by the patient’s gynecologist revealed total estrogen 2,723 pg/mL (reference range [RR] 34-501), testosterone 132 ng/dL (RR 8-60), anti-Mullerian hormone 12.7 ng/mL (RR for age 0.66-8.75), ovulation-phase follicle stimulating hormone 11.5 mIU/mL (RR 4.7-21.5) and luteinizing hormone (LH) 63.3 mIU/mL (RR 14-95.6). Further workup revealed that ovarian tumor markers alpha-fetoprotein and serum human chorionic gonadotropin and other labs including dehydroepiandrosterone sulfate, progesterone 17-OH, lactate dehydrogenase, prolactin, and thyroid stimulating hormone were normal. Transvaginal ultrasound (TVUS) showed a new 2.8 x 1.9 x 2.3 cm complex left ovarian cyst, which, along with the elevated estrogen level, was concerning for ovarian hyperstimulation. Treatment with LH-releasing hormone (LHRH) agonists, surgical consultation, and discontinuation of tamoxifen were offered as potential management strategies, but the patient opted for observation and continued tamoxifen. Two months later, estradiol was 989 pg/mL (RR 85-498), and then three months later decreased to 152 pg/mL with repeat TVUS showing resolution of the left ovarian cyst. The patient’s oligomenorrhea resolved with resumption of regular menstrual cycles. Conclusion: While it is well-known that tamoxifen causes elevated serum estrogen levels and can lead to ovarian hyperstimulation, there is limited research on the management of these side effects. Treatment strategies in past cases have included oophorectomy or medical management with LHRH agonists or gonadotropin-RH agonists. However, this case demonstrates that a tamoxifen-induced ovarian cyst and high estrogen levels can resolve on its own with continued tamoxifen treatment. Conservative management with monitoring via imaging and repeat estrogen levels may be sufficient in management of pre-menopausal women with tamoxifen-induced ovarian hyperstimulation. Presentation: 6/1/2024

Chronic kidney disease associated with extremely premature birth and extremely low birth weight may progress through the burden of growth.

Chronic kidney disease associated with low birth weight and/or premature birth (L/P-CKD) in infants may result from a decreased number of nephrons at birth. These infants may develop acute kidney injury due to exposure to nephrotoxic substances or other events during nephrogenesis in early infancy. Nonetheless, L/P-CKD progression remains unclear. We present three cases of L/P-CKD diagnosed after neonatal intensive care unit (NICU) discharge. Three patients were born extremely prematurely (gestational age, 24-26weeks) with extremely low birth weight (606-906g). They were admitted to the NICU (117-311days) anad received several nephrotoxic medications during the early postnatal period. They showed elevated serum creatinine levels at 4weeks after birth, which decreased to normal levels at NICU discharge. Proteinuria was first detected during adolescence (10-15years) on annual school urine screening, with a remarkable increase in their height (18 - 50.8cm), without known episodes of urinary tract infection, dehydration, lifestyle-related issues, such as excessive salt/protein intake, and extreme lack of exercise that might have caused kidney damage. Their kidneys were smaller than normal on renal ultrasonography. Open renal biopsy findings indicated glomerulomegaly and perihilar glomerulosclerosis in two of the three patients, suggesting glomerular hypertension. The remarkable differences between the body height before CKD and the timing of diagnosis of CKD could contribute to the progress of CKD. Long-term follow-up of low birth weight and extremely premature infants, from NICU discharge until adulthood, should be established.

