Steroid lifting method during endoscopic submucosal dissection: A novel strategy for stricture prevention.

A 73-year-old male patient was referred to us with a long Barrett's esophagus (BE). He had a history of pulmonary embolism under anticoagulant therapy. Esophagogastroduodenoscopy showed a C8M9 BE with no macroscopic lesions. Random biopsies from the BE revealed multifocal high-grade dysplasia. The case was discussed in a multidisciplinary team conference and the decision for full resection of BE with endoscopic submucosal dissection (ESD) was made. Considering the large ESD resection and the high risk of stricture, we developed a novel preventive technique: the "steroid lifting method" for submucosal injection during ESD. Complete circumferential ESD with en bloc resection was performed using the "steroid lifting method", without adverse events. Oral liquids were initiated on day 1 and the patient was discharged on day 4. Oral prednisolone (30 mg per day) was started and tapered for a total of 6 weeks. The pathological examination confirmed multifocal high-grade dysplasia, with radical and curative resection. The patient had neither stricture, dysphagia nor recurrence of Barrett's mucosa at the 2, 6, 12, and 24-month follow-up. International guidelines recommend oral prednisolone and triamcinolone injection to prevent stricture formation in large ESD of esophageal squamous cell carcinoma. However, there is no solid data on BE ESD. The risk factors for stricture formation and the optimal preventive management after large BE ESD is not known. The "steroid lifting method" might be an option in this context. Large prospective studies addressing stricture formation and preventive measures on BE ESD are necessary.

Efficacy and safety of oral cyclophosphamide versus mycophenolate mofetil in childhood nephrotic syndrome: an open-label comparative study.

INTRODUCTION: There is a scarcity of research comparing the efficacy of cyclophosphamide and mycophenolate mofetil in childhood nephrotic syndrome. The aim was to evaluate the efficacy and safety of oral cyclophosphamide (CYC) and mycophenolate mofetil (MMF) in children with steroid-sensitive nephrotic syndrome in terms of the proportion of children who have been off steroids for at least 6 months without proteinuria (responders). METHODS: This open-label retrospective-prospective comparative study was conducted in a pediatric nephrology clinic of a referral center for children between 1 and 18 years of age with FR/SD nephrotic syndrome. Group A consisted of patients who received oral cyclophosphamide (100, 25% female) at a dose of 2-2.5 mg/kg once daily for a period of 8-12 weeks. Group B consisted of patients who received oral mycophenolate mofetil (n = 61, 18% female) (dose: 800-1200 mg/m2) for at least 12 months. Responders were defined as children who were off steroids for at least 6 months along with absence of proteinuria. RESULTS: In the CYC group, 50% of the patients were responders, whereas 54% of the patients in the MMF group were responders (p = 0.614). The time to first relapse with CYC was 7 months (IQR 5.25-11) compared to 7 months (IQR 3.5-12) with MMF (p = 0.092). The relapse rate in the CYC group was 1.77 relapses per patient-year compared to 1.295 relapses per patient-year in the MMF group. The difference in relapse rate was significant (-0.474; 95% CI, 0.09 to 0.86 relapses/person-year) (p value = 0.009). Multivariate analysis revealed that an age of less than 5 years at the start of treatment was a significant factor for a better response to MMF (p value = 0.039, OR = 2.988, CI -1.055-8.468). CONCLUSIONS: The efficacy of MMF was similar to that of CYC in terms of response (6 months without steroids) in children with FR/SD nephrotic syndrome. MMF showed a favorable response in terms of the frequency of relapse and treatment failure. REGISTRATION OF THE STUDY WITH CLINICAL TRIALS REGISTRY OF INDIA: ( http://ctri.nic.in ;CTRI/2021/06/034421) (Dt: 28/06/2021).

Advances and challenges in liquid chromatography-spectrometry (LC-MS) methodology for quantifying androgens and estrogens in human serum and plasma.

Accurate quantification of androgens and estrogens is critical for elucidating their roles in endocrine disorders and advancing research on their functions in human biology and pathophysiology. This review highlights recent advances and ongoing challenges in liquid chromatography- mass spectrometry (LC- MS) methodology for quantifying androgens and estrogens in human serum and plasma. We summarized current approaches for analyzing the different forms of androgens and estrogens, along with their reported levels in publications from 2010 to the present. These published levels pointed out the inconsistencies in reference intervals across studies. To address these issues, advances in derivatization methods and chromatographic separation techniques are reviewed. Future perspectives for improving the accuracy and consistency of hormone quantification in clinical and research settings were also proposed.

