Effects Of Long-term Treatment Research Articles

Cushing's Disease: Long-Term Effectiveness and Safety of Osilodrostat in a Polish Group of Patients with Persistent Hypercortisolemia in the Experience of a Single Center.

Osilodrostat is a potent oral steroidogenesis inhibitor that has emerged as the new medical agent for patients with Cushing's disease (CD) requiring long-term medical therapy for hypercortisolemia control. Its efficacy and safety have been assessed in clinical trials; however, real-world evidence is still scarce. This study aimed to investigate the long-term treatment (156 weeks) clinical and biochemical effect of osilodrostat in six patients with CD at a single center in Poland, initially participating in the LINC4 study. At week 36, all six patients met the key secondary endpoint of the LINC4 trial, achieving normalization of median urinary free cortisol. Osilodrostat treatment allowed for complete disease control in all patients and none of the patients was excluded due to the lack of treatment effectiveness in 156 weeks of follow-up. All patients demonstrated significant improvement from baseline on most metabolic and cardiovascular parameters, which was most evident at week 36 and sustained throughout the study period. This study supports and strengthens the role of osilodrostat as an effective long-term medical treatment in patients with CD. We also present three patient case histories in detail to highlight the clinical situations that endocrinologists might face during osilodrostat therapy.

How are long-term stand structure, fuel profiles, and potential fire behavior affected by fuel treatment type and intensity in Interior Pacific Northwest forests?

Fuel treatments are commonly applied to increase resilience to wildfire in dry and historically frequent-fire forests of western North America. The long-term effects of fuel treatments on forest structure, fuel profiles (amount and configuration of fuels), and potential wildfire behavior are not well known relative to short-term effects. Additionally, long-term treatment effects on the development of stand structure and fuel profiles have rarely been compared to the long-term effects of pre-treatment conditions, treatment intensity, and site productivity. In this study, we addressed these knowledge gaps by resurveying 204 permanent plots at the Northeastern Cascades site of the Fire and Fire Surrogates study 13–18 years (‘long-term’) after burn-only, thin-only, and thin plus burn treatments, and comparing results to pre-treatment conditions and un-treated controls. Methods included ordinations, generalized linear mixed models, and fire models. All treatments shifted long-term average stand structure toward lower tree density, basal area, and crown fire potential, with thin plus burn treatments showing the highest magnitude of effects for most variables. However, the direction and magnitude of trajectories among plots within treatment types were highly variable. Long-term responses of stand structure, fuel profiles, and modelled fire behavior were positively correlated with their pre-treatment values. Treatment intensity strongly affected long-term stand structure and canopy fuel loads. By ∼15 years post-treatment and under 80th percentile fire weather conditions, most plots in all treatments and un-treated controls failed to meet target thresholds for surface flame length, basal area mortality, and torching index, while most plots met thresholds for crowning index. However, live stand structure following wildfire simulated under 80th percentile fire weather conditions was characterized by lower stand density and a shift toward dominance by large-diameter and fire-resistant trees, suggesting that treated stands may be resilient to wildfires occurring under moderate weather. Our study suggests that understanding fuel treatment efficacy and longevity may be improved in future studies by incorporating fine-scale (i.e., plot-level) drivers of variability in stand structure, fuel profiles, and modelled fire behavior, and by using multiple methods of evaluating treatment effectiveness. Thin plus burn treatments and intensely applied burn-only and thin-only treatments can reduce basal area and potential for crown-fire for more than a decade. However, additional maintenance treatments may be needed by 15 years after initial treatment, to further reduce potential for severe surface fire and high tree mortality in subsequent wildfire.

The effect of long-term traditional Chinese medicine treatment on extra-articular lesions of rheumatoid arthritis patients based on propensity score matching: A retrospective cohort study

