Maintenance Treatment Research Articles

Efficacy and safety of anlotinib as maintenance treatment in extensive-stage small cell lung cancer: a single-armed single center retrospective study

IntroductionPatients with extensive-stage small cell lung cancer (ES-SCLC) have a poor Q6 prognosis and there is no standard protocol for maintenance treatment. Anlotinib as a third-line or beyond therapy for ES-SCLC was proved to be effective.MethodsWe retrospectively screened of patients with ES-SCLC who started receiving anlotinib as first-line or second-line therapy at the Second Affiliated Hospital of Chongqing Medical University from November 2018 to December 2022. 30 patients treated with anlotinib based combination therapy and subsequent maintenance therapy were included. The primary study endpoint was progression-free survival (PFS) and the secondary study endpoints were overall survival (OS), clinical response and adverse events (AEs).Results and discussionIn 30 ES-SCLC patients, the median PFS and OS were 7.2 months and 17.6 months respectively. The ORR and DCR were 50.0% (15/30) and 86.7% (26/30) respectively. The median PFS was 8.2 months and 5.6 months for patients who received synchronized immunotherapy or chemotherapy. The median OS was 20.1 months and 15.1 months for patients who received synchronized immunotherapy or chemotherapy. The median time to intracranial progression (TTP) was 7.2 months for patients who were without brain metastases before receiving anlotinib. No unexpected AEs were reported. Grade 3-4 adverse events were reported in 10 patients (33.3%). No treatment-related deaths occurred during this study. Our study has indicated the good efficacy and safety about the application of anlotinib in the maintenance therapy in the first-line or second-line treatment of ES-SCLC and it can also achieve good intracranial control.

Comparative analysis of real-world data on the efficacy and safety of and adherence to ICS/LABA combinations in asthma management

BackgroundChoosing effective devices (inhaled corticosteroid [ICS]-long-acting β2 agonist [LABA] combination inhalers) as maintenance treatment is critical for managing patients with asthma. We aimed to compare ICS/LABA combination efficacy, safety, and adherence across inhaler types and components in patients newly diagnosed with asthma.MethodsUtilizing South Korea’s National Health Insurance Service data, we conducted a population-based cohort study involving patients aged 18–80 years, newly diagnosed with asthma who received ICS/LABA combination therapy between January 2016 and December 2020. Outcomes assessed included treatment adherence, asthma exacerbations, hospitalizations, emergency-department visits, mortality, and safety outcomes within 3-month and 1-year post-index periods.ResultsOverall, 13,850 eligible patients were included, with subgroups categorized and compared according to inhaler type and component (metered dose inhalers [MDIs] vs. dry powder inhalers [DPIs], budesonide vs. fluticasone, and formoterol vs. salmeterol). Efficacy and safety profiles did not significantly differ across device types or ICS/LABA combination components during the 3-month and 1-year follow-up periods. However, the DPI group exhibited a significantly higher mean proportion of days covered (0.67 ± 0.23 vs. 0.62 ± 0.23; P < 0.001) and a lower risk of discontinuation (adjusted hazard ratio, 0.867; 95% confidence interval, 0.804–0.927; P < 0.001) than did the MDI group, with no significant differences observed between the other subgroups.ConclusionsThe choice of inhaler device (MDI vs. DPI) and specific ICS/LABA combination components does not significantly impact efficacy and safety profiles in patients newly diagnosed with asthma. However, DPI use may be associated with improved adherence. These results provide valuable insights for clinicians in selecting appropriate and individually tailored inhaler therapies in real-world settings.Graphical abstract

Population pharmacokinetics of cannabidiol and the impact of food and formulation on systemic exposure in children with drug-resistant developmental and epileptic encephalopathies.

Identifying factors influencing cannabidiol (CBD) exposure can optimize treatment efficacy and safety. We aimed to describe the population pharmacokinetics of CBD in children with drug-resistant developmental and epileptic encephalopathies (DEEs) and assess the influence of environmental, pharmacological, and clinical characteristics on CBD systemic exposure. Data from two pharmacokinetic studies of patients aged 2-18 years with DEEs were included (N = 48 patients). Serial blood samples were collected during maintenance treatment, before and after the morning dose, and up to 6 h after a dose of a purified CBD oil formulation, with or without a normocaloric breakfast. CBD plasma concentrations were also available following administration of a CBD-enriched formulation. Samples were quantified using a validated liquid chromatography/tandem mass spectrometry assay. A CBD population pharmacokinetic model was developed using nonlinear mixed-effects modeling. The effects of formulation, concomitant food intake, and demographic, clinical, and pharmacological factors on CBD pharmacokinetics were evaluated. Simulated maximum plasma concentration (Cmax) and area under the concentration-time curve between 0 and 12 h (AUC0-12) were calculated. A one-compartment model with transit compartments and first-order elimination best described CBD pharmacokinetics. Mean values for CBD apparent clearance (CL/F) and volume of distribution (V/F) were 143.5 L/h and 1892.4 L, respectively. Weight was allometrically scaled for V/F and CL/F, sex was associated with V/F, and both formulation and food condition were associated with F (relative bioavailability). CBD Cmax increased by 41% and AUC0-12 by 45% when CBD was administered with food compared to fasting. Dose-normalized AUC0-12 was approximately 50% lower with CBD-enriched oil compared to purified CBD. In the present study, we described the effects of food and formulation on CBD exposure in children with DEEs. Increased CBD exposure with food intake and significant changes in drug exposure when switching between CBD formulations should be considered in patient management.