7063 Serum Alkaline Phosphatase Level as a Marker for Progressive Central Precocious Puberty

Abstract Disclosure: V.M. Figueredo: None. T. Seeherunvong: None. Background: Precocious puberty is typically associated with a speed up in growth, risk of premature growth plate closure and reduced adult height. Serum alkaline phosphatase (ALP) is a biochemical indicator of bone turnover and studies have shown greater serum ALP levels in pubertal individuals compared to prepubertal controls. We examined serum ALP levels among children with various form of early puberty. We investigated whether serum ALP levels were significantly different between children with premature thelarche or premature adrenarche compared to those with central precocious puberty (CPP). Methods: We conducted a retrospective chart review of patients with early pubertal development attending a pediatric endocrinology clinic between 2017 and 2023. Information on height, weight, serum ALP levels and bone age was obtained. Patients were considered to have CPP based on the results on a GnRH test. Patients with diagnosis of premature adrenarche or premature thelarche were included as controls. This study was approved by Institutional Review Board (IRB). Analysis of data was performed using IBM SPSS Statistics version 29.0.1.0 (171). Results: Among 72 patients included in the study, 22 patients had progressive CPP whereas 50 patients had premature adrenarche or premature thelarche. The prevalence of abnormally elevated serum ALP levels was greater among patients with CPP (22.7%) than among patients with premature adrenarche or premature thelarche (6%). Using logistic binomial regression analysis, serum ALP levels were significantly elevated (p=0.042) in subjects with progressive CPP compared to patients with premature adrenarche or premature thelarche. Both groups had similar BMI values. BMI z-scores and advanced bone age were positively correlated. BMI (p=0.08) and advanced bone age were not significantly different (p=0.12) in the group with CPP compared with the group comprising patients with either premature adrenarche or premature thelarche. Conclusion: These findings suggest that serum ALP levels are helpful as a tool to help distinguish CPP from premature adrenarche or premature thelarche in the evaluation of patients with initial early pubertal development. Presentation: 6/1/2024

Association between serum cotinine and total testosterone in adult males based on NHANES 2011–2016

The relationship between smoking and testosterone levels in adult males remains a topic of ongoing debate. Serum cotinine is considered a reliable marker of both smoking intensity and exposure to tobacco smoke. Therefore, we aim to examine the association between serum cotinine levels and total testosterone concentrations in adult males using data from the U.S. National Health and Nutrition Examination Survey (NHANES) database. Our study assessed the relationship between serum cotinine and total testosterone using weighted linear regression models and subgroup analysis. A fully adjusted model with smooth curve fitting was employed to investigate the potential nonlinear association between serum cotinine and total testosterone. Threshold effects were analyzed to identify the inflection point between serum cotinine and total testosterone. Indeed, a total of 7797 participants were included in our study. After adjusting for potential confounding variables, the findings indicate a positive association between serum cotinine levels and total testosterone levels (β: 0.05, 95%CI: 0.02, 0.09). Furthermore, applying smoothed curve fitting analysis and threshold effects, an inflection point was detected at a serum cotinine level of 487 ng/ml. Above this threshold, total testosterone levels declined with increasing serum cotinine levels. In conclusion, the findings of our study suggest a positive association between elevated serum cotinine levels and total testosterone levels in adult men. However, it is essential to note that this association may be reversed at excessively high serum cotinine concentrations.

Association between serum globulins and diabetes mellitus in American latent tuberculosis infection patients: A cross-sectional study.

Diabetes mellitus (DM) is predisposing to the development of latent tuberculosis infection (LTBI). An understanding of the underlying factors of LTBI-DM is important for tuberculosis prevention and control. This study aims to evaluate the association between LTBI and DM among the noninstitutionalized civilian population in the United States, focusing on the impact of serum globulins. We performed a cross-sectional study design using public data from 2011 to 2012 National Health and Nutrition Examination Survey, focusing on participants diagnosed with LTBI who were aged 20 and above. Weighted Wilcoxon rank-sum and weighted chi-square tests were used to compare group differences. A multivariable logistic regression model was constructed to assess the association between serum globulin and DM, with subgroup analyses and evaluations of nonlinear relationships. Receiver operating characteristic curves were used to assess the predictive power of the models. A total of 694 participants (512 DM and 182 nonDM) were included in our study and the incidence of DM was 22%. Higher serum globulin levels were significantly associated with an increased risk of DM, with a 21% increase in risk for each unit increase in serum globulin (odds ratio = 1.21, 95% confidence interval [1.03, 1.43], P < .001). The relationship between serum globulin and DM was linear, and higher serum globulin levels were associated with a higher risk of DM, particularly in males (P = .043) and obese individuals (P = .019). The area under the curve for serum globulin predicting DM was 0.795, with an optimal cutoff value of 2.9. Elevated serum globulin levels are significantly associated with an increased risk of DM among individuals with LTBI, highlighting the potential role of serum globulin as a predictive biomarker for DM in this population. However, the specific mechanism between globulin and LTBI-DM needs to be further investigated.