ObjectiveTo explore the efficacy of long-term traditional Chinese medicine (TCM) treatment on the occurrence of extra-articular lesions in rheumatoid arthritis (RA) patients. MethodsOur retrospective cohort study included patients diagnosed with RA between January 2018 to December 2019. Patients were divided into TCM treatment group and control group according to whether they received TCM treatment for more than three months. Propensity score matching (PSM) was used to balance covariates between groups. The occurrence time of extra-articular lesions, including interstitial lung disease, Sjögren's syndrome, and anemia, was calculated for both groups after PSM. Additionally, clinical indicators that may affect the occurrence of extra-articular lesions in RA were included in Cox multivariate regression analysis to explore prognostic factors related to RA. ResultsA total of 883 RA patients were initially included in our study, with 481 in the TCM treatment group and 279 in the control group. TCM treatment improved all clinical indicators of RA patients, and there was a higher degree of support, confidence, and lift between TCM treatment and the improvement of clinical indicators. There was no significant difference in the rate of extra-articular lesions occurrence between the two groups. After PSM, the median occurrence time of interstitial lung disease, Sjögren's syndrome and anemia in the TCM treatment group were 30.767, 21.370 and 31.970 months, respectively. While in the control group, it was 15.911, 14.667 and 11.825 months, respectively. Cox multivariate regression analysis indicated that TCM treatment was a protective factor for the occurrence of extra-articular lesions in RA, while abnormally high level of IgG was an independent factor for interstitial lung disease and C4 was an independent factor for Sjögren's syndrome. Moreover, a longer duration of TCM usage was associated with a later occurrence of extra-articular lesions. ConclusionLong-term TCM treatment not only positively affects the occurrence time of extra-articular lesions in RA patients, but also helps reduce the risk of extra-articular lesions occurrence. TCM can be applied flexibly throughout the treatment process for RA patients.

Salt Tolerance and Ion Accumulation in Several Halophytic Plant Species Depending on the Type of Anion

The question of the effect of the anion type on halophyte salt tolerance and ion accumulation is still far from the necessary generalization due to the lack of comparative studies. The aim of the present study was to compare the relatively long-term effect of treatment with various salts formed by different anions on the growth and ion accumulation of several halophyte species in controlled conditions. The main experiments with the largest variety of individual salt types were performed with Cochlearia officinalis L. and two cultivars of Limonium sinuatum (L.) Mill. In addition, experiments with Lobularia maritima (L.) Desv., Plantago maritima L., and Tripolium pannonicum (Jacq.) Dobrocz. focused on the comparison of neutral (NaCl) and alkaline (NaHCO3) salts as well as NaNO3. Acetate salts appeared to be the most toxic, with only Plantago and Tripolium plants being able to withstand full treatment while having a pronounced inhibition in growth. Only the two Limonium cultivars were more susceptible to treatment with alkaline salts in comparison to that with neutral salts. In treatments with alkaline salts, the ion accumulation potential was lower in comparison to plants treated with chlorides and nitrates. It can be concluded that the type of anion is a significant determinant of salinity tolerance and ion accumulation in halophytes, but a high genotype dependence of the responses makes it difficult to generalize the obtained results.

Analysis of gene variation and long-term follow-up in children with phenylalanine hydroxylase deficiency diagnosed by newborn screening.

To retrospectively analyze the variation and characteristics of phenylalanine hydroxylase (PAH) gene, and to observe the long-term treatment effect and follow-up of newborns with PAH deficiency. Clinical data, treatment and follow-up results of 198 patients with PAH deficiency diagnosed by newborn screening in Jinan from 1996 to 2021 were collected. The genetic analysis of 55 patients with PAH deficiency diagnosed by newborn screening in Jinan and 213 patients referred from the surrounding areas of Jinan were summarized. Gene variations were checked by a customized Panel gene detection method. Blood phenylalanine-concentration and physical development indicators including height and weight were regularly monitored. Intellectual development was assessed using a neuropsychological development scale for patients aged 0-6 years and academic performance, and brain injury in patients was assessed using brain magnetic resonance imaging. c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. The genotype of c.158G>A variation is compound heterozygous variation, with mainly a mild hyperpheny-lalaninemia. 168 patients with PAH deficiency who were followed-up regularly had normal physical development without dwarfism or malnutrition. Among the 33 preschool patients who underwent mental development assessment, 2 were mentally retarded and the initial treatment age was older than 6 months. Nine patients with an average age of (17.13±2.42) years completed brain magnetic resonance imaging, one case was normal, and 8 cases were abnormal. There were patchy or patchy hyperintense foci near the bilateral lateral ventricles on T2WI, and the intellectual development was normal. Compared with the other eight patients, the blood phenylalanine concentration of the normal child was better and stably controlled within the ideal range. c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. After standardized treatment, most patients with PAH deficiency diagnosed by screening can obtain normal growth and intellectual development in adolescence, but there are different degrees of organic lesions in the cerebral white matter.

Long-term effects of maxillary skeletal expander treatment on functional breathing.

