Long-term Clinical Benefit Research Articles

Novel Conservative Therapies in Migraine Management: The Impact of Fascia Exercises in a Randomized Controlled Trial

Background/Objectives: Migraine is a complex neurological disorder often associated with autonomic nervous system (ANS) dysfunction. This study aimed to evaluate the effects of fascia exercises on migraine symptoms and explore their potential as a novel conservative treatment approach. Methods: A prospective, randomized controlled trial was conducted with 30 migraine patients who were randomly assigned to a treatment group (fascia exercises) or a control group (conventional physiotherapy). Both groups underwent a six-week intervention consisting of two sessions per week. Pain intensity, migraine-related disability, sleep quality, anxiety, depression, heart rate variability (HRV), and patient satisfaction were assessed before and after the intervention using validated scales. Results: Significant improvements in pain intensity, attack frequency and duration, migraine-related disability, sleep quality, and anxiety levels were observed in both groups (p < 0.05). However, the treatment group demonstrated a more pronounced reduction in depression scores compared to the control group (p < 0.05). While no significant changes in HRV parameters were detected in either group, patient satisfaction was significantly higher in the treatment group (p < 0.05). Conclusions: Fascia exercises represent a promising complementary therapy for migraine management, offering significant improvements in both physical and psychological symptoms. While immediate effects on HRV were not evident, the potential to modulate autonomic balance and address migraine pathophysiology warrants further exploration. These findings highlight the value of fascia exercises as a low-cost, non-invasive approach, emphasizing the need for further research to confirm their long-term clinical benefits and integration into migraine treatment protocols.

Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer.

Neoadjuvant immune checkpoint blockade with nivolumab plus ipilimumab improves overall survival (OS) in non-small cell lung cancer (NSCLC); however, randomized data for resectable lung cancer are limited. We report results from the exploratory concurrently randomized nivolumab plus ipilimumab and chemotherapy arms of the international phase III CheckMate 816 trial. Adults with stage IB-IIIA (American Joint Committee on Cancer seventh edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery. Analyses included event-free survival (EFS), OS, pathologic response, surgical outcomes, biomarker analyses, and safety. A total of 221 patients were concurrently randomly assigned to nivolumab plus ipilimumab (n = 113) or chemotherapy (n = 108). At a median follow-up of 49.2 months, the median EFS was 54.8 months (95% CI, 24.4 to not reached [NR]) with nivolumab plus ipilimumab versus 20.9 months (95% CI, 14.2 to NR) with chemotherapy (HR, 0.77 [95% CI, 0.51 to 1.15]); 3-year EFS rates were 56% versus 44%. Higher rates of EFS events were initially seen, with later benefit favoring nivolumab plus ipilimumab; 3-year OS rates were 73% versus 61% (HR, 0.73 [95% CI, 0.47 to 1.14]); pathologic complete response rates were 20.4% versus 4.6%, respectively. In the respective arms, 83 (74%) and 82 patients (76%) underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 14% and 36% of patients, respectively. Neoadjuvant nivolumab plus ipilimumab showed potential long-term clinical benefit versus chemotherapy, despite early crossing of EFS curves in the preoperative phase and a lower rate of high-grade toxicity.

Fulvestrant Versus Anastrozole in Endocrine Therapy-Naïve Women With Hormone Receptor-Positive Advanced Breast Cancer: Final Overall Survival in the Phase III FALCON Trial.

The randomized phase III FALCON trial demonstrated significant improvement in progression-free survival (PFS) with fulvestrant versus anastrozole in postmenopausal women with endocrine therapy-naïve, hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Herein, the prespecified final overall survival (OS) analysis is reported. After the primary PFS analysis, data were collected on survival, serious adverse events, and health-related quality of life. The final OS analysis was triggered at ≥65% maturity and ≥8 years since the last patient was enrolled. Analyses were descriptive with nominal P values (one-sided α threshold .01845). At the data cutoff (July 11, 2022), 314 (68.0%) of 462 patients had died (fulvestrant, 157/230 [68.3%], anastrozole, 157/232 [67.7%]). The final OS analysis of FALCON demonstrated no significant difference between fulvestrant and anastrozole (medians, 44.8 and 42.7 months, respectively; hazard ratio [HR], 0.97 [95% CI, 0.77 to 1.21]; P = .7579). Among patients with nonvisceral disease (n = 208), a trend showed a 15% reduction in the relative risk of death with fulvestrant versus anastrozole (median OS, 65.2 v 47.8 months; HR, 0.85 [95% CI, 0.60 to 1.20]). Data from FALCON are consistent with published evidence of long-term clinical benefit with fulvestrant and other endocrine therapies in the subset of patients with nonvisceral disease.