Characterizing Loss of Response Occurring in a Small Number of Patients During 3 Years of Long-Term Maintenance Therapy with Baricitinib 4-mg: Results From BRAVE-AA1 and -AA2 Trials

Introduction: Baricitinib, a approved for adults with severe alopecia areata (AA), demonstrated a high level of sustained efficacy (89.1%) at Week 152 among patients who achieved a Severity of Alopecia Tool (SALT) score ≤20 at Week 52 following one year of treatment with once-daily baricitinib 4 mg in phase 3 trials (BRAVE-AA1, BRAVE-AA2). In this post hoc analysis, we characterize patterns of loss of response during maintenance treatment (Weeks 52–152) among the 10.9% (n=14) of patients who demonstrated loss of response (SALT score &gt;20) at Week 152 and explore differences between patients who lost vs maintained response. Methods: Patient records were reviewed to identify patients who demonstrated loss of response at Week 152. Descriptive statistics were used to summarize baseline characteristics and the timing and extent of loss for these patients. Results: Baseline disease characteristics differed between those losing (10.9%, n=14/129) and those maintaining (89.1%, n=115/129) treatment response. Characteristics that were numerically more common among those losing vs maintaining response were a longer baseline duration of current episode (≥4 years; 50.0% vs 20.9%, respectively) and baseline very severe AA (SALT score 95–100; 64.3% vs 35.7%, respectively). Seven patients who lost response had received a COVID-19 vaccination and/or experienced a COVID-19 infection during the maintenance period; four of these patients had a vaccination or infection ≤6 months before their initial loss of response. Overall, time to loss of response varied: six lost response within the first 4 weeks of maintenance treatment (Weeks 52–56); eight lost response at or after Week 88. The magnitude of change in SALT score also varied: 35.7% (n=5) maintained a SALT score ≤30 throughout Weeks 52–152; 21.4% (n=3) worsened to a SALT score &gt;90 at ≥1 maintenance period visit. The median SALT score at Week 152 among patients demonstrating loss of response was 32.5. Conclusions: A small number of patients demonstrated loss of response at Week 152 during the maintenance phase of the BRAVE trials. A third of those who lost response maintained at least 70% scalp coverage throughout the two-year maintenance period, which followed one year of initial treatment. Future research is needed to confirm what factors potentially trigger loss of response on baricitinib monotherapy and to determine the potential role of adjunctive therapies in mitigating this risk.

Daratumumab followed by tocilizumab for treatment of late antibody-mediated rejection in renal transplant recipients with high or moderate levels of de novo donor-specific antibodies: a pilot study

BackgroundEffective treatment of late antibody-mediated rejection (late AMR) is still an unmet medical need. Clearing donor-specific antibody (DSA) and preventing its rebound is the ideal goal of treatment.MethodsWe have summarized the clinical data from seven patients with late or chronic active AMR after renal transplantation who received daratumumab (Dara)-based treatment first (Phase 1) and then tocilizumab (TCZ) therapy (Phase 2). Phase 1 consisted of an intensive treatment period (Dara plus PP/IVIG) and a maintenance treatment period (Dara alone). The main clinical indicators were DSA, Banff scores and renal function.ResultsAfter 4 to 17 weeks of intensive treatment, the MFI values of DSA in five of the seven patients fell below 5,000. During Dara maintenance treatment, only one patient’s DSA became negative, and the remaining six patients’ DSAs remained relatively stable or showed rebound. However, after TCZ treatment was begun, the DSA eventually became negative in three patients and decreased to low levels (< 3,500) in the other three patients. Also, our treatment stabilized renal function in all patients. At 24–28 months after treatment, renal biopsy showed partial remission of microvascular inflammation in four of six patients. In addition, capillary C4d deposition became negative in all patients (P = 0.001), and the mean score of i-IFTA was significantly reduced (P = 0.012). Other chronic injury scores did not change significantly.ConclusionsThis new therapy combining Dara and TCZ achieved a good desensitization effect, providing an important reference point for designing better-optimized treatment of late or chronic active AMR in the future.Trial registrationThis retrospectively study was approved by the Ethics Committee of Tongji Hospital, Wuhan, China (TJ-IRB20230729).