: To investigate the long-term effects of maxillary skeletal expander (MSE) treatment on functional breathing. measures of breathing, the peak nasal inspiratory flow (PNIF), and peak oral inspiratory flow (POIF), and subjective measures of breathing, the visual analog scale (VAS) and nasal obstruction symptom evaluation (NOSE) survey, were used to investigate the long-term effects of MSE in functional breathing. Seventeen patients, mean age 19.4 ± 3.9 years treated at the UCLA Orthodontics Clinic were assessed on their functional breathing at 3 timepoints: pre-expansion (T0), post-expansion (T1), and post-orthodontic treatment (T2). : Immediately after expansion (T1), all the objective functional breathing values were significantly increased in comparison to T0 (P < 0.05). The VAS total, VAS right and VAS left were significantly lower at T1 in comparison to T0 (P < 0.05). At 26.8 ± 3.9 months after MSE expansion (T2), PNIF total, PNIF right, PNIF left, and POIF were significantly higher when compared to T0 (P < 0.05). Also, VAS total, VAS right and VAS left were significantly lower at T2 when compared to T0 (P < 0.05). Additionally, there was a positive correlation between PNIF and the magnitude of expansion at anterior nasal spine and zygomaticomaxillary point (ZMA). There was a positive correlation between total VAS and the magnitude of expansion at the ZMA. There were no significant changes for the NOSE subjective breathing measurement at all time comparisons. : Overall, MSE treatment produces an increased objective and subjective airway improvement that continues to remain stable in the long-term post expansion.

A prospective open label 2–8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache

We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%)≥3 year, 33 (38%)≥5 years and 3 (3%)≥8.5 years. Mean (±SD) follow-up was 4.2±2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We didn't find predictive factors for effectiveness. ONS is a safe, well-tolerated and long-term effective treatment for MICCH. The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial

BackgroundThere is a large population of restless legs syndrome (RLS) patients who are refractory to medication. Whereas experts recommend off-label opioids as an effective long-term treatment for refractory RLS, reducing opioid dose could substantially reduce side effects and risks. Tonic motor activation (TOMAC) is a nonpharmacological therapeutic device indicated for refractory RLS. Here, we investigated if TOMAC could enable opioid dose reduction for refractory RLS.MethodsThis prospective, open-label, single-arm clinical trial [NCT04698343] enrolled 20 adults taking ≤ 60 morphine milligram equivalents (MMEs) per day for refractory RLS. Participants self-administered 30-min TOMAC sessions bilaterally over the peroneal nerve when RLS symptoms presented. During TOMAC treatment, opioid dose was reduced iteratively every 2–3 weeks until Clinician Global Impression of Improvement (CGI-I) score relative to baseline exceeded 5. Primary endpoint was percent of participants who successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Secondary endpoints included mean successful percent opioid dose reduction with CGI-I ≤ 5.ResultsOn average, participants were refractory to 3.2 medications (SD 1.6) and were taking a stable dose of opioids for 5.3 years (SD 3.9). Seventy percent of participants (70%, 14 of 20) successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Mean percent opioid dose reduction with CGI-I ≤ 5 was 29.9% (SD 23.7%, n = 20) from 39.0 to 26.8 MME per day. Mean CGI-I score at the reduced dose was 4.0 (SD 1.4), indicating no change to RLS severity.ConclusionsFor refractory RLS, TOMAC enabled substantial opioid dose reduction without increased RLS symptoms. These results suggest that TOMAC has the potential to reduce the risk profile associated with opioid therapy for refractory RLS.Trial registrationClinicalTrials.gov trial number NCT04698343 registered on January 6, 2021.

Long term effects of continuous positive airway pressure treatment of obstructive sleep apnea-hypopnea syndrome in multiple sclerosis patients