Conservative management of spinal pathology with autologous conditioned serum: A systematic review of the literature.

BACKGROUND: Chronic inflammatory pain is associated with increased expression of interleukin (IL)-1, an inflammatory cytokine, and activity on its receptor (IL-1R). In response, the body produces IL-1R antagonist (IL-1Ra) to reduce this signaling. Autologous conditioned serum (ACS) is the only biologic therapy for spinal pathologies that enhances the action of endogenous IL-1Ra reserves to improve symptoms. This systematic review investigates the effectiveness of ACS in treating pain and disability caused by spinal pathologies. AIM: To evaluate the use of ACS as a conservative management option for spinal pathology. METHODS: A systematic review of PubMed/Medline was performed to identify studies investigating administration of ACS for treatment of any spinal pathology. RESULTS: Six articles were included, comprising 684 patients treated with epidural (n = 133) or transforaminal (n = 551) ACS injections. Patients had an average age of 54.0 years with slight female predominance (53.2%). The lumbar spine was most commonly treated, with 567 patients (82.9%) receiving injections for lumbar radiculopathy (n = 67), degenerative disc disease (DDD) (n = 372), or spinal stenosis (n = 128); cervical injections were performed in 109 patients (15.9%). Mean (SD) follow-up was 21.7 (4.8) weeks from first ACS injection. All studies investigating mechanical lumbar and lumbar or cervical radicular pain reported significant pain reduction at final follow-up compared to baseline. ACS achieved comparable or superior results to lumbar epidural steroid injections. Adverse events were reported in 21 patients (3.1%), with no serious adverse events. CONCLUSION: ACS injection is a safe and effective intervention for pain reduction in many spinal pathologies, including cervical and lumbar radiculopathies.

The Use of Intralesional Corticosteroids in Idiopathic Granulomatous Mastitis: A Systematic Review.

Idiopathic granulomatous mastitis (IGM) is a debilitating, chronic, inflammatory condition of the breast. Several studies have emerged evaluating intralesional steroid (ILS) injection and topical steroid administration as a treatment for IGM. However, there is a dearth of international consensuses with regards to the management of IGM. Therefore, we have systematically reviewed the effectiveness of ILS in the management of IGM. A systematic search was conducted in PubMed and Cochrane Library databases, the Google Scholar website and by citation searching up to June 15th, 2023. Eight articles were selected and analyzed. A total of 397 IGM patients were included in the review. The mean patient age was 35.7 years, ranging from 23-62 years. The mean pre-treatment diameter of lesions was 27.5 mm. A total of 184 patients were treated with ILS. The mean complete clinical response time was 2.6 months. The overall complete response rate was 92.8%. Complications following ILS were minor, with hematoma, skin atrophy and hyperemia being commonly described, while avoiding the systemic side effects of oral steroid use, such as weight gain and hirsutism, which were the most commonly reported side effects with oral steroids. The recurrence rates in the ILS group (6.6%) appear to be lower than in the oral steroid group (25.8%) and surgery group (26.3%). ILS seem to show a favorable outcome in terms of complete response rate, complete clinical response time and has a lower recurrence rate and complication rate when compared to other intervention strategies. However, more comparative studies with standardized protocols are necessary to ascertain the optimum type, dosage and frequency of ILS regimens.

Response to: Correction of Tear Trough Deformity with Minced Orbital Fat Grafts During Transconjunctival Lower Blepharoplasty.

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Perfusion Steroid via Ventilation Tube as Salvage Treatments for Sudden Sensorineural Hearing Loss.

Objectives: Intratympanic steroid injection (ISI) for sudden sensorineural hearing loss (SSNHL) is a relatively popular and effective method, but there is no standardized method for intratympanic steroids for the treatment of SSNHL and no consensus on how to deliver steroids to the middle ear. The purpose of this study was to compare 2 means of intratympanic steroid delivery as therapy for SSNHL. Methods: A retrospective chart review was performed for the period from November 2018 to October 2022 at our Department of Otorhinolaryngology-Head and Neck Surgery. Sixty patients with profound SSNHL who have failed initial steroid therapy were divided into the continuously transtympanic steroid perfusion (TSP) therapy and the intermittent ISI therapy. Results: Posttreatment pure-tone average was 60.3 ± 18.2 dB in the TSP group and 67.5 ± 22.6 dB in the ISI group, 70.0% of subjects in the TSP group, and 46.7% of subjects in the ISI group had improved by 15 dB or more after the therapy. The increased hearing threshold of the TSP group (24.6 ± 14.1 dB) was better than the ISI group (16.6 ± 14.9 dB), and the hearing recovery was significantly different (P < .05) in the 2 groups. Besides the hearing improvement was most obvious in low-frequency areas in the TSP group, the most significant hearing improvement was at 250 Hz, reaching 30.8 ± 3.3 dB. Conclusions: In SSNHL patients who have failed initial steroid therapy, TSP therapy via a ventilation tube can achieve good hearing outcomes and serve as a salvage therapy for patients with SSNHL.