Comparative study of management strategies for immune checkpoint inhibitor-induced inflammatory arthritis: rheumatologists versus oncologists.

Immune checkpoint inhibitors (ICIs) have significantly improved cancer treatment outcomes but are associated with immune-related adverse events (irAEs), such as inflammatory arthritis (ir-IA). Management of ir-IA is evolving, with corticosteroids as the primary treatment, though some cases require steroid-sparing agents. This study aimed to compare initial mean prednisolone doses and disease persistence over 12 months in patients with rheumatoid arthritis (RA)-like ir-IA managed by rheumatologists or oncologists. This retrospective observational study involved patients who developed RA-like ir-IA after ICI treatment for advanced cancers between September 2015 and January 2019 at a tertiary hospital in Brisbane, Australia. Patient records were reviewed up to January 2020 to evaluate chronicity. Data were collected, and statistical analyses compared the management between rheumatologists and oncologists. A total of 871 patients received ICI and 246 had irAEs, with 20 developing RA-like ir-IA. Nine were managed by an oncologist and 11 by a rheumatologist. The mean dose of prednisolone commenced by a rheumatologist was 14 mg compared to 53.3 mg by an oncologist (P = 0.0058). Patients managed by a rheumatologist were more likely to receive conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) (odds ratio 16, P = 0.023). Thirteen patients required ongoing maintenance treatment, while seven had resolution within 12 months of disease onset. RA-like ir-IA comprised 8% of ICI-related irAEs. During the study period, patients managed by rheumatologists received lower initial prednisolone doses and more frequent csDMARD than oncologists. A multidisciplinary involvement between rheumatologists and oncologists in the event of ir-IA is crucial.

Reconsidering remission in recurrent late-life depression: clinical presentation and phenotypic predictors of relapse following successful antidepressant treatment.

Late-life depression (LLD) is characterized by repeated recurrent depressive episodes even with maintenance treatment. It is unclear what clinical and cognitive phenotypic characteristics present during remission predict future recurrence. Participants (135 with remitted LLD and 69 comparison subjects across three institutions) completed baseline phenotyping, including psychiatric, medical, and social history, psychiatric symptom and personality trait assessment, and neuropsychological testing. Participants were clinically assessed every two months for two years while receiving standard antidepressant treatment. Analyses examined group differences in phenotypic measure using general linear models. Concurrent associations between phenotypic measures and diagnostic groups were examined using LASSO logistic regression. Sixty (44%) LLD participants experienced a relapse over the two-year period. Numerous phenotypic measures across all domains differed between remitted LLD and comparison participants. Only residual depressive symptom severity, rumination, medical comorbidity, and executive dysfunction significantly predicted LLD classification. Fewer measures differed between relapsing and sustained remission LLD subgroups, with the relapsing group exhibiting greater antidepressant treatment intensity, greater fatigue, rumination, and disability, higher systolic blood pressure, greater life stress and lower instrumental social support. Relapsing group classification was informed by antidepressant treatment intensity, lower instrumental social support, and greater life stress. A wide range of phenotypic factors differed between remitted LLD and comparison groups. Fewer measures differed between relapsing and sustained remission LLD subgroups, with less social support and greater stress informing vulnerability to subsequent relapse. This research suggests potential targets for relapse prevention and emphasizes the need for clinically translatable relapse biomarkers to inform care.

Evaluation of a Global Initiative for Asthma Education and Implementation Program to Improve Asthma Care Quality (CARE4ALL): Protocol for a Multicenter, Single-Arm Study.