BackgroundObstructive sleep apnea-hypopnea (OSAH) is common in MS patients and is associated with fatigue. We recently published a randomized, controlled trial (RCT) of active vs sham continuous positive airway pressure (CPAP) treatment in MS patients with fatigue, poor sleep quality, and (OSAH) (Mult Scl J 2022;28:82–92). Our aim was to evaluate the long-term effects of CPAP treatment on fatigue (Fatigue Severity Scale, FSS, primary outcome) and other clinical outcomes in MS patients with OSAH. MethodsFollowing the RCT, participants were offered treatment with CPAP and participation in an open label study. Patients were re-evaluated with RCT outcome measures at least 6 months after completion of the RCT. ResultsTwenty-eight of 34 (82 %) RCT-completers participated in this study a mean of 2.7 years after the RCT. Sixteen (57 %) patients were treated with CPAP (mean use 5.4 ± 1.0 h/night during the 6 months prior to follow-up visit), while the other 12 patients declined CPAP use and received no other OSAH treatments. Baseline clinical characteristics, including MS related disability and sleep outcomes, were not significantly different between CPAP-treated vs non-CPAP treated patients. Patients using CPAP at follow-up (n = 16) demonstrated significant improvements from RCT baseline in FSS (p = 0.005), Fatigue Scale for Motor and Cognitive Functions (p = 0.008, p = 0.012), Pittsburgh Sleep Quality Index (p = 0.016), Center of Epidemiological Studies-Depression Scale (p = 0.05), and Multiple Sclerosis Quality of Life-54 (MSQOL-54) physical and mental component scores (p = 0.012, p = 0.023), but no improvements in Epworth Sleepiness Scale, Pain Visual Analog Scale, or Expanded Disability Status Scale. Patients not using CPAP (n = 12) had no significant improvements in outcome measures. Using a linear mixed model, FSS (p = 0.03), morning fatigue (p = 0.048), and MSQOL-54 physical component score (p = 0.02) improved significantly in CPAP treated patients compared with non-CPAP treated patients from RCT baseline. ConclusionIn this post-RCT open label study, long-term CPAP use was associated with improved fatigue (FSS, our primary outcome) and physical quality of life in MS patients with OSAH.

Effect of Ultrasound-Guided Rhomboid Interfascial Plane Block on Pain Severity, Disability, and Quality of Life in Myofascial Pain Syndrome – A Case Series With One-Year Follow-Up

BACKGROUND: Myofascial pain syndrome (MPS) is a condition characterized by trigger points in the taut bands of skeletal muscles, commonly affecting the trapezius, rhomboid, and supraspinatus muscles. Rhomboid intercostal block (RIB), an interfascial plane block used to assist perioperative analgesia might be a potential treatment option in MPS. OBJECTIVES: To investigate the short and long-term effects of ultrasound-guided RIB in reducing the severity of pain, disability, and improving quality of life in MPS patients with trigger points in the rhomboid muscle. STUDY DESIGN: Retrospective study. SETTING: Physical medicine and rehabilitation outpatient clinic in a university hospital. METHODS: Patients with a diagnosis of MPS who received ultrasound (US)-guided RIB between November 2021 and January 2022 were enrolled in this study. All patients reported pain lasting &gt;= 3 months and severity &gt;= 4/10 on numeric rating scale (NRS), without any comorbidities affecting the neuromuscular system. Trigger points in the rhomboid muscle were treated with US-guided RIB. Pain intensity was evaluated using a NRS at pre-treatment and one week, one month and one year after the injection. At pre-treatment, one month, and one year after treatment, self-administered neck pain and disability scale and Nottingham Health Profile were evaluated. RESULTS: A total of 23 patients were included in this study (5 men and 18 women, with an average age of 45). Pain severity was statistically significantly reduced in approximately 90%, 60-70%, and 50% of the chronic MPS patients at the first week, first month, and first year following injection, respectively. Disability scores improved significantly in 70% and 56% of those patients at the first month and first-year follow-up. Improvement in the quality of life was observed at the first month and maintained at the first-year follow-up. LIMITATIONS: The retrospective design of this study is a limitation. Due to the lack of a control group, this treatment option could not be compared with other treatments. CONCLUSIONS: Our study demonstrated that RIB might be an effective long-term treatment option for MPS in the reduction of pain and disability, improvement of quality of life and overall patient satisfaction. KEY WORDS: Myofascial pain syndrome, trigger point, pain, pain management, interventional ultrasound

Effects of Long-term Testosterone Treatment in Transgender People without Gender-Affirming Surgery: the ELANTES study

Effects of Long-term Testosterone Treatment in Transgender People without Gender-Affirming Surgery: the ELANTES study

Application and research progress of artificial intelligence technology in trauma treatment

To review the application and research progress of artificial intelligence (AI) technology in trauma treatment. The recent research literature on the application of AI and related technologies in trauma treatment was reviewed and summarized in terms of prehospital assistance, in-hospital emergency care, and post-traumatic stress disorder risk regression prediction, meanwhile, the development trend of AI technology in trauma treatment were outlooked. The AI technology can rapidly analyze and manage large amount of clinical data to help doctors identify patients' situation of trauma and predict the risk of possible complications more accurately. The application of AI technology in surgical assistance and robotic operations can achieve precise surgical plan and treatment, reduce surgical risks, and shorten the operation time, so as to improve the efficiency and long-term effectiveness of the trauma treatment. There is a promising future for the application of AI technology in the trauma treatment. However, it is still in the stage of exploration and development, and there are many difficulties of historical data bias, application condition limitations, as well as ethical and moral issues need to be solved.