Safety and efficacy of lamivudine/dolutegravir vs. bictegravir/emtricitabine/tenofovir alafenamide in antiretroviral-naive adults with HIV-1 infection in Shanghai, China: a single-centre retrospective study

Introduction. Lamivudine plus dolutegravir (3TC/DTG) and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) regimens are commonly used as first-line treatments for people living with human immunodeficiency virus (HIV) (PLWH) worldwide. Gap Statement. There are limited comparative data on the antiviral activity and safety between these regimens in ART-naive PLWH, particularly in China, where the 3TC/DTG regimen was integrated into first-line therapy in 2021 and gained broader adoption after its inclusion in the National Health Insurance in 2022. Aims. This study aims to provide real-world evidence comparing the 3TC/DTG regimen to the B/F/TAF regimen in ART-naive PLWH in China. Methodology. This retrospective study enrolled PLWH initiating ART with either 3TC/DTG or B/F/TAF in Shanghai from January 2020 to January 2023. Demographic characteristics and clinical information were collected and compared for each patient. Results. A total of 380 eligible, ART-naive PLWH were included, with 190 patients in the 3TC/DTG group and 190 patients in the B/F/TAF group. Following the initiation of ART, most patients (94.1 and 89.3% for 3TC/DTG and B/F/TAF groups, respectively) achieved viral suppression (<50 copies of HIV RNA per millilitre) at week 24. The CD4 cell count significantly increased from a baseline of 301.3±185.8 cells per microlitre to 479.5±229.3 cells per microlitre at week 36 for the 3TC/DTG group and from 289.2±188.8 cells per microlitre at baseline to 487.8±234.2 cells per microlitre at week 36 for the B/F/TAF group. Both groups experienced an increase in blood lipid levels after initiating ART, with higher levels of high-density lipoprotein cholesterol (HDL-C) observed in the 3TC/DTG group compared with the B/F/TAF group. Renal and hepatic function indicators remained stable in both groups. Conclusions. 3TC/DTG demonstrates similar antiviral efficacy to B/F/TAF and does not significantly impact liver and kidney functions. Patients receiving 3TC/DTG showed higher plasma HDL-C levels compared with those on B/F/TAF, which confer long-term clinical benefits in reducing cardiovascular risk.

Effectiveness of Surgical Interventions in Chronic Venous Insufficiency: An Evidence-Based Systematic Review

Chronic Venous Insufficiency (CVI) is a disease that can significantly affect patients' quality of life. Although modern surgical therapies such as endovenous thermal ablation (ETA), iliac vein stenting, and others have been introduced, the effectiveness and safety of each procedure needs to be further evaluated. This study aims to evaluate the effectiveness and safety of modern surgical interventions in the management of CVI, focusing on clinical outcomes such as ulcer healing, pain reduction, and improvement in patient quality of life. This systematic review was conducted following PRISMA guidelines by screening literature from PubMed, ScienceDirect, Google Scholar, and Cochrane Library between 2014 and 2024. Of the 17,500 articles identified, 10 studies were included through a rigorous selection process. Analysis was performed based on study design, population, intervention type, clinical outcomes, and safety profile. Endovenous thermal ablation showed an anatomical success rate of more than 96% with long-term clinical benefits. Iliac vein stenting significantly improved symptoms of deep vein obstruction (VAS: 9 to 2.5) with a primary patency rate of 92%. Methods such as mechanochemical ablation (MOCA) and cyanoacrylate embolization (CAE) offer minimally invasive approaches with low complication rates and fast recovery times. The combination of early ablation and compression therapy accelerates healing of chronic venous ulcers (median healing time: 56 vs. 82 days). Modern surgical interventions are proven effective and safe in the management of CVI, with thermal ablation as the gold standard and iliac vein stenting as the superior option for deep vein obstruction. This evidence-based approach provides important guidance for personalizing CVI therapy in the future. Further research is needed to evaluate long-term sustainability and to optimize evidence-based clinical guidelines.