Poor symptom control and exacerbations of asthma diminish quality of life and pose a significant burden to patients and society. Implementing evidence-based management as recommended by the Global Initiative for Asthma (GINA), especially introducing inhaled corticosteroid-containing treatments, has the potential to vastly reduce exacerbations and the high burden of asthma in China. However, domestic implementation of the GINA recommendations has been unsatisfactory, especially in lower-level hospitals; thus, an enhancement to the awareness of and adherence to the GINA recommendations among Chinese physicians is needed to improve patient outcomes. This study aims to bridge the gap between the GINA recommendations and the current clinical practice in China by demonstrating the benefits of an asthma quality improvement program (QIP). A single-arm study will be conducted at around 30 hospitals across China to assess the impact of a specially designed asthma QIP. Approximately 1500 patients with asthma aged ≥14 years will be enrolled in participating hospitals and followed up for 48 weeks. The QIP-targeted at all pulmonologists and specialist nurses-will include an initial comprehensive training (including a pretraining questionnaire and posttraining quizzes) provided by a dedicated, qualified training team based on the GINA 2021 recommendations, followed by regular reinforcement learnings (integrated into the regular department lectures delivered by department directors), with multiple offline and online approaches (eg, an online patient management platform) provided as supportive tools. During this study, GINA implementation performance will be continuously monitored to inform necessary adjustments at the hospital level. The primary end point is change from baseline in the proportion of participants with an inhaled corticosteroid-based maintenance or reliever treatment at week 48. Secondary end points and exploratory end points include changes in clinical practice and patient outcomes such as treatment patterns, asthma control, and hospitalization rates due to exacerbations. This study has been completed, with 1500 patients enrolled and 1271 patients completing the study. The last visit of the last patient was on September 3, 2024, and the database lock was on September 28, 2024. Final analysis of data has started in October 2024. The Change Asthma Clinical Practice through GINA Education and Implementation for All Patients With Asthma (CARE4ALL) study will hopefully help improve asthma management and patient outcomes in China by bridging the gap between evidence-based GINA recommendations and the current clinical practice. ClinicalTrials.gov NCT05440097; https://clinicaltrials.gov/study/NCT05440097. DERR1-10.2196/65197.

"We Need Gentleness": Isolation, Loneliness, and Implications for Psychosocial Counseling Among People with HIV who are on Methadone Maintenance Treatment and Experience Common Mental Disorders in Vietnam.

The psychological experiences and needs of people with human immunodeficiency virus (HIV) who use methadone maintenance treatment and have common mental disorders in Hanoi, Vietnam remain unknown. Due to limited services for common mental disorders, optimal delivery methods for psychotherapy are also unknown. Accordingly, this qualitive study explored both symptoms of common mental disorders among this population and the preferred qualifications and characteristics of a mental health counselor. We interviewed patients, their family members and caretakers, clinic providers, and clinic directors to answer these questions. Feelings of loneliness, isolation, sadness, hopelessness, and a general lack of motivation were common among patient participants. Patient participants had no preference among counselor professional qualifications. Three key qualities‒gentleness, enthusiasm, and understanding ‒ emerged as preferred counselor characteristics. The results from this work will help inform the future tailoring of mental health interventions among a population with unique care needs in Hanoi as well as other populations of people with HIV with common mental disorders.

Niraparib as First-Line Maintenance Therapy in Patients with Stage III Ovarian Cancer and No Visible Residual Disease: AR1ZE Real-World Study.

Niraparib was approved for first-line (1L) maintenance (1LM) treatment of patients with advanced epithelial ovarian cancer (EOC) following the PRIMA/ENGOT-OV26/GOG-3012 (PRIMA) trial. PRIMA was restricted to patients at higher risk of progression (excluded stage III EOC with no visible residual disease [NVRD] after primary cytoreductive surgery [PCS]). This retrospective study evaluated the potential impact of excluding stage III EOC with NVRD from PRIMA by assessing real-world treatment outcomes following 1LM niraparib monotherapy in this patient population. Data from a US-nationwide electronic health record-derived deidentified database comprised adult patients diagnosed with stage III/IV EOC who received 1L platinum-based chemotherapy and initiated niraparib 1LM monotherapy (01Jan2017-28Feb2023). Patients were classified as PRIMA-like (EOC with higher-risk prognostic factors for disease progression) or stage III disease with NVRD after PCS. Real-world time to next treatment (rwTTNT) and progression-free survival (rwPFS), assessed from the end date of 1L platinum-based chemotherapy, were measured via Kaplan-Meier methods. Among 453 patients who received niraparib 1LM (PRIMA-like cohort, n = 390; stage III NVRD cohort, n = 63), median follow-up from index was 14.9 (interquartile range [IQR], 7.3-25.1) and 18.4 (IQR, 9.3-29.1) months in the PRIMA-like and stage III NVRD cohorts, respectively. Median rwTTNT was significantly longer in the stage III NVRD cohort (22.5 [95% confidence interval (CI), 17.3-not reached] months) than in the PRIMA-like cohort (11.7 [95% CI, 10.8-12.9] months; P < 0.001). Median rwPFS in the stage III NVRD cohort (25.2 [95% CI, 12.6-not reached] months) was more than double that in the PRIMA-like cohort (10.1 [95% CI, 9.1-11.9] months; P < 0.001). In the stage III NVRD cohort, rwTTNT and rwPFS were significantly longer than in the PRIMA-like cohort, consistent with clinical expectation. Results suggest niraparib clinical benefit may have been underestimated in PRIMA because of the exclusion of patients with stage III EOC with NVRD after PCS.