A randomized, prospective, active-controlled study comparing intramuscular long-acting paliperidone palmitate versus oral antipsychotics in patients with schizophrenia at risk of violent behavior

ObjectivePaliperidone palmitate (PP) is an effective long-acting antipsychotic injection, but its impact on the behavior of schizophrenia patients with dangerous tendencies requires further investigation. This study aims to explore the effects of long-term antipsychotic treatment on this population in the community. MethodsThis 49-week, randomized controlled trial was conducted across 21 communities in Wuhan and enrolled 134 schizophrenia patients at risk for violent behavior. With a fixed block size of 10, participants were randomly assigned to receive either intramuscular PP 1-month formulation (PP1M) or oral antipsychotic medication (OAP) at a 1:1 ratio. Changes in patients' risk for violent/aggressive behavior, family burden, social, and cognitive functioning were measured using VRAPP, MOAS, PANSS, FBS, PSP, and RBANS scales from baseline to endpoint. Longitudinal data from multiple repeated measures were analyzed using linear mixed-effects models. ResultsThe study protocol was completed by 77.6% of the patients overall. Significant improvements were observed in the risk assessment scores, MOAS total score, PANSS total score, PSP total score, and FBS total score of patients in the PP1M group from baseline to the end of treatment (all P < 0.05). Importantly, compared to patients in the OAP group, the improvements in these measures were also significantly greater in the PP1M group. Commonly observed AEs, such as hyperprolactinemia (70.3% vs. 62.65%) and muscle tension (45.3% vs. 57.8%), were considered to be the PP-related AEs. Nonetheless, the differences between the two groups did not reach statistical significance, and no new safety concerns emerged. ConclusionsOur study suggests that PP long-acting injection (LAI) is a safe and effective treatment option for community-dwelling schizophrenia patients with impulsive violence and risky behaviors.

Long-term dopamine agonist treatment fails to restore altered central sensory processing in restless legs syndrome: Evidence from current perception threshold measurements

ObjectivesAlthough some studies have examined the impact of short-term dopamine agonist treatment on altered central sensory processing in patients with restless legs syndrome (RLS), there is a scarcity of research investigating the effect of long-term treatment with these drugs. The aim of this study is to investigate the long-term impact of dopamine agonist treatment on altered central sensory processing in RLS patients using current perception threshold (CPT) testing. MethodsWe conducted a study of 24 RLS patients, measuring their CPT values before and after dopamine agonist treatment for at least 2 months. Patients were classified as responders or non-responders based on their decrease in International Restless Legs Syndrome (IRLS) score. Clinical parameters were collected and compared pre- and post-treatment. ResultsThe mean duration of treatment with dopamine agonist was 13.6 ± 11.0 months. Our results showed that dopamine agonist treatment significantly improved clinical parameters, including the IRLS score, Visual Analogue Scale, and RLS Quality of Life questionnaire. However, CPT values did not show significant changes for all stimulus frequencies after treatment. Furthermore, we did not find any difference in CPT values before and after treatment in both responders and non-responders. ConclusionsOur study demonstrated that long-term treatment with dopamine agonists effectively reduces RLS symptoms, but does not reverse the altered central sensory processing observed on CPT testing in RLS patients. These results support the notion that the pathophysiology of RLS is multifactorial and not solely driven by dopaminergic dysfunction.

Adapting and implementing breast cancer follow-up in primary care: protocol for a mixed methods hybrid type 1 effectiveness-implementation cluster randomized study