Characterisation of older patients that require, but do not undergo, emergency laparotomy: a multicentre cohort study

BackgroundOlder adults (≥65 yr) account for the majority of emergency laparotomies in the UK and are well characterised with reported outcomes. In contrast, there is limited knowledge on those patients that require emergency laparotomy but do not undergo surgery (NoLaps). MethodsA multicentre cohort study (n=64 UK surgical centres) recruited 750 consecutive NoLap patients (February 15th - November 15th 2021, inclusive of a 90-day follow up period). Each patient was admitted to hospital with a surgical condition treatable by an emergency laparotomy (defined by The National Emergency Laparotomy Audit (NELA) criteria), but a decision was made not to undergo surgery (NoLap). ResultsNoLap patients were predominately female (452 patients, 60%), of advanced age (median age 83.0 yr, interquartile range 77.0–88.8), frail (523 patients, 70%), and had severe comorbidity (750 patients, 100%); 99% underwent CT scanning. The commonest diagnoses were perforation (26%), small bowel obstruction (17%), and ischaemic bowel (13%). The 90-day mortality was 79% and influencing factors were >80 yr, underweight BMI, elevated serum lactate or creatinine concentration. The majority of patients died in hospital (77%), with those with ischaemic bowel dying early. For the 21% of NoLap patients that survived to 90 days, 77% returned home with increased care requirements. ConclusionsThis study reports that the NoLap patient population present significant medical challenges because of their extreme levels of comorbidity, frailty, and physiology. Despite these complexities a fifth remained alive at 90 days. Further work is underway to explore this high-risk decision-making process. Clinical trial registrationISRCTN14556210.

B-314 Utility of he4 in differential diagnosis of pleural effusions

Abstract Background The usefulness of tumor markers in the differential diagnosis of cancer in patients with pleural effusions (PE) remains controversial. Few studies have reported the measurement of human epididymal protein 4 (HE4) in pleural fluid. HE4 is a tumor marker associated with different types of cancer. An elevated serum concentration has been observed in ovarian and lung cancers. Other benign pathologies can increase HE4 levels, which can be detect with different laboratory tests identified with adenosine deaminase (ADA), C-reactive protein (CRP), % polynuclear cell count (%PMN) and glomerular filtration rate (GFR) can be used in order to detect possible false positives. The objective of this study was to assess the diagnostic usefulness of HE4 in malignant pleural effusions by comparing HE4 concentrations between benign and malignant samples, while considering the causes of HE4 false positives. Methods HE4, ADA, differential leukocyte count, CRP and GFR concentrations were determined in 238 pleural effusion samples. Diagnostic efficacy analysis using receiver operating curves (ROC) identified the ability of HE4 to detect malignancy, searching for cut-off points with 100% specificity. Results HE4 concentrations showed significant differences (P&amp;lt;0.01) between malignant (median 1065pmol/L) and benign (median 699pmol/L) pleural effusions. Significant differences (P&amp;lt;0.01) were found in HE4 concentrations for gynecological and lung cancer origin (median 7397 pmol/L and 5150 pmol/L respectively) and other malignant pleural effusions (median 1065 pmol/L). Patients with benign diseases with renal failure showed a higher HE4 concentration (median 964pmol/L) than in patients without these pathologies (median 696pmol/L) identified with GFR&amp;lt;30 mL/min. No differences were demonstrated in HE4 concentration levels using ADA, differential leukocyte count or CRP, so only glomerular filtration rate was considered cause of false positives. A sensitivity of 23% was obtained for HE4, with a cut-off point of 3050pmol/L and a specificity of 100% for the whole group. In the potential false positive group, the sensitivity of HE4 was 28% with a cutoff point of 3050 pmol/L with a specificity of 100%. In the group without potential false positives, we obtained a sensitivity of 30% with a specificity of 100% for a cutoff point of 1992pmol/L. When we used a specific cut-off point for each group, we obtained a sensitivity of 38% with a specificity of 100%. Conclusions HE4 levels are higher in malignant pleural effusions compared to other pathologies. HE4 levels allow the identification of malignant pleural effusions with moderate sensitivity and maximum specificity. HE4 levels can differentiate between tumors of gynecological or lung origin and others. Glomerular filtration rate (GFR&amp;lt;30 mL/min) was considered the main cause of false positives. If we identify possible false positives, we can use specific cut-offs and improve sensitivity up to 38% with maximum specificity compared to using a single cut-off for all effusions.