Steroid pulse therapy in idiopathic nephrotic syndrome in the era of modern immunosuppressive treatment-still up to date?

BACKGROUND: Intravenous steroid pulses (SP) are successfully used for the treatment of patients with idiopathic nephrotic syndrome (INS) resistant to oral prednisone. METHODS: We performed a retrospective analysis of all patients in the three pediatric nephrology centers of the Paris region from 2002 to 2022 who were resistant to a 30-day course of oral prednisone and who received SP for their first INS flare and analyzed their disease course over 4 years. RESULTS: Forty-seven patients (17 girls), median age 3.4 years, were analyzed. Of them, 68% reached remission within 7 days of SP. No significant short-term side effects were noted. Half of the patients started immunosuppressive treatment immediately after their first remission and 62% of them relapsed at least once, whereas all the patients who did not receive immunosuppressive treatment since their first remission relapsed. Among the SP-sensitive patients, 75% needed calcineurin inhibitor (CNI) or B-cell depletion during their disease course to achieve stable remission. Forty-two percent of the whole cohort received B-cell-depleting agents. Among the 15 SP-resistant patients, all received CNI. Twelve/fifteen patients reached remission. After 4 years, 68% among the SP-sensitive patients and 87% of SP-resistant patients still had an active disease. CONCLUSIONS: SP are helpful to obtain rapid remission in pediatric INS patients resistant to oral steroids. However, as most SP-sensitive patients need immunosuppressive drugs, mainly CNI and B-cell-depleting agents it could be interesting to discuss the possibility to start CNI directly after the 30-day course of prednisone instead of SP.

Non-ischemia Cardiomyopathy and Polycythemia Secondary to Anabolic-Androgenic Steroid Use.

Athletes and bodybuilders use anabolic-androgenic steroids (AAS) to increase muscle mass and enhance performance. Its use is widespread among competitive athletes in order to enhance athletic performances. However, the use of AAS has been linked to many deleterious adverse effects, including cardiomyopathy and polycythemia. We present the case of a young man in his late 20s who presented with uncontrolled hypertension and elevated hemoglobin. He was found to have a reduced left ventricular ejection fraction of 20-25%. Further workup showed dilated cardiomyopathy and low normal erythropoietin (EPO) levels. Evaluation for polycythemia vera was negative, and there was no evidence of ischemic cardiomyopathy. The patient later admitted to using injected AAS for professional bodybuilding. The coexistence of both these conditions can be challenging to diagnose and treat. While primary and secondary polycythemia can lead to hyperviscosity and result in ischemic cardiomyopathy from coronary occlusion, anabolic steroids can directly result in cardiomyopathy and polycythemia. This case points to the importance of identifying cardiomyopathy and polycythemia from illicit drug use, which can often be missed, and the workups needed to identify the etiology.

Effects of perioperative steroid use on surgical stress and prognosis in patients undergoing hepatectomy: a systematic review and meta-analysis of randomized controlled trials.

The objective of this study was to evaluate the clinical effects of perioperative steroid hormone usage in hepatectomy patients through a comprehensive systematic review and meta-analysis. Prospective randomized controlled trials (RCTs) investigating the perioperative use of steroid hormones in hepatectomy patients were systematically searched using various databases, including PubMed, Medline, Embase, the Cochrane Library, the Chinese Biomedical Literature Database, Wanfang Data, and the CNKI database. Two researchers independently screened and extracted data from selected studies. Data analysis was performed using RevMan 5.3 software. The results revealed significantly lower levels of total bilirubin (standard mean difference [SMD] = -0.7; 95% CI: -1.23 to -0.18; and p = 0.009), interleukin-6 (SMD = -1.02; 95% CI: -1.27 to -0.77; and p < 0.001), and C-reactive protein (SMD = -0 .65; 95% CI: -1 .18 to -0.11; and p = 0.02) on postoperative day 1 (POD 1), as well as a reduced incidence of postoperative complications in the steroid group compared to the placebo group. No significant differences were observed between the two groups regarding alanine aminotransferase (ALT) levels, aspartic aminotransferase (AST) levels, or specific complications such as intra-abdominal infection (p = 0.72), wound infection (p = 0.1), pleural effusion (p = 0.43), bile leakage (p = 0.66), and liver failure (p = 0.16). The meta-analysis results indicate that perioperative steroid usage can effectively alleviate liver function impairment and inflammation response following hepatectomy while improving patient prognosis.