Treatment Strategies for Chronic Inflammatory Demyelinating Polyneuropathy

Three main treatments are available for management of chronic inflammatory demyelinating polyneuropathy (CIDP). Both induction and maintenance therapies should be considered for treatment of CIDP. Plasma exchange and intravenous immunoglobulin therapy are effective as induction treatments for CIDP, and corticosteroid administration, such as daily oral or pulse therapies, may be effective for both induction and maintenance. Recently, repeat intravenous or subcutaneous immunoglobulin infusion therapy has been introduced as maintenance treatment. Treatment strategies, including combinations of the aforementioned approaches, are required as induction and maintenance therapies for patients with CIDP.

Maintenance treatment with vedolizumab in paediatric inflammatory bowel disease (VEDOKIDS): 54-week outcomes of a multicentre, prospective, cohort study.

Infliximab and adalimumab are the only biologics thus far approved for paediatric patients with inflammatory bowel disease (IBD), so other biologics, such as vedolizumab, are prescribed off-label. Despite its frequent use, prospective data for vedolizumab treatment in children are available only for short-term induction outcomes. We aimed to evaluate the long-term efficacy and safety of maintenance therapy with vedolizumab in paediatric patients with IBD. In this multicentre, prospective, cohort study (VEDOKIDS), children younger than 18 years with Crohn's disease, ulcerative colitis, or IBD unclassified (analysed with the ulcerative colitis group) who had initiated intravenous vedolizumab were enrolled from 17 centres in six countries (Israel, the USA, Italy, Ireland, Denmark, and Slovenia). Patients initiating vedolizumab to prevent postoperative recurrence were excluded. Vedolizumab dose or schedule were not standardised, and concomitant treatment with any other medication was permitted. Patients were prospectively followed up for 54 weeks, with repeated biosampling. The primary outcome was complete remission at week 54, defined as clinical remission (weighted Paediatric Crohn's Disease Activity Index [wPCDAI] of <12·5 points in Crohn's disease and Paediatric Ulcerative Colitis Activity Index [PUCAI] of <10 in ulcerative colitis) without the need for surgery, exclusive enteral nutrition for children with Crohn's disease, or steroids (steroid-free and exclusive enteral nutrition-free clinical remission) plus CRP concentration lower than 1·5 times the upper limit of normal (ULN) of 0·5 mg/dL. In cases of missing data on CRP, ESR was used instead (concentrations <1·5 times the ULN, which was 25 mm/h). Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT02862132. Between May 19, 2016, and April 1, 2022, we enrolled 142 patients. Five children who had received only one or two infusions of their three-infusion induction before switching drugs due to COVID-19 pandemic-related reasons were excluded, leaving 137 children (64 [47%] with Crohn's disease, 64 [47%] with ulcerative colitis, and nine [7%] with IBD unclassified; 63 [46%] male and 74 [54%] female; age range of 0·7-17·6 years) in the intention-to-treat population. The median wPCDAI score in children with Crohn's disease decreased from 35 (IQR 18 to 49) at baseline to 13 (0 to 25; median of differences -14 [95% CI -33 to 0]) at week 54, and the median PUCAI score in children with ulcerative colitis decreased from 25 (IQR 15 to 50) at baseline to 5 (0 to 25) at week 54 (median of difference -10 [-30 to 0]). Improvements in disease activity were significant by week 6, with no further significant changes between visits. At week 54, 16 (25%) of 64 children with Crohn's disease and 34 (47%) of 73 with ulcerative colitis or IBD unclassified were in complete remission. 38 vedolizumab-related adverse events were recorded in 29 (21%) of 137 children, the most common being headache (n=7), myalgia (n=4), and fever (n=4), and none were serious. Vedolizumab maintenance seems safe and efficacious in children, with a higher efficacy in those with ulcerative colitis than in those with Crohn's disease. The European Crohn's and Colitis Organisation, the European Society for Paediatric Gastroenterology Hepatology and Nutrition, and Takeda.

Panitumumab plus 5-fluorouracil and folinic acid or 5-fluorouracil and folinic acid alone as maintenance therapy in RAS wild-type metastatic colorectal cancer (PanaMa, AIO KRK 0212): final efficacy analysis of a randomised, open-label, phase 2 trial.