BackgroundAdvances in detection and treatment for breast cancer have led to an increase in the number of individuals managing significant late and long-term treatment effects. Primary care has a role in caring for patients with a history of cancer, yet there is little guidance on how to effectively implement survivorship care evidence into primary care delivery.MethodsThis protocol describes a multi-phase, mixed methods, stakeholder-driven research process that prioritizes actionable, evidence-based primary care improvements to enhance breast cancer survivorship care by integrating implementation and primary care transformation frameworks: the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework and the Practice Change Model (PCM). Informed by depth interviews and a four round Delphi panel with diverse stakeholders from primary care and oncology, we will implement and evaluate an iterative clinical intervention in a hybrid type 1 effectiveness-implementation cluster randomized design in twenty-six primary care practices. Multi-component implementation strategies will include facilitation, audit and feedback, and learning collaboratives. Ongoing data collection and analysis will be performed to optimize adoption of the intervention. The primary clinical outcome to test effectiveness is comprehensive breast cancer follow-up care. Implementation will be assessed using mixed methods to explore how organizational and contextual variables affect adoption, implementation, and early sustainability for provision of follow-up care, symptom, and risk management activities at six- and 12-months post implementation.DiscussionStudy findings are poised to inform development of scalable, high impact intervention processes to enhance long-term follow-up care for patients with a history of breast cancer in primary care. If successful, next steps would include working with a national primary care practice-based research network to implement a national dissemination study. Actionable activities and processes identified could also be applied to development of organizational and care delivery interventions for follow-up care for other cancer sites.Trial registrationRegistered with ClinicalTrials.gov on June 2, 2022: NCT05400941.

Long-term effects of mavacamten treatment in obstructive hypertrophic cardiomyopathy (HCM): updated cumulative analysis of the EXPLORER cohort of MAVA-long-term extension (LTE) study up to 120 weeks

Abstract Introduction Mavacamten was efficacious and well tolerated in patients (pts) with obstructive HCM over a median follow-up of 62 weeks in a previous interim analysis of the ongoing MAVA-LTE study (NCT03723655) (data cut-off; August 31, 2021). Here, we report an updated cumulative analysis of the EXPLORER cohort of MAVA-LTE up to 120 weeks. Methods Pts who completed EXPLORER-HCM (NCT03470545) could enroll in MAVA-LTE. All pts initiated the study with mavacamten 5 mg/day per protocol; dose adjustments to 2.5, 10, or 15 mg were based on site-read Valsalva left ventricular outflow tract (LVOT) gradient and LV ejection fraction (LVEF). Results In total, 231 pts (median age, 61 years; 39% female) enrolled in the EXPLORER cohort of MAVA-LTE. Median time on study was 101 weeks at data cut-off (May 31, 2022) with variations due to differences in enrollment timing. At data cut-off, 215 pts remained on treatment (total adjusted exposure: 475 pt-years). Mavacamten dosing of pts who reached week 120 (n=80) was: 2.5 mg (27.5%); 5 mg (31.3%); 10 mg (26.3%); 15 mg (12.5%). Between weeks 48–120, 34 of 231 (14.7%) pts underwent dose adjustments. Mavacamten treatment showed sustained improvements in mean [SD] change from baseline to week 120 in LVOT gradients (resting, −35.3 [33.0] mmHg; Valsalva, −47.0 [37.3] mmHg), left atrial volume index (−8.5 [10.3] mL/m2) and E/e’ average (−3.9 [5.0]) (Table). At week 120, 83.5% of pts had a Valsalva LVOT gradient ≤30 mmHg. Mavacamten was associated with sustained reduction from baseline to week 120 in N-terminal pro B-type natriuretic peptide (NT-proBNP) level (Table); 75.9% of pts improved by ≥1 class New York Heart Association class (Figure). Mean (SD) LVEF decreased by 9.1% (7.1) from baseline to week 120 but remained in the normal range. Since the previous interim analysis (data cut-off: August 31, 2021), 1 additional transient reduction in LVEF &amp;lt;50% occurred resulting in temporary treatment interruption (a total of 13 pts [5.6%] experienced LVEF &amp;lt;50% from study initiation). The pt resumed treatment at a lower dose 4 weeks after the event. In total, 74 serious adverse events (SAE) were reported in 47 pts (20.3%), with 18 new SAEs and 13 additional pts (5.6%) with SAEs since the previous interim analysis, including 1 new SAE (atrial fibrillation) considered drug related. No new safety signals were identified. One additional death (leading to a total of 4) occurred, due to intracranial hemorrhage. Like the previous 3 deaths (due to acute myocardial infarction, cardiac arrest, and bacterial endocarditis) the event was considered unrelated to the study drug. Conclusions Long-term mavacamten treatment up to 120 weeks showed sustained improvements in LVOT obstruction, symptoms, and NT-proBNP levels in pts with symptomatic obstructive HCM consistent with the findings of the parent study. Mavacamten treatment continues to be well tolerated with no new safety signals observed.