Influence of Frailty Status on the Efficacy of Epidural Steroid Injections in Elderly Patients With Degenerative Lumbar Spinal Disease.

Background: The global increase in the elderly population has led to a higher prevalence of degenerative lumbar spinal diseases. Epidural steroid injection (ESI) is a widely used procedure for managing lower back pain. This study investigated the association of preprocedural frailty status with the efficacy of ESI in elderly patients diagnosed with degenerative lumbar spinal diseases. Methods: This retrospective observational study included patients aged 65 years and older who underwent lumbar ESI. Frailty status (robust, prefrail, and frail) assessed via the Frailty Phenotype Questionnaire was collected along with demographic and clinical parameters. Good analgesia was defined as a ≥ 50% reduction in pain score at 4-week follow-up evaluation. Multivariable logistic regression analyses were performed to identify factors associated with poor analgesia. Results: We included 289 patients in this study. Frailty status correlated with analgesic outcomes, with worsening frailty status correlating with increasingly poor analgesia after the injection (robust = 34.5%, prefrail = 40.8%, and frail = 60.0%, p=0.003), predominantly in female patients. After adjusting for demographic and clinical factors, frail patients demonstrated much higher odds of poor analgesia than robust individuals (adjusted odds ratio [aOR] = 2.673, 95% confidence interval [CI] = 1.338-5.342, p=0.005). Conversely, prefrail patients did not show a significant association with analgesic outcome (aOR = 1.293, 95% CI = 0.736-2.272, p=0.372). Conclusions: Frailty, but not prefrailty, appeared to be an independent factor associated with poor analgesic efficacy of ESI in elderly patients with symptomatic degenerative lumbar spinal disease receiving conservative care.

Rare Superior Mesenteric Artery Syndrome in an Eight-Year-Old Girl With Henoch-Schönlein Purpura: A Case Report.

Henoch-Schönlein purpura (HSP) is a systemic vasculitis characterized by palpable purpura, arthralgia or arthritis, GI symptoms, and renal involvement. Superior mesenteric artery (SMA) syndrome, a rare condition, occurs when the third part of the duodenum is compressed between the aorta and the SMA, leading to upper intestinal obstruction. This case report describes the clinical presentation, diagnostic process, and management of an eight-year-old girl with HSP complicated by SMA syndrome. The patient initially presented with abdominal pain and vomiting, eventually developing the characteristic rash of HSP. While initial management was supportive, her condition deteriorated. Treatment with intravenous methylprednisolone resulted in significant symptom improvement and resolution of both SMA syndrome and HSP manifestations. This case highlights the need to recognize SMA syndrome as a potential complication of HSP and demonstrates the effectiveness of steroid therapy in managing this condition. Further research is needed to develop comprehensive treatment guidelines for HSP patients with SMA syndrome.

Sex steroid hormone residues in milk and their potential risks for breast and prostate cancer.

Milk was a source of important nutrients for humans and was especially important for children and adolescents. The modern dairy animal production pattern had contributed to residual sex steroid hormones in milk. When this milk was consumed by humans, these hormones entered the body leading to hormonal disruptions and potentially increasing the risk of various types of cancers. This article reviewed the presence of residual sex steroid hormones in milk, their potential risks on human health, and their possible association with the incidence of breast and prostate cancer. The potential linkage between dairy consumption and these cancers were described in detail. The hormones present in dairy products could affect the development and progression of these types of cancer. Sex steroid hormones could interact with different signaling pathways, influencing carcinogenic cascades that could eventually lead to tumorigenesis. Given these potential health risks, the article suggested appropriate consumption of dairy products. This included being mindful not just of the amount of dairy consumed, but also the types of dairy products selected. More scientific exploration was needed, but this review provided valuable insights for health-conscious consumers and contributed to the ongoing discussion on dietary guidelines and human health.

Practice Patterns of Physicians who Perform Caudal Epidural Steroid Injections.