Novel endpoints based on tumor size ratio to support early clinical decision-making in oncology drug-development.

In oncology drug development, overall response rate (ORR) is commonly used as an early endpoint to assess the clinical benefits of new interventions; however, ORR benefit may not always translate into a long-term clinical benefit such as overall survival (OS). Most of the work on developing endpoints based on tumor growth dynamics relies on empirical validation, leading to a lack of generalizability of the endpoints across indications and therapeutic modalities. Additionally, many of these metrics are model-based and do not use data from all the patients. The objective of this work is to use longitudinal tumor size data and new lesion information (that is, the same information used by the ORR) to develop novel endpoints that can improve early clinical decision-making compared to the ORR. We investigate in this work multiple candidate novel endpoints based on tumor size ratio that utilize longitudinal tumor size data from all the patients regardless of their follow-up, rely only on tumor size and new lesion information, and are model-free. An extensive simulation study is conducted, exploring a wide spectrum of tumor size data and overall survival outcomes by modulating a variety of trial characteristics such as slow vs fast tumor growth, high vs low drug efficacy rates, variability in patients' responses, variations in the number of patients, follow-up periods, new lesion rates and survival curve shapes. The proposed novel endpoints based on tumor size ratio consistently outperform the ORR by having a comparable or higher correlation with the OS. Further, the novel endpoints exhibit superior accuracy compared to the ORR in predicting the long-term OS benefit. Retrospective empirical validation on BMS clinical trials confirms our simulation findings. These findings suggest that the tumor size ratio-based endpoints could replace ORR for early clinical decision-making in oncology drug development.

EGFR slope modelling predicts long-term clinical benefit with nefecon in a real-world IgAN population

Abstract Background Nefecon is an oral, targeted-release formulation of budesonide approved to reduce kidney function loss in patients with immunoglobulin A nephropathy (IgAN). In the phase 3 NefIgArd trial, 9 months of nefecon treatment preserved estimated glomerular filtration rate (eGFR) and reduced urine protein–creatinine ratio versus placebo, for 15 months post-treatment. A modelling analysis was conducted to predict nefecon's long-term benefits on clinical outcomes. Methods A published linear regression model was used to extrapolate nefecon's effect on eGFR slope in NefIgArd to predict its effect on the clinical outcome of kidney failure, eGFR <15 mL/min/1.73 m2, or sustained doubling of serum creatinine. This model was applied to registry data from patients with IgAN at Leicester General Hospital (LGH), whose records were matched to individual NefIgArd patients based on their urine protein–creatinine ratio and eGFR values. Results 1684 LGH-NeflgArd ‘matched-pairs’ were obtained. Nefecon was predicted to delay the time to clinical outcome by 12.8 years (95% confidence interval 4.8–27.9), with median time to outcome of 9.6 years for patients receiving supportive care only versus 22.4 years for nefecon-treated patients. The NeflgArd 2-year eGFR slope yielded a log hazard ratio for the clinical outcome of 0.38 (95% confidence interval 0.21–0.63), a 62% risk reduction versus placebo. 52% of patients receiving supportive care only were modelled to have a clinical outcome within 10 years versus 24% of nefecon-treated patients. Conclusion This modelling analysis indicates that the eGFR benefit seen with nefecon predicts a substantial delay in progression to kidney failure.

Early coronary angiography in patients with myocardial infarction without ST elevation after out-of-hospital cardiac arrest: a systematic review and meta-analysis.