Serum TNFα and IL-17A levels may predict increased depressive symptoms: findings from the Shika Study cohort project in Japan

BackgroundLow-grade systemic inflammation may be a key player in the immune activation that has been reported for mental health deterioration. We hypothesised that elevated serum levels of inflammatory cytokines increase neuroinflammation and exacerbate depressive symptoms.MethodsThe participants were part of a cohort study for whom data was available for both 2015 and 2019. In 2015, blood samples were collected from 232 participants. Their depressive symptoms were assessed both 2015 and 2019 using the Centre for Epidemiologic Studies Depression Scale (CES-D) (n = 33). The multiplex immunoassay system (Luminex® 200) was used to measure the serum concentrations of IL-6, IL-10, IL-12, IL-17A and TNFα. Data were analysed using linear models with the level of significance considered to be p < 0.05.ResultsAfter controlling for age, BMI, smoking and alcohol consumption, in 2015 the serum concentrations of IL-17A and TNFα in 2015 were significantly positively associated with the CES-D scores of women (standardised β (B) = .027, p < 0.01 and B = 0.26, p < 0.01, respectively). The serum concentrations of IL-17A and TNFα of men were significantly positively associated with the CES-D scores of 2019 (B = 0.62, p = 0.02 and B = 0.59, p = 0.02, respectively).ConclusionsIn this cross-sectional study, we found a significant positive correlation between the depressive symptoms and serum TNFα and IL-17A levels of women. In addition, our longitudinal findings suggest the possibility that TNFα and IL-17A could elevate the depressive symptoms of men.

Do Intra-articular Metal Ion Levels Predict Adverse Local Tissue Reaction in Revision Total Hip Arthroplasty for Mechanically Assisted Crevice Corrosion?

BackgroundMechanically assisted crevice corrosion is a complication that may occur in vivo at modular metal interfaces following metal-on-polyethylene total hip arthroplasty (THA). Metal ions released in vivo may be associated with adverse local tissue reactions (ALTRs). While there is no definitive value, high serum ion levels are implicated as contributors to ALTR, and various screening levels have been recommended. The purpose of this investigation was to evaluate the relationship between synovial fluid (SF) cobalt and chromium ion levels and the risk of developing ALTR. MethodsThis was a retrospective cohort study of 552 patients who underwent 621 metal-on-polyethylene primary THAs. A total of 69 patients underwent revision THA due to symptomatic primary failure with elevated serum metal ions levels. There were 28 who had preoperative serum and intraoperative SF chromium and cobalt samples. Patient demographics, surgical, and laboratory data were collected. Descriptive statistics, Mann-Whitney U, analysis of variance tests, and linear regression analyses were performed. ResultsThere were 40.6% of revisions that had preoperative serum and intraoperative SF samples. The mean time to revision was 5.7 (range, 3.8 to 7.6) years. Mean SF cobalt and chromium levels were 870.9mcg/L (range, 1.1 to 8,300.0) and 573.5mcg/L (range, 1.3 to 10,000.0). Mean serum and SF cobalt-chromium ratios were 4.0 (range, 0.9 to 7.1) and 6.4 (range, 0 to 15.1), respectively. Elevated serum cobalt levels were predictive of ALTR (P = 0.002), SF levels were not. Analysis of preoperative serum to SF cobalt-chromium ratios showed poor correlation (R2 = 0.05). ConclusionsThere was no correlation between SF ion levels and ALTR. Also, serum and intra-articular ion levels did not correlate. The SF levels did not provide additional value over serum levels for diagnosis or prognosis of mechanically assisted crevice corrosion. Further studies are needed to better understand the relationship between serum and SF ion levels and its relationship to ALTR.

Perioperative chemotherapy and nivolumab in non-small-cell lung cancer (NADIM): 5-year clinical outcomes from a multicentre, single-arm, phase 2 trial