Introduction: Caudal epidural steroid injections (ESIs) are commonly employed in the management of low back pain and radiculopathy. Despite their widespread use, practice patterns among physicians performing caudal ESIs can vary significantly. This study aims to identify variability in injection techniques utilized by physicians during caudal ESIs, focusing on steroid use, needle selection, and catheter use. This study also looks at major permanent neurological injuries related to caudal ESIs. Methods: A survey was distributed to a cohort of physicians who regularly perform ESIs. The survey comprised questions regarding the type of needle primarily used, steroid selection, the use of catheters, and major neurological injuries from caudal ESIs. The respondents included a diverse group of pain management physicians from various specialties and practice settings. Results: The results revealed a predominant preference for the use of particulate steroids (72.41%) when performing caudal ESIs. Additionally, physicians primarily prefer to use spinal needles (72.41%) compared to other needle types. A majority of physicians (65.12%) reported that they never use a catheter when performing caudal ESIs to access higher pathology. Finally, all physician responders (100%) reported that they have never caused a permanent neurological injury when performing a caudal ESI. Conclusion: This survey provides initial data among physicians who perform caudal ESIs. Our results demonstrate the majority of physicians favor using particulate steroids and a spinal needle, with fewer opting to use a catheter during these procedures. There were no reported major permanent neurological injuries, demonstrating that caudal ESIs are a safe interventional option for managing lumbosacral pain complaints.

A systematic review of steroid use in peripheral nerve pathologies and treatment.

Background: The use of corticosteroids has become a part of the standard of care in various pathologies but their use in peripheral nerve injury treatment is limited. Given corticosteroids' anti-inflammatory properties and their regulatory role in neuronal protein production and myelination, corticosteroids could serve as an adjunct therapy for peripheral nerve injuries. This review aims to systematically investigate the current use of corticosteroid treatment in peripheral nerve pathologies. Methods: The systematic search was performed on PubMed, MEDLINE, EMBASE, Scopus, Cochrane, and Web of Science using keywords such as "corticosteroid treatment," "peripheral nerve damage," "peripheral neuropathy," and "complications." The PRISMA guidelines were used to conduct the systematic review and all articles were reviewed by the corresponding author. After the initial search, individual study titles and abstracts were further screened and categorized using an inclusion and exclusion criteria followed by a final full-text review. Results: Out of the total 27,922 identified records, 203 studies were included based on the selection criteria. These studies focused on the use and efficacy of steroids across a spectrum of compression and non-compression peripheral neuropathies such as cubital tunnel syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Various studies noted the promising role of steroids in offering pain relief, nerve block, and nerve regeneration effects. Additionally, safety considerations and potential complications regarding steroid use in peripheral nerve injuries were analyzed. Conclusion: While there is currently limited clinical utilization of corticosteroids in peripheral nerve pathologies, the anti-inflammatory and regenerative effects that steroids provide may be a beneficial tool in managing various peripheral neuropathies and their associated pain. Additional clinical trials and investigation into the mechanism of action could improve the reputation of steroid use as peripheral nerve injury treatment.

Superiority of Avacopan and Mepolizumab to Glucocorticoid Tapering in the Treatment of Anti-neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis: A Systematic Review.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a spectrum of autoimmune diseases, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies have shown that avacopan and mepolizumab are promising therapeutics for partial or complete replacement of glucocorticoids (GC), with sustained remission while completely weaning off GC. Avacopan inhibits C5aR in the complement pathway, preventing neutrophil migration, while mepolizumab targets IL-5R, reducing eosinophil activity. Additionally, complement inhibition has not only contributed to the recovery of renal function and alleviation of physical symptoms but has also enhanced patients' overall quality of life and mental well-being. This systematic review explores the pathogenesis of AAV, traditional treatments, and the potential of emerging complement and interleukin antagonist therapies such as avacopan and mepolizumab in revolutionizing AAV management.

Gender-specific alteration of steroid metabolism and its impact on viral replication in a mouse model of hepatitis B virus infection.