Early coronary angiography (CAG) in post-cardiac arrest patients without ST-segment elevation is a topic of debate. This meta-analysis aimed to assess its impact on outcomes. A search of Medline and Cochrane up to February 2023 was conducted to identify randomized controlled trials and observational studies comparing patients undergoing early CAG vs. delayed/no CAG after experiencing out-of-hospital cardiac arrest. A random-effects model pooled odds ratios (ORs) with 95% confidence intervals (CIs). Meta-regression explored factors modifying effect sizes. We identified 16 studies (7 RCTs, 9 observational studies) involving 4,737 patients. Early CAG significantly reduced long-term mortality [OR: 0.66 (0.51-0.85)], and increased favorable cerebral performance category (CPC) 1-2 at discharge [OR: 1.49 (1.09-2.03)]. Observational study subgroup showed decreased short-term mortality, long-term mortality, and CPC 1-2 at discharge, unlike RCT subgroup. Meta-regression revealed type 2 diabetes mellitus and follow-up time influencing short-term mortality and CPC 1-2 at discharge, respectively. Early CAG in post-cardiac arrest patients without ST elevation is associated with long-term clinical benefits, particularly evident in observational studies. Interpretation should be cautious.

Current Status of Glucagon-like Peptide-1 Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: A Clinical Perspective.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.

Digital Mental Health Interventions for Adolescents in Low- and Middle-Income Countries: Scoping Review.

Digital mental health interventions (DMHIs) are increasingly recognized as potential solutions for adolescent mental health, particularly in low- and middle-income countries (LMICs). The United Nations' Sustainable Development Goals and universal health coverage are instrumental tools for achieving mental health for all. Within this context, understanding the design, evaluation, as well as the barriers and facilitators impacting adolescent engagement with mental health care through DMHIs is essential. This scoping review aims to provide insights into the current landscape of DMHIs for adolescents in LMICs. The Joanna Briggs Institute scoping review methodology was used, following the recommendations of the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews). Our search strategy incorporated 3 key concepts: population "adolescents," concept "digital mental health interventions," and context "LMICs." We adapted this strategy for various databases, including ACM Digital Library, APA PsycINFO, Cochrane Library, Google Scholar (including gray literature), IEEE Xplore, ProQuest, PubMed (NLM), ScienceDirect, Scopus, and Web of Science. The articles were screened against a specific eligibility criterion from January 2019 to March 2024. We analyzed 20 papers focusing on DMHIs for various mental health conditions among adolescents, such as depression, well-being, anxiety, stigma, self-harm, and suicide ideation. These interventions were delivered in diverse formats, including group delivery and self-guided interventions, with support from mental health professionals or involving lay professionals. The study designs and evaluation encompassed a range of methodologies, including randomized controlled trials, mixed methods studies, and feasibility studies. While there have been notable advancements in DMHIs for adolescents in LMICs, the research base remains limited. Significant knowledge gaps persist regarding the long-term clinical benefits, the maturity and readiness of LMIC digital infrastructure, cultural appropriateness, and cost-effectiveness across the heterogeneous LMIC settings. Addressing these gaps necessitates large-scale, co-designed, and culturally sensitive DMHI trials. Future work should address this.

Long-term patient clinical benefits and healthcare utilization after pulsed field ablation in paroxysmal atrial fibrillation: sub-analyses from the multicenter inspIRE trial