Perioperative immunotherapy improves short-term outcomes in resectable non-small-cell lung cancer (NSCLC). We now report 5-year survival from the NADIM trial to assess its long-term benefit. NADIM was a multicentre, single-arm, phase 2 trial conducted across 18 hospitals in Spain. Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had histologically or cytologically confirmed, treatment-naive, resectable stage IIIA NSCLC (American Joint Committee on Cancer, 7th edition criteria). The neoadjuvant treatment consisted of three cycles of intravenous paclitaxel (200 mg/m2) and carboplatin (area under the curve 6 mg/mL per min) with nivolumab (360 mg). After surgery, 1 year of adjuvant treatment with intravenous nivolumab monotherapy was administered (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was 24-month progression-free survival, with 5-year progression-free survival and overall survival as secondary endpoints, assessed in the intention-to-treat population (ie, all patients who received neoadjuvant treatment). Toxicity profile was also assessed as a secondary endpoint. This trial is registered at ClinicalTrials.gov (NCT03081689) and is complete; this is the final report of the trial. Between April 26, 2017, and Aug 25, 2018, 51 patients were assessed for eligibility, of whom 46 comprised the intention-to-treat population (34 [74%] male and 12 [26%] female, median age 63 years [IQR 58-70]). Follow-up was concluded at 60 months (data cutoff July 11, 2023; median follow-up 60·0 months [IQR 60·0-60·0]). 5-year progression-free survival in the intention-to-treat population was 65·0% (95% CI 49·4-76·9), and overall survival was 69·3% (53·7-80·6). Disease progression occurred in 11 (24%) patients; 14 (30%) patients died, including nine (20%) from disease relapse and five (11%) from non-tumour-related causes. Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 14 (30%) of 46 patients during neoadjuvant treatment and in seven (19%) of 37 during adjuvant treatment. The most common grade 3 or worse TRAEs were increased lipase and febrile neutropenia (three [7%] each) during neoadjuvant treatment, and elevated serum lipase (four [7%]) and elevated serum amylase (three [8%]) during adjuvant treatment. Serious TRAEs included elevated serum lipase and neutropenia (one [2%] each) during neoadjuvant treatment, and elevated serum lipase (one [3%]) during adjuvant treatment. No treatment-related surgery delays, deaths, or unexpected long-term toxicities were reported. Perioperative chemoimmunotherapy showed a promising long-term benefit with no concerning safety data, reinforcing its use in resectable stage IIIA NSCLC. Bristol-Myers Squibb, Spanish Ministry of Science, Instituto de Salud Carlos III, European Union.

Anaphylaxis induced by indocyanine green during abdominal surgery: A case report

Since 2011, indocyanine green (ICG) has been increasingly used in surgery as a diagnostic tool. Although allergic reactions to this fluorescent dye are considered rare, they can result in anaphylactic shock. We report the case of a 33-year-old woman who developed anaphylaxis immediately after ICG administration during laparoscopic-assisted high anterior resection. The patient was treated with intravenous adrenaline, and the surgery continued. Elevated plasma histamine and serum tryptase levels immediately after ICG administration and intradermal testing identified ICG as the causative agent. The frequency of ICG use is increasing, and anesthesiologists should recognize ICG as a prevalent perioperative allergen.

Periodontitis adversely affects lipoprotein subfractions – results from the cohort study SHIP-TREND: Periodontitis adversely affects lipoprotein subfractions

AimWe aimed to investigate the medium-term associations of periodontitis and the number of missing teeth with serum lipoproteins and their plasma subfractions using follow-up data from the population-based Study of Health in Pomerania (SHIP-TREND). MethodsA total of 2,058 participants with 7-year follow-up data underwent periodontal examinations, serum lipid panel tests, and proton nuclear magnetic resonance (1H-NMR) spectroscopy of plasma lipoproteins and their subfractions. Generalized models with gamma distribution and loglink were used to analyze associations between periodontal variables and lipoproteins and their subfractions, adjusting for confounders using propensity score weighting. ResultsPeriodontal variables were consistently associated with elevated follow-up serum levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. When plasma lipoprotein subfractions were evaluated, periodontal variables were associated with elevated levels of triglycerides and cholesterol-enriched apolipoprotein B-containing lipoprotein particles, particularly small dense low-density lipoprotein, very-low-density lipoprotein and intermediate density lipoprotein. In addition, altered high-density lipoprotein particle composition was observed, suggesting potential functional changes. ConclusionThis study provides evidence for causal effects of periodontitis on conventional serum lipids and plasma lipoprotein subfractions. As the underlying biological mechanisms are not fully understood, further research is needed.

Downregulation of type I interferon signalling pathway by urate in primary human PBMCs.

Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-β were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-β did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.