Hepatitis B virus (HBV) is a sex-specific pathogen that is more severe in males than in females. Sex disparities in HBV infection have been attributed to hormonal differences between males and females. However, whether HBV infection affects the metabolic signatures of steroid hormones and how these influences viral replication remains unclear. In this study, we investigated whether HBV infection alters steroid metabolism and its effects on HBV replication. Serum samples from male and female mice obtained after the hydrodynamic injection of replication-competent HBV plasmids were subjected to quantitative steroid profiling. Serum steroid levels in mice were analyzed using an in vitro metabolism assay with the mouse liver S9 fraction. The alteration of steroids by HBV infection was observed only in male mice, particularly with significant changes in androgens, whereas no significant hormonal changes were observed in female mice. Among the altered steroids, dehydroepiandrosterone (DHEA) levels increased the most in male mice after HBV infection. An in vitro metabolism assay revealed that androgen levels were significantly reduced in HBV-infected male mice. Furthermore, the genes involved in DHEA biosynthesis were significantly upregulated in HBV-infected male mice. Interestingly, reduced dihydrotestosterone in male mice significantly inhibits viral replication by suppressing HBV promoter activity, suggesting a viral strategy to overcome the antiviral effects of steroid hormones in males. Our data demonstrated that HBV infection can cause sex-specific changes in steroid metabolism.

Protective potential of Bacillus subtilis (NMCC-path-14) against extraarticular manifestations during acute and sub-acute phase of arthritis using mice model.

Extra-articular manifestations (EAM), which are associated with rheumatoid arthritis (RA), affect the quality of life of patients and are one of the critical causes of early mortality. This study was aimed at investigating whether Bacillus subtilis NMCC-path-14 (1 × 108 CFU/animal/day) could serve as a valuable therapeutic agent in managing EAM using complete Freund's adjuvant (CFA) induced arthritis during acute and sub-acute phases. Arthritis was induced using intra-dermal administration of CFA in the right hind paw of mice on day 1. Dexamethasone (Dexa) (5 mg/kg/day/animal) was used as a standard treatment. Animals in Dexa and Bacillus subtilis concurrent treatment (BS-CT) received treatments on day 1. The Bacillus subtilis pre-treatment (BS-PT) group received a probiotic dose 7 days before arthritis induction. Parameters like body weight, relative organ weight, colon length, hematology, serum biochemistry, antioxidant capacity, and histopathology of liver, kidney, spleen, colon, stress-related behavioral changes, and cortisol levels were evaluated on days 7 (acute) and 14 (sub-acute). Dexa failed to manage the EAM in arthritic mice and instead exacerbated them. On the other hand, B. subtilis NMCC-path-14 significantly declined EAM with no notable side effects, highlighting its safety and effectiveness. The current data show that B. subtilis NMCC-path-14 may be an alternative option for arthritis treatment that can reduce systemic symptoms associated with arthritis. More studies are required to comprehend the underlying mechanisms of mitigating the EAM by B. subtilis NMCC-path-14.

Effects of zuranolone on next-day simulated driving in healthy adults.

RATIONALE: Zuranolone is an oral positive allosteric modulator of GABAA receptors. Due to its central nervous system (CNS) activity, zuranolone may impact activities requiring complex cognition, including driving. OBJECTIVE: Evaluate the effect of zuranolone on simulated driving performance. METHODS: In this randomized, double-blind, active- and placebo-controlled, four-period crossover study, treatments included once-nightly zuranolone 50 mg on days 1-7, zuranolone 50 mg on days 1-6 and zuranolone 100 mg on day 7, zopiclone 7.5 mg on days 1 and 7, and placebo on days 1-7. Driving was assessed using a validated simulator. Primary endpoint was standard deviation of lateral position (SDLP), evaluated 9 h post-dose on days 2 and 8. Secondary endpoints included additional driving assessments, cognitive tests, pharmacokinetics, and safety. RESULTS: Healthy adults (N = 67) enrolled and received ≥ 1 dose. Zuranolone 50 mg increased SDLP versus placebo on days 2 (least squares mean difference [LSMD]: 7.4 cm; p < 0.0001) and 8 (LSMD: 4.6 cm; p = 0.0106). Zuranolone 100 mg evoked a larger increase in SDLP versus placebo on day 8 (LSMD 18.9 cm; p < 0.0001). Reduced performance in other driving assessments and cognition were observed with zuranolone 50 mg on day 2; many resolved by day 8. Despite the SDLP observations, most participants judged themselves capable of driving. Frequent adverse events (≥ 20%) were CNS-related; most were mild/moderate. CONCLUSION: Zuranolone impaired simulated driving and reduced cognitive function versus placebo 9 h after administration. Although many impairments resolved after 7 days of dosing, driving remained impaired. These results may inform prescriber decision-making.

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma - the DUCT study protocol.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients. METHODS: This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome. DISCUSSION: The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022. PROTOCOL VERSION: Current protocol version 4.0, February 21, 2024.