Causal relationships between pain, medical treatments, and knee osteoarthritis: A graphical causal model to guide analyses

ObjectiveRandomized controlled trials (RCTs) are a gold standard for estimating the benefits of clinical interventions, but their decision-making utility can be limited by relatively short follow-up time. Longer-term follow-up of RCT participants is essential to support treatment decisions. However, as time from randomization accrues, loss to follow-up and competing events can introduce biases and require covariate adjustment even for intention-to-treat effects. We describe a process for synthesizing expert knowledge and apply this to long-term follow-up of an RCT of treatments for meniscal tears in patients with knee osteoarthritis (OA). MethodsWe identified 2 post-randomization events likely to impact accurate assessment of pain outcomes beyond 5 years in trial participants: loss to follow-up and total knee replacement (TKR). We conducted literature searches for covariates related to pain and TKR in individuals with knee OA and combined these with expert input. We synthesized the evidence into graphical models. ResultsWe identified 94 potential covariates potentially related to pain and/or TKR among individuals with knee OA. Of these, 46 were identified in the literature review and 48 by expert panelists. We determined that adjustment for 50 covariates may be required to estimate the long-term effects of knee OA treatments on pain. ConclusionWe present a process for combining literature reviews with expert input to synthesize existing knowledge and improve covariate selection. We apply this process to the long-term follow-up of a randomized trial and show that expert input provides additional information not obtainable from literature reviews alone.

Statistical Challenges from Trials of Potentially Curative Treatments: Validation of Cure Assumptions When Analyzing Zuma-7 Follow-up Data of Axi-Cel and Standard of Care Therapy

Introduction: ZUMA-7 is the largest randomized controlled trial (RCT) for chimeric antigen receptor (CAR) T-cell therapy which compared axicabtagene ciloleucel (Axi-cel) to standard of care (SoC) including autologous stem cell transplant (ASCT) for the treatment of relapsed or refractory DLBCL. Both arms of ZUMA-7 contained potentially curative treatments; however, differences in the treatment completion rate (94% received axi-cel and 36% received ASCT) and timing to receive definitive treatment led to differences in the extent and timing of cure. Furthermore, 57% of the SoC arm received potentially curative CAR-T therapies in subsequent lines of therapy leading to a delayed cure in that fraction of the population. The resulting event-free survival (EFS) and overall survival (OS) curves can pose challenges in interpretation and extrapolation for the purpose of simulations of long-term treatment effects and cost-effectiveness. Mixture cure modeling (MCM) has been suggested as a superior method to evaluate treatments of a curative nature to allow for part of the population to achieve long-term remission. This method has been shown to be useful both in designing and powering clinical studies of curative therapies but also for extrapolation of long-term outcomes in simulation studies. However previous iterations of this method did not account for differences in timing of curative therapies. ZUMA-7 had two pivotal analyses separated by nearly 2-years of follow-up: a primary EFS (datacut 1) and a primary OS analyses (data cut 2). The aim of this study was to use the two data cuts of ZUMA-7 to validate MCM in 2L LBCL and describe differences that may have arisen due to treatment specific timing and extent of cure. Methods: Overall survival individual patient-level data from the ZUMA-7 trial for axi-cel and SoC from both data cut 1 (median follow-up: 24.9 months) and data cut 2 (median follow-up: 47.2 months) were used in this analysis. Three different parametric modeling approaches were applied and compared in both data cuts: standard parametric model, spline-based model, and MCMs. Modeling approaches were evaluated for plausibility across a range of metrics, across the two data cuts, including visual fit, plausibility of long-term estimates, statistical goodness of fit, inspection of hazard plots, point-estimate accuracy, and conditional survival estimates. Additionality, the ability of the early data cut extrapolation to predict the actual data was assessed by comparing the model predictions with the latest KM estimator in both trial arms. Differences between trial arms were evaluated. Results: Cure-based and spline models provided the best fit based on the percentage inaccuracy of extrapolations fitted with data cut 1 in comparison to 5-year OS Kaplan-Meier estimates confirmed by data cut 2. In the axi-cel treatment arm, the percentage inaccuracy range between 2% and 27% (Figure 1). Based on data cut 1, cure fractions ranged considerably across the MCM extrapolation forms considered for both treatment arms (range: 24-54% [Figure 2] and 35-49% for axi-cel and SoC, respectively). Notably, the range of cure fractions narrowed considerably based on extrapolations performed on the more mature data cut 2 (range: 50-54% [Figure 2] and 41-50% for axi-cel and SoC, respectively). Overall, the uncertainty in the estimate of cure fractions based on MCMs was reduced from data cut 1 to data cut 2 for axi-cel vs. SoC, suggesting clinical input is needed to validate early extrapolations using less mature data cuts. Conclusion: Our analysis suggests that MCMs are helpful in making accurate predictions of survival based on immature data when a plateau in the survival curve is clinically plausible. However, this analysis also highlights the importance of considering clinical plausibility to guide specific curve selection in the presence of immature survival data, as there was a high degree of variability in the early extrapolations which was reduced with the longer-term follow-up. The ability to reliably extrapolate from early data may improve clinical decision making and reduce delays in patient access to potentially lifesaving treatments as more mature follow-up data are being collected.