Randomized Phase II Trial of Amrubicin Plus Irinotecan Versus Cisplatin Plus Irinotecan in Chemo-naïve Patients With Extensive-Disease Small-Cell Lung Cancer: Results of the Japan Multinational Trial Organization (JMTO) LC 08-01

BackgroundWe conducted a randomize phase II study to evaluate the efficacy and safety of topoisomerase II inhibitor amrubicin plus topoisomerase I inhibitor irinotecan (AI) compared with cisplatin plus irinotecan (PI) as first-line therapy in patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and MethodsChemo-naïve patients with pathologically proven ED-SCLC (including limited disease (LD) SCLC with malignant effusion) were enrolled. Patients were randomized 1:1 to receive either AI (amrubicin 90mg/m2 on day 1 and irinotecan 50mg/m2 on days 1 and 8 of a 21-day cycle) or PI (cisplatin 60mg/m2 on day 1 and irinotecan 60mg/m2 on days 1, 8 and 15 of a 28-day cycle). The primary endpoint was overall survival proportion at 1 year. ResultsA total of 100 patients were randomly assigned to AI (n = 50) or to PI (n = 50). The 1-year overall survival proportions were 68.0% (95% confidence interval (CI): 56.2-82.2%) for AI and 59.2% (46.9-74.7%) for PI (1-sided P = .18). Median survival time was 14.8 months for AI and 13.5 months for PI with a hazard ratio (HR) of 0.618 (0.398-0.961, stratified log-rank test P = .031). Median progression-free survival time was 4.8 months for AI and 5.4 months for PI (stratified log-rank test, P = .54). Objective response rate was 70.0% (55.4-82.1%) for AI and 55.1% (40.2-69.3%) for PI (Fisher exact test, P = .15). There was no significant difference in hematological toxicity, whereas rates of vomiting, loss of appetite, diarrhea, and elevated serum creatinine are more frequent in PI. Interstitial lung disease (Grade 2 or 3) developed in 5 patients in AI and in 1 patient in PI. There was no treatment-related death. ConclusionAlthough the study did not meet its primary endpoint, AI showed promising efficacy and good tolerability in chemo-naïve patients with ED-SCLC.

Associations Between CYP3A5 (c.6986A>G) Gene Polymorphism and Kidney Impairment in Hypertensive Adults Without Cystatin C Elevation.

This study aimed to explore the potential role of CYP3A5 (c. 6986A>G) gene polymorphism in predicting kidney function impairment in patients with hypertension who did not have elevated serum cystatin C. We recruited a group of patients with hypertension who did not have elevated cystatin C and analyzed the CYP3A5 (c. 6986A>G) gene polymorphism. Chi-square tests were used to compare the clinical characteristics and genotypic distribution between the two groups. Logistic regression analysis was used to explore the association between CYP3A5 (c.6986A>G) gene polymorphism and renal function impairment in hypertension with non-elevated cystatin. In patients with hypertension who participated in the study, there was a significant association between CYP3A5 (c. 6986A>G) gene polymorphism and kidney function impairment (p < 0.05). Patients with the CYP3A5 (c. 6986A>G) mutation display a greater risk of kidney function impairment. CYP3A5 (c. 6986A>G) gene AA homozygote polymorphism significantly increases risk of kidney function impairment in patients with hypertension with normal cystatin C. However, further studies are needed to validate this association and to further understand the mechanism of CYP3A5 (c. 6986A>G) gene polymorphism in kidney function impairment in patients with hypertension.

Elevated Serum Growth Differentiation Factor 15 Levels as a Potential Biomarker of the Efficacy of Imeglimin in Individuals With Type 2 Diabetes Mellitus: An Exploratory Study.

The aim of the present study was to conduct a prospective observational study to explore the effects of imeglimin on systemic energy metabolism/body composition and to identify potential mitochondria-related biomarkers of the efficacy of the drug in clinical settings. In this prospective observational study, 16 participants with type 2 diabetes mellitus in the diabetes clinic of Kyoto University Hospital were enrolled. Individuals were started on imeglimin as monotherapy or add-on therapy. After 3 months under imeglimin treatment, there was no significant change in basal metabolism or body composition. However, serum levels of growth differentiation factor 15 (GDF15) were higher while those of serum fibroblast growth factor 21 and urine 8-hydroxy-2'-deoxyguanosine were not changed. Additional in vitro examination revealed that imeglimin induces GDF15 protein release from human hepatocytes. Three-month imeglimin treatment increased serum GDF15 levels in clinical type 2 diabetes mellitus patients along with little change in basal metabolism or body composition, suggesting GDF15 as a potential marker for the efficacy of imeglimin.

Elevated serum GDF15 level as an early indicator of proximal tubular cell injury in acute kidney injury

Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK−2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl2. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl2-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl2-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.