Abstract Background/Introduction The treatment of atrial fibrillation (AF) with pulsed field ablation (PFA) aims to prevent AF recurrence while reducing complications from the ablation modality. Similar to thermal ablation, PFA has proven to be safe and effective for treatment of paroxysmal AF (PAF); however, there is scarce evidence on patient-related clinical benefits, including healthcare utilization, using this new energy modality. Purpose The objective of this study is to assess long-term clinical improvements in patient care, symptoms, and quality-of-life (QOL) after PFA ablation in PAF. Methods InspIRE was a multicentre study evaluating the safety and efficacy of variable loop PFA catheters integrated with a 3D mapping system for treatment of symptomatic PAF. Patients were followed for up to 12 months for the following QOL and healthcare utilization endpoints: Atrial Fibrillation Effect on Quality-of-Life (AFEQT) score, Class I/III AAD utilization, repeat ablation, incidence of direct current cardioversion (DCCV), and cardiovascular (CV) hospitalization. Post-hoc Kaplan-Meier estimates for clinical benefit success at 12 months were provided. Success was defined as composite freedom from occurrence of the following events post-blanking: repeat ablation, CV hospitalization, AAD utilization, and DCCV post-blanking. Predictors of clinical benefit success were explored via multivariate logistic regression analysis. Results A total of 186 enrolled patients (59±10 years; 70.0% male; CHA2DS2-VASC score 1.3±1.2) underwent PVI. Compared to baseline: 1) improvements in the AFEQT composite score were seen at 12 months (P<0.001); 2) Class I/III AAD use was reduced from 81.7% to 20.1% at 6-12 months (P<0.05); and 3) the proportion of subjects with DCCV decreased from 13.7% up to 12 months before the index procedure to 3.3% up to 12 months after the index procedure (P<0.001, Figure 1). Minimal clinically important difference in QoL (≥5 points improvement in AFEQT) was achieved in 85.2% of patients. Patients free from 12-month AF/AT/AFL recurrence (asymptomatic and symptomatic) had significantly greater improvements in AFEQT scores from baseline to 12 months versus those with recurrence (P=0.01). The clinical benefit success rate at 12 months was 87.5% (Figure 2). Patients who failed the clinical benefit endpoint were counted, including those with repeat ablation (7.5%), those on new or higher dose of AAD (6.5%), those hospitalized for CV (4.8%), and those who had DCCV post-blanking (1.6%). Multivariate logistic regression analysis showed that left ventricle ejection fraction <60% (OR: 0.22; 95% CI: 0.08-0.62; P<0.05) and incidence of diabetes (OR: 7.25; 95% CI: 2.00, 26.3; p<0.05) were associated with a higher risk of clinical benefit failure. Conclusions PFA ablation of PAF patients led to a clinical benefit success rate of 87.5%, with clinically meaningful improvement in QOL, as well as a reductions in AAD use, cardioversion, and hospitalization.Figure 1.Improvements in QoL and HealthFigure 2.Kaplan-Meier Analysis of Time

The long-term clinical benefit of early versus delayed invasive strategies in elderly patients with non-ST-segment elevation myocardial infarction who have undergone percutaneous coronary intervention

Abstract Background The data regarding long-term outcomes of early versus delayed invasive strategies in elderly patients who have undergone percutaneous coronary intervention (PCI) for non-ST-segment elevation myocardial infarction (NSTEMI) is limited. Purpose We aimed to investigate the long-term clinical benefit of early versus delayed invasive strategies in elderly patients who underwent PCI for NSTEMI. Methods From a nationwide, prospective, real-world registry of 13,104 patients with acute myocardial infarction (MI) who underwent PCI, 2818 elderly patients (aged ≥70 years) who underwent PCI for NSTEMI were included. Of these, 2299 patients were treated with an early invasive strategy (early invasive group), and 519 were treated later (delayed invasive group). The incidence of major adverse cardiac events (MACE; all-cause death, recurrent MI, any revascularization, stroke, readmission due to heart failure [HF], or definite/probable stent thrombosis [ST]) and the components of MACE were compared using multivariable Cox regression, propensity score (PS) matched, and PS-adjusted analyses. Results During a median follow-up of 1047 days, MACE, all-cause death, and cardiac death occurred in 1018 (36.1%), 660 (23.4%), and 423 patients (15.0%), respectively. The early invasive group showed significantly lower risks of MACE (entire: 35.0% vs. 41.2%, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.66-0.90, p=0.001; PS-matched: n=984, 33.3% vs. 40.8%, HR 0.75, 95% CI 0.62-0.91, p=0.005), all-cause death (entire: 22.5% vs. 27.4%, HR 0.76, 95% CI 0.63-0.92, p=0.004; PS-matched: 21.8% vs. 27.2%, HR 0.75, 95% CI 0.58-0.90, p=0.005), cardiac death (entire: 13.8% vs. 20.2%, HR 0.64, 95% CI 0.51-0.79, p<0.001; PS-matched: 13.1% vs. 19.4%, HR 0.67, 95% CI 0.55-0.86, p=0.011), and readmission due to HF (entire: 6.5% vs. 9.2%, HR 0.64, 95% CI 0.46-0.89, p=0.007; PS-matched: 6.7% vs. 9.4%, HR 0.68, 95% CI 0.51-0.96, p=0.017) than the delayed invasive group. There were no significant differences in the risks of recurrent MI, any revascularization, stroke, and definite/probable ST between the groups. Furthermore, in patients aged ≥80 years, the early invasive group had significantly reduced rates of MACE (42.9% vs. 49.5%, HR 0.71, 95% CI 0.55-0.91, p=0.039), all-cause death (31.7% vs. 39.0%, HR 0.71, 95% CI 0.55-0.92, p=0.010), and cardiac death (20.9% vs. 31.0%, HR 0.59, 95% CI 0.44-0.80, p=0.001) compared to the delayed invasive group. Conclusions In elderly patients with NSTEMI, an early invasive intervention strategy was associated with favorable long-term clinical outcomes compared to a delayed invasive intervention strategy.