Efficacy and Safety of Reduced-Dose Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) in Patients over 80 with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Background: The standard treatment for newly diagnosed DLBCL has been R-CHOP for many years. Recently, Pola-R-CHP using polatuzumab vedotin has been reported to have superior efficacy to R-CHOP and is available as first-line treatment for DLBCL. However, the patients in the phase 3 POLARIX trial were under 80, and the efficacy and safety for patients over 80 are not established. To investigate the efficacy and safety of Pola-R-CHP in the elderly, we conducted this study. Patients and Methods: From September 2022 to March 2023, we retrospectively analyzed patients with newly diagnosed DLBCL treated with Pola-R-CHP at Anjo Kosei Hospital. Patients previously treated for hematologic malignancies were excluded. The dosages of polatuzumab vedotin and rituximab were not reduced, and the dosages of cyclophosphamide, doxorubicin, and prednisone or treatment schedules were determined by the treating physician. The primary endpoint was the rate of treatment continuation without early termination, and secondary endpoints were efficacy, progression free survival (PFS), and safety. Results: A total of 29 patients (younger group: under 80, n = 21; elderly group: over 80, n = 8) were consecutively enrolled. The median age in the younger group was 64 (range 42-78) and in the elderly group was 82.5 (range 80-94). Patient characteristics, including history of malignancy (24% vs 13%, p=0.50), lifestyle diseases (43% vs 50%, P = 0.73), and sanctuary lesions (10% vs 25%, P = 0.28), were comparable in both groups. However, advanced disease was significantly higher in the younger group (76% vs 38%, P = 0.05). The Revised IPI scores were similar in both groups (Very good: 5% vs 0 %, Good: 29% vs 50%, Poor: 67% vs 50%, P = 0.50). Cyclophosphamide, doxorubicin, and prednisone were administered at full dose in 71% of the younger group, but were reduced in all patients in the elderly group (P = 0.001). Peg-GCSF was administered during treatment in all cases in the elderly group. The median days to the 6th cycle were 111 (range 105-126) in the younger group and 114.5 (range 107-124) in the elderly group, with no significant difference (P = 0.37). The rate of treatment continuation until the 6th cycle was 86% in the younger group and 100% in the elderly group, with no significant difference (P = 0.27, Fig A). Three patients in the younger group discontinued treatment due to deterioration of comorbidities (n=1), early death due to infection (n=1), and insufficient treatment effect leading to regimen change (n = 1). In the positron emission tomography (PET) / computer tomography (CT)-based response evaluation after treatment, complete metabolic response was observed in 48% of the younger group and 50% of the elderly group, and partial metabolic response was observed in 19% and 13% respectively (P = 0.90, Fig B). The CT based response were evaluated during the treatment. After 2 cycles of treatment, partial response was achieved 86% of patients in younger group and 75% of those in elderly group (P = 0.50). In the elderly group, complete response was confirmed in 75% of the patients at the end of cycle 6. The 6-month PFS after treatment initiation was 95% in the younger group (95% confidence interval, 71-99%) and 100% in the elderly group (p = 0.54). The incidence of grade 3 or higher non-hematologic toxicity was 28% in the younger group and 48% in the elderly group (P = 0.27). The incidence of febrile neutropenia or grade 3 or higher infection was 76% in the younger group and 75% in the elderly group (P = 0.95), and one case of grade 5 sepsis was observed in the younger group. There were no cases of cytomegalovirus reactivation or infection. Peripheral neuropathy occurred in 3 cases (14%) in the younger group but not in the elderly group. Conclusion: Pola-R-CHP is a feasible and effective treatment in clinical practice for patients over 80 with newly diagnosed DLBCL, with efficacy equivalent to that in younger patients. Further confirmation of long-term treatment effects and safety is necessary, but reduced-dose Pola-R-CHP is a reasonable choice as a standard treatment for newly diagnosed DLBCL in the elderly.

Lithium Treatment Induces Cardiac Dysfunction in Mice.

Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes' size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.