The PanaMa trial aimed to compare the efficacy of 5-fluorouracil and folinic acid (FU/FA)±panitumumab maintenance in untreated RAS wild-type metastatic colorectal cancer (mCRC) patients. In this final phase 2 trial analysis, adult mCRC patients responding to six cycles of FU/FA, oxaliplatin and panitumumab were randomized (1:1, open-label) to maintenance of either FU/FA+panitumumab or FU/FA alone. The primary endpoint was superiority of progression-free survival of maintenance (PFS; time from random assignment to progression/death) in favour of FU/FA+panitumumab. Secondary endpoints included PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS) and overall survival (OS). The trial is registered with ClinicalTrials.gov (NCT01991873). In 248 patients of the Full Analysis Set recruited between May 2014 and February 2021, with a median observation of 64.0 (range 12.5-86.3) months and 59.7 (range 3.7-97.3) months in the treatment arms, 230 events for PFS (92.7%) and 196 events for OS (79.0%) were recorded. Adding panitumumab to FU/FA resulted in significantly longer PFS (8.8 versus 5.8 months, HR=0.73 (95% CI 0.56-0.94), P=0.015), shorter PFS re-ind. (4.1 versus 7.4 months, HR=1.93 (95% CI 1.33-2.82), P<0.001), comparable TFS (17.1 versus 15.7 months, HR=0.98 (95% CI 0.68-1.42), P=0.92) and numerically longer OS (29.9 versus 24.7 months, HR=0.85 (95% CI 0.64-1.12), P=0.24). The most frequent adverse event (AE) grade ≥3 was rash (FU/FA+panitumumab: n=15, 12.0%, FU/FA: n=17, 6.9%). 141 patients (37.3%) experienced at least one serious AE One treatment-related death occurred (neutropenic sepsis, FU/FA). Panitumumab plus FU/FA might be considered a standard of care maintenance regimen since a potential re-induction therapy with panitumumab cannot be guaranteed at the time of maintenance treatment decision. Amgen.

Long-term effects of antipsychotics on serum BDNF levels in patients with schizophrenia.

Brain-derived neurotrophic factor (BDNF) is implicated in the etiology of schizophrenia, and peripheral BDNF levels are affected by the short-term antipsychotic treatment. However, the data on their long-term effects on BDNF levels are scarce, and there is no information whether BDNF levels change during sustained remission in relation to values in healthy individuals. The aim of the present study was to compare serum BDNF levels in patients in long-term remission and healthy controls. This study is an extension of our previous research on the effects of olanzapine and risperidone on serum BDNF in acute-episode patients with schizophrenia. Patients who remained in remission for at least 3 years on the same antipsychotic regimen (40 % of the initial cohort) were included. Symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured by ELISA in patients in remission (N = 20), evaluated at baseline, after 6 weeks of treatment and after 3 years of treatment, and in healthy individuals (N = 40). At baseline (p = 0.046) and after 6 weeks of treatment (p = 0.028), patients had significantly lower BDNF levels than controls. However, after 3 years of continuous antipsychotic maintenance treatment, serum BDNF levels were increased compared to baseline and values after 6 weeks of treatment in remitted patients, and were also significantly higher in patients than in healthy controls (p = 0.002). Antipsychotic medications appear to have distinct effects on serum BDNF levels in short-and long-term treatment. It remains to be determined if such finding may be related to potential neuroprotective effects of antipsychotic maintenance treatment.

Appraising annual post-maintenance functional performance of asphalt roadway based on causal inference approach

ABSTRACT To maintain good functional pavement performance and extend the service life of asphalt pavements, the long-term performance of pavements under maintenance policies needs to be evaluated and favourable options need to be chosen based on the condition of the pavement. A major challenge in evaluating maintenance policies is to produce valid treatments for the outcome assessment under the control of uncertainty of vehicle loads and the disturbance of freeze-thaw cycles in the climatic environment. In this study, a novel causal inference approach, combining a classical causal structural model and a potential outcome model framework, is proposed to appraise the annual post-maintenance performance of four preventive preservation treatments of pavements for longitudinal cracking over a 5-year period of upkeep. Three fundamental issues were brought to our attention: detection of causal relationships prior to variables under environmental loading (identification of causal structure); obtaining direct causal effects of treatment on outcomes excluding covariates (identification of causal effects) and sensitivity analysis of causal relationships. The results show that the method can accurately evaluate the effect of preventive maintenance treatments, assess the maintenance time to cater well for the functional performance of different preventive maintenance approaches and develop appropriate maintenance strategies for pavements.

Factors Influencing the Duration of Maintenance Therapy in Metastatic Colorectal Cancer.