Long-term survival following anti-PD-(L)1 monotherapy in advanced urothelial cancer and an assessment of potential prognostic clinical factors: a multicentre observational study

BackgroundAnti-PD-(L)1 agent are approved as first- and second-line treatment options in advanced urothelial cancer (UC), but information about long-term survival is scarce. There is a need for prognostic factors, as these may help in the decision-making concerning anti-PD-(L)1 in patients with UC. Here, we examined long-term survival following anti-PD-(L)1 in advanced UC and assessed clinical factors for their correlation with survival.MethodsWe collected data from patients with advanced UC treated with anti-PD-(L)1 between 2013 and 2023. Overall- and progression-free survival (OS, PFS) were determined using the Kaplan-Meier method. Independent variables were analysed by uni- and multivariate Cox regression for their association with OS and PFS.ResultsSurvival analyses included 552 patients. Patient characteristics in our cohort were consistent with those of a typical advanced UC population. After median follow-up of 49 months, five-year OS and PFS rates were 16.0% and 6.9% respectively. The absence of visceral and/or bone metastases and elevated C-reactive protein level, gamma-glutamyltransferase level and neutrophil-to-lymphocyte ratio were identified as favourable prognostic factors for OS.ConclusionsA selected subset of patients with advanced UC may experience long-term clinical benefit from anti-PD-(L)1 treatment. We identified prognostic factors that might be used for risk assessment and clinical trial stratification.

First-line pembrolizumab with or without chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up of the Japanese population of KEYNOTE‑048

BackgroundPreviously reported results from phase III KEYNOTE-048 demonstrated similar or improved overall survival (OS) with pembrolizumab or pembrolizumab-chemotherapy versus cetuximab-chemotherapy (EXTREME) in Japanese patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We report results in Japanese patients from KEYNOTE-048 after 5 years of follow-up.MethodsPatients with R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Primary endpoints were OS and progression-free survival. Efficacy was evaluated in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, PD-L1 CPS ≥ 1, and total Japanese populations.ResultsIn Japan, 67 patients were enrolled (pembrolizumab, n = 23; pembrolizumab-chemotherapy, n = 25; EXTREME, n = 19). Median follow-up was 71.0 months (range, 61.2–81.5); data cutoff, February 21, 2022. 5-year OS rates with pembrolizumab versus EXTREME were 35.7% versus 12.5% (hazard ratio [HR] 0.38; 95% CI 0.13–1.05), 23.8% versus 12.5% (HR 0.70; 95% CI 0.34–1.45), and 30.4% versus 10.5% (HR 0.54; 95% CI 0.27–1.07) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. 5-year OS rates with pembrolizumab-chemotherapy versus EXTREME were 20.0% versus 14.3% (HR 0.79; 95% CI 0.27–2.33), 10.5% versus 14.3% (HR 1.18; 95% CI 0.56–2.48), and 8.0% versus 12.5% (HR 1.11; 95% CI 0.57–2.16) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively.ConclusionAfter 5 years of follow-up, pembrolizumab and pembrolizumab-chemotherapy showed long-term clinical benefits; results further support these treatments as first-line options for Japanese patients with R/M HNSCC.Clinical trial registrationNCT02358031.

Estimating the benefit of esketamine nasal spray versus real-world treatment on patient-reported functional remission: results from the ICEBERG study.

Treatment resistant depression (TRD) affects approximately 10-30% of patients with major depressive disorder, and most patients with TRD do not respond to real-world treatments (RWT). Treatment with esketamine nasal spray (NS) plus a selective serotonin or serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) has significant long-term clinical benefit over RWT in patients with TRD. However, the impact on patient-reported function remains to be determined. The ICEBERG analysis was an indirect treatment comparison performed using data from two studies of patients with TRD: SUSTAIN-2 (esketamine NS; NCT02497287) and the European Observational TRD Cohort (EOTC; RWT; NCT03373253; clinicaltrials.gov). Here, patient-reported functional remission, assessed using the Sheehan Disability Scale (SDS), was defined as SDS ≤6 at Month 6. Analyses were conducted using propensity score re-weighting and multivariable models based on 18 covariates. At Month 6, the probability of functional remission in esketamine NS-treated patients from SUSTAIN-2 (n=512) was 25.6% (95% confidence interval [CI] 21.8-29.4), while the adjusted probability for RWT patients from the EOTC (n=184) was 11.5% (95% CI 6.9-16.1; relative risk: 2.226 [95% CI 1.451-3.416]; p=0.0003). In the total combined population (N=696), patients who did not achieve clinical response or remission had a low probability of achieving functional remission (5.84% and 8.76%, respectively). However, for patients who did achieve clinical response or remission, the probability of achieving functional remission was greater (43.38% and 54.15%, respectively), although many still did not achieve this status. For patients with TRD, esketamine NS had a significant functional benefit versus RWT after 6 months of treatment. Irrespective of treatment, achievement of clinical response or remission was insufficient to attain functional remission. Nevertheless, clinical remission increased the likelihood of achieving functional remission, further supporting an important role for clinical remission in for the path towards functional recovery.

Changes in Use of Migraine Medications, Healthcare Resource Utilization, and Associated Direct Costs Over 12Months Following Initiation of Erenumab: A US Retrospective Real-World Analysis.

Erenumab-aooe is approved for the preventive treatment of migraine in adults. Recent publications have evaluated migraine medication use during the 6 months after starting erenumab, but longer-term follow-up data are limited. The objective of this study was to describe 12-month medication use and changes in healthcare resource utilization (HRU) and associated direct costs among patients initiating erenumab. We identified adult patients with an erenumab claim in the Merative MarketScan Commercial and Medicare Databases from May 2018 through September 2019. Eligible patients had ≥ 12months of continuous medical and pharmacy coverage before (pre-index period) and after (post-index period) the index date (first erenumab claim) in addition to pre-index evidence of migraine. Patients were stratified by post-index-period adherence to erenumab, defined as ≥ 80% of days covered (adherent) or < 80% of days covered (non-adherent). Outcomes were measured pre- and post-index, and differences between these periods were described. Among 7528 eligible patients, the mean (standard deviation) age was 45.1 (11.4) years and 85.4% were female; 38.5% of patients were adherent to erenumab. Most patients used acute or traditional migraine-preventive medications pre-index, with reductions in use observed post-index (acute medication was used by 95.6% of patients pre-index, compared to 92.3% post-index; traditional preventive medication was used by 89.6% of patients pre-index, compared to 81.9% post-index). Reductions were observed for HRU of emergency room visits (-3.8%) and brain- and other head-imaging studies (-7.5%). Overall costs associated with acute and traditional preventive medications were reduced (-$764), but costs for HRU increased slightly ($76). When stratifying by adherence and combining costs for acute and traditional preventive medications and HRU, adherent patients had cost decreases (-$1947), while non-adherent patients had cost increases ($101). Most patients initiating erenumab had prior use of acute and traditional migraine-preventive therapies. The reduction in acute and traditional migraine-preventive medication use and HRU over the 12-month follow-up supports the long-term clinical benefits of erenumab in the real-world setting.

Inhibition of hTERT/telomerase/telomere mediates therapeutic efficacy of osimertinib in EGFR mutant lung cancer.