Metastatic colorectal cancer (mCRC) is mainly treated with 5-Fluoro-Uracil (5-FU), Oxaliplatin and Irinotecan chemotherapies and anti-Epidermal Growth Factor Receptor (EGFR) or anti-Vascular Endothelial Growth Factor (VEGF) targeted therapies. Due to chemotherapy-related toxicity, patients receive induction treatment to achieve tumour response followed by maintenance therapy with less cytotoxic molecules or a chemotherapy-free interval to reduce chemotherapy-related toxicity. In this study, the aim was to determine the patient, cancer and treatment factors that influence the duration of maintenance therapy (DMT). We collected retrospective data on a cohort of 133 patients treated at the Centre Georges François Leclerc (CGFL) cancer centre in Dijon between March 2014 and June 2022. Patients had unresectable or potentially resectable diseases. They received first-line induction treatment with chemotherapy and/or targeted therapy and maintenance treatment, defined as the interruption of at least one chemotherapy agent. In the multivariate analysis, age (HR: 1.02, 95% CI 1.00-1.04, p = 0.031), N2 nodal status (HR: 1.78, 95% CI 1.09-2.89, p = 0.021) and the presence of peritoneal metastases (HR: 2.05, 95% CI 1.25-3.36, p = 0.004), as well as baseline carcino-embryonic antigen (CEA) level (HR: 1.10, 95% CI 1.00-1.20, p = 0.052), were significantly associated to poor DMT. Local treatment of liver metastases also significantly reduced the DMT (HR: 0.49, 95% CI 0.28-0.86, p = 0.013). In our cohort, induction triplet chemotherapy significantly increased the CEA delta (70% vs. 44%, p = 0.047) compared to doublet chemotherapy and led to a higher rate of liver surgery (40% vs. 21%, p = 0.014) and a trend for a higher rate of local treatment of metastases (62% vs. 45%, p = 0.059). Duration of maintenance therapy is determined by the initial patient and colorectal cancer characteristics. However, it is significantly increased by local treatment of liver metastases. By reducing the tumour burden, a triplet induction chemotherapy regimen increases the rate of liver metastase resection.

Comparative Effectiveness of Fluticasone Furoate/Umeclidinium/Vilanterol and Budesonide/Glycopyrrolate/Formoterol Fumarate among US Patients with Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is associated with exacerbations which can reduce quality of life and increase mortality. Single-inhaler triple therapy (SITT) is recommended for maintenance treatment of COPD among patients experiencing exacerbations despite dual-therapy use. This real-world comparative effectiveness study compared the impact of SITTs, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), and budesonide/glycopyrrolate/formoterol fumarate (BUD/GLY/FORM), on COPD exacerbations and mortality. Medicare Fee-for-Service (FFS) patients with COPD initiated on FF/UMEC/VI or BUD/GLY/FORM were identified from the Komodo Research healthcare claims dataset (01/01/2016-12/31/2023). Overlap weighting based on high-dimensional propensity scores evaluated from patient characteristics was used to adjust for baseline confounding. Primary outcome was annualized rate of moderate-severe COPD exacerbations (per patient-year; PPY) compared using rate ratios (RRs) with 95% confidence intervals (CIs) from weighted Poisson regression models. Secondary and exploratory outcomes were risk of moderate-severe COPD exacerbations and all-cause mortality, respectively, evaluated using Kaplan-Meier analysis and hazard ratios (HR) with 95% CIs from Cox proportional hazard models. A secondary analysis was conducted among a mutually exclusive population with Medicare Advantage, Medicaid, or commercial insurance. Overall, 32,312 FF/UMEC/VI and 12,230 BUD/GLY/FORM Medicare FFS patients were included. After weighting, median follow-up was 9months. Compared with BUD/GLY/FORM, FF/UMEC/VI users had a 12% lower rate of annualized moderate-severe COPD exacerbations [0.80 and 0.91 PPY; RR (95% CI): 0.88 (0.85-0.92); P<0.001] and a 10% lower risk of moderate-severe exacerbations at 12months post-initiation [HR (95% CI): 0.90 (0.87-0.93); P<0.001], driven by moderate exacerbations. FF/UMEC/VI compared with BUD/GLY/FORM users had 11% lower risk of all-cause mortality at 12months post-initiation [5.6% vs. 6.4%; HR (95% CI): 0.89 (0.80-0.98); P=0.020]. Results were consistent among patients with Medicare Advantage, Medicaid, or commercial insurance. In this real-world comparative effectiveness study, FF/UMEC/VI was associated with significantly lower rate and risk of COPD exacerbations than BUD/GLY/FORM.