The inevitable acquired resistance to osimertinib (AZD9291), an FDA-approved third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating or T790M resistant mutations, limits its long-term clinical benefit. Telomere maintenance via telomerase reactivation is linked to uncontrolled cell growth and is a cancer hallmark and an attractive cancer therapeutic target. Our effort toward understanding the action mechanisms, including resistance mechanisms, of osimertinib has led to the identification of a novel and critical role in maintaining c-Myc-dependent downregulation of hTERT, a catalytic subunit of telomerase, and subsequent inhibition of telomerase/telomere and induction of telomere dysfunction in mediating therapeutic efficacy of osimertinib. Consequently, osimertinib combined with the telomere inhibitor, 6-Thio-dG, which is currently tested in a phase II trial, effectively inhibited the growth of osimertinib-resistant tumors, regressed EGFRm NSCLC patient-derived xenografts, and delayed the emergence of acquired resistance to osimertinib, warranting clinical validation of this strategy to manage osimertinib acquired resistance.

The Adenosinergic Pathway in Non-Small Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 and CTLA-4 have revolutionized the systemic treatment of non-small cell lung cancer (NSCLC), achieving impressive results. However, long-term clinical benefits are only seen in a minority of patients. Extensive research is being conducted on novel potential immune checkpoints and the mechanisms underlying ICI resistance. The tumor microenvironment (TME) plays a critical role in modulating the immune response and influencing the efficacy of ICIs. The adenosinergic pathway and extracellular adenosine (eADO) are potential targets to improve the response to ICIs in NSCLC patients. First, this review delves into the adenosinergic pathway and the impact of adenosine within the TME. Second, we provide an overview of relevant preclinical and clinical data on molecules targeting this pathway, particularly focusing on NSCLC.

A Phase II Placebo-Controlled Study of the Effect and Safety of Nanvuranlat in Patients with Advanced Biliary Tract Cancers Previously Treated by Systemic Chemotherapy.

To evaluate the efficacy and safety of nanvuranlat [an L-type amino acid transporter 1 inhibitor] monotherapy as a later-line treatment in advanced, metastatic, and refractory biliary tract cancers. A multicenter, randomized, double-blind, placebo-controlled phase II study was conducted across fourteen leading Japanese cancer centers and hospitals. Nanvuranlat 25 mg/m2/day or placebo was given intravenously in cycles of 5 consecutive days, followed by 9 days off. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and disease control rate. Subgroup analysis was performed in patients with high L-type amino acid transporter 1 expression and biliary tract cancer subtypes. A total of 211 patients were screened, of which 105 eligible patients were randomized. Among these, 70 received nanvuranlat and 35 received placebo. Nanvuranlat demonstrated an improvement in PFS when compared with placebo (HR, 0.56; 95% confidence interval, 0.34-0.90; P = 0.02). Grade 3 or higher adverse events were reported in 30.0% and 22.9% of those in the nanvuranlat and placebo groups, respectively. The overall survival was not statistically different between nanvuranlat- and placebo-treated patients. An exploratory analysis indicated that nanvuranlat is warranted to evaluate its long-term clinical benefit in patients with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. Compared with placebo, nanvuranlat improved PFS in patients with advanced and refractory biliary tract cancer with an acceptable safety profile. Further studies of this promising compound are warranted in the population of patients who are exhausted from treatment options.

Major pathologic response and long-term clinical benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after neoadjuvant chemotherapy

BackgroundThe majority of HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2-breast cancer after neoadjuvant chemotherapy. MethodsWe analyzed HR+/HER2-breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3–5 and positive lymph node ratio of ≤10 %, was used as a pathological evaluation indicator. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS. ResultsFrom January 2010 to December 2020, 386 patients were included in the final analysis. 28 patients (7.3 %) achieved pCR and 118 patients (30.6 %) achieved MPR. The median duration of follow-up was 54.4 months,5-year EFS was 87 % in the MPR group vs. 68 % in the non-MPR group. Multivariate analysis showed that low PR expression, high clinical stage, lower Miller–Payne grades and Positive lymph node ratio were independent poor prognostic factors for EFS (all P values < 0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95 % confidence interval (CI), 0.26–0.76; P = 0.008), In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51–9.84; P = 0.28). ConclusionMPR may be a novel pathologic end point in HR+/HER2-breast cancer after neoadjuvant chemotherapy, holding greater applicability in the prognosis evaluation than pCR.