Review and External Evaluation of Population Pharmacokinetic Models for Vedolizumab in Patients with Inflammatory Bowel Disease: Assessing Predictive Performance and Clinical Applicability

Background/Objectives: Several population pharmacokinetic models of vedolizumab (VDZ) are available for inflammatory bowel disease (IBD) patients. However, their predictive performance in real-world clinical settings remains unknown. This study aims to externally evaluate the published VDZ pharmacokinetic models, focusing on their predictive performance and simulation-based clinical applicability. Methods: A literature search was conducted through PubMed to identify VDZ population pharmacokinetic models. A total of 114 VDZ concentrations from 106 IBD patients treated at the University Medical Center “Zvezdara”, Republic of Serbia, served as the external evaluation cohort. The predictive performance of the models was assessed using prediction- and simulation-based diagnostics. Furthermore, the models were utilized for Monte Carlo simulations to generate concentration–time profiles based on 24 covariate combinations specified within the models. Results: Four published pharmacokinetic models of VDZ were included in the evaluation. Using the external dataset, the median prediction error (MDPE) ranged from 13.82% to 25.57%, while the median absolute prediction error (MAPE) varied between 41.64% and 47.56%. None of the models fully met the combined criteria in the prediction-based diagnostics. However, in simulation-based diagnostics, pvcVPC showed satisfactory results, despite wide prediction intervals. Analysis of NPDE revealed that only the models by Rosario et al. and Okamoto et al. fulfilled the evaluation criteria. Simulation analysis further demonstrated that the median VDZ concentration remains above 12 μg/mL at week 22 during maintenance treatment for approximately 45–60% of patients with the best-case covariate combinations and an 8-week dosing frequency. Conclusions: None of the published models satisfied the combined criteria (MDPE, MAPE, percentages of prediction error within ±20% and ±30%), rendering them unsuitable for a priori predictions. However, two models demonstrated better suitability for simulation-based applications.

Integrated Analysis of Vonoprazan Safety for Symptomatic Gastro‐Oesophageal Reflux Disease or Erosive Oesophagitis

ABSTRACTBackgroundPatients with erosive oesophagitis, and those with persistent symptomatic non‐erosive gastro‐oesophageal reflux disease, require long‐term maintenance treatment with acid‐suppressing agents.AimTo evaluate the safety of vonoprazan, a potassium‐competitive acid blocker, in an integrated analysis of data from clinical trials in adults.MethodsWe included 14 clinical trials of vonoprazan conducted in multiple countries. Mean duration of exposure in person‐years to vonoprazan (n = 5318) was 2068, to comparators lansoprazole (n = 1925) or esomeprazole (n = 86) was 751, and to placebo (n = 779) was 59. We report adverse events, serum gastrin, and liver enzyme levels as the main outcomes. Post‐marketing safety data from December 26, 2014 (date of commercialisation in Japan) to December 25, 2023, are also provided.ResultsNasopharyngitis was the only adverse event reported by at least 5.0% of patients (6.94% vonoprazan, 5.07% proton pump inhibitor (PPI), 4.49% placebo). Incidence rates per 100 person‐years for serious adverse events were 10.39 for vonoprazan, 10.65 for PPIs, and 1.69 for placebo. One patient each on vonoprazan and lansoprazole was diagnosed with gastric cancer. Mean serum gastrin levels were higher on vonoprazan than lansoprazole but normalised by 4 weeks after discontinuation. Elevated liver enzyme levels were infrequent and of low magnitude with no differences between vonoprazan and PPIs. There were four deaths; none was considered related to study drug.ConclusionsVonoprazan was well tolerated. Its safety profile from both clinical trial and post‐marketing data were consistent and comparable to that of its PPI comparators with respect to treatment‐emergent adverse events.

Addiction treatment and harm reduction programs in prisons: lessons from Iran.

Substance use disorder is one of the most prevalent health issues among prison populations. In this regard, addiction treatment and harm reduction programs have been implemented in Iranian prisons since 2002. The purpose was to describe the practical experience of implementing harm reduction programs in Iran's prisons, emphasizing the impact of policy decisions on it. The study was qualitative study. In addition to analyzing 16 documents, the authors conducted face-to-face semi-structured interviews with 11 key informants who were asked questions about the evolution of treatment and harm reduction programs in prisons. The authors analyzed the data using the content analysis method and MAXQDA-10 software. The HIV outbreak in Iranian prisons in the late 20th century posed a significant challenge. Initially, policymakers' responses were varied from denying the issue to solving it, reflecting the prevailing abstinence paradigm among drug experts and politicians. However, a legal amendment was eventually issued based on evidence-based health literature. Despite initial obstacles such as financial constraints and lack of human resources, the successful implementation of large-scale harm reduction measures, including methadone maintenance treatment and interventions targeting infectious diseases, has led to the development of a unique health model in the Persian Gulf region. This model, born out of the Iranian experience, offers hope for the future of prison health. Lessons from the Iran case could provide valuable insight for countries about the role of policy in implementing harm reduction programs in prisons. Policy advocacy and reform is one of the main measures to provide evidence-based health interventions in prisons.